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https://f1000research.com/articles/13-533/v1
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24 May 24
|
{
"type": "Software Tool Article",
"title": "ZARP: A user-friendly and versatile RNA-seq analysis workflow",
"authors": [
"Maria Katsantoni",
"Foivos Gypas",
"Christina J Herrmann",
"Dominik Burri",
"Maciej Bąk",
"Paula Iborra",
"Krish Agarwal",
"Meriç Ataman",
"Máté Balajti",
"Noè Pozzan",
"Niels Schlusser",
"Youngbin Moon",
"Aleksei Mironov",
"Anastasiya Börsch",
"Mihaela Zavolan",
"Alexander Kanitz",
"Maria Katsantoni",
"Foivos Gypas",
"Christina J Herrmann",
"Dominik Burri",
"Maciej Bąk",
"Paula Iborra",
"Krish Agarwal",
"Meriç Ataman",
"Máté Balajti",
"Noè Pozzan",
"Niels Schlusser",
"Youngbin Moon",
"Aleksei Mironov",
"Anastasiya Börsch"
],
"abstract": "Background RNA sequencing (RNA-seq) is a widely used technique in many scientific studies. Given the plethora of models and software packages that have been developed for processing and analyzing RNA-seq datasets, choosing the most appropriate ones is a time-consuming process that requires an in-depth understanding of the data, as well as of the principles and parameters of each tool. In addition, packages designed for individual tasks are developed in different programming languages and have dependencies of various degrees of complexity, which renders their installation and execution challenging for users with limited computational expertise. Workflow languages and execution engines with support for virtualization and encapsulation options such as containers and Conda environments facilitate these tasks considerably. The resulting computational workflows can then be reliably shared with the scientific community, enhancing reusability and the reproducibility of results as individual analysis steps are becoming more transparent and portable.\n\nMethods Here we present ZARP, a general purpose RNA-seq analysis workflow that builds on state-of-the-art software in the field to facilitate the analysis of RNA-seq datasets. ZARP is developed in the Snakemake workflow language and can run locally or in a cluster environment, generating extensive reports not only of the data but also of the options utilized. It is built using modern technologies with the ultimate goal to reduce the hands-on time for bioinformaticians and non-expert users and serve as a template for future workflow development. To this end, we also provide ZARP-cli, a dedicated command-line interface that may make running ZARP on an RNA-seq library of interest as easy as executing a single two-word command.\n\nConclusions ZARP is a powerful RNA-seq analysis workflow that is easy to use even for beginners, built using best software development practices, available under a permissive Open Source license and open to contributions by the scientific community.",
"keywords": [
"bioinformatics",
"data analysis",
"high-throughput",
"transcriptomics",
"RNA-seq",
"computational workflow",
"reproducibility",
"usability"
],
"content": "Introduction\n\nRecent years have seen an exponential growth in new bioinformatics tools,1 a large proportion of which are dedicated to High Throughput Sequencing (HTS) data analysis. For example, there are tools to quantify the expression level of transcripts and genes from RNA-seq data,2,3 identify RNA-binding protein (RBP) binding sites from crosslinking and immunoprecipitation (CLIP) data,4 identify alternative polyadenylation sites and/or quantify their usage,5,6 or analyze single cell RNA-seq data.7 Such tools are written in different programming languages (e.g., Python, R, C, Rust) and have distinct library requirements and dependencies. In most cases, the tools expect the input to be in one of the widely used genomics file formats (e.g., FASTQ,8 BAM9), but custom formats are also frequently used. Combining such tools into an analysis protocol is a time-consuming and error-prone process. But as the analysis of HTS data (and other Big Data in the life sciences) has become such a common problem,10,11 and as the datasets continue to increase in size and complexity, there is an urgent need for expertly curated, well-tested, maintained and easy-to-use reusable computational workflows and registries to share and access them.12–14\n\nA number of modern, feature-rich workflow specification languages and corresponding management systems,15,16 like Snakemake17 and Nextflow,18 are now gaining popularity in the life sciences, as they make the analyses easier to develop, test, share, deploy and execute. To facilitate the installation and execution of workflows across different hardware architectures and host operating systems, modern workflow management systems make use of virtualization and encapsulation techniques relying on containers (e.g., Docker19 and Singularity/Apptainer20) and/or package managers, Conda in particular. An added advantage of using workflow specification languages is that the metadata and general provenance information is stored along with the main outcomes. These may be invaluable for a more fine-grained attribution of researcher contributions, reproducibility of analysis results and insights, and cost optimization of computing resources. Ongoing work at formalizing these metadata artifacts and adding support for such standardized schemas in workflow management systems21 is very much in line with current efforts to FAIRify research data and software.22,23 All of these advantages ultimately lead to more reusable code and reproducible results, while fostering cooperativity and collaboration, both on scientific projects and on the development of Open Source Software.\n\nA number of workflows for the analysis of bulk RNA-seq data have been developed by the community.24–30 However, out of these, some are too complex for many users to deploy, run and/or interpret, while others do not easily allow customizations and/or the analyses of large numbers of samples. Here we present ZARP, a flexible, easy-to-use workflow for bulk RNA-seq data processing that enables rapid initial insights into the data. The inclusion of the most widely used and best performing tools for the various processing steps minimizes time spent by users on making tool choices. The implementation in a widely used workflow language ensures reproducibility and reliable execution of each analysis and facilitates (meta) data management and reporting. A dedicated command-line interface tool (ZARP-cli) allows for even easier execution of the workflow and management of ZARP runs. ZARP is useful to experimental biologists who want to rapidly assess the results of their high-throughput sequencing experiments and to bioinformaticians who can not only use the preliminary results in their downstream analyses, but also adapt the analysis workflow according to their needs. Note that a preprint of this article is deposited at BioRxiv.31\n\n\nMethods\n\nZARP (Zavolan-Lab’s Automated RNA-seq Pipeline) is a general purpose RNA-seq analysis workflow that allows users to carry out the most common steps in the analysis of Illumina RNA-seq libraries with minimum effort. The workflow is developed in Snakemake,17 a widely used workflow language,15 and follows best practice recommendations for workflow development.32 Importantly, ZARP relies on publicly available bioinformatics tools that each can be considered state-of-the-art in their specific tool class,33 and it handles bulk, stranded, single- or paired-ended RNA-seq data.\n\nZARP requires two distinct inputs: (i) A “sample table”, a tab-delimited file with sample-specific information, such as paths to the sequencing data (FASTQ format), reference genome sequence (FASTA format), transcriptome annotation (GTF format) and additional experiment protocol- and library-preparation specifications like adapter sequences or fragment size; (ii) A configuration file in YAML format containing workflow-related parameters, such as results and log directory paths, as well as user-related information, like a contact email address. Advanced users can take advantage of ZARP’s flexible design to provide tool-specific configuration parameters via an optional third input file, which allows for adjusting the behavior of the workflow to their specific needs. Detailed information on the input files can be found in the documentation available in the ZARP repository on GitHub.\n\nA general schema of the ZARP workflow in its current version is presented in Figure 1. For a more comprehensive representation that includes all steps, see Figure 2. Table 1 below lists the main functionalities of ZARP and the tools that provide these functionalities, roughly in the order in which they are executed:\n\nGiven the input files specified in a sample table, ZARP preprocesses and maps RNA-seq reads, quantifies RNA expression levels, assesses the quality, and returns various outputs. Color legend: inputs - yellow, outputs - blue, analysis tools - gray, tools for quality control - turquoise.\n\nGraph-based representation of the ZARP workflow, including all of its steps (“rules”), as produced by running Snakemake with the --rulegraph option. Steps for both the single- and the paired-ended workflows are shown.\n\nSee main text for more information on use cases for each tool and why we chose those tools to be included in ZARP and ZARP-cli. Versions at time of writing are indicated.\n\nPer-sample statistics obtained by applying FastQC directly to the input files (FASTQ format) provide a quick assessment of the overall sample quality. Statistics include GC content, overrepresented sequences, and adapter content. An excessive bias in GC content may affect downstream analyses and may have to be corrected for.34 Overrepresented sequences may reflect contamination or PCR duplication artifacts, which, if excessive, could lead to sparse coverage and skewed expression estimates of the transcripts of interest. Information about adapter content can help identify issues that may occur during sample preparation. For more information on the metrics that FastQC reports and how they can be interpreted, please refer to the FastQC documentation. Trimming of 5’ and/or 3’ adapters as well as poly(A/T) stretches with Cutadapt35 helps determine the proportion of informative sequences in the library and ensures a more reliable alignment of reads to a set of reference sequences to determine their biological origin. The adapters and poly(A/T) stretches to be removed need to be provided by the user as part of the sample table.\n\nSTAR36 infers the genomic origin of the reads by aligning them against an appropriate reference genome and a database of splice junctions that STAR prepares based on the corresponding gene model annotations. The reference genome and gene annotations need to be provided by the user as part of the sample table. STAR has been chosen for its very competitive performance in terms of accuracy, compared to other aligners,37 as well as for its extensive feature set and documentation. For enabling fast random access of the resulting Binary Alignment Map (BAM) alignment files, e.g., to explore them in genome browsers, ZARP then uses SAMtools9 to sort alignments by their genomic position and index them.\n\nThe sorted, indexed BAM files are further converted into the BigWig format with BedGraphtoBigWig from the UCSC tools suite.38 BigWig files allow for easy library normalization and are considerably smaller than the corresponding BAM files, thus making them convenient for visualizing and comparing coverages across multiple samples. The aligned reads are also used to calculate per-transcript transcript integrity numbers (TIN),39 a metric to assess the degree of RNA degradation in the sample, on a per-transcript basis. This is done with tin-score-calculation, which is based on a script originally included in the RSeQC package,40 but modified by us to enable multiprocessing for increased performance. To provide a high-level topographical and functional annotation of the gene segments (e.g., coding regions, untranslated regions, intergenic) and biotypes (e.g., protein coding genes, rRNA) that are represented by the reads in a given sample, ZARP includes ALFA.41\n\nEstimating transcript abundances from RNA-seq data not only allows for subsequent differential analysis on the transcript level but also improves gene level inferences42 and is preferable to counting read alignments.2 Out of the various tools developed for that purpose,2,3 the alignment-free or “pseudoalignment”-based tools kallisto43 and Salmon44 have emerged as the state of the art for the inference of transcript abundance, due to their similarly compelling performance, ease of use, fast runtimes and memory efficiency.3 As both tools are widely used and are fairly low on resource requirements, we have decided to include both for the quantification of transcript and gene level expression. The main output metrics provided by either tool are estimates of normalized transcript/gene expression, in Transcripts Per Million (TPM),45 as well as raw read counts. For convenience, ZARP aggregates transcript and gene expression estimates across all samples with the aid of Salmon and merge_kallisto, generating summary tables that can be plugged into a variety of available tools, e.g., for differential gene/transcript expression, differential transcript usage or gene set enrichment analyses.\n\nWithin ZARP, TPM estimates are used for performing principal component analyses (PCA) with the help of zpca, a tool we created for use in ZARP, but packaged separately so that it can be easily used on its own or as part of other workflows. PCAs on gene/transcript expression levels can help users assess the relationship between samples, to detect batch effects and inform the way in which samples should be compared in downstream analyses.\n\nQuality assessments, read alignments, genome coverages, and transcript and gene abundances can be used in downstream applications in a myriad ways, particularly when different cohorts are compared, e.g., in differential gene expression analyses. But given that such analyses require more complex inputs (e.g., experiment design tables) and are difficult to configure generically for a wide range of experiments, we deliberately decided not to include these in ZARP.\n\nZARP produces two user-friendly, browser-based, interactive reports: one with a summary of sample-related information generated by MultiQC,46 the other with estimates of utilized computational resources generated by Snakemake itself. Note that for the tin-score-calculation, ALFA and zpca tools, we have created plugins that enable the interactive exploration of their respective results through MultiQC.\n\nZARP comes with ZARP-cli, a dedicated command line interface to further simplify its usage by giving it the look and feel of a single executable.47 See Figure 3 for a general schematic outline of its functionalities and Table 1 for a list of the core tools providing them.\n\nZARP-cli consolidates different input references and compiles a sample table and a configuration file, i.e., the inputs to ZARP. Along the way, where necessary, it fetches remote libraries, attempts to infer sample metadata, including the sample source organism, and downloads the corresponding genome resources.\n\nAt the core of ZARP-cli lies its cascading configuration management: Upon first use, users set up default parameters that include sample metadata to be used if no better source is provided (or can be inferred). Configuration parameters can be overridden, on a per-run basis, with command line arguments, which in turn can be overridden, on a per-sample basis, by entries in a sample table. This design ensures that the most accurate information can be easily passed and consumed.\n\nOnce configured, ZARP-cli compiles the set of samples to analyze from the positional command line arguments specified by the user. These “sample references” can point to sequencing libraries available either locally or on the Sequence Read Archive,48 or they can point to partially or fully complete ZARP sample tables. Figure 4 illustrates all of the different ways that sample references can be passed to ZARP-cli.\n\nOnce the sample set has been assembled, ZARP-cli iteratively completes a sample table by filling in any missing information. To that effect, ZARP-cli first makes use of the SRA Toolkit to fetch any remote sequencing libraries from the Sequence Read Archive48 and convert them to FASTQ, yielding the local paths for both single- and paired-ended libraries.\n\nNext, ZARP-cli triggers HTSinfer, a tool developed by us for the inference of RNA-seq metadata that is important for downstream analyses from the sequencing data itself. While still in an experimental/pre-release stage, HTSinfer is often able to extract, infer or assert the following: (i) whether two FASTQ files contain “mate pairs” of the same paired-ended sequencing library, (ii) the source organism from which the library is derived (out of currently more than 400 supported organisms), (iii) the relative orientation of reads with respect to the RNA transcript from which they originate and, for paired-ended libraries, one another, (iv) the frequency of commonly encountered 3’ adapters, and (v) read length statistics. Importantly, ZARP-cli uses the derived information only where such metadata is not provided by the user as part of the configuration or sample table.\n\nOf note, both the SRA download and metadata inference steps are packaged as independent Snakemake workflows that are currently available along with the main ZARP workflow in the same GitHub repository.\n\nAfter inferring sample metadata, ZARP-cli uses genomepy49 to fetch the genomes and gene model annotations from Ensembl.50 The genome version to be fetched for a given organism is pre-configured in a data file shipped with ZARP-cli; it can be easily updated or amended manually, via a text editor. To ensure consistent use of the same gene annotation version in all analyses of RNA-seq libraries within a given group, time frame or project, a default gene model annotation version can be pre-configured during ZARP-cli initialization. If no default version is set, genome resources (annotations and genomes!) are always fetched (and never reused across runs). Gene model annotation versions can also be set via a dedicated command line argument, overriding any default version set in the user configuration.\n\nFinally, ZARP-cli assembles a sample table and a configuration file and triggers the ZARP run. In extreme cases, a ZARP-cli command can be as short as two words, zarp (the name of the program) and a single sample reference. However, making it easier to start ZARP runs is not the only benefit of using the command line interface: ZARP-cli also enforces a file and directory structure that makes it easy to find information from older ZARP runs and prevents accidental workflow re-runs for samples that have already been analyzed. Likewise, genome resources and remote libraries can be configured to be fetched only once. Finally, group- or project-specific ZARP configurations can be easily enforced, e.g., to make sure that sequencing libraries are consistently analyzed with the same set of genome resources.\n\nZARP development follows best practices for scientific analysis workflows.32 First of all, we chose to develop the workflow in Snakemake,17 a widely adopted workflow management system16 that allows for robust and scalable execution of computational analyses. To further enhance reusability and portability of the workflow, i.e., that it can be deployed in various scenarios, such as “on premise” High Performance/Throughput Computing (HPC/HTC) clusters or in the cloud,51 for each step (referred to as “rule” in Snakemake) of the workflow we have defined both a “rule-specific” Conda environment recipe file and a container image. The corresponding tool binaries and images are primarily hosted by the Bioconda52 and BioContainers53 registries for improved access metrics and long term preservation plans. For container images, Snakemake converts the indicated Docker images to the Singularity Image Format20 on the fly, where needed, enabling seamless execution of the workflow in environments with limited privileges (e.g., HPC/HTC clusters). Users can choose between Conda- and container-based54 execution by selecting or preparing an appropriate profile when/before running a workflow. In the current version, we include profiles only for the Slurm job scheduler. However, we will gladly accept new profiles provided by the community, and therefore we encourage users to propose the addition of their own profiles back to the original ZARP repository via raising pull requests. To reduce the storage footprint of data generated by ZARP, intermediate files can be optionally cleaned up. On the other hand, as they use a Snakemake workflow, ZARP runs generate extensive log files and workflow run metadata. This information is relevant for accounting, telemetry and provenance purposes, with current efforts ongoing at standardizing such information for improved reproducibility of workflow runs.21\n\nThe software described here follows the 4OSS Recommendations55: ZARP and ZARP-cli are hosted in their own GitHub repositories, are published under the permissive Apache, Version 2.0 free and open source software license, and follow Semantic Versioning, with each release accompanied by extensive, up-to-date documentation. We have deposited ZARP at the WorkflowHub, a registry specialized in hosting computational analysis workflows.13 It is also available in the “Standardized Usage” section of the Snakemake Workflow Catalog. ZARP-cli and any custom tools/scripts that may be useful beyond the scope of ZARP, have been largely developed according to best practice recommendations56 and deposited at Bioconda,52 which ensures that they are also available on BioContainers.53 We embrace community contributions to all of our software and try our best to ensure that all contributions are duly acknowledged in our communication. Finally, to facilitate attribution and guard against software regression and degradation, we are committed to software development best practices, such as the use of version control systems and automated continuous integration, testing and deployment workflows. In particular, for both ZARP-cli and ZARP, we provide and routinely execute extensive sets of unit and integration tests.\n\nZARP and ZARP-cli require a Linux operating system (tested with CentOS 8, Debian 11, 12; Ubuntu 20.4, 22.4). To install dependencies, we strongly recommend installing a flavor of Conda, e.g., Miniforge. See the installation instructions for ZARP and ZARP-cli for further details. Of note, the current ZARP version is not compatible with Snakemake 8+, because the latest Snakemake major version introduced a number of breaking changes that we are not yet supporting.\n\nFor running individual workflow steps with Conda, we further recommend installing Mamba, in line with Snakemake recommendations. Conversely, for running workflow steps inside containers, SingularityCE or Apptainer is required.\n\nFor analyzing large numbers of samples of any size and from any source, we strongly recommend running ZARP on an HPC/HTC, as the horizontal scaling and extensive multithreading will significantly reduce the wall clock time. A standard laptop or desktop machine (8 GB RAM, 4-core CPU) will be sufficient for small to medium runs (<100 samples) if only used as a Snakemake “head node”, i.e., the machine that coordinates the execution of workflow runs but leaves demanding computations to an HPC/HTC or the cloud (untested). If run entirely on a single machine, we recommend at least 32 GB (processing samples derived from certain organisms may not be possible), but preferably 128+ GB of RAM. But even then, the throughput will be limited due to reduced potential for horizontal scaling and multithreading. See section “Use Cases” below for further details on performance.\n\n\nUse cases\n\nZARP is very well suited to analyze large RNA-seq experiments or even run meta-analyses across multiple different experiments. To demonstrate how ZARP can be used to gain meaningful insights into typical RNA-seq experiments, we tested it on an RNA-seq dataset that was generated by Ham et al. (GEO accession number GSE139213) while analyzing the role of mTORC1 signaling in the age-related loss of muscle mass and function in mice.57 The dataset consists of 20 single-ended RNA-seq libraries (read length: 101 nt, gzipped FASTQ file sizes ranging from 0.8 to 3.2 Gb; library sizes ranging from 18.5 to 75.3 million reads), corresponding to four cohorts of 5 biological replicates each of muscle tissue from 3-months old mice: (i) wild-type, (ii) rapamycin-treated, (iii) tuberous sclerosis complex 1 (TSC1) knockout and (iv) rapamycin-treated TSC1 knockout. The reads were mapped against Ensembl’s50 GRCm39 genome primary assembly and corresponding gene annotations (release: 111) for standard mouse chromosomes. Other parameters for populating the ZARP sample table were mined from the metadata provided in the GEO accession entry for the sample set. Sample tables, instructions on how to start the ZARP run either via a Snakemake call or via the ZARP-cli command line interface, and select results for the test run are publicly available.58\n\nIn Figure 5, we present a subset of the outputs that ZARP generated for this dataset. One observation is the presence of slightly AU-rich reads (Figure 5A), although all samples pass the FastQC-defined threshold for GC bias, and the GC content does not exhibit a strong bias across samples. Transcript integrity across samples is also uniform and high (Figure 5B), with the highest density of expressed transcripts at TIN scores of 75 to 85. There is also no evidence of extensive sequencing of residual adapters (“adapter contamination”; Figure 5C), as less than 1% of reads in each sample have been discarded for being too short after adapter trimming. Similarly, alignment statistics as reported by STAR are also consistently high (Figure 5D), with rates of reads mapped uniquely against the mouse genome of more than 72% across all samples (<4% unmapped), irrespective of sequencing depth. As expected, ALFA analysis of transcript categories shows that uniquely mapped reads overwhelmingly originated from protein-coding genes (over 86% for all samples) (Figure 5E). Taken together, these metrics indicate that all samples are of sufficiently high quality for downstream analysis.\n\nShown are (A) GC content, (B) Transcript integrity numbers (TIN), (C) adapter removal report, (D) alignment statistics, and (E) biotypes for the test run described in the main text. Figures have been slightly edited for visibility and accessibility: some labels have been increased, cohort names have been simplified, samples have been grouped according to cohorts, and cohorts are highlighted in different colors via the MultiQC “Highlight” functionality. Additionally, some biotypes have been omitted from (E) as they are not meaningfully represented. Note that in (B), transcripts that are not expressed are assigned a TIN score of 0. The complete raw HTML report can be found at Zenodo.58 Cohort names correspond to the mouse sample cohorts described above as follows, CTRL: wild-type, CTRL RAPA: rapamycin-treated, TSCmKO: tuberous sclerosis complex 1 (TSC1) knockout, TSCmKO RAPA: rapamycin-treated TSC1 knockout.\n\nIn addition to sample-specific metrics, ZARP also performs principal component analyses across samples (Figure 6). For the test run, the distribution of samples in the space of the first two principal components shows a clustering by condition, with a clear separation between knockout and wild type, as well as between the untreated and rapamycin-treated TSC1 knockout mice. This separation is more pronounced at the gene expression level (Figure 6A), but is also present at the transcript level (Figure 6B). This shows that the differences across conditions are more pronounced than any replicate biases (multiplicative noise, sequencing errors), which strongly increases the likelihood that any subsequent analyses (e.g., differential gene/transcript expression analysis) will provide targets of biological importance.\n\nPCA at the (A) gene and (B) transcript level. PC1 and PC2 correspond to the first and second principal components, respectively. Variances explained by each of them are stated in the parentheses of the corresponding axes labels. Expression levels used in this figure are those reported by kallisto, but ZARP also generates corresponding PCA plots for Salmon-based quantifications. The figure has been slightly edited for visibility and accessibility: some labels have been increased, cohort names have been simplified and different colors for cohorts have been chosen via MultiQC’s “Highlight” functionality.\n\nThe total wall clock time to execute the entire test run was over one hour (1 h 12 min; see Figure 7) for all 20 samples on our institution’s Slurm-managed HPC cluster, where we could make heavy use of ZARP’s parallelization capabilities. This translates to a total CPU time of 71.65 h, out of which 8.32h were not sample-specific, i.e., jobs that had to be executed only once for all samples. The accumulated sample-specific CPU time used for each sample varied between 1.6h and 5h (mean: 3.2h). While the actual runtime may differ considerably across different compute environments, we project that most users would be able to run even large-scale analyses with dozens to hundreds of samples in less than a day on an HPC/HTC cluster or in the cloud, with very little hands-on time. Maximum memory usage for any of the steps and across all samples was 30.2 Gb for rule map_genome_star, which is in accordance with STAR requirements.36 With <32 Gb, this indicates that ZARP is suitable for execution on state of the art desktop and and even laptop computers, albeit at considerably higher runtimes due to the need for serial execution of individual steps and limited use of multithreading. Also, steps requiring a lot of memory are typically those that index or otherwise process genomes and/or gene annotations, so that memory requirements are higher for samples sourced from organisms with larger genomes or higher resolution annotations. None of the jobs took longer than ~35 min (wall clock time) for any of the samples (Figure 7). Among the most time-consuming steps are the creation of indices for STAR, Salmon, and kallisto (from 10min to 35 min), which, however, typically have to be performed only once per set of genome resources - and would be reused across additional runs if the same working directory is used (use ZARP-cli to enforce the consistent use of the same directory for your ZARP runs). Among the sample-specific steps, the calculation of the transcript integrity number (TIN) was the most time-consuming. However, we had already considerably reduced its runtime by adding parallelization capabilities to the original script (see Methods for further details).\n\nLeft: Creation date of the files of each of the rules as generated by Snakemake’s reporting functionality. Right: Runtime (in seconds; wall clock time) of the different steps (“rules”) of the workflow run are depicted for each sample, as generated by Snakemake’s reporting functionality. Axis sizes were modified using Vega Editor, a functionality available directly from the Snakemake report. Differences observed across samples are a function of sample sizes, but also include sources of variation such as the time that individual jobs spent queuing on our Slurm-managed HPC cluster, as well as the hardware specifications of the cluster nodes these jobs eventually ended up on.\n\nTriggering the test case run with an appropriate Snakemake call is easy enough, yet still requires users to fetch sample libraries and genome resources manually, from the Sequence Read Archive48 and Ensembl,50 respectively. These steps can be automated by passing the sample table to ZARP-cli instead – slightly modified to replace sample names with SRA run identifiers, and leaving the sample library and genome resource path columns empty. The modified sample table for use with ZARP-cli is also provided in our example data repository.58 Preparing a sample table is straightforward when the necessary metadata is readily available. However, in our own experience, due to a lack of widely adopted reporting standards that would reliably enable at least the most common types of downstream analyses for RNA-seq data, this is rarely the case when data is fetched from external sources. Especially for large sample sets from different cohorts, preparing a correct sample table will at the very least require painstaking literature mining. To address this issue, and to make ZARP even more accessible, we have included in ZARP-cli our RNA-seq “metadata sniffer” HTSinfer, which attempts to infer important (and widely underreported) metadata, such as the read orientation and 3’ adapters, from the sample libraries themselves. Our supplementary data repository58 includes an example of how this functionality allows ZARP users to work with a sparse sample table with parts or even all of the metadata missing, across samples from multiple organisms and prepared according to different protocols, in a single run. For quick checks, and in its most simple invocation, ZARP-cli can be called with a “two word” command like zarp SRR23590181. Examples of how ZARP-cli can be called are summarized in Figure 4.\n\nWe note that HTSinfer is still experimental, as its attempts at inferring metadata will often fail, most commonly because the data is compatible with more than one outcome and there is insufficient resolution in our inference metrics to distinguish them (e.g., a sample is compatible with two or more source organisms). Nevertheless, even the partial information that HTSinfer does provide saves substantial time on the part of the user. Moreover, ZARP(-cli) will continuously be updated with the latest version of HTSinfer to ensure that the most accurate metadata inference is made available to its users.\n\nIn summary, our test cases demonstrate how ZARP can be used to quickly gain informative insights (Figures 5 & 6) from non-trivial real-world RNA-seq datasets in a reasonable timeframe (Figure 7) and how the dedicated ZARP command line interface can be used to trigger RNA-seq analyses with unprecedented ease (Figure 4).\n\n\nConclusions/Discussion\n\nZARP is a general purpose, easy-to-use, reliable and efficient RNA-seq processing workflow that can be used by molecular biologists with minimal programming experience and bioinformatics experts alike. Scientists with access to a UNIX-based computer with at least 32 GB RAM (Linux and 128+ GB RAM preferred), or to a computing cluster or commercial cloud service, can run the workflow to get an initial view of their data on a relatively short time scale. For laboratories frequently generating RNA-seq data, running ZARP on incoming data can be easily incorporated into an automated data acquisition workflow through ZARP-cli’s Python API. Similarly, ZARP-cli is particularly well suited for analyzing large-scale systematic studies that rely on hundreds or even thousands of sequencing libraries. ZARP has been specifically fine-tuned to process bulk RNA-seq datasets, allowing users to run it out of the box with default parameters. At the same time, ZARP allows advanced users to customize workflow behavior, thereby making it a helpful and flexible tool for edge cases, where a more generic analysis with default settings is unsuitable. The outputs that ZARP provides can serve as entry points for other project-specific analyses, such as differential gene and transcript expression analyses. ZARP and ZARP-cli are publicly available under a permissive open source license (Apache License, Version 2.0), and contributions from the bioinformatics community are welcome. Please address all development-related inquiries as issues at the official GitHub repositories for ZARP and ZARP-cli.\n\nZARP’s ease of use, coupled with its versatility, the use of state-of-the-art tools and modern technologies, its high level of adherence to best software development, Open Source and Open Science practices, and its strict focus on a well defined problem make it stand out among its competition, in particular with respect to analyzing large numbers of samples in a reproducible manner.\n\n\nEthics and consent\n\nEthical approval and written informed consent were not required.",
"appendix": "Data and software availability\n\n\n\n• Gene Expression Omnibus 59 : The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia [TSCmKO data set] (Mus musculus; samples: GSM4134108 to GSM4134127). Accession number GSE139213; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139213. 60\n\n• Gene Expression Omnibus: SM_STG1_T0_2 (Zea mays; series: Nitrogen fixation and mucilage production on maize aerial roots is controlled by aerial root development and border cell functions). Accession number GSM5137669; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM5137669. 61\n\n• Gene Expression Omnibus: Naive_Propy_20uM_Myeloid TAGCGCTC_ATAGCCTT (Danio rerio; series: RNAseq analysis of the herbicide propyzamide on a pre-clinical model of IBD on Danio rerio model). Accession number GSM5835373; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM5835373. 62\n\n• Gene Expression Omnibus: C. elegans, with bacteria, 0h, rep1 (Caenorhabditis elegans; series: Long-term imaging reveals behavioral plasticity during C. elegans dauer exit). Accession number GSM6601040; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM6601040. 63\n\n• Gene Expression Omnibus: 95Cb.del_rep2 (Drosophila melanogaster; series: Deletions of singular U1 snRNA gene significantly interfere with transcription and 3′-end mRNA formation rather than pre-mRNA splicing). Accession number GSM7051046; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM7051046. 64\n\n• Gene Expression Omnibus: B-P-D6-1h-9_S36 (Mus musculus; series: Transmission of stimulus-induced epigentic changes through cell division are coupled to changes in transcription factor activity). Accession number GSM7058404; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM7058404. 65\n\nZenodo. 66 ZARP: Supplementary materials. 10.5281/zenodo.10797372. 58\n\nThis project contains the following extended data:\n\n• zarp_use_cases.zip: Includes instructions, convenience scripts and input data required to reproduce the use cases described in this article.\n\n• mouse_sarcopenia_example_outputs.zip: Contains the cross-sample outputs (gene/transcript expression tables, PCA, MultiQC report and Snakemake report) produced by a ZARP run for the described mouse sarcopenia RNA-seq experiment (not including indexes), as well as the sample-specific outputs for the smallest of the 20 samples.\n\n• zarp_cli_example_outputs.zip: Contains a representative fraction of the outputs produced by the described ZARP-cli runs; in particular, it contains the artifacts generated by the SRA download workflow for a single C. elegans sample (SRR21711080), the outputs produced by the HTSinfer workflow for all 25 samples (20 from the mouse sarcopenia dataset and 5 from the metadata inference demonstration run), the genome resources created by genomepy for the C. elegans genome WBcel235, and the C. elegans-specific ZARP workflow results, including indexes.\n\nData and code/scripts are available under the terms of the CC-BY 4.0 and Apache License, Version 2.0 licenses, respectively. More detailed license information is provided in the record itself.\n\nSource code available from: https://github.com/zavolanlab/zarp (ZARP) and https://github.com/zavolanlab/zarp-cli (ZARP-cli)\n\nArchived source code at time of publication: 10.5281/zenodo.10797025 (ZARP v1.0.0-rc.1) 67 and 10.5281/zenodo.10789819 (ZARP-cli v1.0.0-rc.1) 68\n\nLicense: Apache License, Version 2.0.\n\nOn both GitHub (source code) and Zenodo (code archives), the software is accessible for anyone to download without prior registration. For most purposes, we recommend fetching the software from GitHub, as it will host the most up-to-date code.\n\n\nAcknowledgements\n\nCalculations were performed at the sciCORE scientific computing center at the University of Basel. We would like to thank the sciCORE team for their time and efforts to aid us in this project. We would also like to express our deepest gratitude towards all members of the Zavolan Lab who contributed to this work with numerous pieces of advice and feedback, during the initial development, as well as by testing the workflow in later stages. Finally, we would like to thank the Bioconda community for helping us package and distribute some of the custom tools we developed.\n\n\nReferences\n\nLevin C, Dynomant E, Gonzalez BJ, et al.: A data-supported history of bioinformatics tools. arXiv [cs. DL]. 2018 Jul. Publisher Full Text\n\nKanitz A, Gypas F, Gruber AJ, et al.: Comparative assessment of methods for the computational inference of transcript isoform abundance from RNA-seq data. Genome Biol. 2015 Jul 23; 16: 150. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTeng M, Love MI, Davis CA, et al.: A benchmark for RNA-seq quantification pipelines. Genome Biol. 2016 Apr 23; 17: 74. 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}
|
[
{
"id": "293726",
"date": "10 Jul 2024",
"name": "Silvia Liu",
"expertise": [
"Reviewer Expertise Genomic data analysis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have established an RNA-seq workflow by integrating several state-of-the-art software in the field. This workflow is designed for easy install and compatible with multiple running environments and large sample size. However, here are some major concerns.\n\n1. In the background introduction, the author described that: “A number of workflows for the analysis of bulk RNA-seq data have been developed by the community. (citation 24–30).” The rational is unclear and weak. The authors didn’t list some existing platforms/ workflows and pinpoint their detailed limitations. Besides the RNA workflows listed in citation 24-30, there are a lot of popular platforms, such as nf-core (https://nf-co.re/rnaseq/3.14.0/), Illumina Engine, CLC Genomics Workbench (QIAGEN), Partek Flow (Partek), etc. Most of these platforms provide both graphical user interface and command-line interface for both biologists and bioinformaticians. Besides, these platforms will provide more tool options. For example, only Cutadapt is embedded in ZARP for data trimming and only STAR is integrated for reference-based alignment, but no other alternative popular tools are available. In addition, in the result section, there is no comparison with the current workflows. What’s the rationale and advantages of the proposed ZARP workflow over the existing ones? Version control. If some tools embedded with the ZARP workflow are updated to the new version, can it be easily updated in the ZARP workflow? In case the users want to apply some customized versions of the tools, is it easy to select? Parameter adjustment. Will the workflow only run on default parameter settings of each tool, or the users can customize the settings? Do the users have to run all the tools in the workflow, or optional? For example, can users only run reference-based analysis (STAR), but not run the other branch (Salmon/ Kallisko)? Or the other way around? Can the authors specify computing sources (such as number of cores/ CPUs, maximum memory usage, etc) to be applied?\n\nIs the rationale for developing the new software tool clearly explained? Partly\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
},
{
"id": "293730",
"date": "15 Jul 2024",
"name": "Bo Li",
"expertise": [
"Reviewer Expertise Single-cell and spatial transcriptomics data analysis methodology",
"Bioinformatics algorithm evaluation and software development",
"Computational drug repurposing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript titled \"ZARP: A User-Friendly and Versatile RNA-seq Analysis Workflow\" presents ZARP, an RNA-seq analysis workflow developed to streamline the process of RNA-seq data analysis. The authors emphasize ZARP's ease of use, flexibility, and integration of state-of-the-art tools, aiming to minimize hands-on time for both bioinformaticians and non-experts. Major Comments:\n(1) The manuscript highlights the challenges in RNA-seq data analysis, particularly the complexities of tool dependencies and the need for user-friendly workflows. The development of ZARP in Snakemake, with a command-line interface, is a significant contribution to the field. However, it would be beneficial to include a comparative analysis with other existing workflows to quantitatively demonstrate ZARP's improvements in usability and performance. (2) The author mentions that among the many published workflows, some are too complex for users to deploy, run, and/or interpret, while others are not easy to customize and/or analyze large numbers of samples. Please specify which workflows exhibit these characteristics. (3) The description of the methods is comprehensive, detailing each step of the workflow from quality control to expression quantification. However, the manuscript would benefit from a more detailed explanation of the modifications made to the tin-score-calculation script for multiprocessing. Additionally, providing benchmarking results for ZARP's performance on different hardware configurations could enhance the manuscript's impact. (4) The authors have made commendable efforts to ensure reproducibility and accessibility through the use of containers and Conda environments. But, providing a detailed user guide that includes information about the installation process, potential pitfalls, and troubleshooting tips is essential for users to successfully deploy ZARP. (5) The manuscript provides an overview of ZARP's functionalities and the tools integrated within the workflow. However, the authors should enrich their manuscript with more comprehensive case studies or real-world applications to strengthen the validation of the workflow. Furthermore, applying the workflow to diverse RNA-seq datasets, including single-cell RNA-seq, would enhance its utility and appeal. (6) It would be better to provide a detailed table in the operation section of the manuscript, including minimum specifications, recommended configurations, and installation guidelines for different environments to improve user-friendliness. (7) The figures and tables included are informative but could be improved for clarity. For instance, Figure 1 provides a schematic overview of the workflow, but a more detailed flowchart with step-by-step annotations would be beneficial. Tables listing the tools and their versions are helpful, but adding columns for the specific tasks each tool performs and any dependencies would provide a more comprehensive overview. Minor Comments:\n(1) The abstract is well-written but could be more concise. Reducing redundancy and focusing on the key contributions of ZARP would make it more impactful. (2) I suggest splitting the first column (tool) in Table 1 into two columns, namely the software (tool) and version (version) columns, which is clearer. (3) The references are appropriate and cover relevant literature. Ensuring all references are up-to-date and including any recently published related works would be beneficial. (4) When authors cite datasets stored on Zenodo in their paper and provide corresponding reference information (such as reference 58), please indicate the DOI number to facilitate readers to search and repeat experiments. (5) I strongly suggest that the author give more example codes, such as the installation of ZARP and each subsequent step of operation, which is very important for beginners. Only by doing this can it be called truly easy-to-use. Overall, the manuscript presents a valuable tool for RNA-seq data analysis. Addressing the comments above will strengthen the manuscript, making it more robust and impactful.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Partly\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-533
|
https://f1000research.com/articles/13-110/v1
|
19 Feb 24
|
{
"type": "Method Article",
"title": "Exploring and analyzing the role of hybrid spectrum sensing methods in 6G-based smart health care applications",
"authors": [
"Arun Kumar",
"Raminder Kaur",
"Nishant Gaur",
"Aziz Nanthaamornphong",
"Arun Kumar",
"Raminder Kaur",
"Nishant Gaur"
],
"abstract": "Background Researchers are focusing their emphasis on quick and real-time healthcare and monitoring systems because of the contemporary modern world’s rapid technological improvements. One of the best options is smart healthcare, which uses a variety of on-body and off-body sensors and gadgets to monitor patients’ health and exchange data with hospitals and healthcare professionals in real time. Utilizing the primary user (PU) spectrum, cognitive radio (CR) can be highly useful for efficient and intelligent healthcare systems to send and receive patient health data.\n\nMethods In this work, we propose a method that combines energy detection (ED) and cyclostationary (CS) spectrum sensing (SS) algorithms. This method was used to test spectrum sensing in CR-based smart healthcare systems. The proposed ED-CS in cognitive radio systems improves the precision of the spectrum sensing. Owing to its straightforward implementation, ED is initially used to identify the idle spectrum. If the ED cannot find the idle spectrum, the signals are found using CS-SS, which uses the cyclic statistical properties of the signals to separate the main users from the interference.\n\nResults In the simulation analysis, the probability of detection (Pd), probability of a false alarm (Pfa), power spectral density (PSD), and bit error rate (BER) of the proposed ED-CS is compared to those of the traditional Matched Filter (MF), ED, and CS.\n\nConclusions The results indicate that the suggested strategy improves the performance of the framework, making it more appropriate for smart healthcare applications.",
"keywords": [
"Smart hospitals",
"Spectrum Sensing",
"Cognitive Radio",
"Hybrid Spectrum sensing"
],
"content": "1. Introduction\n\nSixth-generation (6G)-based smart hospitals require substantial spectrum resources for ultra-reliable and low-latency communications. Utilizing a diverse range of frequency bands, including millimeter waves (mm) and terahertz frequencies, is crucial to support real-time medical data exchange, remote surgeries, and AI-driven healthcare applications, ensuring the highest level of patient care and safety.1,2 The spectrum is vital for wireless applications because it provides essential electromagnetic frequencies for transmitting data wirelessly. It determines the data capacity, speed, and coverage. Efficient spectrum allocation ensures reliable communication, supports the growing demand for wireless services, and enables innovations such as the fifth generation (5G), the internet of things (IoT), and wireless broadband to enhance connectivity and productivity. Obtaining high spectral access faces challenges owing to spectrum scarcity and allocation inefficiencies. The crowded frequency bands, legacy systems, and regulatory constraints limit the available spectrum. Efficient sharing mechanisms, interference management, and international coordination are needed to optimize spectral access, enabling the growth of wireless technologies, such as 5G and beyond.3 Spectrum sensing (SS) makes 5G-based healthcare apps more dependable and effective by facilitating more effective data transmissions. By enabling devices to recognize and make use of available frequency bands, interference is reduced, and dependable connectivity is guaranteed. This is necessary for telemedicine, remote surgery, and real-time monitoring where continuous data flow is essential. By providing priority access to medical records, spectrum sensing helps in emergency scenarios by guaranteeing patient safety. In conclusion, it improves network efficiency, lowers latency, and increases the standard and accessibility of healthcare services in the context of 5G. Cognitive radio-based spectrum sensing plays a pivotal role in achieving high spectral access by enabling dynamic and intelligent spectrum allocation. These systems continuously monitor the radio frequency environment and detect unused or lightly utilized spectral bands. When such spectrum opportunities are identified, cognitive radios can instantly adapt their transmissions to access these frequencies and optimize their spectrum utilization while minimizing interference. This technology enhances spectral efficiency, accommodates more users, and fosters better coexistence among wireless services, ultimately increasing overall spectral access and network performance.4 Energy detection (ED) is a spectrum-sensing technique that determines the presence of a signal by measuring the power within a given frequency band. It is a simple and widely used method suitable for detecting signals with unknown characteristics. Matched filter (MF) is a signal-processing filter optimized to maximize the signal-to-noise ratio (SNR) when a known signal is present in noise. It is particularly effective when the signal shape is known, making it useful in scenarios where signal patterns are well defined, such as radar or communication systems. Cyclostationary (CS) spectrum sensing analyzes statistical periodicities in the received signal, exploiting CS features, such as symbol rate, to detect and identify signals. This method is advantageous when dealing with modulated signals because it provides improved signal detection and interference mitigation in dynamic spectrum environments. Conventional SS algorithms, such as ED, MF, and CS, are fundamental techniques used in cognitive radio systems to detect and utilize the available spectrum opportunistically while avoiding interference with primary users. These algorithms serve as the foundation for dynamic spectrum access. These conventional spectrum sensing algorithms are valuable for enabling cognitive radiologists to make informed decisions about spectrum usage.5 However, each has limitations that researchers continue to address through advancements in cognitive radio technology, signal processing techniques, and machine learning to improve spectrum-sensing accuracy, adaptability, and efficiency in dynamic and complex wireless environments.6 The suggested article is organized as follows: the article’s background, motivation, and contributions are covered in Section 1, related work is covered in Section 2, a system model is shown in Section 3, and the simulated outcomes and the proposed article’s conclusion are covered in Sections 4 and 5.\n\nThe SS plays a crucial role in enhancing healthcare applications across various scenarios by ensuring reliable and efficient wireless communication. Here are different scenarios in which spectrum sensing benefits healthcare7–9:\n\n• Emergency response and disaster recovery: During natural disasters or emergencies, dedicated spectrum sensing helps healthcare providers prioritize and allocate spectrum resources. This ensures that first responders and medical teams have uninterrupted communication to coordinate rescue efforts and provide critical medical assistance, even in congested or disrupted networks.\n\n• Wireless medical devices: Spectrum sensing is essential for wireless medical devices, such as remote patient monitors, wearable health trackers, and smart healthcare implants. These devices rely on spectrum sensing to identify the most suitable and interference-free frequency bands, thereby ensuring real-time data transmission and accurate patient monitoring.\n\n• Telemedicine: Spectrum sensing is vital for telemedicine applications where doctors and patients communicate remotely. This enables healthcare professionals to maintain consistent and high-quality video and audio connections, even in crowded wireless environments. This ensures that telemedicine consultations and remote diagnostics are conducted without interruptions, thereby improving the accessibility of healthcare services.\n\n• IoT healthcare devices: IoT has revolutionized healthcare with devices such as smart pill dispensers, medication trackers, and patient location monitors. Spectrum sensing ensures that these IoT devices can operate in less-congested bands, facilitating the reliable transmission of health-related data to healthcare providers and caregivers.\n\n• Wireless imaging and diagnostics: Healthcare facilities increasingly rely on wireless technologies for transmitting large medical imaging files, including magnetic resonance imaging MRIs, computed tomography (CT), and X-rays. Spectrum sensing helps allocate suitable spectrum resources, ensuring that these critical files are transmitted efficiently and promptly, thus allowing for quicker diagnosis and treatment planning.\n\n• Mobile clinics: Spectrum sensing is beneficial for mobile healthcare clinics operating in remote or underserved areas. These clinics can use spectrum sensing to identify the best available spectrum for their wireless communication needs, ensuring that healthcare professionals can access patient records, medical databases, and telemedicine consultations without network disruption.\n\n• Healthcare robotics: Spectrum sensing is essential in healthcare robotics, including robotic surgical systems and remote-controlled medical robots. It ensures precise and real-time control during medical procedures where any signal interference or delay can have critical consequences.\n\n• Ambulance communication: Ambulances equipped with advanced medical equipment and communication systems that rely on spectrum sensing. It helps these vehicles maintain connectivity, allowing paramedics and emergency medical personnel to transmit patient information, vital signs, and other critical data to hospitals, thus ensuring seamless patient care transitions.\n\nSpectrum scarcity is a problem that cognitive radio (CR) is designed to address for various wireless services and applications. Smart healthcare solutions that use CR technology can transmit and receive monitoring data over the primary user (PU) frequency range without interfering with PU transmission. Smart healthcare based on CR solves two fundamental problems. First, based on the findings of spectrum sensing, it enables monitoring sensors (secondary users) to wirelessly communicate data while the PU does not use the spectrum. Second, it increases the effectiveness of spectrum usage.10 Implementing a proposed hybrid approach such as the ED-CS and DMF techniques for 6G-based smart hospital applications offers several valuable contributions to the healthcare industry.\n\n1. The hybrid approach provides superior SS by leveraging the sensitivity of the ED to detect energy in a frequency band and precision CS to confirm the presence of specific signals. This results in a comprehensive and accurate view of the spectral environment within a smart hospital. A high probability of detection in 6G-based smart healthcare applications is crucial for seamless and ultra-reliable connectivity. These algorithms minimize interference, enabling real-time high-quality data transmission from medical devices. This will enhance telemedicine, remote patient monitoring, and precision diagnostics, ultimately improving healthcare accessibility and patient outcomes in the advanced 6G era.\n\n2. The hybrid ED-CS ensures reliable detection of wireless medical devices and sensors. This is crucial for monitoring patients’ vital signs, enabling timely intervention, and enhancing patient safety.\n\n3. By using SS methods to validate the detected signals, the hybrid approach reduces false alarms and positives in spectrum sensing. This is particularly important in healthcare settings, where erroneous alarms can lead to unnecessary interventions and disruptions. Reducing the probability of false alarms in 6G-based smart healthcare applications through spectrum-sensing algorithms ensures accurate threat detection and minimizes unnecessary disruptions. This heightened reliability is essential for patient monitoring and telemedicine, improving healthcare delivery, data integrity, and patient trust, thus optimizing the overall care quality in the advanced 6G ecosystem.\n\n4. As 6G technology evolves, the hybrid approach ensures that smart hospitals are well equipped to adapt to the increasing demands of advanced wireless communication. It future-proof healthcare infrastructure, allowing hospitals to stay at the forefront of technology by enhancing the throughput of the framework. High-throughput SS algorithms in 6G-based smart healthcare applications facilitate rapid data transmission, supporting real-time remote monitoring, and medical data exchange. This enables complex diagnostic procedures, telemedicine, and seamless healthcare services, offering enhanced patient care and health outcomes in a high-speed low latency 6G environment.\n\n5. Real-time and accurate spectrum sensing enhances patient care by enabling continuous monitoring and data transmission from medical devices. This contributes to early detection of medical issues, faster response times, and better overall patient outcomes.\n\n6. With accurate spectrum sensing, smart hospitals can optimize their wireless networks and devices, leading to improved operational efficiency and reduced downtime and cost savings.\n\n7. The high-power spectral density in spectrum sensing algorithms is beneficial for 6G-based smart healthcare applications. This allows for a more efficient use of the available bandwidth, ensuring robust and reliable communication between healthcare devices. This leads to faster data transfer, reduced latency, and improved connectivity, thereby enhancing the effectiveness of remote patient monitoring and telemedicine services.\n\n\n2. Literature review\n\nThe literature review of SS in this section provides a thorough understanding of the research, methods, and developments in this area. Table 1 provides the condensed structure for this review.\n\n\n3. Methods\n\nThe proposed hybrid SS combines ED and CS techniques for spectrum sensing in cognitive radio systems. ED measures the power of the received signal, while CS detection analyzes the cyclic statistical properties. Hybrid spectrum sensing, which combines ED and CS analysis, can significantly enhance healthcare services. ED ensures the detection of wideband signals, whereas CS analysis identifies specific signal characteristics, enhances signal reliability, and reduces false alarms. In healthcare, this approach can improve the quality of service by ensuring the reliable and timely transmission of critical medical data, optimizing resource allocation, and reducing interference. For telemedicine, remote monitoring, and emergency response, the hybrid technique offers a robust and efficient solution that provides consistent connectivity and minimizes the risk of data loss or delays, ultimately leading to improved patient care and safety in 5G-based healthcare applications. In this approach, the received signal is first processed using ED to quickly detect the presence of the primary signal. If energy-based detection is inconclusive, CS detection is applied to exploit signal-specific cyclic features. This hybrid approach enhances detection accuracy, especially in low signal-to-noise ratio (SNR) scenarios, making it suitable for dynamic spectrum access, where reliable primary signal detection is critical for efficient spectrum sharing. A diagram of the proposed Ed-CS is shown in Figure 1.\n\nThe detection performance of ED is analyzed in the following conditions:\n\nEquations (1) and (2) indicate the non-availability and availability of the Primary User (PU), z(n) is the original signal, x(n) is the transmitting signal, and σn is the noise variance in the Rician channel. The threshold estimation is given by\n\nThe factor Q(.) is defined as:\n\nThe PSD of the signal z(n) is given by:\n\nThe Pd and Pfa for the CS is given by:\n\nTo calculate Pfa, when only noise or noncyclostationary interference is present, the threshold (λD) is utilized as follows:\n\nThe PSD of the CS is related to the cyclic autocorrelation function by taking the Fourier transform with respect to the cyclic frequency (β), given as\n\nTo enhance the efficiency of CR, we propose a hybrid SS algorithm known as ED-CS. In the proposed algorithm, the ED estimates the availability of the PU. If the ED fails to estimate the occurrence of a PU, then the CS method is used to detect the PU. Hence, it is concluded that CS is used if the ED is unable to detect the PU. Therefore, the Pd for the cognitive user undergoing CS-SS is given by\n\nThe probability that cognitive user undertake CS is given by:\n\nEquation (15) denotes the prospect that the K-cognitive user out of M is subjected to the CS spectrum-sensing approach.\n\n\n4. Results\n\nIn this section, we estimate the performance of the proposed ED-CS spectrum using Matlab (Matlab 2016) or Python as an alternative option (https://jupyter.org). For the simulation, we used 20000 samples, 64-QAM, 64-FFT, overlapping factor = 4, and a NOMA waveform under a Rician channel. In Figure 2, we analyze the detection performance of the ED-CS and the conventional methods. Enhancing Pd in spectrum-sensing methods for smart hospitals would lead to more reliable and responsive communication networks. This improvement ensures that vital medical data and alerts are consistently detected and transmitted accurately, facilitating faster response times and critical decision-making. Patients benefit from timely care, reduced risks, and improved overall healthcare quality, making smart hospitals more effective and dependable in emergencies and routine care. Algorithms that obtain maximum detection at a low SNR are considered the best SS methods. In this case, the maximum detection is obtained at a SNR of -2 dB for the proposed ED-CS, 2.1 dB for CS, 4.2 dB for MF, and 6.2 dB for ED. Hence, it is concluded that the ED-CS outperforms the CS, MF, and ED by obtaining a gain of 4.1 dB, 6 dB, and 7.9 dB, respectively.\n\nThe Pfa curves for the proposed SS technique are shown in Figure 3. If the Pfa is high, the algorithm misrepresents the noise as a PU signal. Reducing Pfa in spectrum-sensing methods within smart hospital applications would enhance the reliability of critical communication systems. This means fewer false alerts or disruptions in monitoring, ensuring seamless connectivity between medical devices and personnel. It increases patient safety, minimizes data errors, and optimizes healthcare workflows, ultimately improving the quality of care in smart hospitals. In this case, it is noted that the Pd is maximum at the Pfa of 0.1, 0.3, 0.55 and 0.62 for ED-CS, CS, MF and ED. Therefore, it is concluded that the proposed ED-CS works efficiently under high false alarm conditions compared to conventional approaches.\n\nTo analyze the throughput performance of the SS methods, a bit error rate (BER) curve was estimated, as shown in Figure 4. The main aim of this study is to optimize BER performance for a reliable framework. Enhancing the BER in smart hospital applications can significantly improve efficiency. A lower BER indicates improved data transmission reliability, which is crucial for accurate real-time communication in healthcare settings. This leads to reduced data errors in patient monitoring, diagnostics, and treatment, enabling healthcare professionals to make informed decisions promptly. Ultimately, this enhances patient care quality and overall operational efficiency in smart hospitals. The SNR gains of 2.4 dB, 3.1 dB, and 3.1 dB are obtained at the BER of 10−4 by the ED-CS as compared with the CS, MF, and ED algorithms, respectively.\n\nThe PSD of the NOMA waveform is shown in Figure 5. The sidelobes of NOMA are greatly reduced by the ED-CS methods, resulting in spectral efficiency. The PSD values of the NOMA waveform were -978, -1134, -1286, -1418, and -1621 for the ED, CS, MF, ED, and original NOMA waveforms, respectively. Enhancing PSD performance and utilizing SS methods in smart hospitals improve wireless communication reliability. This reduces signal interference, supports more devices, extends the battery life, and enhances patient monitoring. An enhanced PSD ensures data accuracy and enables precise diagnosis and treatment. It also ensures network reliability, enables timely responses in emergencies, improves healthcare efficiency, and ultimately enhances patient care and hospital operations.\n\nComparing ED, CS, MF, and ED-CS for smart healthcare applications involves considering their strengths and weaknesses in the context of specific requirements. The complex equations provided a high-level comparison of the computational loads for each method. However, the actual complexity can vary significantly depending on factors such as the specific algorithms, hardware, and software optimization used in the implementation. A brief comparison is presented in Table 2.22\n\n\n\n1. Simplicity and low complexity.\n\n2. Suitable for wideband and unknown signal types.\n\n3. Works in non-cooperative and dynamic environments.\n\n\n\n1. Susceptible to high false alarm rates, especially in low SNR conditions.\n\n2. May not be ideal for detecting weak or intermittent signals.\n\n\n\n1. Effective in distinguishing between modulated and non-modulated signals.\n\n2. Can exploit signal CS for improved detection.\n\n3. Moderate complexity and can be adapted to various signal types.\n\n\n\n1. Requires some knowledge of the signal's cyclic properties.\n\n2. May still face challenges in low SNR or rapidly changing environments.\n\n\n\n1. Ideal for detecting known signals with minimal noise.\n\n2. Provides optimal detection performance in terms of signal-to-noise ratio.\n\n\n\n1. Limited to known signal waveforms and may not adapt well to diverse signals.\n\n2. Complexity increases with signal diversity.\n\n\n\n1. Combines the advantages of both ED and CS techniques.\n\n2. Can adapt to a wide range of signals, making it suitable for smart healthcare applications with diverse signal sources.\n\n3. Potentially improved detection performance compared to individual methods.\n\n\n\n1. Increased complexity compared to individual techniques.\n\n2. Requires careful design and parameter tuning.\n\n\n5. Conclusions\n\nIn this study, we propose a hybrid ED-CS algorithm to enhance and optimize the spectral performance of the 6G NOMA waveform. Under a Rician channel, the proposed ED-CS method was compared with the traditional CS, ED, and MF methods. It can be observed that the ED-CS method performs better than the traditional SS methods in terms of Pd, Pfa, BER, and PSD. It can be seen that the ED-CS obtained efficient signal detection at a low SNR and was also able to minimize the Pfa effect. The throughput and PSD of the framework were also enhanced, and efficient performance was achieved, making it suitable for smart healthcare applications. The proposed solutions for 6G-based smart-hospital applications offer numerous advantages. The utilization of these methodologies facilitates highly dependable and minimally delayed communication, which is of utmost importance in the context of remote surgical procedures and the continuous monitoring of patients in real time. These technologies facilitate the establishment of connections and implementation of an extensive IoT infrastructure for monitoring medical equipment and patient information. Moreover, the implementation of advanced spectrum-sensing techniques enhances the overall efficiency and capacity of the network, thereby guaranteeing uninterrupted connectivity in densely populated and ever-changing hospital settings. Consequently, this advancement contributes to the improvement of healthcare services and patient care within smart hospitals provided by 6G technology.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nAgiwal M, Roy A, Saxena N: Next Generation 5G Wireless Networks: A Comprehensive Survey. IEEE Commun. Surv. Tutor. third quarter 2016; 18(3): 1617–1655. Publisher Full Text\n\nAlghamdi R, Alhadrami R, Alhothali D, et al.: Intelligent Surfaces for 6G Wireless Networks: A Survey of Optimization and Performance Analysis Techniques. IEEE Access. Oct 19, 2020; 8: 202795–202818. Publisher Full Text\n\nKumar A, Venkatesh J, Gaur N, et al.: Analysis of Hybrid Spectrum Sensing for 5G and 6G Waveforms. Electronics. 2023; 12(1): 138. Publisher Full Text\n\nMitola J, Maguire GQ: Cognitive radio: making software radios more personal. IEEE Pers. Commun. Aug. 1999; 6(4): 13–18. Publisher Full Text\n\nArjoune Y, Kaabouch N: A Comprehensive Survey on Spectrum Sensing in Cognitive Radio Networks: Recent Advances, New Challenges, and Future Research Directions. Sensors. 2019; 19(1): 126. Publisher Full Text\n\nRamamoorthy R, Sharma H, Akilandeswari A, et al.: Analysis of cognitive radio for lte and 5g waveforms. Comput. Syst. Sci. Eng. 2022; 43(3): 1207–1217.\n\nJabbar MA, Shandilya SK, Kumar A, et al.: Applications of cognitive internet of medical things in modern healthcare. Comput. Electr. Eng. September 2022; 102: 108276.\n\nRaza A, Ali M, Ehsan MK, et al.: Spectrum Evaluation in CR-Based Smart Healthcare Systems Using Optimizable Tree Machine Learning Approach. Sensors. 2023; 23(17): 7456. Publisher Full Text\n\nSurekha S, Ur Rahman MZ, Lay-Ekuakille A, et al.: Energy Detection for Spectrum Sensing in Medical Telemetry Networks using Modified NLMS algorithm. 2020 IEEE International Instrumentation and Measurement Technology Conference (I2MTC). 2020; pp. 1–5. Publisher Full Text\n\nRaza A, Ali M, Ehsan MK, et al.: Spectrum Evaluation in CR-Based Smart Healthcare Systems Using Optimizable Tree Machine Learning Approach. Sensors. 2023; 23(17): 7456. Publisher Full Text\n\nYadav K, Roy SD, Kundu S: Hybrid cooperative spectrum sensing with cyclostationary detection for cognitive radio networks. 2016 IEEE Annual India Conference (INDICON). 2016; pp. 1–6. Publisher Full Text\n\nBani B, Kulkarni V: Hybrid Spectrum Sensing Using MD and ED for Cognitive Radio Networks. J. Sens. Actuator Netw. 2022; 11(3): 36. Publisher Full Text\n\nLima DL, Silveira LFQ, Xavier-de-Souza S: Spectrum sensing with a parallel algorithm for cyclostationary feature extraction. Comput. Electr. Eng. 2018; 71: 151–161.\n\nJaber M, Nasser A, Charara N, et al.: One-Class based learning for Hybrid Spectrum Sensing in Cognitive Radio. 2020 28th European Signal Processing Conference (EUSIPCO). 2021; pp. 1683–1686. Publisher Full Text\n\nKumar A, Venkatesh J, Gaur N, et al.: Cyclostationary and energy detection spectrum sensing beyond 5G waveforms. Electron. Res. Arch. 2023; 31(6): 3400–3416. Publisher Full Text\n\nKockaya K, Develi I: Spectrum sensing in cognitive radio networks: threshold optimization and analysis. J. Wirel. Commun. Netw. 2020; 255. Publisher Full Text\n\nLiu Y, Zhong Z, Wang G, et al.: Cyclostationary Detection Based Spectrum Sensing for Cognitive Radio Networks. J. Commun. January 2015; 10(1).\n\nNeshe NH, Singh M: Hybrid Spectrum Sensing Techniques in 5G cognitive Radio Networks in Soft Computing: A Review. Comput. Intell. Mach. Learn. April 2021; 2(1).\n\nKumar A, Albreem DH, Le DN: A comprehensive study on the role of advanced technologies in 5G based smart hospital. Alex. Eng. J. 2021; 60: 5527–5536.\n\nLi M, et al.: Distributed Artificial Intelligence Empowered Sustainable Cognitive Radio Sensor Networks: A Smart City on-demand Perspective. Sustain. Cities Soc. 2021; 75. Publisher Full Text\n\nOuattara D, Krief F, Chalouf MA, et al.: Spectrum Sensing Improvement in Cognitive Radio Networks for Real-Time Patients Monitoring. Wireless Mobile Communication and Healthcare, MobiHealth 2012, Lecture Notes of the Institute for Computer Sciences, Social Informatics and Telecommunications Engineering. Springer; Berlin, Heidelberg: 2013; vol. 61. . Publisher Full Text\n\nYawada PS, Wei AJ: Comparative study of spectrum sensing techniques base on techniques non-cooperative in cognitive radio networks. 2016 5th International Conference on Computer Science and Network Technology (ICCSNT). 2016; pp. 517–520. Publisher Full Text"
}
|
[
{
"id": "263428",
"date": "17 Apr 2024",
"name": "Fahad Ahmad",
"expertise": [
"Reviewer Expertise 6G",
"smart healthcare applications",
"artificial intelligence",
"quantum computing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMinor:\nIntroduces a novel ED and CS spectrum sensing combination for cognitive radio in smart healthcare, enhancing precision in data transmission. Relevant to 6G technology applications in healthcare, addressing the need for quick, real-time monitoring systems.\nMajor:\nThe study primarily utilizes simulations for testing, which raises concerns about its relevance to real-world scenarios. Simulations, although useful, might not fully capture the complexities and unpredictabilities encountered in practical environments, leading to potential gaps in the method's applicability and effectiveness when applied outside a controlled setting. There is a lack of in-depth comparative analysis with established traditional methods like Membrane Filtration (MF), Electrodialysis (ED), and Crystallization (CS). Such analysis is crucial for understanding how the new method stands against these conventional techniques in terms of efficiency, cost-effectiveness, and potential limitations, particularly in practical applications. The discussion around the implementation challenges and the computational resources required by the new method is insufficient. This omission raises questions about its feasibility in real-world applications. Understanding the computational demands and logistical hurdles is essential for assessing the method's viability and scalability. While the conclusion acknowledges the potential for future improvements, it falls short of a comprehensive discussion on the method's current limitations and areas needing further research. This oversight restricts the study's perspective on how the method can be refined and applied more broadly, limiting its contribution to the field's advancement.\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? No",
"responses": [
{
"c_id": "11435",
"date": "29 Apr 2024",
"name": "Arun Kumar",
"role": "Author Response",
"response": "Thank you for giving me the opportunity to answer the inquiries. Please find below the response to the comment given: 1. The study primarily utilizes simulations for testing, which raises concerns about its relevance to real-world scenarios. Simulations, although useful, might not fully capture the complexities and unpredictabilities encountered in practical environments, leading to potential gaps in the method's applicability and effectiveness when applied outside a controlled setting. Ans. Thank You Sir. Simulation results offer valuable insights for analyzing concepts by providing a controlled environment to explore hypothetical scenarios. They allow researchers to observe outcomes under various conditions, offering a deeper understanding of complex systems or theories. Through simulations, one can test assumptions, validate models, and predict behaviors, aiding in decision-making processes across diverse fields such as economics, engineering, and medicine. These results enable researchers to study phenomena that are difficult or impossible to replicate in real-world settings, facilitating innovation and the refinement of theories. Ultimately, simulations serve as powerful tools for advancing knowledge and enhancing comprehension of intricate concepts. 2. There is a lack of in-depth comparative analysis with established traditional methods like Membrane Filtration (MF), Electrodialysis (ED), and Crystallization (CS). Such analysis is crucial for understanding how the new method stands against these conventional techniques in terms of efficiency, cost-effectiveness, and potential limitations, particularly in practical applications. Ans. Thank you, sir. We have not used the above terms (membrane filtration (MF), electrodialysis (ED), and crystallization (CS)) in our paper. In our paper, ED = Energy Detection, MF=Matched Filter, and CS = Cyclostationary Spectrum Sensing, which are all well defined in the paper, please see Table 2. 3. The discussion around the implementation challenges and the computational resources required by the new method is insufficient. This omission raises questions about its feasibility in real-world applications. Understanding the computational demands and logistical hurdles is essential for assessing the method's viability and scalability. Ans. Thank You, sir. To address the critique regarding implementation challenges and computational resources required by the new method, it's crucial to provide a comprehensive analysis, which we have done in the paper. In the proposed article, we are analyzing the performance of the proposed algorithm for the smart health care system. We have analyzed the probability of detection, false alarm, BER, PSD, and complexity. Further, we have compared the other algorithms with the proposed one, and it is evident that the proposed algorithm shows a substantial improvement as compared with the conventional. 4. While the conclusion acknowledges the potential for future improvements, it falls short of a comprehensive discussion on the method's current limitations and areas needing further research. This oversight restricts the study's perspective on how the method can be refined and applied more broadly, limiting its contribution to the field's advancement. Ans. Thank you, sir. In Table . 2, we have already cited the limitations of the proposed algorithms based on simulation results. i.e., 1. increased complexity compared to individual techniques; and 2. requires careful design and parameter tuning. Further, the following can be added: A limitation of the proposed hybrid spectrum sensing method is the increase in complexity, which compromises the reliability of real-time healthcare data transmission and communication due to the dynamic design and parameters of the framework. Further we are \"Exploring and analyzing the role of hybrid spectrum sensing methods in 6G-based smart health care applications\". We are not claiming to design of hardware model so we have no simulations."
}
]
},
{
"id": "263432",
"date": "07 May 2024",
"name": "H. ALSHARIF",
"expertise": [
"Reviewer Expertise Wireless communications"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nResearchers are focused on quick and real-time healthcare and monitoring systems because of the contemporary modern world’s rapid technological improvements. Utilizing the primary user (PU) spectrum, cognitive radio (CR) can be highly useful for efficient and intelligent healthcare systems to send and receive patient health data. This paper deals with a hot area of investigation at the moment. I have looked at the mathematics and it looks sound. I would have liked to have seen a longer conclusion that discussed the effects of the various methods investigated. At this point, I recommend these parts be revised again and be expressed more analytically in a revised version.\n\n1. Section 1.2 (1.2. Contributions) The contribution points should be summarized in 4 points instead of 7 points be sharp and narrow and reflect the content and the results well. 2. Table 2 (validation table) The comparison of the proposed technique is given based on which studies in the literature. 3. The authors did not describe well how spectrum sensing plays a crucial role in enabling smart healthcare applications in the context of 6G networks. 3. What are the primary challenges faced by healthcare applications in terms of spectrum availability and efficiency, and how can hybrid spectrum sensing address these challenges? 4. The potential benefits of integrating hybrid spectrum sensing methods into 6G-based smart healthcare systems were not explained well; and deserve more discussion. 5. Section 5. (Conclusion) should discuss the limitations and disadvantages of the proposed technique and how this can be overcome by this shortcoming in future studies.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "11628",
"date": "28 May 2024",
"name": "Arun Kumar",
"role": "Author Response",
"response": "Author Response for Reviewer 2 Peer Review Report: Reviewer Comments: Researchers are focused on quick and real-time healthcare and monitoring systems because of the contemporary modern world’s rapid technological improvements. Utilizing the primary user (PU) spectrum, cognitive radio (CR) can be highly useful for efficient and intelligent healthcare systems to send and receive patient health data. This paper deals with a hot area of investigation at the moment. I have looked at the mathematics and it looks sound. I would have liked to have seen a longer conclusion that discussed the effects of the various methods investigated. At this point, I recommend these parts be revised again and be expressed more analytically in a revised version. 1. Section 1.2 (1.2. Contributions) The contribution points should be summarized in 4 points instead of 7 points be sharp and narrow and reflect the content and the results well. Author Ans. Thank You Sir. It is updated as given below: The hybrid approach provides superior SS by leveraging the sensitivity of ED to detect energy in a frequency band and the precision CS to confirm the presence of specific signals. This results in a comprehensive and accurate view of the spectrum environment within the smart hospital. High probability of detection in 6G-based smart healthcare applications is crucial for seamless, ultra-reliable connectivity. These algorithms minimize interference, enabling real-time, high-quality data transmission from medical devices. This enhances telemedicine, remote patient monitoring, and precision diagnostics, ultimately improving healthcare accessibility and patient outcomes in the advanced 6G era. The hybrid ED-CS ensures the reliable detection of wireless medical devices and sensors. This is crucial for monitoring patients' vital signs, enabling timely interventions, and enhancing patient safety. With accurate spectrum sensing, smart hospitals can optimize their wireless networks and devices, leading to improved operational efficiency, reduced downtime, and cost savings. As 6G technology evolves, the hybrid approach ensures that smart hospitals are well-equipped to adapt to the increasing demands of advanced wireless communication. It future-proofs healthcare infrastructure, allowing hospitals to stay at the forefront of technology by enhancing the throughput of the framework. High-throughput SS algorithms in 6G-based smart healthcare applications facilitate rapid data transmission, supporting real-time remote monitoring and medical data exchange. This enables complex diagnostic procedures, telemedicine, and seamless healthcare services, offering enhanced patient care and health outcomes in the high-speed, low-latency 6G environment. Real-time and accurate spectrum sensing enhances patient care by enabling continuous monitoring and data transmission from medical devices. This contributes to early detection of medical issues, faster response times, and better overall patient outcomes. 2. Reviewer Comments: Table 2 (validation table) The comparison of the proposed technique is given based on which studies in the literature. Author Ans. Thank You Sir: it is given as below: Table 2 presents a validation of the proposed technique by comparing it with previous studies in the literature. This comparison serves as a benchmark to evaluate the effectiveness and performance of the proposed approach in addressing similar problems: 3. Reviewer Comments: The authors did not describe well how spectrum sensing plays a crucial role in enabling smart healthcare applications in the context of 6G networks. Author Ans. Thank You Sir. It is revised in the proposed work: In the framework of 6G networks, spectrum sensing is essential for developing smart healthcare applications. 6G-enabled healthcare systems may dynamically distribute spectrum resources to medical equipment, guaranteeing uninterrupted connectivity and real-time data transfer, by effectively identifying and analyzing underutilized or unused spectrum bands. This feature makes it easier for telemedicine, IoT devices for healthcare, and remote patient monitoring to proliferate, promoting prompt and accurate healthcare delivery. Additionally, spectrum sensing improves spectrum reliability and efficiency, which is essential for enabling the ultra-low latency and large data rates needed by developing healthcare applications in 6G networks [6]. Further motivations are also given which address the above question: 1.1. Motivation SS plays a crucial role in enhancing healthcare applications across various scenarios by ensuring reliable and efficient wireless communication. Here are different scenarios where spectrum sensing benefits healthcare [7-9]: Emergency Response and Disaster Recovery: During natural disasters or emergencies, dedicated spectrum sensing helps prioritize and allocate spectrum resources for healthcare providers. This ensures that first responders and medical teams have uninterrupted communication for coordinating rescue efforts and providing critical medical assistance, even in congested or disrupted networks. Wireless Medical Devices: Spectrum sensing is essential for wireless medical devices like remote patient monitors, wearable health trackers, and smart healthcare implants. These devices rely on spectrum sensing to identify the most suitable and interference-free frequency bands, ensuring real-time data transmission and accurate patient monitoring. Telemedicine: Spectrum sensing is vital for telemedicine applications, where doctors and patients communicate remotely. It enables healthcare professionals to maintain consistent and high-quality video and audio connections, even in crowded wireless environments. This ensures that telemedicine consultations and remote diagnostics are conducted without interruptions, improving the accessibility of healthcare services. IoT Healthcare Devices: The IoT has revolutionized healthcare with devices such as smart pill dispensers, medication trackers, and patient location monitors. Spectrum sensing ensures these IoT devices can operate in less congested bands, facilitating the reliable transmission of health-related data to healthcare providers and caregivers. Wireless Imaging and Diagnostics: Healthcare facilities increasingly rely on wireless technologies for transmitting large medical imaging files, including MRIs, CT scans, and X-rays. Spectrum sensing helps allocate suitable spectrum resources, ensuring that these critical files are transmitted efficiently and promptly, allowing for quicker diagnosis and treatment planning. Mobile Clinics: Spectrum sensing is beneficial for mobile healthcare clinics that operate in remote or underserved areas. These clinics can use spectrum sensing to identify the best available spectrum for their wireless communication needs, ensuring that healthcare professionals can access patient records, medical databases, and telemedicine consultations without network disruptions. Healthcare Robotics: Spectrum sensing is essential for healthcare robotics, including robotic surgical systems and remote-controlled medical robots. It ensures precise and real-time control during medical procedures, where any signal interference or delay can have critical consequences. Ambulance Communication: Ambulances equipped with advanced medical equipment and communication systems rely on spectrum sensing. It helps these vehicles maintain connectivity, allowing paramedics and emergency medical personnel to transmit patient information, vital signs, and other critical data to hospitals, ensuring seamless patient care transitions. 3. Reviewer Comments: What are the primary challenges faced by healthcare applications in terms of spectrum availability and efficiency, and how can hybrid spectrum sensing address these challenges? Author Ans. Thank You Sir. It is included in the introduction section as: Healthcare applications encounter significant challenges regarding spectrum availability and efficiency. The increasing demand for wireless healthcare services exacerbates spectrum congestion, leading to potential interference and degraded performance. Moreover, strict regulatory constraints limit the available spectrum for medical use. Hybrid spectrum sensing presents a promising solution by combining multiple sensing techniques, such as energy detection, matched filtering, and cyclostationary feature detection. By leveraging the strengths of each method, hybrid sensing enhances spectrum awareness, enabling healthcare systems to detect and utilize idle spectrum more effectively. This approach also improves spectrum utilization efficiency by accurately identifying and dynamically accessing available spectrum resources while mitigating interference risks. Additionally, hybrid spectrum sensing enhances reliability by providing robust detection in diverse environmental conditions and mitigating the effects of fading and shadowing. Overall, hybrid spectrum sensing offers a comprehensive solution to address the spectrum-related challenges faced by healthcare applications, ensuring reliable and efficient wireless connectivity for critical medical services [3]. 4. Reviewer Comments: The potential benefits of integrating hybrid spectrum sensing methods into 6G-based smart healthcare systems were not explained well; and deserve more discussion. Author Ans. Thank You Sir. It is included in the beginning of literature section as given below: Integrating hybrid spectrum sensing methods into 6G-based smart healthcare systems offers a multitude of benefits. Firstly, it enhances spectrum efficiency by intelligently utilizing available spectrum resources, ensuring optimal allocation for healthcare applications amidst growing demand and spectrum scarcity. Secondly, hybrid sensing improves reliability by mitigating interference and dynamically adapting to changing wireless environments, thereby enhancing the quality and consistency of healthcare data transmission. Thirdly, it enables seamless connectivity and coverage extension, crucial for supporting remote patient monitoring, telemedicine, and IoT devices in diverse healthcare settings. Additionally, hybrid spectrum sensing enhances security and privacy by identifying and mitigating potential threats and unauthorized access attempts. Moreover, by optimizing spectrum usage and improving connectivity, it facilitates innovative healthcare services and applications, fostering advancements in medical diagnostics, treatments, and patient care delivery. Overall, the integration of hybrid spectrum sensing into 6G-based smart healthcare systems promises to revolutionize healthcare delivery, ensuring efficient, reliable, and secure wireless communication for improved patient outcomes. 5. Reviewer Comments: Section 5. (Conclusion) should discuss the limitations and disadvantages of the proposed technique and how this can be overcome by this shortcoming in future studies. Author Ans. Thank You Sir, it is included in the conclusion section as: The proposed hybrid spectrum sensing methods in 6G-based smart healthcare applications face limitations, including increased computational complexity and energy consumption due to the integration of multiple sensing techniques. Moreover, hybrid sensing may require sophisticated hardware and signal processing algorithms, potentially increasing system cost and complexity. To overcome these challenges, future studies can focus on developing more efficient algorithms and hardware implementations tailored to the specific requirements of healthcare applications. Additionally, advancements in machine learning and artificial intelligence can be leveraged to optimize hybrid sensing performance while minimizing computational overhead and energy consumption, ensuring cost-effective and scalable solutions for smart healthcare systems."
}
]
}
] | 1
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https://f1000research.com/articles/13-110
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https://f1000research.com/articles/11-354/v1
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24 Mar 22
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{
"type": "Research Article",
"title": "An investigation of syrinx morphometry and sound frequency correlation during the chirping period in lovebirds (Agapornis fischeri)",
"authors": [
"Cytra Meyliana Surya Dewi",
"Yeni Dhamayanti",
"Faisal Fikri",
"Agus Purnomo",
"Shafia Khairani",
"Shekhar Chhetri",
"Muhammad Thohawi Elziyad Purnama",
"Cytra Meyliana Surya Dewi",
"Yeni Dhamayanti",
"Faisal Fikri",
"Agus Purnomo",
"Shafia Khairani",
"Shekhar Chhetri"
],
"abstract": "Background: In the issue of biodiversity, the domestication of birds as pets and trade animals requires special attention as a conservation effort. Lovebirds (Agapornis fischeri) are popular birds worldwide, due to their varied ornamentation and melodic chirping sound. Syrinx structure is suspected to be the main source of sound production during the chirping period. This study aimed to investigate syrinx morphometry and its correlation with sound frequency produced in lovebirds. Methods: A total of 24 lovebirds of different ages and gender were investigated. Polymerase chain reaction method was performed to determine lovebird gender, meanwhile bird age was identified based on post-hatch recordings at the breeding farm. Thus, we enrolled male (n=12) and female (n=12) lovebirds aged 2 (n=4), 3 (n=4), and 4 (n=4) months in the investigation group, respectively. Fast Fourier Transform (FFT) was performed to evaluate sound frequency during chirping period. Then, syrinx morphometry was identified using a topographic approach and methylene blue staining. Each variable was evaluated with Image J software and vernier caliper. Results: Based on a topographical approach, we reported the general cartilage structure of the tracheosyringeal, bronchosyringeal, paired protrusions, tracheolateral muscles, sternotracheal muscles, and syringeal muscles in lovebird syrinx. In particular, the tympaniform membranes lateral lead a crucial role in modulating the frequency of male lovebirds more significantly (p=0,009) compared to female. On the other hand, the tympaniform membranes lateral dexter (p=0,02) and sinister (p=0,05) in females showed wider compared to male. We also reported a negative correlation between sound frequency compared to tympaniform membranes lateral dexter (y = -913,56x + 6770,8) and sinister (y = -706,16x + 5736). Conclusions: It can be concluded that the tympaniform membranes lateral produced the lovebirds’ primary sound. The sound frequency of male lovebirds was higher compared to female, however negatively correlated with the area of tympaniform membranes lateral.",
"keywords": [
"Agapornis fischeri",
"biodiversity",
"lovebird",
"sound frequency",
"syrinx morphometry"
],
"content": "Introduction\n\nIn the last decade, various birds have been domesticated as pets. In Indonesia, lovebirds (Agapornis fischeri) are popularly reared in captivity and are traded pets. Lovebird is an attractive ornamental bird because it has a characteristic feather color pattern and distinctive behavior. In addition, the sound of birds chirping and variations in sound can attract the attention of breeders to rear lovebirds.1 Lovebird is a small parrot that often participates in chirping contests, thereby increasing its economic value as a traded pet. In Indonesia, the lovebird contest is not only based on beautiful feather color criteria but is based on the chirps produced.2\n\nIn some groups of avians, the syrinx is a crucial organ for producing sound and melody during chirping.3 The chirping variation is a manifestation of the articulation formed by the syrinx cartilage. In previous studies, syrinx organs were morphometrically revealed in pigeons,4 parakeets and canaries,5 chickens and rock dove,6 sparrows7 and penguins.8 The syrinx will stimulate the vibrations reflected from each cartilage to produce sound frequency.9 Lovebirds voice articulation develops in five phases from 0 to 91 days old, thereafter lovebirds can produce clear sound with different configurations. The duration of the sound and chirping frequency produced by the syrinx is significantly increased due to the reflection of the tympaniform membrane lateral.10\n\nA pair of tympaniform membrane lateral are found in the lateral wall of the syrinx at the tracheobronchial junction. This structure extends from the tympanum to the first bronchial ring in chickens and pigeons or is composed of short membranes between the bronchosyringeal rings.11 The tympaniform membrane medial connects the pessulus to the medial portion of the primary bronchus. This structure connects the ring portion of the bronchosyringeal cartilage dorsoventrally.12 The labia are a pair of elastic cords found in the lateral and medial tympaniform membranes that physiologically produce the primary sound.13\n\nThe difference between male and female lovebirds requires further information, in particular, to determine the eligible age for the Lovebirds contest. Age may influence syrinx morphometry and normal function of the tympaniform membrane lateral to produce sound. In addition, it is very important to investigate the correlation of syrinx morphometry and sound frequency. This study was expected to provide an evidence of syrinx topography and morphometry in lovebirds and their correlation on the sound frequency produced with differences in gender and age.\n\n\nMethods\n\nThis study was approved by the Ethical committee of animal care and use, Universitas Airlangga (No.445/HRECC.FODM/X/2020). This study was also reported according to the Animal Research: Reporting of in vivo Experiments (ARRIVE) guidelines 2.0: author checklist (see Reporting guidelines45). All efforts were made to ameliorate any suffering of animals.\n\nBased on legislation from the Ministry of Forestry and Biodiversity, Republic of Indonesia with reference number (No.20/2018) and Government Regulation with reference number (No.8/1999), Fischer’s Lovebird is not included in the red list in Indonesia. In addition, the owners of the rearing farm held special conservation permission and is reported periodically with an increase in the Fischer’s Lovebird population at the rearing farm.\n\nThis study was conducted over five months (November 2020 - March 2021). These lovebirds were reared in Mr. Sutoro farm, Solo, Central Java, Indonesia (7°33′29.6″S 110°51′43.0″E). Sound frequencies evaluation and syrinx morphometry were investigated at the biology laboratory, Universitas Surakarta (UNSA).\n\nThe sample size was determined using Federer’s formula: t(n-1) ≥ 15 with a combination of age and gender for six groups. There were four replications in each group, meaning a total of 24 lovebirds of different ages and gender (12 males and 12 females) were investigated. Inclusion criteria were that the birds were healthy (no animals were excluded). These lovebirds were reared in a fenced enclosure, fed millet seeds, and fresh water ad libitum. Our study was conducted on 2, 3, and 4-month-old (mo) birds based on post-hatch recordings at the breeding farm. Meanwhile, sexing was performed on feather samples using the polymerase chain reaction (PCR) method. Deoxyribonucleic acid (DNA) isolation was performed using the Gsync DNA Extraction Kit protocol (Geneaid Biotech Ltd, Taiwan). DNA extraction was carried out overnight to produce clear DNA bands. DNA fragment amplification was carried out targeting the CHD gene using primers and reference primary markers (Table 1). The reaction mixture of bird DNA was mixed as much as 25 μl consisting of 12,5 μl MyTaq™ DNA Polymerase (Labgene Scientific SA, Switzerland), 1 μl forward primer, 1 μl reverse primer, and 9,5 μl isolated DNA. Thereafter, the mixture was incubated in a PCR machine followed by pre-denaturation at 94°C for 2 mins, denaturation at 94°C for 20 sec, annealing at 46°C for 30 sec, extension at 72°C for 40 sec, and final extension at 72°C for 10 mins. All stages were repeated for 40 cycles. The results of the electrophoresis were then determined by comparing all samples with a 100 bp HyperLadder™ marker (Bioline, UK). The results of the electrophoresis are available in Underlying data.46 Visualization was revealed PCR products of 400 bp and 350 bp for females, meanwhile only 400 bp for males. Of the 33 samples, only male (n=12) and female (n=12) lovebirds aged 2 (n=4), 3 (n=4), and 4 (n=4) mo were enrolled in the investigation group, respectively.46 Randomization and blinding were performed in replicated gender and age groups using the following steps: (1) Lovebird populations aged 2, 3, and 4 months in the respective fenced enclosures were assigned as the investigated group, (2) lovebirds were caught one by one randomly and then their gender was determined using the PCR method, (3) only 4 male and 4 female lovebirds in the respective age were enrolled and labeled as samples, (4) this method was repeated for the 3 and 4 month age groups.\n\nWe evaluated each bird separately. The Fast Fourier Transform (FFT)16 method was performed to record the lovebirds’ sound frequency in an insulation room to avoid noise. The analog recording process was performed in an interval of 30 mins to record the number of bird sounds. Analog data on the recording device was transferred to a computer using a soundcard and then converted into WAV (Microsoft Waveform Audio Files) format files using Microsoft Sound Recording software (Windows Voice Recorder for Windows 10, Microsoft Corporation) (see Underlying data47). The visualization of voice phrases described the characteristics of the sound in a time interval in the form of a spectrogram (see Underlying data48). In addition, the visualization of sound phrases was observed as a continuous wave to reduce errors due to noise and phase differences in the FFT method.\n\nEuthanasia was performed by injection of a lethal dose (LD50) of 99.5 mg/kg BW of ketamine intramuscularly.18 The dissection procedure was performed on the dorsal recumbency with a focus on the thoracic cavity and then the topography of the dorsal, ventral, and lateral site of the syrinx was observed. The lower respiratory organs were dissected and then stored for 2 × 24 h using 10% formalin solution, then as a stopping point, moved the organs into 70% alcohol solution. Syrinx organs were immersed in 1% methylene blue for 15 mins and then rinsed using 50% and 70% alcohol.\n\nTopographical anatomical observations of the syrinx were performed for the following variables: tympanum (Ty), processus tympanicus (PT), tracheosyringeal (TS), bronchosyringeal (BS), bronchus (B), trachea bifurcation (BT), tracheolateral muscle (TLm), sternotracheal muscle (STm), profundal syringeal muscle (SPm), and superficial syringeal muscle (SSm). Meanwhile, syrinx morphometric were evaluated for the following variables: tympaniform membrane lateral dexter (TMLd), tympaniform membrane lateral sinister (TMLs), upper trachea (upT), middle trachea (mT), lower trachea (loT), paired protrusions dorsal (PPd), and paired protrusions ventral (PPv). Each variable was observed using a stereo microscope and then evaluated using Image J version 1.8.0 software.19\n\nThe area of tympaniform membrane lateral dexter and sinister were determined according to the curved line around the lateral side of the tympaniform membrane lateral. The cranial and caudal margins of the tympaniform membrane lateral are the paired protrusions and bronchosyringeal cartilages (Figure 1A).4 The length of the paired protrusions dorsal and paired protrusions ventral were determined according to the cranial to caudal line. This line is emphasized from the end profundal syringeal muscle to the bronchosyringeal-1 cartilage (Figure 1B).5 For trachea diameter, evaluation was performed on the upper trachea, middle trachea, and lower trachea sides using a vernier caliper (Figure 1C).\n\n(A) area of tympaniform membrane lateral (TML), (B) length of paired protrusions (PP), (C) trachea diameter.\n\nAll the data were expressed as mean ± standard error (SE) then analyzed using multivariate analysis of variance (MANOVA) followed by Duncan’s comparison test. Values were considered significantly different at p < 0,05. The sound frequency of male and female were analyzed using independent T-test with a significance level (p < 0,05). Meanwhile, to investigate the correlation between the area of tympaniform membrane lateral and the lovebirds sound frequency produced, a regression test with R-square (R2) was performed. Statistical analysis was performed using SPSS v.25 software (IBM, USA).\n\n\nResults\n\nThe raw, uncropped images associated with syrinx morphometry and topography are available in Underlying data.44 The topographical observations of lovebird syrinx showed that there was no anatomical topographic variation across the various age and gender groups. Syrinx location in the thoracic cavity tends to the left side compared to the esophagus, on the dorsocranial of the heart and caudal of the crop. Tracheal organs were found in the ventral esophagus. The trachea in the cervical region was found on the left side of the esophagus, before the thoracic cavity of the trachea is on the dorsal side of the esophagus. The crop continues to the caudal side of the transformed esophagus parallel to the syrinx. The esophagus continues to the caudal side by crossing to the dorsal bifurcation of the trachea then being on the ventral of the lung and transformed into the proventriculus (Figure 2).\n\nUsing methylene blue staining, clearly visible tympaniform membrane lateral was observed from both primary bronchi. The cranial margin of the tympaniform membrane lateral is paired protrusions covered by profundal syringeal muscle and the caudal margin of the tympaniform membrane lateral is the bronchosyringeal-1 cartilage. An evidence revealed that pessulus and labia were not found in the lovebird syrinx. It was found tympanum modification in the form of caudal protrusion called processus tympanicus on the dorsal and ventral sides. Processus tympanicus structure was found between a pair of paired protrusions which are tympanic plates and are connected to the cranial side of the tympaniform membrane lateral. Paired protrusions and tympanum structures are part of the tracheosyringeal cartilage. Paired protrusions is tracheosyringeal-1 cartilage, meanwhile tympanum is composed of three cartilages i.e. tracheosyringeal 2-4 (Figure 3). Bronchosyringeal cartilage was found on the cranial side of the trachea bifurcation and the caudal side of the tympaniform membrane lateral. All samples from each gender and age group had three pairs of bronchosyringeal cartilage on the right and left sides (Figure 4).\n\nTML= tympaniform membrane lateral, Ty = tympanum, PT = processus tympanicus, PP = paired protrusions, TS1-4 = tracheosyringeal 1-4, BS1-3 = bronchosyringeal 1-3.\n\nBS1-3 = bronchosyringeal 1-3, B1-2 = bronchus 1-2, BT = trachea bifurcation.\n\nObservation of the muscles revealed that in all gender and age groups the lovebird syrinx was identified as tracheolateral muscle, sternotracheal muscle, profundal syringeal muscle and superficial syringeal muscle. Tracheolateral muscle was found on the lateral side of the trachea. Meanwhile, sternotracheal muscle was found on the lateral side of the lower trachea and then split into two in the dexter and sinister syrinx (Figure 5). The muscular structure gets thinner on the mediastinal side and eventually forms the sternotracheal muscle tendon, which then attaches to the lungs and extrapulmonary bronchi. Sternotracheal muscle on both sides looks asymmetrical, however the sinister is more inclined to the dorsal compared to the dexter is inclined ventrally. Profundal syringeal muscle was found from tympanum to paired protrusions with the caudal end of the muscle connected to the cranial portion of the tympaniform membrane lateral. Superficial syringeal muscle was identified from the lateral side of tympanum to the primary bronchus. The difference was found in the location of the connection of the caudal end of the profundal syringeal muscle and the bronchial cartilage. In groups aged 2 and 3 mo, both male and female, it was reported that there was a connection of the caudal end of the profundal syringeal muscle with the bronchus-2 cartilage, meanwhile, in the aged 4 mo group, both male and female, it was found in the bronchus-3 cartilage (Figure 6).\n\nTLm = tracheolateral muscle, STm = sternotracheal muscle, SPm = profundal syringeal muscle, SSm = superficial syringeal muscle.\n\nTML = tympaniform membrane lateral, PP = paired protrusions, SPm = profundal syringeal muscle, SSm = superficial syringeal muscle, BS1-3 = bronchosyringeal 1-3, B1-3 = bronchus 1-3.\n\nIn this syrinx morphometric study, it was reported that the area of the tympaniform membrane lateral dexter and sinister increased with the increasing age of lovebirds. Tympaniform membrane lateral dexter and sinister in female lovebirds were observed more widely compared to male lovebirds. In the paired protrusions variables, upper, middle, and lower tracheal diameters, there was no significant difference reported in gender and age groups (Table 2). The full data associated with the Syrinx morphometry and sound frequency evaluation is available in Underlying data.43\n\nIn this present study, the evaluation of sound frequency was performed only on lovebirds aged 4 mo because at that age they are considered a mature lovebird during contest. The sound frequency produced by male lovebirds (3500,00 ± 204,12) was significantly higher compared to female lovebirds (2687,50 ± 62,50) (Table 3). This study also revealed that there was a negative correlation between sound frequencies compared with the area of tympaniform membranes lateral dexter (y = -913,56x + 6770,8) and sinister (y = -706,16x + 5736) (Figure 7). This finding indicated that the smaller area of lateral tympaniform membranes followed by an increase in the sounds frequency produced by the syrinx cartilage articulation.\n\n\nDiscussion\n\nThe syrinx is a vocal organ in the avian family with the physiological principle of flowing air from the lungs across the narrow bronchotracheal tract and vibrating the tympaniform membranes lateral and medial.20 In respective bird species there is a variety of sounds due to differences in the syrinx anatomical structure.21 In this present study, we observed a modified syrinx cartilage in the form of processus tympanicus and paired protrusions which are only owned by the Psittacidae bird family.22 Paired protrusions are classified into tracheosyringeal cartilages with a composition similar to the tympanum compared to the structure of the bronchosyringeal cartilages.23\n\nIn a previous study involving male Budgerigars (Melopsittacus undulatus), the tympanum was composed of six elements,24 meanwhile in this study the tympanum was only composed of three elements. Lovebird syrinx was found on the caudal side of the lower trachea and not yet connected to the trachea bifurcation. The syrinx type in the Psittacidae family has a single set of membranes so that it produces only a single sound, unlike other bird species with the tracheobronchial syrinx type and can produce multiple sounds independently.25 The sternotracheal muscle was identified from the lower trachea and then transformed into a tendon that connects to the lung area near the end of the extrapulmonary bronchus called the septum obliquum.26\n\nIn another study, the sternotracheal muscle appeared asymmetrical because the syrinx crossed with the esophagus, thus the muscle junction was not parallel between the dexter and sinister sides.27 Another characteristic of the Psittacidae family, it has the Syringeal profundus and superficial muscle which is found in all gender and age groups with insertions starting from the cranial tympanum. Lovebirds only have two intrinsic muscles, i.e. the syringeal profundus and superficial muscles compared to other species of chirping birds due to the muscle structure is more complex, i.e. the tracheobronchial dorsal, ventral and brevis muscles and the syringeal dorsal and ventral muscles.28\n\nIn this syrinx morphometric study, there were significant differences in the area of tympaniform membranes lateral dexter and sinister in lovebirds aged 2, 3, and 4 mo. The area of the tympaniform membranes lateral increases with age in both male and female lovebirds. Tympaniform membranes lateral are functional membranes that produce melodic sounds in the Psittacidae family.29 The development of the tympaniform membranes lateral is triggered by the development of the chirping sound. The rapid development that occurs in pubertal birds will then decrease gradually at aged 9 mo.30\n\nIn another study, tympaniform membranes lateral were reported to be larger in male pigeons than in female pigeons.31 This is supported by studies of the duration and number of chirping periods being greater in females than males. Studies on artificial vocal cords reported that the larger area of the vibrating membrane produces lower sound frequencies.32 The area of the tympaniform membranes can be one of the factors that trigger the difference in the sound of chirping in male and female lovebirds. In addition, the body weight of female lovebirds is significantly heavier than males. Generally, bird species with larger bodies have lower sound frequencies.33 Hormonal factors also affect the character of the sound produced.34 Repeated administration of testosterone in perdix birds resulted in a longer duration of chirping with a lower frequency.35 The same study stated that birds treated with testosterone showed a significant widening of the lumen of the trachea and bronchi and a thicker syrinx membrane.36\n\nTympaniform membranes lateral in chickens are composed of connective tissue and an extracellular matrix consisting of carbohydrates, hyaluronic acid and collagen.37 The vocal folds are sensitive to the hormone estrogen. The decrease in estrogen has an impact on changes in the expression of molecules in the extracellular matrix, whereas testosterone does not affect the extracellular matrix.38 Studies on sparrows after hatching at 3, 10 and 17 days old showed that androgen receptors can be found in the muscles around the syrinx and estrogen receptors are found in many syrinx chondrocytes.39 Estrogens and androgens can affect the development of the syrinx of birds after hatching in the skeletal and muscular parts, but their effect on the differentiation process is unidentified. Hormones have an influence on the nervous system which controls sound production. Testosterone has two effects, i.e. anatomically controlling the growth of vocal control stations and physiologically controlling the number of enzymes required during neural transmission.40\n\nVocal control stations on the central nervous system have androgen and estrogen receptors that affect sound sensitivity.41 Studies on adult canaries require estrogen to produce a chirp with a high rate of repeating syllables.42 The duration of the chirp, the length of the chirping element and the frequency range can be influenced by the hormone testosterone but only in certain species so that there are differences in the expression of hormone receptors in the central nervous system which differ in each species and even gender. Various factors that influence the anatomical and morphometric differences of the lovebird syrinx and its relation to the characteristics of the chirping sound produced need to be studied further.\n\n\nConclusions\n\nIn conclusion, we identified tympanum, processus tympanicus, tracheosyringeal cartilage, bronchosyringeal, bronchi, trachea bifurcation, paired protrusions, tracheolateral muscle, sternotracheal muscle, profundal and superficial syringeal muscle in lovebird syrinx. Tympaniform membranes lateral were revealed to be larger in female lovebirds compared to males, however in correlation the sound frequency of males was higher compared to females. These findings emphasized the crucial role of the tympaniform membranes lateral as sound producers, in particular for male lovebirds aged 4 mo.\n\n\nData availability\n\nFigshare: Syrinx morphometry and sound frequency evaluation. https://doi.org/10.6084/m9.figshare.18382925.v4.43\n\nThis project contains the following underlying data:\n\n• Syrinx morphometry and sound frequency evaluation.xlsx\n\nFigshare: Syrinx morphometry and topography. https://doi.org/10.6084/m9.figshare.18386744.v2.44\n\nThis project contains the following underlying data:\n\n• 1a.png (Figure 1A Tympaniform membrane lateral evaluation).\n\n• 1b.png (Figure 1B Paired protrusions evaluation).\n\n• 1c.png (Figure 1C Trachea evaluation).\n\n• 2a.png (Figure 2A Location of the syrinx compared to the heart in the thoracic cavity).\n\n• 2b.png (Figure 2B Location of the syrinx compared to the esophagus in the thoracic cavity).\n\n• 3a.png (Figure 3A Syrinx structures with methylene blue staining on dorsolateral view).\n\n• 3b.png (Figure 3B Syrinx structures with methylene blue staining on ventrolateral view).\n\n• 4.png (Figure 4 Bronchosyringeal cartilage).\n\n• 5a.png (Figure 5A Syrinx muscle structures on dorsal view).\n\n• 5b.png (Figure 5B Syrinx muscle structures on ventral view).\n\n• 6a.png (Figure 6A Lovebird syrinx aged 2 months on lateral view).\n\n• 6b.png (Figure 6B Lovebird syrinx aged 3 months on lateral view).\n\n• 6c.png (Figure 6C Lovebird syrinx aged 4 months on lateral view).\n\nFigshare: Gel electrophoresis result to determine Lovebird gender. https://doi.org/10.6084/m9.figshare.19248182.v1.46\n\nThis project contains the following underlying data:\n\n• Gel session 1.jpeg (Gender determination of sample number 1-12).\n\n• Gel session 2.jpeg (Gender determination of sample number 13-24).\n\n• Gel session 3.jpeg (Gender determination of sample number 25-33).\n\nFigshare: Individually recorded Lovebird sounds in WAV format. https://doi.org/10.6084/m9.figshare.19327490.v1.47\n\nThis project contains the following underlying data:\n\n• ML1.wav (Sound recording for male lovebird sample No.1).\n\n• ML2.wav (Sound recording for male lovebird sample No.2).\n\n• ML3.wav (Sound recording for male lovebird sample No.3).\n\n• ML4.wav (Sound recording for male lovebird sample No.4).\n\n• FL1.wav (Sound recording for female lovebird sample No.1).\n\n• FL2.wav (Sound recording for female lovebird sample No.2).\n\n• FL3.wav (Sound recording for female lovebird sample No.3).\n\n• FL4.wav (Sound recording for female lovebird sample No.4).\n\nFigshare: Spectrogram analysis in respective bird sound. https://doi.org/10.6084/m9.figshare.19327856.v1.48\n\nThis project contains the following underlying data:\n\n• ML1.PNG (Spectrogram figure for male lovebird sample No.1).\n\n• ML2.PNG (Spectrogram figure for male lovebird sample No.2).\n\n• ML3.PNG (Spectrogram figure for male lovebird sample No.3).\n\n• ML4.PNG (Spectrogram figure for male lovebird sample No.4).\n\n• FL1.PNG (Spectrogram figure for female lovebird sample No.1).\n\n• FL2.PNG (Spectrogram figure for female lovebird sample No.2).\n\n• FL3.PNG (Spectrogram figure for female lovebird sample No.3).\n\n• FL4.PNG (Spectrogram figure for female lovebird sample No.4).\n\nFigshare: ARRIVE checklist for ‘An investigation of syrinx morphometry and sound frequency correlation during the chirping period in lovebirds (Agapornis fischeri)’. https://doi.org/10.6084/m9.figshare.18394103.v2.45\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nWe thank Mr. Sutoro who allowed us to perform the experiments on their lovebird farm. Last but not least, thanks to Aulia, Dara, Sera, Teja for all facilities support and mini equipment during this study.\n\n\nReferences\n\nVan der Zwan H, Visser C, Van der Sluis R: Plumage colour variations in the Agapornis genus: a review. Ostrich. 2019; 90(1): 1–10. Publisher Full Text\n\nHanesia WI, Hidayat B, Sunarya U: Klasifikasi Suara Lovebird Dengan Metode Mel Frequency Cepstral Coefficient (mfcc) Dan Fuzzy Logic. Proc. Eng. 2015; 2(2): 2968.\n\nSuthers RA, Zollinger SA: Producing song: the vocal apparatus. Ann. N. Y. Acad. Sci. 2004; 1016(1): 109–129. PubMed Abstract | Publisher Full Text\n\nAlonso RG, Kopuchian C, Amador A, et al.: Difference between the vocalizations of two sister species of pigeons explained in dynamical terms. J. Comp. Physiol. 2016; 202(5): 361–370. PubMed Abstract | Publisher Full Text\n\nGündemir O, Alpak H: Macroanatomic and histological examination of the trachea and syrinx in budgerigars and canaries. Harran Üniv. Vet. Fak. Derg. 2020; 9(1): 19–23. Publisher Full Text\n\nMaksoud A, Ibrahim A, Hussein M, et al.: The Gross Anatomy of the Syrinx of Adult Male Domestic Fowl Gallus gallus domesticus. J. Vet. Res. Med. 2019; 1(1): 1–5.\n\nRiede T, Goller F: Functional morphology of the sound-generating labia in the syrinx of two songbird species. J. Anat. 2010; 216(1): 23–36. PubMed Abstract | Publisher Full Text\n\nKriesell HJ, Le Bohec C, Cerwenka AF, et al.: Vocal tract anatomy of king penguins: morphological traits of two-voiced sound production. Front. Zool. 2020; 17(1): 1–11.\n\nSoobramoney S, Perrin M: A comparison of the alarm calls of five species of African lovebirds: genus Agapornis. Trans. Royal Soc. South Africa. 2014; 69(1): 9–18. Publisher Full Text\n\nHongzhen Y, Dongfeng L, Jinchang J: The call development of Psittacula agapornis. Shengwu Wuli Xuebao. 2006; 22(2): 101–109.\n\nCasteleyn C, Cornillie P, Van Cruchten S, et al.: Anatomy of the upper respiratory tract in domestic birds, with emphasis on vocalization. Anat. Histol. Embryol. 2018; 47(2): 100–109. PubMed Abstract | Publisher Full Text\n\nMohamed R: Sexual dimorphism in the anatomical features of the Syrinx in the White Pekin ducks (Anas platyrhynchos). Int. J. Agric. Sci. Vet. Med. 2017; 5(5): 78–85.\n\nLadich F, Winkler H: Acoustic communication in terrestrial and aquatic vertebrates. J. Exp. Biol. 2017; 220(13): 2306–2317. PubMed Abstract | Publisher Full Text\n\nSigeman H, Ponnikas S, Hansson B: Whole-genome analysis across 10 songbird families within Sylvioidea reveals a novel autosome–sex chromosome fusion. Biol. Lett. 2020; 16(4): 20200082. PubMed Abstract | Publisher Full Text\n\nGan HM, Falk S, Morales HE, et al.: Genomic evidence of neo-sex chromosomes in the eastern yellow robin. GigaSci. 2019; 8(9): giz111. PubMed Abstract | Publisher Full Text\n\nPrapcoyo H, Putra BPA, Perwira RI: Implementation of Mel Frequency Cepstral Coefficient and Dynamic Time Warping For Bird Sound Classification. In Conference SENATIK. 2019; 5(1): 139–148. Publisher Full Text\n\nAbdel-Maksoud FM, Hussein MM, Hamdy A, et al.: Anatomical, Histological, and Electron Microscopic Structures of Syrinx in Male Budgerigars (Melopsittacus undulatus). Micros. Microanal. 2020; 26(6): 1226–1235. PubMed Abstract | Publisher Full Text\n\nAlatrushi AN, Naser AS: The Safety Profile of the Anesthetic Effect of Alfaxalone and its Interaction with Xylazine and Ketamine in Chick’s Model. Maced. Vet. Rev. 2021; 44(2): 203–209. Publisher Full Text\n\nRiede T, Olson CR: The vocal organ of hummingbirds shows convergence with songbirds. Sci. Rep. 2020; 10(1): 1–14.\n\nKingsley EP, Eliason CM, Riede T, et al.: Identity and novelty in the avian syrinx. Proc. Nat. Acad. Sci. 2018; 115(41): 10209–10217. PubMed Abstract | Publisher Full Text\n\nDegrange FJ: A revision of skull morphology in Phorusrhacidae (Aves, Cariamiformes). J. Vertebr. Paleontol. 2020; 40(6): e1848855. Publisher Full Text\n\nGaban-Lima R, Höfling E: Comparative anatomy of the syrinx in the tribe Arini (Aves: Psittacidae). J. Morphol. Sci. 2017; 23(3): 501–512.\n\nMcInerney PL, Lee MS, Clement AM, et al.: The phylogenetic significance of the morphology of the syrinx, hyoid and larynx, of the southern cassowary, Casuarius casuarius (Aves, Palaeognathae). BMC Evol. Biol. 2019; 19(1): 1–18.\n\nAbdel-Maksoud FM, Hussein MM, Hamdy A, et al.: Anatomical, Histological, and Electron Microscopic Structures of Syrinx in Male Budgerigars (Melopsittacus undulatus). Microsc. Microanal. 2020; 26(6): 1226–1235. PubMed Abstract | Publisher Full Text\n\nCrosta L: Respiratory Diseases of Parrots: Anatomy, Physiology, Diagnosis and Treatment. Vet. Clin. Exotic. Anim. Pract. 2021; 24(2): 397–418. PubMed Abstract | Publisher Full Text\n\nMonte A, Cerwenka AF, Ruthensteiner B, et al.: The hummingbird syrinx morphome: a detailed three-dimensional description of the black jacobin’s vocal organ. BMC Zool. 2020; 5(1): 1–15. Publisher Full Text\n\nDoğan GK, Takaci I: Anatomy of respiratory system in poultry. Vet. J. Mehmet. Akif. Ersoy. Univ. 2018; 3(2): 141–147.\n\nKumar R, Singh M: Bird fancier’s lung: clinical-radiological presentation in 15 cases. Adv. Respir. Med. 2015; 83(1): 39–44. Publisher Full Text\n\nIbrahim IAA, Hussein MM, Hamdy A, et al.: Comparative morphological features of syrinx in male domestic fowl Gallus gallus domesticus and male domestic pigeon Columba livia domestica: A histochemical, ultrastructural, scanning electron microscopic and morphometrical study. Micros. Microanal. 2020; 26(2): 326–347. Publisher Full Text\n\nPutranto HD, Brata B, Yumiati Y: Study on contour feathers growth of White-rumped Shama during fledgling phase. In IOP Conf. Ser. Earth Environ. Sci. 2021; 788(1): 012085. Publisher Full Text\n\nAl-badri AMS: Macroscopic study of syrinx in the common bulbul (Pycnontus barbatus) and indigenous pigeon (Columba domestica). Al-Qadisiyah J. Vet. Med. Sci. 2014; 13(1): 88–93. Publisher Full Text\n\nZhang YS, Takahashi DY, Liao DA, et al.: Vocal state change through laryngeal development. Nat. Commun. 2019; 10(1): 1–12.\n\nWalløe S, Chakraborty M, Balsby TJ, et al.: A Relationship between the Characteristics of the Oval Nucleus of the Mesopallium and Parrot Vocal Response to Playback. Brain Behav. Evol. 2021; 96(1): 37–48. Publisher Full Text\n\nGhosh R, Mishra RC, Choi B, et al.: Exposure to sound vibrations lead to transcriptomic, proteomic and hormonal changes in Arabidopsis. Sci. Rep. 2016; 6(1): 1–17.\n\nChiver I, Schlinger BA: Sex-specific effects of testosterone on vocal output in a tropical suboscine bird. Anim. Behav. 2019; 148(1): 105–112. Publisher Full Text\n\nGahr M: How hormone-sensitive are bird songs and what are the underlying mechanisms?. Acta Acust. United Acust. 2014; 100(4): 705–718. Publisher Full Text\n\nGoller F: Sound production and modification in birds–Mechanisms, methodology and open questions. Comparative Bioacoustics: An Overview. Brown C, Riede T, editors. Sharjah, United Arab Emirates: Bentham Science Publishers; 2016; 165–230.\n\nKunduk M, Vansant MB, Ikuma T, et al.: The effects of the menstrual cycle on vibratory characteristics of the vocal folds investigated with high-speed digital imaging. J. Voice. 2017; 31(2): 182–187. PubMed Abstract | Publisher Full Text\n\nTehrani MA, Veney SL: Intracranial administration of the G-protein coupled estrogen receptor 1 antagonist, G-15, selectively affects dimorphic characteristics of the song system in zebra finches (Taeniopygia guttata). Develop Neurobiol. 2018; 78(8): 775–784. PubMed Abstract | Publisher Full Text\n\nCornez G, Shevchouk OT, Ghorbanpoor S, et al.: Testosterone stimulates perineuronal nets development around parvalbumin cells in the adult canary brain in parallel with song crystallization. Horm. Behav. 2020; 119(1): 104643. PubMed Abstract | Publisher Full Text\n\nCaras ML, Remage-Healey L: Modulation of peripheral and central auditory processing by estrogens in birds. Hear Horm. 2016; 57(4): 77–99. Publisher Full Text\n\nKo MC, Van Meir V, Vellema M, et al.: Characteristics of song, brain-anatomy and blood androgen levels in spontaneously singing female canaries. Horm. Behav. 2020; 117(1): 104614. PubMed Abstract | Publisher Full Text\n\nPurnama MTE, Dewi CMS, Dhamayanti Y, et al.: Syrinx morphometry and sound frequency evaluation. figshare. Dataset. 2022. Publisher Full Text\n\nPurnama MTE, Dewi CMS, Dhamayanti Y, et al.: Syrinx morphometry and topography. figshare. Figure. 2022. Publisher Full Text\n\nPurnama MTE, Dewi CMS, Dhamayanti Y, et al.: ARRIVE report checklist: Syrinx morphometry and sound frequency evaluation during chirping period in Lovebirds (Agapornis fischeri). figshare. 2022. Online resource. Publisher Full Text\n\nPurnama MTE, Dewi CMS, Dhamayanti Y, et al.: Gel electrophoresis result to determine Lovebird gender. figshare. Figure. 2022. Publisher Full Text\n\nPurnama MTE, Dewi CMS, Dhamayanti Y, et al.: Individually recorded Lovebird sounds in WAV format. figshare. Media. 2022. Publisher Full Text\n\nPurnama MTE, Dewi CMS, Dhamayanti Y, et al.: Spectrogram analysis in respective bird sound. figshare. Figure. 2022. Publisher Full Text"
}
|
[
{
"id": "144637",
"date": "02 Aug 2022",
"name": "Abdulmojeed Yakubu",
"expertise": [
"Reviewer Expertise Animal Breeding and Genetics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract: Background:\nI thought the location of study will be a thing of interest.\nMethods:\nA brief description of the statistical analysis is required under Methods.\n\nThis sentence appears incomplete: ‘On the other hand, the tympaniform membranes lateral dexter (p=0,02) and sinister (p=0,05) in females showed wider compared to male’\n\nYou gave regression equations without the corresponding correlation values, except you want to replace ‘correlation’ with ‘association’.\nConclusions:\nPlease try and conclude in the context of the biological implication of your findings.\n\nIntroduction:\nPlease expatiate on ‘Lovebirds contest’.\n\nMethods: Experimental design:\nTry and separate experimental design from PCR part of the study.\n\nProvide a reference for the Federer’s formula: t(n-1) ≥ 15, and why is it adopted in this study considering the sample size of only 24 lovebirds?\n\nWhat gel and dye were used for the PCR?\n\n‘Of the 33 samples’. There is a need to elaborate on this.\n\nBriefly describe the term ‘blinding’.\nMethylene blue staining:\nHow soon does lethal dose (LD50) have effect on the bird?\nStatistical analysis:\nDid you test for the homogeneity of variance and normality of your data?\n\nYou are mixing up Correlation and Regression (Association). Although the two has to do with ‘Relationship’, they provide different values.\n\nResults: Sound frequency evaluation:\nYou should have tested sound frequency for other ages as it would have provided additional information for comparison.\n\nDiscussion:\nBriefly discuss syrinx morphometrics in the context of adaptation before relating with sound frequency.\n\nConclusions:\nTry and beef up this section especially as it relates to biological implication and future study.\n\nReferences\nPlease revisit for accuracy and correct formatting.\n\nNB: There is a need for language editing of the entire text.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "9218",
"date": "10 Mar 2023",
"name": "Muhammad Thohawi Elziyad Purnama",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for your valuable comments and suggestions on the manuscript entitled: \"An investigation of syrinx morphometry and sound frequency association during the chirping period in lovebirds (Agapornis fischeri)\" We welcome feedback. We have made modifications to the study on the following points: Background: I thought the location of study will be a thing of interest. Response: We have added the location and study period to the background abstract and methods section. Methods: A brief description of the statistical analysis is required under Methods. Response: We have added a brief description of the statistical method to the abstract. This sentence appears incomplete: ‘On the other hand, the tympaniform membranes lateral dexter (p=0,02) and sinister (p=0,05) in females showed wider compared to male’ Response: We have modified the interpretation of these results. You gave regression equations without the corresponding correlation values, except you want to replace ‘correlation’ with ‘association’. Response: We have revised that the association test was used in the present study. Conclusions: Please try and conclude in the context of the biological implication of your findings. Response: We have modified the conclusions according to crucial information on syrinx morphometry and biologic implications. Introduction: Please expatiate on ‘Lovebirds contest’. Response: We have added crucial information about lovebird contests and information gaps from this study. Methods: Experimental design: Try and separate experimental design from PCR part of the study. Response: We have separated the experimental design section from the sex determination method. Provide a reference for the Federer’s formula: t(n-1) ≥ 15, and why is it adopted in this study considering the sample size of only 24 lovebirds? Response: We have added references and reasons why this formula was implemented in determining the sample for this study. What gel and dye were used for the PCR? Response: We have added manufacturing information for gel products and dyes used. ‘Of the 33 samples’. There is a need to elaborate on this. Response: We have added a description of why the number of birds was collected, then determined the sex as a qualification for the sample studied. Briefly describe the term ‘blinding’. Response: We have described the randomization and blinding stages of the sample. Methylene blue staining: How soon does lethal dose (LD50) have effect on the bird? Response: We have added information on the onset of action LD50 at the euthanasia stage. Statistical analysis: Did you test for the homogeneity of variance and normality of your data? Response: We added a brief description of the Shapiro-Wilk test for homogeneity analysis in the present study. You are mixing up Correlation and Regression (Association). Although the two has to do with ‘Relationship’, they provide different values. Response: We have revised that the association test was used in the present study. Results: Sound frequency evaluation: You should have tested sound frequency for other ages as it would have provided additional information for comparison. Response: A limitation of our study was not evaluating the frequency of birdsong at all ages due to the full rearing period up to 4 months of age prior to euthanasia. However, we will use this design for further studies so that we can provide more comprehensive information and compare it to other ages. Discussion: Briefly discuss syrinx morphometrics in the context of adaptation before relating with sound frequency. Response: We have added a brief description of the adaptive context of the syrinx morphometrics prior to its physiological function in producing sound vibrations. Conclusions: Try and beef up this section especially as it relates to biological implication and future study. Response: We have modified the conclusions according to crucial information on syrinx morphometry and biological implications. References Please revisit for accuracy and correct formatting. Response: We have revised and reformatted the references according to the guidelines."
}
]
}
] | 1
|
https://f1000research.com/articles/11-354
|
https://f1000research.com/articles/12-23/v1
|
09 Jan 23
|
{
"type": "Research Article",
"title": "Interactions between special education teachers and children with chronic complex conditions: A qualitative study",
"authors": [
"Haruo Fujino",
"Megumi Matsumoto",
"Aya Mieno",
"Megumi Matsumoto",
"Aya Mieno"
],
"abstract": "Background: The number of children with complex medical conditions has increased in recent decades. In this context, a complex chronic condition is characterized by multiple morbidities that require intensive or continuous health care according to the level of severity. Given their various health conditions, it is challenging to provide special education to these children, but there is still insufficient evidence regarding the practical experiences of educators. The aim of this study was to investigate special education teacher’s perceptions, experiences, and challenges while developing interpersonal relationships and communicating with children who have complex chronic conditions.\n\nMethods: We recruited and interviewed 21 special education school teachers. The transcripts of the interviews were analyzed using thematic analysis.\n\nResults: Our analysis revealed four themes, including “searching for the meaning,” “complex chronic conditions as a difficult reality,” “widening experience for the future,” and “priority for interacting with children.” These themes reflect the perceptions, experiences, and challenges of the special education teachers.\n\nConclusions: In cases where children have severe functional limitations, it is more challenging to understand child-teacher interactions. This highlights the importance of searching for meaning in educational practices used among children with complex chronic conditions. Our findings may provide helpful insight into the experiences and challenges faced by special educators who engage with these children.",
"keywords": [
"chronic illness",
"children",
"special education",
"interaction",
"child health",
"profound intellectual and multiple disabilities"
],
"content": "Background\n\nThe number of children with complex medical conditions has increased in recent decades, although the rate of prevalence varies based on the definition and study context, ranging from 5–30% (Beers et al., 2003). While various categorizations and definitions exist in the literature (van der Lee et al., 2007), complex chronic conditions (CCC) is defined according to the International Classification of Diseases (Feudtner et al., 2000; Feudtner et al., 2014). In an earlier study, Feudtner et al. (2000) proposed the following definition for CCC:\n\n“Any medical condition that can be reasonably expected to last at least 12 months (unless death intervenes) and to involve either several different organ systems or 1 organ system severely enough to require specialty pediatric care and probably some period of hospitalization in a tertiary care center.”\n\nTo date, the revised description of CCC covers various complex medical conditions, including neurological and neuromuscular disorders, cardiovascular disorders, congenital and genetic defects, and technology dependence (e.g., tracheostomy) (Feudtner et al., 2014). In this framework, an epidemiological survey in the United States found that approximately 10% of children had one or more CCC, while 2% had multiple CCC (Bjur et al., 2019). In Japan, relevant data show that around 20,000 students (~0.002% of children) with health disorders receive special education in accordance with their special health care needs (MEXT, 2018). Although many children with severe CCC who receive inpatient treatment appear to attend special needs schools, educational statistics on this issue are currently unavailable in Japan. While the exact rate of prevalence depends on the population, it is clear that there is an increasing number of children with CCC, which has therefore become an important area of focus in medicine and education (Feudtner et al., 2014; O'Connor et al., 2019).\n\nChildren with multiple CCC generally exhibit more severe functional impairment and limited participation because of their disorders. Moreover, some children with CCC and severe intellectual disabilities are classified as having profound intellectual and multiple disabilities (PIMD), which is characterized by very severe cognitive and neuromotor impacts (van Timmeren et al., 2016). For example, the causes of PIMD include genetic disease, brain malformation, oxygen deficiency, and/or intractable epileptic seizure. Such conditions vary across a range of factors, including severity, trajectory, multiple organ involvement, medical and technological assistance, and special needs to address psychological and developmental difficulties (McPherson et al., 1998; van der Lee et al., 2007). Thus, children with CCC may have a variety of special needs that require more attention and educational support in the school setting.\n\nSchools for sick children play cardinal roles in the education and development of those with health disorders that require long-term treatment or frequent hospitalization. Although inclusive education is emphasized in the general school setting, challenges still arise when educating children with CCC (Seki et al., 2017). As emphasized in special needs education, higher expertise and continuous learning are also expected in the Japanese educational system (Isogai, 2017). Given these factors, those with CCC or severe conditions often receive individualized education at special needs schools that are located in or adjacent to hospitals.\n\nSince communication and interpersonal relationships are essential components in child development, the Japanese special education system aims to establish both (MEXT, 2017). However, teachers who educate children with CCC may have difficulty achieving these goals due to functional limitations that arise under complex medical conditions. Moreover, children with very limited functioning require special curricula on a daily basis as well as continued intervention to improve their arousal, positioning, motor function, and communication (Yeh et al., 2019). Despite the fact that scholars have identified a gap between expected educational standards and actual practice, there is still a lack of evidence on the difficulties and challenges experienced by teachers (Taniguchi, 2011b). In addition to the perspectives of parents and children, it is essential to investigate those held by teachers, as these latter points of view can help clarify practical roles when educating students with chronic conditions (Runions et al., 2020). While previous studies have focused on general difficulties in this context, there is still a lack of evidence on specific challenges that arise when attempting to establish interpersonal relationships and communicate with children with CCC, especially in the Japanese educational system (Takeda, 2006; Taniguchi, 2011a). To improve special education practices when teaching children with CCC, it is therefore critical to investigate how teachers themselves understand and experience interactions and communication difficulties.\n\nThis study investigated current perceptions, experiences, and educational challenges that special education teachers encounter when developing interpersonal relationships and communicating with children with CCC. We first developed the following qualitative research questions:\n\n• What difficulties do teachers have when interacting and communicating with children with CCC?\n\n• How do teachers perceive their experiences and educational practices when engaging with children with CCC?\n\n\nMethods\n\nThis study adopted a cross-sectional qualitative design with semi-structured face-to-face interviews conducted on an individual basis from August 2018 to February 2019.\n\nThe study participants were teachers who provided special needs education to sick children in Japan. We set the following inclusion criteria: 1) experience teaching sick children and/or those with CCC and 2) work in special needs schools for health disorders. In cooperation with their school principals, we selected participants with diverse backgrounds (i.e., elementary, middle, and high school levels and years in experience). The potential participant teachers were selected by the school principals based on the teachers’ experience and backgrounds. Ultimately, we recruited a total of 21 participants from three schools for hospitalized children with health disorders, including 15 from School 1, two from School 2, and four from School 3. All 21 teachers participated in this study after the researchers fully explained the study. We selected School 1 because it was the only school for hospitalized children with health disorders in Oita prefecture, Japan, where this study was conducted. However, Schools 2 and 3 were located in Oita and Hokkaido prefectures and they were selected based on differences in the conditions of children therein.\n\nMore specifically, School 1 was a special needs facility for children admitted to an adjoining hospital. The conditions of their disorders varied, including internal organ diseases (e.g., kidney diseases), neuromuscular disorders, and neurological disorders. As for functioning, their restrictions ranged from mild (e.g., physical activities and food intake) to severe (e.g., multiple severe disabilities). Of note, the severe conditions included a permanent vegetative state caused by hypoxic encephalopathy or traumatic brain injury. School 2 was a special needs facility for students who received outpatient treatment in Oita, while School 3 was a special needs facility in Hokkaido (another northern area in Japan) that received inpatient children with muscular dystrophies.\n\nTable 1 lists demographic information for the study sample. As shown, 10 (48%) of the participants were women. Across the sample, teaching experience ranged from eight to 40 years (median 19, interquartile range [IQR] 13–29), while experience with special needs education for children with health disorders ranged from less than one year to 35 years (median 6, IQR 3–7). As for grade level, their work included students from elementary to secondary school. Table 2 summarizes the conditions of children from relevant experiences of the teachers.\n\nThis study adopted a cross-sectional qualitative design with semi-structured face-to-face interviews, as conducted on an individual basis from August 2018 to February 2019. As such, we asked the participants about their practical experiences and difficulties when engaging with students with CCC. We transcribed and audio-recorded all interviews for analysis. To draw narratives from their experiences, we developed an interview guide to capture potential challenges and personal beliefs regarding communication and interpersonal practices with children with special health care needs. This included questions about difficulties that may arise during teacher-student interactions, restrictions, and personal thoughts and practices (e.g., “Please describe your experiences when teaching children with complex chronic conditions, including any challenges you confronted during communication and when developing interpersonal relationships”). Specifically, we developed the interview guide using knowledge about the domain of interest, a literature review, and educator opinions. Domain knowledge included the conceptualization of education for sick children, knowledge of the diseases of children with CCC, and resources in Japanese educational systems. Although we used this guide to elicit experiential narratives, we also encouraged the participants to talk freely about any relevant views, ideas, experiences, and challenges. The interviews lasted from 43 to 71 minutes (median 52). They were conducted by the authors and a research assistant in Japanese. A copy of the interview guide can be found under Extended data (Fujino, 2022).\n\nWe analyzed the interview data through a thematic analysis. This allowed us to identify themes pertaining to the beliefs and challenges expressed by participants when teaching children with CCC at special needs schools. Using the thematic analysis approach, researchers aim to explore experiences and perceptions based on qualitative data (Braun & Clarke, 2006; Clarke & Braun, 2013; Terry & Hayfield, 2021). In this study, we familiarized ourselves with the interview data by repeatedly reading the transcripts. Prior to identifying themes, we inductively coded the transcripts to identify relevant features based on our study topic. We did not generate a priori codes. The first author coded the transcribed text, then discussed the coding with another team member to develop a codebook. Because the codes were modified during this discussion, the original text was recoded to confirm the data context. We ultimately finalized the themes and codes through this iterative process. As an exploratory analysis, we also investigated differences based on years of experience educating sick children. In these processes, we used MAXQDA 2022 (VERBI Software GmbH, Berlin, German), a software for qualitative data analysis, in coding and integrating the transcripts. After completing the qualitative data analysis in Japanese (the original language of the data), the excerpts were translated into English for presentation in this article.\n\nThe key assumption was that teachers may confront challenges when teaching children with CCC. In this context, challenges related to communication and interpersonal relationships may be central issues; moreover, these factors may be compounded by restrictions in the educational environment (Takeda, 2006; Taniguchi, 2011a). The first author is a psychologist who works with children and adolescents with disabilities, focusing on psychological support and special educational needs. The second author is a clinical psychologist with experience providing psychological support to individuals with neurodevelopmental disabilities and mental disorders. The third author is a special education teacher.\n\nThis study was carried out in accordance with the ethical standards set forth in the 1964 Declaration of Helsinki and its later amendments. The protocol was approved by Oita University Faculty of Education Research Ethics Committee (approval number: H30-001-013). We obtained written informed consent from all participants prior to study enrollment. Participants agreed to the following treatment of data: the materials obtained in the interviews will be partially reported but personally identifiable information will be processed, and the materials will not be publicly available. We removed any identifying information from the interview transcripts before presenting them in this manuscript.\n\n\nResults\n\nWe identified four themes from the narrative interview data, including “searching for the meaning,” “CCC as a difficult reality,” “widening experience for the future,” and “priority for interacting with children.” In the following subsections, we explain these themes and provide direct quotes from participants. As we did not identify clear relationships between the thematic contents and number of years educating children with CCC, we omitted this subgroup analysis from our discussions. Participant demographic data can be found under Underlying data (Fujino, 2022).\n\nThis theme describes beliefs about teacher-child interactions. The central concept pertains to the “true” meaning of responses and interactions with children with CCC, especially among those with severe conditions. In particular, it can be difficult to interpret responses from children with minimal communicative abilities (i.e., recognized responses are very subtle). Although objective evaluations are required in professional practice and may be useful for identifying consistency in reactions, subjective interpretations are also essential when attempting to find the meaning of the interactions.\n\nIn regard to communication difficulties, the central experience pertained to how teachers comprehended subtle responses from children with CCC. Some participants discussed questions about this issue when describing interaction problems. For example, children with profound disabilities often have minimal physical functioning and may only be capable of slight movements in the fingers or eyes. At the same time, comorbid intellectual and/or sensory disabilities complicate the process of understanding their actions and responses. In such cases, teachers may have difficulty interpreting the meanings of ambiguous or weak responses:\n\nThe truth could be different from what I am thinking, but I do it [interacting] based on my own interpretation of the situation … it is difficult to say whether some sort of interaction with the intention of communication was actually established. (…) If someone were to ask me how I really think about the situation, I have to admit that I am not sure. I really don’t know. (P10, 6–10 years of experience with sick children)\n\nFrom this perspective, the “true” meaning of subtle physical responses is unknown. More difficult cases occur when interacting with children who exhibit “hardly any such movements,” at times in association with a disorder of consciousness. One participant said the following: “Although there are some of them who are like this [who react with small movements], there are also those who cannot even express themselves in this way. It becomes really difficult in such cases” (P13, 6-10 years of experience for sick children). Teachers who successfully interact with students with CCC may experience a “really a wonderful feeling.” While the participants intricately explained their beliefs and emotional experiences in the context of interacting with children with children with CCC (Table 3, quote 1), their attempts were not always successful, especially in cases where children had minimal functioning. For example, one participant said the following about interacting with children who had disorders of consciousness: “feels like I am talking to myself and putting on a one-man show.” This seems to describe an overly exhausting practical experience.\n\nDespite various difficulties during teacher-child interactions, the participants insisted that they made attempts (Table 3, quote 2). To avoid subjective interpretations made solely based on impressions, objective observations or physiological responses (e.g., heart rate and SpO2) may also be used to assess the status and reactions of children (Table 3, quotes 3–4). By contrast, several participants described the need to make their communications into “a story.” Such narratives are also related to difficulties and questions pertaining to their engagement with children, especially among those with minimal functioning. One participant described the meaning of an interaction with a child with disorder of consciousness, wherein the lack of “readable” responses made it difficult to conceive the existence of an interpersonal interaction. As an alternative to objective assessments of responses/reactions, the participants sought more subjective individualized “stories” to derive meaning from their practices (Table 3, quote 5). One said the following:\n\nThus, objectively there is something there, and if there should be a reaction to it, and I can’t react back at all… so, in that respect, that’s why, when it comes to how to interact, whether something is there or not could just be more a problem from my side. It could be that something really is there, and I just can’t read it. That’s why [I think] a “story” is necessary here. It’s not that I am able to communicate with a person because I understand, but they are already there, existing, and they have a story. (P08, 6–10 years of experience with sick children)\n\nWithout any such meaning, the practice becomes “quite uninteresting.” Therefore, creating or finding “a story” is an essential aspect of making interactions more meaningful. This constitutes an element of support for teachers who engage with children with minimal functioning and/or CCC.\n\nThis theme describes experiences with children’s illnesses and the conditions of their disorders. The participants valued thinking about the children’s experiences with their own disease as well as how they experienced the disease as an observer. For example, teachers may experience a child’s disease progression, perhaps even leading to death. Such descriptions reveal unique concepts that emerge when working with severely ill children.\n\nThe conditions of disorders certainly affect functioning and create limitations for children. Those with severe conditions may need to live in the hospital for years. Given these factors, the participants strongly recognized their participatory limitations. One described some common environmental limitations and discussed how children may experience them:\n\nThey are children who spend all their time in a really small space [hospital room], in a similar [flow of time]. It’s summer vacation now, so I go to see them sometimes, but every day that they don’t come to school, they’re often asleep even when I go to see them, during the day. It’s hard to see anything but the world on their own bed. (…) They spend a lot of time alone. (P02, 6–10 years of experience with sick children)\n\nAs some CCC are progressive in nature, cases in which conditions worsen can be “the most difficult,” both for the teachers and children. In fact, teachers may avoid talking about the progressive nature of such diseases altogether (Table 4, quotes 6 and 7). For example, one participant described their difficulty with a child who had begun to lose ambulation due to Duchenne muscular dystrophy (a genetic progressive muscular disorder) (Table 4, quote 8). From the teacher’s perspective, the emotional impacts of disease progression were recognized as “tough” due to various emotional and behavioral issues. When children have life-threatening illnesses, teachers may even experience their death. In fact, several participants had experienced the death of children with CCC. Even when participants had relevant expertise, these cases were very difficult, often evoking negative emotions, psychological distress, and grief:\n\nI knew that [the death] would happen; after all, there are severely ill children in the program, and several students have died since I came to the school. I don’t experience that kind of thing much at other schools. That’s what I don’t like about this school. I have to say goodbye [to children]. Well, it’s hard. (P10, 6–10 years of experience with sick children)\n\nIn addition to the medical condition itself, educational systems sometimes become barriers for teachers. Teachers make individualized educational plans for children; however, the educational practice with the children does not proceed as originally planned. Realization of the plan is often not possible. Sometimes, there are “a lot of days off,” and “things don’t go well in terms of their health.” Because variability of the functioning and disabilities changes the ways of interaction and communication, teachers are required to have different ways of interacting with each child (Table 4, quote 9).\n\nCooperation with medical care was considered another major environmental barrier. Although different professionals or organizations must collaborate to support children with CCC, cooperative engagement between medical professionals was perceived as challenging: “Really, I think it is a bit of a difficult issue as to what real cooperation is. I can’t say they are cooperating, but I can’t say they aren’t” (P11, 6–10 years of experience with sick children). Meanwhile, differences in language, attitudes, and values can hinder interprofessional cooperation (Table 4, quote 10).\n\nThis theme describes beliefs about children’s experiences in their daily lives, special education schools, and hospitals. Because of various environmental and hospital-related restrictions, the participants valued the idea of widening their experiences with children with CCC. For such children, essential developmental components included time and interaction with other children, enhanced motivation to interact with surrounding individuals, and improved communication.\n\nA central concept of this theme is rooted in the fact that most children with severe CCC spend “most of their time in the hospital” to receive inpatient treatment. As a result, the range of their experiences and activities tends to be limited. Although the participants eagerly tried to create opportunities for interactions with other people, such efforts were often difficult due to environmental limitations, including the hospitalization itself:\n\nThey don’t have a lot of opportunities to interact with people, and since they are basically one-on-one with the teacher, it’s hard for them to broaden their relationships with other people. I was thinking that it would be nice if I could do something to help them expand their relationships with others, such as students, [and] nurses at the hospital. (P20, 1–5 years of experience with sick children)\n\nOpportunities to interact with peers were considered essential, and therefore encouraged (Table 5, quote 11). The participants hoped to widen interactions with other children and facilitate interactions with surrounding adults, as each student was used to being accompanied by a teacher (Table 5, quote 12). However, it is also important to note that adult-student relationships sometimes hindered children from behaving independently or spontaneously (Table 5, quote 13). For that reason, the participants carefully made their attempts: “[I tried] to help as much as possible, but sometimes, I also tried to wait until the patient was willing to move his/her hand as much as possible” (P09, 6–10 years of experience with sick children).\n\nFrom the future-oriented perspective, teachers value continued developmental goals for children, but those with CCC often take longer to achieve them, in some cases years. One participant said: “Sometimes it is the year to create a starting point, and other times it is the year when we have to produce an achievement” (P02, 6–10 years of experience with sick children). Even if the teacher cannot identify significant improvements in targeted behaviors or performances, some progress may still result in future developmental gains for children with severe CCC. In the long-term context, such perceptions may support teachers who engage with these children.\n\nThis theme describes beliefs about interactions and relationships with children with CCC. We also identified two subthemes. The first is “relationship as a basis for interacting with children,” referring to the belief that a positive child-teacher relationship creates a fundamental basis for meaningful interactions and educational practices. The second is “child’s life after leaving the school/hospital,” referring to the idea that the supportive relationship will end once the child graduates from school or is discharged from the hospital.\n\nRelationship as a basis for interacting with children\n\nSince relationships are viewed as a critical basis for interaction and communication, the participants valued the process of building them with children with CCC “rather than teaching any classes first.” Given that illness directly affects the lives of these children, one participant pointed out the importance of giving them time to adapt to life in the hospital (Table 6, quote 14), especially because this environment often increases anxiety.\n\nMany hospitalized children have a range of conditions that require inpatient treatment. Thus, facing medical difficulties is also a critical aspect of building trusting relationships with those who have severe conditions. For children with life-threatening diseases such as cancer, teachers sometimes face suffering, but also share hopes, feelings, and emotions. While this was discussed as a particularly “hard and painful” experience (Table 6, quote 15), the participants continued to believe in the meaning of teachers maintaining their presence with children and working toward supportive relationships.\n\nChild’s life after leaving the school/hospital\n\nThe children were also seen as having life in future contexts. As most were enrolled at schools for hospitalized children, their attendance was not considered firm. Some remained for very short periods (e.g., two to several weeks), while others stayed much longer (e.g., six months to multiple years). As teachers are therefore given limited time to involve themselves with these children, they tend to think about their lives after school or the hospital. One participant said: “I guess the present situation is that temporary, a place to come” (P08, 6–10 years of experience with sick children). In this sense, the children were viewed as going away for a short period of time, in contrast to schools where they would be expected to remain until graduation. According to another participant, continued relationships are associated with medical conditions that do not sufficiently improve for hospital discharge. Thus, leaving the school and ending the relationship implies that the child’s condition has improved (Table 6, quote 16).\n\nThe concept of life after leaving school also contextualized a range of experiences outside the school setting. Both at the school for sick children and in the hospital, conditions were well-understood by teachers and other professionals, but efforts were often required to avoid their recurrence after leaving. One participant said: “Even though I am getting older and have been a teacher for a long time, I still have concerns about where doing this will lead [in the child’s future]” (P11, 6–10 years of experience with sick children). In this regard, even experienced teachers may have difficulty predicting children’s long-term needs and incorporating them into their educational practices.\n\n\nDiscussion\n\nFocusing on areas of interaction and communication, this study investigated current perceptions, experiences, and educational challenges encountered by special education teachers who work with children with CCC. We identified four main themes, including “searching for the meaning,” “CCC as a difficult reality,” “widening experience for the future,” and “priority for interacting with children,” each of which summarizes aspects that are relevant to schools for sick children in the Japanese context.\n\nThis study focused on interactions and communications between teachers and children with CCC. The process of supporting sick children can generally act as a source of motivation and satisfaction for teachers (Lopez & Corcoran, 2014; Małkowska-Szkutnik et al., 2021), but our results suggest that interactions with children with CCC often lead to difficulties, especially in cases involving severe or complex conditions. To ensure that communication is reciprocal, teacher must focus on careful communicative approaches and responses when working with children with severe disabilities (Fylkesnes & Ytterhus, 2021). However, this process can be extremely difficult when children have severe limitations, as suggested in this study. In cases where children cannot or do not respond, teachers may find it very difficult to receive tangible feedback on their efforts. In their practices with these children, our participants questioned and searched for the meaning of both their involvement and the employed educational approach. In such cases, objective evaluations may help clarify the state and usefulness of those approaches (Nozaki & Kawasumi, 2013). In the same instance, one may therefore find it useful to discuss the issue from a value perspective (i.e., finding meaning and value in educational practices).\n\nA theoretical consideration rooted in phenomenological perspectives on subjectivity and objectivity may provide insight into interactions with children who have minimal functioning (Evensen, 2021). One direction of interaction and communication was taken from the perspective that communication is a form of pure technique. This makes children’s expressions more accessible to unfamiliar individuals. In turn, the same perspective is important for sharing with other individuals who are involved with the child (e.g., medical professionals), as also described by our participants. Another direction is offered by the perspective that considers contextual impressions and relational/interactional stimuli (Evensen, 2021), which entails a more subjective nature of perceptions and interpretations. In sum, professionals who work in special needs education should integrate objective and subjective perspectives during their interactions with children, especially when searching for meaning in their practices.\n\nCCC is a critical aspect that affects the challenges and difficulties encountered by special education teachers and their students. As several participants in this study described, teachers may experience cases in which the child mentally and physically collapses, perhaps leading to worsened health or death. Because they tend to have emotional involvement with these children, such relational aspects may lead to other challenging experiences (Benigno & Fante, 2020; Hart & Garza, 2013; Małkowska-Szkutnik et al., 2021; Steinke et al., 2016). Teachers who witness physical and psychological pain in children may also incur psychological impacts due to their relational involvement. While developments in medical treatment have reduced the occurrence of such cases, they are still difficult for teachers to experience, and often characterize the educational practices they employ for sick children (Hart & Garza, 2013). In these situations, teachers are required to be resilient and sufficiently cope with their emotional responses (Benigno & Fante, 2020; Hart & Garza, 2013). To better position themselves for this, they may refer to professional experiences, train to improve coping strategies, and seek support from colleagues (Małkowska-Szkutnik et al., 2021).\n\nTo widen the child’s experience, teachers may also need to improve their own skills. As discussed above, teachers must adopt particular values or philosophies in their educational practices (Hillel Lavian, 2015). In the absence of these elements, the process of educating students with complex needs may evoke strong emotional responses in teachers, potentially leading to emotional fatigue and burnout (Hillel Lavian, 2015). To avoid this, special education teachers who work at in-hospital schools should seek further development by availing of support from colleagues, sharing beliefs relevant to the support of children, and altering their own teaching values (Soejima et al., 2020). In turn, this may support emotional adaptation and enhance their professional capacity.\n\nIn Japan, efforts to accumulate professional experience and improve self-efficacy are urgently needed in special education for sick children, as teachers currently have limited experience in this field (Nagae, 2016; Takeda & Kasahara, 2001). In addition to general training for health disorders, specific training is required for some conditions, including rare genetic diseases and those associated with severe functional limitations (Garvey et al., 2020).\n\nAlthough peer interactions are essential features in educational practice, children at hospital-based schools tend to have limited opportunities for this. Meanwhile, environmental restrictions create educational issues (Knauer et al., 2015). In this study, teachers believed it was important for students to have opportunities to be with or interact with other children. Indeed, research has shown that opportunities for peer interactions are important in child-child interactions, even if their disabilities are severe and multiple in nature, as this may increase spontaneous attention or approaches toward other children (Nijs et al., 2016). At the same time, these interactions are expected to widen the experiences of children and facilitate their relational and emotional development (Buysse & Bailey, 2016; Justice et al., 2014). Despite the various environmental limitations, teachers should therefore help hospitalized children engage in peer interactions and value activities that widen the potential for social relationships.\n\nCoordination with other professionals is a long-standing issue in special needs education for sick children. While interdisciplinary communication and cross-organizational relationships, particularly with medical professionals, are emphasized in literature, this is often a challenging practice at schools in many countries (Ballard & Dymond, 2018; Małkowska-Szkutnik et al., 2021; McClanahan & Weismuller, 2015; Pufpaff et al., 2015). According to reports, the lack of a collaborative process is partly due to insufficient time for collaboration and inadequate interprofessional communication (Garvey et al., 2020). Moreover, cooperative engagements between individuals in different professional roles often lead to conflict, and are influenced by divergent opinions, leadership, and counseling abilities (Weiss et al., 2018). These issues should be discussed and negotiated based on the expectations and needs of stakeholders. Earlier education programs for interprofessional collaboration may also facilitate the development of a foundation for accepting and balancing the weakness and strengths of each professional.\n\nDevelopments in communications technology may support the objective evaluation of children with profound disabilities. While some technologies help us communicate and interplay with children, the actual degree of technology use is influenced by whether the teacher perceives its value in special needs education (Anderson & Putman, 2020). Therefore, it is still important to assess their values on how and what is used, as well as how the interactions are performed. In addition, continuous education for various learning approaches may stimulate the skills and creativity of teachers in the context of individualized and differentiated teaching (Weiss et al., 2018). To develop expertise in education for seriously ill children, this emphasizes the need to continue accumulating experience in the field. In this regard, seasoned professionals may serve as role models to help teachers with limited experience (Soejima et al., 2020; Takeda & Kasahara, 2001).\n\nThis study also had some limitations. First, the range of children’s characteristics may strongly affect the difficulty experienced by special education teachers. Several of our participants experienced educational practices with children with profound disabilities (e.g., a disorder of consciousness), while others experienced relatively acute conditions. In this regard, the characteristics of disorders and/or functioning may have affected the findings. A more focused approach among a more targeted population may reveal additional context-dependent issues. Second, we did not include the parents of children with CCC. Because interactions are based on phenomena constructed by two or more individuals, the involvement of individuals in these positions may reveal a more complex nature. It may also be important to consider that discrepancies exist between children, parents, and teachers (Maciver et al., 2019; O'Connor et al., 2016). Third, the transferability of this study may be limited in certain conditions. As the education systems for children with CCC and teacher training may differ between countries, the experiences of teachers may vary by location. However, the core themes identified in this study should be similar in other settings (e.g., difficulty interpreting limited responses from children and facing difficult conditions). Despite these limitations, this study provides valuable insight into the conditions experienced by teachers working in education for children with CCC.\n\n\nConclusion\n\nThis study conducted interviews with special education teachers to investigate the qualitative aspects of experiences with children with severe CCC. In sum, our findings suggest that teaching beliefs and values are strongly connected with actual practice. At the same time, severe functional limitations in children often lead to major challenges when professionals attempt to find meaning in interactions between teachers and children with CCC. This study may clarify important challenges and experiences encountered by special education teachers who work with these children.",
"appendix": "Data availability\n\nThe raw transcripts from the interviews are not publicly available to protect participants' privacy. Excerpts of the transcripts were included in the article. Transcripts in Japanese (the original language of the interview) are available from the corresponding author upon reasonable request at fjinoh@kokoro.med.osaka-u.ac.jp. Contact details, aims to use the transcripts, and data security management will be required.\n\nOSF: Interactions between teachers and children with CCC. https://www.doi.org/10.17605/OSF.IO/WQNFV. (Fujino, 2022)\n\nThis project contains the following underlying data:\n\n- Participant_demographic.csv\n\nThis project contains the following extended data:\n\n- Interview_guide.pdf\n\n\nAcknowledgements\n\nThe authors would like to thank the participants of this study.\n\n\nReferences\n\nAnderson SE, Putman RS: Special Education Teachers’ Experience, Confidence, Beliefs, and Knowledge About Integrating Technology. J. Spec. Educ. 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PubMed Abstract | Publisher Full Text\n\nSoejima M, Takehana Y, Asakura T: The process of growth and development in teachers of in-hospital schools. Japanese Journal of School Health. 2020; 62: 11–24. Publisher Full Text\n\nSteinke SM, Elam M, Irwin MK, et al.: Pediatric Hospital School Programming: An Examination of Educational Services for Students who are Hospitalized. Physical Disabilities: Education and Related Services. 2016; 35(1): 28–45. Publisher Full Text\n\nTakeda T: Breaking the impasse over Jiritsu-Katsudo in education for sick children. Japanese Journal of Special Education. 2006; 44(3): 165–178.\n\nTakeda T, Kasahara Y: Callenges and support for teachers of in-hospital schools. Japanese Journal on Developmental Disabilities. 2001; 23(1): 126–135.\n\nTaniguchi A: Difficulties in educational practice for hospitalized children. Kyoiku-Jissengaku Kenkyu [Journal of Applied Educational Research]. 2011a; 16: 1–7. Publisher Full Text\n\nTaniguchi A: Recent advances of educational psychology in special education. Annual Report of Educational Psychology in Japan. 2011b; 50: 145–154. Publisher Full Text\n\nTerry G, Hayfield N: Essentials of Thematic Analysis. American Psychological Association;2021.\n\nvan Timmeren EA , van der Putten AA , van Schrojenstein Lantman-de Valk HM, et al.: Prevalence of reported physical health problems in people with severe or profound intellectual and motor disabilities: a cross-sectional study of medical records and care plans. J. Intellect. Disabil. Res. 2016; 60(11): 1109–1118. Publisher Full Text\n\nWeiss S, Markowetz R, Kiel E: How to teach students with moderate and severe intellectual disabilities in inclusive and special education settings: Teachers’ perspectives on skills, knowledge and attitudes. Eur. Educ. Res. J. 2018; 17(6): 837–856. Publisher Full Text\n\nYeh N, Slomine BS, Paasch V, et al.: Rehabilitation in Children with Disorder of Consciousness. Curr. Phys. Med. Rehabil. Rep. 2019; 7(2): 94–103. Publisher Full Text"
}
|
[
{
"id": "209533",
"date": "09 Oct 2023",
"name": "Lina Diaz-Castro",
"expertise": [
"Reviewer Expertise Mental Disorderds. / Public Health. / Research in Health Systems."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Author,\nI am sending you the review of the article \"Experiences and Challenges of Special Education Teachers in Supporting Children with Complex Chronic Conditions: A Qualitative Study\".\nGeneral comments:\n\nThe study investigates the experiences and challenges faced by special education teachers in Japan when providing support to children with complex chronic conditions (CCC). It employs a qualitative research design involving semi-structured face-to-face interviews with 21 special education teachers who work with sick children. The study identifies four main themes: \"searching for the meaning,\" \"CCC as a difficult reality,\" \"widening experience for the future,\" and \"priority for interacting with children.\" These themes reveal the complexities of teacher-child interactions, the unique challenges posed by CCC, the importance of widening children's experiences, and the significance of building positive relationships with these children.\nReplicability and Generalizability:\nReplicability: The study provides a detailed description of its methods, including data collection and analysis, which makes it replicable for researchers interested in conducting similar qualitative studies.\nGeneralizability: The generalizability of the study's findings may be limited by the specific context of Japanese special education schools for children with CCC. Further research in diverse settings and with larger sample sizes would enhance the generalizability of the findings.\nIn summary, the article presents valuable insights into the experiences and challenges faced by special education teachers when working with children with CCC. To enhance the scientific soundness of the article, the authors should consider the following:\n\nImprove the clarity of certain sections, particularly those related to the thematic analysis process.\n\nClarify details of the data analysis, including the coding process.\n\nConsider making the source data underlying the results available for reproducibility.\n\nEncourage further research in diverse settings to enhance the generalizability of findings.\n\nThe study contributes to the understanding of teacher-child interactions in the context of special education for children with complex chronic conditions and offers important implications for teacher training and support in this field.\n\nSpecific comments\nIs the work clearly and accurately presented and does it cite the current literature?\nThis work demonstrates clarity, accuracy, and appropriate citation of relevant literature up to my knowledge cutoff date. The article reads well and maintains a logical flow. However, consider using subheadings within sections to break up the text further and improve the readability.\nIs the study design appropriate and is the work technically sound?\nThe study's design and methodology appear to be well-suited to its research objectives and maintain technical soundness, based on the provided information.\nAre sufficient details of methods and analysis provided to allow replication by others?\nIn my opinion, additional information is typically required in a research study to facilitate replication:\nSampling Details: While the study mentions inclusion criteria for participants, it's helpful to provide more information about how participants were selected, and recruited, and any potential biases in the selection process.\nInterview Guide: The study mentions the use of an interview guide but does not provide the full list of questions or prompts included in the guide. Sharing the complete guide would help others understand how the interviews were conducted and structured.\nData Collection Procedures: Detailed information on the interview process, including how interviews were scheduled, conducted, and audio-recorded, is essential for replication. Additionally, information on any piloting or pre-testing of the interview guide should be included.\nData Analysis: While the study mentions thematic analysis and the use of MAXQDA software, it lacks a step-by-step description of the analytical process. Replicators would typically need to know how codes were generated, how themes were identified, and the criteria used for theme selection.\nIf applicable, is the statistical analysis and its interpretation appropriate?\nThe study does not mention the use of statistical analysis.\nThe description of the thematic analysis process is well-detailed, and it's good that the authors followed an inductive approach without preconceived codes. Mentioning the software (MAXQDA) used for data analysis is helpful. Authors might want to provide a brief explanation of the number of coders involved and their qualifications to ensure the rigor of the analysis.\nTranslation: The authors mentioned that excerpts were translated into English for presentation in the article. It's important to acknowledge that translation can introduce some degree of interpretation bias. Mentioning that a qualified translator, preferably bilingual, was involved in the process can help address potential concerns about translation accuracy.\nAuthors might want to provide a bit more detail about the roles each author played in the research process, especially in data analysis.\nAre all the source data underlying the results available to ensure full reproducibility?\nThe provided text does not indicate whether the source data underlying the results of this study are available for full reproducibility. In many cases, qualitative research studies may not make their raw data, such as interview transcripts, publicly available to protect the privacy and confidentiality of study participants.\nHowever, it is common practice in qualitative research to provide detailed descriptions of the research methods, including the process of data collection (interviews in this case), coding procedures, and thematic analysis, so that other researchers can understand how the results were derived and potentially replicate the study using their own data if desired.\nAre the conclusions drawn adequately supported by the results?\nThe conclusions drawn in the study appear to be adequately supported by the results and findings presented. The study conducted interviews with special education teachers and identified key themes related to their experiences and challenges when working with children with complex chronic conditions (CCC).\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10751",
"date": "16 Jan 2024",
"name": "Haruo Fujino",
"role": "Author Response",
"response": "Reviewer Report 09 Oct 2023 | for Version 1 Lina Diaz-Castro, National Institute of Psychiatry Ramón de la Fuente Muñiz, Mexico City, Mexico Dear Author, I am sending you the review of the article \"Experiences and Challenges of Special Education Teachers in Supporting Children with Complex Chronic Conditions: A Qualitative Study\". General comments: The study investigates the experiences and challenges faced by special education teachers in Japan when providing support to children with complex chronic conditions (CCC). It employs a qualitative research design involving semi-structured face-to-face interviews with 21 special education teachers who work with sick children. The study identifies four main themes: \"searching for the meaning,\" \"CCC as a difficult reality,\" \"widening experience for the future,\" and \"priority for interacting with children.\" These themes reveal the complexities of teacher-child interactions, the unique challenges posed by CCC, the importance of widening children's experiences, and the significance of building positive relationships with these children. Replicability and Generalizability: Replicability: The study provides a detailed description of its methods, including data collection and analysis, which makes it replicable for researchers interested in conducting similar qualitative studies. Generalizability: The generalizability of the study's findings may be limited by the specific context of Japanese special education schools for children with CCC. Further research in diverse settings and with larger sample sizes would enhance the generalizability of the findings. In summary, the article presents valuable insights into the experiences and challenges faced by special education teachers when working with children with CCC. To enhance the scientific soundness of the article, the authors should consider the following: Improve the clarity of certain sections, particularly those related to the thematic analysis process. Clarify details of the data analysis, including the coding process. Consider making the source data underlying the results available for reproducibility. Encourage further research in diverse settings to enhance the generalizability of findings. The study contributes to the understanding of teacher-child interactions in the context of special education for children with complex chronic conditions and offers important implications for teacher training and support in this field. Response: Thank you for considering our manuscript. Based on the reviewers’ comments, we have revised the manuscript. Please refer to our responses for the specific comments. Specific comments Is the work clearly and accurately presented and does it cite the current literature? 1. This work demonstrates clarity, accuracy, and appropriate citation of relevant literature up to my knowledge cutoff date. The article reads well and maintains a logical flow. However, consider using subheadings within sections to break up the text further and improve the readability. Response: Thank you for your suggestions. We have added subheadings in the manuscript to improve readability. Is the study design appropriate and is the work technically sound? 2. The study's design and methodology appear to be well-suited to its research objectives and maintain technical soundness, based on the provided information. Response: Thank you for your positive evaluation of our study. Are sufficient details of methods and analysis provided to allow replication by others? 3. In my opinion, additional information is typically required in a research study to facilitate replication: 3-1. Sampling Details: While the study mentions inclusion criteria for participants, it's helpful to provide more information about how participants were selected, and recruited, and any potential biases in the selection process. Response: Based on the reviewer’s suggestion, we have included additional details in the Participants section and discussed potential biases in the Limitations section. In Participants section, The potential participant teachers were selected by the school principals or a senior teacher based on the teachers’ experience and backgrounds. Teachers with minimal experience in this area were excluded. In Limitations section, This issue may be also related to the method by which the teachers were recruited. Since the participants were selected by school principals or a senior teacher, the sample of this study might be biased to teachers who were likely to be more capable. Inclusion of participants with wider experience and capabilities may expand the rage of their experiences. 3-2. Interview Guide: The study mentions the use of an interview guide but does not provide the full list of questions or prompts included in the guide. Sharing the complete guide would help others understand how the interviews were conducted and structured. Response We have shared this information in the Extended Data section (OSF repository, https://www.doi.org/10.17605/OSF.IO/WQNFV). 3-3. Data Collection Procedures: Detailed information on the interview process, including how interviews were scheduled, conducted, and audio-recorded, is essential for replication. Additionally, information on any piloting or pre-testing of the interview guide should be included. Response We have included further details of these procedures. The interview guide was not pilot tested before the interview; it was developed by two of the authors, who have different professional backgrounds. In Procedures section, The interview-guide was developed by two researchers (first and third authors), who had different professions. However, it was not performed in this study. Although we used this guide to elicit experiential narratives, we also encouraged the participants to talk freely about any relevant views, ideas, experiences, and challenges. 3-3. Data Analysis: While the study mentions thematic analysis and the use of MAXQDA software, it lacks a step-by-step description of the analytical process. Replicators would typically need to know how codes were generated, how themes were identified, and the criteria used for theme selection. Response: Based on the reviewer’s comment, we included this information in the analysis section. In Data analysis section, Before the data were coded, impressions of the interview transcripts were discussed between the first and third authors. In the coding process, the authors tried to create codes that summarized the data meaning based on the research questions of this study. The first author coded the transcribed text, then discussed the coding with the second author. Because the codes were modified during this discussion, the first author re-coded the original text to confirm the data context. Only the first author coded all the transcripts based on the approach employed in thematic analysis ( Braun & Clarke, 2021; Clarke & Braun, 2013). The themes were developed by repeatedly reviewing the content of the code, creating tentative themes, comparing the theme to the code, and repeating the review to ensure that each theme reflected a central organizing concept ( Clarke & Braun, 2013). If applicable, is the statistical analysis and its interpretation appropriate? 4. The study does not mention the use of statistical analysis. The description of the thematic analysis process is well-detailed, and it's good that the authors followed an inductive approach without preconceived codes. Mentioning the software (MAXQDA) used for data analysis is helpful. Authors might want to provide a brief explanation of the number of coders involved and their qualifications to ensure the rigor of the analysis. Response: Thank you for your suggestions. Accordingly, we have added a short explanation of the coder and the approach of the thematic analysis in the Analysis section. In Data analysis section, Only the first author coded all the transcripts based on the approach employed in thematic analysis ( Braun & Clarke, 2021; Clarke & Braun, 2013). 5. Translation: The authors mentioned that excerpts were translated into English for presentation in the article. It's important to acknowledge that translation can introduce some degree of interpretation bias. Mentioning that a qualified translator, preferably bilingual, was involved in the process can help address potential concerns about translation accuracy. Response: We have added information about the translator in the manuscript. In Data analysis section, After completing the qualitative data analysis in Japanese (the original language of the data), the excerpts were translated into English for presentation in this article by a professional bilingual translator. 6. Authors might want to provide a bit more detail about the roles each author played in the research process, especially in data analysis. Response: We have clarified the roles of the authors in the data analysis section. In Data analysis section, Before the data were coded, impressions of the interview transcripts were discussed between the first and third authors. In the coding process, the authors tried to create codes that summarized the data meaning based on the research questions of this study. The first author coded the transcribed text, then discussed the coding with the second author. Because the codes were modified during this discussion, the first author re-coded the original text to confirm the data context. Only the first author coded all the transcripts based on the approach employed in thematic analysis ( Braun & Clarke, 2021; Clarke & Braun, 2013). The themes were developed by repeatedly reviewing the content of the code, creating tentative themes, comparing the theme to the code, and repeating the review to ensure that each theme reflected a central organizing concept ( Clarke & Braun, 2013). Are all the source data underlying the results available to ensure full reproducibility? 7. The provided text does not indicate whether the source data underlying the results of this study are available for full reproducibility. In many cases, qualitative research studies may not make their raw data, such as interview transcripts, publicly available to protect the privacy and confidentiality of study participants. However, it is common practice in qualitative research to provide detailed descriptions of the research methods, including the process of data collection (interviews in this case), coding procedures, and thematic analysis, so that other researchers can understand how the results were derived and potentially replicate the study using their own data if desired. Response: Thank you for your understanding. We have revised the section and added more detailed information in the Methods section. Please also refer to our responses to Comments 3-3, 4, and 6. Are the conclusions drawn adequately supported by the results? 8. The conclusions drawn in the study appear to be adequately supported by the results and findings presented. The study conducted interviews with special education teachers and identified key themes related to their experiences and challenges when working with children with complex chronic conditions (CCC). Response: Thank you for your comment."
}
]
},
{
"id": "209534",
"date": "27 Nov 2023",
"name": "Angelica Moè",
"expertise": [
"Reviewer Expertise Teacher motivation and well-being"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe MS presents a study conducted with special education teachers to catch their experiences with children with severe complex chronic conditions (CCC).\nThe topic is interesting and it deserves investigation for its practical implications and the paucity of studies on it.\nHence. I am positive about indexing pending the revisions listed below.\nBackground. I would report more recent data on the prevalence of the diseases. They refer to 20 years ago: Beers et al., (2003). Overall, I would refer mostly on recent literature. Maybe specific reference to similar studies should be made more explicit by adding texts (as it is now it appears pretty short).\nDiscussion. I would report in more detail which programs or interventions suggested for helping teachers in facing the burdens due to interacting with CCC children.\nGeneralization: They found those results in a specific context. Do the AA think they can be applied worldwide?\nOverall. I would refer to a specific theory. Maybe the SDT theory regarding the autonomy-support vs. control could help (e.g., Ryan & Deci, 2020) because it states different supportive or less functional modalities (e.g., Moè et al., 2022). Referring to self-efficacy could be a further option (e.g., Kasalak & Dagyar, 2020).\nSuggested references:\nKasalak, G., & Dagyar, M. (2020). The relationship between teacher self-efficacy and teacher job satisfaction: A meta-analysis of the teaching and learning international survey (TALIS). Educational Sciences: Theory and Practice, 20(3), 16-33.\nMoè, A., Consiglio, P., & Katz, I. (2022). Exploring the circumplex model of motivating and demotivating teaching styles: The role of teacher need satisfaction and need frustration. Teaching and Teacher Education, 118, 103823.\nRyan, R. M., & Deci, E. L. (2020). Intrinsic and extrinsic motivation from a self determination theory perspective: Definitions, theory, practices, and future directions. Contemporary Educational Psychology, 101860.\nI wish the AA the best with their research!\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10752",
"date": "16 Jan 2024",
"name": "Haruo Fujino",
"role": "Author Response",
"response": "Reviewer Report 27 Nov 2023 | for Version 1 Angelica Moè, University of Padova, Padua, Italy APPROVED WITH RESERVATIONS General comments: The MS presents a study conducted with special education teachers to catch their experiences with children with severe complex chronic conditions (CCC). The topic is interesting and it deserves investigation for its practical implications and the paucity of studies on it. Hence. I am positive about indexing pending the revisions listed below. Response: We appreciate your encouraging comments on our manuscript. 1. Background. I would report more recent data on the prevalence of the diseases. They refer to 20 years ago: Beers et al., (2003). Overall, I would refer mostly on recent literature. Maybe specific reference to similar studies should be made more explicit by adding texts (as it is now it appears pretty short). Response: Based on the reviewer’s suggestion, we added a recent report from the United States (Ghandour et al., 2022). In Background section, The number of children with complex medical conditions has increased in recent decades. However, the rate of prevalence varies based on the definition and study context, ranging from 5% to 30% ( Beers et al., 2003). A recent report showed that 18.8% of children in the United States had special health care needs ( Ghandour et al., 2022). 2. Discussion. I would report in more detail which programs or interventions suggested for helping teachers in facing the burdens due to interacting with CCC children. Response: Unfortunately, we could not find any specific program for teachers of children with CCC. Based on Comments 2 and 4, we have added a discussion of the potential contributions of motivating their practice. In Discussion section, Unfortunately, a validated program for improving interaction with CCC for special education teachers is not widely available. Self-determination theory, a theory of human motivation that has been applied across research fields, posits three basic psychological needs as being necessary for psychological health and well-being: autonomy, competence, and relatedness ( Deci and Ryan, 1980; Deci et al., 2017; Ryan & Deci, 2020). Based on this framework, one study reported that teachers experiencing higher relatedness with students engaged more in work and show less emotional exhaustion ( Klassen et al., 2012). Although there are limitations to the application of self-determination theory in special education, it may be useful to explore the satisfaction or frustration of teachers’ basic psychological needs based on this theoretical framework devising support measures. 3. Generalization: They found those results in a specific context. Do the AA think they can be applied worldwide? Response: The findings are based on interviews with Japanese teachers within a certain educational context; therefore, the generalizability of the findings is more context-dependent, rather than being generalizable. However, future comparisons with other cultures or contexts may provide meaningful insights into the current findings. We have clarified the context in the summary of the results (Discussion section) and Conclusions, and discussed it in the Limitations section. In Discussion section, Focusing on areas of interaction and communication, this study investigated current perceptions, experiences, and educational challenges encountered by special education teachers who work with children with CCC in Japan. In Limitations section, Additionally, future comparisons between other countries or meta-synthesis of studies could yield meaningful insights into the current findings. In Conclusion section, This study conducted interviews with Japanese special education teachers to investigate the qualitative aspects of experiences with children with severe CCC. 4. Overall. I would refer to a specific theory. Maybe the SDT theory regarding the autonomy-support vs. control could help (e.g., Ryan & Deci, 2020) because it states different supportive or less functional modalities (e.g., Moè et al., 2022). Referring to self-efficacy could be a further option (e.g., Kasalak & Dagyar, 2020). Suggested references: Kasalak, G., & Dagyar, M. (2020). The relationship between teacher self-efficacy and teacher job satisfaction: A meta-analysis of the teaching and learning international survey (TALIS). Educational Sciences: Theory and Practice, 20(3), 16-33. Moè, A., Consiglio, P., & Katz, I. (2022). Exploring the circumplex model of motivating and demotivating teaching styles: The role of teacher need satisfaction and need frustration. Teaching and Teacher Education, 118, 103823. Ryan, R. M., & Deci, E. L. (2020). Intrinsic and extrinsic motivation from a self determination theory perspective: Definitions, theory, practices, and future directions. Contemporary Educational Psychology, 101860. I wish the AA the best with their research! Response: Thank you for the suggestion. Based on the reviewer’s comment, we have discussed the findings with reference to self-determination theory. In Discussion section, Unfortunately, a validated program for improving interaction with CCC for special education teachers is not widely available. Self-determination theory, a theory of human motivation that has been applied across research fields, posits three basic psychological needs as being necessary for psychological health and well-being: autonomy, competence, and relatedness ( Deci and Ryan, 1980; Deci et al., 2017; Ryan & Deci, 2020). Based on this framework, one study reported that teachers experiencing higher relatedness with students engaged more in work and show less emotional exhaustion ( Klassen et al., 2012). Although there are limitations to the application of self-determination theory in special education, it may be useful to explore the satisfaction or frustration of teachers’ basic psychological needs based on this theoretical framework devising support measures. In Implication for practice section, As discussed above, satisfaction or frustration of basic psychological needs (i.e., autonomy, competence, and relatedness) may be essential factors in understanding the experience of teachers and for supervisors to provide support ( Moè et al., 2022; Ryan & Deci, 2020)."
}
]
}
] | 1
|
https://f1000research.com/articles/12-23
|
https://f1000research.com/articles/12-499/v1
|
15 May 23
|
{
"type": "Opinion Article",
"title": "The ELIXIR Biodiversity Community: Understanding short- and long-term changes in biodiversity",
"authors": [
"Robert M. Waterhouse",
"Anne-Françoise Adam-Blondon",
"Bachir Balech",
"Endre Barta",
"Katharina F. Heil",
"Graham M. Hughes",
"Lars S. Jermiin",
"Matúš Kalaš",
"Jerry Lanfear",
"Evangelos Pafilis",
"Aristotelis C. Papageorgiou",
"Fotis Psomopoulos",
"Niels Raes",
"Josephine Burgin",
"Toni Gabaldón",
"Anne-Françoise Adam-Blondon",
"Bachir Balech",
"Endre Barta",
"Katharina F. Heil",
"Graham M. Hughes",
"Lars S. Jermiin",
"Matúš Kalaš",
"Jerry Lanfear",
"Evangelos Pafilis",
"Aristotelis C. Papageorgiou",
"Fotis Psomopoulos",
"Niels Raes",
"Josephine Burgin",
"Toni Gabaldón"
],
"abstract": "Biodiversity loss is now recognised as one of the major challenges for humankind to address over the next few decades. Unless major actions are taken, the sixth mass extinction will lead to catastrophic effects on the Earth’s biosphere and human health and well-being. ELIXIR can help address the technical challenges of biodiversity science, through leveraging its suite of services and expertise to enable data management and analysis activities that enhance our understanding of life on Earth and facilitate biodiversity preservation and restoration. This white paper, prepared by the ELIXIR Biodiversity Community, summarises the current status and responses, and presents a set of plans, both technical and community-oriented, that should both enhance how ELIXIR Services are applied in the biodiversity field and how ELIXIR builds connections across the many other infrastructures active in this area. We discuss the areas of highest priority, how they can be implemented in cooperation with the ELIXIR Platforms, and their connections to existing ELIXIR Communities and international consortia. The article provides a preliminary blueprint for a Biodiversity Community in ELIXIR and is an appeal to identify and involve new stakeholders.",
"keywords": [
"White Paper",
"ELIXIR Strategy",
"Community Roadmap",
"Biodiversity Networks",
"Biodiversity Informatics",
"Environmental Systems",
"Data Science"
],
"content": "Introduction\n\nBiological diversity—or biodiversity—refers to the variety and variability of life on Earth, encompassing genetic and species diversity at the levels of populations, communities, and ecosystems. Biodiversity reflects the ever-changing natural balance that has evolved over billions of years, sustaining communities of interdependent and interacting organisms. Those balances form the basis of a healthy Earth, including the ecosystem functions that support human well-being (i.e., ecosystem services). With growing demands on nature due to human activities, the Anthropocene is upsetting this balance and is consequently witnessing an unprecedented loss of biodiversity globally (WWF, 2022; Johnson et al., 2017). These declines pose a grave threat to humanity, the severity of which is increasingly recognised by international organisations, regional bodies, national governments, and society.\n\nStrategies to protect and restore biodiversity are wide-ranging in scope and scale, with policies and actions that require broad support to be feasible and effective e.g., goals 12-15 of the 17 Sustainable Development Goals (SDGs) adopted by the United Nations (UN, 2015). Biodiversity research aimed at building the knowledge and resources that inform management practices and policy is equally wide-ranging, often bringing together researchers from different disciplines, such as taxonomists, ecologists, evolutionary biologists, and informaticians. This is particularly true for the growing field of interdisciplinary research taking advantage of molecular sequence data, which recognises the relevance of and advantages offered by genetic and genomic data in biodiversity assessment, monitoring, conservation, and restoration (Hoban et al., 2021; Lewin et al., 2022). Connecting such molecular sequence data with biodiversity research infrastructures (see Extended Data (Waterhouse, 2023)) and resources is a critical step towards facilitating exchange of knowledge, sharing, and interoperability of large and complex datasets (Waterhouse et al., 2022).\n\nThe need for informatics solutions to address these challenges inspires many scientists from across the ELIXIR Nodes to increasingly engage in different aspects of biodiversity research. This stems from a natural alignment with ELIXIR’s overarching mission to support the management of public research data, integrate and coordinate life science resources, and foster the development of innovative services and technical solutions in Europe (Harrow et al., 2021). Here we present the ELIXIR Biodiversity Community, comprised of researchers from different disciplines, united by a shared recognition of the main societal and informatics challenges, as well as key scientific and organisational opportunities; how these connect with ELIXIR Platforms and other ELIXIR Communities, as well as with the wider “ecosystem” of biodiversity projects and infrastructures; and set out our roadmap for building on ELIXIR expertise to grow the ELIXIR Biodiversity Community and engage with the development of resources and infrastructures to support biodiversity research.\n\nBiodiversity represents the variety of organisms on the planet at all taxonomic levels, a result of a long and complex evolutionary process. Biodiversity is essential for life itself, for the adaptation of populations, species, communities, and ecosystems towards rapid change in biotic and abiotic parameters, including climate change. From a human standpoint, biodiversity forms the foundation of ecosystem services that are indispensable for human well-being and a healthy planet, and has long been a source of adaptive solutions or innovations in several critical areas such as food production. Despite its importance, biodiversity has been declining at a mass-extinction-level rate (IPBES, 2019) over the last decades. The unsustainable human development model has increased pressures on biodiversity, through climate change (IPCC, 2022; Wezel et al., 2020), invasive species, habitat loss and degradation, and the depletion of natural resources (IPBES, 2019). The decline of biodiversity at this rate often creates unpredictable threats and changes to ecological oscillations, such as the increased risk of new human diseases (Frumkin & Haines, 2019), the collapse of ecosystem services, the degradation of natural resources, and the increased possibility of a global food crisis (FAO, 2019).\n\nAt the same time, scientists and naturalists do not even know what is being lost, as around 80% of biodiversity at the species and population levels remains undescribed and/or underrepresented in inventories and databases (Mora et al., 2011; Costello et al., 2013; Moura & Jetz, 2021; Bispo et al., 2022; Boekhout et al., 2022; Chimeno et al., 2022). Furthermore, most research and monitoring efforts tend to focus on a limited number of biodiversity levels or elements. While there is significant literature around biodiversity loss (e.g., a Scopus query [13.09.2022] for “biodiversity loss” returns 33,324 documents), there is a very limited effort in reviewing biodiversity using high-throughput data (Scopus query [13.09.2022] for “Biodiversity loss” AND (“omics” OR “genomics” OR “metagenomics”) returns only 1,795 documents). This clearly indicates a bias in reporting, which has repercussions on the decision-making process pertaining to biodiversity conservation efforts (Gadelha et al., 2021). This brings forward an additional challenge of shifting perspectives from narrow, low-throughput efforts towards more holistic, high-throughput initiatives, including better citizen scientist contributions towards these efforts. Humanity may miss important solutions to key problems for its survival, such as the loss of important genetic variants among wild plants, animals, and microbes for agriculture (Nic Lughadha et al., 2020) and for dealing with health issues (Marselle et al., 2021).\n\nFollowing the 1992 United Nations Convention on Biological Diversity (CBD), governments and international organisations have responded to the decline of biodiversity with policies, and restoration and protection strategies. However, the initial goals of these have not been reached and biodiversity decline continues accelerating (IPBES, 2019; Turvey & Crees, 2019; WWF, 2022). For the new targets set by the post-2020 global biodiversity framework (GBF, 2023) to succeed, research is considered to be key, especially the interaction between science, society, and policy makers (Blicharska et al., 2019; Hermoso et al., 2022; Nature, 2022), with net improvements by 2050 to achieve the CBD’s vision of “living in harmony with nature by 2050”. Today, scientists recognise the important roles that genetic and genomic data can play in biodiversity discovery, assessment, monitoring, conservation, and restoration, to ensure the long-term resilience of ecosystems (Hoban et al., 2020; Gadelha et al., 2021; Segelbacher et al., 2022; Formenti et al., 2022; Theissinger et al., 2023). The contribution of genomics and bioinformatics towards these targets, and many of the associated technical and scientific challenges are described in Waterhouse et al. (2022), together with the possible contribution of the ELIXIR European Strategy Forum for Research Infrastructures to meet them.\n\nBiodiversity researchers are increasingly realising the potential offered by modern technologies, particularly in genomics, to create new opportunities for developing tools and resources that will transform the field. These opportunities lie primarily in the types of scientific applications that are becoming more feasible and scalable through continued advances in genomics technologies alongside enhanced data management systems. A long-term vision sees a future where sequence-based biodiversity monitoring at scale becomes the default and provides the means for ecosystem biodiversity characterisation in space and time. In support of realising these opportunities, ongoing global and regional efforts are building capacity to generate catalogues of reference DNA barcodes (International Barcode of Life, iBOL, BIOSCAN) (Hobern, 2021) and genomes by the Earth BioGenome Project (EBP) (Lewin et al., 2018, 2022) as well as the European Reference Genome Atlas (ERGA, 2023), or both by the Biodiversity Genomics Europe (BGE, 2023) project. Along with this increased production, concurrent development of the necessary tools and resources will greatly enhance our abilities to:\n\n• Maintain and query increasingly comprehensive reference DNA barcode and genome catalogues, improving taxonomic coverage and differentiation (including of cryptic species), and coordinating the efforts of various initiatives under global and regional umbrellas;\n\n• Connect and integrate these molecular resources with other biodiversity data (traits, observations, literature, etc.), using an increasingly standardised and harmonised taxonomic framework as the common backbone;\n\n• Use these integrated resources for applied data-driven science to understand the diversity of extant life on Earth, how that diversity functions and interacts, and how it responds to changing environmental pressures;\n\n• Implement monitoring of lesser-known or complex ecosystems, including for enhancing understanding of species interactions and dynamics, as well as for species discovery and exploration of “dark taxa” e.g., Rahman et al. (2022);\n\n• Include assessments of within-species, population-level genetic diversity to support characterisations of their evolutionary histories and predictions of their future prospects in the face of ongoing climatic changes;\n\n• Operationalise the assessment of Essential Biodiversity Variables (EBVs) across taxa and spatiotemporal scales, focusing on species distribution and abundance (Kissling et al., 2018; Jetz et al., 2019);\n\n• Engage with naturalists and citizen scientist groups through the use of new technologies that help build a democratised monitoring framework and improve characterisation of ecosystem biodiversity in space and time (Robinson & Peres, 2021);\n\n• Evaluate biodiversity declines, as well as population-level adaptation and migration processes, in the context of anthropogenic activities (e.g., climate change and urbanisation consequences), and understand key aspects necessary to restore ecosystem functions to help prioritise biodiversity conservation, restoration, and “rewilding” efforts (e.g., particularly relevant to at-risk biodiversity hotspots).\n\nThe field of biodiversity assessment and research, from an organisational context, is broad, complex, and distributed. There are a multitude of organisations that operate across international borders, within countries, and at a local level (see Extended Data (Waterhouse, 2023)). This landscape is further demarcated along scientific and technical lines, with organisations that focus on taxonomies, ecology, molecular sciences, and method development (necessitated by the increasingly large and complex amount of data being generated). ELIXIR, perhaps uniquely, stands as a hub for the molecular sciences and bioinformatics at an international and national level across many scientific disciplines (Waterhouse et al., 2022). Biodiversity research and infrastructures increasingly rely on molecular data, so ELIXIR is well placed to lead organisational alignments and collaborations: from a core set of partners across Europe mainly within the field of molecular sciences, to an expanding variety of partner organisations that focus on other biodiversity-related research and resources (see below for examples from the ecosystem of biodiversity projects, resources, and infrastructures). Importantly, this extends beyond the data themselves as FAIRification of digital research objects, championed by ELIXIR’s Services and Platforms, is increasingly recognised as essential in biodiversity research. Opportunities to help coordinate and align organisational activities in the biodiversity domain arise naturally from ELIXIR’s established European-wide “network of networks” approach, connecting to existing initiatives at both the national and international levels. With ELIXIR’s strengths in molecular sciences, a “hub and spokes” model would help augment opportunities to connect molecular-focused bioinformatics tools, protocols, and resources with the many other biodiversity-related infrastructure and stakeholder organisations.\n\nThe variety of existing biodiversity data infrastructures and resources is a testament to the long-standing recognition by multiple stakeholders of their importance, currently reflected in the growing European and global commitments to prevent further biodiversity decline and ensure the long-term health of ecosystem services. This heterogeneity, however, gives rise to many challenges, both technical in terms of data analysis (due to inadequacies of existing methodologies), data integration and data interaction, and at the level of the scientific community, which faces a heterogeneous landscape of infrastructures and resources that can be difficult to navigate. The methodological and logistical challenges range from scaling up (needed to be able to process the increasing amounts of complex molecular data) to the management of these data and working on connecting them to other biodiversity research infrastructures (Waterhouse et al., 2022). The biodiversity community needs to proactively seek common solutions (without unnecessary duplication of effort) that enable molecular technologies to advance biodiversity research. To this end, informatics solutions will need to be developed to address the practicalities of common challenges, such as:\n\n• The need to constantly incorporate knowledge-based updates and resolve conflicts to maintain standardised taxonomies that serve as a dynamic framework that facilitates interoperability across research infrastructures;\n\n• Building data and metadata brokering services that support coordinated community engagement to ensure good data management through technical infrastructures for aiding and automating data submission;\n\n• Developing the means, through text mining and curation, to identify and liberate in digital form invaluable historical or baseline data trapped in the literature (including those published in non-English sources), or in museum and other natural history collections;\n\n• Improving the accessibility of research results through publications (e.g., by making published traits, tables, treatments, specimens, figures etc.), citable and reusable (e.g., through nanopublications), and including identifiers of cited elements (genes, specimens, taxonomic names, treatments);\n\n• Improving and harmonising currently highly heterogeneous metadata collection standards to promote the adoption of community best practices that will maximise findability, accessibility, interoperability, and reusability of digital research objects (i.e., drive biodiversity research towards FAIR compliance);\n\n• Scaling up of services for data and metadata management to keep pace with and accommodate the increases in data production (e.g., genomics) and collection (e.g., Essential Biodiversity Variables);\n\n• Developing frameworks that deliver an increasingly integrated and interconnected landscape of biodiversity research infrastructures, utilising developments in application programming interfaces and Semantic Web services;\n\n• Ensuring widespread access to high-performance computing (HPC) and HPC-deployable software and data-management systems, including containers and workflows, to enable decentralised efforts while promoting standardisation.\n\n\nThe ELIXIR Biodiversity Community: An “ecosystem” of projects\n\nTackling the biodiversity crisis at a general level is not going to be resolved through a single action, but instead requires a complex set of interacting actions that are co-dependent but usually funded separately. ELIXIR can assume a key leading role in a subset of those actions, focused on data management and the molecular sciences, but even at the level of ELIXIR, there are a multitude of funded projects at a transnational, national, and local level. These form a complex network of interacting projects that have distinct but related aims, usually focused on establishing communities and connections and/or building new technical solutions to help with data access, storage, or analysis. ELIXIR can serve a critical function here, as a fundamental aspect of its mission is to make connections and coordinate across complex activities. Table 1 lists a subset of ongoing projects across Europe and within ELIXIR member states that illustrate the breadth of activities underway.\n\n\nConnections with ELIXIR Platforms and Communities\n\nELIXIR as a Research Infrastructure is structured around (technological) Platforms as well as (user) Communities. Both of these interact on an ongoing basis, mutually supporting each other’s efforts. The ELIXIR Biodiversity Community is already collaborating with some of these and aims to broaden interactions to fully leverage the available potential and resources. Some examples of current and future interactions with ELIXIR Platforms (Tools, Compute, Data, Training, and Interoperability) are:\n\n• The Tools Platform provides services for finding software tools and web portals (Bio.tools (Ison et al., 2019), including the https://biodiversity.bio.tools subdomain to be populated by the ELIXIR Biodiversity Community), software containers (BioContainers (da Veiga Leprevost et al., 2017)), and workflows (WorkflowHub (Goble et al., 2021)); for assessing tools (OpenEBench (Capella-Gutierrez et al., 2017)); and the best practices in providing research software (Jiménez et al., 2017)). EDAM ontology enables annotation and search of tools and other research objects by application domain, task, or data (Black et al., 2022); and an extended coverage of biodiversity research concepts could be achieved via engagement with the Biodiversity Community.\n\n• Specifically for the Compute Platform: User accessible compute, potentially controlled user access via Authentication and Authorisation Infrastructure (AAI).\n\n• Community data-management support, and integration with ELIXIR Core and Deposition Data resources. The European Nucleotide Archive (ENA) is a critical data deposition resource for biodiversity genomics data. A concrete example of metadata management workflow is that developed between biodiversity scientists, the Data Platform, and the Biodiversity Community Integrated Knowledge Library (BiCIKL) project (Penev et al., 2021): a metadata management workflow employs the PlutoF tool for biodiversity data and metadata management (Abarenkov et al., 2010), and the ELIXIR Data Platform services.\n\n• Networks of tool/infrastructure users and developers to augment the Training Platform offerings (e.g., with specific courses covering aspects such as: genome annotation, meta-data brokering, etc.) and more complete learning paths, covering entire workflows (e.g., from sequencing to annotation, possibly covered via Galaxy).\n\n• A growing necessity in the biodiversity field towards connected data, as championed by the Interoperability Platform, concretely touching on resources like: RO-Crate and link to specimens, RDMkit, FAIRsharing, Bioschemas and the FAIRcookbook. The ELIXIR Biodiversity Community aims to bring together researchers producing the data, in all their varied forms, with informaticians developing interoperability solutions, to help overcome the challenges of data heterogeneity in the field.\n\nWith regards to links between the ELIXIR Biodiversity Community and other ELIXIR Communities, these are already foreseen, and a number of synergies have been clearly identified. Some examples can be found in Table 2.\n\n\nA global network of biodiversity projects and infrastructures\n\nELIXIR entered the European Strategy Forum for Research Infrastructure’s (ESFRI) first roadmap in 2006 and reached its Landmark status in 2016 (ELIXIR, 2021). As a distributed research infrastructure, ELIXIR coordinates, integrates, and sustains bioinformatics resources across European countries and helps address the Grand Challenges across life sciences, from marine research, via plants and agriculture, to health research, medical sciences, and biodiversity informatics. ELIXIR provides services in seven scientific domains including “Evolution and phylogeny” and “Genes and genomes” (https://elixir-europe.org/services) that link the activities of the ELIXIR community to the wider landscape of life-science research infrastructures (RIs) and international projects. As RIs mature and FAIRness has become the standard to achieve interoperability between RIs, it is opportune to outline the global network of interrelated projects and infrastructures, in which ELIXIR operates to maximise synergy and to avoid redundancy.\n\nThe relationships between different aspects of biodiversity data are well captured by the biodiversity knowledge graph of Roderic Page (Figure 1). The key activities of ELIXIR are captured by the molecular domain; the biodiversity knowledge graph clearly indicates how molecular data are related to the wider spectrum of biodiversity data that are targeted by other RIs and projects. The ELIXIR Biodiversity Community benefits from connections to RIs and projects in the biodiversity domain, an overview of which can build on the landscape analyses of the ESFRI roadmaps of ESFRI 2018 (ESFRI, 2018) and 2021 (ESFRI, 2021), the partners of the Alliance for Biodiversity Knowledge, and the research infrastructure contact zones analysis between 10 biodiversity infrastructures, including ELIXIR (Smith et al., 2022). Additional to the data types considered by Page (Figure 1), the contact zones analysis considers ‘observations’ and ‘collections’, or groups of specimens, as elements of the biodiversity data domain. This recognition of the variety of types of biodiversity data and the importance of integration has been key to the establishment of many RIs and research projects, for example: the Alliance for Biodiversity Knowledge; Biodiversity Genomics Europe; Biodiversity Heritage Library; Biodiversity Community Integrated Knowledge Library; iBOL BIOSCAN; Biodiversity Literature Repository; Catalogue of Life; Data Observation Network for Earth; Distributed System of Scientific Collections; Earth BioGenome Project; European Marine Biological Resource Centre; Environmental Research Infrastructures; Encyclopedia of Life; European Open Science Cloud; European Reference Genome Atlas; Europa Biodiversity Observation Network; Global Biodiversity Information Facility; Global Earth Observation System of Systems; Global Soil Biodiversity Initiative; International Barcode of Life; iNaturalist; LifeWatch ERIC; Long-Term Ecosystem Research in Europe; Microbial Resource Research Infrastructure; National Ecological Observatory Network; Open Traits Network; Plazi; Pôle national de données de biodiversité; Swiss Institute for bioinformatics Literature Services; Soil Biodiversity Observation Network; TreatmentBank; World Register of Marine Species.\n\nGenomics data comprise one facet of the biodiversity knowledge graph, where questions and approaches in biodiversity research traverse the paths in this graph, and where all parts of the graph are constantly ‘evolving’ and growing. Wikimedia Commons CC-BY-4.0.\n\nIn addition to the above examples and in the context of ELIXIR the following two examples highlight ongoing activities in the field of biodiversity and in the context of the European research sphere.\n\nSeveral ELIXIR Nodes are involved in European projects with focus on biodiversity. The BiCIKL project is building the Biodiversity Knowledge Hub (BKH) - a single knowledge portal to interlinked machine-readable FAIR data - using unique stable identifiers on specimens, sequences, taxonomy and publications (Penev et al., 2021). A set of core global biodiversity databases (GBIF, ENA, PlutoF, Plazi, DISSCO, OpenBioDiv, ToL, etc.) are contributing with the aim to develop services to augment the interlinking of biodiversity contents, starting with biotic interactions. The project is also financing competitive implementation studies to develop transnational resources.\n\nThe European Open Science Cloud initiative (2023) intends to offer a federated and open multi-disciplinary environment where tools, data and services can be published, sought, and re-used. Via enabling seamless access and FAIR management EOSC aims to develop a Web of FAIR Data and services for science, innovation and education in Europe through which value-added services can be offered. The EOSC-Life initiative connects 13 life science ‘ESFRI’ research infrastructures to create an open, digital and collaborative space for biological and medical research. Among the EOSC-Life “FAIR” published data and catalogued services (by participating RIs), ones related to biodiversity are included. The workflow for marine Genomic Observatories data analysis is such an example (EBI, 2021).\n\n\nConclusions: A roadmap for the ELIXIR Biodiversity Community\n\nConsidering the context discussed above, the ELIXIR Biodiversity Community aims to contribute towards the global aim of tackling the biodiversity crisis by making possible a future where:\n\n• Large-scale sustainable data production services are meeting the routine needs of hundreds of laboratories and thousands of citizen scientists for sequence-based biodiversity research and monitoring;\n\n• A set of well-connected, stable and long-term infrastructures among which ELIXIR is supporting a growing portfolio of stakeholders by improving their access to, and integration of well-curated, high-quality, richly annotated and connected molecular data.\n\n• State-of-the-art computational tools are available for large-scale projects related to biodiversity, including data standardisation initiatives.\n\nTo advance towards these ambitious goals, longer-term and within one year of the Community establishment, the ELIXIR Biodiversity Community proposes a roadmap. Table 3 shows five long-term objectives for the ELIXIR Biodiversity Community to address. The current focus is on the informatics, databases, and tools more than on the biological questions, so as the Community grows, it will be important to widen the diversity of its membership to ensure that the technical developments will serve the needs of biodiversity researchers.\n\n\n\n• Support alignment of large-scale projects and transcending initiatives to result in high-quality, interoperable data and metadata\n\n• Build routes for the community to access and add to the knowledge (curation) of growing resources e.g., trait measurements, observations beyond geolocations\n\n• Include primary production sectors affecting biodiversity\n\n\n\n• Identify infrastructures contributing to the worldwide effort to sequence and catalogue biodiversity data\n\n• Leverage ELIXIR networks and Communities to facilitate linking between infrastructures through collaborative projects\n\n• Increase interoperability in biodiversity infrastructures through alignment of taxonomies and data/metadata standards\n\n• Include relevant citizen science infrastructures (e.g., Atlas of Living Australia, iNaturalist, eBird)\n\n\n\n• High-level alignment of strategy and policy in the biodiversity data domain\n\n• Support reconciliation of the interests of primary producers in biodiversity-rich environments\n\n\n\n• Identify gaps in the platforms/frameworks that exist to support the biodiversity data life cycle\n\n• Address all ELIXIR tools and services and where they can be plugged into the biodiversity data ecosystem\n\n• Coordinate and integrate services that support workflows through all stages of the process: from sampling, taxonomic identification and vouchering, sequence generation, annotation, cataloguing and further application of the data\n\n• Result in a network of services that meet the route needed by hundreds of labs and thousands of citizen scientists\n\n\n\n• Establish the network of Nodes\n\n• Invest in training\n\n• Focus on community integration and re-use (rather than disjointed efforts)\n\n• Connect with other ongoing ELIXIR efforts",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nFigshare: Extended Data 1: Biodiversity RIs & Projects. https://doi.org/10.6084/m9.figshare.22723432 (Waterhouse, 2023).\n\nThis project contains the following extended data:\n\n- Extended_Data_1_Biodiversity_RIs_Projects.xlsx (A non-exhaustive list of biodiversity research infrastructures, collected as part of the development of the ELIXIR Biodiversity Community white paper 2022-2023.)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nThe authors thank all members of the ELIXIR Biodiversity Community, the ELIXIR Hub, and the ELIXIR Heads of Nodes, for useful feedback during the development of this Community White Paper.\n\n\nReferences\n\nAbarenkov K, et al.: PlutoF—a Web Based Workbench for Ecological and Taxonomic Research, with an Online Implementation for Fungal ITS Sequences. Evol. 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Bioinformatics. 2017; 33: 2580–2582. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWaterhouse RM, et al.: Recommendations for connecting molecular sequence and biodiversity research infrastructures through ELIXIR. F1000Res. 2022; 10: 1238. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWaterhouse RM: Extended Data 1: Biodiversity RIs & Projects. [Dataset]. figshare. 2023. Publisher Full Text\n\nWezel A, et al.: Agroecological principles and elements and their implications for transitioning to sustainable food systems. A review. Agron. Sustain. Dev. 2020; 40: 40. Publisher Full Text\n\nWWF: The Living Planet Report 2022 – Building a nature-positive society. Almond REA, Grooten M, Juffe Bignoli D, et al., editors. WWF; Reference Source2022."
}
|
[
{
"id": "218316",
"date": "13 Feb 2024",
"name": "Patrick Comer",
"expertise": [
"Reviewer Expertise Biodiversity Conservation",
"Landscape Ecology",
"Biodiversity status assessment",
"Climate change vulnerability and adaptation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPeer Review: The ELIXIR Biodiversity Community: Understanding short- and long-term changes in biodiversity – RM Waterhouse et al\nThis article provides a concise overview of the ELIXIR Biodiversity Community which can serve as a hub for the molecular sciences and bioinformatics as it applies to biodiversity science. ELIXIR’s overarching mission has been stated to “support the management of public research data, integrate and coordinate life science resources, and foster the development of innovative services and technical solutions in Europe” (Harrow et al., 20211). Given unprecedented and escalating loss in biodiversity, there is increasing urgency for new scientific discovery, data processing, and data sharing of biodiversity information among scientists, conservation practitioners, and policy makers. This opinion piece summarizes biodiversity threats, societal challenges and global responses, and scientific opportunities in biodiversity research. It then discusses informatics challenges facing biodiversity infrastructures and resources, organizational opportunities for ELIXIR partners, and connections with ELIXIR platforms and communities. The piece concludes with a roadmap listing key goals and long-term objectives for the ELIXIR Biodiversity Community.\n\nThe article might best be viewed in the context of the large and growing field of scientists, practitioners, and policy analysts, in government, academic, and non-government (NGO) sectors responding to the emerging crisis of biodiversity loss. Starting in the mid-20th century with many academic researchers who initially documented biodiversity declines, biodiversity science - and biodiversity conservation - has been steadily mainstreamed worldwide (Locke et al.,20192). One of the founders of “conservation biology” the late Michael Soulé described this science as a “discipline with a deadline” working against accelerating extinctions to sustain the wellbeing of society and the environment (Soulé and Wilcox,19803). While encompassing the full spectrum from basic to applied, biodiversity conservation science has often emphasized practical ways to identify key information suitable for action on the ground. One good example coming from the North American NGO NatureServe network is the practical methods for systematic field inventories for natural communities and species to characterize their location, health, and status (Stein et al., 20004). In full disclosure, I have spent most of my working life in this network, first established by The Nature Conservancy in the 1970s.\nWith much biodiversity conservation initially focused on identifying local areas for nature preserves, the maturing disciplines of landscape ecology, meta-population dynamics, and now climate change research, forced consideration of increasing broader scales of conservation action (Lindenmayer and Franklin, 20135). With rapidly advancing technology and data, and emphasis on remote sensing and modeling with spatial data have become routine (Wiens et al., 20096). And increasingly (one could say belatedly), the value of social science been acknowledged as it has deepened our understanding of complex interactions of people and nature that underlay nearly all conservation strategies (Sandbrook et al., 20137).\nTherefore, while I found this piece to be factual, accurate, and well supported by the current literature, it would benefit from a broader interpretation of biodiversity science and more directed treatment of ELIXIR’s potential contributions to the “broader ecosystem” of biodiversity conservation. For example, the rapid advances in genomic science and its application to biodiversity conservation has many parallels to several allied fields previously mentioned, such as in remote sensing and several variants of the social sciences. The ELIXIR Biodiversity Community could gain by considering this prior experience. Thus, avoiding prior mistakes and replicating prior successes. Among the many ways expanding genomic science could affect biodiversity conservation include ecosystem characterization and monitoring, support to biodiversity status assessment, and evaluating progress of conservation actions.\n\nThe article states that “A long-term vision sees a future where sequence-based biodiversity monitoring at scale becomes the default and provides the means for ecosystem biodiversity characterisation in space and time.” One area where we may see near-term progress here is in the links between genomic data and remote sensing; where our current forms of ecosystem characterization centered on measures of species composition, ecosystem structure, and environmental setting may be enhanced by remotely-sensed data (hyperspectral and others) indicating patterns within and among readily observed communities and species (Yamasaki et al., 20178). Relationships between measurable genetic diversity and detectable light spectra will always be complex and challenging, but with increasing frequency of remote data collection one can now envision substantial opportunities to identify leading indicators of ecosystem change through their combination.\nCurrent standards to assess and document endangerment status of species and ecosystems – such as those of red listing under IUCN - require documented knowledge of changing health of populations and communities (IUCN 20129; Bland et al., 201710). These standards attempt to simplify complex ecological phenomena into standard categories to provide a reliable status assessment for use by policy makers and engaged stakeholders. Once clear health markers are identified with genomic data, this could contribute substantially to the rigor, efficiency, and impact of biodiversity status assessment.\nThis naturally follows on to the potential benefit of genomic data to contribute to evaluating success (or failure) of conservation actions. As noted in the article, that these data should contribute to understanding “population-level adaptation and migration processes, in the context of anthropogenic activities (e.g., climate change and urbanisation consequences), and understand[ing] key aspects necessary to restore ecosystem functions.” It is in planning and implementation of conservation actions where one can surely recognize biodiversity conservation as inherently a human-driven process, so once again, the information used must be clear and compelling to all involved, regardless of their interests and biases.\nPrior experience in related fields suggest at least several considerations for the ELIXIR Biodiversity Community. As noted in the article, “ELIXIR can serve a critical function here, as a fundamental aspect of its mission is to make connections and coordinate across complex activities.” And “the biodiversity community needs to proactively seek common solutions (without unnecessary duplication of effort) that enable molecular technologies to advance biodiversity research. I would underscore the importance of limiting duplication of effort. Much of the history of biodiversity conservation in marked by unnecessary competition, stove-piping, and duplicated effort among those involved.\nAnd while ELIXIR’s “current focus is on the informatics, databases, and tools more than on the biological questions, . . . as the Community grows, it will be important to widen the diversity of its membership to ensure that the technical developments will serve the needs of biodiversity researchers,” I would encourage this community to begin early to seek out and identify feedback loops from the full spectrum of user communities. As noted above, the users of genomic data for biodiversity conservation will be diverse and demanding, so deeper consideration of user needs (Dubois et al., 202011), and participatory biodiversity science (Zoellick et al., 201212) could have substantial payoffs into the future.\nBiodiversity conservation is based on both ecological and social science that is both urgent and time sensitive. It is that applied side of the spectrum that requires urgent support from the ELIXIR Biodiversity Community.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly",
"responses": [
{
"c_id": "11517",
"date": "20 Jun 2024",
"name": "Robert Waterhouse",
"role": "Author Response",
"response": "This article provides a concise overview of the ELIXIR Biodiversity Community which can serve as a hub for the molecular sciences and bioinformatics as it applies to biodiversity science. ELIXIR’s overarching mission has been stated to “support the management of public research data, integrate and coordinate life science resources, and foster the development of innovative services and technical solutions in Europe” (Harrow et al., 20211). Given unprecedented and escalating loss in biodiversity, there is increasing urgency for new scientific discovery, data processing, and data sharing of biodiversity information among scientists, conservation practitioners, and policy makers. This opinion piece summarizes biodiversity threats, societal challenges and global responses, and scientific opportunities in biodiversity research. It then discusses informatics challenges facing biodiversity infrastructures and resources, organizational opportunities for ELIXIR partners, and connections with ELIXIR platforms and communities. The piece concludes with a roadmap listing key goals and long-term objectives for the ELIXIR Biodiversity Community. RESPONSE ⇒ We thank the reviewer for their positive summary. The article might best be viewed in the context of the large and growing field of scientists, practitioners, and policy analysts, in government, academic, and non-government (NGO) sectors responding to the emerging crisis of biodiversity loss. Starting in the mid-20th century with many academic researchers who initially documented biodiversity declines, biodiversity science - and biodiversity conservation - has been steadily mainstreamed worldwide (Locke et al.,20192). One of the founders of “conservation biology” the late Michael Soulé described this science as a “discipline with a deadline” working against accelerating extinctions to sustain the wellbeing of society and the environment (Soulé and Wilcox,19803). While encompassing the full spectrum from basic to applied, biodiversity conservation science has often emphasized practical ways to identify key information suitable for action on the ground. One good example coming from the North American NGO NatureServe network is the practical methods for systematic field inventories for natural communities and species to characterize their location, health, and status (Stein et al., 20004). In full disclosure, I have spent most of my working life in this network, first established by The Nature Conservancy in the 1970s. With much biodiversity conservation initially focused on identifying local areas for nature preserves, the maturing disciplines of landscape ecology, meta-population dynamics, and now climate change research, forced consideration of increasing broader scales of conservation action (Lindenmayer and Franklin, 20135). With rapidly advancing technology and data, and emphasis on remote sensing and modeling with spatial data have become routine (Wiens et al., 20096). And increasingly (one could say belatedly), the value of social science been acknowledged as it has deepened our understanding of complex interactions of people and nature that underlay nearly all conservation strategies (Sandbrook et al., 20137). RESPONSE ⇒ We thank the reviewer for the additional background, and have taken the opportunity to mention the ideas of Soulé and the field of conservation biology in the introduction. ADDED: “The urgency to act is recognised particularly in the field of conservation biology, which has been described as a “discipline with a deadline” (Soulé & Wilcox 1980).” Therefore, while I found this piece to be factual, accurate, and well supported by the current literature, it would benefit from a broader interpretation of biodiversity science and more directed treatment of ELIXIR’s potential contributions to the “broader ecosystem” of biodiversity conservation. For example, the rapid advances in genomic science and its application to biodiversity conservation has many parallels to several allied fields previously mentioned, such as in remote sensing and several variants of the social sciences. The ELIXIR Biodiversity Community could gain by considering this prior experience. Thus, avoiding prior mistakes and replicating prior successes. Among the many ways expanding genomic science could affect biodiversity conservation include ecosystem characterization and monitoring, support to biodiversity status assessment, and evaluating progress of conservation actions. RESPONSE ⇒ While, we agree with the reviewer’s ideas to highlight better the “broader ecosystem” of biodiversity conservation,the role of the ELIXIR Biodiversity Community has been clearly defined in the section “Organisational opportunities and ELIXIR’s roles” as we recognise that there is a plethora of initiatives already tackling exactly these kinds of issues. Rather, the Community is focused on the data management aspects, in particular with regards to molecular data, that are needed to effectively support and grow the many existing activities in the domain of biomonitoring and ecosystem health. We have made changes to the text to ensure that there is clarity to the role that the ELIXIR Biodiversity Community plays (data science support versus frontline conservation actions). The article states that “A long-term vision sees a future where sequence-based biodiversity monitoring at scale becomes the default and provides the means for ecosystem biodiversity characterisation in space and time.” One area where we may see near-term progress here is in the links between genomic data and remote sensing; where our current forms of ecosystem characterization centered on measures of species composition, ecosystem structure, and environmental setting may be enhanced by remotely-sensed data (hyperspectral and others) indicating patterns within and among readily observed communities and species (Yamasaki et al., 20178). Relationships between measurable genetic diversity and detectable light spectra will always be complex and challenging, but with increasing frequency of remote data collection one can now envision substantial opportunities to identify leading indicators of ecosystem change through their combination. RESPONSE ⇒ This example is an excellent case study of how different data types - if made available and interoperable - can be co-interrogated to improve how we measure and monitor biodiversity. We have revised the text to more clearly indicate the complementarity of different types of data and their applications. EDITED ⇒ A long-term vision sees a future where sequence-based biodiversity monitoring at scale becomes a default and provides the means for ecosystem biodiversity characterisation in space and time, complemented and enhanced by other biomonitoring technologies. Current standards to assess and document endangerment status of species and ecosystems – such as those of red listing under IUCN - require documented knowledge of changing health of populations and communities (IUCN 20129; Bland et al., 201710). These standards attempt to simplify complex ecological phenomena into standard categories to provide a reliable status assessment for use by policy makers and engaged stakeholders. Once clear health markers are identified with genomic data, this could contribute substantially to the rigor, efficiency, and impact of biodiversity status assessment. This naturally follows on to the potential benefit of genomic data to contribute to evaluating success (or failure) of conservation actions. As noted in the article, that these data should contribute to understanding “population-level adaptation and migration processes, in the context of anthropogenic activities (e.g., climate change and urbanisation consequences), and understand[ing] key aspects necessary to restore ecosystem functions.” It is in planning and implementation of conservation actions where one can surely recognize biodiversity conservation as inherently a human-driven process, so once again, the information used must be clear and compelling to all involved, regardless of their interests and biases. RESPONSE ⇒ We agree that this is a key goal in biodiversity genomics, being able to get the most out of the data to improve the way assessments are made and how to interpret the results for policy makers and engaged stakeholders. We see the role of ELIXIR here as focused on helping to build systems that will ensure access to data and tools and services that enable experts to perform assessments and make decisions based on the best available data and methods. We have made changes to ensure clarity to this distinction (data science support versus frontline conservation actions). Prior experience in related fields suggest at least several considerations for the ELIXIR Biodiversity Community. As noted in the article, “ELIXIR can serve a critical function here, as a fundamental aspect of its mission is to make connections and coordinate across complex activities.” And “the biodiversity community needs to proactively seek common solutions (without unnecessary duplication of effort) that enable molecular technologies to advance biodiversity research. I would underscore the importance of limiting duplication of effort. Much of the history of biodiversity conservation in marked by unnecessary competition, stove-piping, and duplicated effort among those involved. RESPONSE ⇒ We thank the reviewer for highlighting this important point. One of the strengths of ELIXIR’s operations and activities in other domains like human health has been to contribute to better coordinated efforts across Europe. It is a cornerstone of the principle of distributed infrastructure for life-science data and we have incorporated your suggestions. ADDED ⇒ A key part of this is the building of distributed infrastructures for life-science data that avoid or minimise unnecessary duplication of effort to be able to advance efficiently towards common goals. And while ELIXIR’s “current focus is on the informatics, databases, and tools more than on the biological questions, . . . as the Community grows, it will be important to widen the diversity of its membership to ensure that the technical developments will serve the needs of biodiversity researchers,” I would encourage this community to begin early to seek out and identify feedback loops from the full spectrum of user communities. As noted above, the users of genomic data for biodiversity conservation will be diverse and demanding, so deeper consideration of user needs (Dubois et al., 202011), and participatory biodiversity science (Zoellick et al., 201212) could have substantial payoffs into the future. Biodiversity conservation is based on both ecological and social science that is both urgent and time sensitive. It is that applied side of the spectrum that requires urgent support from the ELIXIR Biodiversity Community. RESPONSE ⇒ Since this manuscript was first published the Community has embarked on its first Implementation Study, within which there is a dedicated effort to describe the landscape of stakeholders ELIXIR is working with or needs to better engage with and to establish a functional “network of networks” for biodiversity research. Following your suggestions, we have revised the last section of the manuscript, highlighting the needs to engage beyond ELIXIR members and interact with other communities of practice in the domain. ADDED ⇒ Beyond the ELIXIR Biodiversity Community itself, it is also vital to engage with other communities in the domain, including with stakeholders such as practitioners and citizen science initiatives in order to contribute towards bridging the gaps between research and implementation (Dubois et al., 2020; Fraisl et al. 2022)."
}
]
},
{
"id": "223867",
"date": "22 Feb 2024",
"name": "Abigail Benson",
"expertise": [
"Reviewer Expertise biodiversity informatics",
"open science",
"data standards"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe ELIXIR Biodiversity Community: Understanding short- and long-term changes in biodiversity highlights the need for biodiversity informatics to address challenges facing our world and provides lists of projects and entities working to contribute biodiversity informatics solutions.\nWe were really interested in this work and excited to read it. However, we struggled with finding the conceptual thread that tied the disparate sections together. The introduction provided an important summary about biodiversity but was missing the summarization of the current landscape of biodiversity informatics that would provide the foundation for where ELIXIR fits into the puzzle. The lists of tools are valuable but too extensive and missing the connective text that was needed to understand why these projects were being listed. One challenge we had as readers is that we are new to ELIXIR and it’s not spelled out or described in the text. We were confused about the connection between ELIXIR and the threats and challenges that were described. We were left wondering which ones ELIXIR addresses and how? We had expected based on the title to learn about the ELIXIR community, how it’s organized, how it interacts, and what makes it a community but we didn’t find that information in the paper so we were left wondering what the ELIXIR community is?\nWe also felt that the text could use more supporting references. There are times when strong statements are provided but are not backed up with needed citations.\nWe would suggest the authors narrow the focus in the challenges section to the ones the ELIXIR community is best poised to address and make those connections explicit in the text. We also would find it beneficial for ELIXIR to be described and more thoroughly contextualized. We also found it confusing when the paper mentions another project or RI as an official collaborator with ELIXIR, and when they merely serve as example. Perhaps replacing Figure 1 with some visual explanation of the community structure would help.\nWe are hopeful that the paper can be revised.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nAre arguments sufficiently supported by evidence from the published literature? Partly\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly",
"responses": [
{
"c_id": "11518",
"date": "20 Jun 2024",
"name": "Robert Waterhouse",
"role": "Author Response",
"response": "The ELIXIR Biodiversity Community: Understanding short- and long-term changes in biodiversity highlights the need for biodiversity informatics to address challenges facing our world and provides lists of projects and entities working to contribute biodiversity informatics solutions. We were really interested in this work and excited to read it. However, we struggled with finding the conceptual thread that tied the disparate sections together. The introduction provided an important summary about biodiversity but was missing the summarization of the current landscape of biodiversity informatics that would provide the foundation for where ELIXIR fits into the puzzle. The lists of tools are valuable but too extensive and missing the connective text that was needed to understand why these projects were being listed. One challenge we had as readers is that we are new to ELIXIR and it’s not spelled out or described in the text. We were confused about the connection between ELIXIR and the threats and challenges that were described. We were left wondering which ones ELIXIR addresses and how? We had expected based on the title to learn about the ELIXIR community, how it’s organized, how it interacts, and what makes it a community but we didn’t find that information in the paper so we were left wondering what the ELIXIR community is? RESPONSE ⇒ We thank the reviewers for their interest and apologise that some aspects were not covered in enough detail to provide complete answers, especially to readers who are new to ELIXIR. The section in the introduction “Informatics challenges facing biodiversity infrastructures and resources” was intended to briefly summarise the current landscape of biodiversity informatics, pointing to a previous output of the ELIXIR Biodiversity Community (Waterhouse et al, 2022) where we covered this topic in much more detail. In the introduction we outlined global challenges and potential solutions, and only later in the text we describe how ELIXIR might fit into these landscapes - with a focus on molecular data and their integration into the broader biodiversity knowledge graph. To clarify ELIXIR’s operational standing and Community model, we have added a detailed description to the section immediately following the introduction: ‘The ELIXIR Biodiversity Community: An “ecosystem” of projects’. The substantially revised roadmap section at the end of the paper is also designed to clarify the goals and practical aspects of what the Community aims to tackle and how. Regarding the named/listed tools, projects, platforms, and other communities - this is primarily for the benefit of ELIXIR members who review the Community’s White Paper as part of the formal process of becoming an ELIXIR Community. We hope these changes now provide a clearer picture, especially to readers who are new to ELIXIR. ADDED ⇒ ELIXIR Communities are groups of experts across ELIXIR Nodes and beyond that represent a scientific or technological theme which drives the development of standards, services, and/or training in and across services offered by ELIXIR, thereby connecting the infrastructure services to research domains (Heil & Garrard, 2024). The ELIXIR Biodiversity Community was first launched in 2019 as a Focus Group to develop and coordinate ELIXIR Nodes’ tools, resources, and research work connected to the biodiversity domain. As part of the process of maturing from a Focus Group to a Community, members initiated activities including: (1) cataloguing ELIXIR Services that support biodiversity research; (2) developing and publishing their “Recommendations for connecting molecular sequence and biodiversity research infrastructures through ELIXIR” (Waterhouse et al., 2022); (3) coordinating ELIXIR Node participation in Horizon Europe project proposals - The Biodiversity Community Integrated Knowledge Library (BiCIKL) and Biodiversity Genomics Europe (BGE); and (4) beginning to establish connections with key external partners/projects in the biodiversity domain (such as those listed in Table 1); leading to the formal recognition in 2022 as an ELIXIR Community (Waterhouse et al., 2023). ADDED ⇒ Operationally, monthly online meetings coordinated by the Community co-leads with support from the ELIXIR Hub serve as the primary forum for interactions, complemented by discussions and notifications on the ELIXIR Slack Workspace’s Biodiversity Community channel. These include sharing information on members’ participation in ongoing or planned biodiversity-related projects and initiatives, including the Community-led Implementation Study “Biodiversity Networks for ELIXIR”. The online meetings also feature presentations on tools and services developed by ELIXIR Nodes as well as hosting invited speakers representing key external partners/projects. The Community’s Implementation Study encompasses four key areas of work to drive Community activities: (1) to survey and catalogue Research Data Management (RDM) elements relevant to the biodiversity domain, with a focus on molecular data; (2) to catalogue, review, and categorise tools, services, and analytical workflows currently in use by ELIXIR Nodes and the wider community, that process and analyse biodiversity-related data; (3) to describe the landscape of stakeholders ELIXIR is working with or needs to better engage with to establish a “network of networks” for biodiversity research and services; and (4) to leverage the strengths of ELIXIR’s training experience to help support the growth of the Biodiversity Community through network-driven sharing of training experiences and knowledge transfer and materials. Together, these actions are serving to enhance ELIXIR’s network of networks in helping to deliver connected data to advance biodiversity research. ADDED ⇒ In terms of informatics solutions connected to such projects, the ELIXIR Biodiversity Community is guided by themes emerging from surveying approaches by which molecular technologies are helping to inform understanding of biodiversity (Waterhouse et al., 2022): biodiversity-related and informatics infrastructures need to develop close and strategic collaborations; work on taxonomy needs to be better aligned and standardised across different infrastructures and fields of study; metadata urgently needs harmonisation and common approaches to research data management must be widely adopted; current data science solutions need to be scaled up to address the rapidly accumulating amounts of molecular data; bioinformatics support for biodiversity research needs to be made widely available and properly maintained; user training on biodiversity research tools, services, and infrastructures needs to be prioritised; and community initiatives need to be collaborative, proactive, and solution-driven. We also felt that the text could use more supporting references. There are times when strong statements are provided but are not backed up with needed citations. RESPONSE ⇒ We have included a number of additional references in the revised manuscript. If there are additional specific recommendations we would be happy to incorporate them into the text as needed. We would suggest the authors narrow the focus in the challenges section to the ones the ELIXIR community is best poised to address and make those connections explicit in the text. We also would find it beneficial for ELIXIR to be described and more thoroughly contextualized. We also found it confusing when the paper mentions another project or RI as an official collaborator with ELIXIR, and when they merely serve as example. Perhaps replacing Figure 1 with some visual explanation of the community structure would help. RESPONSE ⇒ We designed the introduction to first encompass the broader perspectives on key challenges in biodiversity research, including highlighting what is needed to advance the status quo, and then follow that up with “ELIXIR’s roles”, i.e. where ELIXIR activities could contribute to meeting these challenges. We have revised the text in parts to clarify the motivation to contribute to the wider landscape of efforts, bringing expertise in data management solutions, particularly with respect to molecular data. We added some context on ELIXIR as a whole (introduction), and we now describe the Community operations and key themes that guide Community activities connected to biodiversity-related projects and initiatives. The considerable re-working of the concluding roadmap section is aimed at narrowing the focus on where the ELIXIR Biodiversity Community is best poised to contribute. The use of Rod Page’s Biodiversity Knowledge graph as figure 1 emphasises why data connectivity is important and that the ELIXIR Community’s current focus on molecular data does not imply that other facets are less important. We hope that the added operational description of the Community now addresses the community structure and how it interfaces with other research infrastructures and key projects/initiatives in the biodiversity domain. ADDED (Introduction) ⇒ As a European life sciences infrastructure, ELIXIR strives to coordinate bioinformatics resources from across Europe to enable researchers to access and analyse life science data, to improve the value and impact of life science research on public health, the environment, and the economy. ADDED (‘The ELIXIR Biodiversity Community: An “ecosystem” of projects’.) ⇒ See the added text in the response above. We are hopeful that the paper can be revised. RESPONSE ⇒ We thank the reviewers for their helpful comments and suggestions, particularly from the perspective of researchers not already familiar with ELIXIR and its operations. We hope that the resultant additions and revisions address your concerns."
}
]
},
{
"id": "232449",
"date": "05 Mar 2024",
"name": "Cher FY Chow",
"expertise": [
"Reviewer Expertise macroecology",
"biodiversity data",
"ecoinformatics",
"marine ecology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nWaterhouse et al. present here an opinion article presenting ELIXIR as a solution that can help standardise biodiversity monitoring at scale for the European region and globally. This paper first describes the current landscape of challenges and responses to biodiversity monitoring, and later presents the efforts undertaken by the ELIXIR consortium that can address this. There is a demonstrated need to detect biodiversity change in a coordinated manner at a large spatial scale as emphasised by priorities set by IPBES, Global Biodiversity Framework, and the UN Sustainable Goals. The authors outline the current needs in biodiversity research and policy efforts and highlight the utility of incorporating more “omics” and molecular techniques. They discuss a complex landscape of biodiversity informatics, where challenges exist from data collection to data management and linkages across sources. They present the ELIXIR consortium infrastructure and network of projects/initiatives which help address these challenges.\nI first would like to commend the authors for their effort in tackling a complex set of challenges. I appreciate the practical nature of this article, and I can envision it targeted as a relevant reference for European governmental bodies and researchers. However, the article currently needs further development in order to demonstrate to readers 1) the authors’ concept of biodiversity informatics, 2) where in this network there are gaps or challenges, and finally 3) how its breadth of initiatives, tools, and platforms can be used by scientists or environmental managers. I outline below my general concerns and questions I would like the authors to respond to.\nArticle aim: I understand this article is currently presented as an opinion article. The authors state their aim the in the abstract as “[to present] a set of plans, both technical and community-oriented, that should both enhance how ELIXIR Services are applied in the biodiversity field and how ELIXIR builds connections across the many other infrastructures active in this area.” However, from my reading, it is unclear to me what questions or knowledge gaps the authors are tackling, or presented opinions, and secondly, what the authors want me to take away from the article. Are they presenting the results from the ELIXIR consortium? If the aim is to provide some roadmap of resources within biodiversity informatics, I find the latter half of the article difficult to interpret and apply from a user perspective. It is unclear to me how some projects listed in Table 1, e.g. a barcoding project based in the Norfolk Broads on page 6, meets informatics or infrastructure challenges outlined previously. This needs to be made clearer and more explicit to the reader. Furthermore, I find the title a mismatch from the article contents and would suggest the authors adjust it to better reflect the aims.\nIntroduction of ELIXIR: Please include a section that introduces ELIXIR and its structure. As it is presented, the consortium is mentioned and introduced in parts interspersed throughout the first five pages but not completely.\nBiodiversity change and molecular approaches: The authors introduce biodiversity change, global policy responses, and the need for incorporating molecular techniques. However, the authors have not demonstrated a clear conceptual link between molecular approaches and the crisis of biodiversity loss and extinction. There are several facets to biodiversity and change is occurring in a myriad of patterns and scales (e.g. [1]; [2] ; [3]; [4]; [5]. Genetic diversity assessments, enhancing species detections through eDNA, and resolved taxonomy are examples of critical components to understanding biodiversity change. The authors hint at these but not in a clear, demonstrated manner. How is a lack of high-throughput and -omics approaches failing our understanding of biodiversity? How can genetic diversity data be linked with the research examples listed under “Scientific opportunities in biodiversity research”? Are there examples where this potential is demonstrated?\nThe network of biodiversity knowledge: I like Figure 1 as a conceptual figure to ground the idea of how biodiversity monitoring or research requires a network of components. From my knowledge of biodiversity informatics, this concept forms the basis of the first five pages. However, the authors should clearly state this conceptual landscape in the introduction before presenting challenges. This can then demonstrate to the reader how molecular approaches fit into that framework.\nCitations needed: Page 5 can be improved by engaging and contextualising its ideas with existing literature on biodiversity informatics and data management. The ELIXIR consortium is not alone in researching how to improve infrastructure for biodiversity data. The ideas presented in this article build upon previous work. This should be recognised. For example:\nPage 4 under “Biodiversity research and infrastructures increasingly rely on molecular data”: [12];[13]; [7] Page 5: “FAIRification of digital research objects… is increasingly recognised as essential in biodiversity research”: [8]; [9] Page 5: “This heterogeneity, however, gives rise to many challenges, both technical in terms of data analysis (due to inadequacies of existing methodologies), data integration and data interaction, and at the level of the scientific community, which faces a heterogeneous landscape of infrastructures and resources that can be difficult to navigate.”: [11]; [12]; [10]\n\nMinor comments I appreciate that ELIXIR is an extensive research infrastructure project and have been well-represented in other published works. This paper should stand alone without relying on previously published works for introduction. There are several instances of unintroduced abbreviations which assumes that the reader is already familiar with the organisations involved. Please include clearer introductions of ELIXIR as a consortium and mentioned nodes.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? No\n\nAre arguments sufficiently supported by evidence from the published literature? Partly\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": [
{
"c_id": "11519",
"date": "20 Jun 2024",
"name": "Robert Waterhouse",
"role": "Author Response",
"response": "Waterhouse et al. present here an opinion article presenting ELIXIR as a solution that can help standardise biodiversity monitoring at scale for the European region and globally. This paper first describes the current landscape of challenges and responses to biodiversity monitoring, and later presents the efforts undertaken by the ELIXIR consortium that can address this. There is a demonstrated need to detect biodiversity change in a coordinated manner at a large spatial scale as emphasised by priorities set by IPBES, Global Biodiversity Framework, and the UN Sustainable Goals. The authors outline the current needs in biodiversity research and policy efforts and highlight the utility of incorporating more “omics” and molecular techniques. They discuss a complex landscape of biodiversity informatics, where challenges exist from data collection to data management and linkages across sources. They present the ELIXIR consortium infrastructure and network of projects/initiatives which help address these challenges. RESPONSE ⇒ We thank the reviewer for their positive summary. I first would like to commend the authors for their effort in tackling a complex set of challenges. I appreciate the practical nature of this article, and I can envision it targeted as a relevant reference for European governmental bodies and researchers. However, the article currently needs further development in order to demonstrate to readers 1) the authors’ concept of biodiversity informatics, 2) where in this network there are gaps or challenges, and finally 3) how its breadth of initiatives, tools, and platforms can be used by scientists or environmental managers. I outline below my general concerns and questions I would like the authors to respond to. RESPONSE ⇒ We thank the reviewer for their appreciation of our efforts to describe the goals of the Community and how they fit in the broader landscape. The section in the introduction “Informatics challenges facing biodiversity infrastructures and resources” was intended to briefly summarise the current landscape of biodiversity informatics, pointing to a previous output of the ELIXIR Biodiversity Community - “Recommendations for connecting molecular sequence and biodiversity research infrastructures through ELIXIR” (Waterhouse et al, 2022) - where we covered this topic in much more detail, including outlining the gaps and challenges. We have now summarised these primary “needs” as emerging themes from our prior survey (included in the much extended section ‘The ELIXIR Biodiversity Community: An “ecosystem” of projects’. We also summarised the activities of the Community Implementation Study, which exemplifies how ELIXIR tools and services are being developed and connected for use by researchers. ADDED ⇒ ELIXIR Communities are groups of experts across ELIXIR Nodes and beyond that represent a scientific or technological theme which drives the development of standards, services, and/or training in and across services offered by ELIXIR, thereby connecting the infrastructure services to research domains (Heil & Garrard, 2024). The ELIXIR Biodiversity Community was first launched in 2019 as a Focus Group to develop and coordinate ELIXIR Nodes’ tools, resources, and research work connected to the biodiversity domain. As part of the process of maturing from a Focus Group to a Community, members initiated activities including: (1) cataloguing ELIXIR Services that support biodiversity research; (2) developing and publishing their “Recommendations for connecting molecular sequence and biodiversity research infrastructures through ELIXIR” (Waterhouse et al., 2022); (3) coordinating ELIXIR Node participation in Horizon Europe project proposals - The Biodiversity Community Integrated Knowledge Library (BiCIKL) and Biodiversity Genomics Europe (BGE); and (4) beginning to establish connections with key external partners/projects in the biodiversity domain (such as those listed in Table 1); leading to the formal recognition in 2022 as an ELIXIR Community (Waterhouse et al., 2023). ADDED ⇒ Operationally, monthly online meetings coordinated by the Community co-leads with support from the ELIXIR Hub serve as the primary forum for interactions, complemented by discussions and notifications on the ELIXIR Slack Workspace’s Biodiversity Community channel. These include sharing information on members’ participation in ongoing or planned biodiversity-related projects and initiatives, including the Community-led Implementation Study “Biodiversity Networks for ELIXIR”. The online meetings also feature presentations on tools and services developed by ELIXIR Nodes as well as hosting invited speakers representing key external partners/projects. The Community’s Implementation Study encompasses four key areas of work to drive Community activities: (1) to survey and catalogue Research Data Management (RDM) elements relevant to the biodiversity domain, with a focus on molecular data; (2) to catalogue, review, and categorise tools, services, and analytical workflows currently in use by ELIXIR Nodes and the wider community, that process and analyse biodiversity-related data; (3) to describe the landscape of stakeholders ELIXIR is working with or needs to better engage with to establish a “network of networks” for biodiversity research and services; and (4) to leverage the strengths of ELIXIR’s training experience to help support the growth of the Biodiversity Community through network-driven sharing of training experiences and knowledge transfer and materials. Together, these actions are serving to enhance ELIXIR’s network of networks in helping to deliver connected data to advance biodiversity research. ADDED ⇒ In terms of informatics solutions connected to such projects, the ELIXIR Biodiversity Community is guided by themes emerging from surveying approaches by which molecular technologies are helping to inform understanding of biodiversity (Waterhouse et al., 2022): biodiversity-related and informatics infrastructures need to develop close and strategic collaborations; work on taxonomy needs to be better aligned and standardised across different infrastructures and fields of study; metadata urgently needs harmonisation and common approaches to research data management must be widely adopted; current data science solutions need to be scaled up to address the rapidly accumulating amounts of molecular data; bioinformatics support for biodiversity research needs to be made widely available and properly maintained; user training on biodiversity research tools, services, and infrastructures needs to be prioritised; and community initiatives need to be collaborative, proactive, and solution-driven. Article aim: I understand this article is currently presented as an opinion article. The authors state their aim the in the abstract as “[to present] a set of plans, both technical and community-oriented, that should both enhance how ELIXIR Services are applied in the biodiversity field and how ELIXIR builds connections across the many other infrastructures active in this area.” However, from my reading, it is unclear to me what questions or knowledge gaps the authors are tackling, or presented opinions, and secondly, what the authors want me to take away from the article. Are they presenting the results from the ELIXIR consortium? If the aim is to provide some roadmap of resources within biodiversity informatics, I find the latter half of the article difficult to interpret and apply from a user perspective. It is unclear to me how some projects listed in Table 1, e.g. a barcoding project based in the Norfolk Broads on page 6, meets informatics or infrastructure challenges outlined previously. This needs to be made clearer and more explicit to the reader. Furthermore, I find the title a mismatch from the article contents and would suggest the authors adjust it to better reflect the aims. RESPONSE ⇒ We thank the reviewer for their frank assessment, and apologise for some lack of clarity with respect to the purpose of the White Paper publication, which would be particularly unclear to readers who are new to ELIXIR. Much of the parts dedicated to outlining other initiatives, projects, tools, services, and connections with ELIXIR Platforms and other Communities are primarily for the benefit of ELIXIR members who review the Community’s White Paper as part of the formal process of becoming an ELIXIR Community. The aim is not to present results of ELIXIR actions but rather to outline where ELIXIR might be well-placed to contribute and how as a Community we can begin to develop initiatives in the domain of biodiversity research and services by connecting and growing ELIXIR Node activities in data science that can support the field. The substantially revised roadmap section at the end of the paper is designed to articulate the goals and practical aspects of what the Community aims to tackle and how. We hope these changes now provide a clearer picture, especially to readers who are new to ELIXIR. ADDED ⇒ The revisions to this final section are rather extensive, please see the new content of “Conclusions: A roadmap for the ELIXIR Biodiversity Community” for all the details. Introduction of ELIXIR: Please include a section that introduces ELIXIR and its structure. As it is presented, the consortium is mentioned and introduced in parts interspersed throughout the first five pages but not completely. RESPONSE ⇒ We have now included a brief introduction of ELIXIR and its structure. ADDED (Introduction) ⇒ As a European life sciences infrastructure, ELIXIR strives to coordinate bioinformatics resources from across Europe to enable researchers to access and analyse life science data, to improve the value and impact of life science research on public health, the environment, and the economy. Biodiversity change and molecular approaches: The authors introduce biodiversity change, global policy responses, and the need for incorporating molecular techniques. However, the authors have not demonstrated a clear conceptual link between molecular approaches and the crisis of biodiversity loss and extinction. There are several facets to biodiversity and change is occurring in a myriad of patterns and scales (e.g. [1]; [2] ; [3]; [4]; [5]. Genetic diversity assessments, enhancing species detections through eDNA, and resolved taxonomy are examples of critical components to understanding biodiversity change. The authors hint at these but not in a clear, demonstrated manner. How is a lack of high-throughput and -omics approaches failing our understanding of biodiversity? How can genetic diversity data be linked with the research examples listed under “Scientific opportunities in biodiversity research”? Are there examples where this potential is demonstrated? RESPONSE ⇒ The background in the introduction was designed to be concise and general, so we avoided detailed explanations of the different facets and how they might come together to address our understanding of biodiversity change. Instead, these more technical points are presented in an earlier output of the community, emerging from surveying approaches by which molecular technologies are helping to inform understanding of biodiversity (Waterhouse et al., 2022). We have now included a summary of these themes in the much extended section describing the ELIXIR Biodiversity Community. For the examples listed in this section without references we have now added supporting references where appropriate. The network of biodiversity knowledge: I like Figure 1 as a conceptual figure to ground the idea of how biodiversity monitoring or research requires a network of components. From my knowledge of biodiversity informatics, this concept forms the basis of the first five pages. However, the authors should clearly state this conceptual landscape in the introduction before presenting challenges. This can then demonstrate to the reader how molecular approaches fit into that framework. RESPONSE ⇒ The use of Rod Page’s Biodiversity Knowledge graph as figure 1 was intended as a highly recognisable way to emphasise how data connectivity is important and that the ELIXIR Community’s current focus on molecular data does not imply that other facets are less important. The introduction sets the scene, while the main focus is on the establishment, operations, and goals of the ELIXIR Biodiversity Community in the context of that scene. Now that we have added the operational description of the Community to more clearly describe the community structure and how it interfaces with other research infrastructures and key projects/initiatives in the biodiversity domain, and greatly elaborated the Community goals we hope it is much clearer why this figure is used here rather than in the general introduction. Citations needed: Page 5 can be improved by engaging and contextualising its ideas with existing literature on biodiversity informatics and data management. The ELIXIR consortium is not alone in researching how to improve infrastructure for biodiversity data. The ideas presented in this article build upon previous work. This should be recognised. For example: Page 4 under “Biodiversity research and infrastructures increasingly rely on molecular data”: [12];[13]; [7] Page 5: “FAIRification of digital research objects… is increasingly recognised as essential in biodiversity research”: [8]; [9] Page 5: “This heterogeneity, however, gives rise to many challenges, both technical in terms of data analysis (due to inadequacies of existing methodologies), data integration and data interaction, and at the level of the scientific community, which faces a heterogeneous landscape of infrastructures and resources that can be difficult to navigate.”: [11]; [12]; [10] RESPONSE ⇒ We thank the reviewer to pointing us to these key references that we now use to support the statements being made. Minor comments I appreciate that ELIXIR is an extensive research infrastructure project and have been well-represented in other published works. This paper should stand alone without relying on previously published works for introduction. There are several instances of unintroduced abbreviations which assumes that the reader is already familiar with the organisations involved. Please include clearer introductions of ELIXIR as a consortium and mentioned nodes. RESPONSE ⇒ We thank the reviewer for this observation that we need to bring more clarity especially for readers less familiar with ELIXIR, so we have taken measures to remedy this throughout, including a brief definition presented early in the introduction. ADDED (Introduction) ⇒ As a European life sciences infrastructure, ELIXIR strives to coordinate bioinformatics resources from across Europe to enable researchers to access and analyse life science data, to improve the value and impact of life science research on public health, the environment, and the economy."
}
]
}
] | 1
|
https://f1000research.com/articles/12-499
|
https://f1000research.com/articles/12-1505/v1
|
27 Nov 23
|
{
"type": "Case Report",
"title": "Case Report: Effect of rTMS on urinary incontinence in major vascular neurocognitive disorder",
"authors": [
"Xiaohong Ni",
"Hongyan Ke",
"Yu Tian",
"Lei Zhou",
"Xin Chen",
"Yuangao Liao",
"Xiaohong Ni",
"Hongyan Ke",
"Yu Tian",
"Lei Zhou",
"Xin Chen"
],
"abstract": "Background: Many efforts had been made to combat the symptoms of incontinence over the past decades, yet difficulties still remain. To stimulate the cortical urination center might theoretically be useful for regulating urination process. In this case of urinary incontinence with major vascular neurocognitive disorder, repetitive transcranial magnetic stimulation (rTMS) on the bilateral paracentral lobule was applied and therapeutic effect was obvious. Case report: A 67-year-old female farmer suffered from urinary incontinence over two weeks. She was diagnosed with major vascular neurocognitive disorder. The patient received rTMS on the bilateral paracentral lobule. Stimulation was administered at 20 Hz with 25 stimulation trains of 30 stimuli each with a 30-second intertrain interval. After a 5-day course of rTMS intervention, the patient reported full awareness of her urination, but her neurocognitive decline had not improved at all. Conclusions: rTMS on bilateral paracentral lobule could be used for treating urinary incontinence in major vascular neurocognitive disorder patients.",
"keywords": [
"repetitive transcranial magnetic stimulation",
"urinary incontinence",
"vascular neurocognitive disorder"
],
"content": "Introduction\n\nEfforts to combat the symptoms of incontinence have been made over the past decades, yet difficulties still remain. In this case study, we reported the case of a patient with urinary incontinence comorbid with major vascular neurocognitive disorder who received repetitive transcranial magnetic stimulation (rTMS) on the bilateral paracentral lobule. After five sessions of rTMS, the patient was fully aware of her urination, but her neurocognitive decline did not improve at all.\n\nTo the best of our knowledge, there are no reports of treating urinary incontinence with major vascular neurocognitive disorder through rTMS on bilateral paracentral lobule. In this case of urinary incontinence with major vascular neurocognitive disorder, no therapeutic effects were found of intravenous levofloxacin and pelvic floor electrical stimulation. After applying rTMS on the bilateral paracentral lobule, therapeutic effects had presented in the first rTMS session. Here we reported this case for peer discussion.\n\n\nCase report\n\nA 67-year-old female Chinese Han farmer suffered from urinary incontinence over two weeks. She had received intravenous levofloxacin (Levofloxacin Lactate and Sodium Chloride Injection, Zhejiang Medicine Co., Ltd., 0.4 g qd) and pelvic floor electrical stimulation for a week before her admission, but little therapeutic effect was produced. She was hospitalized in Huanggang Central Hospital of Yangtze University. She had no awareness of her urination. Her caregiver noticed her urination from her soaked clothes and sheets. She was not unconscious and had no paralysis, numbness or ataxia. She did not complain of headache, dizziness, diplopia, or tinnitus and had no difficulty swallowing. She was poor in spirit, appetite and sleep, and her bowel movements required medical assistance. She had no medical records of hypertension, diabetes, heart disease, cerebrovascular disease or head trauma and no substance abuse or mental stimulation. However, over the past several years, she had experienced insidious onset and gradual progression of impaired cognitive function, manifesting in language, memory and perceptual-motor domains.\n\nAt admission, she was aware but had little interaction with her surroundings. A significant decline in most cognitive domains was found. She had difficulty making out others’ words, and her sentences were hard to understand. Her recent memory was heavily impaired. She hardly made decisions or planned instrumental activities. She scored seven on the mini-mental state examination (MMSE) test with partially preserved language. Her clock drawing task scored therewith only irregularly rounded shape and several numbers out of circle. Her clinical dementia rating (CDR) test score was two.\n\nThe routine blood tests were normal. The urine routine test showed no inflammatory variation. Serum liver function, kidney function, electrolytes and homocysteine were normal. Serum triglycerides and total cholesterol were elevated to 4.83 mmol/L and 7.0 mmol/L, respectively. Fasting plasma glucose was normal, while serum glycosylated hemoglobin was increased up to 7.2%. Serum thyroid-stimulating hormone, free triiodothyronine and free tetraiodothyronine were normal. Serum vitamin B12 decreased to 129.0 pg/ml. The serum was negative for antibodies against hepatitis C, syphilis, and AIDS. Electrocardiography showed sinus rhythm with no abnormalities in QRS intervals or QT intervals or ST-T changes. Chest computed tomography examination manifested as chronic bronchitis. Color Doppler ultrasound examination of the heart, digestive system, urinary system, and carotid vertebral artery was normal. Magnetic resonance imaging (MRI) of the brain showed patchy lesions around the lateral ventricle and scattered point lesions in the basal ganglia, corona radiata and frontal and parietal subcortical white matter, with features of hypointensity on T1-weighted images and hyperintensity on T2-weighted images. Mild frontal and temporal atrophy were detected, while the midbrain, pons and medulla were retained. Magnetic resonance angiography (MRA) detected carotid and intracranial atherosclerosis with no significant local stenosis.\n\nAccording to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), we diagnosed the case as probable major vascular neurocognitive disorder. The most pressing issue was urinal incontinence.\n\nThe patient received treatment with repetitive transcranial magnetic stimulation (rTMS). A B65-type figure-eight coil connected to a MagPro X100 stimulator (Magventure Inc.) was used. Resting motor threshold (RMT) was determined by standard methods and not repeated during the treatment course. Active treatment was delivered at 90% RMT intensity. Stimulation was administered at 20 Hz with 25 stimulation trains of 30 stimuli each with a 30-second intertrain interval. The hot spot of stimulation was located at the bilateral paracentral lobule. In addition, intramuscular injection of vitamin B12 and oral medications to control blood sugar and cholesterol were carried out during the rTMS intervention.\n\nThe symptom of urinal incontinence was markedly improved since the third rTMS therapeutic day. After a five-day course of rTMS intervention, the patient reported full awareness of her urination. Another two five-day courses of rTMS were administrated, her urinal incontinence did not relapse but her neurocognitive decline had not improved at all. The scores of MMSE and CDR were the same as before treatment.\n\n\nDiscussion\n\nIn this case, an elderly female patient suffering from urinal incontinence had received intravenous antibiotics and pelvic floor electrical stimulation for a week before her admission, but little therapeutic effect was produced. After her admission, high-frequency rTMS on the bilateral paracentral lobule was conducted, and her urination function recovered in one week. During the two weeks of rTMS treatment, the symptom of urinal incontinence disappeared without any fluctuation. Therefore, we speculated that rTMS in cortical urologic centers is useful for the remission of urinary incontinence.\n\nAccording to the definitions from International Continence Society Standardization of Terminology reports,1 the patient was classified into the type of continuous urinary incontinence from her storage symptoms. Multiple factors may contribute to the formation of this patient’s condition. In addition to the normal structure of the bladder and urethral canal, proper function of the detrusor muscle, internal and external urethral sphincters, and nervous system plays important roles during the whole urination process. The cerebral cortex and pontine nucleus coordinate the activities of sympathetic and parasympathetic networks with the somatic nervous system through spinal cord conduction tracts.2\n\nTo relieve symptoms of urinary incontinence, many methods have emerged in past decades, such as physiotherapy, psychological care, manual assistance, behavior therapy, drug therapy, urethral catheterization, and surgical treatment.3,4 Among those invasive methods, pelvic floor muscle training (PFM) was proven to be effective and recommended as the first option,5–7 and a novel PFM program was launched.8 Based on a series of clinical trials on intravaginal electrical stimulation,9 transcutaneous electrical nerve stimulation,10 neuromuscular electrical stimulation11 and transcutaneous tibial nerve stimulation,12 Ali et al.,4 summarized that electrical stimulation was beneficial for improving the symptoms of urge urinary incontinence among people with multiple sclerosis and those with stroke. To cure voiding dysfunction due to spinal cord lesions, sacral neuromodulation (SNM) system implantation is considered to be a safe and effective method in clinical practice.13–16 Averbeck et al., reviewed recent literature and regarded SNM as a promising therapy for neurogenic lower urinary tract dysfunction in carefully selected patients with incomplete lesions.17\n\nrTMS was also attempted to treat urinary incontinence. Yani et al., reported that high-frequency rTMS in the supplementary motor area (SMA) of the cortex decreased pelvic floor tone, while low-frequency rTMS in the SMA increased pelvic floor tone.18 A randomized controlled study was ongoing to explore the effect of PTNS and rTMS on the neurogenic bladder with multiple sclerosis.19 According to a review by Pericolini et al., spinal cord stimulation (SCS) and TMS for treating lower tract symptoms in MS patients were effective despite a small number of studies.20 El-Habashy et al., saw that cortical as well as sacral magnetic stimulation showed a significant effect on lower urinary tract dysfunction in MS patients with underactive bladder rather than overactive bladder.21 Vacher et al., collected data from the literature and found that TMS may have a role in the management of pelvic and perineal disorders.22\n\nThrough administrating a series of impulses at specific intensity and frequency on selected brain cortex,23 rTMS could generate post stimulation changes that affect the resting membrane potential and action potential of the selected area. Then, rTMS may induce morpho-functional modifications by increasing synaptic connectivity and modulating synaptic plasticity.24–27 Cirillo et al.,28 reported that brain rTMS was a valuable tool for cognitive rehabilitation of mild cognitive impairment through the long-term modulation of the metalloprotease- and metalloprotease-related tissue inhibitor 1 system. In this case of urinary incontinence in a patient with major vascular neurocognitive disorder, we administered high-frequency rTMS to the bilateral paracentral lobule, and the symptom of urinary incontinence disappeared quickly. We speculated that the therapeutic mechanism was in line with the effect of rTMS on morpho-functional modifications of neural cells and brain networks.\n\nAfter all, there were several factors that could be attributed to the recovery of the patient’s urinal incontinence. Firstly, that vitamin B12 supplementation and professional nursing care might help to improve the patient’s urinal symptom. Secondly, the clinical manifestation of vascular neurocognitive disorder tends to fluctuate, so, the urinal incontinence symptom may disappear along with the temporarily relief of vascular neurocognitive disorder. Thirdly, intravenous levofloxacin and pelvic floor electrical stimulation before admission might have an effect on the mitigation of urinal symptoms. Whatever, the patient’s urinary incontinence began to recover and disappeared just after rTMS treatment was added. For rTMS we focused on the bilateral paracentral lobule, which is the cortical center of urination. So we regarded that rTMS being applied to the bilateral paracentral lobule could be used for treating urinary incontinence in patients with major vascular neurocognitive disorder. More clinical case collections and controlled trials are needed to verify this result.\n\n\nInformed consent\n\nWritten informed consent for publication of their clinical details was obtained from the daughter of the patient.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nAcknowledgments\n\nWe thank AJE (https://china.aje.com/) for linguistic assistance during the preparation of this manuscript.\n\n\nReferences\n\nAbrams P, et al.: The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Am. J. Obstet. Gynecol. 2002; 187(1): 116–126. PubMed Abstract | Publisher Full Text\n\nLeslie SW, Tadi P, Tayyeb M: Neurogenic Bladder and Neurogenic Lower Urinary Tract Dysfunction. StatPearls. Treasure Island (FL): 2022.\n\nXiang L, et al.: Rehabilitation care of patients with neurogenic bladder after spinal cord injury: A literature review. World J. Clin. Cases. 2023; 11(1): 57–64. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAli MU, et al.: Effects of nonsurgical, minimally or noninvasive therapies for urinary incontinence due to neurogenic bladder: a systematic review and meta-analysis. Ther Adv Chronic Dis. 2022; 13: 20406223211063059.\n\nPaiva LL, et al.: Pelvic floor muscle training in groups versus individual or home treatment of women with urinary incontinence: systematic review and meta-analysis. Int. Urogynecol. J. 2017; 28(3): 351–359. Publisher Full Text\n\nAyeleke RO, Hay-Smith EJ, Omar MI: Pelvic floor muscle training added to another active treatment versus the same active treatment alone for urinary incontinence in women. Cochrane Database Syst. Rev. 2015; 2015(11): CD010551. PubMed Abstract | Publisher Full Text\n\nDumoulin C, Cacciari LP, Hay-Smith EJC: Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women. Cochrane Database Syst. Rev. 2018; 10(10): CD005654. PubMed Abstract | Publisher Full Text\n\nPapanikolaou DT, et al.: Pelvic floor muscle training: Novel versus traditional remote rehabilitation methods. A systematic review and meta-analysis on their effectiveness for women with urinary incontinence. Neurourol Urodyn; 2023.\n\nLa Rosa VL, et al.: A comparison of sacral neuromodulation vs. transvaginal electrical stimulation for the treatment of refractory overactive bladder: the impact on quality of life, body image, sexual function, and emotional well-being. Prz Menopauzalny. 2019; 18(2): 89–93. PubMed Abstract | Publisher Full Text\n\nSlovak M, Chapple CR, Barker AT: Non-invasive transcutaneous electrical stimulation in the treatment of overactive bladder. Asian J. Urol. 2015; 2(2): 92–101. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuo GY, Kang YG: Effectiveness of neuromuscular electrical stimulation therapy in patients with urinary incontinence after stroke: A randomized sham controlled trial. Medicine (Baltimore). 2018; 97(52): e13702. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAraujo TG, et al.: Transcutaneous tibial nerve home stimulation for overactive bladder in women with Parkinson’s disease: A randomized clinical trial. Neurourol. Urodyn. 2021; 40(1): 538–548. PubMed Abstract | Publisher Full Text\n\nWang XH, et al.: Application of the first rechargeable sacral neuromodulation system for treatment of neurogenic lower urinary tract dysfunction in China: a case report. Am. J. Transl. Res. 2023; 15(1): 324–329. PubMed Abstract\n\nChen G, et al.: Effectiveness and safety of sacral neuromodulation on neurogenic bladder and bowel dysfunction in patients with spina bifida. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2021; 35(11): 1374–1379. PubMed Abstract | Publisher Full Text\n\nShan S, et al.: Video-urodynamics efficacy of sacral neuromodulation for neurogenic bladder guided by three-dimensional imaging CT and C-arm fluoroscopy: a single-center prospective study. Sci. Rep. 2022; 12(1): 16306. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMasood I, et al.: Sacral Neuromodulation in Patients With Neurogenic Lower Urinary Tract Dysfunction: A Multicenter Retrospective Study From China. Neuromodulation. 2021; 24(7): 1278–1283. PubMed Abstract | Publisher Full Text\n\nAverbeck MA, Moreno-Palacios J, Aparicio A: Is there a role for sacral neuromodulation in patients with neurogenic lower urinary tract dysfunction? Int. Braz. J. Urol. 2020; 46(6): 891–901. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYani MS, et al.: Motor cortical neuromodulation of pelvic floor muscle tone: Potential implications for the treatment of urologic conditions. Neurourol. Urodyn. 2019; 38(6): 1517–1523. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAtak Cakir P, et al.: Effect of transcutaneous posterior tibial nerve stimulation and repetitive transcranial magnetic stimulation on neurogenic overactive bladder symptoms in female patients with multiple sclerosis: The study protocol of a randomized controlled study. Front. Neurol. 2022; 13: 1011502. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPericolini M, et al.: Cortical, Spinal, Sacral, and Peripheral Neuromodulations as Therapeutic Approaches for the Treatment of Lower Urinary Tract Symptoms in Multiple Sclerosis Patients: A Review. Neuromodulation. 2022; 25(8): 1065–1075. PubMed Abstract | Publisher Full Text\n\nEl-Habashy H, et al.: The effect of cortical versus sacral repetitive magnetic stimulation on lower urinary tract dysfunction in patients with multiple sclerosis. Acta Neurol. Belg. 2020; 120(1): 141–147. PubMed Abstract | Publisher Full Text\n\nVacher P, et al.: Interest of transcranial stimulation in pelvic and perineal disorders. Prog. Urol. 2019; 29(7): 349–359. PubMed Abstract | Publisher Full Text\n\nChou YH, Ton That V, Sundman M: A systematic review and meta-analysis of rTMS effects on cognitive enhancement in mild cognitive impairment and Alzheimer’s disease. Neurobiol. Aging. 2020; 86: 1–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCirillo G, et al.: Neurobiological after-effects of non-invasive brain stimulation. Brain Stimul. 2017; 10(1): 1–18. PubMed Abstract | Publisher Full Text\n\nEsposito S, et al.: Repetitive Transcranial Magnetic Stimulation (rTMS) of Dorsolateral Prefrontal Cortex May Influence Semantic Fluency and Functional Connectivity in Fronto-Parietal Network in Mild Cognitive Impairment (MCI). Biomedicines. 2022; 10(5). PubMed Abstract | Publisher Full Text | Free Full Text\n\nNagerl UV, et al.: Bidirectional activity-dependent morphological plasticity in hippocampal neurons. Neuron. 2004; 44(5): 759–767. PubMed Abstract | Publisher Full Text\n\nMalenka RC, Bear MF: LTP and LTD: an embarrassment of riches. Neuron. 2004; 44(1): 5–21. Publisher Full Text\n\nCirillo G, et al.: Long-Term Neuromodulatory Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Plasmatic Matrix Metalloproteinases (MMPs) Levels and Visuospatial Abilities in Mild Cognitive Impairment (MCI). Int. J. Mol. Sci. 2023; 24(4). PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "239435",
"date": "26 Feb 2024",
"name": "Elizabeta B Mukaetova Ladinska",
"expertise": [
"Reviewer Expertise dementia",
"Alzheiemr's disease",
"treatment",
"diagnosis"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract is not connected to the case report. Especially the introduction requires rephrasing of some statements required. i.e. ‘To stimulate the cortical urination centre might theoretically be useful for regulating urination process.’ The background last sentence. In this case of urinary incontinence with major vascular neurocognitive disorder, repetitive transcranial magnetic stimulation (rTMS) on the bilateral paracentral lobule was applied and therapeutic effect was obvious.’ is best suited to conclusion.\nCase report: Introduction needs rewriting, raising the importance of addressing incontinence in both ageing and people with dementia. This needs to be better documented, and concentrating on introducing the importance of the topic, and therapeutic issues around it. I would suggest the authors to avoid sentences that do not add much to the text, i.e. ‘Efforts to combat the symptoms of incontinence have been made over the past decades, yet difficulties still remain.’ If using such statements, please rephrase it and document it. The second part of the introduction is part of the discussion/conclusion, and not introduction. The case report needs to be better structured I wonder why authors did not exclude hypoactive delirium as one of he differential diagnosis? Vitamin B12 deficiency can lead to delirium and authors’ discussion points towards its regulation contributing to improvement in both physical and mental state. There is not documentation of CRP, or the reasons why patients required inpatient admission (the latter points towards seriousness of patient’s physical state), or when the Vitamin B12 blood levels were normalised, i.e. whether this coincided with regulation of urine incontinence. Also, why implementing rTMS before physical state is normalised? Was the patient assessed for delirium with CAM or AT4? The case presentation and discussion indicate that the use of rTMS in this case are highly speculative, with other studies conducted in this areas requiring further confirmation.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": [
{
"c_id": "11567",
"date": "26 Jun 2024",
"name": "yuangao liao",
"role": "Author Response",
"response": "Dear Elizabeta B Mukaetova Ladinska, We would sincerely thank you for your time and effort that you have put into reviewing the previous version of this manuscript. Your suggestions have enabled us to improve our work. According to your nice suggestions, we have made extensive corrections to our previous draft and the detailed corrections are labeled on the new version of the manuscript which we hope to meet with approval. For details about the corrections according to your suggestions, here we list them as follows. 1) Firstly, the ABSTRACT have been rewritten in which some statements was rephrased and the last sentence of BACKGROUND was been substituted into CONCLUSION. 2) Secondly, almost all of the INTRODUCTION have been rewritten that would be matched to the criterion of introduction in our perspective. 3) Thirdly, that we did not make differential diagnosis about hypoactive delirium in part of CASE REPORT was an irreparable deficiency. The reason that we did not assess the patient with CAM or AT4 was that we had experientially excluded the diagnosis of delirium at our first glance. In fact, we might do more to improve our scientific strictness when preparing an academic report. 4) Fourthly, it was about the effect of vitamin B12 supplement on patient’s psychiatric status. We had mentioned in the last paragraph of DISCUSSION that all other symptoms except for urinary incontinence did not alleviate at all. Based on this, we speculated that vitamin B12 supplement did not effect on urinary incontinence improvement in our observational period. 5) Lastly, there were others questions in part of CASE REPORT such as documentation of CRP, reasons of inpatient admission and implementing rTMS before physical state normalized. We hardly make comprehensive explanations to them, but we declare that we did those clinical practices according to our team decision and oral consent from the patient’s family. Thank you a lot for your sincerely instructions which would help us to improve our abilities in clinical practice and research work. Hope you kindly accept our new version. Yours sincerely, Yuangao Liao. Department of neurology, Huanggang Center Hospital, Huanggang, Hubei, China. liaoygd@hotmail.com."
}
]
},
{
"id": "233454",
"date": "17 Apr 2024",
"name": "Penghui Wei",
"expertise": [
"Reviewer Expertise perioperative neurocognitive disorders",
"surgery",
"tDCS",
"elderly patients",
"postoperative delirium"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for inviting me to review the case. The authors introduced an interesting case for resolving the urinary incontinence in major vascular neurocognitive disorder by the repetitive transcranial magnetic stimulation (rTMS). The case actually provided a new idea and method for the major clinical issue. Authors need to address the following concerns before acceptance for indexing.\nMajor concern: did the authors not obtain ethical or family consent before starting the rTMS? As rTMS is a new method uncommonly used for urinary incontinence in clinical practice, it is essential for obtaining the ethical consent.\nMinor concerns: 1) Abstract: \"Many efforts had been made to combat the symptoms of incontinence over the past decades, yet difficulties still remain\", the incontinence should be clarified as urinary incontinence; 2) Abstract: there are a lack of treatments before rTMS; 3) Abstract: the conclusion was too absolute since a case was obviously not for a clear result and further studies are still needed. 4) Introduction: the paragraph 1 of the section was almost Duplicated with Abstract. The therapeutic effect was not discussed in the INTRODUCTION. The authors should introduce the conventional method for treating urinary incontinence and emphasized the necessity of rTMS; 5) ethical consent should be added in the section of case report.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "11568",
"date": "26 Jun 2024",
"name": "yuangao liao",
"role": "Author Response",
"response": "Dear Penghui Wei, We would sincerely thank you for your time and effort that you have put into reviewing the previous version of this manuscript. Your suggestions have enabled us to improve our work. According to your nice suggestions, we have made extensive corrections to our previous draft and the detailed corrections are labeled on the new version of the manuscript which we hope to meet with approval. For details about the corrections according to your suggestions, here we list them as follows. 1) Firstly, as a matter of fact, we did not obtain ethical consent before starting the rTMS. However, we did all of the treatment on patient according to our clinical team decision and oral consent from the patient’s family. Since rTMS were used in patients of almost all kinds of disease and were proven to be a safe therapeutic way in the past decades, we were not asked to obtain ethical consent before starting rTMS from Ethic Committee of our hospital. Hope you accept our irretrievable deficiency. 2) Secondly, the ABSTRACT and INTRODUCTION have been rewritten that would be matched to the criterion of medical thesis in our perspective. 3) Thirdly, we have rephrased some sentences adopting your sensible suggestion. Thank you a lot for your sincerely instructions which would help us to improve our abilities in clinical practice and research work. Hope you kindly accept our new version. Yours sincerely, Yuangao Liao. Department of neurology, Huanggang Center Hospital, Huanggang, Hubei, China. liaoygd@hotmail.com."
}
]
}
] | 1
|
https://f1000research.com/articles/12-1505
|
https://f1000research.com/articles/13-308/v1
|
22 Apr 24
|
{
"type": "Research Article",
"title": "Artificial Intelligence Model Chatgpt-4: Entrepreneur Candidate and Entrepreneurship Example",
"authors": [
"Muhammet SAYGIN",
"Mustafa BEKMEZCİ",
"Evren DİNÇER",
"Mustafa BEKMEZCİ",
"Evren DİNÇER"
],
"abstract": "Background Although artificial intelligence technologies are still in their infancy, it is seen that they can bring together both hope and anxiety for the future. In the research, it is focused on examining the ChatGPT-4 version, which is one of the most well-known artificial intelligence applications and claimed to have self-learning feature, within the scope of business establishment processes.\n\nMethods In this direction, the assessment questions in the Entrepreneurship Handbook, published as open access by the Small and Medium Enterprises Development Organization of Turkey, which focuses on guiding the entrepreneurial processes in Turkey and creating the perception of entrepreneurship, were combined with the artificial intelligence model ChatGPT-4 and analysed within three stages. The way of solving the questions of artificial intelligence modelling and the answers it provides have the opportunity to be compared with the entrepreneurship literature.\n\nResults It has been seen that the artificial intelligence modelling ChatGPT-4, being an outstanding entrepreneurship example itself, has succeeded in answering the questions posed in the context of 16 modules in the entrepreneurship handbook in an original way by analysing deeply.\n\nConclusion It has also been concluded that it is quite creative in developing new alternatives to the correct answers specified in the entrepreneurship handbook. The original aspect of the research is that it is one of the pioneers of the study on artificial intelligence and entrepreneurship in literature.",
"keywords": [
"ChatGPT-4",
"Entrepreneurship",
"Entrepreneurship Handbook",
"Artificial Intelligence"
],
"content": "Introduction\n\n“We call ourselves Homo Sapiens - man the wise - because our intelligence is so important to us.” (Russell & Norvig, 2010). Looking at history, it is possible to see that various adversities that threaten the existence of human beings have been overcome with a new and innovative development and progress effort. All renewal efforts that were carried out after crisis periods such as wars, pandemics, and similar crises that affected all humanity actually formed today's scientific and technological infrastructure. Scientific and technological developments that accelerated after the Covid-19 pandemic have made change mandatory and opened the way for paradigm shifts in many sectors. In this process, organizations have questioned their crisis preparedness levels and started to search for new and innovative methods. Educational processes, in which activities independent of the place gain importance, have also been directly affected. In addition, the management styles and business establishment processes of enterprises have started to change in a similar way, with artificial intelligence technologies replacing the systems that allow remote working and learning today.\n\nEntrepreneurship is the process of developing new concepts, goods, or services that lead to commercial prospects. Entrepreneurs take chances, put fresh ideas into practice, launch new firms, and work to expand them. In this process, business owners frequently need to locate funding, plan their ventures, develop marketing plans, and oversee operational tasks. There are many benefits and difficulties in the dynamic world of entrepreneurship.\n\nWhen implementing their business ideas, entrepreneurs assume some risk. Financial, operational, and competitive hazards abound when beginning and expanding a new firm. In addition, there are unknowns in the realm of entrepreneurship. Entrepreneurs may need to adjust swiftly to changes in elements including market conditions, client preferences, and competitive environment. While starting and expanding their firms, entrepreneurs must also adjust to the fast-paced working environment. Over the past decade, there has been a notable surge in entrepreneurship research, encompassing diverse themes and issues. Artificial intelligence research is having both positive and negative effects on sustainable development (Gupta et al., 2023). There is a glaring absence of systematization in academic literature regarding this correlation, despite the growing consensus regarding the disruptive potential of artificial intelligence (AI) and its favourable influence on entrepreneurship (Giuggioli & Pellegrini, 2022). As Zen et al. (2023) emphasize, entrepreneurship education is crucial both in theory and practice.\n\nIt would be appropriate to explain what entrepreneurship means. Shane & Venkataraman (2000) define the entrepreneurship as the discovery and utilization of commercial opportunities within the individual-opportunity nexus while van Praag & Versloot (2007) emphasize the innovation, economic and societal growth of nations, and the creation of jobs all depend on entrepreneurship. As Naudé (2008) questions entrepreneurship’s role in economic growth, the possible response might be given as entrepreneurs help convert low-income, primary-sector communities into high-income service and technology-based society. Furthermore, it should elucidate the role of entrepreneurs in fostering both innovative growth and addressing stagnant development. The development of the private sector, entrepreneurship, and small and medium-sized businesses (SMEs) are at the centre of any country in transition's political and economic reform. SMEs are crucial to innovation and the high-tech industry, and many of them grew into huge corporations thanks to their adaptability and creativity (Tan & Yıldıran, 2018).\n\nMoreover, it is useful to express how important it is in the entrepreneurship of public institutions. In industrialized nations, the public sector is not solely responsible for job creation. Although recent studies indicate that even the largest and oldest private enterprises are unable to offer new chances to battle the high rate of unemployment, the private sector appears to play a significant role in finding solutions to the problem of unemployment. One such collaboration is known in Turkey as KOSGEB (Small and Medium Enterprises Development Organization). Through its Entrepreneur Support Program, KOSGEB, a state-owned organization, offers tremendous chances to aspiring entrepreneurs who want to launch a new firm (Akpomi, 2018).\n\nIt is widely acknowledged that supporting women's entrepreneurship is essential for ensuring both economic and social progress. However, a lot of societal and financial obstacles prevent women from starting their own businesses. Despite these challenges, there are numerous governmental and non-governmental organizations as well as international organizations that assist and support women. One of these agencies and organizations, KOSGEB encourages female business owners (Durukan, 2021). SMEs, which make up the majority of the Turkish economy and serve as its foundation, appear to be structures that are easily adaptable to change and competition in the modern world. their varying economic structures and sizes. However, both industrialized and emerging nations must recognize the potential they provide for nations, particularly in terms of employment and production. One of the main objectives of governments and state institutions is to improve the competitiveness and adaptability of SMEs, which are crucial for our nation and the rest of the world. SMEs are supported by a variety of aids provided by KOSGEB which was actually created to boost the share of SMEs in serving the requirements of people and businesses (Kandemir et al., 2017).\n\nThe support provided by KOSGEB is crucial to the establishment, development, competition, and innovation processes of entrepreneurs and SMEs. These assistance and educational programs aid companies in overcoming financial challenges, gaining a competitive edge, and achieving sustainable growth. In the study, the Entrepreneurship Handbook, which is very important for business owners and is provided by KOSGEB as open access to all of its stakeholders, was looked at, and the evaluation questions were assessed using an artificial intelligence model. Thus, the effectiveness of ChatGPT-4, an artificial intelligence application that exemplifies entrepreneurship, as an entrepreneur candidate has been established.\n\n\nLiterature review\n\nA field called artificial intelligence is intended to give computer systems human-like intelligence. Artificial intelligence is seen to be capable of carrying out tasks including pattern recognition, problem solving, learning, and decision-making based on data analysis. This technology is employed across a wide range of industries, including automotive, health, finance, and education. According to the formal definition, the term “artificial” refers to something that is made by humans by analogy with natural examples. The term “intelligence” refers to all the cognitive abilities of an individual, including thinking, reasoning, perception of objective facts, judgment, and drawing conclusions (Turkish Language Association, 2023). Artificial intelligence (AI) is a concept that emerged in the 1960s and is considered one of the fundamental concepts of Industry 4.0 philosophy. AI encompasses a range of methods for solving complex problems arising from the intelligent behaviour of computers (Skrop et al., 2018). AI involves the use of computer programs to perform problem-solving tasks that humans traditionally perform. One of the newest areas of science and engineering is artificial intelligence. Currently, AI covers a vast array of subfields, from the broad to the narrow (Russell & Norvig, 2010).\n\nSince the invention of artificial intelligence in 1956, there have been two opposing paradigms: symbolism and connectionism (or sub-symbolism). By the end of the 1980s, symbolism predominated AI research, but connectionism gained traction in the 1990s and is now steadily displacing symbolism (Zhang et al., 2023). As Jiang et al. (2022) mention, over the past 65 years, scientists and engineers have been actively researching artificial intelligence. The straightforward argument is that machines made by humans are capable of becoming intelligent like humans and of performing tasks that require a lot of manual labour. Whether we are aware of it or not, artificial intelligence has a significant impact on how we live our lives, playing unique roles in a variety of public-facing sectors like business, healthcare, transportation, and education.\n\nIndustry 4.0, a paradigm incorporating contemporary technologies and advances, can now be regarded a reality. Artificial intelligence is the key driver of the industrial transformation because it enables intelligent machines to do functions like self-monitoring, interpretation, diagnosis, and analysis on their own (Ahmed et al., 2022). Artificial intelligence is advancing rapidly at the moment and will soon become a man's unavoidable companion. The usage of software and technology nowadays significantly improves human capacities (Aggarwal et al., 2022). In numerous situations, such as identifying street views, extracting roadways, and understanding medical images, artificial intelligence models have outperformed traditional data management. Many well-known theories and techniques emerged from the first generation of AI research in the 1980s, but due to computer constraints, the initial models were too laborious to train. AI has advanced scientific developments and discoveries in medicine, biology, and economics thanks to the recent rapid growth of hardware and software (Sun et al., 2022).\n\nPowerful language models like Chat Generative Pre-Training Transformer, Google's BARD, and Ernie, which have proven to be excellent at many diverse language tasks, have been made possible by recent advances in Natural Language Processing (Rahaman et al., 2023). Baidoo-Anu & Owusu Ansah (2023) identify that ChatGPT made its first appearance in 2022 in the public domain and within a week had more than a million subscribers. The globe was taken aback by the advanced ability of the generative AI tool ChatGPT to complete remarkably complex jobs. Teachers have conflicting sentiments about ChatGPT's amazing capacity to carry out complicated tasks in the realm of education because this development in AI appears to revolutionize current educational praxis. The fourth version in OpenAI's numbered “GPT-n” series of Generative Pre-Trained Transformer foundation models, Generative Pre-Trained Transformer 4 (GPT-4) is a multimodal big language model which has become available on March 14, 2023 and published as the most advanced algorithm from OpenAI, generating safer and more helpful responses (OpenAI, 2023).\n\nThe application of artificial intelligence application ChatGPT is being tried in many different fields and different findings are reached. It would be correct to say that the product has become a subject of interdisciplinary study apart from the effect it creates. For instance, the research in which AI has been treated as a medical doctor, it is emphasized that online medical consultations have grown in popularity recently so, an increasing number of people may inquire about their diseases, symptoms, and differential diagnoses using the lately popularized ChatGPT. During the research process, clinical case vignettes, including some uncommon case presentations, were used to test ChatGPT's diagnostic precision and found that ChatGPT 4 resolves every typical case in just two suggested diagnoses (Mehnen et al., 2023).\n\nBesides that, another research dealing with the engineering field analyses the possibility of ChatGPT’s passing the engineering exams. The authors state that with the introduction of OpenAI ChatGPT-4, the engineering community has recently witnessed the development of chatbot technology. It is investigated if these chatbots can pass the Fundamentals of Engineering Principles and Practice of Engineering exams, despite the fact that they have been claimed to perform well and even pass a variety of standardized tests, including the legal and medical exams. It seems clear that ChatGPT-4 in its current form has a chance of passing the Fundamentals of Engineering (FE) test (Naser et al., 2023).\n\nWhile Nune et al. (2023) discuss whether ChatGPT has the capacity to react to human instructions after collecting data, analysing the information, and using machine learning (ML) techniques, the research of Holterman & van Deemter (2023) in which argues the theory of mind which is the capacity to comprehend human thought and decision-making, clarify that ChatGPT-4 compared to the previous versions was demonstrated to arrive at the right answers more frequently than would be predicted simply on chance.\n\nThe use of language models in interdisciplinary studies can facilitate quick and effective access to information and support finding solutions to problems by bringing together expertise in different fields. Therefore, ChatGPT can be used to answer questions in a variety of disciplines, as the courses are trained based on a large dataset containing specialist knowledge from different fields and It can also be used interdisciplinary in written communication fields such as language models, text production and editing. It might be said that ChatGPT has already become the subject of interdisciplinary study; for example, Huang et al. (2023) try to benchmark ACR Radiation Oncology In-Training Exam, Törnberg (2023) deals with the Text analysis of Political Messages on Twitter, Teebagy et al. (2023) research the evaluation of Ophthalmology exam as well as Zhang & Gosline (2023) try to identify perception of the people by using ChatGPT. As Dowling & Lucey (2023) identified, for the researchers looking to develop new insights and ideas, ChatGPT might be useful tool.\n\n\nMethods\n\nAs mentioned by Fitria (2023), an artificial intelligence model, which can be regarded as a chatbot, is simple to use by logging in with an email address. Any question or statement can be entered into the available dialogue field, and ChatGPT will provide an instantaneous response. The study examined the Entrepreneurship Handbook, which is openly accessible on the official website of the Small and Medium Enterprises Development and Support Administration. This handbook comprises 16 chapters that cover various dimensions of entrepreneurship. The chapters were authored by scholars and sector representatives affiliated with universities in Turkey. At the conclusion of each chapter, under the heading “Let's test ourselves,” readers are presented with 10 questions accompanied by answer keys. The primary research approach employed was content analysis, a qualitative research method. The utilization of artificial intelligence to examine the questions individually served as a novel and distinct method. Consequently, the primary aim of the research was to assess the effectiveness of ChatGPT-4 in addressing entrepreneurship-related questions. The inclusion of all 160 questions within the research scope and their analysis through artificial intelligence application supports the conclusion that the census method is preferred.\n\nThe underlying assumption of the research is whether ChatGPT-4 can successfully answer entrepreneurship exam questions in Turkish without prior knowledge loading. Consequently, the hypotheses formulated within the scope of the research are as follows:\n\nH1: ChatGPT-4 demonstrates success in the entrepreneurship exam.\n\nH2: ChatGPT-4 can employ the self-learning method in the entrepreneurship exam.\n\nH3: Language preference influences the success level of ChatGPT-4.\n\nH4: ChatGPT-4 exhibits equal success in all subtopics of the entrepreneurship exam.\n\nIn the process of data analysis, it was observed that all the questions were originally written in the native language (Turkish), and the analysis was conducted using the Turkish language. Subsequently, the questions and answers were translated into English language at the 2nd stage. Language experts proficient in English linguistics were involved in the translation process. The artificial intelligence application ChatGPT-4 was then utilized to translate the questions. The analysis procedure consisted of three stages. In the first stage, the accuracy of the answers provided by ChatGPT-4 was determined by comparing them to the correct answers. In the second stage, questions that were answered incorrectly were re-evaluated and reviewed. In the third stage, the questions that still received incorrect answers after the first two stages underwent a systematic process. Preliminary information regarding these questions was uploaded to the system, and the questions were re-examined. At the conclusion of the third stage, it was observed that ChatGPT-4 provided correct answers for all questions. The analysis process of the questions followed these steps.\n\nStage 1: Initial Analysis with Dataset\n\nStage 2: Re-analysis of Incorrect Answers\n\nStage 3: Final Analysis of Incorrect Answers with Content Assistance\n\nIn this process, specific commands are provided to the ChatGPT-4 model before each query. The pre-command used before answering the questions is as follows:\n\nStage 1: “Think like an aspiring entrepreneur and a scholar specializing in entrepreneurship. Analyse each question below thoroughly and provide the most appropriate answer along with its rationale.”\n\nInitially, it was observed that ChatGPT-4 provided correct answers to 144 questions without any intervention. The fact that 144 correct answers were obtained in the initial application indicates the highly successful performance of the artificial intelligence model. However, to further evaluate its self-learning capability, a retest was conducted for the questions that were initially answered incorrectly, and the questions were redirected. It was observed that ChatGPT-4 tended to review the incorrect answers initially provided and offer alternative responses. Moving on to the second stage, the 16 questions that were previously answered incorrectly were compiled into a single file and reanalysed using the following pre-command. At this stage, questions were asked by using both Turkish and English languages.\n\nStage 2: “Think like an aspiring entrepreneur and a scholar specializing in entrepreneurship. Reanalyse each question, considering alternative answers, and provide the most appropriate answer along with its rationale.”\n\nAfter identifying the content of the questions that were initially answered incorrectly in the Entrepreneurship Handbook and uploading them as paragraphs into the system, correct answers were obtained for all questions. In the third stage, the pre-command loaded into the system is as follows:\n\nStage 3: “Carefully read the paragraph. Rethink like an aspiring entrepreneur and a scholar specializing in entrepreneurship. Analyse each question below thoroughly and provide the most appropriate answer along with its rationale.”\n\nThus, the primary focus of the research is to determine the level of success of the ChatGPT-4 model in the entrepreneurship assessment and to examine language variations. Additionally, it aims to assess the significance of the self-learning ability in the\n\n\nResults\n\nIn this part of the study, the findings pertaining to the questions answered by ChatGPT-4 are presented. Throughout the research process, the questions from each chapters were initially compiled into separate files. Then, sets of 10 questions from each chapter were posed to the ChatGPT-4 model using the Turkish language. As it incorporates a self-learning method, no prior information was loaded when querying the model with questions related to the chapters. This means that the content of the questions was not uploaded into the system in any way, and direct questions were asked to obtain answers.\n\nThe dataset was analysed in three stages, and it was observed that correct answers were provided for all questions by the end of the third stage. The stages of the answering process are illustrated in the table below.\n\nAs indicated in Table 1, ChatGPT-4 initially demonstrated success in passing the Entrepreneurship exam. In the subsequent stages, the researcher attempted to identify all the correct answers based on the exam requirements. In the final round, it was observed that providing the relevant content of the questions increased the accuracy of responses. However, it would be more meaningful to analyse the questions posed to ChatGPT-4 in the first stage without introducing any “self-learning” conditions. Therefore, this chapter focuses on the interpretation of the data obtained in the initial stage of the research process. A total of 160 questions were asked, out of which 16 questions were answered incorrectly. The chapters of the Entrepreneurship Handbook are as follows:\n\nChapter 1 - Basic Concepts of Entrepreneurship\n\nChapter 2 - Seeing Entrepreneurship Opportunities and Generating/Developing Ideas\n\nChapter 3 - Feasibility Analysis\n\nChapter 4 - Business Models, Customers, Value Propositions and Sources of Revenue\n\nChapter 5 - Economy, Industry, Competition and Customer Analysis\n\nChapter 6 - Legal Background\n\nChapter 7 - Ethical Foundations of the Enterprise\n\nChapter 8 - Marketing Principles and Management\n\nChapter 9 - Networking\n\nChapter 10 - Determination and Management of the Financial Structure of the Enterprise\n\nChapter 11 - Access to Financial Resources for Start-ups\n\nChapter 12 - Innovation Management\n\nChapter 13 - Intellectual Property Rights\n\nChapter 14 - Professional Management of Enterprise and Strategic Management in SMEs\n\nChapter 15 - Management of the Growth Process and Growth Strategies\n\nChapter 16 - Developing a Business Plan\n\nThe correct answers of 144 questions were found by the artificial intelligence application ChatGPT-4 is shown in Figure 1.\n\nAs depicted in Figure 1, the language model exhibited a high level of success in answering the majority of the 160-question dataset across 16 chapters. Notably, in Chapter 8, focusing on Marketing Principles and Management, and Chapter 10, addressing the Determination and Management of the Financial Structure of the Enterprise, ChatGPT-4 accurately answered all questions in the first stage. This data, as shown in Figure 1, highlights the model's particularly strong performance in the areas of marketing and finance, where it achieved a perfect score from the outset. Nevertheless, it is crucial to examine some of the questions that ChatGPT-4 initially answered incorrectly. For instance, in Chapter 1 there were 10 multiple-choice questions. ChatGPT-4 correctly answered 8 out of the 10 questions in the first stage. When reviewing the two questions that were answered incorrectly, it is worth considering that the 8th question could possibly be deemed correct. According to Özdemir et al. (2007) businesses that employ 1-250 people or have a certain turnover or financial balance sheet are referred to as SMEs. Therefore, it is plausible to interpret the 8th question as correct, aligning with the mentioned definition of SMEs.\n\nThe 8th Question (Chapter 1): “How is the size of a business with 45 employees and a turnover of 20 million TL defined in our current laws?”\n\nCorrect Answer by Source: “Small Business”\n\nCorrect Answer by ChatGPT-4: “SME”\n\nUpon examining the 8th question in the 1st chapter, according to the provided source, the correct answer is designated as “Small Business”. However, ChatGPT-4 identifies the correct answer as “SME”. When asked to explain the reasoning behind its answer, the artificial intelligence application indicates that a business with 45 employees and a turnover of 20 million TL falls under the category of a “medium-sized enterprise” based on both employees count and annual net sales criteria. It is worth noting that in Turkey, such businesses are also considered within the scope of SMEs. Considering the answer provided by both the source and the artificial intelligence, it can be inferred that a business with 45 employees and a turnover of 20 million TL can be classified as both a small business and an SME. Therefore, although there is a discrepancy in the correct answers, it can be argued that the artificial intelligence application has answered this question correctly by taking into account the broader definition of an SME.\n\n10th Question (Chapter 1): “Which of the following is not a misconception about entrepreneurship?”\n\nCorrect Answer by Source: “No matter how valuable, the business idea alone has no value”\n\nCorrect Answer by ChatGPT-4: “If the business idea is very complex, success is guaranteed”.\n\nBased on the data presented above, it appears that there is a discrepancy in determining the correct answer to the 10th question. Upon examining the source of the questions, it states that the statement suggesting that a valuable business idea alone will not have any value is not one of the well-known misconceptions about entrepreneurship. On the other hand, the artificial intelligence application, ChatGPT-4, attempted to identify the incorrect statements among the options by providing the following explanation: “There seems to be some confusion with the phrase (not one of the known mistakes), but let's try to identify the incorrect statements in the options'.”\n\nUpon analysing the answers provided by ChatGPT-4, the following ideas can be inferred:\n\n(a) A simple and understandable business idea has a better chance of success.\n\n(b) Failure is a natural part of the entrepreneurial process, and individuals need to learn to cope with failure.\n\n(c) Not every entrepreneur is inclined to take risks, and some prefer less risky business ideas.\n\n(d) A good business idea can hold significant value and serve as the foundation for a successful enterprise.\n\n(e) While money is undoubtedly an important factor in entrepreneurship, it is possible to establish a successful venture without it.\n\nWhen examining the source material, specifically Chapter 1 - Basic Concepts of Entrepreneurship written by Özgül (2022) within the Entrepreneurship Handbook (Erdoğan, 2022) it becomes apparent that there is a significant amount of outdated or incorrect information concerning entrepreneurship. Such material, often spread through word of mouth or the internet, can distort people's perceptions about entrepreneurship. It is crucial for both current business owners and aspiring entrepreneurs to be aware of these common misconceptions. The entrepreneurship myths outlined by Erdoğan (2022) are as follows:\n\nMyth 1: The most important issue in the entrepreneurial process is the business idea.\n\nMyth 2: Success is guaranteed if the business idea is very complex.\n\nMyth 3: If no one has the product, success is guaranteed.\n\nMyth 4: It is unnecessary to prepare a business plan if the business is to be established with equity.\n\nMyth 5: Don't share your business idea with anyone.\n\nMyth 6: The failed entrepreneur cannot be trusted\n\nMyth 7: Entrepreneurs like to take risks\n\nMyth 8: Entrepreneurship is for those with money\n\nHowever, due to the ambiguity within the question itself, it has become difficult to determine the correct answer, resulting in ChatGPT-4 providing a response indicating confusion at the second stage: “There is some confusion with the expression, but let's try to identify the wrong statements in the options.” Therefore, ChatGPT-4 gave an incorrect answer for this question. It is important to acknowledge that the language used in the question itself lacks clarity in terms of its semantic purposes.\n\nIf we consider the questions that were answered incorrectly by the artificial intelligence application in general, it can be observed that the complexity of the business idea does not guarantee success. Likewise, it is incorrect to claim that an unsuccessful entrepreneur cannot be trusted, as failures often contribute to gaining valuable experience. Taking risks is a characteristic commonly associated with entrepreneurship. Additionally, the business idea is indeed a key element in the entrepreneurial process. It is incorrect to state that entrepreneurship is solely for those who have money since financial capital is just one component of the overall picture. Entrepreneurs also require intangible capital elements for success.\n\nIn summary, the inaccuracies in the incorrect answers provided by ChatGPT-4 highlight the importance of considering the nuances and complexities of language in order to arrive at accurate interpretations and responses. Samples of incorrect answers from other chapters of Entrepreneurship Handbook are as follows:\n\n3rd Question (Chapter 2): “Which of the following is never asked during customer discovery?”\n\nCorrect Answer by Source: “We took out shampoo so that your dog does not smell bad, would you buy it?”\n\nCorrect Answer by ChatGPT-4: “What do you do if your dog smells bad?”\n\nIn the 2nd Chapter of the handbook, which focuses on entrepreneurial opportunities and generating ideas. it was found that only the 3rd question was answered incorrectly by the artificial intelligence application. Upon examining the relevant source, it was observed that different answers were provided by the application due to the use of expressions that are generally subjective and not backed by scientific citations within the chapter created by a private sector representative. Moreover, the question itself contains relative and subjective expressions. The question is presented as follows (Ünsal, 2022):\n\n“Imagine you produce a dog shampoo that gives canines a fantastic scent. You took the first prototype in your hands, but you also walked out on the street to get a better understanding of the customer. If you say, ‘Hello, can I ask you a few questions?’ to someone while they are walking their dog. Would you buy a dog shampoo that we created that makes your dog smell so good and stops them from smelling bad? To avoid offending you, they might answer ‘yes’ to this question, but you won't learn anything in this method.”\n\nChatGPT-4 initially failed to provide the correct answer for this question. However, when the question was revisited in the 2nd stage of the research, a different answer was generated. Therefore, although it is acknowledged that the question was initially answered incorrectly, it is believed that it is challenging to direct the response to a single correct answer due to the subjective nature of the question and the absence of a definitive solution in terms of common consensus.\n\n4th Question (Chapter 3) “Customers don't buy a product, but buy the benefit that product provides.” What is the name given to the lack of this view, which forms the basis of value creation and the marketing view?\n\nCorrect Answer by Source: “Marketing Blindness”\n\nCorrect Answer by ChatGPT-4: “Product Blindness”\n\nIn the 3rd chapter of the handbook, which covers feasibility analysis and is written by Aygören (2022), ChatGPT-4 answered only 1 question incorrectly, similar to the previous chapter. However, it was observed that the artificial intelligence application provided comprehensive and insightful answers due to the details included in the responses, even for the question that was initially considered incorrect. At the 2nd stage of the research, ChatGPT-4 offered a reasonable explanation by stating that “product blindness is caused by the company's over-focus on its own products, while marketing blindness is caused by the company's inability to focus enough on the needs of its customers.”\n\nProduct blindness refers to a situation where a company becomes excessively focused on its own products during the product development phase. This can lead to the company having extensive knowledge about its products, including their functionality, features, and manufacturing process. However, customers may not possess this same level of understanding and may have different needs and preferences. As a result, the company may struggle to align its offerings with the actual needs of customers, leading to a disconnect.\n\nOn the other hand, marketing blindness occurs when a business fails to comprehend the needs and behaviours of its customers. Instead of prioritizing and addressing the real needs of customers, the company may overly emphasize the features of its products and overlook the genuine requirements of its target market. In essence, product blindness stems from the company's excessive focus on its own products, while marketing blindness arises from its failure to adequately prioritize and cater to the needs of its customers. Therefore, it can be concluded that ChatGPT-4's response, which highlighted the distinction between product blindness and marketing blindness, provides a reasonable and accurate understanding of these concepts.\n\n6th Question (Chapter 4): “Which of the following is not a benefit of using business models?”\n\nCorrect Answer by Source: “Preparation of a long-term, comprehensive and detailed plan.”\n\nCorrect Answer by ChatGPT-4 “To be able to see what kind of alternatives the business idea can have”\n\n4th Chapter focuses on business models, customers, value propositions and revenue streams (Oran, 2022). When the questions within the scope of the chapter were examined, it was seen that 6th question was answered incorrectly by ChatGPT-4 by giving the reasons like: “One of the benefits of using business models is that alternatives to the business idea can be seen. Other options are among the benefits of using business models. Option (a) provides a clearer understanding of business ideas by putting them on paper. Option (b) ensures that important points are detailed without skipping. While option (c) helps devise a long-term plan (d) helps identify the assumptions necessary for the business idea to be successful.”\n\nWhen considering the assessment questions in other chapters of the Entrepreneurship Handbook in general, the analysis was similarly completed with a maximum of two incorrect answer processes per chapter. In general, there were 16 incorrect answers in the first stage, while a decrease was observed in the number of incorrect answers in the second stage. The reason for this situation is thought to be the translation of the questions from Turkish to English, which may have eliminated the ambiguity. In the third stage, it was observed that the correct answers to the questions could be obtained by examining the chapters related to the incorrectly answered questions and transferring the sections with the answers to ChatGPT-4. When considering the research hypotheses, it was found that this chatbot application was successful in the entrepreneurship exam, as it succeeded in most of the questions that make up the dataset. Therefore, the hypothesis “H1: ChatGPT-4 demonstrates success in the entrepreneurship exam” was accepted.\n\nAs mentioned before, to determine whether ChatGPT-4 has a self-learning method, the dataset was examined in three stages. The processes of directing the questions, posing the questions by repetition and language change, and ultimately re-directing the questions with the help of the contents were followed. The increase in the number of correct answers obtained indicates the self-learning ability of the system. Therefore, the hypothesis “H2: ChatGPT-4 can employ the self-learning method in the entrepreneurship exam” was accepted.\n\nAnother assumption of the research is whether language preferences will affect the success of the artificial intelligence application in exam questions. The increase in the number of correct answers obtained by asking the 16 questions again in English that were answered incorrectly before can be considered as an indicator. However, it should be noted that much more data is needed to determine whether the questions translated from Turkish to English can be understood more clearly by ChatGPT-4 in terms of semantic and syntactic features. Therefore, it is worth mentioning that the clarification in the meaning units of the questions may be predicted by using different language structures together with the existing dataset. Hence, hypothesis 3 was neither fully accepted nor rejected based on the current dataset. The hypothesis that ChatGPT-4 shows equal success within the scope of entrepreneurship exam areas has been rejected. This is because there are sections in the first stage of the dataset analysis where all questions are answered correctly by ChatGPT-4. Therefore, all of the questions in Chapter 8 - Marketing Principles and Management and Chapter 10 - Determination and Management of the Financial Structure of the Enterprise have been answered correctly. With this finding, although it is possible to say that ChatGPT-4 is more successful in solving questions on marketing and finance, it is thought that whether each question is semantically understandable, regardless of the subject of the questions, is a phenomenon that should be examined by linguists.\n\n\nDiscussion\n\nIn conclusion, artificial intelligence technologies hold both promise and anxiety for the future. ChatGPT, exemplifying innovative problem-solving abilities in the light of entrepreneurial traits, itself is an example of entrepreneurship and has the ability to influence many stakeholders. At the same time, when this artificial intelligence application is evaluated as an entrepreneur candidate, it has been seen that ChatGPT-4 can effectively address a significant portion of entrepreneurship exam questions. In other words, ChatGPT-4, with its self-learning capabilities, represents a transformative tool in the field of AI and has the potential to be both an entrepreneurial example and an entrepreneurial candidate by gaining more and more talent every day.\n\nThis research focused on examining the ChatGPT-4 version, a well-known AI application with self-learning capabilities, within the context of business establishment processes. By combining the Entrepreneurship Handbook questions with the ChatGPT-4 model, the study analysed the model's problem-solving abilities and the originality of its answers compared to the entrepreneurship literature. The research found that ChatGPT-4, as an exemplary entrepreneurship AI model, successfully answered the questions posed in the Entrepreneurship Handbook, demonstrating deep analysis and creativity in developing alternative solutions. This study pioneers the exploration of the relationship between artificial intelligence and entrepreneurship. The research examined the Entrepreneurship Handbook, which consists of 16 chapters covering different aspects of entrepreneurship. Using content analysis, this study evaluated the effectiveness of ChatGPT-4 in addressing entrepreneurship-related questions.\n\nAll 160 questions in the handbook were analysed, and ChatGPT-4 demonstrated its ability to provide accurate answers. The data analysis process involved three stages: initial analysis with the dataset, re-analysis of incorrect answers with language exchange, and final analysis of incorrect answers with content assistance. In the first stage, it was able to answer 91.25% of all questions correctly. Upon completion of the second stage, this rate increased to 93.75%. At this point, the most notable issues were ChatGPT-4's comments on the use of language in some questions. For example, ChatGPT-4 stated that there were expressions that could create ambiguity in his answer to a question written in the mother tongue. This showed that the artificial intelligence application has superior language capacity in different languages. Its language usage skills and capacity to correctly understand and solve questions were found to be very important and meaningful. Adapting artificial intelligence applications to everyday devices and equipment holds the potential to enhance various aspects of daily life, such as improving efficiency, convenience, and accessibility. It is essential to recognize the potential ethical implications associated with the deployment of artificial intelligence applications, as evidenced by findings from the data set analysis. Instances such as privacy concerns, bias in decision-making, and misuse of personal data highlight the need for ethical oversight and regulation in AI development and implementation. Overall, this research highlights the potential of AI in addressing entrepreneurship-related questions and generating original solutions. The findings contribute to the understanding of the intersection between artificial intelligence and entrepreneurship, particularly within the context of the literature.\n\nIn related literature there are many interdisciplinary studies dealing with the capabilities of ChatGPT. For example, one of the researches claims that professional licensing exam, also known as “the Bar Exam,” is almost universally required in the US as a prerequisite for the practice of law and the famously difficult common core of US professional legal accreditation examinations was determined to be passable by this artificially intelligent tool (Bommarito II & Katz, 2022). One another study dealing with how definitions of crowdsourcing, alternative finance, and community finance differ from or agree with responses provided by actual people in academic literature (Wenzlaff & Spaeth, 2022) while a medical paper discusses the contributions of ChatGPT’s coding assistance (Shen et al., 2023). Based on the findings and methodology outlined in the research, several predictions can be made for future studies on artificial intelligence and entrepreneurship. Future studies could examine and compare different AI models, such as GPT-5 or other advanced models, to assess their effectiveness in addressing entrepreneurship-related questions, comparisons between different models could provide insights into their performance, strengths, and limitations. Future studies could investigate the impact of different languages on AI model performance. Also, examining how language variations affect the accuracy and effectiveness of AI models in entrepreneurship-related tasks can help researchers gain a better understanding of linguistic influences. The research mentioned the self-learning capabilities of ChatGPT-4. Future studies could conduct long-term assessments to understand how AI models continuously improve their performance over time through self-learning. Tracking the model's learning progress and evaluating its ability to adapt and provide more accurate answers can offer valuable insights into the potential of AI for entrepreneurship-related tasks. Besides that, given the success of ChatGPT-4 in addressing questions from the Entrepreneurship Handbook, scholars can explore the integration of AI models in entrepreneurship education. Designing AI-powered tools or platforms that provide real-time feedback, suggestions, and explanations to aspiring entrepreneurs can enhance their learning experiences and problem-solving abilities.\n\nFuture studies should prioritize investigating the ethical considerations and potential biases associated with AI models in entrepreneurship. Assessing the fairness and inclusivity of AI systems is essential to mitigate any unintended biases and ensure that AI tools contribute to a diverse and equitable entrepreneurial ecosystem. Interdisciplinary collaboration is strongly recommended for scholars interested in studying artificial intelligence and entrepreneurship. Artificial intelligence and entrepreneurship are multifaceted fields, and collaborating with experts from various disciplines, including computer science, business, and psychology, can offer a more comprehensive understanding of their intersection. Foster interdisciplinary collaboration to leverage diverse perspectives and expertise. By adhering to these recommendations and focusing on the evolving landscape of AI and entrepreneurship, scholars can significantly contribute to the advancement of knowledge and understanding in this dynamic and rapidly evolving field.\n\n\nEthical considerations\n\nEthical approval and written consent were not required.",
"appendix": "Data availability statement\n\nFigshare: Entrepreneurship Questions.docx, https://doi.org/10.6084/m9.figshare.25303393.v1 (Saygın, 2024).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nfigshare: Artificial Intelligence model Chatgpt-4: entrepreneur candidate and entrepreneurship example, Prisma Checklist, https://doi.org/10.6084/m9.figshare.25550961\n\n\nReferences\n\nAggarwal K, Mijwil MM, Al-Mistarehi A-H, et al.: Has the future started? The current growth of artificial intelligence, machine learning, and deep learning. Iraqi Journal for Computer Science and Mathematics. 2022; 3(1): 115–123.\n\nAhmed I, Jeon G, Piccialli F: From artificial intelligence to explainable artificial intelligence in industry 4.0: A survey on what, how, and where. IEEE Trans. Industr. Inform. 2022; 18(8): 5031–5042. 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Publisher Full Text\n\nNaser MZ, Ross B, Ogle J, et al.: Can AI Chatbots Pass the Fundamentals of Engineering (FE) and Principles and Practice of Engineering (PE) Structural Exams? (arXiv:2303.18149). arXiv. 10.48550/arXiv.2023; 2303.18149.\n\nNaudé W: Entrepreneurship in economic development. WIDER Research Paper No. 2008/20.2008.\n\nNune A, Iyengar KP, Manzo C, et al.: Chat generative pre-trained transformer (ChatGPT): Potential implications for rheumatology practice. Rheumatol. Int. 2023; 43(7): 1379–1380. PubMed Abstract | Publisher Full Text\n\nOpenAI: ChatGPT-4.2023. Reference Source\n\nOran A: İş Modelleri, Müşteriler, Değer Önerileri ve Gelir Kaynakları. KOSGEB Girişimcilik El Kitabı. KOSGEB; 2022. Reference Source\n\nÖzdemir S, Ersöz H, Sarıoğlu H: Küçük girişimciliğin artan önemi ve KOBİ’lerin Türkiye ekonomisindeki yeri. J. Soc. Policy Conf. 2007; 53: 173–230.\n\nÖzgül E: Girişimcilikte Temel Kavramlar. KOSGEB Girişimcilik El Kitabı. KOSGEB; 2022. 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Econ. 2007; 29(4): 351–382. Publisher Full Text\n\nWenzlaff K, Spaeth S: Smarter than Humans? Validating how OpenAI’s ChatGPT Model Explains Crowdfunding, Alternative Finance and Community Finance (SSRN Scholarly Paper No. 4302443).2022. Publisher Full Text\n\nZen A, Kusumastuti R, Metris D, et al.: Implications of Entrepreneurship Education as a Field of Study for Advancing Research and Practice. J. Educ. 2023; 5(4): Article 4. Publisher Full Text\n\nZhang B, Zhu J, Su H: Toward the third generation artificial intelligence. SCIENCE CHINA Inf. Sci. 2023; 66(2): 1–19. Publisher Full Text\n\nZhang Y, Gosline R: People’s Perceptions (and Bias) Toward Creative Content Generated by Ai (ChatGPT-4), Human Experts, and Human-AI Collaboration (SSRN Scholarly Paper No. 4453958).2023. Publisher Full Text"
}
|
[
{
"id": "275011",
"date": "15 May 2024",
"name": "Ivan Diryana Sudirman",
"expertise": [
"Reviewer Expertise Management Information system",
"data science",
"marketing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe application of ChatGPT in the setting of entrepreneurial processes is investigated in this paper. ChatGPT is integrated into the study to address questions across 16 modules using the Entrepreneurship Handbook published by Turkey's SME Development Organization. This approach enables a comparison of solutions produced by AI with well-established entrepreneurship literature. The results show how well ChatGPT does in offering fresh, in-depth examinations of the questions in the handbook and how imaginatively it proposes fresh solutions to the given ones. Because it pioneers the nexus of artificial intelligence and entrepreneurship research, the study is important.\nSome references use the year 2018 and below, such as Russell & Norvig, 2010.\nThis research is technically sound.\nMethod is clear and simple, allowing for replication easily.\nNo need for statistical analysis because it's just like giving an exam on ChatGPT and then seeing the test results.\nWhile the conclusion of the research is well articulated, it is embedded within the discussion section rather than being presented in a distinct conclusion section. Typically, conclusions should be presented in a dedicated section to clearly summarize the findings and implications.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11588",
"date": "29 Jun 2024",
"name": "Muhammet Saygın",
"role": "Author Response",
"response": "I would like to appreciate the Reviewer for the comments and constructive suggestions aimed at making the study more comprehensive. A revised version of the article has been submitted to the journal. This article provides a comprehensive analysis of the capabilities and implications of artificial intelligence (AI), particularly focusing on the ChatGPT-4 model within the context of entrepreneurship. In response to the reviewer's feedback, several revisions have been made to enhance the clarity, comprehensiveness, and coherence of the discussion section. Primarily, adjustments have been made to the subtitle, renaming the section as \"Conclusion and Discussion\". This change aims to clearly delineate the conclusion from the broader discussion, ensuring a more structured presentation of the research findings and implications. With this revised structure, the conclusion and discussion section now succinctly summarizes the research findings and their implications, thereby addressing the reviewer's suggestion for a dedicated conclusion section. These enhancements aim to improve the overall readability and coherence of the article. This version maintains clarity while directly addressing the reviewer's comments and outlining the specific changes made to the manuscript."
}
]
}
] | 1
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https://f1000research.com/articles/13-308
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https://f1000research.com/articles/12-1311/v1
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11 Oct 23
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{
"type": "Research Article",
"title": "Comparison between premortem histopathology findings in rats with and without traumatic brain injury: prospective application in forensic medicine",
"authors": [
"Taufik Suryadi",
"Kulsum Kulsum",
"Kulsum Kulsum"
],
"abstract": "Background: The aim of this study was to compare pre-mortem histopathology findings in rats with and without traumatic brain injury (TBI) and its prospective application in forensic medicine. Methods: This study involved 12 rats with 6 rats for each treatment group. This type of study is a laboratory experimental study with a case control design. The control group were rats that did not experience TBI. The case group was a group of rats with TBI. The subjects of this study were Rattus norvegicus rats, adult males, 4-8 weeks old, weighing 150-200 grams. On the 8th day after the rats experienced traumatic brain injury, the rats were then euthanized using the cervical dislocation method, after euthanasia the rats were given craniotomy and brain tissue was taken for histopathology examination. Results: The description of histopathology changes in the brain organs in the group of rat without TBI found that neuron cells looked normal although there were also degeneration (21.16 ± 2.56/FV), necrosis (5.75 ± 0.98/FV), apoptosis (2.91 ± 0.80/FV), congestion ( 0.91 ± 0.49/FV), inflammatory cells (4.58 ± 1.15/FV) and hemorrhage (2.41 ± 1.11/FV). Changes in the rat traumatic brain injury group showed a lot of damage to neuron cells in the form of degeneration (48.41 ± 3.27/FV), necrosis (36.66 ± 2.89/FV), apoptosis (18.91 ± 1.24/FV), congestion (2.50 ±0.31/FV), inflammatory cells (11.41 ± 1.71/FV) and hemorrhage (10.08 ± 2.17/FV). Based on the results of statistical analysis, it can be seen that in all parameters there is a significant difference (p ≤ 0.001). Conclusions: The premortem histopathology findings in rats with and without TBI which can be used for the benefit of forensic medicine in determining whether TBI is present or not. It is necessary to look more closely at the histopathology changes in the form of necrosis, apoptosis and hemorrhage.",
"keywords": [
"forensic medicine",
"histopathology findings",
"premortem",
"TBI"
],
"content": "Introduction\n\nDetermining the presence of trauma in forensic medicine is very important in assisting the criminal investigation process.1 Trauma cannot always be determined through external examination, so an internal examination (autopsy) is needed.2 Macroscopic examination of organs or body tissues that have been traumatized sometimes does not show satisfactory results. It is necessary to carry out a microscopic examination so that evidence of trauma is more accurate.3 Forensic pathologists are always challenged to prove whether a person died as a result of trauma or not, and the opinion of the forensic pathologists is very important for medico legal purposes.1,4 In determining the cause of death, including traumatic brain injury (TBI) is usually carried out by internal examination (autopsy), but this is still incomplete because it only leads to the level of epidemiological causes of death not yet leading to causality.3 Histopathology changes in injuries such as TBI are still being discussed. In general, if TBI occurs when a victim has not died (premortem), then the histopathology changes will be obvious, but if there is postmortem, then there is no inflammatory response.4\n\nAlthough research on the human body has often been carried out in forensic medicine, the accuracy of whether or not trauma is present still needs to be improved. Given the similarities in anatomy and physiology with humans, experimental animals can be considered in translation research from biomedical to clinical. The frequency of using experimental animals in forensic medical research published in scientific journals is around 4%.5 In order to investigate a premortem histopathology changes in TBI, rats were euthanized. The definition of a premortem is a condition that occurs shortly after death, but the time limit is still controversial.6\n\nTBI induces a complex cascade of immunologic or tissue inflammatory responses that mimic ischemic reperfusion injury7 Primary head injury and secondary head injury activate the release of cellular mediators in the form of prostaglandins, pro inflammatory cytokines, and free radicals. In secondary injuries, there are disturbances in the processes of metabolism and homeostasis of brain cell ions, intracranial hemodynamics, and cerebro-spinal fluid (CSF) compartments which begin after the trauma but are not clinically apparent immediately after the trauma.7,8\n\nDeaths due to TBI are some of the most common cases encountered by forensic pathologists. TBI is routinely implicated in cases classified as accidents, as well as in suicides and homicides. Recently, cases of traumatic brain injury have increased in both developed and developing countries. Therefore, it is very useful for evaluating the clinical and pathological features of head injuries. To carry out an investigation of the causes of death in traumatic brain injury cases, a comprehensive examination is needed, one of which is histopathology findings. Histopathology changes in deaths from traumatic brain injury are very important to determine the qualification of whether there was a TBI before death. Therefore, it is necessary to carry out research related to the comparison of premortem histopathology findings using experimental rats with and without traumatic brain injury.\n\n\nMethods\n\nResearchers conducted laboratory experiments on animals with a case-control comparative study design by comparing the case group with the control group. The control group were rats that did not have traumatic brain injury administered to them. The case group is a group of rats that have been administered of traumatic brain injury.\n\nThe subjects of this study were 12 healthy Rattus norvegicus rats (6 each group), male, adult, 4-8 weeks old, weighing 150-200 grams, no visible anatomical abnormalities, no signs of previous infection, no other diseases. Exclusion criteria: deformed male white rat (Rattus novergicus) Wistar strain, rats during the study did not want to eat. Prior to treatment, the fur was given a number to be used in a simple randomization process, then adaptation was carried out for 10 days, homogenization was carried out in the cage, the temperature in the cage was adjusted to room temperature, and every day the rats were fed BR 1 feed. BR 1 is a standard feed for animal model that contains a number of nutrients, such as crude protein, fat and crude fiber.\n\nThe rat model of traumatic brain injury was made using the Feeney weight drop mode method (Figure 1) by shaving the scalp of the male rat Rattus norvegicus and then topical anesthesia was given before incision. The incision was done on the right frontoparietal measuring 4 mm to get bone exposure. The center of the skin opening was 1.5 mm posterior to the bregma and 2.5 mm lateral to the midline, then the rat was dropped from a height of 1 meter with a 2.5 mm diameter load. The administration of TBI in the study is a routine procedure for animal cases within the animal laboratory of Veterinary Faculty of Syiah Kuala University that implemented the principles of replacement, reduction, and refinement (3R) and also the principles of five freedom from Farm animal welfare council UK, 1993 which consist of (1) freedom from hunger and thirst, (2) freedom from discomfort, (3) freedom from pain, injury and disease, (4) freedom from fear and distress, and (5) freedom to express natural behavior. The procedures are in accordance with the 2017 Health Research Ethics Committee Guideline by the Ministry of Health of Republic of Indonesia and the 2016 Council for International Organization of Medical Sciences (CIOMS) ethical guidelines.\n\nOn the 8th day after the rats experienced traumatic brain injury or not, the rats were then euthanized using the cervical dislocation method, after euthanasia the rats were given craniotomy and the brain tissue was taken. The brains taken were weighed and recorded. The entire procedure is performed by the same operator using micro surgical instruments.\n\nAfter weighing, the part of the brain case group and control group are included in a 10% neutral buffered formalin (NBF) fixation solution with a ratio of 1:9 for making premortem histopathology preparations. The fixation solution used was 10% formalin (a mixture of 10 cc of 40% formaldehyde with 90 cc of distilled water). The brain organ was immersed in a 10% neutral buffer formalin solution, which serves to provide a hard consistency so that the tissue can be sliced thinly and to provide staining and optical differentiation. The tissue was fixed for 24 hours. Continued with cutting (trimming) organ sample into smaller size. Dehydration using graded ethanol starting from 70%, 90%, and 96%. Purification with xylol solvent. The cleaning process was done by immersing the tissue in a solution of xylene I and II for two hours. Paraffin infiltration is soaking the tissue in melted paraffin at a temperature of 58-60°C for 30 minutes to 6 hours, to remove the clearing agent from the tissue so as to make the tissue resistant to cutting. Blocking is the process of freezing a preparation so that it can be cut with a microtome. Sectioning is cutting the block of preparations using a microtome. The paraffin block was then cut using a rotary microtome with a thickness of 5 μm. Finally hematoxylin eosin (HE) staining and observed under a microscope with 400× magnification. Step by step description of histopathology preparation can be found on Protocols.io).\n\nThe research results were analyzed using the Shapiro-Wilk normality test. Statistical analysis was carried out using ANOVA (analysis of variance) if the data were normally distributed. If the data is not normally distributed, then the Kruskal wallis hypothesis test is carried out. If there is a difference, then the analysis is continued with a post hoc test to find out the different data pairs. This research is significant if the p value < 0.05. All the statistical analyses were carried out using SPSS (IBM, New York, US). A proprietary free alternative that can be suggested is PSPP.\n\nThis study was approved by the Health research ethics committee at the Faculty of Medicine, Universitas Syiah Kuala No. 038/EA/FK/2023.\n\n\nResults\n\nThis study involved 12 rats for each treatment group with and without traumatic brain injury. Table 1 shows the development of rat body weight before acclimatization, after acclimatization and rat brain weight after treatment. Macroscopically, there were differences between the two treatment groups as can be seen in Figure 3. The histopathology findings in both groups of rats can be seen in Figure 4. Quantitatively, the processes of degeneration, necrosis, apoptosis, congestion, inflammatory cells and hemorrhage in the two groups can be seen in Table 2. The average quantitative processes of degeneration, necrosis, apoptosis, congestion, inflammatory cells and hemorrhage in all groups can be seen in Table 3.\n\nA. Group 1 (non TBI): It was seen that there were no changes in the rat brain and there were no lesions in the brain; B. Group 2 (TBI): There is a lesion in the right side of the brain due to head trauma (blue arrow).\n\n(A) represents the group without treatment. (B) represents the treatment group with traumatic brain injury. Black arrow = congestion, white arrow = degeneration, headed arrow = necrosis, concave arrow = apoptosis, yellow arrow = hemorrhage and green arrow = inflammatory cells. Hematoxylin Eosin Staining with 400× Magnification.\n\n* Shapiro-Wilk.\n\n** Anova.\n\n*** Kruskal Wallis Test.\n\nMicroscopically, there were differences between the two treatment groups as can be seen in Figure 3.\n\nHistopathology findings in both groups of rats can be seen in Figure 4.\n\nThe histopathology changes in the brain organ in the non TBI group showed normal neuron cells (Figure 4A). Changes in the TBI group showed a lot of damage to neuron cells that were necrotic and some experienced apoptosis, in addition to blood congestion (congestion), hemorrhage and visible degeneration of the brain (Figure 4B). Quantitatively the process of degeneration, necrosis, apoptosis, congestion, inflammatory cells and hemorrhage in the five groups can be seen in Table 2.\n\nThe results of the statistical tests on histopathology changes in the form of degeneration, necrosis, congestion apoptosis, inflammatory cells and hemorrhage in all groups can be seen in Table 3.\n\nThe description of histopathology changes in the brain organs in the group of rat without TBI found that neuron cells looked normal although there were also degeneration (21.16 ± 2.56/FV), necrosis (5.75 ± 0.98/FV), apoptosis (2.91 ± 0.80/FV), congestion (0.91 ± 0.49/FV), inflammatory cells (4.58 ± 1.15/FV) and hemorrhage (2.41 ± 1.11/FV). Changes in the rat traumatic brain injury group showed a lot of damage to neuron cells in the form of degeneration (48.41 ± 3.27/FV), necrosis (36.66 ± 2.89/FV), apoptosis (18.91 ± 1.24/FV), congestion (2.50 ± 0.31/FV), inflammatory cells (11.41 ± 1.71/FV) and hemorrhage (10.08 ± 2.17/FV). Based on the results of statistical analysis, it can be seen that in all parameters there is a significant difference (p ≤ 0.001).\n\n\nDiscussion\n\nTraumatic brain injury is a condition of injury to the head caused by external mechanical forces which results in abnormalities in brain tissue. According to the path-mechanism of head injury, it is divided into primary injuries which are head injuries as a direct result of a trauma, which can be in the form of a direct impact or an acceleration-deceleration process of head movement or it can also be caused by a coup and counter-coup event. Secondary injuries are injuries that occur as a result of various pathological processes that arise as an advanced stage of primary brain damage in the form of bleeding, brain edema, ongoing neuronal damage, ischemia. and neuron-chemical changes. Abnormalities in brain tissue in humans can result in changes in physiological function of the brain and can lead to pathological and histopathology conditions of the brain.9–11\n\nClinically, these changes in brain function can cause clinical symptoms in the form of periods of loss or decreased level of consciousness, signs of memory loss immediately before or after the incident, neurological deficits in the form of muscle weakness, balance disturbances, changes in vision, paralysis, sensory loss, aphasia, and so on, and there is a change in mental status at the time of injury such as confusion, disorientation, slow thinking, and so on. This disorder can be permanent or temporary.9–11\n\nIn this study of the treatment of head injuries using the Feeney model, rats were dropped from a height of one meter with the right side as the fulcrum so that the right side of the brain experienced TBI. The desired sample is 12 rats. In this study, macroscopic rat brains showed the location of the lesion on the right brain. In TBI rats, bruises and abrasions appear on the surface of the brain, swelling (cerebral edema) on the surface of the brain, extensive subdural and subarachnoid hemorrhages, visible dilation of blood vessels, and visible bleeding from the cerebrum, cerebellum to the brainstem.12\n\nIn rats that experienced TBI, bruises and abrasions appeared. Bruises indicate the location of a focal injury where the place is in contact with the surface of the blunt object that injured it. Blisters occur due to the displacement of the brain parenchyma and can also be combined with bruises on the surface of the brain.13 In the TBI group rats appeared to have brain edema after 8 days of head injury treatment. Brain edema is an important risk factor for determining the prognosis of TBI, brain edema indicates an inflammatory reaction.12 Bleeding and hematoma formation occur as a result of torn brain blood vessels during head injury. Bleeding into the subarachnoid space is common in cases of cerebral vascular trauma after head injury. Intraventricular and intracerebral bleeding are also common after trauma.12,13\n\nMicroscopically, traumatic brain injury shows a lesion in the form of significant degeneration of neurons in the neocortical area with increased vacuolization.14 The degenerating neuronal cells are characterized by bright eosinophilic cytoplasm with condensed nuclei, in addition, there is vacuolization inside the cells showing swelling/degeneration. Neuronal cells that experience death are characterized by shrinking cell nuclei and nuclei experiencing pyknotic or karyorrhexis.15 Traumatic brain injury lesions in other cases also show extensive edema, neuronal necrosis, karyolysis and vacuolar changes, and widened inter-cell gaps.16 In severe TBI, brain intraparenchymal hemorrhage may be found. Inflammation that occurs as a result of injury is a response from damaged tissue, triggering the release and activation of cytokines and chemokines as well as activation and proliferation of microglia. Elevated cytokines and other inflammatory mediators such as IL-1α, IL-6, and TNF-α were also confirmed in other studies of traumatic brain injury, in which the traumatic stress response was one of the causes. Metabolic disorders, including hypoxia and oxidative stress can lead to neuronal apoptosis, disruption of the blood brain barrier and brain edema following traumatic brain injury.17,18\n\nCell degeneration is a type of cell damage that occurs in the mitochondria and cytoplasm due to a minor injury that can be repaired if the cause is removed. This cell degeneration is a decline in cell function that interferes with cell metabolism which is reversible.18 In this study all treatment groups showed different numbers of degenerated cells, statistically the ANOVA test found significant differences (p < 0.001).\n\nCell necrosis is a permanent cell in the form of dead tissue. If the degeneration is reversible, then necrosis is irreversible, which means the dead cells cannot be repaired. With histopathology examination, the presence of dead cells can be determined so that if a healing process is needed immediately can be handled by removing the dead cells. In TBI there is an obstacle to the supply of blood and oxygen to the cells so that the cells die. This condition is caused by various things, such as injury, infection, extreme environment, to certain medical conditions that cause damage to the cells so that the cells die and can no longer function normally.18,19 The statistical test results using the Kruskal Wallis test obtained a significant value (p < 0.001) as in Table 3. This p value indicates that there were differences from all TBI treatment groups in causing necrosis, statistically significant differences were found because the p value < 0.05.\n\nApoptosis is a component of the series of events following cerebral trauma and one of the main pathways leading to cell death. If necrosis occurs for some reason, apoptosis generally lasts a lifetime.20 In this study all TBI treatment groups showed different numbers of cells undergoing apoptosis, statistically the ANOVA test found a significant difference (p = 0.001).\n\nCongestion in general means there is blood damming in the tissue with a marked abundance of blood in the blood vessels in a particular region. Congestion is often also called hyperemia, when viewed microscopically the capillaries in the hyperemic tissue appear dilated and filled with blood. Cell congestion means there is congestion at the cellular level.19 Investigating micro vascular congestion, blood vessels are carefully examined to see if they are small, medium or large containing red blood cells.21 In this study on TBI rat, there were several variations in the level of cell congestion with significant differences for all groups. Statistical test results using the Kruskal Wallis test obtained a significant value (p = 0.001) as in Table 3. This p value indicates that there were differences from all TBI treatment groups in causing congestion, statistically significant differences were found because the p value < 0.05.\n\nInflammation is a natural response of the immune system when an injury or disease occurs. When rats experience TBI, they secrete inflammatory cells as a defense mechanism of the body that plays a role in the healing process of wounds which on histopathology examination are often called inflammatory cells. When mice get an infection due to TBI, there are many cells of the immune system that are involved, which then release various substances known as inflammatory mediators.22 The statistical test results using the Kruskal Wallis test obtained a significant value (p = 0.001) as in Table 3. This p value indicates that there were differences from all TBI treatment groups in causing inflammatory cells to occur, statistically significant differences were found because the p value < 0.05.\n\nHemorrhage is the body’s response when injured by bleeding as a result of leaking blood vessels.23 In this study all treatment groups showed different numbers of hemorrhagic cells, statistically the ANOVA test found significant differences (p < 0.001). In this study, quantitative differences were seen in degeneration, necrosis, apoptosis, congestion, inflammatory cells and hemorrhage in rat brain cells in each treatment. This shows a different inflammatory response from each treatment. The greater the number of degeneration, necrosis, congestion apoptosis, inflammatory cells and hemorrhage in rat brain cells, the greater the severity of inflammation caused by traumatic brain injury in rats.\n\nDetermining whether or not TBI is very important in the practice of forensic medicine. The results of histopathology analysis can be an alternative to determining causality in a short period of time at low cost. However, in the not TBI group, there were also histopathology changes indicating a different mechanism in the not TBI group. This study showed an increase in the level of cell damage in the TBI group compared to the not TBI group. Sequentially the comparison of the TBI group with the not TBI group is degeneration (2.28;1), necrosis (6.38:1), apoptosis (6.28:1), congestion (2.72:1), inflammatory cells (2.49:1) and hemorrhage (4.17:1).\n\nThe limitation of the study is that it has limited literature on premortem histopathology so that the discussion in this study is less than optimal. So further research is needed to increase the amount of literature.\n\n\nConclusions\n\nWe conclude that the damage to neuronal cells is more severe in premortem rats with traumatic brain injury, especially necrosis, apoptosis and hemorrhage. There is a significant difference between premortem histopathology findings in rats with and without traumatic brain injury which can be used for the benefit of forensic medicine in determining whether TBI is present or not. It can be said that to determine the presence of TBI, it is necessary to look more closely at the histopathology changes in the form of necrosis, apoptosis and hemorrhage.",
"appendix": "Data availability\n\nZenodo. Master Data for Histopathology, https://doi.org/10.5281/zenodo.8260204. 24\n\nThis project contains the following underlying data:\n\n• MASTER DATA.docx. (Master Data for Histopathology)\n\nZenodo: ARRIVE checklist for ‘Comparison between premortem histopathology findings in rats with and without traumatic brain injury: prospective application in forensic medicine’, https://doi.org/10.5281/zenodo.8351638. 25\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nWe thank Sukmawan Fajar Santosa, a staff of the Research Laboratory, Faculty of Veterinary Medicine, for their assistance and technical help in histopathology identification. We also thank Rachmad Suhanda, Head Department of Public Health, Faculty of Medicine, for their assistance in statistical analysis.\n\n\nReferences\n\nKhalkho SK, Pathak MK: Death due to traumatic asphyxia in Varanasi, India. Int. J. Med. Toxicol. For. Med. 2019; 9(2): 51–56.\n\nPramanik P: Elder homicide by unique combination of different mechanisms of asphyxia. Int. J. Appl. Basic Med. Res. 2015; 5(1): 61–64. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOzevren H, Deveci E, Tuncer MC: Histopathological changes in the choroid plexus after traumatic brain injury in the rats: a histologic and immunohistochemical study. Folia Morphol. (Warsz). 2018; 77(4): 642–648. PubMed Abstract | Publisher Full Text\n\nAl Salh MA, Al Jameel WH: Histopatological changes as tools to discriminate antemortem and postmortem wounds in rats: Prospective applications in forensic medicine. Iraqi. J. Vet. Sci. 2023; 37(1): 197–204.\n\nDerakhshanfar A, Kian M, Dehghan Z, et al.: Comparison of two methods of euthanasia on postmortem change in rats: histopathological and molecular findings. Comp. Clin. Pathol. 2022; 31: 815–826. Publisher Full Text\n\nAnindita SR, Machroes BH, Haryanto JL: Intravital, perimortem and postmortem histopathological features of incised wounds on the skin and back muscles of Wistar novergicus rats. Proceedings of the Annual Scientific Meeting. Indonesian Association of Forensic Doctors. 2017; pp. 269–275.\n\nFirdaus R, Theresia S, Austin R, et al.: Propofol effects in rodent models of traumatic brain injury: A systematic review. Asian Biomed. 2021; 15(6): 253–265. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLin PH, Kuo LT, Luh H: The roles of neurotrophins in traumatic brain injury. Life. 2022; 12: 1–22.\n\nMa X, Aravind A, Pfister BJ, et al.: Animal models of traumatic brain injury and assessment of injury severity. Mol. Neurobiol. 2019; 56: 5332–5345. PubMed Abstract | Publisher Full Text\n\nDas M, Mohapatra S, Mohapatra SS: New perspectives on central and peripheral immune responses to acute traumatic brain injury. J.Neuroinflammation. 2012; 9(236): 1–12.\n\nDewan MC, Rattani A, Gupta S, et al.: Estimating the global incidence of traumatic brain injury. J.Neurosurg. 2018; 1(1): 1–18.\n\nSong YM, Qian Y, Su WQ, et al.: Difference in pathological changes between two rat models of severe traumatic brain injury. Neural Regen. Res. 2019; 14: 1796–1804. Publisher Full Text\n\nMcKee AC, Daneshvar DH: The neuropathology of traumatic brain injury. Handb. Clin. Neurol. 2015; 127: 45–66. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLopez NE, Krzyzaniak MJ, Blow C, et al.: Ghrelin prevents disruption of the blood-brain barrier after traumatic brain injury. J. Neurotrauma. 2012; 29(2): 385–393. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarman RH: Histology of the central nervous system. Toxicol. Pathol. 2011; 39(1): 22–35. Publisher Full Text\n\nShao X, Hu Q, Chen S, et al.: Ghrelin ameliorates traumatic brain injury by down-regulating bFGF and FGF-BP. Front. Neurosci. 2018; 12(412): 445. Publisher Full Text\n\nLiu M, Zhang C, Liu W, et al.: A novel rat model of blast-induced traumatic brain injury simulating different damage degree: implications for morphological, neurological, and biomarker changes. Front. Cell. Neurosci. 2015; 9: 168.\n\nStriebel JF, Race B, Williams K, et al.: Microglia are not required for prion-induced retinal photoreceptor degeneration. Acta Neuropathologica Com. 2019; 7(48): 1–15.\n\nAndini A, Veterini L, Wikurendra EA, et al.: Histopathological findings of the liver and kidneys of wistar rat exposed to insect repellent. Bali. Med. J. 2023; 12(2): 1330–1333.\n\nGaluzzi L, Vitale I: Molecular mechanism of cell death; recommendation of the nomenclature committee on cell death 2018. Cell Death Differ. 2018; 25: 486–541. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPonsford MJ, Medana IM, Pranpansilp P, et al.: Sequestration and micro vascular congestion are associated with coma in human cerebral malaria. JID. 2012; 205: 663–671. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXu SY, Liu M, Gao Y, et al.: Acute histopathological responses and long-term behavioral outcomes in mice with graded controlled cortical impact injury. Neural Regen. Res. 2019; 14(6): 997–1003. PubMed Abstract | Publisher Full Text\n\nKahriman A, Bouley J, Smith TW, et al.: Mouse closed head traumatic brain injury replicates the histological tau pathology pattern of human disease: characterization of a novel model and systematic review of the literature. Acta Neuropathol. Commun. 2021; 9(1): 118. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSuryadi T: Master Data for Histopathology [Data set]. Zenodo. 2023. Publisher Full Text\n\nSuryadi T: Arrive guideline for animal study report. [Dataset]. Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "220553",
"date": "14 Nov 2023",
"name": "Putri Dianita Ika Meilia",
"expertise": [
"Reviewer Expertise Forensic medicine",
"forensic pathology",
"clinical forensic medicine",
"forensic epidemiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting article detailing an experimental study about signs of traumatic brain injury in an animal model (rats). There are only some minor points that I would like to address:\nTo the best of my knowledge, this is not a case-control study. Rather, it is an experimental study using 2 independent groups. A case-control study is a form of observational study in which the starting point is 1 group of subjects who have a certain condition of interest and 1 group that does not, and then the exposure(s) or risk factors of interest are traced back.\n\nThe wording in the \"statistical analysis part\" is still in future tense, i.e., \"If the data is not normally distributed, then the Kruskal-Wallis hypothesis test is carried out. If there is a difference, then the analysis is continued with a post hoc test to find out the different data pairs.\" Because at the time of writing, the authors should already have the data, that sentence should be changed into a more definitive form.\n\nThe conclusion as to whether the results of this study could benefit forensic medicine could be more clearly elaborated, e.g., what kinds of assumptions are needed to be able to draw an animal model-to-human inference.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11597",
"date": "29 Jun 2024",
"name": "Taufik Suryadi",
"role": "Author Response",
"response": "Dear Dr.Putri Ika Dianita Meilia Thank you very much for your generous comment. I was greatly helped by your suggestions, and I revised my article manuscript according to your suggestions. Yes, I agree with your suggestion, that this research is experimental with two independent groups, I will revise it in the study design section. Yes, I agree with you, I will revise the sentence on statistical analysis with: The research results were analyzed using the Shapiro-Wilk normality test. Statistical analysis was carried out using ANOVA (analysis of variance) on normally distributed data. For data that is not normally distributed, the Kruskal Wallis hypothesis test is carried out. Post hoc test analysis was carried out on different data pairs. In the conclusion, I add information about: The results of this study are relevant in animal models, further research will be carried out to find their relevance in human subjects so that they are useful for forensic medicine. In relation to determining the mechanism of death due to traumatic brain injury, a histopathological examination is needed to ensure a stronger causal relationship. Best regards Taufik Suryadi"
}
]
},
{
"id": "268142",
"date": "16 May 2024",
"name": "Ankita Guleria",
"expertise": [
"Reviewer Expertise Forensic Science",
"Forensic Anthropology",
"Osteology",
"Physical Anthropology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI would like to extend my sincere thanks to you for selecting me as a reviewer for F1000. I am truly honored to have this opportunity to contribute to the peer-review process. This is a very interesting topic with its importance in forensic medicine. I have read the manuscript and I have some suggestions for this manuscript. This study will sound technically more correct if following suggestions will be considered which I have found missing in the manuscript. I suggest authors to incorporate the following recommendations in their study:\n\nAuthors should focus more on their introductions. This part needs to be strengthened and should provide a concise justification of the objective, goal, and significance of your study Rattus novergicus is not italicized in the section under \"Animal model.\" Authors should confirm the rat species whether it is ‘novergicus’ or ‘norvegicus’. Technically and scientifically, the discussion part is incorrect. Writers have only exclusively defined scientific terminology. I advise the authors to focus more on their discussion, specific research findings, and comparisons with other studies. The conclusion has to be revised to reflect the forensic significance of this work and to be more specific.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "11596",
"date": "29 Jun 2024",
"name": "Taufik Suryadi",
"role": "Author Response",
"response": "Dear Prof.Ankita Guleria Thank you very much for your generous comment. I was greatly helped by your suggestions, and I revised my article manuscript according to your suggestions. 1. At the end of the introduction section, I added some information: The aim of this study was to compare the results of premortem histopathological findings in animal model with or without traumatic brain injury. The target of the research is for forensic pathologists to be better able to provide evidence of traumatic brain injury to investigators so that the investigation process is optimally successful. The significance of this research is that it provides additional information for forensic pathologists in determining the mechanism of death if this research can later be applied to humans. 2. Yes, we agree that the words \"Rattus norvegicus\" are not written in italics, I corrected them in our manuscript. We also stated that the correct one is \"Rattus norvegicus\" not \"Rattus novergicus\" and we standardized it in the article. 3. At the end of the discussion section, I added some information from other research that is relevant to this research: This research is in line with studies conducted by Ibrahim et al., which stated that there were signs of inflammation in the form of haemorrhage and inflammation as well as necrosis in tissue as the body's response to significant antemortem stress, this also showed enzymatic changes in tissue. Meanwhile, for postmortem cells, there is tissue necrosis and severe cell damage. A combination of antemortem and postmortem histopathology showed changes in fatality in mice subjected to hypothermia. This research is also in line with the study conducted by Al Salh & Al-Jameel, which stated the difference between antemortem and postmortem wounds, with antemortem characteristics being bleeding, increased macrophages and neutrophils, while postmortem showed tissue degeneration, bleeding and autolysis. 4. In the conclusion, I add information about the specifics of the findings: In relation to determining the mechanism of death due to traumatic brain injury, a histopathological examination is needed to ensure a stronger causal relationship. Best regards, Taufik Suryadi"
}
]
}
] | 1
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https://f1000research.com/articles/12-1311
|
https://f1000research.com/articles/12-1438/v1
|
06 Nov 23
|
{
"type": "Research Article",
"title": "Co-rotating twin screw process for continuous manufacturing of solid crystal suspension: A promising strategy to enhance the solubility, permeation and oral bioavailability of Carvedilol",
"authors": [
"Prerana D. Navti",
"Gasper Fernandes",
"Soji Soman",
"Ajinkya N. Nikam",
"Sanjay Kulkarni",
"Sumit R Birangal",
"Namdev Dhas",
"Gautham G. Shenoy",
"Vinay Rao",
"Kunnatur Balasundara Koteshwara",
"Srinivas Mutalik",
"Prerana D. Navti",
"Gasper Fernandes",
"Soji Soman",
"Ajinkya N. Nikam",
"Sanjay Kulkarni",
"Sumit R Birangal",
"Namdev Dhas",
"Gautham G. Shenoy",
"Vinay Rao",
"Kunnatur Balasundara Koteshwara"
],
"abstract": "Background: In the current work, co-rotating twin-screw processor (TSP) was utilized to formulate solid crystal suspension (SCS) of carvedilol (CAR) for enhancing its solubility, dissolution rate, permeation and bioavailability using mannitol as a hydrophilic carrier.\nMethods: In-silico molecular dynamics (MD) studies were done to simulate the interaction of CAR with mannitol at different kneading zone temperatures (KZT). Based on these studies, the optimal CAR: mannitol ratios and the kneading zone temperatures for CAR solubility enhancement were assessed. The CAR-SCS was optimized utilizing Design-of-Experiments (DoE) methodology using the Box-Behnken design. Saturation solubility studies and in vitro dissolution studies were performed for all the formulations. Physicochemical characterization was performed using differential scanning calorimetry , Fourier transform infrared spectroscopy, X-ray diffraction studies, and Raman spectroscopy analysis. Ex vivo permeation studies and in vivo pharmacokinetic studies for the CAR-SCS were performed. Stability studies were performed for the DoE-optimized CAR-SCS at accelerated stability conditions at 40 ºC/ 75% RH for three months.\nResults: Experimentally, the formulation with CAR: mannitol ratio of 20:80, prepared using a KZT of 120 ºC at 100 rpm screw speed showed the highest solubility enhancement accounting for 50-fold compared to the plain CAR. Physicochemical characterization confirmed the crystalline state of DoE-optimized CAR-SCS. In-vitro dissolution studies indicated a 6.03-fold and 3.40-fold enhancement in the dissolution rate of optimized CAR-SCS in pH 1.2 HCl solution and phosphate buffer pH 6.8, respectively, as compared to the pure CAR. The enhanced efficacy of the optimized CAR-SCS was indicated in the ex vivo and in vivo pharmacokinetic studies wherein the apparent permeability was enhanced 1.84-fold and bioavailability enhanced 1.50-folds compared to the plain CAR. The stability studies showed good stability concerning the drug content.\nConclusions: TSP technology could be utilized to enhance the solubility, bioavailability and permeation of poor soluble CAR by preparing the SCS.",
"keywords": [
"Twin screw processor",
"solid crystal suspension",
"carvedilol",
"mannitol",
"solubility",
"in vitro dissolution",
"ex vivo permeation",
"in vivo pharmacokinetics"
],
"content": "Introduction\n\nThe bioavailability of drugs via the oral route majorly depends on the drug solubility and the dissolution rate. Solubility acts as a rate-determining step for the effective therapeutic response of the drug.1 Specifically, the drugs belonging to the biopharmaceutical classification system (BCS) class II suffer from poor absorption and low bioavailability. Therefore, there is a concern about increasing the solubility of these drug candidates.2 Many approaches like co-solvency, surfactants, micronization, complexation, hydrotropy, salt formation, cocrystals, and co-amorphous technology have been extensively utilized for the solubility enhancement.1,3,4\n\nA new theory known as solid crystal suspensions (SCS) has recently been proposed wherein the ground drug is homogeneously distributed in the crystalline carrier matrix using hot-melt extrusion (HME) without aiding in any drug and the crystalline matrix interaction, forming a stable product having a better dissolution rate compared to the bulk drug.5 Highly hydrophilic carriers enhance the drug solubility in the SCS. The enhanced wetting and drug particle size reduction improve the dissolution and solubility of the poorly soluble drug.5 This system differs from that of the amorphous solid dispersions,4–6 which are thermodynamically unstable because of their ability to get converted to a more stable crystalline form. Also, moisture absorption for the amorphous forms is more severe than the crystalline state and results in agglomeration of the amorphous form. Since no amorphous phase is involved, the physical stability of SCS is higher.\n\nCarvedilol is an alpha and beta-blocker utilized in hypertension treatment belonging to BCS class II with high permeability and low solubility. The bioavailability of carvedilol is very low orally, which accounts for only 25%. Hence, there is an immense need to enhance its solubility and improve bioavailability.3,7,8 The approaches utilized for solubility and dissolution rate improvement of carvedilol include micronization,7 solid dispersion,9,10 cyclodextrin inclusion complex,11,12 cocrystallization,3,13 co-amorphous technology14 and nanotechnology.8 To date, the SCS approach has not been explored for solubility enhancement of carvedilol.\n\nHME technology has previously been reported for the preparing SCS of several drugs such as efavirenz,5 griseofulvin,6 and griseofulvin, phenytoin, and spironolactone.4 However, the HME machines reported in earlier studies for SCS preparation consisted of a single barrel with only one heating zone in which temperature variation is quiet difficult.4–6 There are no reports on the application of twin-screw processor (TSP) technology using different heating zones in the preparation of SCS. Twin screw processing refers to directing the raw materials in the machine consisting of one or two rotating screws wherein the starting materials are exposed to different temperatures, followed by passing the material via the die to give the product.15,16 The fed material creates a melt pool inside the melting zone of the extruder facilitating the interaction and homogenous mixing between the raw materials.16 This technology has been used for the solubility/dissolution enhancement of poorly soluble drugs by crystal engineering, cyclodextrin complexation and by cocrystal manufacture.16 Different heating zones in the barrel allow heat distribution, heat optimization, and adaptation of the processing section for the product.17 Because of this reason, altering the temperature in a barrel is essential. Typically, the temperature in the melting and kneading zone is greater compared to the conveying zone.17 In the present work, we utilized a co-rotating TSP instrument having different heating zones in contrast to above listed previous reports.\n\nThe goal of this work was to enhance the oral bioavailability of the BCS Class II drug, carvedilol by exploring the theory of SCS using a water-soluble crystalline carrier by employing TSP technology. The polyols (sorbitol and mannitol) were explored as crystalline carriers in the current study for SCS formation. Mannitol was screened as the main crystalline carrier owing to the higher enhancement in the solubility of the CAR in the crystalline suspension obtained with mannitol compared to sorbitol in the trials taken. The SCS of carvedilol using mannitol was prepared and evaluated by utilizing Design of experiments (DoE) methodology. Box-Behnken design (BBD) was utilized for the optimization wherein kneading zone temperature, screw speed, and CAR: mannitol ratio were selected as the independent factors, and solubility was the response. The aspects of in-silico molecular dynamics (MD) were applied to study the interactions between the CAR and mannitol in different ratios of CAR: mannitol (20:80, 35:65, and 50:50) at various kneading zone temperatures (120°C, 130°C, and 140°C) to predict the optimal ratios for preparing CAR-SCS formulation which would yield higher solubility, on the basis of hydrophilicity and hydrophobicity report for all the formulated SCS formulations of CAR generated from in-silico MD studies. Also, the stability of the experimentally optimized CAR-SCS (F8), was assessed using in-silico MD studies. There are no reports available on the use of such in-silico MD studies for the preparation of SCS. The DoE optimized CAR-SCS (F8) was characterized for different physicochemical properties i.e. differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray Diffraction (P-XRD) and nuclear magnetic resonance (NMR) analysis. The CAR-SCS (F8) was subjected to ex vivo permeation and in vivo pharmacokinetic (PK) study to understand the dissolution and absorption rate of CAR.\n\n\nMethods\n\nCAR was obtained as a gift sample from Zydus Cadila Healthcare Ltd, Kundaim, Goa, India. Mannitol and sorbitol were purchased from Universal Laboratories Private Ltd, Mumbai, India. Methanol, acetonitrile (ACN), Triethylamine (TEA) and ortho-phosphoric acid (OPA) were obtained from Loba Chemie Pvt Ltd (Mumbai, India). 0.22 μ membrane filters were obtained from Chemixol agencies, Mangaluru. All the chemicals and solvents utilized were of analytical grade.\n\nA TSP instrument (O-Micron 10P, Steer Engineering, Bangalore, India) with co-rotating screws having an outer to the inner diameter (Do/Di) of 1.71 was utilized for the study. A few initial trials were taken using sorbitol and mannitol as hydrophilic carriers by preparing a 50:50 mixture using mortar and pestle. The TSP consisted of four zones (B1, B2, B3 and B4). The B1, B2 and B4 was set at 31°C, 100°C, 95°C respectively. The B3 (kneading zone) temperature range was selected as 70-110°C for sorbitol and 120-140°C for mannitol, considering the melting point of the crystalline polyols, and the screw rpm was varied from 50-150 rpm (Table 1). From the results obtained by solubility studies for both the polyols, mannitol was screened as the primary hydrophilic carrier for formulating the CAR-SCS using DoE (Table 1).\n\nBBD was utilized to systematically evaluate the effect of TSP instrument parameters like kneading zone temperature, screw rpm, and formulation-related parameter (CAR: mannitol ratio) on the solubility of CAR from SCS formulations (response). The experimental runs and data analysis were performed utilizing Design-Expert software (Version 9.0.3.1) (Chemoface is a free alternative software that may be able to perform similar functions). ANOVA was utilized to find the significant effect of the factors on response regression coefficients.\n\nCAR and mannitol physical mixtures at the ratios of 50:50, 35:65, and 20:80 were prepared, blended using mortar and pestle, and extruded from the TSP die. The kneading zone temperature range of 120-140°C was used. The TSP zones B1, B2 and B4 were set at 32°C, 100°C and 95°C respectively. Zone B3 (kneading zone) temperature and screw rpm were set as per the runs suggested by the Design-Expert software (Table 2).\n\nThe molecular dynamics (MD) simulation studies of CAR with mannitol at different ratios, i.e., 50:50, 35:65, and 20:80 with different kneading zone temperatures, were performed using Schrodinger software Suite (version 2023-2) (Schrodinger LLC, New York) in the Maestro module (version 13.6.121, MMShareVersion 6.2.121, Release 2023-2, Platform Linux-x86_64) (An alternative free software able to perform similar tasks is Gromacs RRID:SCR_014565). The guest molecule CAR and mannitol structures were built using the 2D sketcher and were optimized with LigPrep by using default settings at pH 7.0 coupled with Epik calculations. The optimization of the geometry of the CAR-SCS in the various ratios of CAR with mannitol (i.e. 50:50, 35:65, and 20:80) was individually done utilizing the Macro Model minimization tool by keeping default settings.\n\nThe two-dimensional structure of CAR and mannitol was built in the Maestro structure builder by referring to the Pubchem database (PubChem CID: 2585)44 and (PubChem CID: 6251).45 The optimization of the structures was done by employing OPLS4 forcefield LigPrep/Epik.18\n\nCAR and mannitol were selected in DSB. In the components setting, 50 molecules of CAR with mannitol were prepared in the ratios: 20:80, 35:65, and 50:50. A new orthorhombic periodic boundary condition with dimension 40 Å was created. Then OPLS4 force field was used to build the CAR-SCS, and all other settings were kept on default. The formed CAR-SCS was taken for MD simulation studies.\n\nThe Desmond Module (Version 22.4) of Schrodinger was utilized for running the MD simulations. The MD was conducted for 0, 25, 75, and 100 ns at different kneading zone temperatures used, i.e., 395.15K (120°C), 403.15K (130°C), and 413.15K (140°C) with 1.013 bar pressure kept by utilizing the Nose Hoover Chain thermostat and Matrtyna-Tobias-Klein barostate. For studying the stability of the CAR-SCS, CAR binding mode to mannitol in the CAR-SCS at different CAR and mannitol ratios, i.e., 20:80, 35:65, and 50:50 at different kneading zone temperatures, i.e., 393.15 K (120°C), 403.15 K (130°C), 413.15 K (140°C), pressure (bar) 1.01325 and for 100 ns simulation time period was predicted; thus generating 1000 structural frames of SCS formulation which were saved in trajectory. The MD simulation was run on CAR and mannitol in the SCS. The trajectory generated after the simulations was utilized for calculating the root mean square deviation (RMSD) to show the stability of the optimal CAR-SCS formulation.\n\nThe CAR-SCS formulations were collected, and the practical yield (%) was found out employing the formula3:\n\nDSC analysis was done utilizing DSC-60 Plus with TA-60WS thermal analyzer (Shimadzu Corporation, Kyoto, Japan) for pure CAR, mannitol, physical mixture (PM) of CAR and mannitol at 1:1 ratio, and the DoE optimized CAR-SCS (F8), for the analysis of solid-state.18 A 5 mg sample was enclosed in an aluminum pan and sealed. An empty pan was utilized as a blank. The heating of the samples was achieved at a of 10°C/min rate from room temperature to 300°C in a nitrogen environment at a 10 mL/min flow rate. The DSC thermograms were recorded for the individual samples.46\n\nTGA was performed to evaluate the thermal stability of CAR, PM, and CAR-SCS (F8). The analysis was done using DTA-TG device (DTG-60H, Shimadzu Co., Japan). About 4 mg of the sample was heated between 25-800°C at a 10°C/min heating rate under dynamic nitrogen atmosphere. Experiments were done at the flow rate of 50 mL/min.\n\nFTIR spectra were recorded for pure CAR, mannitol, 1:1 PM of CAR and mannitol, and DoE optimized CAR-SCS (F8) using Alpha II, ECO-ATR (Bruker, Germany) at the wavelength range of 4000-900 cm-1 for investigation of interactions of the CAR and the mannitol. FTIR spectra was also recorded for the DoE-optimized F8 formulation. The powdered sample was placed on the stage, and a focused image was obtained. The images were obtained using OPUS 8.0 software (provided with the equipment used).\n\nXRD was utilized to estimate the CAR’s physical form in the CAR-SCS (F8) formulation. The instrument used was Malvern PANalytical, Netherlands, with Empyrean 3rd generation model. X-ray diffraction was carried out for CAR, mannitol, CAR-mannitol physical mixture (ratio: 1:1), and optimized CAR-SCS (F8) formulation with a 40 kV voltage and 15 mA tube current at 7-50° (2θ) range.46\n\nEVO MA18 with Oxford EDS (Zeiss, Germany) scanning electron microscope was utilized for assessing the surface morphology of plain CAR, plain mannitol, and optimized CAR-SCS (F8). The samples were placed onto the aluminum stub employing double-sided adhesive tape, and a vacuum at ten torr was applied. The samples were then scanned with an electron beam and SEM images were taken. Samples were tested utilizing both SEM and EDS.\n\nRaman spectrometric analysis was performed for the CAR, mannitol, and optimized CAR-SCS (F8) formulation using I-Raman Plus (B&W TEK, Plainsboro, NJ, USA) fitted with an Ar-Ne instrument. For all the experiments, the excitation wavelength of 785 nm of 35 mW power was utilized, and the integration time was 10 sec.\n\nProton NMR (1H) was done for CAR, mannitol, and the CAR-SCS (F8) by dissolving an appropriate amount of the samples separately in dimethyl sulfoxide, and the analysis was performed using a 400 MHz-Bruker ASCEND TM 400 NMR analyzer (Billerica, MA, USA).\n\nThe saturation solubility of plain CAR and all the formulations was assessed in pH 6.8 phosphate buffer. Excess amounts of CAR and CAR-SCS formulations were separately incorporated in 2 mL of pH 6.8 phosphate buffer in the Eppendorf tubes, and the tubes were kept in a tube rotator (Neuation, i Roll PR35, Gandhinagar, Gujarat, India) for 48 h at 50 rpm speed. Later, the solutions were centrifuged at 10,000 rpm for 7 min. The supernatant was appropriately diluted and analyzed by a UV spectrophotometer at 241 nm.\n\nThe micrometric properties of CAR and optimized CAR-SCS (F8), including tap density, angle of repose, bulk density, and Hausner’s ratio, were evaluated. Tap density and compressibility index were assessed by the tapping method. Tap density was estimated using tap density tester (Electrolab ETD-1020, Mumbai, Maharashtra, India). The CAR and CAR-SCS was transferred using a funnel to a graduated 100 mL cylinder. The weight was determined using weighing balance (Wensar,Bengaluru, India) and the volume was recorded visually for the bulk density determination. The cylinder was tapped 1000 times and tap density calculation was done according to the formula below.19–22\n\nHausner’s ratio is the ratio of tap density to the bulk density. Carr’s index (CI) is a measure of particle size, flow rate and cohesiveness. It was calculated using the formula:\n\nThe fixed funnel methodology was utilized for measuring the angle of repose3 wherein a funnel was fixed onto a stand such that the funnel tip was 2.5 cm above the flat surface on which a graph paper was placed. The powders were allowed to freely fall until the tip of the heap touched the funnel. The radius and height of the heap was measured. The formula utilized for the calculation was as follows20,23:\n\n10 mg CAR-SCS were dissolved in little amount of methanol, and diluted using 0.1N HCl to 100 mL. This solution was sonicated using an ultrasonic bath (Antech,GT sonic, Panacea Instruments Pvt Ltd, New Delhi, Delhi, India) for 10 min. After diluting 0.1 mL of the solution to 1 mL with 0.1N HCl, it was filtered and analyzed using UV spectrophotometer (UV-1800 UV/Vis spectrophotometer, Shimadzu, Kyoto, Japan) at 241 nm3.\n\nDissolution studies were done utilizing USP type II dissolution apparatus (Electrolab TDT-08L Dissolution Tester) for CAR and all the CAR-SCS separately in both pH 1.2 HCl solution and phosphate buffer pH 6.8. Sodium lauryl sulfate (SLS) at 0.1% concentration was incorporated in both the dissolution solutions. A quantity of CAR and all CAR-SCS corresponding to 6.25 mg of CAR was loaded into the capsules of Size 4, and the capsules were placed in the 500 mL of dissolution medium maintained at 37 ± 0.5°C with a 50-rpm paddle speed. 5mL of samples were taken at 0.25 h, 0.5 h, 0.75 h, 1 h, and 2 h, and the equivalent fresh medium was incorporated into the dissolution jar. The collected samples were filtered using 0.45 micron filter and were analyzed by utilizing a UV spectrophotometer at 241 nm.3,24\n\nEighteen healthy male Wistar rats (eight weeks old) with body weight of 200-250 g were utilized for this study. The ex vivo study (n=3 per group/experiment with two groups) and in vivo pharmacokinetic study protocol (n=4 per group with three groups) was approved by Institutional Animal Ethics committee, Kasturba Medical College, Manipal (IAEC Registration No.: 94/PO/RReBi/S/99/CPCSEA). The number of rats per group for the respective experiments was decided based upon the existing literature.16,25,26 Each group consisted of four animals maintained in a cage for the in vivo pharmacokinetic studies and three animals per cage for ex vivo intestinal permeation studies at optimal conditions of 25°C and 50% RH with a 12 hour light/dark cycles with continuous access to reverse osmosis (RO) water and pellets rat food (VRK Nutritional Solutions, Sangli, Maharashtra, India). The cages were labelled with the individual experiment title and the group names prior to the start of experiment to avoid error. The experiments were conducted in accordance to the Committee for the purpose of control and supervision of Experiments on Animals (CPCSEA) rules.47\n\nThe rats were randomly assigned to two groups i.e Group I: Plain CAR (n=3) and Group II: CAR-SCS (F8) (n=3). The number of animals per group was decided according to the existing literature.26 These rats were euthanized ethically by giving an intraperitoneal injection of thiopental sodium overdose (50 mg/kg),19,26 and the abdominal area was shaved and an incision of 5 cm was done. The intestine was removed and the ileocaecal junction was identified. This segment was then cleaned thoroughly by using the blunt end of the syringe and transferred to the Petri plate with Kreb’s Ringer buffer solution pH 7.4. This intestinal segment was then cut into pieces. One end was tightly tied with the thread. From the other side, 1 mL of the CAR, equivalent to 6.25 mg dispersed in the Kreb’s Ringer buffer solution pH 7.4 was added. Another end of the intestinal segment was sealed. Similarly, 1 mL of the CAR-SCS (F8), equivalent to 6.25 mg dispersed in the Kreb’s Ringer buffer solution pH 7.4, was added to another intestinal segment, followed by sealing of the intestine. The non-everted sacs were kept in 50 mL of Kreb’s Ringer buffer solution pH 7.4 in a magnetic stirrer with a 50 rpm speed aerated with oxygen utilizing a laboratory aerator (Atlas Air Pump 6000, Mumbai, Maharashtra). The samples were taken from the serosal compartment, i.e., outside the sac, at 20, 40, 60, 80, 120, and 180 min, and a similar quantity of the fresh medium was incorporated. The samples were analyzed by UV-spectroscopy after filtration using 0.45 micron filters. The permeability of CAR from the CAR-SCS (F8) was obtained from the plot of the cumulative amount of CAR permeated from the rat intestine vs. time in min. The apparent permeability coefficient calculation was done as per the Equation 1 below.27\n\nWhere A refers to the cross-sectional area of the intestinal segment (cm2), F refers to permeation flux, C0 is the initial CAR concentration in μg/ml\n\nThe rats were classified into three groups with each group containing 4 animals ((n=4 per group; total number of groups: 3).\n\nGroup A: Plain CAR (40 mg/kg)\n\nGroup B: CAR-Mannitol PM (powder equivalent to 40 mg/kg of CAR)\n\nGroup C: CAR-SCS (F8) formulation (powder equivalent to 40 mg/kg of CAR).\n\nAll the above samples were administered orally in the form of 0.2% carboxy methyl cellulose suspension. At the time intervals of 0.5, 1, 2, 4, 6, 12 and 24 hours, 200 μL of blood was collected from the retroorbital plexus in the centrifuge tubes with 10% EDTA. 100 μL of plasma was collected by centrifugation at 10,000 rpm for 10 min.16,25\n\nPlasma samples were analyzed for CAR by using high performance liquid chromatography (HPLC). The HPLC system (SHIMADZU LC2010-CHT, Schimadzu Corporation, Kyoto, Japan) with the dual piston pump, autosampler and a UV-visible detector was utilized. The obtained chromatograms were analyzed using the postrun icon in the LC solutions software version 5.57 (provided with the equipment used). The mobile phase utilized was Acetonitrile and water adjusted to pH 3.0 with trifluoroacetic acid (45:55). The flow rate used was 1 ml/min at the UV detector wavelength of 241 nm. A Kromasil C18 Reverse Phase column was utilized for the analysis.\n\nThe plasma samples were processed by protein precipitation method. 300 μL of methanol (precipitation agent) was incorporated into the tubes and was centrifuged for 1 min utilizing vortex mixer. This was centrifuged at 10,000 rpm for 10 min and separation of the supernatant. The supernatant was injected in the HPLC system.16,28 The calibration plot for CAR in the plasma was plotted in the concentration range of 25 to 5,000 ng/mL, and showed a R2 value of 0.983, depicting its linearity with the equation y=0.0014x+0.0897, where ‘x’ is the CAR conc. and ‘y’ is the peak area ratio of CAR to IS (Quetiapine).\n\nOptimized CAR-SCS (F8) was incorporated into the hard gelatin capsules, and the capsules were stored in the glass bottle at 40°C/75% RH for three months in a stability chamber (Thermolab Scientific Equipments, 500 L capacity). The drug content and DSC analysis for the samples was done at intervals of one, two, and three months.\n\n\nResults and discussion\n\nInitial trials were taken using mannitol and sorbitol as hydrophilic carriers for the preparation of CAR-SCS. CAR: hydrophilic carrier at a 50:50 ratio was extruded through the TSP. The kneading zone (B3) temperatures of 120-140°C were selected for the preparation of CAR-mannitol SCS and 70-110°C was used for CAR-sorbitol SCS based on the melting point of the hydrophilic carriers. Initially, the effect of different kneading zone temperatures on the SCS was assessed. For CAR-mannitol SCS, with the increase in kneading zone temperature to 140°C the product formed was sticky, and the yield was much less owing to the loss of the product by sticking to the barrel. The increase in solubility was seen with the increase in kneading zone temperatures for CAR-mannitol and CAR-sorbitol.\n\nThe impact of screw speed on the CAR-SCS was also examined. Screw speeds of 50-150 rpm were utilized. With an increase in the screw rpm to 150 rpm, the product yield was found to be more due to the decreased residence time in the TSP barrel resulting in the extrusion of fine powder. Additionally, the solubility of the product also enhanced which might be because of the increased surface area and improved interaction of the polymer with the drug at higher temperature. The solubility was found to be significantly enhanced with mannitol compared to sorbitol. Hence mannitol was selected as the hydrophilic carrier for preparing the CAR-SCS. From the initial trials (Table 1), screw speed and the kneading zone temperature were found to have an effect on the solubility.\n\nBBD was employed to examine the influence of the three factors i.e., CAR: mannitol ratio, kneading zone (B3) temperature, and screw rpm, on the solubility in 15 runs. The CAR: mannitol ratios selected were 20:80, 35:65, and 50:50. The kneading zone temperature and screw rpm ranged from 120-140°C and 50-150 rpm, respectively. The response variable was the solubility of CAR. For generating the statistical experimental design, Design Expert v.9.0.3.1 software was used. Different trials generated by Design Expert Software (R1 to R15), using the factors CAR: mannitol ratio, kneading zone temperature, and screw rpm, and the corresponding response, solubility is depicted in Table 2. The ANOVA results depicted that the model is significant with a F value of 34.47 and a p-value of <0.0001.\n\nThe 3D response surface plots are shown in Figure 1. The CAR: mannitol ratio, kneading zone temperature, and screw rpm were found to affect the solubility of CAR significantly. The response factor solubility was found to increase with decreasing kneading zone temperatures and increasing screw rpm. Solubility was slightly affected by the CAR: mannitol ratio and showed a slight decrease with the increase in CAR: mannitol ratio. As the CAR: mannitol ratio increases, there is insufficient coverage of the drug particles by the water soluble carrier, causing a decrease in wettability and solubility.29 ANOVA analysis was done to estimate the effect of individual factors on the response. For the response, individual factors and model sum of squares was computed for linear, 2-factor interaction, quadratic and cubic models. Model F-value of 34.47 and p values less than 0.05 indicated that the model terms are significant. A linear model was selected. The R2 value for the selected model was found to be 0.904. The coded equation in terms of the actual factors generated by DoE was as follows:\n\nWhere C:M represents CAR:mannitol ratio, KZT represents kneading zone temperature and rpm represents screw rpm.\n\nThe validation of the model was done by performing the trial generated by the DoE software and calculating % residual by using the Equation 2:\n\nThe validation trial conducted using the 20:80 ratio of Drug: mannitol at a kneading zone temperature of 120°C showed a saturation solubility of 2.45. The solubility predicted by the software was 2.1 mg/mL. This accounted for the % residual of ±14.3%. The DoE software showed the desirability for the optimized factors as 1.00.\n\nIn the starting phase of MD simulation, the CAR-SCS was stabilized. According to the hydrophilic and hydrophobic report generated for all CAR-SCS from the in-silico MD studies, as depicted in the Table 3, the CAR-SCS with a 20:80 ratio of CAR: mannitol, prepared at the kneading zone temperatures of 120°C, 130°C and those prepared with 35:65 ratio of CAR:mannitol with the kneading zone temperatures of 120°C, 140°C were predicted to be the optimal ones which could enhance the CAR solubility. These CAR-SCS were found to show more hydrophilicity and less hydrophobicity compared to the other CAR-SCS as per the in-silico hydrophilic and hydrophobic report.\n\nThe results of the in-silico molecular simulation studies were similar to the experimental results. As per the experimental results, the CAR-SCS formulation prepared using a 20:80 ratio of CAR: mannitol at the kneading zone temperatures of 120°C showed the best results. The hydrophilicity and hydrophobicity generated from the in-silico MD studies of the CAR-SCS (F8) prepared using 20:80 ratio of CAR: mannitol at the kneading zone temperatures of 120°C is depicted in Figure 2. As illustrated by the molecular simulation studies, hydrophilic portion is represented in white color and the orange color depicts the hydrophobic portion. The hydrophilicity and hydrophobicity of all the CAR-SCS formulations predicted by in silico MD studies are illustrated in Table 3. For assessing the stability of the CAR-SCS structures during the MD simulation, the structures from the trajectory were aligned with mannitol atoms, and the root mean square deviation (RMSD) calculation was done separately for CAR and CAR-SCS at different temperatures and ratios with respect to the preliminary frame. The fluctuation in the RMSD values was found to be less than 5Å. This indicated a very low fluctuation showing the stability of CAR-SCS complex. Figure 3 demonstrates the MD simulation done for the CAR-SCS formulation prepared using a 20:80 ratio of CAR: mannitol at the kneading zone temperatures of 120°C. The RMSD graphs were plotted for the original CAR structure and the MD simulation computed structures of optimum CAR-SCS. The RMSD plots for optimum CAR-SCS prepared using a 20:80 ratio of CAR: mannitol at the kneading zone temperatures of 120°C are indicated in Figure 4. The MD simulation studies showed the stability of the CAR-SCS with the least fluctuation in the RMSD values.\n\n(Hydrophilic portion is represented in white color and the orange color depicts the hydrophobic portion).\n\nDifferential scanning calorimetry (DSC)\n\nDSC thermograms of CAR, mannitol, PM, and the CAR-SCS (F8) are depicted in Figure 5. A sharp endotherm at 117.67 °C was observed for CAR revealing the crystallinity of the drug. Mannitol exhibited a characteristic endotherm at 171.66°C, confirming the crystallinity of mannitol. Two melting endotherms were seen in the DSC spectra of the PM and the CAR-SCS (F8). In CAR-SCS (F8), the melting endotherm of mannitol and the CAR were less intense and was slightly shifted to the low temperature compared to the plain mannitol. This was attributed to the presence of the molten form of mannitol reducing the melting point of higher melting point substances.4,5 The DSC results for the CAR-SCS (F8) indicate that both components occur as distinct crystalline phases. The least melting point depression shows that mannitol creates a very poor solvating environment for CAR but is effective in aiding the efficient wetting of the CAR.4\n\nPhysical mixture-Carvedilol: mannitol physical mixture CAR-SCS-Optimized Carvedilol-solid crystal suspension (F8).\n\nThermogravimetry analysis (TGA)\n\nTGA was performed to assess the thermal stability of CAR, PM and CAR-SCS (F8). The TGA curves of CAR, PM and the CAR-SCS (F8) are shown in Figure 6 which shows that a slight loss in the weight by 5% w/w for all the samples was observed at 245-275°C which is due to the presence of absorbed water and water of crystallization. The TGA curve revealed that the drug is thermally stable up to 222°C which is similar to the previously reported value.30 The decomposition range of carvedilol was from 300-800°C.31 The decomposition of PM containing the CAR and mannitol started at 219°C and for F8 formulation, the decomposition started at 245°C. At the temperatures above 300°C, the samples showed 70% of weight loss.\n\nThe overlay FTIR spectra of CAR, mannitol, PM, and CAR-SCS (F8) is illustrated in Figure 7. FTIR spectrum of CAR exhibited typical peaks as reported previously in the literature32: a peak at 3342.33 cm-1 depicting the –N-H stretch; the C-H stretch in the region is 2922.83 cm-1; the peaks from 1251.69 cm-1 to 1453.40 cm-1 relating to the C-C stretch were observed. The band from 1453.4 cm-1 to 1501.8 cm-1 was allocated to C=C stretch. The FTIR spectra of mannitol exhibited the characteristic peaks as reported earlier in literature33 with a peak at 2948.06 cm-1 depicting the –C-H group, and at 1077.66 cm-1 depicting the C-O stretch. The sharp characteristic peak of CAR at 3342.33 cm-1, which could be seen even in the 1:1 physical mixture of CAR and mannitol, was found to show decreased intensity in the CAR-SCS (F8) indicating the new product formation. Also, the disappearance of some peaks and a shift in the peaks to the lower intensity suggested the CAR-SCS formation.\n\nPhysical mixture-Carvedilol: mannitol physical mixture, CAR-SCS: Optimized Carvedilol-solid crystal suspension (F8).\n\nPowder XRD is a sensitive technique and has been considered a standard method for phase identification as the PXRD pattern is directly linked with the crystal structure of the materials. The significant change in the XRD patterns represents the change in the phase composition.34 The XRD patterns of CAR, mannitol, physical mixture of CAR-mannitol, and CAR-SCS (F8) are depicted in Figure 8. The XRD patterns of CAR, mannitol, CAR-mannitol physical mixture, and CAR-SCS (F8) were found to be sharp, confirming their crystalline nature.\n\nPhysical mixture-Carvedilol: mannitol physical mixture Carvedilol-Solid crystal suspension: Optimized CAR-SCS (F8).\n\nThe PM indicated less intensity of the CAR diffraction peaks suggesting the presence of CAR in the crystalline form and displayed less interaction with the mannitol. 2θ values for the CAR-SCS (F8) were different from the starting materials. Also, the number of peaks, intensity and the positions of the diffraction peaks for CAR-SCS (F8) were less compared to the starting materials indicating the interaction between CAR and mannitol to form CAR-SCS.\n\nThe SEM images of CAR, mannitol, PM and CAR-SCS (F8) are presented in Figure 9. From the SEM analysis, it was observed that CAR showed an irregular shape with a very smooth surface. Mannitol showed needle-like morphology. The physical mixture was more of a mixture of CAR with the hydrophilic carrier mannitol. The SEM image of the formulation revealed consistent dispersion of the CAR in the melted carrier matrix. The data obtained from EDS is illustrated in Table 4. The EDS data for the extruded SCS formulation displayed the presence of carbon, nitrogen, and oxygen in the chemical structure of the CAR and hydrophilic carrier, as can be observed in Figure 10. Since, mannitol does not contain nitrogen, the presence of nitrogen in the CAR-SCS (F8) formulation was concluded to have come from the CAR.\n\nA: Carvedilol; B: Mannitol; C: Carvedilol:Mannitol Physical Mixture; D: Carvedilol-Solid crystal suspension (F8).\n\nThe Raman spectra of CAR, mannitol, physical mixture, and the CAR-SCS (F8) are illustrated in Figure 11. Raman analysis was done to understand the distribution of the CAR in the carrier, and to determine the crystallinity of the CAR in the optimized CAR-SCS (F8) formulation. Usually, CAR shows well-defined peaks in the Raman spectra owing to its crystallinity, whereas the broad spectra is observed if the drug is in the amorphous form.35 The Raman spectra of CAR were found to show sharp peaks characteristic of CAR.35,36 The carrier mannitol was also found to exhibit sharp peaks, as reported in the literature.37 The optimized CAR-SCS (F8) were found to show sharp peaks similar to the CAR and mannitol, indicating the crystallinity of the starting materials and their mixture. The optimized CAR-SCS (F8) showed the distribution of crystalline CAR in the mannitol carrier, showing the presence of characteristic peaks present in CAR and mannitol.\n\nCAR, mannitol and optimized CAR-SCS (F8) were characterized by NMR analysis (Figure 12). A sharp singlet obtained for the sample, CAR at 3.75 ppm was assigned to the three protons of –CH3 group. The multiplets at 6.895-6.942 ppm and 6.680-6.852 ppm owing to the presence of four aromatic protons were seen. The multiplets at 2.859-2.946 ppm and 4.021-4.139 ppm were because of the two –CH2 protons. -NH amine proton displayed a singlet at 2 ppm. –NH indole proton showed a singlet at 11.26 ppm, and a –OH proton showed a doublet at 5.175-5.183 ppm. The four protons from the indole rings showed four doublets at 7.356-7.442, 6.680-6.700, 7.274-7.293, and 7.066-7.085 ppm. A doublet at 8.221-8.241 was assigned to the isolated proton of the indole ring.38\n\nThe NMR spectra of mannitol showed the characteristic hydrogens bonded to the oxygen at 4.140, 4.342, and 4.427 ppm. The symmetrical hydrogens of mannitol were detected at 3.380 ppm, 3.462 ppm, 3.525 ppm, and 3.604 ppm.39 The 1H NMR spectra of the CAR-SCS (F8) visibly depicted presence of proton signals of CAR and mannitol, indicating the non-covalent interaction between CAR and mannitol, thus forming CAR-SCS.\n\nThe solubility of CAR in pH 6.8 buffer after 48 hours was estimated to be 0.05 mg/mL, which was similar to the earlier reported value.40 The CAR-SCS (F8) showed solubility of 2.5 mg/mL, as illustrated in Figure 13. CAR-SCS (F8) showed a 50-fold increase in solubility, probably because of the hydrophilic nature of mannitol facilitating wetting and hydration of the poorly soluble drug.41 Molten mannitol acts as a hydrophilic carrier for CAR in the twin screw processing process, thus intimately mixing with CAR and surrounding it, resulting in improved solubility by enhancing the wetting of drug particles and increasing the surface area compared to the plain CAR.41 The increase in the solubility seen for the CAR-SCS was much higher compared to the previously reported studies.3,42\n\nThe flow properties of the CAR-SCS (F8), including tap density, angle of repose, bulk density, and Hausner’s ratio, were evaluated. These parameters were compared with the pure CAR. The parameters for the plain CAR and the CAR-SCS (F8) are illustrated in the Table 5. The angle of repose for pure CAR showed a value of 47.6°, indicating poor flow. The compressibility index was 24.2% and Hausner’s ratio was 1.32 for the pure drug indicating passable flow. The CAR-SCS (F8) showed an excellent angle of repose of 25.73°, indicating considerably improved flow properties. The compressibility index and Hausner’s ratio of CAR-SCS (F8) formulation were 20.2% and 1.25, respectively demonstrating fair flow properties.43 These results indicated improved micromeritic properties in the CAR-SCS (F8) in comparison with pure CAR.\n\nThe practical percent yield for all the CAR-SCS formulations was found to be between 20.40 to 91.4%. The content of the CAR in all the SCS formulations ranged from 51.20-99.49%. The % practical yield and drug content of all the CAR-SCS is depicted in Table 6. Formulations F8 and F3 showed better % yield and drug content, respectively.\n\nThe dissolution study was conducted in pH 1.2 of HCl solution as well as phosphate buffer solution of pH 6.8. Sodium lauryl sulfate (SLS) was incorporated in the dissolution medium as the addition of surfactant helps to accelerate the dissolution rate by acting as solubilizing agents.40 The dissolution characteristics of all the formulations indicated a better dissolution rate than the bulk drug in both pH 1.2 and pH 6.8 buffer (Figure 14). The comparative dissolution profiles of the drug and the CAR-SCS (F8) formulation in pH 1.2 HCl solution and pH 6.8 buffers are represented in Figure 15 (A) and (B). The in vitro dissolution studies for the CAR-SCS (F8) revealed a 6.03- and 3.40-times enhancement in dissolution rate as compared to the plain CAR in pH 1.2 HCl solution and pH 6.8 phosphate buffer respectively. Release of pure CAR was found to be 14.90 ± 0.98% in 120 min in pH 1.2 HCl solution and 28.65 ± 1.8% in 120 min from pH 6.8 buffer. The release of CAR from the CAR-SCS (F8) was found to be 89.85 ± 1.35 % in 120 min in pH 1.2 HCl solution and 94.4 ± 1.5 % in 120 min in pH 6.8 buffer. A high dissolution rate of the CAR-SCS (F8) compared to the CAR can be attributed to the formation of SCS, wherein the crystalline drug is suspended in the melted crystalline hydrophilic carrier. The presence of the crystalline hydrophilic carrier around CAR enhances the polarity and decreases the interfacial tension between CAR and the dissolution medium, thus improving the dissolution rate and solubility.41\n\nPD: Plain Carvedilol.\n\n(A) pH 6.8 buffer and (B) HCl solution (pH 1.2).\n\nThe permeation profile of the optimized CAR-SCS via the non-everted intestinal segment at different time intervals is depicted in Figure 16. The apparent permeability coefficient (Papp) values for plain CAR and CAR-SCS (F8) formulation were found to be 0.066 cm/min and 0.122 cm/min. The Papp for optimized CAR-SCS (F8) was 1.84 folds higher than plain CAR which could be possibly due to the higher permeation of the CAR-SCS (F8) formulation via the intestinal membrane owing to its better solubility and dissolution rate compared to the plain CAR. Drug absorption is a result of the capacity of the drug to diffuse through the lipophilic membrane of the intestine and its solubility in the aqueous milieu. Hence, the drug must be dissolved adequately to ensure higher permeation and bioavailability.44 The higher permeation of the CAR-SCS (F8) compared to the CAR could be because of the higher solubility of CAR in the melted hydrophilic carrier mannitol which helps in wetting of the CAR particles.\n\nNote: Data represented as mean± SD (n=3).\n\nThe in vivo performance of CAR-SCS (F8) was evaluated and is represented in Figure 17. Compared to CAR alone and PM, CAR-SCS showed improved in vivo PK profile. Figure 17 indicates the concentration-time profile of the CAR, PM and the CAR-SCS (F8). The Cmax and tmax after administering single dose of 40 mg/kg of CAR were 2459.95 ± 35.00 ng/mL and 0.75 ± 0.353 h respectively. The Cmax of PM and CAR-SCS (F8) was enhanced 1.176-fold and 3.07-fold respectively in comparison to the Cmax of plain CAR. The difference in the tmax and Cmax values for the CAR, PM and CAR-SCS (F8) was statistically significant (p < 0.05). The t1/2 of CAR-SCS (F8) were higher than the plain CAR depicting that the CAR-SCS showed a prolonged residence time in the body. The AUC0-24 for the CAR-SCS enhanced 1.50-fold than the plain CAR, indicating a noteworthy enhancement in the oral bioavailability. The pharmacokinetic parameters are represented in Table 7. This enhanced oral bioavailability may be due to the (i) enhancement in the solubility and dissolution of the CAR in the CAR-SCS, (ii) enhanced passive diffusion of CAR via the intestinal membrane owing to the increased concentration gradient.\n\nNote: Data represented as mean± SD (n=4).\n\nThe stability studies were performed on the CAR-SCS (F8) formulation at accelerated stability conditions (40°C/75% RH) for 3 months (Thermolab stability chamber, 500 L). The DSC studies revealed the crystallinity of the CAR-SCS (F8) even after 3 months. The same DSC pattern was observed throughout the stability period (Figure 18). The drug content for the CAR-SCS (F8) after a period of 1 month, 2 months and 3 months was found to be 77.73 ± 0.98 %, 77.70 ± 1.00 %, and 77.50 ± 1.00 %. The results indicated that the CAR-SCS (F8) was stable for three months with no change in its appearance and drug content.\n\n\nConclusions\n\nSolid crystal suspensions offer a unique way for the solubility enhancement for the poorly aqueous soluble drugs. There are no reports on the preparation of SCS by a TSP process that utilizes co-rotating twin screws with different heating zones within the barrel. The solubility of CAR is affected by the high crystal lattice energy, and the solubility of CAR was considerably enhanced with mannitol. The optimized CAR-SCS (F8), prepared by utilizing a 20:80 ratio of CAR: mannitol at the kneading zone temperatures of 120°C and 100 rpm screw speed, showed higher hydrophilicity and lesser hydrophobicity, which could be the possible reason for the increase in the solubility of CAR in the optimized CAR-SCS (F8). DSC studies revealed the presence of CAR in the stable crystalline form in the CAR-SCS (F8). The in vitro dissolution studies for the optimized formulation (F8) revealed a 6.03 times enhancement in dissolution rate compared to plain CAR in pH 1.2 HCl solution and a 3.40 times enhancement in pH 6.8 buffer. The results of the permeation studies illustrated that the Papp for optimized F8 formulation was higher than plain CAR. The cumulative amount of drug permeated from the plain CAR and CAR-SCS (F8) at the end of 180 min was 47.67% and 98.85% respectively. The in vivo pharmacokinetic study indicated a 3.07-fold enhancement in the Cmax of the CAR-SCS (F8) compared to the plain CAR depicting a significant enhancement in the oral bioavailability. The present platform technology and expertise involving co-rotating TSP instrument with different heating zones used in the development of CAR-SCS could be applied to various drug candidates with poor solubility.",
"appendix": "Data availability\n\nCarvedilol data is available from: (no date) National Center for Biotechnology Information. PubChem Compound Database. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/carvedilol (Accessed: 09 September 2023). 44\n\nMannitol data is avaialble from: (no date) National Center for Biotechnology Information. PubChem Compound Database. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/MANNITOL (Accessed: 09 September 2023). 45\n\nFigShare. Raw data, DOI: https://doi.org/10.6084/m9.figshare.23613693. 46\n\nThis project contains the underlying data:\n\na. The in vivo pharmacokinetic data for the CAR, PM and the CAR-SCS (F8)\n\nb. The ANOVA data generated by the Design Expert software\n\nc. FTIR raw data for (i) plain CAR (ii) Mannitol (iii) PM and (iv) CAR-SCS (F8)\n\nd. DSC raw data for (i) plain CAR (ii) Mannitol (iii) PM and (iv) CAR-SCS (F8) and\n\ne. XRD raw data for (i) plain CAR (ii) Mannitol (iii) PM and (iv) CAR-SCS (F8).\n\nData is available under the terms of Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nFigShare: Untitled Item. https://doi.org/10.6084/m9.figshare.23936067. 47\n\nThis project contains the following ARRIVE guideline files:\n\n- ARRIVE09.09.2023.pdf\n\n\nAcknowledgments\n\nThe authors sincerely thank – (i) All India Council for Technical Education (AICTE), Government of India for providing National Doctoral Fellowship to Prerana D. Navti, (ii) Department of Science and Technology, Government of India, for the INSPIRE fellowship to Soji Soman, (iii) Board of Research in Nuclear Science (BRNS), Department of Atomic Energy, Government of India for providing a research grant (No. 54/14/06/2021-BRNS/10342) and Junior Research Fellowship to Sanjay Kulkarni and (iv) Manipal Academy of Higher Education (MAHE), Manipal for providing Dr. T.M.A Pai Doctoral Fellowship to Gasper Fernandes, Ajinkya N Nikam, and Sumit Birangal. The authors are grateful to Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal and SteerLife Bangalore for providing the facilities and support.\n\n\nReferences\n\nKumar AMS, Kulyadi GP, Mutalik S, et al.: Application of hot melt extrusion for the solubility enhancement of a BCS class II drug. Res. J. Pharm. Technol. 2019; 12(8): 3751–3754. 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Publisher Full Text\n\nNavti PD, Fernandes G, Soman S, et al.: Co-rotating twin screw process for continuous manufacturing of solid crystal suspension: A promising strategy to enhance the solubility, permeation and oral bioavailability of Carvedilol. figshare. ARRIVE guideline files.pdf. 2023. Publisher Full Text"
}
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[
{
"id": "227292",
"date": "18 Jan 2024",
"name": "Kensaku Matsunami",
"expertise": [
"Reviewer Expertise Pharmaceutical engineering",
"process systems engineering",
"experimental design",
"data analysis",
"mechanistic modeling"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper presents the application of the co-rotating twin-screw process toward the enhancement of the solubility, permeation, and oral bioavailability of Carvedilol. The authors have worked on a large variety of experimental studies (e.g., in-vivo and ex-vivo studies) as well as simulations. The paper is indeed interesting. On the other hand, the paper does not show sufficient discussion and conclusion. It seems like the authors have performed different approaches and shown all results. To be approved as a research article, the authors need to revise the discussion and the conclusion sessions to make sure \"what each result means in terms of the objective of the study\" and \"what is the general conclusion obtained through different types of studies.\"\nWhile the reviewer understands the value of MD or in-silico approaches, it is not clear why in-silico approaches are necessary for your study. The introduction should be improved so that the readers can understand the necessity of MD studies.\nThe followings are minor comments.\nTable 1: Better to add units on the top (especially for temperature).\nFormulation of Solid crystal suspension of Carvedilol (CAR-SCS) by TSP using BBD: the authors wrote \"TSP instrument parameters like kneading zone temperature, screw rpm, and formulation-related parameter (CAR: mannitol ratio),\" but were there any parameters the authors assessed? If not, it is better to clarify that they are \"the\" parameters the authors considered.\nResults- Statistical analysis and optimization using BBD: The results of ANOVA analysis are not clear. Normally, ANOVA results tell which main effects and interactions are statistically significant. However, no value is shown for each factor.\nThe authors did only one trial for the validation. The reviewer wonders if it is not sufficient to validate the model and the authors do either more validation or other analysis to prove the accuracy of the model.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11115",
"date": "13 Apr 2024",
"name": "Srinivas Mutalik",
"role": "Author Response",
"response": "Dear Sir/ Madam, We thank you for the thoughtful review of our manuscript and constructive comments. We appreciate your valuable feedback and suggestions. We have carefully addressed your comments and made revisions. Here, is our detailed response to the comments: To be approved as a research article, the authors need to revise the discussion and the conclusion sessions to make sure \"what each result means in terms of the objective of the study\" and \"what is the general conclusion obtained through different types of studies.\" Reply: We have made changes in terms of what every result means and changes in the conclusion regarding the different studies. it is not clear why in-silico approaches are necessary for your study. The introduction should be improved so that the readers can understand the necessity of MD studies. Reply: We have included in-silico molecular dynamics (MD) aspects for studying the interactions between the CAR and mannitol in different ratios of CAR: mannitol (20:80, 35:65, and 50:50) employed in the study at various kneading zone temperatures (120 °C, 130 °C, and 140 °C) to predict the optimal ratios for preparing CAR-SCS formulations. This information is given in Introduction section as suggested. Minor Comments Table 1: Better to add units on the top (especially for temperature). Reply- The units for the temperature (°C) have been added. Formulation of Solid crystal suspension of Carvedilol (CAR-SCS) by TSP using BBD: the authors wrote \"TSP instrument parameters like kneading zone temperature, screw rpm, and formulation-related parameter (CAR: mannitol ratio),\" but were there any parameters the authors assessed? If not, it is better to clarify that they are \"the\" parameters the authors considered. Reply-The parameters screw rpm and kneading zone temperature was selected on the basis of the preliminary trials conducted. However, we considered varying CAR:mannitol ratio as a formulation related parameter to check whether varying the mannitol concentrations could have impact on the CAR-SCS. This has been mentioned in the Experimental design section. Results- Statistical analysis and optimization using BBD: The results of ANOVA analysis are not clear. Normally, ANOVA results tell which main effects and interactions are statistically significant. However, no value has been shown for each factor. Reply- The details of ANOVA data and the value for each factor has been included the raw data uploaded with the DOI link https://doi.org/10.6084/m9.figshare.23613693. The suggested changes have been made in the manuscript. The ANOVA details have been included in the ‘Statistical analysis and optimization using BBD’ section. We thank you for your valuable feedback, expertise and time in reviewing our manuscript and we believe that the revisions have improved the manuscript significantly."
}
]
}
] | 1
|
https://f1000research.com/articles/12-1438
|
https://f1000research.com/articles/13-529/v1
|
22 May 24
|
{
"type": "Research Article",
"title": "Evaluating the effect of the addition of Nano-cellulose fibers on certain properties of heat-cured acrylic resin denture base material",
"authors": [
"Maysem H. Fadhel",
"Ihab N.Safi",
"Maysem H. Fadhel"
],
"abstract": "Background Polymethylmethacrylate (PMMA) is the most often used polymer for denture bases because to its inexpensive cost, lightweight nature, insolubility in mouth fluid, outstanding cosmetic features, and ease of repairability. However, various limitations such as insufficient surface hardness, low strength, brittleness, weak flexural strength, poor impact strength, and low fatigue resistance have a detrimental impact on acrylic resins.\n\nMethod This research examined the impact strength, transverse strength, surface hardness, surface roughness, and color stability of heat-cured acrylic denture base material after 0.5% and 1% by wt. CNFs were added. The cellulose nanofibers were combined with a PMMA monomer for 5 minutes in a probe sonicator. One group of samples was made without cellulose nanofibers in PMMA, while two groups were prepared with 0.5% and 1% CNFs by weight, and tests of the impact strength, transverse strength, surface hardness, surface roughness, and color stability of the samples were carried out. The data were analyzed using descriptive statistics, including the mean and standard deviation, and bar charts were used to visualize the results. Sample interactions and fiber dispersion were assessed using FTIR and FE-SEM.\n\nResults Compared to the control group, 0.5% by wt. and 1% by wt. CNF improved the impact and transverse strength substantially, while shore D surface hardness was not improved. Hue (a) and chroma (b) were substantially influenced by CNF at 0.5% by weight compared to the control group, although surface roughness and color value (L) were not. Surface roughness, color value (L), and color hue (a) were substantially impacted by 1% compared to the control group; however, color chroma (b) was not.\n\nConclusions This research found that 0.5% and 1% by wt. CNF in PMMA resin increased the impact strength, transverse strength, surface hardness, surface roughness, color value, hue, and chroma of heat-cured polymethyl methacrylate denture base material.",
"keywords": [
"Cellulose nanofibers",
"CNF",
"PMMA",
"Impact",
"transverse",
"hardness",
"roughness",
"Color stability"
],
"content": "1. Introduction\n\nPolymethyl methacrylate (PMMA) has long been used to construct partial or complete edentulous denture bases because of its good color matching with the gum, low cost of manufacture, and biocompatibility within the oral environment.1,2 In addition, PMMA is dimensionally stable, tasteless and odorless, non-irritating and non-toxic, and is insoluble in saliva.3,4 PMMA has deficiencies in certain mechanical and physical properties, including impact resistance, flexural strength, fatigue fracture,5,6 insufficient surface hardness, low strength, and brittleness upon impact.7 Dentures lose their effectiveness in a significant number of cases (63–68%) due to fractures brought on by chewing forces or impacts from dropping them on hard surfaces while they are out of the mouth.8,9 Important physical characteristics, such as color stability, must be considered when conducting research to improve the properties of PMMA denture bases via various reinforcing techniques.\n\nPreviously, in an effort to prevent fractures, strategies such as metal wires have been used to reinforce the PMMA denture base, but a lack of adhesion between the wire surface and the PMMA matrix has been a problem.10 Despite the strong impact resistance of butadiene styrene for enhancement of the denture base,11,12 the bending strength of a copolymer of polymethyl methacrylate and butadiene styrene was found to be lower than that of PMMA and standard acrylic resin.\n\nMicro- or nano-sized fibers and fillers have been used to try to make PMMA denture base materials better in terms of their mechanical and physical properties.13\n\nBased on recent research, incorporating natural fibers into polymers to improve their properties is an effective technique. Because natural fibers are renewable, affordable, abundant in nature, extremely biocompatible, and possess favorable mechanical properties,14 the use of natural fibers (ramie fiber or oil palm empty fruit cluster fiber) as strengtheners can enhance the flexural capabilities of heat-polymerizing PMMA denture base material.15,16\n\nSeveral nanoparticles have been used to improve the mechanical and physical properties of polymer composites. Among them, cellulose nanomaterial has been dubbed “the future of materials” and has been the subject of numerous studies in the past two decades.17,18\n\nMany researchers are interested in cellulosic nanomaterials due to their natural abundance and biodegradability, as well as their many other properties that contribute to the functionality and improvement of material performance. The creation of polymer nanocomposites utilizing nano-cellulose has grown in popularity due to the unique properties of these nanoparticles, such as their abundance of surface OH groups. Compared to other synthetic fibers, cellulose nanofibers have superior mechanical properties, high aspect ratios, and are a readily available material resource.19 Using chemical and mechanical procedures, cellulose from any source, such as wood pulp,20 is converted into cellulose nanofibers which is also known as cellulose nanofibril or nanofibrilated cellulose. CNFs have notable potential in dental applications. Their unique shape, which incorporates nano- and microscale capabilities, supports their use as a mechanical reinforcement.21\n\nCNFs have a diameter on the nanometer scale and a length of a few micrometers.22,23 The aim of this study was to look at how mechanical and physical properties change in heat-cured acrylic resin with 0.5% and 1% cellulose nanofibers by weight added to it. As far as the authors are aware, no prior research has examined the impact of adding CNFs to heat-cured denture base material.\n\nThe null hypothesis of this study was that adding 0.5–1% by weight of CNFs would have no significant effect on the impact strength, transverse strength, surface hardness, surface roughness, and color stability of PMMA heat-cured denture base material.\n\nFigshare: checklist for (Evaluating the effect of the addition of Nano-Cellulose fibers on certain properties of heat-cured acrylic resin denture base material), https://doi.org/10.6084/m9.figshare.25048673.v1.61\n\n\n2. Methods\n\nIn this investigation, a conventional acrylic resin denture base material (Supracryl Plus, Czech Republic, catalogue N. 129 4328411) was used, and cellulose nanofibers (Nanografi Nano Technology Company, Germany, NG01NC0201) (CNFs; diameter: 40–80 nm; length: 2–5 μm) were added to the PMMA liquid at two different concentrations, 0.5% and 1%.\n\nA total of 0.5, 1, 1.5, and 2 wt.% of CNFs were added to the resin, and then the transverse strength and hardness of each percentage were tested and compared with the control group (acrylic resin without CNFs). The two most appropriate percentages were determined to be 0.5 and 1% wt based on these tests. Therefore, these concentrations were utilized for the study.\n\nA total of 150 samples were created and split evenly into three groups based on the amount of cellulose nanofibers present: 0% CNF (control), 0.5% CNF (test), and 1% CNF (test). The samples were divided into five classes based on the tests of impact and transverse strength, as well as those for surface hardness, surface roughness, and color stability.\n\nSpecimens were prepared in the shape of bars measuring 80 mm × 10 mm × 4 mm for the impact strength test,24 and bar specimens measuring 65 × 10 × 2.5 mm were prepared for the surface hardness, transverse strength, and surface roughness tests.25 A sample disc with a 20 mm diameter and a 2 mm thickness was made and used in the color change experiments. The plastic molds were cut with a laser cutter to the precise dimensions needed for each test.26 All of the samples were created following the standard practice for making removable dentures from acrylic. The molds were made by placing plastic samples in an extra-hard Type IV dental die stone. Samples of acrylic resin were packed using these molds. Control samples of heat-cured acrylic were made by combining the liquid and powder components of PMMA. To ensure that the mold was completely filled with acrylic dough, we used a hydraulic press set at a pressure of 100 Kp/cm2 to gradually squeeze the flask after joining its two halves with a polyethylene sheet. The polyethylene sheet was taken out of the flask after the pressure was released. The extra material was cut away with a razor-sharp wax knife. After removing the polyethylene sheet from the second closure, the flask was pressed (100 Kp/cm2) for five minutes. The flask was sealed and taken to a curing water bath. Following the manufacturer’s guidelines for acrylic resin, the flasks were placed clamped in a thermostatically controlled water bath at room temperature, the temperature was increased to 70 °C, the flasks were left at this temperature for 30 minutes, and finally the temperature was raised to 100 °C. The flasks were kept for 30 minutes in this temperature to complete the curing process. The polymerization flasks were left to cool, and the specimens were kept in distilled water for 48 hours before further testing.\n\nThe CNFs were surface-modified with methyl methacrylate (MMA) to create a homogenized dispersion and prevent agglomeration of the CNFs in the heat-cured acrylic resin polymer.27 CNF-incorporated samples were prepared by adding 0.5% and 1% by weight of CNFs to the liquid of heat-cured acrylic resin denture base material and mixing this mixture in a probe sonicator device (120 W, 60 KHz), (soniprep-150, England) for about 5 minutes, then adding this mixture to the acrylic polymer to manually complete the blending.\n\nImpact strength test\n\nThirty samples were made in total, with ten serving as a control group and the remaining twenty being acrylic samples with varying concentrations of cellulose nanofibers added (0.5% and 1%).\n\nThe Charpy’s impact testing apparatus (Testing Machines Inc., USA) and the method specified in ISO 179-1:200024 were used to conduct the test, which involved holding the specimen horizontally at its ends and striking it with a free-swinging pendulum that could generate a force of 2 joules. A scale measured the amount of impact energy that was absorbed. In order to determine the impact energy in kilojoules per square meter, the following equation was used24:\n\nTransverse strength test\n\nThirty samples were made in total, with ten serving as a control group and the remaining twenty being acrylic samples with varying concentrations of cellulose nanofibers added.\n\nFor this evaluation, a standard Instron device was used. The testing fixture consisted of two parallel supports spaced 50 mm apart, onto which each specimen was placed. A road positioned in the middle of the supports applied the load at a cross-head speed of 1 mm/min, resulting in deflection until fracture. The formula for determining the transverse strength was as follows:\n\nShore D surface hardness\n\nThe surface hardness was measured with a Shore D durometer (HT-5610D, China) which had been verified for use with acrylic resins. A spring-loaded indenter of 0.8 mm in diameter is the main component of this tool. The digital scale with indenter graduated from zero to one hundred. The recommended method involved making a quick, firm press on the indenter to obtain a reading. Each specimen had its center and two ends measured separately, and the average of these three readings was used.\n\nSurface roughness test\n\nThe micro geometry of the samples was examined using a computerized profilometer (LR300, China). The apparatus was connected to a multidirectional metal stand, and this system was linked to a computer. The stylus was adjusted by the metal stand to make contact with specimens and yielded detailed measurements for each specimen. The specimen was placed on a stable and rigid surface before the stylus made contact. Denture base roughness was represented by the parameter Ra, which can be described as the mean arithmetic average of the absolute values of the roughness profile.28\n\nColor stability test\n\nThe contrast between the test samples and the control samples was measured by acquiring digital images of both the control and experimental specimens. The digital images were taken with a Canon EOS Rebel T3i SLR camera and a Sigma 105 mm f/2.8 DG OS HSM Macro lens made in Japan.26 The digital camera was set to manual mode and placed in a perpendicular stand holder so that the shutter speed and f-stop could be adjusted to 1/60 and 5.6, respectively. These measurements were not altered during the photography process.\n\nThe digital images were transferred to a computer and saved as TIFF files. The photos were analyzed using Adobe Photoshop CS6, Version 13.0.1.1 (Adobe Systems, United States). Using mathematical modeling, values for red, green, and blue were acquired and then translated to (L-a-b) or (v-h-c).26 The color deviation (DE) was measured using the CIE (Commission Internationale de l’Éclairage) and the RGB Lab system, as shown in Figure 1.\n\nThe addition of CNF to PMMA was followed by measurements of L, a, and b to determine the color shift in the samples.29 To guarantee consistent and reliable readings, the acrylic sample was attached to and detached from a stable surveyor’s table and then put parallel to the camera lens at regular intervals.30 In order to standardize the calculations, a sixty-pixel square measurement template was created in a sample’s center. The L, a, and b values for the colors were taken from the color picker’s palette window.26\n\nThe color coordinates (L, a, and b) of each sample were measured:\n\nI. Control group: L0, a0, and b0.\n\nII. After the incorporation of 0.5% CNFs to PMMA: L1, a1, and b1 were measured.\n\nIII. After 1% by wt. CNF addition: L2, a2, and b2 were measured.\n\nFourier transform infrared (FTIR) spectroscopy\n\nFourier transform infrared spectroscopy (Fourier-transform, 1800, Sigmadzyu, Japan) was used to determine whether PMMA heat-cured resin and CNFs exhibited any chemical interaction. The modified groups with 1% CNFs, the control group with only PMMA, and the CNF powder-only group were all analyzed.\n\nField-Emission Scanning Electron Microscopy (FESEM)\n\nFour specimens were evaluated in total: one for the control group, two for the experimental groups (0.5% wt. and 1% wt. CNF), and one for the CNF powder. Using a sharp knife, square specimens (2 mm × 10 mm) were used, and 1 nm of gold was applied to the specimens’ testing surfaces. This sputter-coated film enabled uniform and profound electron dispersion throughout the specimen. A field emission scanning electron microscope (INSPECTF50, Netherlands) was used to ascertain the dispersion of CNFs in the polymethylmethacrylate (PMMA).\n\n\n3. Results\n\n3.1.1 Impact strength test\n\nThe average impact strength shown a notable improvement upon incorporation of CNF at 0.5% and 1% by weight concentrations.\n\nAfter 48 hours of incubation in distilled water, the reinforced groups (0.5 and 1% by wt. CNF) exhibited noticeably greater impact strength compared to the control group. Results are displayed in Figure 2(A) from the impact strength test, where the control and experimental groups were compared using the unpaired t-test.\n\n3.1.2 Transverse strength test\n\nThe transverse strength of the control group (PMMA without CNF addition), two reinforced groups (0.5% and 1%), and the results of the unpaired t-test are shown in Figure 2B.\n\nCompared to the control group, the experimental groups showed a considerably increased transverse strength at 0.5% and 1%, respectively. As a whole, the 0.5% group scored the highest, then the 1% group, and lastly the control group.\n\n3.1.3 Shore D surface hardness test\n\nFigure 2(C) displays the results of an unpaired t-test and descriptive statistics applied to the Shore D surface hardness test; these reveal that the control group’s surface hardness did not significantly increase with the addition of 0.5% and 1% by weight CNF, respectively.\n\n3.1.4 Surface roughness test\n\nAfter 48 hours of incubation in distilled water, the surface roughness test revealed that the control group had a value of 2.8660 μm for surface texture roughness, while the 0.5% and 1% groups had values of 2.8977 and 3.3023 μm, respectively. The control group had lower mean values than the experimental groups (0.5 and 1%).\n\nFigure 2(D) displays the findings of the descriptive statistics and statistical test of surface roughness, which compared the control and experimental groups’ means using an unpaired t-test. With a p-value of just 0.0345, the 1% difference between the two groups was statistically significant. The difference between the control group and the group that received specimens with 0.5% reinforced acrylic was not statistically significant (P value = 0.8539).\n\n3.1.5 Color stability test\n\nFor color data studies of color stability, the means and standard deviations of the dependent variables ΔL*, Δa*, and Δb* were determined. The results of the color stability test, including the average and value (L), are shown in Figure 2(E). In terms of mean value, the L2 experimental group came out on top with 32.40, followed by the L1 group with 26.80, and finally the L0 control group with 26.70. While the L0 and L1 groups did not vary statistically, the L0 and L2 groups did, thus the material become lighter in color.\n\nThe a0 group had an average color value of 4,400, the a2 group of 1,500, and the a1 group of 1,100. A statistically significant difference in hue was found between the a0 control group and the experimental groups (a1, a2). This was established using an unpaired t-test. The b chroma was detected. The b0 control group had the highest mean chroma value of 12.00, followed by the b2 group with a value of 11.90 and the b1 group with a value of 7.88.\n\nBased on an unpaired t-test, the chroma levels experienced a significant drop in the b1 group, whereas there was no significant change seen in the b2 or control groups.25\n\n3.1.6 Fourier transforms infrared (FTIR) spectroscopy\n\nThe CNF’s structure includes the functional group OH. As can be seen in Figure 3, the OH stretching vibration can be seen at 3342 cm−1 in the FTIR spectrum of CNF powder, while the OH bending vibration can be seen at 1606 cm−1.\n\nThe fingerprint vibration bands of PMMA are seen at 1732 cm−1 C=O stretching mode. Band at 2949 cm−1 are associated with methylene C-H stretching. The spectra of the nanocomposite (PMMA with 1% CNF) are remarkably similar to that of pure PMMA.\n\n3.1.7 Field-Emission scanning electron microscopy (FE-SEM)\n\nThe field emission scanning electron microscopy (FE-SEM) pictures clearly demonstrated that the fibers had a diameter in the nanometer range, as shown in Figure 4(A&B). The C and D in Figure 4 displayed acrylic in its original state, prior to any modifications. Furthermore, Field Emission Scanning Electron Microscopy (FESEM) demonstrated the successful integration of nanofibers into the PMMA resin by the use of a probe sonicator mixer.\n\n\n4. Discussion\n\nDenture bases are affected by the moist conditions of the oral environment as a result of the constant presence of saliva in the oral cavity, as well as other adverse conditions, such as load from mastication. Improvements in the features of denture acrylic can be achieved through the utilization of nanomaterials. The inclusion of nanofibers or nanotubes has been found to yield more substantial improvements in the properties of polymethyl methacrylate (PMMA) compared to the use of nanoparticle fillers. This is mostly due to the fact that nanotubes and nanofibers possess a greater ratio of surface area to volume than nanoparticle fillers.\n\nThis study was designed to evaluate the effects of various loadings of CNF fibers (0.5% and 1%) on the impact strength, transverse strength, shore D surface hardness, surface roughness, and color stability of PMMA heat-cured denture base material. Additionally, the morphological and structural characteristics were examined using field-emission scanning electron microscopy (FE-SEM) and Fourier transform infrared spectroscopy (FTIR).\n\nConsiderable improvements in the mechanical characteristics were reported in all experimental tests with 0.5% and 1% CNF addition. This was due to the homogenous dispersion of CNFs in the polymeric matrix, which was critical to the composite’s performance. The addition of nanofibers or nanotubes dramatically improved the impact strength of PMMA compared to nanoparticle fillers. This was primarily due to the fact that nanotubes and nanofibers have a higher surface area to volume ratio than nanoparticles (the ratio of nanofibers can be up to 103 times that of microfibers). Superior mechanical performance (such as stiffness and strength) tends to be achieved compared to any other form of the material.31 The nano metric scale can generate massive and extended specific surface areas of up to 1000 m2/g.32 Thus, nanocomposites have a larger interfacial matrix material surface (interphase), which has been reported to play an important role in the interface quality of nanocomposite properties, thereby achieving efficient load transfer from the matrix to the CNF.33 In one study, addition of cellulose nanofibers to epoxy composite increased the impact strength of the epoxy.34 Another study discovered that adding a modest amount (0.3 wt.%) of unmodified cellulose nanofibers from pineapple leaves to PMMA nanocomposite enhanced the impact strength significantly. The researchers attributed this to the hollow structure of the fiber giving an anti-vibration effect.35\n\nThe addition of 0.5% and 1% by wt. CNFs to PMMA significantly increased the transverse strength when compared to the control group. This effect was due to the high tensile strength and elastic modulus of CNFs. These results were consistent with previous findings for PMMA denture base materials combined with microcrystalline cellulose fiber derived from natural oil palm empty fruit bunches.36 They were also consistent with the findings of a study that added cellulose nanofibers to epoxy composites, which resulted in an increase in the transverse strength and epoxy modulus.34 Similar findings were reported for the addition of cellulose nanofibers to thermoplastic and injection molded PMMA heat polymerized acrylic resin denture base material.37 Another study found a significant increase in transverse strength after the addition of 0.5% and 1% by wt. sisal nanofibers to PMMA denture base material.38\n\nThe addition of 0.5% and 1% CNFs caused a small increase in the shore D surface hardness of specimens, which may be attributed to the homogenous distribution of CNFs in the acrylic matrix. The nanofibers were dispersed uniformly throughout the polymer, as shown in Figure 4 (E&F), and developed networks within the polymer over time, thereby reducing the inter-aggregate space and increasing the material’s toughness, stiffness, and hardness.\n\nInterlaminar toughness enhancement in fiber-reinforced composites has been the subject of research for some time, as it is directly related to the composite’s dynamic and damage tolerance performance. A number of strategies have been explored, including stitching,39 Z-pinning,40,41 and interleaving,42 resulting in a substantial increase in toughness and enhancements to mechanical qualities like fatigue life. To achieve the desired interlaminar fracture toughness, other approaches have focused on adjusting the matrix or interface properties. Importantly, toughening the matrix can be achieved either through chemical modification or, more recently, through the addition of chemicals to the matrix material. Grafting can also be utilized to make the fibers and matrix more chemically compatible.43 One study added 0.5% and 1% cellulose nanofibers to maxillofacial silicon material and found a statically significant increase in the shore A surface hardness of the silicon matrix.44 Hussein reported that an increasing nano-filler concentration of zirconia nanoparticles significantly increased the surface hardness.45 The addition of 0.25 wt.% and 0.2 wt.% TiO2 nano-filler, respectively, to the VST50F and Cosmesil M511 elastomers led to a statistically significant increase in their mean values.46 In contrast to these results, PMMA surface hardness was decreased insignificantly with the addition of 1% sisal nanofibers.38\n\nIn this investigation, a profilometer device was utilized, which has been acknowledged as a highly effective method for examining the roughness of the surface of restorative materials. The device provides readings that can be evaluated through statistical analysis and comparison.47 The mean value of surface roughness in the 1% group was the highest, followed by the 0.5% group and the control group. When compared to the control group, adding 0.5% by weight of cellulose nanofibers (CNF) did not make the surface rougher in a way that was statistically significant. However, a significant increase in surface roughness was seen in the 1% group when compared to the control group. The increase in surface roughness of the PMMA denture base material can be attributed to the agglomeration of fibers on the surfaces of the samples, which occurs as the concentration of fibers increases. Additionally, it should be noted that CNFs have small whiskers that extend outward from their surface. The arrangement of CNF fibers during sample preparation is presumed to be random. The presence of various orientations and scattered projecting whiskers on the surface of the PMMA may contribute to the observed increase in the average surface roughness following the addition of cellulose nanofibers. The null hypothesis for surface roughness in this study was rejected because there was a statistically significant difference between the group that did not have nanofibers (PMMA) and the group that had 1% CNFs added to it. Selective dissolving is employed in certain instances to increase the surface roughness of PMMA nanofibers. In this process, polyethylene oxide (PEO) is taken out of a mix of PMMA and PEO. This leaves holes and other irregularities on the surface of the nanofibers.48 Adding nanofibers to PMMA (polymethyl methacrylate) denture base material could have different effects on the surface roughness, depending on the fibers and processing methods used. Adding nanofibers to polymethyl methacrylate (PMMA) has been shown in several studies to make the surface rougher.49 It was found in one study that adding plasma-treated polypropylene fibers to PMMA heat-cured denture bases made the surfaces of the samples rougher.50 In another study,51 it was shown that adding 7% by wt. of ZrO2 nanoparticles (NPs) to PMMA resin made the surface a little rougher. On the other hand, it has been observed that the addition of a specific amount of silicon carbide filler decreases surface roughness.52 The addition of synthesized inorganic, organic, and hybrid nanofibers to PMMA denture base material did not result in a significant effect on the surface roughness of reinforced specimens.53 Addition of 0.5% and 1% nano sisal fiber to PMMA denture base resulted in a significant decrease of surface roughness,38 and it was also found that the addition of burnt sienna intrinsic pigment to silicone elastomer for maxillofacial prostheses did not significantly affect the surface roughness of the silicon matrix.54\n\nFor aesthetic reasons, denture base material should be transparent and have pigmentation allowing it to blend in with natural teeth and gums.55 Additionally, it needs to have excellent color stability in the dynamic oral environment. Adobe Photoshop is often used for digital color analysis in scientific studies of PMMA (polymethyl methacrylate) color stability. Several researchers have examined the effects of various solutions on the optical behavior of 3D-printed resins,56 using Adobe Photoshop as a color assessment tool to evaluate the color stability and wear resistance of provisional restoration.56 In another study, Ali and Safi conducted an assessment of the color stability of maxillofacial silicone following the incorporation of cellulose nanofibers. The evaluation was also performed using Adobe Photoshop software v22.5.8.998 Adobe Systems, USA), https://www.adobe.com/products/photoshop/free-trial-download.html. As indicated by Ref. 44.\n\nAdobe Photoshop can be used for the comparative analysis of color alterations before and after exposure to varying environmental conditions. The software facilitates accurate measurement and analysis of color fluctuations, enhancing the general understanding of the color stability of polymers.\n\nDigital cameras generate images by capturing photographs on a light-sensing medium, resulting in images composed of blue, green, and red RGB values for each individual pixel.57 Based on the findings derived from this investigation, it was evident that color instability occurs in the PMMA, irrespective of whether it is pigmented or not, as shown by ΔE > 1.5. It is worth noting that both intrinsic and external factors have the potential to induce modifications in color value and chromatic alterations.26\n\nWithin the polymer matrix, a denser network forms as the fiber load increases. The fibers tend to occupy any voids or gaps within the polymer. Due to the interaction between light and the polymer, light transmission may be limited. This can cause some light to be partially absorbed and some to be partially reflected. It is the scattering effect of CNFs that reduces light transmission. Because the nanofiber and acrylic polymer have distinct indices of refraction, they cause light to scatter. The scattering effect diminishes the transparency and lightness of the material. Each of the reinforced groups had reduced Chroma and lighter color values compared to the control group.\n\nThe decrease in color saturation (Chroma) was because nanofibers absorb or scatter light.26 This can be caused by the rough surface scattering light in a way that leads to lower color intensity. Additionally, the uneven distribution of nanofibers in the polymer may scatter light more, resulting in lower color intensity.\n\nHighly significant decreases in color hue can have several causes. The size and distribution of nanofillers within the PMMA matrix can impact the way light interacts with the material. Nanofillers of certain sizes may preferentially scatter or absorb specific wavelengths, leading to changes in color. The uniform dispersion of nanofillers is crucial. Aggregation can lead to uneven coloration and affect the overall color hue of the material. In addition, the conditions under which the nanofillers are incorporated into the PMMA matrix can influence their dispersion and, consequently, the optical properties of the resulting material.\n\nThe null hypothesis of this study was rejected, because significant differences was detected among the studied groups. In agreement with this study, significant color change were found to occur after the addition of 1% cellulose nanofibers to vulcanized maxillofacial silicon.39 Significant color variations were also observed between the control group and specimens reinforced with ZrO2 nanoparticles (NPs) in various immersion solutions.58\n\nIn contrast to this study, Safi et al.59 investigated the effect of zirconia nanoparticles on the color properties of polymethyl methacrylate (PMMA), and found no obvious color alterations.\n\nThe FTIR revealed that after adding CNF to PMMA, the peak of the OH stretching vibration disappeared and its intensity diminished. The OH bending vibration at 1606 cm-1 in the CNF spectrum appeared as a new peak after the addition of fibers to the polymer owing to the interaction the OH- functional groups of the CNFs with each other to form physical blending, and the interaction with each (O) pair’s electron in PMMA, as shown in Figure 3. Moreover, the presence of more than one active site of the functional-OH group leads to physical interactions (molecular interaction) by Van de Waals forces and hydrogen bonds, which enhance bonding strength. Both of these increase the adhesive forces and shear strength.60\n\nFE-SEM demonstrated that a 0.5% CNF concentration was well-dispersed and agglomeration-free, as shown in Figure 4 (E&F). Agglomeration and poor distribution of nanofibers was noted in 1.5% CNFs, as shown in Figure 4 (G&H).\n\n\n5. Conclusions\n\nIncorporating different weight percentages of cellulose nanofibers (0.5–1%) wt. into heat-cured denture base material significantly improved some of its mechanical properties, namely, its impact strength and transverse strength, with the optimum improvement obtained at a concentration of 0.5% CNFs by weight. Cellulose nanofibers increased the hardness and surface roughness of the acrylic resin. The increase was directly proportional to the concentration of the nanofibers, and was within an acceptable clinical range, with no effect on the other material properties. The addition of CNFs at 0.5% wt. had no effect into the translucency of the acrylic material, but a concentration of 1% wt. led to a decrease in translucency. The addition of 0.5% and 1% CNFs led to a significant increase in the color hue (a), while 0.5% CNF increased the color chroma (b) significantly.\n\nThe cellulose nanofibers were effectively dispersed inside the acrylic resin according to FE-SEM, and the FTIR analysis demonstrated highly physical blending between the CNFs and the heat-cured acrylic denture base material.\n\n\nAuthor contributions\n\nConceptualization, Ihab Safi; Data curation, Maysem Fadhel; Formal analysis, Maysem Fadhel; Investigation, Maysem Fadhel; Methodology, Maysem Fadhel; Project administration, Ihab Safi; Resources, Maysem Fadhel; Software, Maysem Fadhel; Supervision, Ihab Safi; Validation, Maysem Fadhel; Visualization, Ihab Safi; Writing – original draft, Maysem Fadhel; Writing – review & editing, Ihab Safi.",
"appendix": "Data availability\n\nFigshare: Evaluating the effect of the addition of Nano-Cellulose fibers on certain properties of heat-cured acrylic resin denture base material. https://doi.org/10.6084/m9.figshare.25048673.v1. 61\n\nThis project contains the following underlying data:\n\n• Impact strength (Raw data of impact strength test)\n\n• Transverse strength (Raw data of transverse strength test)\n\n• Surface hardness (Raw data of Surface hardness test)\n\n• Surface roughness (Raw data of Surface roughness test)\n\n• Color stability (All raw data of Color stability test)\n\nData are available under the terms of Creative Commons Attribution 4.0 International license (CC BY 4.0).\n\n\nReferences\n\nKarci M, Demir N, Yazman S: Evaluation of flexural strength of different denture base materials reinforced with different nanoparticles. Journal of Prosthodontics. 2019; 28(5): 572–579. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nJonoobi M, Oladi R, Davoudpour Y, et al.: Different preparation methods and properties of nanostructured cellulose from various natural resources and residues: a review. Cellulose. 2015; 22: 935–969. Publisher Full Text\n\nThomas S, Paul SA, Pothan LA, et al.: Natural fibres: structure, properties and applications. Cellulose Fibers: Bio-and Nano-Polymer Composites. Green Chemistry and Technology; 2011; pp. 3–42. Publisher Full Text\n\nSouza S, Ferreira M, Sain M, et al.: The use of curaua fibers as reinforcements in composites. Biofiber Reinforcements in Composite Materials. 2015; pp. 700–720. Elsevier. Publisher Full Text\n\nSouza SF, Leao AL, Cai JH, et al.: Nanocellulose from curava fibers and their nanocomposites. Molecular Crystals and Liquid Crystals. 2010; 522(1): 42/[342]–52/[352]. Publisher Full Text\n\nISO E: 179-1. 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PubMed Abstract | Publisher Full Text\n\nYetkiner E, Wegehaupt F, Wiegand A, et al.: Colour improvement and stability of white spot lesions following infiltration, micro-abrasion, or fluoride treatments in vitro. European Journal of Orthodontics. 2014; 36(5): 595–602. Publisher Full Text\n\nHallgren K, Akyalcin S, English J, et al.: Color properties of demineralized enamel surfaces treated with a resin infiltration system. Journal of Esthetic and Restorative Dentistry. 2016; 28(5): 339–346. Publisher Full Text\n\nNjuguna J, Pielichowski K, Desai S: Nanofiller-reinforced polymer nanocomposites. Polymers for Advanced Technologies. 2008; 19(8): 947–959. Publisher Full Text\n\nNjuguna J, Pielichowski K, Alcock JR: Epoxy-based fibre reinforced nanocomposites. Advanced Engineering Materials. 2007; 9(10): 835–847. Publisher Full Text\n\nDe Azeredo HM: Nanocomposites for food packaging applications. Food Research International. 2009; 42(9): 1240–1253. Publisher Full Text\n\nSaba N, Mohammad F, Pervaiz M, et al.: Mechanical, morphological and structural properties of cellulose nanofibers reinforced epoxy composites. International Journal of Biological Macromolecules. 2017; 97: 190–200. PubMed Abstract | Publisher Full Text\n\nShih YF, Chou MY, Lian HY, et al.: Highly transparent and impact-resistant PMMA nanocomposites reinforced by cellulose nanofibers of pineapple leaves modified by eco-friendly methods. Express Polymer Letters. 2018 Sep 1; 12(9): 844–854. Publisher Full Text\n\nJohn J, Ann Mani S, Palaniswamy K, et al.: Flexural properties of poly (Methyl Methacrylate) resin reinforced with oil palm empty fruit bunch fibers: a preliminary finding. J. Prosthodont. 2015; 24(3): 233–238. PubMed Abstract | Publisher Full Text\n\nKawaguchi T, Lassila LV, Baba H, et al.: Effect of cellulose nanofiber content on flexural properties of a model, thermoplastic, injection-molded, polymethyl methacrylate denture base material. J. Mech. Behav. Biomed. Mater. 2020 Feb 1; 102: 103513. Publisher Full Text\n\nHameed TM, Al-Dabbagh BM, Jasim RK: Reinforcement of denture base materials with Nano sisal fibers powder. Materials Today: Proceedings. 2022 Jan 1; 61: 1015–1022. Publisher Full Text\n\nJohnson WS: Delamination and debonding of materials: a symposium sponsored by ASTM Committees D-30 on High Modulus Fibers and Their Composites and E-24 on Fracture Testing, Pittsburgh, Pa., 8-10 Nov. 1983: ASTM International.1985.\n\nCartie IK: Partridge. Proc. of 44th AIAA/ASME/ASCE/AHS/ASC Structures, Structural Dynamics, and Materials Conference. Apr 7-10 2003. Norfolk: 2003; 1,707\n\nMarasco AI, Cartié DD, Partridge IK, et al.: Mechanical properties balance in novel Z-pinned sandwich panels: Out-of-plane properties. Composites Part A: Applied Science and Manufacturing. 2006 Feb 1; 37(2): 295–302. Publisher Full Text\n\nChan W, Wang A: A study on the effects of the 90 deg ply on matrix cracks in composite laminates. In27th Structures, Structural Dynamics and Materials Conference.1986; p. 1018.\n\nXu LR, Bhamidipati V, Zhong WH, et al.: Mechanical property characterization of a polymeric nanocomposite reinforced by graphitic nanofibers with reactive linkers. Journal of Composite Materials. 2004 Sep; 38(18): 1563–1582. Publisher Full Text\n\nAli AA, Safi IN: Impact of nano-cellulose fiber addition on physico-mechanical properties of room temperature vulcanized maxillofacial siliconematerial. Journal of Taibah University Medical Sciences. 2023 Dec; 18(6): 1616–1626. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRahman HA: The effect of addition nano particle ZrO2 on some properties of autoclave processed heat cure acrylic denture base material. Journal of Baghdad College of Dentistry. 2015; 27: 32–39. Publisher Full Text\n\nShakir DA, Abdul-Ameer FM: Effect of nano-titanium oxide addition on some mechanical properties of silicone elastomers for maxillofacial prostheses. Journal of Taibah University Medical Sciences. 2018 Jun 1; 13(3): 281–290. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBalamurugan R, Muruganand S: Study of surface roughness by stylus profilometer and binary laser speckle B/D counting techniques. International Journal of Advanced Research in Electrical, Electronics and Instrumentation Engineering. 2015 May; 4(5): 4559–4563.\n\nPhilip P, Jose ET, Chacko JK, et al.: Preparation and characterisation of surface roughened PMMA electrospun nanofibers from PEO-PMMA polymer blend nanofibers. Polymer Testing. 2019 Apr 1; 74: 257–265. Publisher Full Text\n\nGad MM, Fouda SM, Al-Harbi FA, et al.: PMMA denture base material enhancement: a review of fiber, filler, and nanofiller addition. International Journal of Nanomedicine. 2017 May 17; 12: 3801–3812. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIsmail IJ, Muklif O: Studying the effect of addition a composite of silanized Nano-Al2O3 and plasma treated polypropylene fibers on some physical and mechanical properties of heat cured PMMA denture base material. Journal of Baghdad College of Dentistry. 2015; 27(3): 22–27. Publisher Full Text\n\nHameed HK, Abdul Rahman H: The effect of addition nano particle ZrO2 on some properties of autoclave processed heat cures acrylic denture base material. Journal of Baghdad College of Dentistry. 2015; 27: 32–39. Publisher Full Text\n\nAli Sabri B, Satgunam M, Abreeza NM, et al.: A review on enhancements of PMMA denture base material with different nano-fillers. Cogent Engineering. 2021 Jan 1; 8(1): 1875968. Publisher Full Text\n\nAbdel-Karim UM, El-Safty SM, Kenawy ER: Surface roughness, hardness, color Stability, Water Sorption and Water Solubility of PMMA denture base Material reinforced with Synthesized inorganic, organic, and hybrid nanofibers. Egyptian Dental Journal. 2018 Oct 1; 64(4-October (Fixed Prosthodontics, Dental Materials, Conservative Dentistry & Endodontics)): 3593–3608.\n\nAbdullah HA, Abdul-Ameer FM: Evaluation of some mechanical properties of a new silicone elastomer for maxillofacial prostheses after addition of intrinsic pigments. The Saudi Dental Journal. 2018 Oct 1; 30(4): 330–336. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlqutaibi AY, Baik A, Almuzaini SA, et al.: Polymeric Denture Base Materials: A Review. Polymers. 2023 Jul 31; 15(15): 3258. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShishehian A, Firouz F, Khazaee S, et al.: Evaluating the color stability of 3D-printed resins against various solutions. European Journal of Translational Myology. 2023; 33. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJoiner A, Luo W: Tooth colour and whiteness: a review. Journal of Dentistry. 2017; 67: S3–S10. Publisher Full Text\n\nIhab NS, Hasanen KA, Ali NA: Assessment of Zirconium Oxide Nano-Fillers Incorporation and Silanation on Impact, Tensile Strength and Color Alteration of Heat Polymerized Acrylic Resin. Journal of Baghdad College of Dentistry. 2012; 24: 36–42.\n\nSafi IN, Moudhaffar M: Evaluation the effect of modified nano fillers addition on some properties of heat cured acrylic denture base material. Journal of Baghdad College of Dentistry. 2011; 23: 23–29.\n\nBaghaei B, Skrifvars M: All-cellulose composites: A review of recent studies on structure, properties and applications. Molecules. 2020 Jun 19; 25(12): 2836. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFadhel M, Safi I: Evaluating the effect of the addition of Nano-Cellulose fibers on certain properties of heat-cured acrylic resin denture base material. [Dataset]. figshare. 2024. Publisher Full Text"
}
|
[
{
"id": "289060",
"date": "26 Jun 2024",
"name": "Mohammed Alkhafagy",
"expertise": [
"Reviewer Expertise Prosthodontic Dentistry and Dental materials"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1- In page no. 10, {Figure 4. FE-SEM micrograph (A and B) cellulose nanofibers powder at 25000 and 110 000 magnification; (C and D) heat cured acrylic resin controlled specimens at 1000 and 4000 magnification respectively; (E and F) acrylic specimens reinforced with 0.5% CNF at 1000 and 4000 magnification; (G and H) specimens rein[1]forced with 1.5% CNF at 1000x and 4} should change to 1% 2- In page no.12 {FE-SEM demonstrated that a 0.5% CNF concentration was well-dispersed and agglomeration-free, as shown in Figure 4 (E&F). Agglomeration and poor distribution of nanofibers was noted in 1.5% CNFs, as shown in Figure 4 (G&H).} should change to 1%\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "289055",
"date": "05 Jul 2024",
"name": "Rabihah Alawi",
"expertise": [
"Reviewer Expertise Biomaterials"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral comments: Generally, the authors have done studies on physical and mechanical testing on the PMMA incorporated with 0.5 and 1 wt % of CNF and presented the findings in the manuscript as attached. Upon review of the manuscript, there were comments on certain aspects of the writing as stated below. Proof reading is recommended to improve the quality of manuscript. Specific comments: Title: Please be specific on which properties rather than certain properties Abstract Background: Highlight on the CNF in PMMA Methods: -remove this statement. This research examined the impact strength, transverse strength, surface hardness, surface roughness, and color stability of heat-cured acrylic denture base material after 0.5% and 1% by wt. CNFs were added. The tests were mentioned twice whereby all tests were mentioned again in the later part of the paragraph. Sample interactions and fiber dispersion were assessed using FTIR and FE-SEM should be stated in the testing part, before the statistical analysis. Revise sample interactions -statistical analysis, mention what type of statistical test was done and remove bar charts were used to visualize the results. Results: Compared to the control group, 0.5% by wt. and 1% by wt. CNF improved the impact and transverse strength substantially PMMA with 0.5% wt and 1%wt please check for all and clearly state the results Conclusions do not correspond to the findings in results. Keywords: limit to five keywords, and avoid using abbreviations\nIntroduction: highlight how this study is different from the previous studies. Mention also the chemical interaction between PMMA heat-cured resin and CNFs was investigated in this study. Table 1: for pilot study, 1.5% CNF was also used, but not included in table 1 2.1 Study design 0.5, 1, 1.5, and 2 wt.% of CNFs were added to the resin. Please add For a pilot study, 0.5, 1, 1.5, and 2 wt.% of CNFs were added to the resin,. Methodology: Explain CNF incorporation first, followed by sample preparation For the sample size of each test, under specific test subheading, please be consistent .for example, in the impact strength test, authors mentioned thirty samples were made in total, with ten serving as a control group and the remaining twenty being acrylic samples with varying concentrations of cellulose nanofibers added (0.5% and 1%). Then, for transverse strength test, authors mentioned thirty samples were made in total, with ten serving as a control group and the remaining twenty being acrylic samples with varying concentrations of cellulose nanofibers added; whereby percentage of CNF was not stated. And for all other tests, the sample size was not stated For transverse strength test, please mention manufacturer and country for instron machine used, rather than stated a standard Instron device. For statistical analysis, please revise the test used, t test is used for comparison between 2 groups. Results: FTIR results, please label X and Y axis on the graph spectrum and highlight the areas of interest for the interaction SEM images, please add bar scale on images SEM, images for samples with 0.5 %wt and 1.5%wt were attached rather than than 0.5%wt and 1.0%wt 1.5% was used for pilot study The nano size of CNF would be better measured using TEM. Discussion The OH bending vibration at 1606 cm-1 in the CNF spectrum appeared as a new peak after the addition of fibers to the polymer owing to the interaction the OH- functional groups of the CNFs with each other to form physical blending, and the interaction with each (O) pair\\ electron in PMMA, as shown in Figure 3.please revise this statement as interaction of electron cannot be seen on FTIR spectrum. Comparison to the studies on silicon seems to be inappropriate, would be better to compare how the PPMA was reinforced in the previous studies, if available. Using natural resources. Agglomeration and poor distribution of nanofibers was noted in 1.5% CNFs, as shown in Figure 4 (G&H).why discussed for sample used in pilot studies? Conclusion Please revise the conclusion; eg: Incorporating different weight percentages of cellulose nanofibers (0.5-1%) wt. into heat-cured denture base material significantly improved some of its mechanical properties. Please revise, as this study used 0.5% and 1% wt only The increase was directly proportional to the concentration of the nanofibers, and was within an acceptable clinical range, please revise this conclusion as the acceptable clinical range was not discussed or mentioned earlier part of the manuscript. FTIR analysis demonstrated highly physical blending between the CNFs and the heat-cured acrylic denture base material. Please revise this conclusion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-529
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https://f1000research.com/articles/13-527/v1
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22 May 24
|
{
"type": "Study Protocol",
"title": "Study of obesity among adolescents in rural Wardha district",
"authors": [
"Arpana Bhagat",
"Ashok Mehendale",
"Komal Muneshwar",
"Ashok Mehendale",
"Komal Muneshwar"
],
"abstract": "Introduction Obesity is one of the most important global issues affecting children and adolescents. The most serious lifestyle effects of adolescents’ obesity and overweight are health risks that continue into adulthood, including hypertension, dyslipidemia, hyperinsulinemia, type 2 diabetes, behavioural issues, and cardiovascular diseases. India is among the many developing nations where childhood and adolescent obesity has become a serious public health issue. Adolescence is the most important stage in physical activity, growth and development. Adolescence is a start of personal decision-making sense and the development of a customized lifestyle, including the early onset of illness, accounting for approximately 35% of the global disease burden. Many of these behavioural choices have been linked to obesity risk factors, which are mostly controlled for, such as unhealthy eating behaviour, excessive television watching, and lack of activity. While undernutrition and deficiencies in micronutrients are serious public health problems in India, obesity and overnutrition have become major problems in several areas.\n\nAim This study aims to assess Obesity among adolescents in rural Wardha.\n\nMethods A cross-sectional study will be conducted in the rural community area of the Wardha District. A questionnaire-based face-to-face interview will be conducted with participants in the adolescent age group (10-19 years). This study aimed to identify variables associated with demographic data, age group, genetic factors, types of family, parents’ education, occupation, socioeconomic status, physical activity, and various types of food intake.\n\nImplication of study The findings of this study could be significant in the implementation of laws, programs, and initiatives to promote awareness of the associations between adolescent obesity and risk factors for lifestyle diseases. This message focuses on having a balanced diet while exercising in regular physical activity. The prevalence of obesity is reduced by this lifestyle disease.",
"keywords": [
"Childhood obesity",
"overweight",
"prevalence",
"risk factors",
"socio-economic"
],
"content": "Introduction\n\nObesity and overweight are major contributing factors for many chronic illnesses, such as diabetes, heart disease, and cancer. In many developing nations, including India, adolescent obesity has become an important public health problem.1 Obesity, particularly childhood obesity, is a critical global health concern, and various health organizations, including the World Health Organization (WHO), have addressed it as a significant public health problem.2 Significant changes in physical, cognitive, and psychological factors characterize adolescence an essential and dynamic period for human development. This stage, typically occurring between the ages of 10-19 years, is an essential period for adolescent body growth and development. The early appearance of disease in approximately 35 per cent of the worldwide disease burden occurs during adolescence.3 Fast-food consumption is a global phenomenon. The fast-food sector in India is growing at an average of 40% annually. Fast food consumption in India ranks 10th in the world, with each person spending 2.1% of the country’s annual total expenditures on it.4 The persistence of overweight and obesity after adolescence is a major public health concern, with far-reaching consequences associated with health risks.5 Early childhood obesity is important because it increases the risk of obesity in adulthood and frequently results in higher morbidity and mortality in early adulthood.6 According to a World Health Organization (WHO) study, there are 300 million obese people and 1 billion overweight people worldwide. Overweight and obesity are pandemics worldwide, the third-most obese nation in the world in India.7 Obesity is defined as the excessive development of adipose tissue caused by an increase in the number of fat cells, their size, or a combination of both.8 Socioeconomic and psychological factors can also contribute to childhood obesity. The main cause of adolescent obesity is the consumption of high-calorie foods, combined with the absence of physical activity. The psychological factors that can lead to adolescent obesity include social isolation, anxiety, and familial stress. Children also frequently consume too much food to cope with their emotions and problems.9 The development and persistence of obesity in adolescents may be due to a significant effect of lifelong factors, such as food patterns and sedentary activities. Children and adolescents usually eat less fruit and vegetables and more fast food and carbonated drinks than adolescents, which have outdoor games and social activities. This has been caused by a higher risk of obesity in adulthood. Consumption of a large number of fruits and vegetables has been associated with a reduced risk of obesity.10\n\nNumerous studies have been conducted on the risk factors for obesity among adolescents in various regions of India, with many of these studies concentrating on children and adolescents. However, only a few studies have examined potential risk factors, such as, that can result in mental health issues. A study on obesity among adolescents aged 10-19 years in the rural field practice area of the Department of Community Medicine in the Wardha District.\n\nThis study aims to assess obesity among adolescents in rural Wardha.\n\n\n\n1) To study the prevalence of adolescent obesity in the study area.\n\n2) To study the associated risk factors for adolescent obesity.\n\n\nMethods\n\nThe present study will be a cross-sectional study.\n\nThe present study will be conducted in an adolescent age group (10-19 years) in the rural Wardha district.\n\nThis study is expected to span a period of 6 months, including recruitment, data collection and analysis.\n\nBoth the boys and girls of adolescent age group of 10-19 years will be of rural Wardha district.\n\nInclusion criteria: study participants (10-19 years) who were willing to participate.\n\nExclusion criteria: Those not willing to participate in the study.\n\nMinimum sample size required\n\nFormula\n\nProportion = 5.4% Adolescent obesity percentage.\n\nP = 5.4% = 0.054 (As per reference article)\n\nD = estimated error (5%) = 0.05\n\nMinimum sample size required: 79.11\n\nAs a result, a sample size of 79 adolescent obesity patients will be used for interviews.\n\nThis study will be going to use a simple random sampling. A questionnaire will be used to interview the study participants to elicit the information on individual socio-demographic characteristics, physical activity, food habits like age, sex, eating habits, and time spent on watching television and outdoor games. Anthropometric measurements viz. height, weight, waist circumference, hip circumference was measured. An interview technique using the online tool kobo collect (https://www.kobotoolbox.org/) will be used. This will be done until the desired sample size is achieved.\n\nVariables associated with socio-demographic data, age group, genetic factors, family size, economic status, physical activity, and junk food consumption.\n\nAn in-depth interview will be used to conduct among randomly selected participants until data saturation is reached. All important information, variables, data sources, methods are shown in Table 1.\n\n\n\n- Age, gender\n\n- Types of family\n\n- Socio- economic status\n\n- parent’s education and occupation\n\n\n\n- Family history of obesity\n\n\n\n- Snack intake\n\n- Junk food\n\n- Chocolates\n\n- Biscuits\n\n- High protein diet\n\n\n\n- Exercise (walking, swimming, running)\n\n- Watching TV, playing games.\n\nA study focused on assessing various aspects of childhood health, including sociodemographic profile, physical activity, dietary intake, and anthropometric measurements. Using a pre-tested semi-structured questionnaire is a good approach for gathering standardized information. Each child’s assessment of height, weight, triceps skin fold thickness (TSFT) measurements, and waist circumference will be measured.\n\nThose undertaking the survey using their device/phone will have the consent check box before ticking.\n\nThis study participants will be selected using a simple random sampling method from pre-university. Written permission will be obtained from the heads of the selected rural government schools. The questionnaire will be administered to early adolescents who fulfil the eligibility criteria with the help of their respective class teachers. Data will be collected from 5th, 6th, 7th, 8th, 9th, 10th, 11th and 12th grade students. The questionnaires will be provided on the sociodemographic profile, genetic factors, types of family, parents’ education, occupation, physical activity pattern, and dietary intake; then, the filled-up data will be collected, and further process will be initiated.\n\nBais: Information Bias. Recall bias.\n\nThe data will be entered in Microsoft Excel. This data will be encoded, and the data will be analysed using R Statistical software 4.3.2 version (https://www.r-project.org/). The data will be tabulated and visualized through graphs and tables. Inferential statistics like T-test and chi-square tests will be used.\n\nThis study aimed to identify the risk factors associated with obesity and the prevalence of overweight and obesity among adolescents. Also This study also revealed an association between the demographic factors and obesity.\n\nThe approval for carrying out this study has been commenced from Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research, Ref. No. DMIHER (DU) IEC/2023/38) on Dated 20/12/2023.\n\nConsent: Written permission will be obtained from the heads of the identified rural government schools. The written consent will be in local language (Marathi) for more clarity and better understanding. Measures will be taken to ensure confidentiality of the information throughout the study.\n\n\nDiscussion\n\nThe following studies conducted on this subject by recognized researchers were cited in this study. George et al. (2012) conducted a cross-sectional study at the Nehru Memorial Public School in a rural Kollam area in Kerala State. Body mass index (BMI), weight, and height were also measured. Overweight was observed in 15% of girls and 19% of boys. The Obesity prevalence was 8% in females and 6% in boys. In boys, underweight was more common (3%), in girls, it is 10%). Furthermore, compared to females, boys were more likely to be overweight, while girls were more likely to be obese.12\n\nSitaula et al. (2022) conducted institution-based cross-sectional research; 267 adolescents were found to be 14.6% obese and 14.6% overweight. 12.6% Of male children in the study were overweight, compared with 39.6% of the female participants who were in this category of obesity. 16.5% of the participants overall—14.0% of the girls and 20.4% of the males—were underweight. Adolescent girls are almost five times more likely to be overweight than are male adolescents.13\n\nSeema et al. (2018-19), a cross-sectional study, was used in observational research. 6.8% of adolescents were found to be fat and 17.1% to be overweight. 22.3 per participants have been identified as underweight, and the remaining 53.8% were in the normal BMI group. A strong correlation was found between gender, financial position, eating habits, chocolate consumption, when adolescents arrive at school, participation in sports, physical exercise, and screen time. Teens who enjoyed sports and engaged in physical exercise had healthy body mass indices. These were only a few factors contributing to the high rate of obesity among adolescents, were also at greater risk of being fat.6.8% of adolescents were found to be fat, and 17.1% were overweight.14\n\nPathak et al. (2016) conducted a cross-sectional study at private schools in Vadodara, Gujarat, in both urban and rural areas. According to this frequency, these children were underweighted, overweight, obese, and normal. The odds ratio was 17.7 in Favour of urban living, with 65.22% of urban males and 62.26% of urban females being obese or overweight compared to 15.78% of rural men and 3.92% of females. There were statistically significant changes in family yearly income, the more in-person training sessions conducted in a school, and more frequent in restaurant and school canteen meals. There was no statistically significant correlation observed between the two groups and other characteristics, such as eating breakfast before school, enjoying fast food, participating in outside activities, using electronics during meals, and having fat family members.15\n\nShete et al. (2017–18) conducted a cross-sectional study with study participants ranging in age from 11 to 16 years at the Chhatrapati Shahu Vidyalaya in New Palace, Kolhapur, Maharashtra. Among those involved, boys made up 58.9%. The 13–14 age group comprised 66.7% of the student group. 8.7% of adolescents were obese and 46.9% were underweight according to the body mass index. Junk food was consumed more than once per week by 77.3% of individuals.7\n\nThe findings of this study could be significant in the implementation of laws, programs, and initiatives to promote awareness of the associations between adolescent obesity and risk factors for lifestyle diseases. This message focuses on having a balanced diet while exercising in regular physical activity. The prevalence of obesity is reduced by this lifestyle disease.\n\nTo validate these results more precisely, a large number of children will be involved in government schools. In other methods of assessing overweight, such as waist-hip circumference, during the interview, there may be potential behavioural, recall bias for dietary patterns, physical activities, and sedentary behaviour of the participants.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nFigshare: Questionnaire for “Study of Obesity among Adolescents in Rural Wardha District”, https://doi.org/10.6084/m9.figshare.25610652.v1. 16\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nMahajan PB, Purty AJ, Singh Z, et al.: Study of childhood obesity among school children aged 6 to 12 years in Union territory of Puducherry. Indian J. Community Med. 2011; 36: 45–50. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChandrakala P, Soumya A: A S: A study of the prevalence of overweight and obesity in adolescents. Int. J. Contemp. Pediatrics. 2016; 3: 960–964. Publisher Full Text\n\nKotian MS, Ganesh Kumar S, Kotian SS: Prevalence and determinants of overweight and obesity among adolescent school children of south Karnataka, India. Indian J. Community Med. 2010; 35: 176–178. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrajapati K, Nayak S, Dhande N, et al.: Prevalence of overweight and obesity among rural early adolescents in the central part of Vidarbha, Maharashtra- A cross sectional study. Int. J. Med. Res. Rev. 2017; 5: 725–730. Publisher Full Text\n\nLaxmaiah A, Nagalla B, Vijayaraghavan K, et al.: Factors affecting prevalence of overweight among 12 to 17year-old urban adolescents in Hyderabad. India Obesity. 2007; 15: 1384–1390. PubMed Abstract | Publisher Full Text\n\nMistry SK, Puthussery S: Risk factors of overweight and obesity in childhood and adolescence in South Asian countries: a systematic review of the evidence. Public Health. 2015; 129: 200–209. PubMed Abstract | Publisher Full Text\n\nShete JS: Wagh AV: A cross-sectional study to estimate prevalence of obesity and its risk factors in adolescent school children in Western Maharashtra, India. Int. J. Res. Med. Sci. Technol. 2018; 6: 3072–3075. Publisher Full Text\n\nAhmed M, Shah K, Kshirsagar V: Prevalence and risk factor for obesity in urban and rural school going children of Karad taluka, Maharashtra, India. Int. J. Contemp. Pediatrics. 2016; 1389–1393. Publisher Full Text\n\nAbduelkarem AR, Sharif SI, Bankessli FG, et al.: Obesity and its associated risk factors among school-aged children in Sharjah, UAE. PLoS One. 2020; 15: e0234244. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRani MA, Sathiyasekaran BWC: Behavioural determinants for obesity: A cross-sectional study among urban adolescents in India. J. Prev. Med. Public Health. 2013; 46: 192–200. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIncreasing trend of obesity in the adolescents from rural Wardha - Current issue - IJSR. Accessed: October 13, 2023. Reference Source\n\n1521_pdf-libre.pdf.\n\nSitaula D, Dhakal A, Lageju N, et al.: Prevalence and associated factors of adolescent obesity among rural school adolescents in Nepal: A cross-sectional study. Glob. Health Epidemiol. Genom. 2023; 2023: 2957278. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSeema S, Rohilla KK, Kalyani VC, et al.: Prevalence and contributing factors for adolescent obesity in present era: Cross-sectional study. J. Family Med. Prim. Care. 2021; 10: 1890–1894. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPathak S, Modi P, Labana U, et al.: Prevalence of obesity among urban and rural school going adolescents of Vadodara, India: A comparative study. Int. J. Contemp. Pediatrics. 11 June 2018; 5: 1355. Publisher Full Text\n\nBhagat A: Study of Obesity among Adolescents in Rural Wardha District. figshare. 2024. Publisher Full Text"
}
|
[
{
"id": "303953",
"date": "09 Sep 2024",
"name": "Moazzam Tanveer",
"expertise": [
"Reviewer Expertise Overweight and ObesityBody Mass Index (BMI)School SportsSocial-Ecological Model (SEM) (e.g.",
"Intrapersonal",
"Interpersonal",
"School",
"Community)24-Hour Movement BehaviorChildren and Adolescents – The YouthInterventions"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nArticle Title: \"Study of Obesity Among Adolescents in Rural Wardha District.\"\n\n1. Clarification of Methodology: - The methodology section could benefit from more detail regarding the sampling method and the rationale behind the chosen sample size. It would be helpful to specify how participants will be recruited and how random sampling will be implemented in practice.\n2. Data Collection Instruments: - Provide more detail on the validation process for the questionnaire. It’s essential to ensure the questionnaire has been pre-tested or piloted to confirm its reliability and validity.\n3.Statistical Analysis Plan: - While the plan mentions the use of R statistical software, it could be improved by outlining specific statistical tests or models that will be applied to the data. This could include regression analyses, factor analyses, or other relevant techniques depending on the data's nature.\n4.Discussion of Limitations: - The limitations section should explicitly discuss potential biases and limitations related to the study design, such as the self-reported nature of dietary and physical activity data, which might be prone to recall bias.\n5. Ethical Considerations: - Expand on the ethical considerations, especially concerning the privacy and confidentiality of the adolescent participants. It would also be beneficial to mention how parental consent will be handled.\n6. Reference List: - Ensure that all references are up-to-date and relevant. If any older references are used, they should be critically evaluated for their continued relevance in light of more recent research.\n7. Implications of the Study: - The implications section could be enhanced by discussing potential public health interventions that could arise from the findings, and how these interventions could be implemented in similar rural settings beyond Wardha.\n8. Formatting and Language: - Review the document for consistency in formatting, especially regarding headings, subheadings, and citation styles. Also, ensure that the language is clear, concise, and free of any grammatical errors.\n\nIs the rationale for, and objectives of, the study clearly described? No\n\nIs the study design appropriate for the research question? No\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? No",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-527
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https://f1000research.com/articles/13-523/v1
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22 May 24
|
{
"type": "Systematic Review",
"title": "PREVALENCE OF DEPRESSION AMONG MEDICAL STUDENTS IN AFRICA: A SYSTEMATIC REVIEW AND META-ANALYSIS",
"authors": [
"Ivaan Pitua",
"Amelia Margaret Namiiro",
"Raafidha Raizudheen",
"Lorraine Apili",
"Amelia Margaret Namiiro",
"Raafidha Raizudheen",
"Lorraine Apili"
],
"abstract": "Background Depression is among the most common mental health disorders affecting social and academic progress of university students globally. However, the variations in prevalence reported by different published studies leaves the true burden of depression among medical students in Africa unknown.\n\nObjectives This study aimed at conducting a systematic review and meta-analysis to report the true estimate of prevalence of depression among medical students in Africa between 2012 and 2022.\n\nMethods Articles that reported prevalence of depression among medical students in Africa between 2012 and 2022 study period were searched for in PubMed, Google Scholar, African Journals Online, and Embase. Two investigators independently extracted the data for full review and eligible studies were considered for analysis after a consensus, quality of articles was assessed using JBI Critical Appraisal tool [1] for prevalence studies. R version 4.3.2 [2] was used to establish the pooled prevalence using a random effects model, funnel plot and Eggers test were used to check for publication bias.\n\nResults A total of twenty-six cross-sectional studies involving 11386 (Females: 6070, 53.3%) medical students, mean age 23, were included in this study. PHQ9 (n=10), DASS21 (n=7), BDI-II (n=5) were the most used screening instruments. The overall pooled prevalence of depression was 38% (p < 0.00). Sub-group analysis by instrument used i.e. DASS21, PHQ-9, BDI-II, revealed prevalence of 50% (p < 0.01), 39% (p < 0.01) and 32% (p < 0.01) respectively.\n\nConclusion Nearly two-fifths of medical students in Africa suffer from depression. The findings emphasize the urgent need for research into the causes, alongside early diagnosis with standardized tools and targeted interventions to manage depression effectively among this demographic. PROPERO (CRD42022372866).",
"keywords": [
"Depression",
"Depressive symptoms",
"Medical students",
"Africa"
],
"content": "1. Introduction\n\nOver the last decade, there has been an increase in interest in university students’ mental health as depressive symptoms affect between 24 and 34 percent of university students worldwide and has also been reported to be more prevalent among health professions students than in the general population.3 In a recent study, up to 27.2% of medical students had depression globally affecting about a third of medical students worldwide.4 Understanding the burden of psychological morbidity among these students is critical and interventions are especially beneficial in resource-constrained contexts, such as low and middle-income countries (LMICs), where the best solution may not be readily available.5,6 Medical students in Africa have also been found to have a significant prevalence of depression, according to recent studies with more association with the female sex than their male counterparts (5). Olum et al noted a prevalence of 21.5% among medical students at Makerere University, which is similar to related research findings on medical students in Nigeria (17.4%)7 and Sudan (21.5%).8 Academic pressure, demanding workloads, concern about one’s own health, financial concerns, exposure to patients’ suffering, student abuse and mistreatment are all factors associated with psychological morbidity among medical students.9,10 Depression is also associated with higher suicide rates, which may explain why medical professionals have a higher suicide rate than the general population.10,11 Students who are experiencing extreme stress or depression require immediate attention; otherwise, their inability to cope successfully with the enormous stress of education may result in a cascade of personal and professional consequences.11–13 Students’ psychological distress can have a negative impact on their academic performance and quality of life, as well as contribute to alcohol and substance abuse, decreased empathy, and academic dishonesty.12,14 Given the risks and consequences of psychological morbidity on students, as well as the remarkable growth in medical student numbers in Sub-Saharan Africa over the last decade, there is a need to understand the pooled prevalence of depression among these students. However, previous systematic reviews evaluating the prevalence of depression among health professions’ students have been conducted on studies that were carried out in the Brazil,13 Pakistan,3 Canada and other European and Asian countries14 therefore, conducting a systematic review and meta-analysis of prevalence of depression among medical students in Africa is equally essential for informed preventive and treatment measures.\n\n\n2. Methods\n\nThe Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines15 was used by the researchers. The study protocol was registered with PROPERO (CRD42022372866).\n\nStudies carried out between 2012 and 2022 reporting prevalence of depression among medical students in Africa.\n\nReview studies, case reports, case series and studies reporting disorders other than depression like anxiety, suicidal ideation and burn out were strictly excluded.\n\nSimilar studies carried out in continents other than Africa were also excluded from the review.\n\nRelevant sources (PubMed, Google Scholar, African Journals Online and Embase) were used with help of a medical librarian, articles reporting studies conducted between 2012 and 2022 were considered. Only peer-reviewed articles in English were included, review articles, case reports and case series were excluded, cross-sectional studies were included. Authors whose articles were not free access were contacted by email, references to selected studies were searched for manually to obtain more relevant studies. Our search words included; depression, depression among medical students, depressive symptoms, African medical students, prevalence of depression, burden and incidence of depression.\n\nDuplicates of eligible studies were screened off using EndNote v20.5 software and articles were included for full review by NAM and RR, any disagreement was settled by IP and LA. The articles were then shared among paired reviewers (NAM and RR) and (IP and LA), and the lead investigator IP settled disagreements among individuals during the process of synthesis (Figure 1).\n\nAn excel spreadsheet document was used to capture the following information from each study; Study, Study year, Country, Sampling technique, Sample size, Prevalence, Mean Age, Females, Males, Instrument used.\n\nJoanna Briggs Institute (JBI) checklist1 was used to evaluate the risk of bias. It is a 4-point Likert scale with the following questions; 1). Was the sample frame appropriate to address the target population? 2) Were study participants sampled appropriately? 3) Was the sample size adequate? 4) Were the study subjects and settings described in details? 5) Was the data analysis conducted with sufficient coverage of the identified sample? 6) Were valid methods used for the identification of the condition? 7) Was the condition measured in a standard reliable way for all participants? 8) Was there appropriate statistical analysis? 9) Was the response rate adequate, and if not, was the low response rate managed appropriately? “No”, “Yes”, “Unclear” and “Not applicable” are the responses and 1 point is assigned for a Yes, a score less than 5 qualified an article for exclusion (Table 1).\n\nData analysis\n\nR version 4.3.22 was used to perform a random effects model meta-analysis for prevalence of depression. Overall pooled estimate of prevalence was reported as percentage at 95% CI, determined by random effects model when I2 >50 was realized and results were shown in forest plots. Publication bias was visually assessed using corresponding funnel plot and an Eggers test was done to test asymmetry. A subgroup analysis based on screening tools used to diagnose depression was conducted, a comparison was made in relation to prevalence of depression considering p-value < 0.05 as significant.\n\n\n3. Results\n\n26 cross-sectional studies involving 11386 (Females: 6070, 53.3%) medical students with a mean age of 23 met the inclusion criteria, this was out of a total of 87 related studies conducted between 2012 and 2022. Most of the studies were conducted in Nigeria (n=6) and Egypt (n=5). Ethiopia had 4 studies, while Sudan had 3. Both South Africa and Cameroon had 2 studies each, and Libya, Uganda, Namibia, and Tanzania had one study each. PHQ9 (n=10), DASS21 (n=7), BDI-II (n=5) were the most used screening instruments. Table 2 provides a summary of the studies reviewed.\n\nPrevalence of depression\n\nThe overall pooled prevalence of depression was 38% (p < 0.00). Sub-group analysis by instrument used revealed prevalence of 50% (p < 0.01), 32% (p < 0.01) and 39% (p < 0.01) for DASS21, BDI-II, and PHQ-9 respectively Figure 2 and Figure 4.\n\nPHQ = Primary Health Questionnaire, DASS = Depression Anxiety Stress Scale, BDI = Beck Depression Inventory, DASS21 = Depression, Anxiety and Stress Scale – 21, HADS = Hospital Anxiety and Depression Scale, Zung SDS = Zung Self-Rating Depression Scale.\n\nIn assessing the potential for publication bias within our meta-analysis, we conducted Egger’s regression test. The test did not reveal statistically significant evidence of publication bias (p = 0.090), with the intercept from Egger’s test being 1.697 standard errors away from the null hypothesis of no bias (Z = 1.697). These findings suggest that our meta-analytic results are not markedly influenced by publication. Funnel plot of prevalence of depression shown in Figure 3.\n\n\n4. Discussion\n\nThe present study reviewed 26 articles published of studies conducted between 2012 and 2022 (over a ten year period). Included were all studies reporting the prevalence of depression or depressive symptoms among medical students in Africa. A total of 11386 medical students were amassed from different medical schools across universities and colleges in Africa inclusive of 6070 females (53.3%) and 5316 males (46.7%). The studies were mainly carried out in the countries of Egypt, Nigeria, Ethiopia and South Africa, Namibia, Tanzania, Cameroon, Sudan and Uganda which gives a good representation of all regions across the African continent.\n\nThe overall pooled prevalence of depression was 38% (p < 0.00). Sub-group analysis by instrument used revealed prevalence of 50% (p < 0.01), 39% (p < 0.01) and 32% (p < 0.01) for DASS21, PHQ-9 and BDI-II respectively. A similar study conducted in India addressing the depression reviewed a total of 28 original studies published between 2014 and 2018.39 A total of 7046 medical students (3170 females) were considered and it reported a prevalence of 42.6% which is not significantly skewed from our findings though slightly higher than the outcome our analysis of 38%. The sample sizes of the studies considered in this review was ranging from 86 to 444 medical students, compared to our study (164 to 1058). The studies included reported prevalence ranging from 08.9% to 79.2% compared to our study that included articles reporting ranges from 4% to a worrisome 75%. These findings are significantly high and thus worrying as widespread depression is allied to decreased performance and higher incidences of long standing morbidity and even suicidal tendencies especially amongst this population in study.\n\nThe high prevalence of depression among medical students in Africa, as compared to the general population, raises critical questions about the unique stressors and challenges faced by these students. Academic pressures, demanding workloads, and exposure to patient suffering, previously identified as significant factors contributing to psychological morbidity among medical students.9,10 Furthermore, the significant association of depression with higher suicidal ideation and rates among medical professionals10,19,30 highlights the critical importance of early diagnosis, standardized screening, and effective management strategies. These findings advocate for the integration of mental health services and support systems within medical education, emphasizing the necessity of creating environments that not only recognize the mental health needs of students but also actively contribute to their well-being.\n\nOur review also identified the PHQ-9, DASS-21, and BDI-II as the most adopted instruments employed across the studies. Each of these instruments brings distinct strengths to the understanding of depression among medical students. The PHQ-9’s alignment with DSM-IV criteria for depression ensures that it is clinically relevant, while the DASS-21’s broader scope captures a wide range of emotional distress, offering insights beyond mere depressive symptoms. The BDI-II’s focus on cognitive aspects allows for the exploration of thought patterns associated with depression, providing depth to the assessment. However, these tools also have limitations. The PHQ-9’s brevity might overlook nuanced aspects of depression experienced by medical students, especially those related to academic stressors. The DASS-21, while comprehensive, may dilute the focus on depression by encompassing anxiety and stress. The BDI-II’s emphasis on cognition may miss other crucial aspects, such as physical symptoms associated with depression.40–42\n\nComparatively, clinical diagnosis of depression, typically conducted through structured interviews based on DSM-5 criteria, offers a holistic assessment of the individual, considering both psychological and physical symptoms along with functional impairments.43–45 While the screening instruments provide a practical and accessible means of identifying symptoms of depression, they cannot fully replicate the depth of clinical diagnosis, which considers the patient’s complete medical history, co-occurring disorders, and the intricate interplay of symptoms over time.\n\nThe study focused on only published data which had reported different screening instruments and individual demographics, also the study variables inspected were not sufficient to explain heterogeneity. A study involving a larger population randomly screened by clinical diagnosis and formal expert interviews other than self-report questionnaires could achieve a more accurate estimate.\n\nTwo suggestions are noted by the researchers; one is to carry out a multicenter study covering a large population using clinical diagnosis of depression and formal diagnostic interviews in place of self-report questionnaires. Secondly, we suggest studies to be carried out on other students pursuing nonmedical disciplines as well as these have been ignored by most researchers.\n\n\n5. Conclusion\n\nNearly two-fifths of medical students in Africa suffer from depression. The findings emphasize the need for research into the causes, alongside early diagnosis with standardized tools and targeted interventions to manage depression effectively among this demographic.\n\n\nAuthor contributions\n\nConceptualization: Ivaan Pitua (IP), Namiiro Amelia Margaret (AM)\n\nData curation: Ivaan Pitua (IP), Namiiro Amelia Margaret (AM), Raafidha Raizudheen (RR), Lorraine Apili (LA)\n\nData analysis: Ivaan Pitua (IP)\n\nInitial report and manuscript draft: Ivaan Pitua (IP), Namiiro Amelia Margaret (AM), Raafidha Raizudheen (RR), Lorraine Apili (LA)\n\nAll authors reviewed the manuscript for intellectual content and approval of final manuscript.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nAll data can be accessed from Figshare: Checklist for ‘Prevalence of depression among medical students in Africa: A systematic review and meta-analysis’, doi.org/10.6084/m9.figshare.25699332.v1. 46\n\nFigshare: Prevalence of depression among medical students in Africa: A systematic review and meta-analysis, DOI: doi.org/10.6084/m9.figshare.25699332.v1. 46\n\nThis project contains the following extended data:\n\n1. Search strategy-Extended data.docx\n\n2. Figure 1. The PRISMA Flow Diagram.jpeg\n\n3. Figure 2. Forest plot of prevalence of depression.jpeg\n\n4. Figure 3. Funnel plot of prevalence of depression.jpeg\n\n5. Table 1. Joanna Briggs Institute (JBI) checklist scores for included studies.jpeg\n\n6. Table 2 Characteristics of studies reporting prevalence of depression among medical students in Africa between 2012 and 2022.jpeg\n\n7. PRISMA Flowchart - Extended data.docx\n\n8. Sample Data extraction tool-Extended data.docx\n\n9. Figure 4. Forest plot of prevalence of depression sub-grouped by screening tools used.jpeg\n\n10. JBI_Critical_Appraisal-Checklist_for_Prevalence_Studies2017_0.pdf\n\nThe authors followed the PRISMA guidelines for reporting prevalence studies. Checklist can be accessible through Figshare: Checklist for ‘Prevalence of depression among medical students in Africa: A systematic review and meta-analysis’, doi.org/10.6084/m9.figshare.25699332.v1. 46\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nNot applicable.\n\n\nReferences\n\nJBI Critical Appraisal Checklist for Prevalence Studies.2017.\n\nTeam RC: R: A Language and Environment for Statistical Computing.2023. Reference Source\n\nKhan MN, et al.: Prevalence of Depressive Symptoms Among University Students in Pakistan: A Systematic Review and Meta-Analysis. Front. Public Health. 2020; 8: 603357.\n\nPuthran R, et al.: Prevalence of depression amongst medical students: a meta-analysis. Med. Educ. 2016; 50(4): 456–468. PubMed Abstract | Publisher Full Text\n\nRathod S, et al.: Mental Health Service Provision in Low- and Middle-Income Countries. Health Serv. Insights. 2017; 10: 1178632917694350.\n\nJanuary J, et al.: Prevalence of depression and anxiety among undergraduate university students in low- and middle-income countries: a systematic review protocol. Syst. Rev. 2018; 7(1): 57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOssai EN, et al.: How large is the burden of depression in a medical school? A cross-sectional study among medical students in Nigeria. Pan Afr. Med. J. 2021; 40: 71.\n\nDafaalla M, et al.: Depression, Anxiety, and Stress in Sudanese Medical Students: A Cross Sectional Study on Role of Quality of Life and Social Support. Am. J. Educ. Res. 2016; 26: 937–942.\n\nDagnew B, Dagne H, Andualem Z: Depression and Its Determinant Factors Among University of Gondar Medical and Health Science Students, Northwest Ethiopia: Institution-Based Cross-Sectional Study. Neuropsychiatr. Dis. Treat. 2020; 16: 839–845. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDesalegn GT, et al.: Suicide ideation, attempt, and determinants among medical students Northwest Ethiopia: an institution-based cross-sectional study. Ann. General Psychiatry. 2020; 19: 44. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPedrelli P, et al.: College Students: Mental Health Problems and Treatment Considerations. Acad. Psychiatry. 2015; 39(5): 503–511. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTembo C, Burns S, Kalembo F: The association between levels of alcohol consumption and mental health problems and academic performance among young university students. PLoS One. 2017; 12(6): e0178142. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPacheco JP, et al.: Mental health problems among medical students in Brazil: a systematic review and meta-analysis. Braz. J. Psychiatry. 2017; 39(4): 369–378. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRotenstein LS, et al.: Prevalence of Depression, Depressive Symptoms, and Suicidal Ideation Among Medical Students: A Systematic Review and Meta-Analysis. JAMA. 2016; 316(21): 2214–2236. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPage MJ, et al.: The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med. 2021; 18(3): e1003583. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIsara AR, Nwokoye OI, Odaman AO: Prevalence and risk factors of depression among undergraduate medical students in a Nigerian university. Ghana Med. J. 2022; 56(4): 303–310. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAluh DO, Abba A, Afosi AB: Prevalence and correlates of depression, anxiety and stress among undergraduate pharmacy students in Nigeria. Pharm. Educ. 2020; 20: 236–248. Publisher Full Text\n\nElsawy WIH, et al.: Depression among medical students in Alexandria, Egypt. Afr. Health Sci. 2020; 20(3): 1416–1425. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFalade J, et al.: Prevalence and correlates of psychiatric morbidity, comorbid anxiety and depression among medical students in public and private tertiary institutions in a Nigerian state: a cross-sectional analytical study. Pan Afr. Med. J. 2020; 37: 53.\n\nFawzy M, Hamed SA: Prevalence of psychological stress, depression and anxiety among medical students in Egypt. Psychiatry Res. 2017; 255: 186–194. PubMed Abstract | Publisher Full Text\n\nIbrahim MB, Abdelreheem MH: Prevalence of anxiety and depression among medical and pharmaceutical students in Alexandria University. Alexandria J. Med. 2015; 51(2): 167–173. Publisher Full Text\n\nKebede MA, Anbessie B, Ayano G: Prevalence and predictors of depression and anxiety among medical students in Addis Ababa, Ethiopia. Int. J. Ment. Health Syst. 2019; 13: 30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMelaku L, Bulcha G, Worku D: Stress, Anxiety, and Depression among Medical Undergraduate Students and Their Coping Strategies. Educ. Res. Int. 2021; 2021: 9880309.\n\nMohamed E, et al.: Prevalence of Depression Among Medical Students in Sudan International University in May 2017 – August 2017.2019.\n\nMwita, et al.: prevalence-of-depression-and-suicidality-among-medical-students-in-mwanza-tanzania-a-crosssectional-study.2020.\n\nMhata NT, et al.: Prevalence of depression, anxiety and burnout in medical students at the University of Namibia. S. Afr. J. Psychiatry. 2023; 29: 2044.\n\nNgasa SN, et al.: Prevalence and factors associated with depression among medical students in Cameroon: a cross-sectional study. BMC Psychiatry. 2017; 17(1): 216. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTsi N, et al.: Burnout as a correlate of depression among medical students in Cameroon: a cross-sectional study. BMJ Open. 2019; 9(5): e027709. Publisher Full Text\n\nAsuquo E, et al.: Socio-demographic characteristics and other factors associated with depressive illness among medical students at the University of Port Harcourt. Insights Depress. Anxiety. 2020; 4: 040–048. Publisher Full Text\n\nOlum R, Nakwagala FN, Odokonyero R: Prevalence and Factors Associated with Depression among Medical Students at Makerere University, Uganda. Adv. Med. Educ. Pract. 2020; 11: 853–860. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNubi OG, et al.: Depression, Anxiety, and Stress among Sudanese Medical Students during the COVID-19 Lockdown Period. Open Access Maced. J. Med. Sci. 2022; 10: 1365–1371.\n\nPillay N, Ramlall S, Burns JK: Spirituality, depression and quality of life in medical students in KwaZulu-Natal. S. Afr. J. Psychiatry. 2016; 22(1): 6. Publisher Full Text\n\nSherif R, et al.: Prevalence of depression among Libyan medical students. Iberoamerican. J. Med. 2021; 3: 196–203. Publisher Full Text\n\nChikezie U, Okoro T: Prevalence of Depression and Associated Factors among Medical Students in a Southern Nigerian University. Global J. Health Sci. 2021; 13: 12. Publisher Full Text\n\nVan der Walt S, et al.: The burden of depression and anxiety among medical students in South Africa: A cross-sectional survey at the University of Cape Town. S. Afr. Med. J. 2019; 110(1): 69–76. PubMed Abstract | Publisher Full Text\n\nAbdel Wahed W, Hassan S: Prevalence and associated factors of stress, anxiety and depression among medical Fayoum University students. Alexandria J. Med. 2016; 53: 77–84. Publisher Full Text\n\nMohammed HM, et al.: Depressive symptoms and its correlates among medical students in Upper Egypt. Middle East Curr. Psychiatr. 2022; 29(1). Publisher Full Text\n\nWorku D, et al.: Perceived Stress, Depression, and Associated Factors among Undergraduate Health Science Students at Arsi University in 2019 in Oromia, Ethiopia. Psychiatry J. 2020; 2020: 4956234.\n\nDwivedi N, Sachdeva S, Taneja N: Depression among Medical Students of India: Meta-Analysis of Published Research Studies using Screening Instruments. Indian J. Soc. Psychiatry. 2021; 37(2): 183. Publisher Full Text\n\nGarcía-Batista ZE, et al.: Validity and reliability of the Beck Depression Inventory (BDI-II) in general and hospital population of Dominican Republic. PLoS One. 2018; 13(6): e0199750. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChoi SW, et al.: Establishing a common metric for depressive symptoms: linking the BDI-II, CES-D, and PHQ-9 to PROMIS depression. Psychol. Assess. 2014; 26(2): 513–527. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMedvedev ON: Depression Anxiety Stress Scales (DASS-21) in International Contexts. International Handbook of Behavioral Health Assessment. Krägeloh CU, Alyami M, Medvedev ON, editors. Cham: Springer International Publishing; 2023; pp. 1–15. Publisher Full Text\n\nBredström A: Culture and Context in Mental Health Diagnosing: Scrutinizing the DSM-5 Revision. J. Med. Humanit. 2019; 40(3): 347–363. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShabani A, et al.: Psychometric properties of Structured Clinical Interview for DSM-5 Disorders-Clinician Version (SCID-5-CV). Brain Behav. 2021; 11(5): e01894. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBernaras E, Jaureguizar J, Garaigordobil M: Child and Adolescent Depression: A Review of Theories, Evaluation Instruments, Prevention Programs, and Treatments. Front. Psychol. 2019; 10: 543. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIvaan P: Prevalence of depression among medical students in Africa: A systematic review and meta-analysis. figshare. 2024. Publisher Full Text"
}
|
[
{
"id": "281807",
"date": "13 Jun 2024",
"name": "Gerasimos N. Konstantinou",
"expertise": [
"Reviewer Expertise Clinical Psychiatry",
"Brain Stimulation",
"Psychoimmunology",
"Mood and Anxiety Disorders"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe rationale and objectives of the study are well-defined and presented clearly in the manuscript. The authors effectively set the stage by discussing the significance of understanding depression among medical students and highlighting gaps in existing literature. To further enhance the introduction, the authors might consider expanding on the implications of their findings for future research and policy. The methodological rigor of the study is commendable. The methods section provides a thorough description of the inclusion and exclusion criteria, data sources, search strategy, study selection process, data extraction, and quality assessment, allowing replication by others. The use of PRISMA guidelines and registration with PROPERO enhances transparency and replicability. However, the manuscript would benefit from additional details on the process for resolving disagreements during study selection and data extraction. Specifically, clarifying how discrepancies were resolved, whether through discussion or third-party adjudication, would improve clarity. The statistical analysis is robust and appropriate for the data. The use of a random-effects model for meta-analysis is suitable given the heterogeneity of the studies. The subgroup analyses based on screening tools and the assessment of indexed bias using funnel plots and Egger’s test are well-executed. Including a sensitivity analysis to test the robustness of the pooled prevalence estimate, especially considering the variability in study settings and instruments used, would further strengthen the statistical approach. The conclusions drawn are justified based on the results. The conclusion that nearly two-fifths of medical students in Africa suffer from depression is supported by the pooled prevalence estimate of 38%. The discussion contextualizes these findings within the broader literature and highlights the need for targeted interventions. To strengthen the discussion further, the authors could explore potential reasons for the high prevalence rates observed and suggest specific strategies for addressing mental health issues among medical students in Africa. In summary, this systematic review and meta-analysis provide valuable insights into the prevalence of depression among medical students in Africa. The study is methodologically sound and offers important implications for future research and interventions. Addressing the points mentioned above will further strengthen the manuscript and ensure its scientific rigor.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-523
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https://f1000research.com/articles/13-521/v1
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22 May 24
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{
"type": "Case Report",
"title": "Case Report: A rare case of Intracranial tuberculous granuloma (tuberculoma) in a 19-year -old male",
"authors": [
"Vidhata Gothe",
"Ranjana Sharma",
"Ranjana Sharma"
],
"abstract": "A tuberculoma is a clinical sign of tuberculosis that combines tubercles into a solid mass and can resemble several forms of malignant tumors on imaging. They frequently develop in people whose original tuberculosis infection is not well controlled. When they develop intracranially, tuberculomas are symptoms of CNS tuberculosis\nMeningitis, radiculomyelitis, bony spinal disease, and tuberculoma/tuberculous abscess are some of the symptoms of neurological tuberculosis (TB) that can also arise intracranially or in the spinal canal. comparable to other neurological TB symptoms. The majority of the time, the diagnosis of cerebral tuberculoma is presumptive and is based on radiological findings, additional supportive TB evidence from other areas, and treatment response. However, despite adequate TB treatment and concomitant corticosteroid therapy, lesions may persist for many years, as the therapeutic response of tuberculomas is unpredictable. A 19-year-old male patient admitted to the hospital for medical treatment complained of abdominal pain, constipation, nausea and vomiting, generalized weakness, fever, and chills. According to the patient’s complaints, my patient has a history of tonic-clonic seizures dating back a month, as well as a history of typhoid fever and sickle cell disease AS pattern, both of which he had been receiving treatment at a civil hospital. At the time of admission, he had undergone a number of invasive and non-invasive investigations, including a CT brain plane and an MRI brain with contrast. Brain computed tomography (CT) revealed a persistent lacunar infarct in the left corona radiata. Acute infarct in the right corona radiata, abnormal meningeal enhancement on post-contrast with meningitis, multiple ring-enhancing lesions in the bilateral cerebral hemisphere, cerebellum, corpus callosum, and intracranial tuberculous granuloma are all revealed by MRI with contrast. left corona radiata chronic infarction.",
"keywords": [
"Tuberculoma",
"disorders",
"Case report"
],
"content": "Introduction\n\nMycobacterium tuberculosis, an infectious disease of pandemic size, causes tuberculosis (TB). It has consistently been among the top 10 infectious agents causing death for many years.1 TB cases have decreased in some regions of the world, but the emergence of drug-resistant TB has created new problems. The most severe form of TB, known as CNS-TB, affects the central nervous system and accounts for 1% of all reported cases of TB, despite the fact that it can also affect other organs of the body. Tuberculosis (TB) is primarily a pulmonary disease.2\n\nThe formation of tuberculosis granulomas, the histopathological hallmark of the disease, is typically a defining feature of Mycobacterium tuberculosis infection, which kills hundreds of thousands of people annually. Our understanding of granulomas, which are a biologically diverse body of pro and anti-inflammatory cells from the host immune response, is primarily based on examination of lungs in studies on both humans and animals, but little is known about their counterparts from other organs of the TB patient, such as the brain.3\n\nGranulomas are reactions of the body to protracted exposure to antigenic stimuli. They serve as a histopathologic hallmark of TB because they are the body’s initial response to Mycobacterium tuberculosis infection they are composed of a mixture of specialized immune cells that are affected by both pro and anti-inflammatory responses.4\n\nThe quantity and distribution of these cells, as well as other underlying diseases in the host, can have an impact on granuloma formation. For example the release of cytokines by a high number of B lymphocytes contributes to the development of tuberculous granulomas.1\n\n\nCase report\n\nA 19-year-old male patient was treated in a hospital for fever and chills, generalized weakness, body pain, restlessness, nausea and vomiting, constipation, and abdominal pain. According to the patient’s complaints, he had a history of tonic-colonic seizures, typhoid fever, sickle cell disease, and AS pattern. He received treatment from a civil hospital, and there was no record of syncopal episodes at home. When the patient was admitted, he underwent several invasive and non-invasive investigations, including a CT brain plane and an MRI brain with contrast.\n\nA computed tomography (CT) brain scan showed a chronic lacunar infarct in the left corona radiata (Figure 1).\n\nMRI with contrast findings showed acute infarct in the right corona radiata, abnormal meningeal enhancement on post-contrast with meningitis, multiple ring-enhancing lesions in the bilateral cerebral hemisphere, cerebellum, corpus callosum, and intracranial tuberculous granuloma. chronic infarct in the left corona radiata (Figure 2).\n\nAfter admission, the patient also underwent various investigations such as CSF microscopy and culture, complete blood count (cbc), APTT ESR, LFT, KFT lipid profile, and CSF analysis showed that glucose-CSF 20 and protein-CSF 141, ph-7.2, no pus cell, and no RBC, culture-growth of Achromobactin xyloidine gram-negative bacteria. CBC investigation finding shows that HB% -11.4, WBC- 13800, MCHC -32.4, MCV -70.6, MCH -22.8, total platelet count- 2.68, haematocrit (HCT)- 35.2, KFT finding shows that Urea -15 mg/dl, Creatinine- 0.6 mg/dl, sodium (Na)-132 meq/lit, potassium(k)m- 4.6 meq/lit, LFT finding shows that ALT-12 U/lit, AST -34 U/lit total protein -7.6 gm/dl, globulin-4.3 gm/dl total bilirubin 0.9 gm/dl, APTT-36.4, ESR -13.\n\nAll investigations were performed after all patients were diagnosed with intracranial tuberculous granuloma (tuberculoma) and were on medical treatment, such as antitubercular therapy, antibiotic therapy, anticonvulsant therapy, antiplatelet therapy, steroid therapy, antipyretic, and analgesic therapy. In the CNS examination, the patient is oriented to the time place and person, the patient is in a mild confusion state, there is no type of injury, rashes, pigmentation, or scar formation, and symmetrical in size and shape of head, hearing activity was normal, eye examination revealed blurred vision at night, and he was instructed to have a CT brain and MRI brain with contrast. The patient was given the opinion of a neurophysician after all assessments and investigations had been completed.\n\nThe main goal is to prevent the development of infection by using all sterile technique procedures, article and equipment, and patients on a Foley catheter (2-way catheter 14 No.), catheter care given every 4–6 hours, and maintaining negative intake and output balance by monitoring the patient’s intake and output chart on an hourly basis. Every 4 hrly, vital parameters such as temperature, pulse, respiration, and blood pressure were monitored. Antitubercular, antibiotic, anticonvulsant, antiplatelet, steroid, antipyretic, and analgesic therapies.\n\nInj.Piptaz 4.5 gm intravenous 8 h, Inj. Streptomycin 150 mg once a day (OD), Tab levofloxacin 150 mg once daily, Tab Ethambutol 800 mg once daily, Inj. Dexamethasone 6 mg once daily, Inj. Pantoprazole 40 mg once daily (OD), Tab Acetazolamide 250 mg 8 hrly, Tab Sodium bicarbonate 2 tab once a day, Tab Aspirin 75 mg once a day.\n\n\nDiscussion\n\nSince the development of anti-tuberculosis drugs, the risk of mortality and morbidity from tuberculosis has decreased dramatically. However, central nervous system involvement continues to bear the weight of mortality and neurological morbidity. As a highly oxygenated organ, the brain is the target of Mycobacterium Tuberculosis, an aerobic organism. The innate immune system is activated, and granulomas are produced as a result of the interaction between the organism and alveolar macrophages in the lung after it has been acquired and deposited there.5\n\nThe development of tuberculous foci in the brain parenchyma, meninges, or spinal cord is the first step in the development of central nervous system tuberculomas. The most common manifestation of central nervous system tuberculosis (TB) is tuberculous meningitis. Microglial cells are the primary target cells of the central nervous system are microglial cells.5\n\nThe clinical presentation was confirmed by radiological investigations. When used alone, a brain CT scan has an 80% false-positive rate for the diagnosis of tuberculoma owing to its relatively low specificity (13). Treatment for symptoms, anti-tuberculosis medication, and potential surgical resection of the lesion is all part of the management of intracranial tuberculomas. Clinically, the use of glucocorticoids, such as dexamethasone, is advised to reduce cerebral edema, inflammation risk, and intracranial pressure.6\n\nThe symptoms of a 19-year-old male patient being treated in a hospital included fever and chills, generalized weakness, body pain, restlessness, nausea and vomiting, constipation, and abdominal pain. According to the patient’s complaints, he had a history of tonic-clonic seizures, typhoid fever, and sickle cell disease as well as an AS pattern.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details as obtained from the patient study.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nClinical Tuberculosis - 6th Edition - Lloyd N. Friedman - Martin Dedic.[cited 2024 Apr 29]. Reference Source\n\nThwaites G, Fisher M, Hemingway C, et al.: British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J. Infect. 2009 Sep; 59(3): 167–187. PubMed Abstract | Publisher Full Text\n\nSholeye AR, Williams AA, Loots DT, et al.: Tuberculous Granuloma: Emerging Insights From Proteomics and Metabolomics. Front. Neurol. 2022 Mar 21; 13: 804838. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMarakalala MJ, Raju RM, Sharma K, et al.: Inflammatory signaling in human Tuberculosis granulomas is spatially organized. Nat. Med. 2016 May; 22(5): 531–538. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRock RB, Olin M, Baker CA, et al.: Central Nervous System Tuberculosis: Pathogenesis and Clinical Aspects. Clin. Microbiol. Rev. 2008 Apr; 21(2): 243–261. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBouchama A, al-Kawi MZ, Kanaan I, et al.: Brain biopsy in tuberculoma: the risks and benefits. Neurosurgery. 1991 Mar; 28(3): 405–409. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "303469",
"date": "07 Aug 2024",
"name": "Divya M Radhakrishnan",
"expertise": [
"Reviewer Expertise I am a neurologist. My research areas include movement disorders",
"neuroinfections",
"and electrophysiology of movement disorders"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for asking me to review the manuscript titled “Case Report: A rare case of Intracranial tuberculous granuloma (tuberculoma) in a 19-year-old male.” Upon reviewing the manuscript, I must express my disappointment, as it is poorly written and contains significant deficiencies and errors in its scientific content. I am uncertain why the authors reported this case, as it does not provide any new insights or learning points. First, the case report lacks essential details regarding the patient’s history and a proper neurological examination. Any examination findings that are mentioned appear to be sketchy and are only presented after the investigations. For instance, the authors briefly mention that the patient experienced blurred vision at night during an eye examination. It is disheartening to see that the authors did not prioritize a thorough neurological examination, especially the examination of the patient’s eyes (didn’t comment on extraocular movements, pupils or fundus), considering the diagnosis of CNS tuberculosis. There is no mention of the meningeal signs or focal neurological deficits.\n\nThe CSF report does not provide any information about cell counts or tests for fungal elements, such as cryptococcus. The manuscript does not report corresponding blood sugar levels and CXR findings. However, the most concerning aspect is the lack of information regarding the treatment the patient received. There is no mention of rifampicin, isoniazid, or pyrazinamide in the treatment regimen, and the dosage of levofloxacin is also unclear. It is possible that the patient experienced a drug-induced liver injury, which resulted in modifications to the medication. Antiseizure medications are also not included in the list. What was the role of acetazolamide and sodium bicarbonate?\nThe discussion is loosely written and the final paragraph, “The symptoms of a 19-year-old male patient being treated in a hospital included fever and chills, generalized weakness, body pain, restlessness, nausea and vomiting, constipation, and abdominal pain. According to the patient’s complaints, he had a history of tonic-clonic seizures, typhoid fever, and sickle cell disease as well as an AS pattern.”, makes little sense.\n\nThe label for Figure 2, which says MRI, is a CT scan bony window cut.\nThe clarity of figure 1 is also questionable, and the CT image was obtained at a single level. The authors should make a correction that it is a CT brain ‘plain’, not ‘plane’.\n\nThe abstract refers to acute infarcts on the MRI, but this detail is not included in the main text.\nThere are several fundamental concerns with the manuscript that should not have been present. Therefore, based on the lack of novelty, originality, and overall scientific content, my final recommendation is to should not be indexed the manuscript.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
},
{
"id": "293605",
"date": "27 Aug 2024",
"name": "Sofiati Dian",
"expertise": [
"Reviewer Expertise clinical infectious disease in neurology especially TB"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe author has written a report on a case of tuberculoma in a young patient. To improve its quality, the author should consider adhering to the CARE guidelines for case reporting. There are several comments that I would like to address: Here are my main concerns: Major:\nLack of Unique Aspects: The case report lacks a unique aspect, unusual finding, or notable diagnostic or treatment challenge, as tuberculoma is not a rare condition, particularly in endemic areas like India (one of the top three countries with the highest TB burden, according to the WHO Global Report). This unique aspect should be highlighted in both the abstract and introduction. Superficial Discussion: The discussion section is superficial and lacks substantial or important analysis. For instance, the author does not explain why WHO recommendations for CNS TB treatment were not followed, instead, they choose levofloxacin, streptomycin, piperacillin/tazobactam, and ethambutol. The author should also clarify why acetazolamide was used for this patient, as there is no clear indication provided. It is also unclear diagnosis and treatment for the seizures. The superficial analysis may also result from the lack of a unique aspect of the case. Incomplete Patient History: There is a lack of relevant past interventions, history of previous TB infection, TB contact, and history of TB treatment, despite the author's assertion that tuberculoma results from inadequate TB treatment (which I disagree with, given well-documented evidence of tuberculoma in paradoxical response cases). Additionally, the report omits important past medical, family, and psychosocial history, if available. Missing Timeline: The case report lacks a timeline of historical and current information from this episode of care, which could be organized in a figure or table. Absence of Strengths and Limitations: The report does not address the strengths and limitations of the case. For example, the author refers to a lumbar puncture (LP) but does not clearly state that it was an invasive procedure. Patient's Perspective: The report lacks the patient’s perspective on their condition and treatment. Incomplete Follow-Up: There is no follow-up or outcome data, including information on anti-TB drug compliance, any adverse events, and clinical outcomes, such as functional status or mortality.\nMinor:\nTypos: There are several typos, such as \"colonic\" instead of \"clonic.\" Choppy Sentences: The sentence \"...comparable to other neurological TB symptoms\" is unclear and appears to be misplaced. Figures: The figure needs an arrow or marker to indicate the specific lesion, which I was unable to identify. Language: The author should avoid using \"my patient\" when describing the case.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-521
|
https://f1000research.com/articles/13-291/v1
|
18 Apr 24
|
{
"type": "Brief Report",
"title": "Pyuria in hospitalized general medical patients without urinary tract infection",
"authors": [
"Praveenkumar Thyagaraju",
"Jharna Mandal",
"Hariswar Pari Thenmozhi",
"Surendran Deepanjali",
"Praveenkumar Thyagaraju",
"Jharna Mandal",
"Hariswar Pari Thenmozhi"
],
"abstract": "Urine microscopy for detecting pus cells is a common investigation ordered in hospitalized general medical patients as part of routine care. A few previous studies have shown that sterile pyuria is not uncommon in this population. We studied the prevalence of pyuria among patients hospitalized with non-urinary tract infection (UTI) diagnosis in the medical wards. We excluded patients with asymptomatic bacteriuria (ASB). Pyuria was quantified in uncentrifuged urine using the chamber counting method, and ≥ 10 pus cells per mm3 was considered significant. We also compared this method with the commonly used but less accurate method of counting pus cells/high power field using centrifuged urine (routine method). We studied 196 patients; 113 (57.7%) were males. Most (175[89.3%]) patients were hospitalized for an infection. We found that 18.4% of the study group had sterile pyuria, and it was strongly associated with the presence of concomitant microscopic hematuria (unadjusted odds ratio, 3.74 [1.65 to 8.50]; P=0.002). We found no association of pyuria with female gender, diabetes, acute kidney injury, or current antibiotic use. By routine method, 56 (28.6 %) patients had significant pyuria. In comparison to the chamber counting method, the routine method was 69.4(63—75.8) % sensitive and 80.6(75.1—86.2) % specific. The positive and negative predictive values were 44.6 (37.7— 51.6) % and 92.1 (88.4 — 95.9) %. We concluded that sterile pyuria and microscopic hematuria could be present in a proportion of hospitalized general medical patients without UTI or ASB. Clinical judgment is essential in interpreting the significance of abnormal urinalysis reports.",
"keywords": [
"microscopic pyuria",
"urinalysis",
"urinary tract infection",
"asymptomatic bacteriuria",
"general medical patients"
],
"content": "Introduction\n\nUrinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission. In a retrospective cohort study using a national dataset of inpatient admissions from 263 hospitals in the United States from 2009 to 2014, Horstman et al. found that urinalysis was ordered in 47% of admissions.1 They also found that the test is frequently repeated during hospital stay suggesting large-scale overuse. More recent studies show that urinalysis is often ordered without proper indication in the emergency department.2,3\n\nIn patients with classic clinical symptoms and signs of UTI, the presence of pyuria and significant bacteriuria helps in ascertaining the diagnosis of UTI. However, in those without typical clinical features of UTI, the presence of pus cells in urine detected by a routinely done microscopy examination often leads to diagnostic confusion. This is especially so if pyuria is accompanied by bacteriuria, which is detected by a urine culture. This condition, which was proposed to be called ‘Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS),’ is indeed not so uncommon in hospital settings.4\n\nIn a previous study including hospitalized general medical patients done in our centre, almost 80% patients who had asymptomatic bacteriuria (ASB) also had pyuria.5 Even in the absence of a positive urine culture, a significant proportion of hospitalized patients could have pyuria, often referred to as ‘sterile pyuria.’ In a retrospective study done including 210 consecutive patients (both adults and children) with infections outside of the urinary tract and who were admitted under medical and surgical services of an academic medical center in Oklahoma, nearly one-third had >5 white blood cells (WBCs) per high-power field (hpf) of urine.6\n\nPyuria can occur in non-infectious conditions like interstitial nephritis, diabetic nephropathy, and malignant hypertension also.7 With this background, we studied the prevalence of significant microscopic pyuria among patients hospitalized with non-UTI diagnosis. We defined sterile pyuria as ≥ 10 WBCs per mm3 of uncentrifuged urine using the chamber counting method, which is a more accurate method of quantifying pyuria. We also compared this with the commonly practiced method of reporting the number of WBCs per high power field (hpf) in centrifuged urine sample (referred to as ‘routine method’ hereafter).\n\n\nMethods\n\nWe did a prospective observational study between April 2021 to June 2022 among adult patients presenting to casualty and who were subsequently admitted under the Department of Medicine, JIPMER. The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021). Written informed consent was obtained from all study participants and the study was conducted in compliance with the Declaration of Helsinki. Our study population included adult patients hospitalized with a non-UTI diagnosis. We excluded patients who had a positive UTI symptom screening at admission as well as those on indwelling urinary catheter. We defined positive UTI as the presence of at least two or more typical symptoms or signs suggestive of UTI like dysuria, urinary frequency, urgency, hesitancy, lower abdominal pain, loin pain, suprapubic tenderness, and renal angle tenderness.\n\nOnce the patients were recruited in the study, one of the investigators (TP) collected the clinical details from the patients. Patients submitted a fresh mid-stream urine sample (about 50 mL) in a sterile vial. A portion of this sample was further divided between 2 more sterile vials. One was sent to microbiology lab for culture. The second one was to the medicine side lab, where a portion of the sample was subjected to dipstick analysis of proteinuria and glucosuria. The other portion was centrifuged at a rate of 1500 to 2000 rpm for 3 to 5 minutes, and then it was resuspended. From this re-suspended urine sample, a drop was placed in a clean glass slide using a micropipette and then covered by a coverslip. This slide preparation was then counted for a total number of pus cells under 40× magnification of a compound microscope by trained and experienced technicians (routine method). The presence of ≥5 WBCs/hpf was considered significant pyuria by this method. Microscopic hematuria was defined as presence of ≥3 red blood cell/hpf.\n\nUsing the third urine sample, TP performed a microscopic examination of uncentrifuged urine loaded in a Neubauer’s chamber under 40× magnification (chamber counting method). The number of WBCs per mm3 was calculated by multiplying the total number of WBCs in the four corner squares of the chamber by a factor of 2.5.8 Significant pyuria by this method was defined as ≥10 WBCs per mm3.9\n\nAmong patients without a positive UTI symptom screening, we further excluded those in whom urine culture showed significant growth of organisms that could represent asymptomatic bacteriuria. We also excluded patients with contaminated urine cultures and those in whom the treating team administered any UTI-directed antibiotics.\n\nWorkup and treatment decisions were taken by the treating medical units. We followed the patients during their hospital stay and noted their discharge diagnosis.\n\nThe data were compiled using Microsoft Excel and analyzed using Stata/IC 12.1 for Windows (StataCorp. 2012. Stata Statistical Software: Release 12.1. College Station, TX). Categorical variables were expressed as percentages and frequencies, and continuous variables were reported as mean and standard deviation or median with the interquartile range as appropriate. The Shapiro-Wilk test was used to assess the normality of continuous variables. Categorical variables were compared using the Chi-square test. The strength of association was expressed as odds ratios with their 95% confidence intervals. A P-value less than 0.05 was considered statistically significant.\n\n\nResults\n\nDuring the study period, 256 patients with suspected non-UTI diagnosis were recruited. The STROBE diagram (Figure 1) shows the enrolment of patients in the study. Finally, 196 patients with an unambiguous diagnosis of a non-UTI condition were chosen as the study group. Of 196 patients, 113 (57.7%) were males. The median (IQR) age of the study population was 42 (29-55 years). Most (175[89.3%]) patients were hospitalized for an infection. The major co-morbidities in the study population were diabetes mellitus 48(24.5%), systemic hypertension 29(14.8%), chronic kidney disease 14(7.1%), coronary artery disease 10(5.1%), autoimmune diseases 10(5.1%), malignancy 8(4.1%), chronic liver disease 7(3.6%) and HIV infection 6(3.1%). The final diagnosis at discharge of these patients can be found at https://doi.org/10.6084/m9.figshare.24454228.v2.\n\nBy routine method, 56 (28.3%) patients had significant pyuria. Of them, 29 (52%) had 5-10 pus cells/hpf, 19 (34%) had 11-20 pus cells/hpf, and 8 (14%) had ‘plenty’ of us cells/hpf. By chamber counting method, 36 (18.2%) had significant pyuria. Considering the chamber counting method as the gold standard, the routine method was 69.4(63–75.8) % sensitive and 80.6(75.1–86.2) % specific. The positive and negative predictive values were 44.6 (37.7–51.6) % and 92.1 (88.4–95.9) %.\n\nWe compared the distribution of previously known and clinically intuitive risk factors for significant pyuria among patients with and without it (Table 1). The microscopic hematuria was the only factor significantly associated with pyuria (Odds ratio 3.74[1.65–8.50]; P=0.002).\n\na Significant pyuria by chamber counting method.\n\n\nDiscussion\n\nIn this prospective study including hospitalized general medical patients with a non-UTI diagnosis, we observed that about 1 out of 5 patients had significant pyuria. Further, microscopic hematuria was observed to be significantly associated with pyuria. We did not observe any association with pyuria and female sex, diabetes mellitus, hypertension, AKI, and infections.\n\nIn the study done by Hooker et al., including hospitalized patients with infections outside the urinary tract, nearly one-third of adults (43 of 144; 29.9%) patients had pyuria (≥5 WBCs/hpf).6 They found that pyuria was more common in women and patients with genital tract infections. In their study, urine culture was positive in 42% of adult patients, and 38% were reclassified as UTI. We excluded patients with symptoms and signs of UTI, those with a positive urine culture, and also those patients who received UTI-directed antibiotics. Hence, we did not reclassify anyone as UTI. Moreover, we have included patients with non-infectious diseases also. Using the routine method, we found 28% had significant pyuria of >5 cells/hpf. However, using the chamber counting method, the proportion was noted to be 18%.\n\nPyuria expressed as pus cells/mm3 using unspun urine is a more accurate and reproducible method than counting the number of pus cells per hpf in using centrifuged urine.10,11 We found that the diagnostic performance characteristics of the routine method is modest in comparison to chamber counting method with a sensitivity of 70% and specificity of 81%. As early as 1962, Stansfeld had reported that the co-efficient of variation of the chamber counting method is 8.8%, while it is 21% for the routine method.8 In the context of UTI diagnosis, studies have shown that more than 96% of symptomatic UTI with significant bacteriuria had ≥10 cells/mm3, while this finding was present in less than one percent of asymptomatic non-bacteriuric patients.12\n\nIt is important to note that 18% of hospitalized patients had significant pyuria in our study. The cause of pyuria in this population is neither UTI nor ASB. Microscopic hematuria was found to be strongly associated with pyuria, and thus, we can infer that microscopic urinary abnormalities are not uncommon in this population. In a recent review on sterile pyuria, gynaecological infections, urethritis, balanitis, viral infections of the genitourinary tract, prostatitis, genitourinary tuberculosis, and current use of antibiotics have been listed as causes related to infection for this finding.9 The causes unrelated to infection are urinary catheter use, urological procedures, urinary tract stones or neoplasms, papillary necrosis, inflammatory diseases like SLE, etc. Most of these conditions were absent in our study population. However, it is possible that asymptomatic infections of urinary tract and/or urological abnormalities like clinically silent renal stones could have been present in a proportion of them. Of note, previous studies have found that pyuria is more common with female sex and diabetes.6,13 We did not find these associations in our study population, but this could possibly because the study was underpowered to a significant difference.\n\nFinding pyuria might also trigger the ordering of urine cultures even when patients have no clinical features suggestive of UTI. A positive urine culture in such a setting most likely represents ASB, a condition that accounts for 20-45% of positive urine cultures in hospitalized patients.5,14 Inappropriate use of antibiotics for ASB is quite common in hospital settings, and the presence of concomitant pyuria is an important driver for this.15,16 Thus, un-indicated urinalysis should be avoided in hospitalized patients.\n\nOur study has the merit that pyuria was ascertained using the chamber counting method. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. However, our study would have been more informative had we checked for persistent pyuria and other urinary casts.\n\nIn conclusion, we found that abnormal microscopic urinalysis findings like pyuria and hematuria can be present in a proportion of hospitalized patients across a wide range of diagnostic categories. Unnecessary ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context.\n\nThe study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021).\n\nWritten informed consent was obtained from all study participants.\n\n\nAuthor contributions\n\nStudy design: Surendran Deepanjali, Jharna Mandal\n\nData acquisition: Praveenkumar Thyagaraju, Hariswar Pari Thenmozhi\n\nData analysis: Surendran Deepanjali, Hariswar Pari Thenmozhi\n\nDrafting of manuscript: Surendran Deepanjali, Hariswar Pari Thenmozhi, Praveenkumar Thyagaraju\n\nCritical revision of the manuscript: Jharna Mandal",
"appendix": "Data availability\n\nFigshare: Sterile pyuria in hospitalized general medical patients, DOI https://doi.org/10.6084/m9.figshare.24454228.v2.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nWe thank the medicine side lab technicians for helping in conduct of study.\n\n\nReferences\n\nHorstman MJ, Spiegelman A, Naik AD, et al.: National Patterns of Urine Testing During Inpatient Admission. Clin. Infect. Dis. 2017 Oct 1; 65(7): 1199–1205. PubMed Abstract | Publisher Full Text\n\nvan Horrik TMZXK , Laan BJ, Huizinga AB, et al.: Why Are We Frequently Ordering Urinalyses in Patients without Symptoms of Urinary Tract Infections in the Emergency Department? Int. J. Environ. Res. Public Health. 2022; 19(17): 10757. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMunigala S, Jackups RR Jr, Poirier RF, et al.: Impact of order set design on urine culturing practices at an academic medical centre emergency department. BMJ Qual. Saf. 2018; 27(8): 587–592. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJohnson JR, Drekonja DM: Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS): Common, but Currently Nameless. Am. J. Med. 2017; 130(5): e201–e204. PubMed Abstract | Publisher Full Text\n\nGogulamudi PR, Deepanjali S, Mandal J, et al.: Asymptomatic bacteriuria among medical inpatients: Data from an Indian teaching hospital. Trop. Dr. 2021; 51(4): 535–538. PubMed Abstract | Publisher Full Text\n\nHooker JB, Mold JW, Kumar S: Sterile pyuria in patients admitted to the hospital with infections outside of the urinary tract. J. Am. Board Fam. Med. 2014; 27(1): 97–103. PubMed Abstract | Publisher Full Text\n\nDieter RS: Sterile pyuria: a differential diagnosis. Compr. Ther. 2000; 26(3): 150–152. Publisher Full Text\n\nStansfeld JM: The measurement and meaning of pyuria. Arch. Dis. Child. 1962; 37(193): 257–262. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWise GJ, Schlegel PN: Sterile pyuria. N. Engl. J. Med. 2015; 372(11): 1048–1054. PubMed Abstract | Publisher Full Text\n\nRubin RH, Shapiro ED, Andriole VT, et al.: Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration. Clin. Infect. Dis. 1992; 15 Suppl 1: S216–S227. PubMed Abstract | Publisher Full Text\n\nSobel JD, Brown P: Urinary Tract Infections.Bennett JE, Dolin R, Blaser MJ, editors. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Vol. 1. . Philadelphia: Elsevier; 2019; p. 974.\n\nStamm WE: Measurement of pyuria and its relation to bacteriuria. Am. J. Med. 1983; 75: 53–58. PubMed Abstract | Publisher Full Text\n\nOzdem S, Bayraktar T, Oktay C, et al.: The prevalence of asymptomatic pyuria in diabetic patients: comparison of the Sysmex UF-100 automated urinalysis analyzer with Fuchs-Rosenthal hemacytometer. Clin. Biochem. 2006 Sep; 39(9): 873–878. PubMed Abstract | Publisher Full Text\n\nLee MJ, Kim M, Kim NH, et al.: Why is asymptomatic bacteriuria overtreated? A tertiary care institutional survey of resident physicians. BMC Infect. Dis. 2015 26; 15: 289. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIrfan N, Brooks A, Mithoowani S, et al.: A Controlled Quasi-Experimental Study of an Educational Intervention to Reduce the Unnecessary Use of Antimicrobials For Asymptomatic Bacteriuria. PLoS One. 2015; 10(7): e0132071. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLim LL, Goyal N: Hospital clinical practice around urinalysis is an important opportunity for antimicrobial stewardship improvement activities. Infect. Dis. Health. 2021; 26(4): 243–248. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "273337",
"date": "10 May 2024",
"name": "Rani Diana Sahni",
"expertise": [
"Reviewer Expertise Genitourinary infection diagnostics",
"antimicrobial susceptibility"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear authors,\n\nThank you for submitting your work for review.\n\nIn our daily work we come across protocols that are sometimes questionable but have not been revised due to a lack of sufficient evidence to change the norm. This topic is one such issue.\n\nPlease find below the comments / suggestions of this review.\n\n1. Introduction:\n\n\"Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission..........More recent studies show that urinalysis is often ordered without proper indication in the emergency department.\"\n\nThe opening statement in the introductory section and the last sentence in the same paragraph, suggests that these tests are over ordered and without a reasonable clinical basis. However, urine microscopy to detect \"pyuria\" has its merits and is ordered as a cheaper and quicker method to \"rule out\" a urinary tract pathology rather than to \"rule-in\" an infective or non-infective disease in an emergency department and can be used as the only test in a resource limited setting. Therefore, the introductory passage needs to be modified.\n\n2. Methodology:\n1. The study has been carried out among hospitalized patients; however, this test is more relevant in an out-patient/emergency setting. Please explain why the hospitalized patient subset was chosen for this study.\n2. Pus cells / WBC can be produced in other non-infective and inflammatory clinical settings and therefore does not always indicate an infection (UTI). Therefore, the reasons for hospitalization, need to be addressed. Please include the same. It is relevant as they could contribute to the presence of inflammatory cells in urine. To name a few: Renal pathology inclusive of calculi and tumors, BPH, Bacterial vaginosis, urethritis. As these were all asymptomatic participants, the reason most likely to be associated with pyuria may then be determined.\n\n3. Pus cells may also be seen in patients with a recent history of UTI / recent catheter removals or urosepsis without a lower UTI presentation. The exclusion criteria should include: patients who have been on antibiotics in the last two weeks / history of UTI in the last 2-4 weeks / urosepsis. Please explain if these were a part of the exclusion criteria.\nConcluding remark: The ultimate sample size is small to describe the differences between two microscopic methods and reasons for pyuria. However, The most relevant information in the manuscript seems to be the comparison between the 2 microscopic methods which may be highlighted with a description of the clinical cases that may benefit from a urine microscopy test.\n\nBest wishes.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11555",
"date": "25 May 2024",
"name": "Surendran Deepanjali",
"role": "Author Response",
"response": "Response to reviewer We are grateful to the reviewer for the critical appraisal of our manuscript and for providing valuable feedback. We hope to address the concerns raised by the reviewer as much as possible and make modifications in the revised version of our manuscript which will be uploaded after obtaining further comments from more reviewers (as advised by the editorial team). Please find the point-to-point responses for your comments below. Please note that the parts planned to be modified are italicized and bolded for ready reference. Comment 1. Introduction: \"Urinalysis for detecting pyuria is a commonly ordered test in hospitalized patients. It is considered one of the ‘routine’ or ‘default’ investigations after hospital admission..........More recent studies show that urinalysis is often ordered without proper indication in the emergency department.\" The opening statement in the introductory section and the last sentence in the same paragraph, suggests that these tests are over ordered and without a reasonable clinical basis. However, urine microscopy to detect \"pyuria\" has its merits and is ordered as a cheaper and quicker method to \"rule out\" a urinary tract pathology rather than to \"rule-in\" an infective or non-infective disease in an emergency department and can be used as the only test in a resource limited setting. Therefore, the introductory passage needs to be modified. Response We agree with the reviewer that urinalysis is a cheap and quick ‘rule-out’ test in the ED (except in those with obstructive uropathy or absolute neutropenia). To that effect, we will modify the Introduction as given below. We will also add a new reference to point this out. The second paragraph of Introduction: “In patients with classic clinical symptoms and signs of UTI, the presence of pyuria and significant bacteriuria helps in ascertaining the diagnosis of UTI. Also, it has been observed that urinalysis serves as a useful “rule-out” test for UTI (Advani SD, North R, Turner NA, Ahmadi S, Denniss J, Francis A, Johnson R, Hasan A, Mirza F, Pardue S, Rao M, Rosshandler Y, Tang H, Schmader KE, Anderson DJ. Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all? Clin Infect Dis. 2024 Apr 26:ciae230.) However, in those without typical clinical features of UTI, the presence of pus cells in urine detected by a routinely done microscopy examination often leads to diagnostic confusion. This is especially so if pyuria is accompanied by bacteriuria, which is detected by a urine culture. This condition, which was proposed to be called ‘Bacteriuria/Pyuria of Clinically Undetermined Significance (BPCUS),’ is indeed not so uncommon in hospital settings.4” Comment 2. Methodology: 1. The study has been carried out among hospitalized patients; however, this test is more relevant in an out-patient/emergency setting. Please explain why the hospitalized patient subset was chosen for this study. 3. Pus cells may also be seen in patients with a recent history of UTI / recent catheter removals or urosepsis without a lower UTI presentation. The exclusion criteria should include: patients who have been on antibiotics in the last two weeks / history of UTI in the last 2-4 weeks / urosepsis. Please explain if these were a part of the exclusion criteria. Response We thank the reviewer for pointing this out. All patients were recruited from the emergency department setting within 24 hours of presentation. We confirm that we have excluded patients on urinary catheter (already mentioned as an exclusion criterion) and those with urosepsis (excluded all patients with suspected/confirmed urosepsis). Further, we did exclude patients who have been hospitalized or treated with antibiotics in the previous 2 weeks of admission to our hospital. Please find the modifications effected below. Methods We did a prospective observational study between April 2021 to June 2022 among adult patients presenting to casualty and who were subsequently admitted under the Department of Medicine, JIPMER. The study protocol was reviewed and approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry (No. JIP/IEC/2020/202; dated April 19, 2021). Written informed consent was obtained from all study participants and the study was conducted in compliance with the Declaration of Helsinki. Our study population included adult patients hospitalized with a non-UTI diagnosis. We excluded patients who had a positive UTI symptom screening at admission as well as those on indwelling urinary catheter. We also excluded who had a recent (past 2 weeks) hospitalization or exposure to antibiotics. Patients were recruited within 24 hours of hospitalization. We defined positive UTI as the presence of at least two or more typical symptoms or signs suggestive of UTI like dysuria, urinary frequency, urgency, hesitancy, lower abdominal pain, loin pain, suprapubic tenderness, and renal angle tenderness. Comment 2. Pus cells / WBC can be produced in other non-infective and inflammatory clinical settings and therefore does not always indicate an infection (UTI). Therefore, the reasons for hospitalization, need to be addressed. Please include the same. It is relevant as they could contribute to the presence of inflammatory cells in urine. To name a few: Renal pathology inclusive of calculi and tumors, BPH, Bacterial vaginosis, urethritis. As these were all asymptomatic participants, the reason most likely to be associated with pyuria may then be determined. Response The reviewer is correct in pointing out that pus cells in urine is not always indicative of UTI and that non-infective and inflammatory conditions can cause it. Our study shows that infections other than UTI also could also result in urine pus cells. We would like to bring to the kind attention of the reviewer that we do discuss regarding other possible causes of pyuria like urethritis and renal calculi in the Discussion section of the manuscript, which we are quoting here, “In a recent review on sterile pyuria, gynaecological infections, urethritis, balanitis, viral infections of the genitourinary tract, prostatitis, genitourinary tuberculosis, and current use of antibiotics have been listed as causes related to infection for this finding.9 The causes unrelated to infection are urinary catheter use, urological procedures, urinary tract stones or neoplasms, papillary necrosis, inflammatory diseases like SLE, etc. Our study population did not include those with these diagnoses. However, it is possible that asymptomatic infections of urinary tract and/or urological abnormalities like clinically silent renal stones could have been present in a proportion of them. “ The presenting complaints at admission and the discharge diagnosis of all the study participants are available in the open access dataset attached with the manuscript. It was not possible to tabulate all diagnoses to be included in the manuscript. However, we will include the major diagnostic categories for all 196 participants the Results section as follows: “Most (175[89.3%]) patients were hospitalized for an infection. The major diagnostic categories in the remainder (21 patients) were metabolic disorders like diabetic ketoacidosis in 5, connective tissue disorders in 4, cardiovascular diseases in 3, hepatic diseases in 2, malignancies in 2 and central nervous system, renal and gastrointestinal involvement in one patient each.” Concluding remark: The ultimate sample size is small to describe the differences between two microscopic methods and reasons for pyuria. However, The most relevant information in the manuscript seems to be the comparison between the 2 microscopic methods which may be highlighted with a description of the clinical cases that may benefit from a urine microscopy test. Response The primary objective of the study was to see the frequency of pyuria in patients with a non-UTI diagnosis and the sample size may not have been adequate to test the diagnostic performance characteristics of the ‘routine’ method. We do discuss about the merits of chamber counting method for pyuria detection in Paragraph 3 of Discussion section. However, as the reviewer suggested we will include this point in Conclusion section. Further, we will give a suggestion regarding the utility of this test as a ‘rule-out’ rather than a ‘rule-in’ test for UTI. Please read the modified Conclusion here: “In conclusion, we found that abnormal microscopic urinalysis findings like pyuria and hematuria can be present in a proportion of hospitalized patients across a wide range of diagnostic categories. Estimating the number of pus cells per high power field in centrifuged urine has only modest diagnostic performance compared to the chamber counting method. Urinalysis may be best used as a ‘rule-out’ test for UTI rather than a specific test for diagnosing UTI. Unnecessary ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Comment Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? No Response We believe we have explained the methods and analysis in detail; however, we will be happy to clarify them further if deemed necessary by the reviewer. Thank you once again for reviewing our study and providing constructive comments!!"
}
]
},
{
"id": "273342",
"date": "13 May 2024",
"name": "Kartikeya Cherabuddi",
"expertise": [
"Reviewer Expertise Infectious diseases"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in detailing the introduction, methods, results and discussion.\n\nSome recommendation to further enhance the article: 1. Please list a reference for this statement: using the chamber counting method, which is a more accurate method of quantifying pyuria. Please include a newer reference than #8 if available.\n\n2. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. Would a cut-off of >= 10 WBCs/hpf in the routine method be comparable to the chamber counting method?\n\n3. Consider modification to: Unnecessary and routine ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Finally, a positive urinalysis with pyuria in an asymptomatic patient should not prompt urine culture testing and/or antibiotic treatment.\n\n4. Consider listing the limitations of the chamber counting method - time, need for training/ expertise etc as relevant.\n\n5. Were patients with recent urinary catheterisation excluded? If so, please state it.\n\n5. Minor typographical errors a) had ‘plenty’ of us cells/hpf. b) medicine side lab\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11562",
"date": "25 May 2024",
"name": "Surendran Deepanjali",
"role": "Author Response",
"response": "Response to reviewer Comment This is an important study and article detailing the high presence of asymptomatic pyuria in a hospitalised population. The authors have done a superb job in detailing the introduction, methods, results and discussion. Response We are very grateful to the reviewer for his very kind words of appreciation. Comment 1. Please list a reference for this statement: using the chamber counting method, which is a more accurate method of quantifying pyuria. Please include a newer reference than #8 if available. Response We did a repeat literature search whether any more recent studies comparing the two methods of pyuria have been published, but could not find any. However, we found a study more recent than reference 8 which describes that chamber counting method is more accurate and hence we will include this reference in the modified version of the manuscript. (Saito A, Kawada Y. Reliability of pyuria detection method. Infection. 1994;22 Suppl 1:S36-7.) Comment 2. We found that using a cut-off of ≥5 WBCs/hpf would lead to overdiagnosis of pyuria in about 10% more patients. Would a cut-off of >= 10 WBCs/hpf in the routine method be comparable to the chamber counting method? The reviewer is correct in postulating that a cut-off of ≥ 10 cells/hpf would be more comparable to the chamber counting method. Such a cut-off would be more specific and have a better positive predictive value. We could have done this analysis using our dataset; however, our lab reports the pus cells/hpf as 5-10 and 11-20 etc, hence it is not possible to find out how many had exactly 10 WBCs/hpf. We came across this comparison (between 5 versus 10 WBCs/hpf) in the study quoted in the previous response, where Saito et al observed a sensitivity of 52% and a specificity of 86% for ≥5 WBCs/hpf versus a sensitivity of 48% and 87% for ≥10 WBCs/hpf. Nevertheless, we would like to bring to the kind attention of the reviewer that presence of ≥5 WBCs/hpf in urine has been reiterated as an entry criterion for UTI in a very recently published consensus definition for UTI (Bilsen MP, Conroy SP, Schneeberger C, et al.; UTI Reference Standard Consensus Group. A reference standard for urinary tract infection research: a multidisciplinary Delphi consensus study. Lancet Infect Dis. 2024 Mar 5:S1473-3099(23)00778-8.) Comment 3. Consider modification to: Unnecessary and routine ordering of urinalysis should be avoided, and the presence of pyuria has to be interpreted in the light of the given clinical context. Finally, a positive urinalysis with pyuria in an asymptomatic patient should not prompt urine culture testing and/or antibiotic treatment. We will be happy to make this change in the Conclusion section. Comment 4. Consider listing the limitations of the chamber counting method - time, need for training/ expertise etc as relevant. Response In the Discussion section of the manuscript (Paragraph 3) we plan to include the following statements: “However, detecting pyuria using the chamber counting method could be time -consuming and requires expertise. Moreover, operators should be cognizant of possible calibration and observer errors while using a hemocytometer.” (Gadeholt H. Counting of cells in urine. The variability of haemocytometer counts. Acta Med Scand. 1968 Jan-Feb;183(1-2):9-16.) Comment 5. Were patients with recent urinary catheterisation excluded? If so, please state it. Response Yes, they were excluded. We will state it in exclusion criteria. Comment 5. Minor typographical errors a) had ‘plenty’ of us cells/hpf. b) medicine side lab Response We thank the reviewer for pointing them out. The lab in our department is actually called a ‘side lab’, but we will change this to ‘medicine lab’ to avoid confusion. We thank the reviewer again for his constructive comments."
}
]
}
] | 1
|
https://f1000research.com/articles/13-291
|
https://f1000research.com/articles/12-361/v1
|
03 Apr 23
|
{
"type": "Research Article",
"title": "Knowledge, attitude and practices towards COVID-19 among Indian medical undergraduates: a questionnaire-based study",
"authors": [
"Sharada Rai",
"Rakshatha Nayak",
"Anusha S Bhatt",
"Kudurugundi Basavaraju Vatsala",
"Chaithra Gowthuvalli Venkataramana",
"Animesh Jain",
"Sharada Rai",
"Anusha S Bhatt",
"Kudurugundi Basavaraju Vatsala",
"Chaithra Gowthuvalli Venkataramana",
"Animesh Jain"
],
"abstract": "Background: The Coronavirus disease-19 (COVID-19) infection of severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) has emerged as a recent pandemic, increasing the need for epidemiological studies and studies on public health. Only some studies have evaluated the awareness of medical undergraduates in India and other countries, leading to a lack of literature. Methods: This study is a descriptive cross-sectional questionnaire-based study conducted in Kasturba Medical College, Mangalore, India, between June to August 2020. An online survey using google forms was circulated among undergraduate medical students in India by a convenient sampling method for data collection. Descriptive analysis was derived based on frequencies and percentages, and the association with age, gender, and year of undergraduate training medical course was derived using the chi-square test. Results: Altogether, 630 students from India responded to the survey, with a maximum response from students studying in the second year (38.7%). Nearly 63.85% of responders identified themselves as females. Knowledge regarding the human-to-human transmission of the virus, symptoms, complications, definition of \"close contact, quarantine, and its indications was adequate among the students, with more than 70% correct responses. However, one-fourth of the students needed to gain more knowledge about masks. Respiratory hygiene was poor among 24.8%. Nearly 40% of students were unaware of the management of patients with COVID-19. Conclusion: There is a need for regular quality training and institutional programs on infection control of COVID-19 and other infectious diseases across all Indian medical colleges to educate undergraduate medical students, who are future healthcare professionals, thus minimizing the risk of transmission and providing optimal care for patients.",
"keywords": [
"Covid-19",
"Public Health",
"Prevention",
"Infectious disease",
"Pandemic"
],
"content": "Introduction\n\nThe Coronavirus disease-19 (COVID-19), a recent pandemic due to severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) infection caused major health threats worldwide during the year 2020-2021.1 The disease’s accelerated and extensive geographic spread during the pandemic posed significant challenges for administrative authorities and healthcare professionals.\n\nAll healthcare workers have a higher risk of infection due to patient exposure. Although undergraduate medical students are not actively involved in patient care, the possibility of them acquiring and transmitting the disease within healthcare centers and on medical college campuses is high.2 Vaccinations like Covishield, Covaxin, Sputnik V, Corbevax, etc., are effectively used in India. Of these, Covishield is the most used, accounting for 81% of the total doses given.3–5 It has drastically declined the number of new cases.6 However, due to new variants like omicron, emerging frequently, and the Peltzman effect in the country, several cities are still facing on-and-off spikes in incidence and mortality rate, which has caused a shortage of healthcare facilities and front-line doctors.6,7 Under the worst-case scenario, voluntary recruitment of medical undergraduates as a potential solution for lacking human resources may be beneficial.2 The student’s and patient’s safety is of significant concern in such emergent circumstances.8,9\n\nAwareness about the disease, its transmission, risk factors, prevention, infection control, guidelines, and practices during patient care among healthcare workers and students is fundamental to preventing healthcare-associated transmission and infection.10–13 Studies have been done to assess the understanding of COVID-19 among healthcare workers and the general population in various countries.14–22 But there are only few studies that have been done evaluating the awareness of medical undergraduates in India, leading to a need for more literature.2,8,9 The objective of the study is to determine the Knowledge, Attitudes, and Practices (KAP) of Indian medical undergraduate students regarding the COVID-19 pandemic, which can help us to recognize faulty practices and attitudes of the students towards COVID-19. In addition, it can help us plan and review our policies to implement best practices for controlling the COVID-19 disease.\n\n\nMethods\n\nWe obtained online written informed consent from all participants and approval from the Institutional Ethics Committee. (Kasturba Medical College, Mangalore, Reg. No. ECR/54/Inst/KA/2014/RR-17, Protocol No. IECKMCMLR-07/2020/218)\n\nThis study is a descriptive cross-sectional study. An online survey using Google Forms was circulated among 630 medical undergraduate students in India. With an assumption of 50% of the Indian Medical undergraduates having adequate awareness and 10% relative precision, for a 95% confidence interval, the sample size was calculated to be 384. Adding 20% non-response rate, the final sample size came to be 460. A self-administered questionnaire was developed which consisted of socio-demographic questions, 20 questions based on knowledge, 7 questions based on attitude, and 12 questions on practices related to COVID-19 disease, adapted from the current interim guidance and information for healthcare workers published by the World Health Organisation (WHO), updated on 12th June 202023–33 The authors approached their colleagues from other institutions throughout the country through whom the medical undergraduates were identified. Social media platforms like Facebook, WhatsApp, Twitter were also used to identify common groups containing medical undergraduates from the country. The survey was circulated through social media by creating a link to the questionnaire. Non-random (convenience and snowball) sampling was done. Undergraduates who were studying in India and willing to participate in the survey irrespective of their age, sex, gender or institution were included in the study. The gender and age of the students were considered based on the responses given by them in the online forms. The online responses were collected over a period of two months duration from 16th June to 15th August 2020.\n\nWe analyzed the collected data using the Statistical Package for the Social Sciences, version 25. Only complete responses were considered for data analysis. Descriptive analysis using frequencies and percentages was done. At the same time, the chi-square test was done for association between KAP concerning age, gender, and year of undergraduate training medical course.\n\n\nResults\n\nSix hundred thirty students from various medical colleges in India belonging to different states like Karnataka, Kerala, Tamil Nadu, Hyderabad, Gujarat, Rajasthan, Maharashtra, Madhya Pradesh, West Bengal, Goa etc. responded to the survey. Out of these, we accepted only 618 responses and rejected 12 due to incomplete or incorrect answers. Most students were in the second year of their undergraduate training course (38.7%), with the maximum response from students aged 20 years (31.7%). Nearly 63.85% of responders identified themselves as females, and 36.2% identified themselves as males. Most responses were seen from different institutes of Karnataka state, followed by Kerala and Gujarat. The primary source of information on COVID-19 among the students was through news media (78.6%), official international health organization sites (66.7%), social-media (63.6%), official government sites (62.6%), and journals (14.1%). The majority of the students had received formal training in hand hygiene over the last year (73.5%). Most responders (68.4%) knew that the virus causing COVID-19 was Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), although only 50.5% of students knew it was initially called 2019-nCoV. Knowledge regarding the human-to-human transmission of the virus was adequate among the students, with 94.5% responses for droplet transmission, which is the most regular route of transmission, 53.6% responses for contact transmission, and 53.2% responses for airborne transmission. Only 7.9% knew that faeco-oral transmission is also rarely reported in COVID-19. The initial symptoms of COVID-19 were well-known among the students, with maximum responses for fever (88.2%) and sore throat (84.8%). Only 20.7% knew diarrhoea could also be a presenting symptom of COVID-19. Although most students (98.9%) were aware of respiratory complications of COVID-19, only 17.5% were aware of cardiac complications, and 12% were aware of renal complications. Among the respondents, 76.5% were able to define “close contact correctly.” The understanding of home quarantine (97.9%) and indications for quarantine (90.8%) were satisfactory, although the first-year students had lesser knowledge about the same (p<0.05). More than 96% of students were aware of personal protective equipment worn by health care professionals. The majority of students were aware that respirators (76.1%) and surgical masks (58.3%) were effective in preventing transmission in healthcare workers, and three-layered cotton masks are reasonable alternatives in a public setting (73.6%). However, 11.2% believed that single-layered mask and 7.4% of students thought that dust mask was helpful in prevention. 7.8% believed that surgical masks were washable and reusable. Although the majority were aware that respiratory and hand hygiene (99.2%) and personal protective equipment (96.4%) are most effective in preventing infection, few responses for measures like vaccination (28.8%), Prophylactic Chloroquine (26.7%), taking frequent hot water baths (24.3%) were also seen. Among the students 88.7% had knowledge about vulnerable groups who are at higher risk for infection. More than 90% of students were aware that those infected with COVID-19 might not develop severe symptoms, with female students being more aware than males (p<0.05). Final-year students were the most knowledgeable, and first-year students were the least aware (p<0.05). 88.5% knew that asymptomatic patients could transmit the disease, but first and second-year students were least knowledgeable about the same (p<0.05). Nearly 75% of students were unaware that the preferred disinfection method for visibly soiled hands is hand washing with soap rather than alcohol-based hand sanitizer, with final-year students being most aware and first-year students least aware. Only 68.8% knew there was a risk of transmission of the SARS-CoV-2 virus through food delivery/takeaway, with male students being more knowledgeable than females (p<0.05), and 61.7% knew that the risk of transmission from pets is very low. Still, nearly 48.9% of first-year students were unaware of the same (p<0.05). More than 95% of students knew there is currently no effective cure for COVID-19, but early symptomatic and basic treatment can help most patients recover from the infection.\n\nNearly 4.7% of students responded that they would hide their symptoms due to the stigma attached to COVID-19, especially females and those in the age group of 21-23 years. More than 94% of students were willing to seek medical attention if they develop symptoms, despite the stigma attached to COVID-19. Although female students responded that they are more likely to hide their symptoms, they are also more likely to seek medical attention than male students. Nearly 86% of students are aware that despite good immunity, they can get infected if they had contact with an infected patient. However, nearly 16.7% of students who belonged to the age group of 18-20 years were unaware of this. And those in the final year were more aware, which is statistically significant (p<0.05). More than 86% of students feel the urge to update themselves on the virus, especially female students, which is statistically significant (p value<0.05). Nearly 40% of students were unaware how to approach and treat patients with signs and symptoms of COVID-19. Female students and younger students have the least confidence. Students in the final year, especially those above 24 years of age, had maximum confidence, which was statistically significant (p-value <0.05). 94.8% of students were willing to take vaccination against COVID-19 if available. Those belonging to 2nd years and 4th years were more willing than others, which was statistically significant (p<0.05).\n\nAbout 80.3% of students were willing to volunteer as healthcare providers to fight COVID-19. Even though the female students were less confident about the management, they were more eager to volunteer as health care providers compared to their male co-students. The majority of students avoided close contact like a handshake (96.6%), avoid meeting people with symptoms (83.8%) and going to crowded places during the pandemic (89.5%), and followed regular hand hygiene practices like washing with soap (96.8%) and alcohol-based hand sanitizers (86.9%). Female students were more cautious about handshakes and avoided going to crowded places compared to male students, which was statistically significant (p <0.05). Female students also tended to use alcohol-based sanitizers more than male students, which was statistically significant. (p<0.05). However, respiratory hygiene was not followed by 24.8%, of which the majority belonged to their final year and is statistically significant (p <0.05). Nearly 25.1% of students resided with vulnerable people such as elderly individuals and those with co-morbidities, most of whom were final-year students and above the age of 24, which is statistically significant (p <0.05). Nearly 49.7% consumed specific medicine/food to boost immunity, like multivitamins, proteins, herbal drinks, homemade remedies, and ayurvedic medications. Almost 99.4% of students wore a mask when they went outside during the pandemic.\n\n\nDiscussion\n\nThe recent pandemic, COVID-19, caused by SARS-Cov-2, was first diagnosed in December 2019 in Wuhan, China.14 People working in healthcare facilities but not in a clinical setting, like medical students and clerical staff, are also at risk of exposure. Their lack of knowledge can lead to person-person transmission and the spread of the disease. In India, medical colleges have conducted online classes and sessions for undergraduates due to many cases during the pandemic. After the third wave in 2022, the students were recruited back to the campus for regular on-site courses.34 Despite vaccinations like Covishield, Covaxin, Sputnik V, Corbevax etc. effectively bringing down the overall incidence of cases in the country, some high-alert cities like Delhi and Mumbai experienced sudden surges in patients, especially after re-opening of schools and colleges with a significant mortality rate.3–7 It is, therefore, essential to know the attitudes and practices of medical students regarding COVID-19 to avoid further transmission and avoid any fourth wave in the country.\n\nKnowledge about the disease, route of transmission, prevention, identifying the high-risk groups, initial symptoms of illness, and early isolation of suspected individuals are the most critical steps toward disease control.35–37\n\nIn our study, most students were aware of droplet transmission; however, less than half were aware of other common routes like airborne, contact, and faeco-oral transmission.14–21\n\nMost patients with COVID-19 experience a mild flu-like illness. They have a fever, cough, myalgia, and shortness of breath. Rarely some may experience atypical symptoms such as fatigue, reduced alertness, reduced mobility, diarrhoea, loss of appetite, delirium etc. without any febrile episodes.19,20 Few patients are asymptomatic. Nearly 10-20% of patients have been reported to develop severe symptoms characterized by severe pneumonia, septic shock, acute respiratory distress syndrome, metabolic acidosis, multi-organ failure, and coagulation dysfunction demanding intensive care.19,20 In our study, although many were aware of the initial respiratory symptoms and complications, few were knowledgeable about other symptoms like myalgia, diarrhoea, renal failure, and shock. Most students were also aware that not all patients develop the disease, and asymptomatic patients can transmit the disease.\n\nCurrently, no specific antiviral treatment is known to be effective in combating the disease.15,16 However, nearly 20% of our responders believe that antibiotics and other myths, like hand dryers, hot water baths, etc., can prevent viral transmission.\n\nThe understanding of “close contact” and home quarantine and its indication was satisfactory among students.33 There was adequate awareness about high-risk groups, such as those over 60, or with underlying comorbidities, smokers, pregnant women, malnourished and immune-compromised which was noteworthy as many resided with the vulnerable group during the pandemic.19,38,39\n\nPersonal measures like hand hygiene, respiratory etiquette, masks and personal protective equipment, environmental cleaning, and disinfection at home effectively reduce transmission.20 Though this was practiced by many, the standardized hand hygiene techniques for visibly soiled hands, which is handwashing with soap and water were not known by all. Moreover, respiratory hygiene methods, like using sanitary tissue while coughing or sneezing and its proper disposal, were practiced by only few. These faulty practices have to be addressed cautiously.\n\nThe knowledge about personal protective equipment was satisfactory. Almost all the students wore a mask when they go out. Most students were aware of the different masks available for protection, but nearly 20% believed that surgical masks were washable and reusable. Only half the responders knew respirators were the most effective mask for aerosol-generating procedures.40 This could increase the transmission rate in health-care setups if not acknowledged.\n\nMost students practiced social distancing during high-case alerts which was a good practice. Although most students in the study were willing to volunteer as healthcare providers to fight against COVID-19, only a few are aware and confident about proper treatment protocols for infected patients.\n\nCurrently, similar studies on medical students in India and other South Asian countries are limited. Studies show that the knowledge of undergraduate medical students in India about COVID-19 is unsatisfactory.2,8,9 Similarly, this study suggests that despite satisfactory awareness, attitude, and practices among the majority of students, there is still scope for improvement. Moreover, in countries like India, where there is an acute shortage of front-line doctors, recruiting undergraduate medical students to serve in the voluntary front-line team against COVID-19 is a reasonable option.8 Which further demands effective planning and education to enable better adherence to good practices, including pre-exposure and post-exposure prophylaxis, to prevent the spread COVID-19. Regular training courses in infection control, including theory and practical, can help medical teams face unexpected consequences.\n\nThe drawbacks of this study include the less-than-expected response from students and lack of proper representation from entire country, probably due to selection bias as all the institutions and states from the country couldn’t be approached due to lack of contact details. Using social media to share the questionnaire and online survey, also limited the study as not all students had social media accounts and well established internet is not widely available in remote areas of the country.\n\nIt has been three years since the first onset of COVID-19 in China.1 But there is a lot of uncertainty concerning this virus’s key epidemiological, clinical, and virological characteristics, with several ongoing research on its virulence and spread. The cure or vaccination against this disease is still under trial and may require considerable time for its implementation and complete acceptance.4,41 The misinformation provided by spurious organizational bodies and shared on social media has caused confusion and fear among the public.42 Adequate knowledge about COVID-19 and updates on various guidelines among healthcare workers plays a crucial role in infection control and transmission prevention. Medical students can be considered an accessible and approachable source of information to their families and the public. They are essential in forming a link between the medical field and society during any time of health crisis. Necessary policies, educational programs, training, interactive sessions, and evaluation needs to be planned and modulated by administrative authorities, to avoid any unpreparedness in the face of similar emergencies in the future.",
"appendix": "Data availability\n\nFigshare: https://doi.org/10.6084/m9.figshare.22178414.v3. 43\n\nThis project contains the following underlying data:\n\n• Data-Excel.xlsx\n\nFigshare: https://doi.org/10.6084/m9.figshare.22178423.v3. 44\n\nThis project contains the following underlying data:\n\n• Statistical results.doc\n\nFigshare: https://doi.org/10.6084/m9.figshare.22180984.v2. 45\n\nThis project contains the following extended data:\n\n• Questionnaire.docx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nWorld Health Organization: Coronavirus disease 2019 (COVID-19): Weekly Epidemiological Update 18 January 2022. [Accessed 19 January 2022]. Reference Source\n\nModi PD, Nair G, Uppe A, et al.: COVID-19 Awareness Among Healthcare Students and Professionals in Mumbai Metropolitan Region: A Questionnaire-Based Survey. Cureus. 2020; 12(4): e7514. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: The Bharat Biotech BBV152 COVAXIN vaccine against COVID-19: What you need to know. [Accessed 11 February 2023]. Reference Source\n\nVaccine information, ICMR New Delh: COVID-19 vaccine. [Accessed 19 February 2023]. Reference Source\n\nBBC News: Covishield and Covaxin: What we know about India’s Covid-19 vaccines. [Acessed 19 February 2023]. Reference Source\n\nJuyal D, Pal S, Thaledi S, et al.: COVID-19: The vaccination drive in India and the Peltzman effect. J Fam Med Prim Care. 2021; 10(11): 3945–3947. [Acessed 19 February 2023]. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nDeol T: Fourth wave? COVID-19 cases rising in India as mask mandate lifted, schools reopen. [Acessed 19 February 2023]. 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Publisher Full Text\n\nAlzoubi H, Alnawaiseh N, Al-Mnayyis A, et al.: COVID-19 - Knowledge, Attitude and Practice among Medical and Non-Medical University Students in Jordan. J Pure Appl Microbiol. 2020; 14(1): 17–24. Publisher Full Text\n\nZhong BL, Luo W, Li HM, et al.: Knowledge, attitudes, and practices towards COVID-19 among Chinese residents during the rapid rise period of the COVID-19 outbreak: a quick online cross-sectional survey. Int J Biol Sci. 2020; 16(10): 1745–1752. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHezima A, Aljafari A, Aljafari A, et al.: Knowledge, attitudes, and practices of Sudanese residents towards COVID. East Mediterr Health J. 2020; 26(6): 646–651. PubMed Abstract | Publisher Full Text\n\nRugarabamu S, Ibrahim M, Byanaku A: Knowledge, attitudes, and practices (KAP) towards COVID-19: A quick online cross-sectional survey among Tanzanian residents. medRxiv. 2020. [preprint]. 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Reference Source\n\nWorld Health Organization: Algorithm for COVID-19 triage and referral COVID -19 Outbreak. WHO regional office Manila; 2020. [Accessed 11 June 2020]. Reference Source\n\nNational Centre for Disease Control: Guidelines for Setting up Isolation Facility/Ward. Government of India; 2020. [Accessed 12 June 2020]. Reference Source\n\nGovernment of India: Guidelines for home quarantine. 2020. [Accessed 12 June 2020]. Reference Source\n\nJena PK: Impact of pandemic COVID-19 on education in India. International Journal of Current Research. 2020; 12(07): 12582–12586. Reference Source\n\nWorld Health Organisation: Clinical management of COVID-19. Interim guidance; 2020. [Accessed 21 June 2020]. Reference Source\n\nHealth Catalyst: Improving Population Health: Data-Driven Approach to Identifying and Engaging Patients with High Risk of Mortality from COVID-19.2020. [Accessed 13 June 2020]. Reference Source\n\nKar SK, Verma N, Saxena: Coronavirus Infection Among Children and Adolescents.Saxena S, editor. Coronavirus Disease 2019 (COVID-19). Medical Virology: From Pathogenesis to Disease Control. Singapore: Springer; 2020. Publisher Full Text\n\nWorld Health Organization: Multisystem inflammatory syndrome in children and adolescents with COVID-19. Scientific Brief; 2020. [Accessed 16 June 2020]. Reference Source\n\nWorld Health Organization: Smoking and COVID-19. Scientific Brief; 2020. [Accessed 16 June 2020]. Reference Source\n\nSalvi SS: In this pandemic and panic of COVID-19 what should doctors know about masks and respirators? Pune: Pulmocare Research and Education (PURE) Foundation; 2020. [Accessed 13 June 2020]. Reference Source\n\nLahariya C: Third wave of the COVID-19 pandemic in India: What lies ahead? DownToEarth; 2022. [Accessed 19 January 2022]. Reference Source\n\nBanarjee C: India world’s biggest Covid misinformation source: Study. The Times of India; 2021. [Accessed 19 January 2022]. Reference Source\n\nNayak R, Rai S, Jain A: Data table. Epub ahead of print 27 February 2023. Publisher Full Text\n\nNayak R, Rai S, Jain A: Statistical analysis. Epub ahead of print 27 February 2023. Publisher Full Text\n\nNayak R, Rai S, Padmanabha N, et al.: Questionnaire. Epub ahead of print 27 February 2023. Publisher Full Text"
}
|
[
{
"id": "181439",
"date": "07 Aug 2023",
"name": "Bodrun Naher Siddiquea",
"expertise": [
"Reviewer Expertise Both communicable and non-communicable diseases."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMethods\nPlease mention about the validity of the questionnaire (tested or not) in the method section.\n\nPlease clearly mention about options of responses and scoring or of the questionnaire in the method section.\nResults\nResults presented in Tables and short summary will increase the readability of the article.\nDiscussion and conclusion\nPlease compare your results with published literature from other countries.\n\nToo many paragraphs.\n\nPlease write the conclusion under separate heading.\n\nGenerally the paper needs proof reading to improve the grammatical errors.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11507",
"date": "25 May 2024",
"name": "Rakshatha Nayak",
"role": "Author Response",
"response": "Dear sir, Thank you for reviewing our article and providing us with your valuable insights for improvement. As per your suggestions, we have addressed the following: 1. The validity of the questionnaire is mentioned in the method section with reference. 2. The questionnaire with the option of responses is shared as underlying data on a data repository and the reference for the same is mentioned in the main text. 3. The results are summarized in tabular format for the convenience of the audience. 4. The discussion has been improvised with a reduction in the number of paragraphs and adequate comparison with similar studies from other countries with appropriate references. 5. The conclusion is given under a separate heading 6. The article has undergone proof reading to rectify grammatical errors Kindly re-review the newer version of our article for approval and provide your valuable insights."
}
]
},
{
"id": "168658",
"date": "29 Apr 2024",
"name": "Utsav Raj",
"expertise": [
"Reviewer Expertise Public heath"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMethods: Strengths:\n\nThe methodology and statistical analysis are intricately detailed, bolstering the study's reliability. The inclusion of references for questionnaire preparation and data availability, elucidating question details and choices, enhances its credibility and ensures its value for future reference.\nResults:\nWeakness (minor): Presenting the results in paragraphs rather than in tabular format diminishes readability for the audience.\n\nDiscussion and Conclusion: Strengths:\n\nThe discussion adeptly compares and analyses findings in relation to other studies, enriching its depth. The conclusion underscores the imperative of comprehensive training for healthcare professionals worldwide to tackle unforeseen challenges effectively, advocating for the development of safer and better strategies. The study holds relevance for a broad spectrum of reader's\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11506",
"date": "25 May 2024",
"name": "Rakshatha Nayak",
"role": "Author Response",
"response": "Dear sir, Thank you for reviewing our article and providing us with your valuable insights on improvement. As per your suggestions, we have addressed the following: The results are summarized in tabular format for the convenience of the audience."
}
]
},
{
"id": "227468",
"date": "15 May 2024",
"name": "Moawia Gameraddin",
"expertise": [
"Reviewer Expertise 1/Radiological sciences and medical imaging"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI did not find Tables and figures. The results section did not cite the tables and figures. I recommend revising the manuscript to provide the tables and figures, and the citation of them in the results section.\nA paper without tables and figures should be not be considered for indexing.\nIntroduction: suitable and expressive.\nThe objectives are clear, and so is the presentation.\nResults: This part is lacking the Tables and figures. I recommend the following:\nThe authors should add the tables and figures. There is no citations for Tables and Figures in the results section.\nDecision: The paper needs major revision to add the tables and figures.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11576",
"date": "25 May 2024",
"name": "Rakshatha Nayak",
"role": "Author Response",
"response": "Dear Sir, Thank you for reviewing our article and providing us with your valuable insights on improvement. As per your suggestions, we have addressed the following: The results are summarized in tabular format for the convenience of the audience and the reference is cited in the results section. Overall the article has been improvised following suggestions from all reviewers. Kindly go through the new version of the article and provide your valuable remarks as well as your approval."
}
]
}
] | 1
|
https://f1000research.com/articles/12-361
|
https://f1000research.com/articles/13-520/v1
|
22 May 24
|
{
"type": "Research Article",
"title": "A long tail of truth and beauty: A zigzag pattern of feather formation determines the symmetry, complexity, and beauty of the peacock’s tail",
"authors": [
"Rama Singh",
"Santosh Jagadeeshan",
"Santosh Jagadeeshan"
],
"abstract": "Background Darwin assumed that the peacock’s long train was maladaptive and was the indirect effect of selection by female mate choice based on the train’s beauty. While a relationship between the feathers’ elaborate features and mating success has been shown, what features of the train females are attracted to remains controversial.\n\nMethods We used museum specimens to examine the anatomical plan underlying feather development responsible for the symmetry of the train. We developed a model based on an alternate arrangement of primordial feather buds during development and locations of concentric circles of symmetric eyespot distribution using the pattern seen on the train as a template.\n\nResults We observed a zigzag pattern of feather follicles that determined both the number and the hexagonal arrangement of eyespots on the train. Our model explained not only the alternate arrangement of feathers on the train but also the arrangement of the concentric color rings of the eyespots. While the zigzag pattern explains the symmetry, complexity, and structural beauty of the peacock’s train, it also precludes variation in eyespot number except by annual addition of new rows of feathers as a function of age.\n\nConclusions Since eyespot number and feather length are developmentally correlated and an asymptotic function of a male’s age, their effects on female choice would be confounded and inseparable, and male vigor would be a crucial factor affecting male fitness. Females may not always choose males with the largest number of eyespots, as older males may lack vigor. We propose a multimodal model of female choice where females see eyespot and train size not as separate traits but as one complex trait combining both. The new model may be able to explain conflicting results and why eyespot number alone may not be sufficient to explain female choice.",
"keywords": [
"peacock’s tail",
"sexual selection",
"mate choice",
"female choice theory",
"eyespots",
"complexity",
"symmetry"
],
"content": "\n\nBeauty is truth, truth beauty.\n\nKeats\n\n\nIntroduction\n\nThe Indian blue peacock’s, Pavo cristatus, elaborate and long tail (we use tail and train interchangeably, as appropriate- former to signify the long horizontal tail, the latter in expanded vertical position) has long represented a paradigmatic case for the theory of sexual selection by female choice. However, even after 150 years, the problem of the evolution of the peacock’s long tail remains unsolved—we still do not know the basis (target) of female choice in peafowl. Darwin (1859) recognized the peacock’s long tail as a problem for his theory of evolution by natural selection as he conjectured it was too long to be of adaptive use to the animal; therefore, it was maladaptive. Unlike in other animals, where a sexually selected trait may be directly under female choice selection, there are three aspects of the peacock’s tail: length, and structural complexity, and “beauty.” By beauty here we are concerned with the structural arrangement and the color of the eyespots, which adds to the overall beauty of the peacock’s tail. Darwin chose to focus on the beauty of the tail and supplied an explanation through sexual selection: that females may prefer to mate with males who possess more beautiful and elaborate tails (Darwin, 1981). It was thought that this reproductive advantage enjoyed by males with more elaborate tails would compensate for any loss of male fitness such as reduced survivorship due to predation. This explanation sets the stage for research to focus on elucidating how females assess “beauty” or attractive traits (in peacocks and other birds) in their choice of mates (Andersson, 1994).\n\nTwo key requisites for evolutionary theory, be it via natural or sexual selection, are variation and heritability. If the peacock’s train is a target of female choice, then there must be genetic or phenotypic variation in female preference that would directly or indirectly depend on variation in the peacock’s train morphology (size, shape, and/or coloration). Although female choice is widely assumed to be responsible for the evolution of the peacock’s tail, research on this matter has produced mixed results to date. While several researchers have shown a relationship between train features and mating success (Petrie et al., 1991; Petrie and Halliday, 1994; Yasmin and Yahya, 1996; Loyau et al., 2005; Harikrishnan et al., 2010), a comprehensive 7-year re-evaluation by Takahashi et al. (2008) found no evidence of train morphology (either train length or eyespot number) influencing the number of copulations a male achieves. More importantly, this re-evaluation uncovered little variation in train morphology across populations, thereby calling into question the idea that the peacock’s train is a target of female choice (however, see Loyau et al., 2008). Similarly, in another important study based on close observation of eyespot distribution on the train, Dakin and Montgomerie (2011) found that males over the age of four generally produce between 165 and 170 eyespots before the onset of the mating season. They found little variation within and between populations in terms of eyespot number and noted that what little variation existed seemed to be due to extrinsic factors. Dakin and Montgomerie (2011) rather intuitively suggested this lack of variation in train morphology possibly reflects developmental constraints. There may be variation in eyespot number between growing males (Manning, 1989) but the number in adult males appears invariant (Manning, 1989; Takahashi et al., 2008; Dakin and Montgomerie, 2011).\n\nWhile much work has been done to investigate the basis of female choice, less work has addressed the structure of the trait, i.e., the train itself. The peacock’s train is a complex structure, with the upper train coverts comprising a diverse variety of feather types, each varying in structure, iridescence level, color pattern and symmetry (see Lillie, 1942 and Manning and Hartley, 1991 for details). The complexity and the bilateral symmetry of the train (Figure 1) can be appreciated by connecting the eyespots in any direction (see Figure 2A). To achieve this remarkable symmetry in a fan formation, the feather follicles must develop in a specific arrangement at their origin, i.e., on the uropygium. Upon failing to find significant variation within and between populations in terms of eyespot number, Dakin and Montgomerie (2011) inspected the outer surface of a male peacock’s uropygium and found a constant number and uniform arrangement of feathers, which suggests that train feather development may be anatomically determined in all males. This suggests that the extraordinary symmetry of the train (Figures 1 and 2) is dictated by developmental plans which may not allow for intrinsic variation in train morphology.\n\nConcentric circles show spaced-out eyespots towards the periphery (picture from Wikipedia/ThiminduGoonatil lake from Colombo, Sri Lanka).\n\n(Peacock picture from Wikipedia/ThiminduGoonatil lake from Colombo, Sri Lanka).\n\nTo explain the remarkable symmetry of the structural arrangement and iridescence of the train and to understand the nature of variation in eyespot number we investigated the anatomical development plan of peacock train morphology. We uncovered developmental and anatomical evidence demonstrating that the nature of bilateral symmetry in the development of the peacock’s upper-tail covert feathers or train feathers) would preclude genetic variation in the number of individual eyespots. Accordingly, the only source of intrinsic variation in feather and eyespot number would be between age classes, arising from the age-dependent addition of new rows of feathers. On the other hand, feather length—being a quantitative trait—is expected to show variation within as well as between age classes. Thus, all intrinsic between-individual variation in eyespots may be related to animal age, which may reach a developmentally pre-determined limit in all animals (Dakin and Montgomerie, 2011). This would explain why researchers have not found significant (genetic) variation in eyespot number in natural populations (Takahashi et al., 2008; Dakin and Montgomerie, 2011).\n\nIn this report based on observations on museum specimens of peacock tails, we show that a simple zigzag pattern of feather formation giving rise to hexagonal arrangement of eyespots uniquely determines the symmetry, complexity, and beauty of eyespots in the peacock’s tail. The zig-jag arrangement is not unique to train feathers; it is common to all feathers covering the body of the bird and is the result of alternate packing of cells during development. Hexagonal arrangement of cells arises from alternate cell packing, and it was shown to apply to the origin of feathers in birds (Sengel, 1976). By beauty, in this manuscript, we only mean the structural complexity of eyespot color and their distribution and do not want to confuse with everyday and wider meaning of the word beauty. Second, we show that eyespot feathers originate in alternate, zigzagging rows of 10/11 annually, making the total number of eyespots an intrinsically determined trait. Third, we argue that both feather number (Manning, 1989) and feather growth are asymptotic functions of age that—when considered with the male vigor which must peak at reproduction time and then decline—may explain the contradictory results reported between different studies (Loyau et al., 2008; Takahashi et al., 2008). We discuss the implications of these results, especially the lack of genetic variation in eyespot number, for sexual selection theories and how alternative explanations are required to explain the basis of female choice and the evolution of the peacock’s elaborate train. We propose a multimodal model of female choice based on male’s train size, vigor, and beauty that aligns with recent calls for more inclusive and multimodal perspectives to understand how sexual selection operates (Mitoyen et al., 2019), as it highlights the multiple factors which may jointly determine the female choice of best mates. We propose that many conflicting results can be explained by assuming that females do not base their mate choice on eyespot number or train size alone but on a complex trait combining both.\n\n\nMethods\n\nThe data presented in this report are based on observations of the tail structures of museum specimens kept at the Royal Ontario Museum, Toronto, Canada, and the American Museum of Natural History, New York, USA. Only specimens in good condition were included in this study. A total of 21 samples of blue fowl (P. cristatus), including two albinos and two hybrids (between strains originating from Bangkok and Cameroon), were examined. The wild blue fowl samples originated from India (N = 3), Sri Lanka (N = 2), Kenya (N = 1), or were captive samples originating from the United States (N = 4 blue, N = 2 albino). The remaining 11 samples were of unknown origin and included two hybrids. We also had access to seven green fowl (P. muticus) samples at the Natural History Museum, which originated from Malaysia (N = 4), Bangkok (N = 1), or were of unknown origin (N = 2). Wherever dates were noted, most of the field samples were collected during the early 1900s. Conversely, the captive samples were collected as recently as 1942.\n\nWe counted the number of eyespots, eyespot feathers, and fishtail feathers displayed by the included specimens (Figure 3). In the cases where an eyespot was missing due to damage, we counted it as if it were present to estimate the total number of eyespots. Very few of the samples had a uropygium that was in good condition. Of the museum specimens six had intact uropygia in P. cristatus and one in P. muticus. Wherever we were certain that the integrity of the sample had not been compromised, we counted the rows of feather imprints on the uropygium (Figures 2B, 4). Dryad: A long tail of truth and beauty: The developmental basis of complexity, symmetry, and beauty in the evolution of the peacock’s tail. Dryad My Dataset: doi: 10.5061/dryad.1g1jwstwg.\n\nA: Dorsal side showing the newest rows of feathers at the bottom; B: Ventral side depicting alternating rows of 10 or 11 feather cell imprints. The smallest feather row at the bottom of panel A corresponds to the smallest row of follicles at the bottom of panel B. The top 3-5 rows depending on the age of the animal give rise to fishtail feathers and the rest eyespot feathers.\n\nDotted lines represent number of fishtails (30+, 40+, 50+) consisting of 3, 4, and 5 rows of feathers (details provided in the text). Closed bar: eyespot feathers; open bar: fishtail feathers. The hybrid (BC) is between Bangkok and Cameroon.\n\nTo illustrate the eyespot symmetry exhibited by trains in displays (Figure 5), we made use of Adobe Illustrator’s built-in features (Adobe Photoshop and Adobe InDesign) provided by Graphic Designers’ services at Media Production Services, McMaster University. Briefly, Adobe Illustrator was used to map concentric circles following eyespot distribution on the train in the display by using Figure 1 as a template. These sets of concentric circles were used as the basis for text paths to determine how eyespots may distribute themselves upon the unfolding of the train for display.\n\nLayout of feathers on the anchor plate (below) and the resulting eyespot patterns produced by a bilateral symmetrical train (above). The outer spots (green) represent fishtail feathers. (A) 10/11 zigzag pattern; (B) 10/11 parallel pattern; (C) 10/10 zigzag pattern, (D) 11/11 zigzag pattern. Compare the hexagon cellular packing on the uropygium and the expanded train in A with that seen on the animal’s train in Figure 1 (for details see the text).\n\nTo simulate and illustrate the train’s eyespot distribution, we used the following observations and/or assumptions: (1) Based on our overall observations (7 P. cristatus, and 1 P. muticus), we concluded that each cell on the uropygium (Figure 1B) represents the base of a corresponding feather (attempting to determine direct one-to-one correspondence would have required damaging the specimens); (2) we used a row of 10 or 11 dots in the shape of the (oval) uropygium to represent train feathers but we used a flat and not a convex surface as the latter was not possible. In the result section we discuss why using a convex surface in the simulation would not have changed the outcome; (3) In line with our observation (Figure 1), we used an arbitrary constant distance between spots within a row and we progressively increased the size of the dot spots between rows, from the bottom (newest) to the top (oldest) feathers, to represent the size of the eyespots as seen on the train; (4) We assumed that each dot represents an eyespot at the end of the feather which is supported by our observation; and (5) we only simulated 2-dimensional position of eyespot distribution and not their three dimensional distribution on the train surface. We simulated four spatial feather arrangements: 10/11 zigzag, 10/11 parallel, 10/10 zigzag, and 11/11 zigzag (Figure 5). The feather grid was expanded bilaterally symmetrically to mimic the animal’s train expansion. It is important to point out that the simulated surface shown in Figure 5 represents the front, flat face of the train.\n\n\nResults\n\nTo uncover the anatomical development plan that determines the bilateral symmetry of eyespots on the train, we examined the uropygium (N = 6) of museum specimens. The uropygium is a fleshy and bony structure at the posterior extremity of a bird’s body that supports the tail feathers. Tail feathers are attached to the dorsal (convex) side of the oval-shaped uropygium, which serves as an anchor plate (Figure 3). The ventral (concave) side of the anchor plate exhibits several interesting features: 1) It has basal impressions of tightly-packed, parallel rows of feather follicle insertion points; 2) The feather follicles grow progressively larger from the anterior (bottom, younger) to the posterior (top, older) end and are laid out in sequential but alternating rows of 10/11, corroborating the alternate arrangement of 10/11 feathers first reported by Dakin and Montgomerie (2011) except that the alternate rows have a zigzag pattern; 3) The posterior feather follicles radiate in an arch, mimicking the fan formation shape of the train in the display. The convexity of the anchor plate makes the train a three-dimensional structure (i.e., an oval trapezoid-shaped dish), such that the feathers are projected outwards at different angles and lengths. Notably, the anchor plate itself appears to be a product of continuous growth and the sequential addition of new rows of feathers each year. The one-to-one correspondence between the pattern of the feather follicles (size, alternate arrangement, and progression from anterior to posterior) on the ventral side of the anchor plate and the symmetrical positions and size of the feathers on the dorsal side is unmistakable and is supported by our observations (Figure 2).\n\nTo determine whether any variation exists in the anatomical development plan found on the uropygium that would affect the number of eyespots, we examined several specimens from the Royal Ontario Museum and the American Museum of Natural History. The results of this analysis, based on a limited number of specimens in good shape, are summarized in Table 1 and Figure 4. First, the number of feather rows, as determined by the number of follicle rows on the uropygium, varied from 17 to 19 (N = 7), whilst the anterior two to three rows had minor eyespots. Notably, this result is consistent with the findings of Dakin and Montgomerie (2011). The anterior-most rows of eyespots appear minor due to their slow growth and maturity. If one or a few rows of feathers are added each year, then based on the peacock’s longevity of about 20 years in nature (Lindstedt and Calder, 1976) the number of eyespots can reach over 200; however, the late-aged, developmentally immature eyespots (small size and lack of full coloration) will remain insignificant in their effect on female choice.\n\nSecond, the zigzag arrangement of feathers appeared as an invariant trait in our sample (Table 1). While this one-to-one correspondence between clearly visible follicle insertion patterns and train morphology may be expected, our data suggest that the developmental plan does not permit random (one feather at a time) variation in eyespot number (Table 1).\n\nThird, the number of fishtail feathers varied around the modal number of 30, 40, or 50 (N = 21), which is what we would expect if fishtail feathers were produced by three, four, or five rows of feather follicles during development, respectively (Figure 4). In our museum samples, the highest number of fishtail feathers observed was around 40. However, Figure 1 indicates that the number of fishtail feathers can exceed 50.\n\nFourth, the number of eyespot feathers varied from 101 to 161 (N = 21), not counting the minor feathers. This variation is attributable to individual variation in terms of age, time of year at capture, and any damage from prior handling at the museum.\n\nFifth, we speculate that number of eyespot feathers and feather length are independent traits that vary asymptotically as a function of age. This is consistent with Manning’s (1989) finding that eyespot number increases during the first 4 to 7 years of the animal’s life and thereafter increases more slowly or remains effectively constant.\n\nWe also had access to a small number of P. muticus (green peacock) specimens (N = 7) from Southeast Asia (Table 1; Figure 4) for comparative analyses, which could provide clues as to whether peacock train morphology reflects a similar developmental pattern across taxa or whether sexual selection and other environmental factors have resulted in different trajectories of train morphology. In the green peacock, the number of fishtails ranged from 38 to 39 (around the expected mode of 42), while the number of eyespots ranged from 115 to 154.\n\nData from both species appeared to be homogenous (Figure 4). One green peacock specimen was in pristine condition, which enabled us to assess the anatomical development pattern of feather follicle rows in the uropygium. As per the blue peacock, feather follicle rows in the green fowl followed the same alternating 10/11 arrangement, suggesting that this developmental arrangement may be an invariant feature across peafowl species. Interestingly, similar alternating patterns of train feather arrangements are also found in the wild turkey, Meleagris ocellata, a member of the same family (Phasianidae). This observation entertains further research on whether the alternating pattern of feather arrangement might be common across other members of the family and thus an invariant developmental trait.\n\nWe investigated the significance of the arrangement of feathers in rows of 10/11 and their “zigzag” alignment (see Figure 2). To achieve this, we used graphic design software to reconstruct the unfolding of the peacock’s open train based on the developmental layout of the feather follicle insertion points observed in the anchor plate (Figure 5, left). For simplicity, we assumed that the feather follicle insertion points were eyespots without the feather stalks. Using Adobe Illustrator, we modeled the fan formation in “display.” We subjected the eyespot distribution on the anchor plate to a uniform, bilaterally symmetrical force to spread the eyespots to the left, right, and upward, thereby pushing them radially and uniformly outward in a curved semi-circular space to mimic the fanning pattern of the train during display. Remarkably, our reconstruction yielded an eyespot distribution that is very similar to that observed on the peacock train (compare Figure 5A to Figure 2), with five feathers on either side of the mid-feather in each row. As expected, we found a one-to-one correspondence between the condensed, developmental–anatomical layout of the feather follicle insertion points on the uropygium and the symmetrical distribution of eyespots on the train. It is important to point out that the zigzag arrangement of cells, when spread out uniformly, gives rise to the well-known hexagon cellular packing (compare Figure 5A and Figure 1). We did not simulate a convex surface as this was not possible, however doing so would not have changed the distribution pattern (hexagonal) of eyespot as we were simulating 2-D image of eyespots distribution as seen from front and not their 3-D distribution patterns. In other words, the simulation results presented in Figure 5 show what the imprint/picture would look like if an expanded train were compressed on a flat surface. This is what we would see from a distance.\n\nWe further explored what the eyespots distribution pattern would be like if the feathers were arranged in 10/11 parallel rows instead of the zigzag arrangement that we observed in this study. Notably, the train eyespot pattern that we obtained is remarkably different from the 10/11 zigzag pattern. Our reconstruction of a parallel arrangement yielded a palm-leaf-like pattern that fanned out in parallel rows of eyespots rather than the pattern observed in a peacock’s train on display (Figure 5B). While both patterns are striking, the 10/11 zigzag arrangement yields a denser and uniformly symmetrical arrangement of eyespots, as seen in the animal.\n\nBecause the above results raised the question of why 10 or 11 rows were observed, we simulated a 10/10 parallel and 11/11 parallel pattern; the results are shown in Figures 5C and D. Although the 10/10 and 11/11 patterns were like the 10/11 parallel pattern, they showed certain interesting differences. While the feathers lined up in equally spaced, straight lines over the entire span in the 10/11 parallel pattern, the 10/10 and 11/11 parallel patterns resulted in the equal spacing of individual eyespots towards the end of the train, with wavy lines in the center. It is obvious that it was not the zigzag pattern itself but the zigzag pattern of 10/11 that gave rise to the uniform distribution of eyespots on the train. The 10/11 parallel pattern may not be developmentally possible.\n\nFeather is an important non-embryonic model of animal development (for a recent review see Chen et al., 2015), and much research has been done both anatomical and molecular involving the role of genetic and epigenetic mechanisms (Jiang et al., 1999, 2004; Maini et al., 2006; Chen et al., 2015). Feathers develop from feather follicle buds on the surface of the epidermis (Prum, 1999; Chen et al., 2015). Pigmentation based colors in plants and animals can be explained by local variation in gene expression. In birds, movement of melanocytes up the hollow core of the feather is said to control the variation in plumage color (Prum and Williamson, 2002; Chen et al. 2015). In “structural color,” such as in peacock feathers, the colors are the result of light reflection from the modification and anatomical diversity of the barbules’ photonic structures (Zi et al., 2003; Freyer et al. 2018).\n\nWe were motivated by the superficial but interesting structural similarity between the iridescence patterning of the eyespots and that of the body plan of the whole animal with a fully expanded train. The entire peacock resembles one giant eyespot in the sense that it boasts a deep-blue body surrounded by a dense zone of bluish-green eyespots, which corresponds to an individual eyespot with its deep-blue inner circle surrounded by radiating oval rings of mixed colors. The same pattern of blue can be observed in the peacock’s crest crown also (data not shown) which have been shown to be involved in communication (Kane et al., 2018).\n\nWe hypothesized that the rings of eyespots may be determined by the same cellular plans as the color patterning of the whole animal. We took advantage of the similarity between the rings on the individual eyespots and the spatial eyespot rings traced on the train and modeled backward from the eyespot to feather follicles and back to the eyespot (Figure 6). Starting from each eyespot (Figure 6A) we inferred colored rings on the train following the pattern seen in one eyespot (Figure 6B) and from there on the follicle rows on the uropygium (Figure 6C). We inferred that the five feather follicles on each side of the central feather make an inverted palindrome and correspond to the five different structural colors seen in the eyespot (Figure 6D). From this we inferred follicles growth and epidermal invagination giving rise to a concentric ring of structural material (stem cells) (Figure 6E) inside the feathers which expand and create the ring pattern on the eyespot. (Figure 6F) Cellular invagination is a well-known process of embryology (Rauzi et al., 2013; Pearl et al., 2017) but we stress that we are basically connecting dots from eyespot distribution on the train to the concentric rings of individual eyespots and it must remain speculation until further investigated.\n\nA. an eyespot and a bunch of eyespot fine feathers showing their multi-colored structures; B. modelling of eyespot rings using rings observed on the train; C. projection of train rings on the uropygium; D. cellular processes showing origination of 5 structurally different feather follicles, and their inverted tandem duplication; E. cell growth and invagination of a concentric ring of structural material giving rise to eyespot; F. a peacock feather showing internal component of eyespot fine feathers (for details see the text).\n\n\nDiscussion\n\nMating success of peacocks has been shown to be affected by eyespots and train size, which appear to be correlated, but it has not been possible to determine if one or both affect mating success directly (Petrie et al., 1991; Petrie and Halliday, 1994; Yasmin and Yahya, 1996; Loyau et al., 2005; Harikrishnan et al., 2010). Physically reducing the number of eyespots has a negative effect on mating success (Petrie and Halliday, 1994); however, Dakin and Montgomerie (2011) showed that females were insensitive to removal of as many as 20% of the eyespots before responding to the reduction. In the following, after showing that eyespot number and train length are intricately related and their roles are largely inseparable, and that male vigor would be an important factor mediating the relationship between males and females, we present a multimodal model of female choice based on a complex trait combining both train length and eyespots (Andersson, 1994; Candolin, 2003; Bro-Jørgensen, 2010; Mitoyen et al., 2019).\n\nThe zigzag pattern of feather formation observed from the peacock’s uropygium was able to explain both the hexagonal eyespot symmetry on the train and as well as the unique eyespot rings pattern within eyespots.\n\nThe primordial feather follicles arising on the uropygium in rows of 10/11 are arranged in a zigzag manner. It is this zigzag arrangement of 10/11 that creates the complex hexagonal arrangement of eyespots in the peacock’s tail, and thus its complexity and beauty (Figure 5, upper left). Hexagonal arrangement is a well-known feature of cellular arrangement in developmental biology (Sengel, 1976; Classen et al., 2005). The same rule of zigzag arrangement between feather follicles that leads to the complex distribution of eyespots on the train also applies to cellular arrangement of cell lineages within feathers, giving rise to rings on the eyespot, which, in combination with the different structural -iridescence colors, imparts the eyespot its beauty. The qualitative annual growth of eyespot number in rows of 10/11 and the quantitative growth of train length and, essentially, of the former’s dependence on the latter for its presentation and display to females may make the two traits inseparable in their effects on female choice.\n\nThere are two aspects of development that constrain eyespot variation: bilateral symmetry and asymptotic tail growth. The anatomical arrangement and bilateral symmetry of eyespot feathers preclude random genetic variation by addition of single feather at a time and the only apparent source of variation in eyespot number is the annual addition of new feather rows as the animal grows. Thus, as Takahashi et al. (2008) and Dakin and Montgomerie (2011) found, most males produce approximately 165–170 eyespots, and the small amount of eyespot number variation that exists within and between populations is due to extrinsic factors such as breakage or damage from predation. The actual number of eyespots can exceed 200, as suggested by the number of feather rows on the uropygium shown in Figure 3, but many of them would be too small to be visible through photography or to be effective to illicit female response. The idea that the maximum eyespot number in adult animals is invariant within and across populations is consistent with the annual addition of new rows of feathers, which occurs rapidly at a younger age (~4–7 years), while slowed growth or complete cessation of new feather development occurs after a certain age (Manning, 1989). It is important to point out that the lack of variation in eyespot number applies to the lifetime total number for individuals and not to the population, which may contain eyespot variation arising from different age classes.\n\nAsymptotic tail growth is the result of aging, loss of vigor and diminishing return in fitness accruing from tail growth. After a male has reached his peak reproductive age and achieved the threshold train size to begin mating, his mating success will increase as a function of both the size of his train and his vigor in mounting a display. But with declining vigor with age and competition from younger males, the individual fitness function will plateau and decline despite large train size. At this point, the law of diminishing returns will commence, and each additional row of feathers will grow slowly, making them look minor, and exert a minimal effect on the feather length and fitness function. Moreover, limitations with respect to maximum eyespot number and the lack of correlation between train length and mating success may—as suggested by Takahashi et al. (2008)—indicate that these traits have reached a threshold. And since males do vary in mating success (Petrie et al., 1991; Yasmin and Yahya, 1996; Loyau et al., 2008), this variation cannot be due to variation in eyespot numbers and other factors may be involved.\n\nFemale choice theory, in the case of the peacock’s tail, relies on the assumption that eyespot number and train length are correlated, and that female choice based on the former leads to a correlated increase in the latter. However, the results of this study, and others (Takahashi et al., 2008; Dakin and Montgomerie, 2011), suggest that eyespot number is an internally-determined, invariable trait, and thus cannot be the sole factor driving the evolution of the peacock’s long tail. Given that train feathers are rapidly added in rows of 10 or 11 during the first 4–7 years of a peacock’s life (Manning, 1989) to eventually reach 165–170 at adulthood, any variation in feather growth rate could be the basis of female choice if the size of the train were directly or indirectly a criterion of female mate attraction—or attention. As such, rapidly growing males may develop more elaborate trains with bigger size and more eyespots and thus become preferential targets of female choice during the peak period in the first 4–7 years of life, after which feather number may increase at a slower rate (Manning, 1989).\n\nOur study brings out three important results that have implications for how females decide on mates. First, the invariant nature of the total number of eyespots in adult males does not allow for variation in fully adult males for selection; the only available variation is that between age classes in a population. Second, eyespots and train length are developmentally correlated; it is the tail growth that pulls the eyespots up, spreads them out, and makes them visible to females. While eyespot brightness has been shown to affect male mating success (Loyau et al., 2007; Dakin and Montgomerie, 2013), we hypothesize that in deciding on mates, especially from distance, females may be using the size of the “eyespot-studded train” rather than the number of eyespots. This may explain why it has been difficult to separate the effect of eyespots from the effect of train size (Petrie et al., 1991).\n\nFinally, an important and hitherto neglected trait that is likely to mediate male–female interaction is male vigor. Variation in vigor means that a younger youthful male with fewer eyespots may outperform an older and bigger male with more eyespots (Petrie, 1993). The new trait, eyespot–train size, may either influence female choice directly through sensory capture (Kirkpatrick and Ryan, 1991) or indirectly through male vigor and beauty, but not solely based on eyespots (Mitoyen et al., 2019).\n\nWe can consider a two-stage model of female choice, in which females are attracted by male size or train height and sounds from a distance, and exercise mate choice based on eyespot beauty, vigor, and behavior from close proximity. Such a model would be able to explain some of the contradictory results between different studies. It may explain, for example, why females were insensitive to removal of as much as 20% of the eyespots before showing any effect in their behavior (Dakin and Montgomerie, 2011).\n\nThe small sample size of museum specimens used in this study may raise concerns about the validity of our results. The most important results of this study, shown in Figure 5 and Figure 6, are qualitative and/or theoretical modelling, and are unaffected by sample size. Simulation is a form of hypothesis testing, but it lacks direct anatomical testing which is outside the scope of our lab. The zigzag arrangement of feathers and its effect on the train’s symmetry and complexity (Figure 5) were simulated and shown to conform to observations from this work and at least the number and the symmetry of feathers is supported by previous work (Dakin and Montgomerie, 2011). The rudimentary model of eyespot development (Figure 6) would also need to be investigated by developmental work. Future tests can involve (1) anatomical dissection of live animals to test the number and the arrangement of feathers as well as the correspondence between feathers and feather buds, (2) developmental work on young peacocks to test the addition of feather rows as well as feather growth as a function of age, (3) further work on the line of Dakin and Montgomerie (2011) to test the effect of varying eyespot numbers on female choice, and (4) work to test the effect of variation in male vigor as a function of age on female choice.\n\n\nConclusions\n\nTo summarize the results, we showed (1) that a zigzag pattern of feather formation affects the bilateral symmetry, eyespot complexity, and structural beauty of the peacock’s tail; (2) that the same zigzag pattern, remarkably, can also explain the colorful rings of the eyespot; and (3) that the zigzag pattern would preclude intrinsic variation in the total number of eyespots among adult individuals. The only source of variation in eyespot number would be the annual addition of eyespot feathers, in rows of 10 or 11, giving rise to variation between age classes.\n\nThese results led us to three insights that would help explain conflicting results between studies in the literature. First, eyespot number and train size are developmentally connected such that eyespots do not drive train length: it is the other way around—it is the feather/train growth that pulls eyespots up, spreads them out, and makes them visible to the female from afar. Second, we showed that eyespot number and male tail growth both have asymptotic functions, which means that later stage addition of feathers would lead to minor and ineffective eyespots with no added benefit to males. Finally, we argue that male vigor is a crucial factor modulating the effects of male size and beauty. Two males can have the same number of eyespots but differ in their age and vigor. Taken together, these insights can explain many of the conflicting results reported from different studies in the past.\n\nFemales prefer large ornaments (Summers and Ord, 2022) and in case of the peacock the ornament can be the large “eyespots-studded-train” rather than the individual eyespots. Based on our results, we propose a two-stage, multimodal model of female choice based on male size, beauty, and vigor and suggest that females may not be using eyespot number or feather train size but a combined complex trait, “eyespots and train size”, as a basis of mate choice. Females may be attracted by train size from afar and eyespots may come into play when they are in close proximity. Females may be choosing the tallest, most vigorous, and most “beautiful” males. Our results solve the problem of the relationship between eyespot number and tail length and provide a new perspective on the role of male size, vigor, and beauty in female mate choice.\n\n\nAuthor contributions\n\nRSS: Development of concept, collection of data, theoretical–developmental modelling, critical review of sexual selection theories, preparation of the manuscript, and financial support; SJ: literature review, critical analysis of sexual selection theories, data analysis, and preparation of the manuscript.\n\n\nEthics and consent\n\nEthical approval and written consent were not required.",
"appendix": "Data availability statement\n\nDryad: A long tail of truth and beauty: a simple rule of pattern formation explains symmetry, complexity and beauty in the peacock’s tail, https://doi.org/10.5061/dryad.1g1jwstwg (Singh, 2021).\n\nData is available under the terms of the (CC0 1.0) Public Domain Dedication license.\n\n\nAcknowledgements\n\nWe thank Kevin Kerr (Toronto Zoo), Mark Peck (ROM), Paul Sweet, and Lydia Gaetano (AMNH) for their help with our work at the museum. We also extend our sincere thanks to Ellen Larsen, Daniel Hartl, Richard Morton, Bhagwati Gupta, Jonathan Stone, and Dave Rollo for their comments on the manuscript. We owe our gratitude to Robert Montgomerie and Roslyn Dakin for their expert, critical comments on the manuscript. We would like to thank all the anonymous reviewers of the earlier versions of this manuscript; their comments have made us think deeply and look for answers to explain the contradictory results reported from different studies. Michelle Brown provided technical support.\n\n\nReferences\n\nAndersson MB: Sexual selection. Princeton, NJ: Princeton University Press; 1994. Publisher Full Text\n\nBro-Jørgensen J: Dynamics of multiple signalling systems: animal communication in a world in flux. Trends Ecol. Evol. 2010; 25: 292–300. PubMed Abstract | Publisher Full Text\n\nCandolin U: The use of multiple cues in mate choice. Biol. Rev. Camb. Philos. Soc. 2003; 78: 575–595. Publisher Full Text\n\nChen C-F, Foley J, Tang P-C, et al.: Development, regeneration, and evolution of feathers. Annu. Rev. Anim. Biosci. 2015; 3: 169–195. PubMed Abstract | Publisher Full Text | Free Full Text\n\nClassen A-K, Anderson KI, Marois E, et al.: Hexagonal packing of Drosophila wing epithelial cells by the planar cell polarity pathway. Dev. Cell. 2005; 9: 805–817. PubMed Abstract | Publisher Full Text\n\nDakin R, Montgomerie R: Peahens prefer peacocks displaying more eyespots, but rarely. Anim. Behav. 2011; 82: 21–28. Publisher Full Text\n\nDakin R, Montgomerie R: Eye for an eyespot: how iridescent plumage ocelli influence peacock mating success. Behav. Ecol. 2013; 24: 1048–1057. Publisher Full Text\n\nDarwin C: On the origin of species by means of natural selection, or preservation of favored races in the struggle for life. 1st ed.London: John Murray; 1859.\n\nDarwin C: The descent of man, and selection in relation to sex. Princeton, NJ: Princeton University Press; 1981.\n\nFreyer P, Wilts BD, Stavenga DG: Reflections on iridescent neck and breast feathers of the peacock, Pavo cristatus. Interface Focus. 2018; 9(1): 20180043. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarikrishnan S, Vasudevan K, Sivakumar K: Behavior of indian peafowl Pavo cristatus linn. 1758 during the mating period in a natural population. Open Ornithol. J. 2010; 3: 13–19. Publisher Full Text\n\nJiang TX, Jung HS, Widelitz RB, et al.: Self-organization of periodic patterns by dissociated feather mesenchymal cells and the regulation of size, number and spacing of primordia. Development. 1999; 126: 4997–5009. PubMed Abstract | Publisher Full Text\n\nJiang T-X, Widelitz RB, Shen W-M, et al.: Integument pattern formation involves genetic and epigenetic controls: feather arrays simulated by digital hormone models. Int. J. Dev. Biol. 2004; 48: 117–135. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKane SA, Van Beveren D, Dakin R: Biomechanics of the peafowl’s crest reveals frequencies tuned to social displays. PLoS One. 2018; 13: e0207247. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKirkpatrick M, Ryan MJ: The evolution of mating preferences and the paradox of the lek. Nature. 1991; 350: 33–38. Publisher Full Text\n\nLillie FR: On the development of feathers. Biol. Rev. 1942; 17: 247–266. Publisher Full Text\n\nLindstedt SL, Calder WA: Body size and longevity in birds. Condor. 1976; 78: 91–94. Publisher Full Text\n\nLoyau A, Gomez D, Moureau B, et al.: Iridescent structurally based coloration of eyespots correlates with mating success in the peacock. Behav. Ecol. 2007; 18: 1123–1131. Publisher Full Text\n\nLoyau A, Petrie M, Saint Jalme M, et al.: Do peahens not prefer peacocks with more elaborate trains? Anim. Behav. 2008; 76: e5–e9. Publisher Full Text\n\nLoyau A, Saint Jalme M, Cagniant C, et al.: Multiple sexual advertisements honestly reflect health status in peacocks (Pavo cristatus). Beav. Ecol. Sociobiol. 2005; 58: 552–557. Publisher Full Text\n\nMaini PK, Baker RE, Chuong C-M: The Turing Model comes of molecular age. Science. 2006; 314: 1397–1398. PubMed Abstract | Publisher Full Text | Free Full Text\n\nManning JT: Age-advertisement and the evolution of the peacock’s train. J. Evol. Biol. 1989; 2: 379–384. Publisher Full Text\n\nManning JT, Hartley MA: Symmetry and ornamentation are correlated in the peacock’s train. Anim. Behav. 1991; 42: 1020–1021. Publisher Full Text\n\nMitoyen C, Quigley C, Fusani L: Evolution and function of multimodal courtship displays. Ethology. 2019; 125: 503–515. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPearl EJ, Li J, Green JBA: Cellular systems for epithelial invagination. Phil. Trans. R. Soc. B: Biol. Sci. 2017; 372: 20150526. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPetrie M: Do peacock’s trains advertise age? J. Evol. Biol. 1993; 6: 443–448. Publisher Full Text\n\nPetrie M, Halliday T: Experimental and natural changes in the peacock’s (Pavo cristatus) train can affect mating success. Behav. Ecol. Sociobiol. 1994; 35: 213–217. Publisher Full Text\n\nPetrie M, Tim H, Carolyn S: Peahens prefer peacocks with elaborate trains. Anim. Behav. 1991; 41: 323–331. Publisher Full Text\n\nPrum RO: Development and evolutionary origin of feathers. J. Exp. Zool. 1999; 285: 291–306. Publisher Full Text\n\nPrum RO, Williamson S: Reaction–diffusion models of within-feather pigmentation patterning. Proc. Biol. Sci. 2002; 269: 781–792. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRauzi M, Hočevar Brezavšček A, Ziherl P, et al.: Physical models of mesoderm invagination in Drosophila embryo. Biophys. J. 2013; 105: 3–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSengel P: Morphogenesis of skin. Cambridge: Cambridge University Press; 1976.\n\nSingh R: A long tail of truth and beauty: a simple rule of pattern formation explains symmetry, complexity and beauty in the peacock’s tail. Dryad. [Dataset]. 2021. Publisher Full Text\n\nSummers TC, Ord TJ: Female preference for super-sized male ornaments and its implications for the evolution of ornament allometry. Evol. Ecol. 2022; 36: 701–716. Publisher Full Text\n\nTakahashi M, Arita H, Hiraiwa-Hasegawa M, et al.: Peahens do not prefer peacocks with more elaborate trains. Anim. Behav. 2008; 75: 1209–1219. Publisher Full Text\n\nYasmin S, Yahya HSA: Correlates of Mating Success in Indian Peafowl. Ornithology. 1996; 113: 490–492. Publisher Full Text\n\nZi J, Yu X, Li Y, et al.: Coloration strategies in peacock feathers. Proc. Natl. Acad. Sci. USA. 2003; 100: 12576–12578. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "311984",
"date": "08 Oct 2024",
"name": "Joseph Jordania",
"expertise": [
"Reviewer Expertise Evolutionary psychology",
"Behavioural ecology",
"Animal defence strategies",
"Evolutionary musicology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSince the publication of Charles Darwin’s book on human evolution via sexual selection (1871) the striking beauty of the male peafowl (peacock) tail has fascinated generations of scholars. Today there are quite a few hypotheses behind the possible evolutionary reasons of this remarkable phenomenon. But strangely, together with the admiration, this phenomenon suffered one of the longest scholarly neglects from behavioural ecologists. For more than a century after Darwin’s initial hypothesis, scholars did not try to back up Darwin’s hypothesis with any sort of data of experimental or field study. The first study was done in 1991, and we must be grateful to the authors of the pioneer study (Petrie et al. 1991). Unfortunately, the study was very limited in many ways. For example, the researchers studied only one lek (a congregation of males) of 10 males during one month (by the way, the authors of the reviewed article do not mention these limitations). Also, the method employed did not convince everyone – researchers disfigured some of the males’ tail feathers and covered several eyespots to observe the results, and the results appear only after 20 % of the eyespots wee disfigured. It is important to remember the fact (also not mentioned in the reviewed article), that Takahachi et al study was expected to confirm the Petrie et al. 1991 findings with more solid field results. Very unexpectedly for them, the researchers came to a conclusion, that the peahens were totally indifferent to the peacocks’ tail beauty and eyespot numbers, and that generally the tail condition did not correlate with the reproductive success of their bearers.\n\nAuthors of the reviewed article suggest an original idea that for their all-important “female choice” peahens use several elements of male train in combination. As I know, this idea was expressed for the first time in the published literature. So, my congratulations to the authors. At the same time, I would suggest to double-check the crucial premise of the article, (“While a relationship between the feathers’ elaborate features and mating success has been shown…”) this hypothesis is by no means guaranteed. There is a relatively recent publication that suggests that the evolutionary mechanism behind the peacock’s train must be found in natural selection theory, more precisely, on aposematic defense from predators (not sexual selection theory). As known to behavioural ecologists, aposematic species do not try to conceal themselves from predators. On the contrary, they try to “announce” their presence by all the possible modalities: they are often very visible by their body size and contrastive colours; they often make constant sounds as they walk and have very loud voice; and they often have a constant body odour and can produce stronger smell if threatened. Finally, when confronted by a potential predator, instead of running away, they try to intimidate the predator by their suddenly increased body size, threatening sounds, gestures, and fearless behaviour. The author of “aposematic hypothesis” (Jordania, 2011, 2021) proposed that apart from huge and brilliant coloured body with many “eyespots” (visual signals), the peacock has a very strong, piercing voice (audio signal), secretes very smelly droppings if handled against its will (olfactory signal), and often does not go away even if a potential danger, for example, a tiger or a leopard, is nearby (behavioural signal, attested by many scholars, starting from George Schaller). So, aposematic hypothesis should be at least critically discussed in the reviewed article.\nIn short, in my opinion, the presented article is a welcome addition to the scholarly discussion on this important topic. Therefore, I want say that I support indexing of this article, but with certain modifications and additions, as there is a plenty of room to make the article more informative and methodologically more robust. I will condense my comments to several concrete points: (1)\n\nMost importantly, the article misses a mention and discussion of several important publications in the sphere, such as the following works: Ref-1,2,3, 4 (5)\n\nMerle Jacob on the food courting theory, proposing that ocelli remind females blueberries. See: Jacobs, M. (1999) \"A New Look at Darwinian Sexual Selection\". NaturalSCIENCE. Heron Publishing. (6)\n\nAlso, the reviewed article could mention the early works of Huxley and Hingston, who are often mentioned together as they both proposed that peacock train was used to establish dominance among group of males. See: Huxley, J.S. 1938. Darwin's theory of sexual selection and the data subsumed by it in the light of recent research. American Naturalist 72:416-433. Also see: Hingston, R.W.G. 1933. The meaning of animal colour and adornment. Edward Arnold, London.\n\nI am by no means suggesting the authors of the reviewed article to alter in any way their original view on the subject, but I do believe that they should critically discuss the above-mentioned views on the subject. This will make their article more comprehensive and updated with contemporary literature on the subject.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "12615",
"date": "14 Oct 2024",
"name": "Rama Singh",
"role": "Author Response",
"response": "Response to Reviewer (Dr. Joseph Jordania): A peacock manuscript coming from a fruit fly lab must surely appear as odd. Our long term research on sex and reproduction related genes and their role in evolution and speciation led our interest to sexual selection and mate choice. This gave rise important discoveries such as: the faster evolution of sex and reproduction related genes (Haerty et al. 2007. Genetics177: 1321-1335), a theory of male drive (Singh and Kulathinal 2005. BioEssays 27: 518-25; Jagadeeshan et al. 2015. PLoS ONE. doi:10.1371/journal.pone.0144672), and the mate choice theory of menopause (PLoS Com. Biol. https://doi.org/10.1371/journal.pcbi.1003092). A casual observation of a picture of the peacock’s train in a Press Release from our lab drew our attention to the stunning geometric patterns of eyespots formation on the peacock’s train. This led to over three years of investigation that is described in the article under review. We discovered a simple developmental rule behind the symmetry of the train and we thought our findings had important bearing on the theory of sexual selection and female choice. We wrote the paper, submitted it to the journal, and eagerly waited for the response. We got the response and we were disappointed. The main problem was that while the data and the results of the study had to do with anatomical development, their implications were in the area of evolution and sexual selection. When the paper was submitted to developmental journals, we were told to submit it to evolution journals or to anatomy. When we submitted to evolutionary journals, we were told they had difficulty finding reviewers and when they did find reviewers, they had very little to say about what we had found and framed their reviews solely based on what they said were speculations about the significance of our work. We tried many journals (before this submission), and the outcomes were the same. You may ask: what was the main criticism? Simply put, reviewers did not like the hypothesis that the long tail meant tall train which would confer dominance on males which they could use in male-male competition and mate selection. We were forced down to remove almost any mention of male drive and male dominance in mate choice. And yet it is the same theory of male drive which was the basis of the mate choice theory of menopause which drew worldwide attention (Morton et al. 2013). In our opinion, Darwin missed out on the connection between the “mal-adaptive” long tail and the “dominance-conferring” tall train. A tall train allows males to compete against other males as well as serve as a big display to attract females. We thought we were proposing a new angle to look at the tail but it was treated as mere speculation. Evolutionary biology feeds on critical and thoughtful speculations as they become the basis for constructing new hypotheses. Darwin’s big book was all speculations, albeit very thought out and persuasive speculations. When a study is about testing a hypothesis the results and implications can be straightforward. Our study was not about testing a hypothesis; our study was about exploring the rules of pattern formation in the peacock tail and our findings had implications to mate choice, both males and females. Our intention was more than simply to publish a paper. Our intention was to reopen the discussion on the female choice hypothesis which has dominated evolutionary biology for a century and a half and has shaped our thinking and societal sexual norms how mate choice works. We are pleased with the reviewer’s comments and with his Approval (with revisions) of the papers but also for brining tour attention to literatures that we had ignored, in particular, the paper on aposematic hypothesis and its application to the evolution of peacock’s train. We thank the reviewer for considering the publication of this paper and for enabling the discussion on the evolution of peacock’s tail. Reviewers’ comments are all very helpful and they will be taken into consideration in revising the manuscript. We sincerely thank the reviewer for suggesting these interesting papers. All the changes suggested by the reviewer have been made and all the references/works have been included and discussed. This has led to rewriting of the section “Implication for sexual selection theories and a hypothesis” in the Discussion and the conclusions in the Abstract. Rama Singh (Author)"
}
]
},
{
"id": "356816",
"date": "05 Feb 2025",
"name": "Joao Menezes",
"expertise": [
"Reviewer Expertise animal communication",
"sexual selection",
"bioacoustics",
"ornithology",
"macroevolution"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript investigates the anatomical basis of the peacock’s train morphology, proposing that feather follicles follow a zigzag pattern that constrains eyespot number and contributes to the train’s symmetry and complexity. Based on observations of museum specimens and graphical reconstructions, the authors argue that train size and eyespot distribution are largely predetermined by developmental constraints, which may explain inconsistencies in past studies of sexual selection in peafowl.\nThe authors provides intriguing evidence that train morphology is largely constrained by developmental processes, with important implications for how sexual selection operates in peafowl, a textbook example of mate choice. By demonstrating that eyespot number is relatively fixed in adult males, the authors offer a potential explanation for conflicting findings in past studies on mate selection. Additionally, the use of graphical simulations is an original — and visually appealing — approach for visualizing the structural patterns underlying train symmetry.\nHaving said that, while this study seems to present a promising contribution to the sexual selection literature, I found it difficult to fully assess its scientific merit due to the manuscript’s lack of organization and clarity. The way information is presented both within and across sections makes it challenging to follow the logical progression of the study. Below, I outline major issues that, in my view, are preventing an effective communication of the manuscript's findings. I would be happy to assess the further merits of the study in a future, more reader-friendly version.\n*Overall organization* The manuscript lacks a clear and logical structure, making it difficult to navigate. This is most noticeable in the way that introduction, methods, results, and discussion are interwoven across the manuscript.\nFirst, while it is common to provide a brief preview of key findings at the end of the Introduction to help orient the reader, the manuscript dedicates two full paragraphs to presenting and discussing results. Such elaboration should ideally be reserved for the Results and Discussion sections.\nSimilarly, the Results section includes substantial content that would be more appropriate in other sections. For example, details on how museum specimens were selected and how graphical simulations were performed should be in the Methods section, yet these details are scattered throughout the Results. Likewise, several sentences contain citations to previous studies, indicating that they belong either in the Introduction or the Discussion. Among many examples, the authors discuss Takahashi et al. (2008) and Dakin and Montgomerie (2011) when interpreting their own findings (something that should be done in the Discussion) and present background information on feather development (which would be better suited to the Introduction).\nI highly recommend reorganizing the manuscript so that background information is confined to the Introduction, Methods are clearly described in a dedicated section (and only there), and Results present only the study’s objective findings (without citations to external literature or interpretations). Such restructuring would make the paper significantly easier to follow and ensure that each section serves its intended purpose.\n*Logical flow and conciseness* Within sections, the manuscript is often difficult to follow due to unclear sentence structure, awkward phrasing, and abrupt shifts in focus. Many sentences are unnecessarily complex, often including parenthetical remarks that disrupt readability. For example, the opening sentence of the manuscript includes a long parenthetic note that, while potentially relevant, interrupts the flow of the introduction and could be better placed later in the text. Additionally, logical inconsistencies and imprecise wording make several sentences unclear. For instance, in the Introduction, the phrase starting with “Unlike in other animals…” implies either that peacock’s tail cannot be directly under female choice, or that sexually selected traits in other animals cannot have three aspects — neither of which makes much sense. I chose two examples in the first paragraph because this paragraph is crucial to engaging readers, but these issues are present throughout the manuscript.\nThe introduction also frequently presents ideas in a way that lacks explicit connections, making it difficult to follow the logic of the argument. The third paragraph, for example, abruptly moves from discussing previous studies on sexual selection to a description of train symmetry and feather follicle arrangements. The transition between these topics is unclear, and the sudden introduction of figures further disrupts the flow. Particular care should be given to this paragraph because it establishes the goals of the study and therefore is key for full comprehension of the manuscript.\nThe manuscript would greatly benefit from more direct and concise writing, with clearer sentence structures, fewer parenthetical remarks, and better transitions between ideas.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-520
|
https://f1000research.com/articles/13-120/v1
|
19 Feb 24
|
{
"type": "Review",
"title": "Essential growth factor receptors for fibroblast homeostasis and activation",
"authors": [
"Maye F. Cheng",
"Faizah S. Abdullah",
"Matthew B. Buechler",
"Maye F. Cheng",
"Faizah S. Abdullah"
],
"abstract": "Fibroblasts are cells of mesenchymal origin that are found throughout the body. While these cells have several functions, their integral roles include maintaining tissue architecture through the production of key extracellular matrix components, and participation in wound healing after injury. Fibroblasts are also key mediators in disease progression during fibrosis, cancer, and other inflammatory diseases. Under these perturbed states, fibroblasts can activate into inflammatory fibroblasts or contractile myofibroblasts. Fibroblasts require various growth factors and mitogenic molecules for survival, proliferation, and differentiation. While the activity of mitogenic growth factors on fibroblasts in vitro was characterized as early as the 1970s, the proliferation and differentiation effects of growth factors on these cells in vivo are unclear. Moreover, recent work exploring the heterogeneity of fibroblasts raises questions as to whether all fibroblast cell states exhibit the same growth factor requirements. Here, we will examine and review existing growth factors known to influence fibroblast homeostasis to begin unpacking the potential growth factors that may influence in vivo fibroblast cell states.",
"keywords": [
"Fibroblasts",
"growth factors",
"growth factor receptors",
"FGFR",
"PDGFR",
"TGF-b"
],
"content": "Introduction\n\nFibroblasts are non-hematopoietic cells of mesenchymal origin that are essential for the structural integrity of organs. These cells maintain tissue homeostasis and participate in diseases by secreting extracellular matrix (ECM) components and providing signalling cues for other cell types, including immune cells and other non-hematopoietic cells.1 The fibroblast population is diverse and comprised of various context-specific fibroblasts found throughout the body, including pancreatic stellate cells, alveolar fibroblasts, and dermal fibroblasts.2 The heterogeneous nature of fibroblasts has provoked the existence of a progenitor-like population across tissues that can give rise to more specialized fibroblasts.3 Buechler and Pradhan et al. demonstrated the presence of two fibroblast subsets expressing high levels of stemness-associated genes found across many tissues.3 They termed these fibroblasts as universal fibroblasts and proposed that these cells can give rise to more specialized fibroblasts, though this concept has not been thoroughly proven.3 It is also well-established that under certain conditions, such as injuries and cancer, fibroblasts can become activated into myofibroblasts and develop into cancer-associated fibroblasts (CAFs).4 The duality of fibroblasts in both steady and diseased states highlights a challenging aspect in therapeutically targeting cells of the fibroblast lineage in fibrosis, cancer, and other inflammatory diseases. Further investigation of the signals and pathways involved in the homeostasis and activation of fibroblast subsets may open the possibility of specifically eradicating or modulating pathogenic fibroblasts. In this review, we will highlight the biology of common growth factor receptors associated with fibroblasts and their implications for understanding the steady state fibroblast and myofibroblast populations.\n\n\nDermatopontin (Dpt+) fibroblasts may be a reservoir for specialized fibroblasts across tissues\n\nStudying fibroblasts has traditionally been difficult given the heterogeneity of the fibroblast populations within and between tissues and a general lack of specific fibroblast markers.5 A greater appreciation for fibroblast heterogeneity has been revered in the advent of single-cell RNA-sequencing (scRNAseq).1 In a differential expression analysis of data from adult murine heart, skeletal muscle, colon, and urinary bladder, a short-list of commonly expressed fibroblast markers was identified.6 Although none of the listed markers qualify as a pan-fibroblast marker, it is still worth noting that there was greater than 10% of fibroblast-enriched genes overlapped between the four organs.6 In a broader cross-tissue study using mouse scRNAseq data, Buechler and Pradhan et al. observed that two populations of fibroblasts expressing Peptidase inhibitor 16 (Pi16) or Collagen 15a1 (Col15a1) were present in majority of the tissues examined.3 These populations both displayed greater levels of stemness-associated genes and showed an enrichment for dermatopontin (Dpt) expression.3 Due to their ubiquity across tissues, Dpt-enriched fibroblasts were termed ‘universal fibroblasts’3 (Figure 1).\n\nUnder perturbed conditions, fibroblasts can activate to become myofibroblasts with disease-specific functions. Buechler and Pradhan et al. demonstrated the presence of Dpt+ fibroblasts across multiple tissues.3 These fibroblast cell states may be poised to function as early progenitors that can differentiate into various context-specific cells within the body, such as adipocytes, osteoblasts or myofibroblasts. The signals that support Dpt+ fibroblast homeostasis have yet to be uncovered, but the fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) signalling pathways may be crucial for Dpt+ fibroblast proliferation and survival. Myofibroblasts are more contractile cells that can produce excessive amounts of ECM components, such as α-smooth muscle actin (α-SMA) and collagen, under disease conditions. The transition of fibroblasts to activated myofibroblasts can be dependent on the signalling cascade triggered by transforming growth factor-β (TGF-β) stimulation. Myofibroblasts are vital in wound healing and repair, although constitutive overactivation of these cells may lead to fibrosis and other disease phenotypes.\n\nThe presence of these fibroblasts in healthy and perturbed mouse and human tissues suggest a potential lineage trajectory involving a reservoir of Dpt+ fibroblasts that could give rise to specialized and activated fibroblasts in the steady and diseased states, respectively.3 This postulation of a universal fibroblast reservoir pool is further supported in studies that examine the lineage commitment of known differentiated cells from progenitors that include fibroblasts. In a single-cell gene expression analysis examining the development of murine brown adipose tissue, Jun et al. identified a population of embryonic Dpp4+Pi16+ fibroblasts at the onset of adipogenic development that are capable of adipogenesis.7 The authors posited that this population serves as a reserve progenitor population.7 Despite mounting evidence implicating Dpt+ fibroblasts as a precursor population, the signals they require for homeostasis are still poorly understood (Figure 1). Elucidating the growth factors that sustain or expand Dpt+ fibroblasts in vivo may help delineate their functional role across tissues.\n\n\nGrowth factors and their signalling pathways are essential for physiological homeostasis and under pathological conditions\n\nGrowth factors and associated signalling pathways are critical for the development of mammalian tissue and cellular regeneration. The definition of growth factors broadly includes secreted molecules that regulate the cell cycle or induce cell differentiation.8 Many of these growth factors also require an interaction with their corresponding cell surface receptors to trigger an intracellular signal cascade. The resulting cellular responses would include proliferation, differentiation, and gene transcription8 (Figure 2). In addition to directly impacting cellular processes, growth factors can also contribute to wound healing and tissue regeneration through a bi-directional relationship with the ECM.9 The ECM can release molecules, such as heparan sulfate proteoglycans (HSPGs), which have been shown to enhance the activity of growth factors and prevent their degradation.10,11 Indirectly, the ECM can also sequester cells to elicit growth factor expression and response.10 Reciprocally, growth factors, such as TGF-β, may modulate ECM composition by stimulating production of ECM components or increase matrix metalloproteinases synthesis for ECM degradation.10\n\nBinding of respective growth factors to FGFR and PDGFR would induce receptor dimerization and activation of downstream signalling pathways, including the RAS/MAPK, PI3K-PKB/Akt, PLCγ, and JAK/STAT cascades. Under physiological conditions, these pathways promote cell growth, proliferation, and survival in fibroblast populations in a context-dependent manner. TGF-β receptors may initiate the cascading phosphorylation events via SMAD proteins to induce activation, migration, and collagen production in myofibroblasts under diseased states. Crosstalk between PDGFR and TGF-β suggests a tightly regulated system for specific biological processes, such as proliferation and differentiation, in fibroblast populations.\n\nSome of the main growth factor-dependent signalling pathways for fibroblasts are initiated by the binding of fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs), and epidermal growth factors (EGFs) to their respective receptors.12 These growth factors share similar downstream events involving the phosphorylation of the receptor and mediator proteins to activate combinations of intracellular signalling pathways. These conserved signalling pathways involve phosphoinositide-3-kinase protein kinase B/Akt (PI3K-PKB/Akt), the mitogen-activated protein kinase (MAPK), phospholipase C γ (PLC γ) cascades, and transcription factors that include the signal transducers and activators of transcription (STATs) or SMAD proteins12 (Figure 2). The subsequent biological effects of these growth factors are influenced by several parameters, including the concentration of the growth factor and the presence of other stimuli.13 The different circumstances impacting growth factor signalling functions may depend on the specific tissue and cell type implicated. For example, a member of the FGF family, FGF2, can promote cell proliferation in cell types such as pancreatic stellate cells, neural crest cells and mesenchymal stem cells (MSC).14–17 However, FGF2 is also found to play a role in endothelial cell migration and may promote osteocyte differentiation in MSCs.18–20 The tissue and cell-specific activity of growth factors allow for more targeted biological functions under normal, physiological conditions.\n\nGrowth factors are crucial for maintaining homeostasis under healthy conditions; however, they have also been implicated to elicit disease progression. For example, during the transformative process from normal cells to malignant cancer cells, numerous genetic mutations accumulate.21 Usually, these mutations involve the loss of tumour suppressor gene functions or incite oncogene functions, which would eventually lead to failure of DNA repair mechanisms.21 Once premalignant cells begin to accumulate these oncogenic mutations, they can proliferate and clonally expand by the activation of signalling pathways orchestrated by growth factors.21 The expanded cancer cells would eventually migrate and penetrate adjacent tissues, contributing to metastases. During this epithelial-to-mesenchymal transition (EMT), malignant cells would engage the transcription of a mesenchymal genetic program, promoting a transition from exhibiting epithelial features to acquiring mobility as mesenchymal cells.22 This progressive conversion is also supported and mediated by growth factors, such as TGF-β, FGF, and EGF.21 In addition to signalling cancer cells directly, growth factors, such as TGF-β, can also influence the surrounding cancer microenvironment by enriching the presence of myofibroblasts and CAFs.23 In later stages of disease, cancer cells depend on angiogenesis for metastasis and tumour growth, which is further stimulated by mitogenic growth factors including FGF and vascular endothelial growth factor (VEGF).21\n\nGrowth factor-based therapeutic strategies for cancer, fibrosis, and other diseases may have systemic implications due to their wide range of effects in the body. The majority of transgenic animal models with genes eliminated from growth factor family members are embryonically or postnatally lethal.21 Targeting components of aberrant pathways that are causing uncontrolled proliferation or differentiation rather than the growth factors themselves may be a more feasible therapeutic option. Therefore, abrogating the interacting growth factor receptors may provide more focused therapeutic targets. As the first point of contact in the signalling pathway and a key transducer of the mitogenic signal, disrupting receptor activation may yield a more specific response than targeting the downstream signalling cascades shared between multiple growth factors and pathways.\n\n\nFibroblast growth factor receptors\n\nFibroblast growth factors (FGFs) were first discovered in the 1970s when Gospodarowicz demonstrated that a macromolecule isolated from the pituitary and the brain enhanced the growth of 3T3 cells, a mouse fibroblast cell line.24 Since its discovery, this macromolecule named a “fibroblast growth factor” has demonstrated its importance in mediating fundamental processes during embryonic development through to adulthood.25,26 Currently, 23 different FGFs have been identified, with the majority signalling through one of four fibroblast growth factor receptors (FGFRs) – FGFR1, FGFR2, FGFR3, and FGFR4.25 These highly conserved isoforms of FGFR vary based on alternative splicing of the transcripts.26 The differences between each FGFR extracellular domain profoundly affect the specific ligand-binding ability of each receptor.26 Additionally, it has been shown that the expression of FGFR isoforms is dependent on cell type and tissue.26 For example, the FGFR2b isoform is only expressed in epithelial cells, while FGFR2c is exclusively expressed in mesenchymal cells.26 Despite differences in FGFR isoform expression across cell types, FGFR signalling can be detected in all human tissues at varying levels.27\n\nSimilar to other members of receptor tyrosine kinase (RTK) families, FGFRs are single-pass transmembrane proteins that dimerize upon FGF binding.25,28 Canonical FGF signal transduction through FGFR is assisted by heparin and heparan sulfate proteoglycan cofactors. Alternatively, activation of FGFR by endocrine FGFs require Klotho co-receptors as cofactors.25,29 After dimerization and autophosphorylation of tyrosine residues in the cytoplasmic region of the receptor, various downstream signalling pathways activate (Figure 2). Thus, initiating physiological functions including cellular proliferation and differentiation, angiogenesis, and wound healing.30\n\n\nFibroblast growth factor receptors can induce proliferation and differentiation in fibroblast populations\n\nAs potent mitogenic receptors, the FGFR signal transduction pathway is tightly regulated by a negative feedback loop under normal physiological conditions.31 Under circumstances of aberrant FGFR activation, the resulting uncontrolled mitogenic effects contribute to 5-10% of all human cancers.32 The ability of FGFR to induce proliferation and differentiation is suggested in many cell types, especially in fibroblasts, where it was first discovered. An example of FGFR’s role in proliferation is observed when examining the effects of FGFR1 inhibition in MSCs.33 The loss of FGFR1 signalling results in a decrease in MSC expansion, a complete halt in the cell cycle, and has a negative impact on early mesoderm development.33 Taken together, these data suggest FGFR1 signalling may play a role in regulating stemness during proliferation and lineage-commitment in MSCs.33 In models of adipogenesis, inhibition of FGFR1 leads to a decrease in both FGF-1-mediated proliferation and priming for differentiation in human adipose fibroblasts.34 Similarly, Xu and Dai demonstrated that mice with a fibroblast-specific ablation of FGFR2 displayed a decrease in interstitial cell proliferation and apoptosis after being challenged with ischemia/reperfusion injury to induce kidney damage.35 The improvement in kidney fibrosis in the FGFR2 knock-out mice suggests that this was observed due to the inhibition of kidney fibroblast proliferation and activation.35\n\nThe role of FGFR signalling in Dpt+ universal fibroblasts has yet to be addressed. However, the implications of FGFR signalling in early embryogenesis36 and their effects on MSC differentiation33,37 point to its importance for the homeostasis of fibroblast progenitor cells. It is tempting to speculate that autocrine or paracrine FGF2 may enable self-renewal or homeostasis of tissue-wide progenitor fibroblast population in vivo, much like pathways that have been proposed to underlie MSC homeostasis.38–40 Interestingly, Fgfr1 expression was uniquely enhanced in universal fibroblast clusters, but not other members of the FGFR family.3 Therefore, a greater understanding of Dpt+ fibroblast subsets may reveal differential Fgfr expression and further elucidate the signals required by these fibroblast progenitor cells in vivo.\n\n\nPlatelet-derived growth factor receptors\n\nPlatelet-derived growth factors, or PDGFs, have been shown to play an integral role in fibroblast biology.41 It is now appreciated that there are five isoforms of PDGF: the four homodimers PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD, and the heterodimer PDGF-AB.42 These ligands function by binding to two receptors, referred to as platelet-derived growth factor receptor-α (PDGFRα) and platelet-derived growth factor receptor-β (PDGFRβ), which are broadly expressed among mesenchymal cell types, including fibroblasts.42 These receptors dimerize following ligand binding, allowing for autophosphorylation, signal transduction, and the invocation of ubiquitous signalling cascades, such as the JAK/STAT and PI3K/Akt pathways42 (Figure 2). In turn, PI3K/Akt signalling can recruit mediators that are involved in cellular proliferation and survival, such as intracellular components of the Erk/MAPK pathway42 (Figure 2). Initial purification of PDGFRα through the cloning of murine cDNA encoding the receptor identified conserved features, such as a transmembrane domain, extracellular cystine residues, and a tyrosine kinase domain.43 The receptor may undergo a variety of post-translational modifications prior to its expression on the membrane, including O-linked oligosaccharide and ubiquitin addition.43 After ligand binding and downstream signal transduction and amplification, both PDGFRα and PDGFRβ can moderate mitogenicity, chemotaxis, calcium ion mobilization, and edge ruffling, among other key cellular effects.44\n\n\nSignalling through platelet-derived growth factor receptors promote fibroblast maintenance and proliferation\n\nIn the mid-1970s, platelets from rat and human serum were found to enhance growth in 3T3 fibroblasts in vitro.45 This led to the assumption that platelets may contain specific growth-promoting factors that are released upon clotting. These factors, which were later identified to be PDGFs, allow for cellular stimulation and subsequent proliferation upon binding to their receptors.45 The implication of PDGFR signalling on fibroblast proliferation is demonstrated by transgenic mouse models with conditional knock-ins of PDGFRα. Primary embryonic fibroblasts isolated from murine embryos with constitutive PDGFRα signalling activity display greater proliferative ability compared to wild type embryos.46 Additionally, adult mice with constitutive PDGFRα signalling display aberrant levels of fibroblast activity, including connective tissue hyperplasia and excessive ECM production.46 The resulting fibrosis and tissue scarring phenotype signifies the importance of PDGFRα in supporting key fibroblast functions.46\n\nAnimal models with deficient PDGFRα expression further support its importance for fibroblast maintenance and survival. In an inactive state, cardiac fibroblasts are often quiescent and undergo limited proliferation.47 A tamoxifen-induced deletion of PDGFRα in cells expressing the cardiac fibroblast-specific transcription factor 21 (Tcf21mCrem) results in a drastic loss in ventricular cardiac fibroblasts in vivo.47 This implies the need for a basal level of PDGFRα signalling to maintain resident cardiac fibroblast populations.47 It is hypothesized that basal levels of PDGFRα signalling may prevent apoptotic signals that would lead to cell death as represented by a reduction in cell numbers.47 Asli et al. also reported that PDGFRα inhibition in a stem cell-like population of cardiac fibroblasts in vitro demonstrates limited rates of self-renewal.48 However, an enhanced synthesis of ribosomal and ribosomal-related genes, such as Eif1, Eif2s1, and Eif4a1, is observed following in vivo PDGF-AB treatment.48 Taken together, these data suggest that signalling via the PDGFRα pathway may prompt fibroblasts to exit quiescence and instead enter a translationally active state.\n\nIn addition to promoting fibroblast biological processes in steady state, PDGFR signalling may play a role during wound healing. An inhibition of wound closure is observed in scratch-wound assays where dermal fibroblasts lack PDGFRβ expression.49 This may suggest that PDGFRβ signalling is vital to fibroblast migration and proliferation.49 Similarly, activation of PDGFRα is important for fibroblast proliferation during the wound healing process. The proliferation of adipocyte precursor (AP) cells, a subset of fibroblasts with adipogenic potential, is supported by CD301b+ macrophage-derived PDGF-CC through the activation of PDGFRα.50 Ex vivo stimulation of AP cells with PDGF-CC results in an increase in their proliferation, while in vivo injections of PDGF-CC-neutralizing antibodies decrease AP cell numbers.50 While PDGF-CC is indispensable for the expansion of the AP cell population, it is not required for the development of other myofibroblast subsets during wound healing.50 Shook et al. demonstrated that local injections of PDGF-CC-neutralizing antibodies in wounds does not result in significant changes in the proliferation of non-AP myofibroblast subsets, nor in general wound re-revascularization during healing.50\n\nNotably, the expansion of precursor fibroblast populations after PDGFR activation via PDGF-AB and PDGF-CC binding,48,50 may imply the importance of PDGFR signalling in the Dpt+ fibroblast population. To this end, transgenic animal models with selective ablation of PDGFR signalling in Dpt+ fibroblasts may elucidate the importance of this receptor on the proliferation, survival, and activation of universal fibroblasts. Altogether, downstream pathways stimulated through PDGFRα and β signalling may be essential for fibroblast precursor cell states to exit a state of quiescence and activate biological processes, such as cell proliferation, self-renewal, migration, and apoptosis.\n\n\nFibroblasts depend on TGF-β receptor signalling for differentiation into myofibroblasts\n\nWhile fibroblasts participate in essential functions including ECM remodelling and structural support during homeostasis, they can also become activated and transform into myofibroblasts under diseased conditions. In this state, cells can produce several compounds, such as α-SMA, ECM fibers, and collagen. The excessive production of these molecules can then further promote the activation of myofibroblasts in a positive feedback loop, resulting in an uncontrolled, pathological fibrotic state.51 There is a drastic increase in ECM production following the establishment of myofibroblasts in the damaged tissue. Following this, signals within the wound bed can either trigger the cells to transform into a fibrotic phenotype or enter a quiescent state and eventually commit apoptosis.51 Loss of physical stresses would prompt the cells to undergo cell death, while persistent mechanical tension would promote hypertrophic scar formation through the inhibition of apoptosis.52,53 Persistent collagen secretion and fibrotic activity can lead to excessive scar formation and conditions with high disease burdens, such as idiopathic pulmonary fibrosis.54\n\nThere are several factors in the microenvironment that can stimulate the transition of conventional fibroblasts to activated myofibroblasts, including physical and biochemical stresses and ECM remodelling.51 Microenvironmental changes during inflammation also lead to the recruitment and infiltration of immune cells and the subsequent release of cytokines, such as IL-3, IL-4, and TGF-β.51,55 In particular, TGF-β is a crucial mediator in the transition from fibroblasts to myofibroblasts. TGF-β, which exists in three isoforms (TGF-β1, TGF-β2, and TGF-β3), activates homo- or heterodimeric complexes consisting of the type I TGF-β receptor (TβRI) and the type II TGF-β receptor (TβRII)56 (Figure 2). Subsequent transcriptional changes can be exerted through a cascade of phosphorylation events involving the SMAD protein family56 (Figure 2). Fibroblasts cultured in the presence of TGF-β have demonstrated increased levels of myofibroblast-associated molecules, such as α-SMA, procollagen I-α-1, and ED-A fibronectin.57,58 Alternatively, human fibroblasts treated with TGF-β and Lovastatin, a TGF-β inhibitor, prevented the transition of fibroblasts to myofibroblasts.59\n\nThe production of TGF-β and associated cytokines from proximal immune cells is a key contributor to the fibroblast to myofibroblast transition. The release of TGF-β and IL-4 from M2 macrophages in the surrounding environment induces a myofibroblast-specific transcriptional state through the phosphorylation of SMAD3 and the induction of the JAK/STAT and PI3K/Akt signalling cascades55 (Figure 2). Additionally, co-culture of macrophages with human vocal fold fibroblasts has been associated with increased levels of pro-fibrotic compounds, including type I collagen and α-SMA.60 This observation complements the noted amplification of genes involved in ECM productions, including Acta2 and Col1a1.60 The co-culture of fibroblasts with eosinophils also increases the expression of α-SMA through the stimulation of latent TGF-β and upregulates the transcription of fibronectin and collagen; thus, inducing the fibroblast to myofibroblast transition.58,59\n\n\nCrosstalk between platelet-derived growth factor receptors and TGF-β mediates lineage choice for fibrotic progenitors\n\nIn addition to TGF-β mediating the transition of fibroblasts to myofibroblasts, PDGFR signalling may also activate fibroblasts in a context-dependent manner. The overexpression of PDGFR ligands, PDGF-AA and PDGF-BB, has demonstrated varying severity of cardiac fibrotic phenotypes in murine models.60 This difference in fibrotic phenotypes is likely due to the variation in binding affinity between the ligands and PDGFRα.60 Furthermore, the loss of PDGFRα and PDGFRβ in transgenic murine models demonstrates a reduction in the number of differentiated epicardial-derived cardiac fibroblasts. This suggests that PDGFR signalling is essential for the differentiation and activation of fibroblast subsets.60,61 However, a study examining fibro-adipogenic progenitors (FAPs) in interstitial tissues, which express PDGFRα, TβRI, and TβRII, reported a downregulation of PDGFRα expression after TGF-β treatment in multiple fibroblast cell lines.62 Although an increase in ECM synthesis and fibrosis was observed, this downregulation in PDGFRα expression suggests that TGF-β may regulate the activation and differentiation effects from PDGFR signalling in fibroblasts.62 Interestingly, treatment of FAPs with TGF-β also limited the differentiation of this stem cell-like population into adipocytes.62\n\nTaken together, these data indicate that TGF-β may behave in a morphogenic fashion, with its levels balancing myofibroblast and tissue-specific fibroblast levels within the body.62 TGF-β may act in a negative feedback loop with PDGFRα to prevent negative fibrotic outcomes. Increased levels of TGF-β favour myofibroblast differentiation, thus a corresponding decrease in PDGFR expression may limit potential fibrosis driven by fibroblast proliferation. As such, it would be valuable to explore the effects of TGF-β on Dpt+ fibroblasts and elucidate the potential crosstalk between TGF-β and PDGFR or other growth factor receptors on this fibroblast cell state.\n\n\nConclusion\n\nFibroblasts are among the most abundant cell types in the body, yet knowledge of these cells remain elusive. Recent scRNA-seq approaches have suggested that a hierarchy of transcriptional cell states exist within the fibroblast lineage. The role of growth factor receptors in proliferation and maintenance of various cell types is well-characterized, but their functions in discrete fibroblasts cell states remain unclear. Transgenic animal models with modified or eliminated growth factor receptor expressions in fibroblast subsets would be valuable for deciphering the signals required by fibroblasts under different conditions. However, the downstream signaling cascades of receptor tyrosine kinases are commonly shared by multiple growth factor receptors. This can pose challenges in isolating effects from individual growth factor receptors when examining signalling requirements for fibroblasts in in vitro and in vivo models. Nonetheless, exploring growth factor receptor signalling activity within the cell states that comprise the fibroblast lineage will promote the development of more specific and targeted therapies for cancer, fibrosis, and other inflammatory diseases.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nPlikus MV, et al.: Fibroblasts: Origins, definitions, and functions in health and disease. Cell. 2021; 184: 3852–3872. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSherman MH, di Magliano MP : Cancer-Associated Fibroblasts: Lessons from Pancreatic Cancer. Annu. Rev. Cancer Biol. 2023; 7: 43–55. Publisher Full Text\n\nBuechler MB, et al.: Cross-tissue organization of the fibroblast lineage. Nature. 2021; 593: 575–579. PubMed Abstract | Publisher Full Text\n\nOtranto M, et al.: The role of the myofibroblast in tumor stroma remodeling. Cell Adhes. Migr. 2012; 6: 203–219. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJanmaat CJ, et al.: Human Dermal Fibroblasts Demonstrate Positive Immunostaining for Neuron- and Glia- Specific Proteins. PLoS One. 2015; 10: e0145235. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMuhl L, et al.: Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination. Nat. Commun. 2020; 11: 3953. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJun S, et al.: Control of murine brown adipocyte development by GATA6. Dev. Cell. 2023; 58: 2195–2205.e5. PubMed Abstract | Publisher Full Text\n\nStone WL, Leavitt L, Varacallo M: Physiology, Growth Factor. StatPearls. 2023.\n\nKulebyakin KY, Nimiritsky PP, Makarevich PI: Growth Factors in Regeneration and Regenerative Medicine: “the Cure and the Cause.”. Front. Endocrinol. 2020; 11: 384. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchultz GS, Wysocki A: Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen. 2009; 17: 153–162. Publisher Full Text\n\nSarrazin S, Lamanna WC, Esko JD: Heparan Sulfate Proteoglycans. Cold Spring Harb. Perspect. Biol. 2011; 3: a004952.\n\nRodrigues M, Griffith LG, Wells A: Growth factor regulation of proliferation and survival of multipotential stromal cells. Stem Cell Res. Ther. 2010; 1: 32. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCross M, Dexter TM: Growth factors in development, transformation, and tumorigenesis. Cell. 1991; 64: 271–280. Publisher Full Text\n\nColeman SJ, et al.: Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion. EMBO Mol. Med. 2014; 6: 467–481. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMurphy M, Reid K, Ford M, et al.: FGF2 regulates proliferation of neural crest cells, with subsequent neuronal differentiation regulated by LIF or related factors. Development. 1994; 120: 3519–3528. Publisher Full Text\n\nTeixeira BL, Amarante-Silva D, Visoni SB, et al.: FGF2 Stimulates the Growth and Improves the Melanocytic Commitment of Trunk Neural Crest Cells. Cell. Mol. Neurobiol. 2020; 40: 383–393. PubMed Abstract | Publisher Full Text\n\nAhn H-J, Lee W-J, Kwack K, et al.: FGF2 stimulates the proliferation of human mesenchymal stem cells through the transient activation of JNK signaling. FEBS Lett. 2009; 583: 2922–2926. PubMed Abstract | Publisher Full Text\n\nMichaelis UR: Mechanisms of endothelial cell migration. Cell. Mol. Life Sci. 2014; 71: 4131–4148. Publisher Full Text\n\nByun MR, et al.: FGF2 stimulates osteogenic differentiation through ERK induced TAZ expression. Bone. 2014; 58: 72–80. PubMed Abstract | Publisher Full Text\n\nXiao L, et al.: Disruption of the Fgf2 gene activates the adipogenic and suppresses the osteogenic program in mesenchymal marrow stromal stem cells. Bone. 2010; 47: 360–370. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWitsch E, Sela M, Yarden Y: Roles for Growth Factors in Cancer Progression. Physiology. 2010; 25: 85–101. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRoche J: The Epithelial-to-Mesenchymal Transition in Cancer. Cancers. 2018; 10: 52. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKalluri R: The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 2016; 16: 582–598. Publisher Full Text\n\nGospodarowicz D: Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature. 1974; 249: 123–127. PubMed Abstract | Publisher Full Text\n\nHui Q, Jin Z, Li X, et al.: FGF Family: From Drug Development to Clinical Application. Int. J. Mol. Sci. 2018; 19: 1875. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEswarakumar VP, Lax I, Schlessinger J: Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005; 16: 139–149. Publisher Full Text\n\nHughes SE: Differential Expression of the Fibroblast Growth Factor Receptor (FGFR) Multigene Family in Normal Human Adult Tissues. J. Histochem. Cytochem. 1996; 45: 1005–1019. Publisher Full Text\n\nSarabipour S, Hristova K: Mechanism of FGF receptor dimerization and activation. Nat. Commun. 2016; 7: 10262. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu G, et al.: Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment. Cell Prolif. 2021; 54: e13009. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFurdui CM, Lew ED, Schlessinger J, et al.: Autophosphorylation of FGFR1 Kinase Is Mediated by a Sequential and Precisely Ordered Reaction. Mol. Cell. 2006; 21: 711–717. PubMed Abstract | Publisher Full Text\n\nSzybowska P, Kostas M, Wesche J, et al.: Negative Regulation of FGFR (Fibroblast Growth Factor Receptor) Signaling. Cells. 2021; 10: 1342. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXian W, Schwertfeger KL, Vargo-Gogola T, et al.: Pleiotropic effects of FGFR1 on cell proliferation, survival, and migration in a 3D mammary epithelial cell model. J. Cell Biol. 2005; 171: 663–673. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDombrowski C, et al.: FGFR1 Signaling Stimulates Proliferation of Human Mesenchymal Stem Cells by Inhibiting the Cyclin-Dependent Kinase Inhibitors p21Waf1 and p27Kip1. Stem Cells. 2013; 31: 2724–2736. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWidberg CH, et al.: Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes. Am. J. Physiol.-Endocrinol. Metab. 2009; 296: E121–E131. PubMed Abstract | Publisher Full Text\n\nXu Z, Dai C: Ablation of FGFR2 in Fibroblasts Ameliorates Kidney Fibrosis after Ischemia/Reperfusion Injury in Mice. Kidney Dis. 2017; 3: 160–170. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDorey K, Amaya E: FGF signalling: diverse roles during early vertebrate embryogenesis. Development. 2010; 137: 3731–3742. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKähkönen TE, et al.: Role of fibroblast growth factor receptors (FGFR) and FGFR like-1 (FGFRL1) in mesenchymal stromal cell differentiation to osteoblasts and adipocytes. Mol. Cell. Endocrinol. 2018; 461: 194–204. PubMed Abstract | Publisher Full Text\n\nHoch RV, Soriano P: Roles of PDGF in animal development. Development. 2003; 130: 4769–4784. Publisher Full Text\n\nHeldin C-H: Targeting the PDGF signaling pathway in tumor treatment. Cell Commun. Signal. 2013; 11: 97–97. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYarden Y, et al.: Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature. 1986; 323: 226–232. PubMed Abstract | Publisher Full Text\n\nHeldin C-H, Östman A, Rönnstrand L: Signal transduction via platelet-derived growth factor receptors. Biochim. Biophys. Acta (BBA) - Rev. Cancer. 1998; 1378: F79–F113. Publisher Full Text\n\nKohler N, Lipton A: Platelets as a source of fibroblast growth-promoting activity. Exp. Cell Res. 1974; 87: 297–301. PubMed Abstract | Publisher Full Text\n\nOlson LE, Soriano P: Increased PDGFRα Activation Disrupts Connective Tissue Development and Drives Systemic Fibrosis. Dev. Cell. 2009; 16: 303–313. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIvey MJ, Kuwabara JT, Riggsbee KL, et al.: Platelet-derived growth factor receptor-α is essential for cardiac fibroblast survival. Am. J. Physiol.-Hear. Circ. Physiol. 2019; 317: H330–H344. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAsli NS, et al.: PDGFRα signaling in cardiac fibroblasts modulates quiescence, metabolism and self-renewal, and promotes anatomical and functional repair. bioRxiv. 2019; 225979. Publisher Full Text\n\nGao Z, et al.: Deletion of the PDGFR-β Gene Affects Key Fibroblast Functions Important for Wound Healing. J. Biol. Chem. 2005; 280: 9375–9389. PubMed Abstract | Publisher Full Text\n\nShook BA, et al.: Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science. 2018; 362(6417): eaar2971. PubMed Abstract | Publisher Full Text | Free Full Text\n\nD’Urso M, Kurniawan NA: Mechanical and Physical Regulation of Fibroblast–Myofibroblast Transition: From Cellular Mechanoresponse to Tissue Pathology. Front. Bioeng. Biotechnol. 2020; 8: 609653. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGrinnell F, Zhu M, Carlson MA, et al.: Release of Mechanical Tension Triggers Apoptosis of Human Fibroblasts in a Model of Regressing Granulation Tissue. Exp. Cell Res. 1999; 248: 608–619. PubMed Abstract | Publisher Full Text\n\nAarabi S, et al.: Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis. FASEB J. 2007; 21: 3250–3261. Publisher Full Text\n\nWynn TA: Integrating mechanisms of pulmonary fibrosis. J. Exp. Med. 2011; 208: 1339–1350. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSheng J, et al.: M2 macrophage-mediated interleukin-4 signalling induces myofibroblast phenotype during the progression of benign prostatic hyperplasia. Cell Death Dis. 2018; 9: 755. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAttisano L, Wrana JL: Signal Transduction by the TGF-β Superfamily. Science. 2002; 296: 1646–1647. Publisher Full Text\n\nAmara N, et al.: NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFβ1-induced fibroblast differentiation into myofibroblasts. Thorax. 2010; 65: 733–738. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSerini G, et al.: The Fibronectin Domain ED-A Is Crucial for Myofibroblastic Phenotype Induction by Transforming Growth Factor-β1. J. Cell Biol. 1998; 142: 873–881. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMeyer-Ter-Vehn T, Katzenberger B, Han H, et al.: Lovastatin inhibits TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts. Investig. Ophthalmol. Vis. Sci. 2008; 49: 3955–3960. Publisher Full Text\n\nNakamura R, Bing R, Gartling GJ, et al.: Macrophages alter inflammatory and fibrotic gene expression in human vocal fold fibroblasts. Exp. Cell Res. 2022; 419: 113301. PubMed Abstract | Publisher Full Text\n\nKuwabara Y, et al.: Role of Matrix Metalloproteinase-2 in Eosinophil-Mediated Airway Remodeling. Front. Immunol. 2018; 9: 2163. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJanulaityte I, et al.: Asthmatic Eosinophils Alter the Gene Expression of Extracellular Matrix Proteins in Airway Smooth Muscle Cells and Pulmonary Fibroblasts. Int. J. Mol. Sci. 2022; 23: 4086. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGallini R, Lindblom P, Bondjers C, et al.: PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice. Exp. Cell Res. 2016; 349: 282–290. PubMed Abstract | Publisher Full Text\n\nSmith CL, Baek ST, Sung CY, et al.: Epicardial-Derived Cell Epithelial-to-Mesenchymal Transition and Fate Specification Require PDGF Receptor Signaling. Circ. Res. 2011; 108: e15–e26.\n\nContreras O, et al.: The cross-talk between TGF-β and PDGFRα signaling pathways regulates stromal fibro/adipogenic progenitors’ fate. J. Cell Sci. 2019; 132: jcs232157."
}
|
[
{
"id": "252079",
"date": "20 Mar 2024",
"name": "Natalia Pikor",
"expertise": [
"Reviewer Expertise Fibroblast immunobiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this article, Buechler and colleagues review the literature concerning the influence of key growth factors and cytokines on fibroblast sustenance and activation. In light of the author's seminal contribution to defining Dpt+ universal fibroblasts, an emphasis is placed on the potential relevance of each factor on progenitor fibroblasts.\nThe authors have chosen to focus on fibroblast growth factors, platelet-derived growth factors and TGF-beta, in their role for fibroblast homeostasis, maintenance/proliferation and myofibroblastic activation/differentiation. In the introduction an emphasis is placed on universal fibroblasts being a potential progenitor population that can on one hand maintain stemless, and on the other, give rise to both inflammatory fibroblasts and contractile myofibroblasts. Notably, a discussion of the activation factors mediating the differentiation of inflammatory fibroblasts is strikingly missing, despite the wealth of knowledge of tumor necrosis factor superfamily members capable of giving rise to the prototypical inflammatory fibroblast - the fibroblastic reticular cell. Of note, recent studies highlight the presence of the universal progenitor fibroblast population within human and murine lymphoid organs [De Martin A, et.al. 2023 (ref 1), Lütge M, et.al. 2023 (Ref 2)], and several lineage-tracing studies have elucidated the perivascular origin of lymphoid organ FRCs [Cheng HW, et. al. 2019 (ref 3), Prados A, et. al. 2021 (Ref 4)], which is compatible with the paradigm of universal fibroblasts. This section would be a welcome addition to this otherwise comprehensive overview of cues governing fibroblast sustenance and activation.\nAs a minor comment on the referenced literature - in its current form the review references 26 other reviews (42% of the references). To better guide a keen reader to the relevant literature, it may be favourable to replace some of the reviews with the main primary papers.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "11550",
"date": "24 Jun 2024",
"name": "Maye Cheng",
"role": "Author Response",
"response": "We thank both reviewers for dedicating time to provide in-depth and constructive comments for this submission. Their feedback and insight have significantly improved the quality of this review. Reviewer's comments In this article, Buechler and colleagues review the literature concerning the influence of key growth factors and cytokines on fibroblast sustenance and activation. In light of the author's seminal contribution to defining Dpt+ universal fibroblasts, an emphasis is placed on the potential relevance of each factor on progenitor fibroblasts. The authors have chosen to focus on fibroblast growth factors, platelet-derived growth factors and TGF-beta, in their role for fibroblast homeostasis, maintenance/proliferation and myofibroblastic activation/differentiation. In the introduction an emphasis is placed on universal fibroblasts being a potential progenitor population that can on one hand maintain stemless, and on the other, give rise to both inflammatory fibroblasts and contractile myofibroblasts. 1. Notably, a discussion of the activation factors mediating the differentiation of inflammatory fibroblasts is strikingly missing, despite the wealth of knowledge of tumor necrosis factor superfamily members capable of giving rise to the prototypical inflammatory fibroblast - the fibroblastic reticular cell. We thank the reviewer for mentioning this important comment. We have referenced the importance of TNFSF members in promoting activation of inflammatory fibroblasts in lines 489-492. We feel that the contribution of TNFSF members is out of the scope of this review as we focused here on FGFR, PDGFR, and TGFβR. Additionally, TNFSF members and their association with fibroblasts have been recently reviewed in Steele et al. (2023). 2. Of note, recent studies highlight the presence of the universal progenitor fibroblast population within human and murine lymphoid organs [De Martin A, et.al. 2023 (ref 1), Lütge M, et.al. 2023 (Ref 2)], and several lineage-tracing studies have elucidated the perivascular origin of lymphoid organ FRCs [Cheng HW, et. al. 2019 (ref 3), Prados A, et. al. 2021 (Ref 4)], which is compatible with the paradigm of universal fibroblasts. This section would be a welcome addition to this otherwise comprehensive overview of cues governing fibroblast sustenance and activation. We appreciate the reviewer’s comments. We have included remarks (lines 125-130) on the recent studies examining Pi16+ fibroblasts in SLOs as an additional rationale for examining the growth factor requirements for Dpt+ fibroblasts. We have also reviewed and included a section on the origin of FRCs in SLOs in lines 105-112. 3. As a minor comment on the referenced literature - in its current form the review references 26 other reviews (42% of the references). To better guide a keen reader to the relevant literature, it may be favourable to replace some of the reviews with the main primary papers. We agree with the reviewer’s insight. We have added additional references from primary sources. Currently, this submission contains 32% of references from other reviews."
}
]
},
{
"id": "252088",
"date": "23 Mar 2024",
"name": "Michelle D Tallquist",
"expertise": [
"Reviewer Expertise Fibroblast development",
"PDGF receptor signaling",
"fibrosis."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe review by Cheng et al poses the question whether all fibroblast subsets utilize the same growth factors signaling pathways for survival and proliferation. It then discusses three receptor families known to signal in fibroblasts, TGFbR, FGFR, and PDGFR. The review highlights some manuscripts describing the actions of these receptors on a wide range of fibroblast/fibroadipocyte/mesenchymal stem cell populations.\nComments\nWhile the title suggests a comprehensive review on this topic, the review focuses on three growth factor receptor families, TGF-bR, FGFR, and PDGFR. Because of the limited focus of the review, I would recommend revision of the title which more closely reflects the scope of the review.\nThe review places an emphasis on a dermatopontin expressing fibroblast population (Buechler MB, et al 2021 [Ref 1]).\n\nMultiple references focus on mesenchymal stem cells, adipocytes and preadipocytes. The range of fibroblasts discussed is also very broad. It might be helpful to the reader to understand the connection and definition of these different populations of cells.\nThe organ range of fibroblasts discussed is also broad with a mention of prostate, dermis, skeletal muscle, cardiac, pulmonary, kidney, pancreas, and cancer associated fibroblasts.\nFigure 2 is an oversimplification of the receptor pathways illustrated.\nThe history of the growth factor receptor’s discovery seems a bit out of the scope of the review.\nMinor comments\nReference 50 is not Shook et al. Reference 49 does not describe lack of PDGFRbeta\n\nIs the topic of the review discussed comprehensively in the context of the current literature? No\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "11551",
"date": "26 Jun 2024",
"name": "Maye Cheng",
"role": "Author Response",
"response": "We thank both reviewers for dedicating time to provide in-depth and constructive comments for this submission. Their feedback and insight have significantly improved the quality of this review. Reviewer's comments The review by Cheng, et al. poses the question whether all fibroblast subsets utilize the same growth factors signaling pathways for survival and proliferation. It then discusses three receptor families known to signal in fibroblasts, TGFbR, FGFR, and PDGFR. The review highlights some manuscripts describing the actions of these receptors on a wide range of fibroblast/fibroadipocyte/mesenchymal stem cell populations. 1. While the title suggests a comprehensive review on this topic, the review focuses on three growth factor receptor families, TGF-bR, FGFR, and PDGFR. Because of the limited focus of the review, I would recommend revision of the title which more closely reflects the scope of the review. Author Response: We agree with the reviewer’s comment. As suggested, we have revised the title to “Essential growth factor receptors for fibroblast homeostasis and activation: Fibroblast Growth Factor Receptor (FGFR), Platelet Derived Growth Factor Receptor (PDGFR), and Transforming Growth Factor β Receptor (TGFβR)” to reflect the emphasis of the review. 2. The review places an emphasis on a dermatopontin expressing fibroblast population (Buechler MB, et al 2021 [Ref 1]). Multiple references focus on mesenchymal stem cells, adipocytes and preadipocytes. The range of fibroblasts discussed is also very broad. It might be helpful to the reader to understand the connection and definition of these different populations of cells. Author Response: We thank the reviewer for their insightful comment. As suggested, we have added definitions of these cells and a discussion of the crosstalk between these populations in lines 113-124. 4. The organ range of fibroblasts discussed is also broad with a mention of prostate, dermis, skeletal muscle, cardiac, pulmonary, kidney, pancreas, and cancer associated fibroblasts. Author Response: We acknowledge the reviewer’s observation. We included studies across a variety of tissues to broadly examine the effects of growth factor receptors in the body. 5. Figure 2 is an oversimplification of the receptor pathways illustrated. Author Response: We thank the reviewer for their comment. The reviewer is correct and we have revised the figure to include several additional adaptor molecules and significant pathways. 6. The history of the growth factor receptor’s discovery seems a bit out of the scope of the review. Author Response: We thank the reviewer for pointing this out. We have removed some portions of the review discussing the history of each receptor. Minor comments Reference 50 is not Shook et al. Author Response: We thank the reviewer for highlighting this. We have inserted the correct reference (62). Reference 49 does not describe lack of PDGFRbeta Author Response: We thank the reviewer for highlighting this. We have inserted the correct reference (56)."
}
]
}
] | 1
|
https://f1000research.com/articles/13-120
|
https://f1000research.com/articles/12-719/v1
|
21 Jun 23
|
{
"type": "Research Article",
"title": "Integrative transcriptomic and proteomic study of Zika viral infection reveals potential mechanisms for oncolytic therapy in neuroblastoma",
"authors": [
"Matt Sherwood",
"Yilu Zhou",
"Yi Sui",
"Yihua Wang",
"Paul Skipp",
"Carolini Kaid",
"Juliet Gray",
"Keith Okamoto",
"Rob M. Ewing",
"Matt Sherwood",
"Yilu Zhou",
"Yi Sui",
"Yihua Wang",
"Paul Skipp",
"Carolini Kaid",
"Juliet Gray",
"Keith Okamoto"
],
"abstract": "Background: Paediatric neuroblastoma and brain tumours account for a third of all childhood cancer-related mortality. High-risk neuroblastoma is highly aggressive and survival is poor despite intensive multi-modal therapies with significant toxicity. Novel therapies are desperately needed. The Zika virus (ZIKV) is neurotropic and there is growing interest in employing ZIKV as a potential therapy against paediatric nervous system tumours, including neuroblastoma. Methods: Here, we perform extensive analysis of ZIKV infection studies to identify molecular mechanisms that may govern the oncolytic response in neuroblastoma cells. We summarise the neuroblastoma cell lines and ZIKV strains utilised and re-evaluate the infection data to deduce the susceptibility of neuroblastoma to the ZIKV oncolytic response. Integrating transcriptomics, interaction proteomics, dependency factor and compound datasets we show the involvement of multiple host systems during ZIKV infection. Results: We identified that most paediatric neuroblastoma cell lines are highly susceptible to ZIKV infection and that the PRVABC59 ZIKV strain is the most promising candidate for neuroblastoma oncolytic virotherapy. ZIKV induces TNF signalling, lipid metabolism, the Unfolded Protein Response (UPR), and downregulates cell cycle and DNA replication processes. ZIKV is dependent on sterol regulatory element binding protein (SREBP)-regulated lipid metabolism and three protein complexes; V-ATPase, ER Membrane Protein Complex (EMC) and mammalian translocon. We propose ZIKV non-structural protein 4B (NS4B) as a likely mediator of ZIKVs interaction with IRE1-mediated UPR, lipid metabolism and mammalian translocon. Conclusions: Our work provides a significant understanding of ZIKV infection in neuroblastoma cells, which will facilitate the progression of ZIKV-based oncolytic virotherapy through pre-clinical research and clinical trials.",
"keywords": [
"Neuroblastoma",
"oncolytic virotherapy",
"Zika virus",
"transcriptomics",
"proteomics"
],
"content": "Keypoints\n\n\n\n• The Zika virus may provide the basis for an oncolytic virotherapy against Neuroblastoma\n\n• Most paediatric neuroblastoma cell lines are susceptible to Zika viral infection\n\n• We identified molecular mechanisms that may contribute to the oncolytic response in Neuroblastoma\n\n\nContribution to the field\n\nThe ability to both induce direct oncolysis and provoke an anti-tumoral immune response makes oncolytic virotherapy an attractive candidate to combat aggressive and heterogenous cancers, such as high-risk neuroblastoma. To progress oncolytic virotherapy to clinical trial it is essential to understand the host mechanisms the virus manipulates to kill cancer cells, alongside any pathology as a consequence of infection of normal cells. Here, we show that ZIKV efficiently infects and induces oncolysis of paediatric neuroblastoma cells and propose a potential TNF pathway-driven immune response. ZIKV’s specificity for infection of nervous system cancer cells, while rarely causing nervous system-related pathology in young children, addresses many of its safety concerns. The inclusion of more effective and less toxic novel therapies, such as a potential ZIKV-based therapeutic, in multimodal treatment regimens will pave the way for improving patient long-term health and overall survival.\n\n\nIntroduction\n\nNeuroblastoma is the most common extracranial solid cancer in children, accounting for 6–10% of all paediatric cancers and disproportionately causing 12–15% of paediatric cancer-related deaths.1 It is an embryonal tumour originating from transformed cells of neural crest lineage and predominately forms tumours in the adrenal medulla and paraspinal sympathetic ganglia. Whilst the majority of patients are diagnosed by the age of 5 years, the median age of patients is 18 months. Prognosis is highly heterogenous and can be predicted by a number of factors, including the presence of metastatic disease, age, chromosomal aberrations and molecular signatures, such as MYC-N amplification.2 Patients are categorised according to internationally agreed risk groups (INRG), and treatment is stratified accordingly.\n\nOutcome for low- and intermediate-risk neuroblastoma is good, with some patients requiring little or no treatment. However, approximately 50% of patients have high-risk disease, for which prognosis is poor, with overall survival of less than 60%.3 Current high-risk neuroblastoma treatment regimens are aggressive. These include multiple rounds of induction chemotherapy, surgical resection, myeloablative chemotherapy, autologous stem cell transplantation and post-consolidation therapy such as immunotherapy.4 The aggressive nature of this regimen carries significant treatment-related mortality and frequently results in long-term toxicities and sequelae impacting the quality of life for surviving patients. Consequently, there is a clear and unmet need for safer and less toxic treatment regimens to combat high-risk neuroblastoma.\n\nOncolytic virotherapy exploits viruses that preferentially infect and destroy cancer cells via two distinct routes of therapeutic action. Following infection, intense viral replication induces oncolysis, releasing virions into the tumour microenvironment to infect neighbouring tumour cells. Induction of a tumour-specific immune response is a crucial secondary mechanism employed by oncolytic virotherapy that can address highly heterogeneous tumours such as high-risk neuroblastoma and central nervous system (CNS) tumours. There is significant interest in combining immuno-modulating cancer therapies with oncolytic virotherapy to augment the anti-tumoral immune response. Oncolytic virotherapy clinical studies have in general reported low toxicity and minimal adverse effects in patients, mainly low-grade constitutional symptoms.5\n\nZika virus (ZIKV) is a mosquito-borne flavivirus consisting of historical African and epidemic-associated Asian lineages. The latter is neurotropic and can cause microcephaly in the developing foetus through infection of neural stem and progenitor cells, causing cell death and growth reduction.6,7 By contrast, ZIKV rarely causes adverse effects in children and adults, with the majority of cases (50–80%) being asymptomatic.8 In symptomatic children, ZIKV may cause short-term side effects, namely rash, fever and gastrointestinal symptoms, and in rare instances in adults can cause more severe conditions, such as Guillain-Barré Syndrome, meningitis and encephalitis.8,9\n\nSince 2017, the concept of employing the ZIKV as oncolytic virotherapy against brain tumours has gained momentum. ZIKV induces an oncolytic event in infected paediatric brain tumour cells in vitro and in vivo assays and induces an immune response against spontaneous canine brain tumours.10–12 Paediatric neuroblastoma, like paediatric brain tumours, are predominantly tumours of the nervous system consisting of cancerous cells with neural characteristics. An initial study assessing ZIKV infection in multiple neuroblastoma cell lines demonstrated ZIKV’s potential as a novel neuroblastoma oncolytic virotherapy.13 Here, we survey over 35 studies that have used neuroblastoma cell lines to model ZIKV infection. These studies focused on understanding ZIKV pathology and assessing anti-viral compounds. Through re-analysis and integration of the transcriptomics, proteomics and dependency factor screens from these studies, we identify multiple molecular mechanisms implicated in ZIKV infection of neuroblastoma and aim to determine its potential as oncolytic virotherapy.\n\n\nMethods\n\nRNA-Seq data files (.fastq.gz paired-end) of ZIKV-infected paediatric neuroblastoma SH-SY5Y cells were acquired from the European Nucleotide Archive (ENA) (accession: PRJNA630088). Our RNA-Seq processing pipeline consisted of FastQC (V0.11.9-0) (RRID:SCR_014583),14,15 Trim Galore (V0.6.6-0) (RRID:SCR_011847), HISAT2 (V2.2.0) (RRID:SCR_015530),16 SAMTOOLS (V1.11) (RRID:SCR_002105)17 and Subread (V2.0.1) (RRID:SCR_009803).18 Reads were aligned against the Homo sapiens GRCh38 genome.\n\nDifferential gene expression analysis was performed using DESeq2 (RRID:SCR_015687)19 to compare the triplicate of ZIKV-infected SH-SY5Y cells versus the triplicate of non-infected SH-SY5Y control cells. Differentially expressed genes (DEGs) were plotted on bar charts, volcano and scatter plots using GraphPad Prism (9.2.0) (RRID:SCR_002798). DEGs (padj < 0.05, fold change > 1.5) were submitted to Database for Annotation, Visualization and Integrated Discovery (DAVID) (DAVID 2021 (Dec. 2021)) (RRID:SCR_001881)20,21 as official gene symbols for Gene Ontology (GO) (RRID:SCR_002811) (Biological Process Direct),22,23 Kyoto Encyclopedia of Genes and Genomes (KEGG) (RRID:SCR_012773)24–26 and Reactome (RRID:SCR_003485) pathway analysis. ZIKV-induced DEGs were mapped onto Pathview (RRID:SCR_002732).27 ZIKV NS4B host interaction partners were also submitted to DAVID to identify the interaction between NS4B and host pathways. Significance values of DEG and pathway analysis were corrected for multiple testing using the Benjamini and Hochberg method (padj < 0.05).\n\nOverall, 130 high-confidence ZIKV NS4B interactors in SK-N-BE2 paediatric neuroblastoma cells (determined by Bayesian statistical modelling) were sourced from IMEx - The International Molecular Exchange Consortium (RRID:SCR_002805) (IM-26452)28 and mapped in Cytoscape (3.9.1) (RRID:SCR_003032).29 The viral-host interactome was submitted to STRING (RRID:SCR_005223)30 for high confidence (0.7) evidence-based physical subnetwork analysis to identify host-host interactions. The viral-host and STRING derived host-host interactions were integrated to identify the interaction of ZIKV NS4B with host protein complexes. Additional data incorporated into the Cytoscape map include known ZIKV dependency factors and the interaction of ZIKV NS2B-3 with the Mammalian Translocon. ZIKV dependency factors were sourced for paediatric SK-N-BE2 neuroblastoma,31 glioma stem cells (GSCs),32 hiPSC-NPC,33 HEK293FT32 and HeLa cells.34\n\n\nResults and Discussion\n\nZIKV infects and significantly reduces the cell viability of a multitude of neuroblastoma cell lines from both primary tumour and metastatic sites (Table 1). ZIKV can significantly reduce neuroblastoma cell viability at multiplicity of infection (MOI) as low as 0.001.35 The cell viability of 10/15 neuroblastoma cell lines is significantly reduced to below 20% following ZIKV infection and these observations are apparent despite the differences in the cell line, ZIKV strain, viral MOI and the type of assay performed (Table 1). SK-N-Be1 and SK-N-Be2 cells are from bone marrow metastasis from the same patient before and after treatment, respectively, and are both highly susceptible to ZIKV. Thus, Table 1 identifies that ZIKV can target neuroblastoma cells originating from the primary tumour, metastatic sites and metastatic sites that are resistant to standard neuroblastoma therapy. SK-N-AS, T-268 and JFEN are highly resistant (cell viability >80%) to ZIKV infection. Susceptibility is independent of patient sex, cell line origin, morphology and MYC-N status (Table 1). The non-sympathetic nervous system and non-paediatric origin of the T-268 and JFEN cells likely explain their resistance to ZIKV infection, as ZIKV has a tropism for paediatric nervous system cancer cells. The resistance of the paediatric SK-N-AS cell line is governed by CD24 expression, which regulates the basal antiviral state of these cells.13,36 In conclusion, our analysis demonstrates that ZIKV is a strong candidate to employ against paediatric neuroblastoma as oncolytic virotherapy.\n\nCell lines are ranked by the degree to which ZIKV infection reduces their cell viability. Ranking was determined by taking the percentage to which ZIKV either reduced cell viability or induced cell death (depending on the in vitro assay used in the study) and applying a ranking system from 1 to 5, with higher numbers denoting a strong ability of ZIKV to reduce cell viability. Note: 1, >80%; 2, 60-80%; 3, 40-60%; 4, 20-40%; 5, <20%. ZIKV, Zika virus; MYCN, MYCN Proto-Oncogene; NA, not applicable.\n\nThe neurotropism of the Asian lineage makes it the clear choice, over the African lineage, for developing ZIKV oncolytic virotherapy against brain tumours. However, the situation for neuroblastoma is not so apparent. Independent studies have demonstrated inherent differences in the ability of varying ZIKV strains to infect, replicate, and kill neuroblastoma cells.37,38 Here, we assess all published data concerning ZIKV infection of neuroblastoma cells and ranked the viral strains based on their ability to infect neuroblastoma cells, produce fresh viral progeny and reduce cell viability (Table 2). We identify the PRVABC59 Asian, Uganda #976 African and MR766 African strains as the top three candidates (Table 2). Notably, the PRVABC59 Asian strain induces significantly more DEGs and splice events in SH-SY5Y cells compared to the African MR766 strain; including more immune and inflammatory response genes.39 Brain metastases develop in 5–11% of patients with neuroblastoma and are correlated with poor prognosis.40 The neurotropism of the Asian lineage may enhance the therapeutic potential of ZIKV by targeting these brain metastases. The multiple ZIKV pandemics identified that infection by an Asian strain is generally well accommodated by children, thus providing evidence for the safety of employing an Asian strain. Consequently, from those tested to date, we identify that the PRVABC59 strain demonstrates the greatest promise for development as oncolytic virotherapy against paediatric neuroblastoma.\n\nZIKV strains are ranked by their ability to infect (Degree of Infection), replicate within (Viral Titer) and significantly reduce the cell viability (Cell Viability) of a multitude of neuroblastoma cells. Data accordance denotes the degree of similarity of the results between publications that performed cell viability of cell death assays in neuroblastoma cells using the same ZIKV strain. Data accordance of five denotes that the findings of one publication closely support the findings from another, a data accordance of one denotes publications reporting vastly contrasting results. When a viral strain is published in only one paper, it is allocated a data accordance of NA. ZIKV, Zika virus; NA, not applicable.\n\nDifferential gene expression analysis identifies 453 and 256 significantly upregulated and downregulated genes (fold change > 1.5), respectively, in ZIKV-infected paediatric neuroblastoma SH-SY5Y cells (Figure 1A). GO, Reactome and KEGG pathway analysis identifies nine significantly upregulated and 12 significantly downregulated terms (Figure 1B-C). Upregulated processes include “TNF signalling pathway”, lipid metabolism (“Cholesterol biosynthesis”, “Cholesterol biosynthetic process”, “Activation of gene expression by SREBF (SREBP)”), endoplasmic reticulum (ER) stress (“Response to endoplasmic reticulum stress”, “XBP1(S) activates chaperone genes”) and transcription (“BMAL1:CLOCK, NPAS2 activates circadian gene expression”, “Positive regulation of transcription from RNA polymerase II promoter”). The downregulated terms are predominantly cell cycle- and DNA replication-related processes and this downregulation is apparent when the “Cell Cycle” KEGG pathway is plotted for all DEGs (fold change > 0) (Figure 1D). A potential explanation for this observation is that ZIKV can disrupt the cell cycle by targeting the centrioles in neuroblastoma cells.41\n\nVolcano plot of genes differentially expressed in response to ZIKV infection of SH-SY5Y cells, with the top 10 upregulated genes labelled (A). Significantly upregulated (B) and downregulated (C) GO Biological Processes, KEGG and Reactome pathways in response to ZIKV infection in SH-SY5Y neuroblastoma cells. KEGG map of the cell cycle, plotted using all DEGs (fold change > 0) (D). Significance values are corrected for multiple testing using the Benjamini and Hochberg method (padj < 0.05). GO, Gene Ontology; ZIKV, Zika virus; KEGG, Kyoto Encyclopedia of Genes and Genomes; DEG, differentially expressed gene.\n\nOf the top 10 upregulated DEGs in SH-SY5Y cells, four (BIRC3, TNFAIP3, ICAM1 and BCL3) are components of the TNF signalling pathway (Figure 1A). The TNF pathway is particularly noteworthy to consider for oncolytic virotherapy since it may play a role in both oncolysis (direct cell death) and the anti-tumoral immune response. Here, mapping the “TNF Signalling” KEGG pathway for ZIKV-infected SH-SY5Y cannot deduce if ZIKV may activate CASP-mediated apoptosis or CASP-independent necroptosis (Figure 2A). However, ZIKV-infected SH-SY5Y cells clearly show significant upregulation of transcription factors (AP-1, cEBPβ and CREB), leukocyte recruitment and activation (CCL2 and CSF1), intracellular signalling (BCL3, NFKBIA, TNFAIP3 and TRAF1) and cell adhesion genes (Icam1 and Vcam1) (Figure 2A). ZIKV significantly upregulates the expression of multiple Activator protein 1 (AP-1) transcription factors, including members from all four AP-1 subfamilies (ATF, JUN, FOS and MAF) in SH-SY5Y cells (Figure 2B). AP-1 can regulate the expression of a diverse set of genes in response to nutrients, cytokines, stress or pathogen infection, and is involved in innate and adaptive immunity, differentiation, proliferation, survival and apoptosis.42 AP-1 transcription factors can regulate the immune response of tumours, and significant AP-1 upregulation by ZIKV infection potentially identifies AP-1 as a mechanism through which ZIKV could yield an anti-tumoral immune response against neuroblastoma in vivo.43\n\nKEGG Map plotted for the TNF Signalling Pathway, plotted using all DEGs (fold change > 0) (A). Expression levels of TNF Signalling Transcription Factors in SH-SY5Y cells in response to ZIKV infection (B). Expression levels of cytokine signalling in immune system genes in SH-SY5Y cells in response to ZIKV infection (C). Significance values are corrected for multiple testing using the Benjamini and Hochberg method (padj < 0.05). A threshold line of Log2(1.5 Fold Change) has been applied for the expression values. Log2FoldChange (LFC) ± standard error of the LFC estimate (lfcSE), n = 3. ZIKV, Zika virus; KEGG, Kyoto Encyclopedia of Genes and Genomes; DEG, differentially expressed gene; AP-1, activator protein 1; CREB, cAMP response element-binding protein.\n\nHere, we identify CCL2 (MCP-1) to be significantly upregulated by ZIKV infection, and two independent studies have shown CCL2 to be secreted by ZIKV-infected SH-SY5Y cells.44,45 CCL2 is a pro-inflammatory mediator that recruits leukocytes via chemotaxis to infiltrate tissues, including the CNS, to stimulate inflammation.46 A non-neurotoxic herpes simplex virus (HSV)-based oncolytic virotherapy, engineered to express physiologically relevant levels of CCL2 (M010), significantly reduced Neuro-2a neuroblastoma growth in the flank of immune-competent mice and recruited CD4+ and CD8+ T-cells to infiltrate the tumour.46 Additionally, CCL2 is secreted by ZIKV-infected cultured canine glioblastoma cells when in the presence of monocytes and is detected in serum and CSF samples of canines bearing spontaneous brain tumours following ZIKV infection.12 We propose here that CCL2 may be capable of inducing an anti-tumoral immune response against paediatric neuroblastoma during ZIKV infection. Supporting the notion of a ZIKV-induced inflammatory response, 32 genes implicated in cytokine signalling in the immune system are significantly differentially expressed in ZIKV-infected SH-SY5Y cells: 27 upregulated and five downregulated (Figure 2C).\n\nZIKV infection significantly upregulates lipid metabolism-related terms in SH-SY5Y cells; specifically, “Cholesterol biosynthesis” and “Activation of gene expression by SREBF (SREBP)” (Figure 1B). Cholesterol and lipids are essential cellular components and there are complex systems that function to regulate their intracellular abundance and localisation. These systems include regulation of cholesterol biosynthesis by the sterol regulatory element binding protein (SREBP) pathway, intracellular cholesterol trafficking, and cholesterol efflux by the liver X receptor (LXR) pathway. Cholesterol and fatty acids are required for multiple stages of the flavivirus life cycle, including regulating viral entry, the formation of viral replication complexes in the ER membrane and viral egress.47 ZIKV elevates lipogenesis and remodels the composition of the lipid classes in infected SK-N-SH cells.48 Here, we identify several approaches to regulate ZIKV infection of neuroblastoma cells through modification of intracellular lipid levels (Table 3). These include supplementation with pathway regulators (PF-429242, fenofibrate, lovastatin, U18666A and LXR 623) or exogenous lipids (oleic acid, docosahexaenoic acid (DHA) and cholesterol).\n\nList of compounds that regulate lipid homeostasis and are capable of restricting or enhancing ZIKV infection in paediatric neuroblastoma cells. ZIKV, Zika virus; LXR, liver X receptor; SREBP, sterol regulatory element binding protein; DHA, docosahexaenoic acid.\n\nThe SREBP pathway is a principal regulator of fatty acid and cholesterol biosynthesis. The SREBF1 and SREBF2 transcription factors control this pathway, and although they share a small degree of redundancy, they primarily regulate the expression of fatty acid biosynthesis and cholesterol biosynthesis target genes, respectively.49 Both SREBF2 and SREBF2-AS1 are significantly upregulated in ZIKV-infected SH-SY5Y cells (Figure 3A) and pathway analysis identifies significant upregulation of “Cholesterol biosynthesis” (Figure 1B). Three SREBP pathway inhibitors (PF-429242, fenofibrate and lovastatin) reduce the capability of ZIKV to infect SK-N-SH neuroblastoma cells (Table 3). We identify here that the SREBP pathway is essential for ZIKV infection and propose that it may upregulate cholesterol biosynthesis through the SREBF2 transcriptional pathway in neuroblastoma cells.\n\nExpression of SREBP pathway (A) and LXR pathway (B) genes in neuroblastoma cells in response to ZIKV infection. Significance values are corrected for multiple testing using the Benjamini and Hochberg method (padj < 0.05). A threshold line of Log2(1.5 Fold Change) has been applied for the expression values. Log2FoldChange (LFC) ± standard error of the LFC estimate (lfcSE), n = 3. ZIKV, Zika virus; SREBP, sterol regulatory element binding protein; LXR, liver X receptor.\n\nBoth U18666A and exogenous cholesterol restricts ZIKV infection of neuroblastoma cells (Table 3). U18666A is an intracellular cholesterol transport inhibitor that causes the accumulation of cholesterol in lysosomes to hinder the endosomal-lysosomal system.50 Exogenous cholesterol also leads to the inactivation of the late endosomal-lysosomal compartments through a build-up of cholesterol.50 Collectively, this identifies a dependence of the ZIKV life cycle in neuroblastoma cells on intracellular cholesterol for the correct functioning of the endosomal-lysosomal system.\n\nThe LXR pathway agonist (LXR 623) promotes cholesterol efflux (Table 3). Flaviviruses require cholesterol for the restructuring of host membranes, and LXR 623 demonstrates this dependence of ZIKV in neuroblastoma by preventing ZIKV-induced vesicle production and ER expansion in SK-N-SH cells.51 The LXR pathway and expression of its downstream lipid homeostasis genes are regulated by the transcription factors LXR-α (NR1H3) and LXR-β (NR1H2). LXR-α protein is significantly increased by ZIKV infection of SK-N-SH neuroblastoma cells from 48 hr.51 Although LXR-α mRNA is only marginally upregulated in our study, two major cholesterol efflux factors that are downstream of the LXR pathway, ATP-Binding Cassette A1 and G1 (ABCA1 and ABCG1), are significantly upregulated (Figure 3B). This identifies a dependence of ZIKV on the LXR pathway and suggests that ZIKV may manipulate this pathway in neuroblastoma cells to upregulate cholesterol efflux.\n\nWe identify here that lipid abundance, localisation, trafficking and metabolism regulate ZIKV infection of neuroblastoma cells and that ZIKV likely remodels the cellular lipid composition to help produce a favourable environment for efficient replication.\n\nZIKV upregulates ER-stress-related terms in SH-SY5Y cells, principally “Response to endoplasmic reticulum stress” and “XBP1(S) activates chaperone genes” (Figure 1B). The Unfolded Protein Response (UPR) dictates the ER-stress response. The UPR is normally inactive due to the ER chaperone binding immunoglobulin protein (BIP) sequestering three ER stress sensors (IRE1, PERK and ATF6). Under stress conditions BIP releases IRE1, PERK and ATF6 to assist protein folding, allowing them to activate their respective UPR-mediated ER-stress pathways.\n\nActivation of the IRE1-mediated UPR leads to IRE1 splicing a 26 bp region from the ubiquitously expressed XBP1 mRNA. The active transcription factor XBP1(S) then drives the expression of genes to help alleviate ER stress, primarily chaperone and ER-associated protein degradation (ERAD) genes. ZIKV infection significantly upregulates 15 genes of the IRE1-mediated “XBP1(S) activates chaperone genes” Reactome pathway in SH-SY5Y cells (Figure 4A). XBP1 is the most highly upregulated gene and others include the endoplasmic-reticulum-associated protein degradation (ERAD) gene SYVN1 and the chaperones DNAJC3 and DNAJB9 (Figure 4A). Multiple IRE1-mediated UPR genes (EDEM1, SYVN1, SSR1, SRPRB, ATP6V0D1, and EXTL3) are ZIKV dependency factors in hiPSC-NPCs (Table 4). Chemical inhibition of IRE1 by 4μ8C impairs ZIKV infection in vivo.52 Here, we identify that ZIKV significantly upregulates the IRE1-mediated UPR in SH-SY5Y cells and that ZIKV is dependent on this for efficient infection, likely as a means to regulate and combat viral replication-induced ER stress.\n\nExpression levels of the XBP1(S) activates chaperone genes (A) and ATF4 activates genes in response to endoplasmic reticulum stress (B) genes in neuroblastoma cells in response to ZIKV infection. Significance values are corrected for multiple testing using the Benjamini and Hochberg method (padj < 0.05). A threshold line of Log2(1.5 Fold Change) has been applied for the expression values. Log2FoldChange (LFC) ± standard error of the LFC estimate (lfcSE), n = 3. ZIKV, Zika virus; UPR, Unfolded Protein Response; ER, endoplasmic reticulum.\n\nLists of known ZIKV dependency factors across SH-SY5Y (NB), GSC, hiPSC-NPC (NPC), HEK293FT and HeLa cells. ZIKV, Zika virus; GSC, glioma stem cell; NB, neuroblastoma.\n\nPERK-mediated UPR regulates the expression of genes involved in apoptosis, redox, amino acid transport and autophagy through eIF2 phosphorylation and the transcription factor ATF4. ZIKV infection significantly upregulates seven genes of the Reactome pathway “ATF4 activates genes in response to endoplasmic reticulum stress” (Figure 4B), including the ERAD gene HERPUD1 and the transcription factors ATF3, CEBPB and CEBPG. GADD34 (PPP1R15A), which usually dephosphorylates eIF2α in a negative feedback loop, is significantly upregulated here by ZIKV infection, and ZIKV induces eIF2 phosphorylation in SK-N-SH cells.53 ZIKV likely upregulates GADD34 to combat ER stress-induced translational repression, as fresh virions require de novo protein synthesis. C/EBP homologous protein (CHOP) (DDIT3) is a pro-apoptotic protein downstream of the PERK UPR pathway that others have observed to be significantly upregulated in SH-SY5Y and SK-N-SH cells in response to ZIKV infection.39,53,54 CHOP induces apoptotic markers, including Caspase 3, leading to cell death. Notably, multiple PERK-mediated UPR genes (ATF4, EIF2AK1, EIF2AK2, EIF2AK3 and EIF2AK4) are ZIKV dependency factors in hiPSC-NPCs (Table 4).\n\nWe conclude that ZIKV specifically upregulates and is dependent on the IRE1 and PERK branches of the UPR ER stress response in SH-SY5Y cells; conclusions that are supported by others.53,54\n\nTo determine which host mechanisms ZIKV may be dependent on, we cross-referenced the 22 known proteins that ZIKV requires to infect neuroblastoma cells with ZIKV dependency factors from four cell lines (Figure 5A and Table 4). Between 72–94% of the dependency factors identified across the five different cell lines are cell-specific, highlighting how ZIKV utilises differing host factors across different cell types for its life cycle. The sparse overlap of ZIKV dependency factors identifies only one factor common to all five cell types. MMGT1 (EMC5) is a key component of the Endoplasmic Reticulum (ER) Membrane Protein Complex (EMC). The EMC is a hetero-oligomer composed of 10 subunits, has chaperone properties by assisting multi-transmembrane protein folding, and is implicated in ER stress, flavivirus infection and lipid trafficking.55 To assess if ZIKV is dependent on additional EMC subunits during infection, we searched for them in our ZIKV dependency factor dataset. We identify that ZIKV has a strong dependence on the EMC independent of cell type; all 10 EMC proteins are ZIKV-dependency factors in hiPSC-NPC, eight are in HeLa and three in GSC and HEK293FT cells (Figure 5B). The EMC facilitates the expression of ZIKV transmembrane proteins (NS2B, NS4A and NS4B), ZIKV NS4B interacts with EMC subunits, and disrupting the EMC impedes infection by ZIKV and other flaviviruses.56,57 We propose that the EMC stabilises ZIKV proteins through integration into the ER membrane, thus permitting efficient infection in neuroblastoma cells. If investigated, we predict that additional EMC subunits would present as ZIKV dependency factors in neuroblastoma cells.\n\nVenn diagram of known ZIKV dependency factors across NB, GSC, hiPSC-NPC (NPC), HEK293FT and HeLa cells, to identify shared and cell-specific factors and protein complexes that ZIKV is dependent on for infection (A). Diagram of the EMC (B) and V-ATPase (C), based on their crystal structures. For the subunits in B and C, colours are allocated based on the number of cell types in which they act as ZIKV dependency factors (cell types stated in the adjacent tables). ZIKV, Zika virus; NB, neuroblastoma; GSC, glioma stem cell; EMC, endoplasmic reticulum membrane protein complex.\n\nAcidification of the endosomal-lysosomal system by the V-ATPase is a property that viruses can utilise to drive the release of their nucleocapsid into the cytosol. ATP6V0C, a central component of the V-ATPase, is a ZIKV-dependency factor in neuroblastoma, hiPSC-NPC and HEK293FT cells (Figure 5A). A total of 12 additional V-ATPase subunits are ZIKV dependency factors across GSC, hiPSC-NPC and HeLa cells (Figure 5C). These 13 genes consist of multiple subunits from the Vo proton translocation and V1 ATP hydrolytic domains, identifying a functional dependence of ZIKV on the entire V-ATPase complex. The V-ATPase inhibitor Bafilomycin A1 specifically binds ATP6V0C and through V-ATPase inhibition prevents lysosomal acidification and the autophagy-lysosome pathway.58 Bafilomycin A1 inhibits ZIKV infection of SH-SY5Y cells, supporting our observation (Table 3). siRNA silencing of the V-ATPase significantly impairs ZIKV infection of T98G glioblastoma cells, collaborating its requirement for infection of nervous system tumour cells.59 We propose that loss of V-ATPase function impairs ZIKV infection in SH-SY5Y cells due to a perturbed pH gradient in the endosomal system. This likely prevents fusion of the viral envelope with the endosomal membrane for release of the nucleocapsid, therefore, trapping ZIKV for degradation in the lysosome, as observed in Vero cells.60\n\nZIKV NS4B protein is principally responsible for the oncolytic effect in SH-SY5Y cells, via activating the mitochondrial apoptotic pathway.61 Determining the interactions and mechanisms underpinning this may yield opportunities to develop a paediatric neuroblastoma therapy based on ZIKV NS4B. ZIKV NS4B has 130 known host interaction partners in SK-N-BE2 neuroblastoma cells.31 Here, we analyse this interactome and identify multiple pathways that we, and others, have implicated during ZIKV infection of neuroblastoma cells: including mitochondrial-, lipid metabolism- and ER-associated processes (Figure 6). ZIKV NS4B interacts with 10 lipid biosynthesis proteins, three (SCD, SC5D and DHCR7) of which are expressed in response to SREBP pathway activation. This identifies a direct interaction between ZIKV and host lipid metabolism and the SREBP pathway, supporting our previous observations at the transcriptome level.\n\nNodes are grouped and labelled according to any sets of high-confidence interactions between the host proteins, and by pathways they are involved in. Cross-referencing the interactome with the ZIKV dependency factor datasets identifies the interaction of NS4B with dependency factors in neuroblastoma cells (red) and in GSC, hiPSC-NPC, HeLa and HEK293FT cells (collectively termed non-neuroblastoma cells, orange). To aid visualisation, any nodes possessing no high confidence interactions, other than their interaction with NS4B, have been grouped. All nodes within Figure 6 interact with NS4B, thus, to aid visualisation all edges between NS4B and nodes within a group have been condensed into a single edge between NS4B and the grouped set of nodes. ZIKV, Zika virus; NS4B, non-structural protein 4B; GSC, glioma stem cell.\n\nZIKV NS4B recruits BAX to the mitochondria, triggers its activation, and releases Cytochrome c from mitochondria to induce mitochondrial cell death in SH-SY5Y cells.61 ZIKV NS4B interacts with a multitude of mitochondrial genes (Figure 6). Including, electron transport chain proteins (TIMMDC1, MT-CO2, COX15 and OXA1L), mitochondrial translocases that import proteins into the mitochondrial matrix (TOMM22, TIMM23, TIMM50 and TIMM17B) and Solute Carrier Family 25 members for transport of solutes across the mitochondrial membrane (SLC25A1, SLC25A3, SLC25A6, SLC25A11, SLC25A12, SLC25A13 and SLC25A22). Specifically, MT-CO2, COX15 and OXA1L are conserved catalytic core, assembly and accessory subunits of the Cytochrome c oxidase complex, respectively. The Cytochrome c oxidase complex tightly couples Cytochrome c to the inner mitochondrial membrane. We propose that NS4B interacts with Cytochrome c oxidase to uncouple it from Cytochrome c, causing Cytochrome c release through the BAX pore into the cytosol to drive the mitochondrial cell death pathway in neuroblastoma cells.\n\nZIKV NS4B interacts with and is dependent on multiple proteins of the Mammalian Translocon (Figures 5A and 6). The mammalian translocon is primarily composed of the Oligosaccharyl Transferase (OST) complex, the Sec61 complex and the translocon-associated protein (TRAP) complex.62 The multimeric OST complex co-translationally N-glycosylates proteins within the ER to assist protein folding, stability and trafficking. The Sec61 complex, a heterotrimer of Sec61α, Sec61β and Sec61γ, co-translationally translocates newly synthesised proteins across the ER and during ER stress can regulate IRE1α activity. TRAP is a heterotetramer of SSR1, SSR2, SSR3 and SSR4 that assists co-translational translocation of proteins into the ER and can prevent aberrant N-linked glycosylation during ER stress.\n\nSTT3A, a principal component of the OST complex, interacts with ZIKV NS4B and is a ZIKV dependency factor in neuroblastoma, GSC, hiPSC-NPC and HeLa cells (Figures 5A and 6). Regarding the additional OST subunits, ZIKV NS4B interacts with DDOST, RPN1, RPN2 and KRTCAP2, and OSTC and OST4 are ZIKV dependency factors in HeLa cells and GSCs, respectively (Figures 5A and 6). Two forms of the OST complex exist, the STT3A and STT3B OST paralogs. KRTCAP2 and OSTC are STT3A-specific OST factors, which permit interaction of STT3A with the translocon, whilst TUSC3 and MAGT1 are STT3B-specific OST factors.62 STT3A and both STT3A-specific OST factors are ZIKV interaction partners and/or dependency factors, but neither STT3B nor the STT3B-specific OST factors are. In addition to the OST factors, multiple N-linked glycosylation-related proteins (DPM1, DERL3, SYVN1, UBE2G2 and UBE2J1) are also ZIKV dependency factors in non-neuroblastoma cells (Table 4). The OST complex inhibitor NGI-1 blocks ZIKV infection of Huh7 cells, and disrupting ZIKV prM and E protein N-glycosylation impairs the release of infectious ZIKV particles from Vero cells.63,64 Here, we identify that STT3A functions as a bonafide ZIKV dependency factor in multiple cell types, and conclude that efficient infection of neuroblastoma cells by ZIKV is likely dependent on the STT3A OST paralog for N-glycosylation of its viral proteins.\n\nZIKV NS4B interacts with SEC61A1 and SEC61B of the Sec61 complex in neuroblastoma cells and the Sec61α inhibitor Mycolactone impedes ZIKV infection of HeLa cells.65 ZIKV NS4B interacts with SSR3 of the TRAP complex in neuroblastoma cells and ZIKV is dependent on at least two of the four TRAP complex subunits for infection of GSC, hiPSC-NPC and HeLa cells (Figure 5A). Further supporting our observation of ZIKV interacting and being dependent on the mammalian translocon is its dependence on SRPRB, SPCS3 and TRAM1; subunits of the Signal Recognition Particle (SRP), the Signal Peptidase Complex (SPCS) and the Translocating chain-associated membrane protein (TRAM), respectively. Notably, the viral protease NS2B-3 also interacts with subunits of the OST complex (STT3A, RPN1), Sec61 complex (SEC61B) and TRAP complex (SSR3) (Figure 6). These interactions likely facilitate the co-translational cleavage of the viral polypeptide by NS2B-3 into its individual viral proteins.\n\nHere, we identify that ZIKV NS4B and NS2B-3 directly interact with the core complexes of the mammalian translocon and propose that these interactions are essential for the ZIKV life cycle in neuroblastoma cells. The dependency of ZIKV likely stems from the mammalian translocon facilitating viral polyprotein co-translational translocation, viral polyprotein cleavage, viral membrane protein insertion and/or viral protein N-glycosylation. Additionally, ZIKV may utilise its protein interactions with the Sec61 complex, TMEM33 and VAPB, to regulate the IRE1- and PERK-mediated UPR ER stress responses, that we identify to be significantly upregulated at the transcriptome level in ZIKV infected-neuroblastoma cells.\n\n\nConclusions\n\nOur study highlights the strong therapeutic potential of ZIKV, specifically the PRVABC59 strain, against multiple neuroblastoma cell-lines. We identify ZIKV to interact with, and be dependent on, multiple host protein complexes and pathways for its life cycle in paediatric neuroblastoma cells and for inducing oncolysis (Figure 7). Although this area of research is still at an early stage, our extensive survey of neuroblastoma ZIKV infection studies clearly demonstrates the potential of a ZIKV-based therapeutic. There are a few avenues that need to be addressed to progress this area of research, including; (1) assessing ZIKV’s oncolytic effect against neuroblastoma in xenograft mouse models, (2) assessing ZIKV’s capability to induce an anti-tumoral immune response against neuroblastoma in immune-competent in vivo models, and (3) considering the effectiveness and safety of employing different forms of ZIKV-based therapeutics against neuroblastoma. Examples of the latter may include live attenuated ZIKV strains or the construction of a virotherapy that collectively expresses ZIKV NS4B and CCL2, which we show here to hold elements of ZIKV’s oncolytic and immune activation potential, respectively.\n\nHighlighted are the three essential properties of an oncolytic virus; the production of fresh viral particles to infect additional cancer cells (A), the ability to induce cancer cell death (B) and a mechanism through which ZIKV may induce an anti-tumoral immune response (C). ZIKV, Zika virus; EMC, endoplasmic reticulum membrane protein complex; SREBP, sterol regulatory element binding protein; ER, endoplasmic reticulum; NS4B, non-structural protein 4B.",
"appendix": "Data availability\n\nEuropean Nucleotide Archive: Asian Zika virus isolate significantly changes the transcriptional profile and alternative RNA splicing events in a neuroblastoma cell line. Accession number PRJNA630088 (https://identifiers.org/ena.embl/PRJNA630088). 79\n\n\nAcknowledgements\n\nThe authors would like to thank the original curators of the datasets used in this study. The abstract can be found on sciety (https://sciety.org/articles/activity/10.1101/2022.11.14.516401) and an earlier version of this article can be found on bioRxiv (doi: https://doi.org/10.1101/2022.11.14.516401).\n\n\nReferences\n\nJohnsen JI, Dyberg C, Wickström M: Neuroblastoma—A Neural Crest Derived Embryonal Malignancy. Front. Mol. Neurosci. 2019; 12: 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCampos Cogo S, Farias G, da Costa do Nascimento T , et al.: An overview of neuroblastoma cell lineage phenotypes and in vitro models. Exp. Biol. Med. 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Reference Source"
}
|
[
{
"id": "184590",
"date": "17 Aug 2023",
"name": "Griffith D Parks",
"expertise": [
"Reviewer Expertise RNA Viruses"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThere is very high interest in mechanisms for improving the potency and specificity of oncolytic viruses, and much of this interest is in large scale analysis of host cell responses. Thus, there is potential significance for the work described here, in the analysis of transcriptomic changes that occur with Zika virus (ZIKV) infection of neuroblastoma cells in culture. An unfortunate weakness is that the work is not presented as what it is: a review of the literature and not a primary study of ZIKV infection.\nStrengths of the work include the importance of understanding host factors that modulate RNA virus infections such as those by ZIKV, the global omics approach to the study using prior data sets and literature searches, the survey of published results to conclude best virus and cell type, and the identification of distinct pathways. The work is largely well done, with interpretations which are consistent with the data. Figure 7 is particularly useful.\nThe main weakness of the manuscript is the presentation of findings as new and “identified” by the authors. For example, for nearly all the sections there are phrases such as “Here, we identify ZIKV NS4B….directly interact with core complexes….” The authors have not identified a direct interaction, but rather have used prior databases to develop a hypothesis that this may occur. This is a misleading representation of the data presented in this manuscript and there should be a re-write of the text to state that this is from analysis of the literature and data mining.\nThe authors should make it clear in the abstract in title that this is not a new study, but rather an evaluation of the literature and mining of prior data. In fact, the title is misleading by stating it is a study of ZIKV infection, when it is in reality an analysis of the published data (still useful). In reality, there is a major strength in this large amount of work and the authors are to be commended for it. There needs to be a clear statement that this is a review manuscript.\nOther comments.\nThe text states that ZIKV is neurotropic. This should be modified, as this virus appears to have a lot of different host cell types it can infect. Disease is manifested when there is infection of neuro-cells, but this is not tropism.\n\nIn the results of abstract – please clarify “ZIKV is dependent on…” What part of ZIKV is dependent?\n\nThe text does not come to a conclusion on data from Table I other than to say lots of cells can be infected. What is the reason behind the graded difference between the 5 and 4 and 3. The authors speculate on the reason for grade 1, but not the others.\n\nPage 4 text – “the Asian lineage…..is the clear choice for oncolytic therapy.” Not clear where this comes from, and no citation was given.\n\nTable 2 is useful, but has the caveat that it does not list the cells that were tested. It would be very useful to include a column with “shared cell lines tested in publications”\n\nFig 1D and 2A are entirely too small for anyone to read. These should be expanded and used a separate figures, so as to allow a reader to see the results.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "10543",
"date": "20 Nov 2023",
"name": "Rob Ewing",
"role": "Author Response",
"response": "We thank Dr Parks for his review of the paper, and his recognition of the significance of identifying mechanisms that may underlie the oncolytic response to the Zika virus in cancer cells. Our intention has been to integrate and re-analyze many of the omics datasets that have studied Zika viral infection of Neuroblastoma cells rather than review the literature. We believe that re-analysis and integration of the available datasets provides many new insights into the Zika virus – neuroblastoma interaction which are not yet available through the papers published to date. Additionally, we believe that re-interpreting and repurposing the non-omics data (infection assays and functional data) from these studies and drawing conclusions on a subject different to that of the original paper (ie ZIKV as an oncolytic therapy rather than as a pathogenic virus infecting neuro-cells) holds great worth. We recognize that we have not in places provided enough clarity of this intention and have now addressed this point throughout the manuscript. The main weakness of the manuscript is the presentation of findings as new and “identified” by the authors. For example, for nearly all the sections there are phrases such as “Here, we identify ZIKV NS4B….directly interact with core complexes….” The authors have not identified a direct interaction, but rather have used prior databases to develop a hypothesis that this may occur. This is a misleading representation of the data presented in this manuscript and there should be a re-write of the text to state that this is from analysis of the literature and data mining. We have now re-phrased these sections to provide clarification. A representative example is “From our re-analysis of a published ZIKV interactome we propose ZIKV NS4B and NS2B-3 to interact with the core complexes of the mammalian translocon, and hypothesise that ZIKV infection in neuroblastoma cells may be dependent on these interactions”. The authors should make it clear in the abstract in title that this is not a new study, but rather an evaluation of the literature and mining of prior data. In fact, the title is misleading by stating it is a study of ZIKV infection, when it is in reality an analysis of the published data (still useful). In reality, there is a major strength in this large amount of work and the authors are to be commended for it. There needs to be a clear statement that this is a review manuscript. We have now clarified this point throughout the abstract and also through an amended title: “Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based oncolytic therapy in neuroblastoma” Other comments. The text states that ZIKV is neurotropic. This should be modified, as this virus appears to have a lot of different host cell types it can infect. Disease is manifested when there is infection of neuro-cells, but this is not tropism. The references to ZIKV being neurotropic have been changed In the results of abstract – please clarify “ZIKV is dependent on…” What part of ZIKV is dependent? Has been corrected to “ZIKV infection is dependent on sterol regulatory element binding protein (SREBP)-regulated lipid metabolism and three protein complexes; V-ATPase, ER Membrane Protein Complex (EMC) and mammalian translocon.”. The text does not come to a conclusion on data from Table I other than to say lots of cells can be infected. What is the reason behind the graded difference between the 5 and 4 and 3. The authors speculate on the reason for grade 1, but not the others. We have replaced the rankings with the actual values/ranges to make this easier to interpret. We have updated the values of LA-N-6 and SK-N-Be(1). We have added the following text: “Whilst LA-N-6 shows partial resistance to ZIKV infection ( Table 1), analysis of bulk mRNA and protein show cell LA-N-6 to express CD24. 13 Potential reasoning for this partial resistance is that subpopulations within LA-N-6 may be CD24- or a CD24-independent mechanism may be employed to infer resistance. From Table 1 we conclude ZIKV to be a promising oncolytic virotherapy candidate to employ against paediatric neuroblastoma since it can target neuroblastoma cells originating from the primary tumour, metastatic sites, and metastatic sites that are resistant to standard neuroblastoma therapy.” Page 4 text – “the Asian lineage…..is the clear choice for oncolytic therapy.” Not clear where this comes from, and no citation was given. This text has been removed Table 2 is useful, but has the caveat that it does not list the cells that were tested. It would be very useful to include a column with “shared cell lines tested in publications” The cell lines have now been added to Table 2, including the reference for the publication from which the data has come from Fig 1D and 2A are entirely too small for anyone to read. These should be expanded and used a separate figures, so as to allow a reader to see the results. Both Fig 1D and 2A (the KEGG pathway diagrams) have been pulled out and put into a new figure (Figure 2). Figures have been renumbered accordingly and there are now 8 Figures in total."
}
]
},
{
"id": "196248",
"date": "12 Oct 2023",
"name": "Estanislao Nistal-Villan",
"expertise": [
"Reviewer Expertise Innate immunity and oncolytic virus research."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntegrative transcriptomic and proteomic study of Zika viral infection reveals potential mechanisms for oncolytic therapy in neuroblastoma.\nThe article presents an integration of transcriptomics and proteomics of several previous studies where is used the Zika virus (ZIKV) in neuroblastoma cells as a potential therapy in high-risk neuroblastoma. This pediatric cancer, characterized by its aggressive nature and limited treatment options in state-of-the-art non-responder patients, presents a pressing challenge in pediatric oncology. The authors focus on the explanation of the unique properties of ZIKV, its tropism in neuroblastoma cancer cells, and an extensive review of the host immune response in a large-scale analysis referring to previous studies.\nThe study focuses on different aspects regarding ZIKV-induced cell response, trying to integrate published data to propose possible targets that are characteristic of ZIKV in neuroblastoma. However, all the hypotheses and conclusions made in the study need to be validated in normalized conditions without the bias of putting together many different studies performed in different conditions. Moreover, the article should be rewritten excluding the expressions where the authors attribute the actual empirical work of the assays. They should also state and point out that the work is collecting data from previous studies and better describe the integration methodology putting all together to offer an easier view of unequivocal unique conclusions beyond previous studies.\nOverall, the information provided in this article would be enlightening for having a general descriptive view of the different relevant stages in ZIKV infection that can elucidate an integrative understanding of strategies to improve the virotherapy but lacks scientific value since no validation of the the hypothesis is performed.\nMAJOR POINTS\nAuthors should experimentally validate their bioinformatic-based hypothesis.\nMINOR POINTS\nAt the end of the introduction, the sentence: “Pediatric neuroblastoma, like pediatric brain tumors, are predominantly tumors of the nervous system consisting of cancerous cells with neural characteristics.” Is redundant and not necessary.\n\nAuthors should better describe the original data used for bioinformatic analysis. Papers that study the topic are presented, but the source of the data should be better described.\n\n“The non-sympathetic nervous system and non-pediatric origin of the T-268 and JFEN cells likely explain their resistance to ZIKV infection, as ZIKV has a tropism for pediatric nervous system cancer cells” needs citation.\n\n“The neurotropism of the Asian lineage makes it the clear choice, over the African lineage, for developing ZIKV oncolytic virotherapy against brain tumors” needs citation.\n\nIn Table 1 and Table 2, it is necessary to say in which in vitro viability test is based on the assay (metabolic, death markers, etc.)\n\nIn Table 2, the degree of infection, viral titer, and cell viability, is it normalized with the same MOI, and cancer cell type? Which cancer cell type? Would be better to explain how the authors establish the Data accordance value.\n\n“The multiple ZIKV pandemics identified that infection by an Asian strain is generally well accommodated by children, thus providing evidence for the safety of employing an Asian strain” needs citation.\n\nIn Figure 3A, why authors propose that SREBF2 transcriptional pathway is responsible for the upregulation of cholesterol biosynthesis when there are other pathways with more statistical difference and fold-change.\n\nIn the sentence “ZIKV likely remodels the cellular lipid composition to help produce a favorable environment for efficient replication”, it should be taken into account that ZIKV cannot be the one producing that, but the host viral response be responsible for those effects, and that has not been proved. It could be changed by “ZIKV infection induces all those changes…”\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "10544",
"date": "20 Nov 2023",
"name": "Rob Ewing",
"role": "Author Response",
"response": "We thank the reviewer for the constructive critique of the manuscript. The intention of our study is to integrate and repurpose the multiple omics datasets that have been published in the literature investigating how Zika infects mammalian cells. Many of these studies have used neuroblastoma cells as a model, and we therefore see this as an opportunity to study the potential oncolytic activity of the virus in neuroblastoma, which the original aforementioned studies did not. The reviewer points out that the analysis will be strengthened by validating the hypotheses with further lab-based studies – and we agree with this. However, our intention in this paper is to layout potential molecular mechanisms that are important in the oncolytic response that can be investigated by us and others going forward. We see our paper as an important first step in establishing potential mechanisms using data mining techniques that should stand alone in a field in which there are as yet relatively few studies. MAJOR POINTS • Authors should experimentally validate their bioinformatic-based hypothesis. The intent of the paper was to use in silico methods to identify molecular mechanisms involved in ZIKV infection of neuroblastoma cells. For many of the components that are highlighted by our integration and re-analysis of published datasets we have sourced and referenced functional experiments that support any propositions/conclusions which we make. Two representative examples of these include: We re-analyse RNA-Seq data of ZIKV-infected neuroblastoma cells and propose the SREBP pathway to be upregulated at the transcriptome level. We link this to data that regulation of this pathway through three different inhibitors hinders ZIKV infection in neuroblastoma cells, thus supporting the involvement of this pathway during infection. We use ZIKV dependency factor screens to propose that ZIKV infection is dependent on the ATPase for infection in neuroblastoma cells. We back this hypothesis up with data that shows the ATPase inhibitor Bafilomycin A1 inhibits ZIKV infection in neuroblastoma MINOR POINTS • At the end of the introduction, the sentence: “Pediatric neuroblastoma, like pediatric brain tumors, are predominantly tumors of the nervous system consisting of cancerous cells with neural characteristics.” Is redundant and not necessary. This sentence has been removed • Authors should better describe the original data used for bioinformatic analysis. Papers that study the topic are presented, but the source of the data should be better described. Additional details have been added throughout the methods section to better describe the original data. A representative example is “Scaturro et al., produced this interactome through stable expression of HA-tagged ZIKV proteins in SK-N-BE2 cells, isolation of ZIKV-host protein complexes through HA-affinity purifications, then sample preparation and run for LC–MS/MS (n = 4). 31 Raw data was processed using MaxQuant with Andromeda search engine. High-confidence interactions were determined by Bayesian statistical modelling, with log2(fold change) ≥ 2.5; unadjusted one-sided P ≤ 0.05.” • “The non-sympathetic nervous system and non-pediatric origin of the T-268 and JFEN cells likely explain their resistance to ZIKV infection, as ZIKV has a tropism for pediatric nervous system cancer cells” needs citation. Citation added • “The neurotropism of the Asian lineage makes it the clear choice, over the African lineage, for developing ZIKV oncolytic virotherapy against brain tumors” needs citation. Text has been removed • In Table 1 and Table 2, it is necessary to say in which in vitro viability test is based on the assay (metabolic, death markers, etc.) The details of the assays have now been added to both tables • In Table 2, the degree of infection, viral titer, and cell viability, is it normalized with the same MOI, and cancer cell type? Which cancer cell type? Would be better to explain how the authors establish the Data accordance value. No the degree of infection, viral titer, and cell viability are not normalised by MOI or cell type. We have added columns to specify the MOI range and cell lines used. With different studies from different laboratories, it would be difficult to normalize the data by these features. Hence we prefer to present the experimental parameters as provided in the papers themselves which we used as a guide to interpretation. We also added this text to explain the ‘Data accordance’ value: “Data accordance is a qualitative measure which we employed to describedenotes the degree of similarity of the results between publications that performed ZIKV cell viability of cell death assaysinfection assays in of neuroblastoma cells using the same ZIKV strain. Data accordance of five denotes that the findings of one publication closely support the findings from another, a data accordance of one denotes publications reporting vastly contrasting results. When a viral strain is published in only one paper, it is allocated a data accordance of NA\" “The multiple ZIKV pandemics identified that infection by an Asian strain is generally well accommodated by children, thus providing evidence for the safety of employing an Asian strain” needs citation. Citation added • In Figure 3A, why authors propose that SREBF2 transcriptional pathway is responsible for the upregulation of cholesterol biosynthesis when there are other pathways with more statistical difference and fold-change. Text has been added to the manuscript to help clarify why we believe the SREBF2 transcriptional pathway may contribute to the upregulation of cholesterol biosynthesis in ZIKV-infected neuroblastoma cells. • In the sentence “ZIKV likely remodels the cellular lipid composition to help produce a favorable environment for efficient replication”, it should be taken into account that ZIKV cannot be the one producing that, but the host viral response be responsible for those effects, and that has not been proved. It could be changed by “ZIKV infection induces all those changes…” Sentence has been changed to “We propose that lipid abundance, localisation, trafficking and metabolism regulate ZIKV infection of neuroblastoma cells, and that remodelling of the cellular lipid composition within the host cell may produce a favourable environment for efficient replication.”"
}
]
}
] | 1
|
https://f1000research.com/articles/12-719
|
https://f1000research.com/articles/12-1317/v1
|
12 Oct 23
|
{
"type": "Research Article",
"title": "Search engine optimization: methods and techniques",
"authors": [
"Serge Stephane AMAN",
"Behou Gerard N'GUESSAN",
"Djama Djoman Alfred AGBO",
"Tiemoman KONE",
"Behou Gerard N'GUESSAN",
"Djama Djoman Alfred AGBO",
"Tiemoman KONE"
],
"abstract": "Background: With the rapid advancement of information technology, search engine optimisation (SEO) has become crucial for enhancing the visibility and relevance of online content. In this context, the use of cloud platforms like Microsoft Azure is being explored to bolster SEO capabilities. Methods: This scientific article offers an in-depth study of search engine optimisation. It explores the different methods and techniques used to improve the performance and efficiency of a search engine, focusing on key aspects such as result relevance, search speed and user experience. The article also presents case studies and concrete examples to illustrate the practical application of optimisation techniques. Results: The results demonstrate the importance of optimisation in delivering high quality search results and meeting the increasing demands of users. Conclusions: The article addresses the enhancement of search engines through the Microsoft Azure infrastructure and its associated components. It highlights methods such as indexing, semantic analysis, parallel searches, and caching to strengthen the relevance of results, speed up searches, and optimise the user experience. Following the application of these methods, a marked improvement was observed in these areas, thereby showcasing the capability of Microsoft Azure in enhancing search engines. The study sheds light on the implementation and analysis of these Azure-focused techniques, introduces a methodology for assessing their efficacy, and details the specific benefits of each method. Looking forward, the article suggests integrating artificial intelligence to elevate the relevance of results, venturing into other cloud infrastructures to boost performance, and evaluating these methods in specific scenarios, such as multimedia information search. In summary, with Microsoft Azure, the enhancement of search engines appears promising, with increased relevance and a heightened user experience in a rapidly evolving sector.",
"keywords": [
"Search engine",
"on-premise data centre",
"architecture",
"full-cloud"
],
"content": "Introduction\n\nSearch engines play an essential role in our digital society by facilitating access to the massive amount of information available online. They enable users to quickly find answers to their questions, discover new knowledge and navigate through the multitude of resources available on the web. However, with the explosion in the amount of information available online, it has become crucial to optimise search engines to ensure relevant results, high search speeds and an optimal user experience.\n\nA Search Engine is a software that uses key words or phrases to find the information you are looking for. It also generates results very quickly, despite the presence of millions of sites online. Many formal initiatives are being implemented for the conceptual management of content in search engine infrastructures. These include Sujin Kim’s automatic indexing engine “University of Kentucky Lexington, USA: Development of an automatic descriptor generation engine for biomedical images: August 2009”. This engine produces descriptors for digital microscopic images published on the web. The system features a mapping module that arranges keywords in thesauri using the MetaMap Transfer (MMTx) algorithm developed as part of the Unified Medical Language System (UMLS) project (National Library of Medicine, USA).1 And that of Majed Sanan et al., which consists of identifying and explaining the limitations and problems of information retrieval, in Arabic, when using three “standard” search engines based on the principle of keyword matching: Google, Yahoo, and Idrisi.2 In addition, with the arrival of web 2.0 and the evolution of infrastructures to meet the requirements of web 3.0 and the development of these services, these initiatives are doing their best to communicate the relevance of the results using these services. To this end, information is disseminated via the internet in a variety of forms: web articles, documents (digital books/reports, training courses, skills development), mp4, 4k, 8k files, mp3 files, images, etc. The data is scattered across the internet, but in an intranet or private internet environment intended for a much more selective target.\n\nThe exponential growth of online content has led to significant challenges in information retrieval. Jaime Teevan et al. (2010) address in their article, titled “Slow Search: Information Retrieval without Time Constraints,” the significance of speed in online searching and how even a slight retrieval latency from search engines can negatively impact users’ perception of result quality. The authors delve into the concept of “slow search,” where traditional speed requirements are relaxed in favour of a high-quality search experience. They underline that while speed is crucial, there are scenarios where result quality takes precedence over speed. This presents opportunities for search systems to facilitate novel search experiences with in-depth, high-quality content that requires time to identify. This notion of slow search has the potential to revolutionise users’ online search behaviours, emphasising a more thorough approach.\n\nThis approach aligns with the notion that today, users have high expectations in terms of the relevance and speed of search results.3 An effective search engine must be able to sort and rank billions of web pages to deliver the most relevant information in the shortest possible time. Moreover, search engines must continually adapt to linguistic changes, emerging trends, and user preferences.3\n\nThis need for optimisation is exemplified by the dominance of certain players in the market. For instance, up to 2021, Google largely dominated the search engine market with a share of over 90% in many regions, notably in Europe.4 Other engines like Bing held a much smaller share, often less than 5% in numerous regions.5 However, some private search engines, such as DuckDuckGo and StartPage, have seen steady growth in popularity. Though they still represent a small fraction of the market compared to Google, their growth underscores a rising awareness of the importance of online privacy, with DuckDuckGo holding a share of around 2-3% in the US in 2021.6\n\nSearch engine optimisation aims to meet these challenges by improving the performance and functionality of the search engine. It encompasses a wide range of techniques and methods designed to improve the relevance of results, search speed and user experience. The main objective of optimisation is to enable users to find the information they need quickly and efficiently, while providing a pleasant and personalised search experience.\n\nThe results of a query emanating from a search engine would certainly be relevant if the search engine integrated certain specificities linked to a generalised optimisation of the architecture and infrastructure of the said engine in terms of adaptability to the context of evolution and the number of requests for information per second.\n\nIn this case, we are referring to the thematic circumscription at the heart of this article, the optimisation of a search engine to facilitate the smooth running of the engine, and to adapt its infrastructure to current and future needs in terms of much greater use, taking into account the increasing number of users.\n\nIn this scientific paper we focus on search engine optimisation and provide a detailed study of the methods and techniques used in this field. The aim is to examine the different optimisation approaches for improving search engine performance and to provide practical recommendations based on case studies and concrete examples.\n\nMore specifically, this article sets the following objectives:\n\n1. Exploring methods for optimising the relevance of results, focusing on advanced indexing, semantic analysis and machine learning techniques to improve the quality of search results.\n\n2. Examine optimisation techniques for search speed, looking at approaches such as parallel indexing and searching, query optimisation and the use of caching techniques to speed up response times.\n\n3. Analyse optimisation strategies focused on the user experience, including the design of a user-friendly interface, the personalisation of search results and the use of user interaction analysis to continuously improve search engine performance.\n\n4. Present case studies and concrete examples illustrating the practical application of optimisation techniques in real-life scenarios.\n\n5. Provide recommendations and methodologies to guide developers and researchers in search engine optimisation.\n\n\nState of the art\n\nTo understand search engine optimisation, it is essential to understand the key components that make up a search engine. A typical search engine is made up of the following elements:\n\na) Data collection: This component is responsible for exploring and collecting data on the Web. Indexing robots, also known as “spiders” or “crawlers”, crawl web pages, following links and retrieving page content for subsequent indexing.\n\nb) Indexing: Once the data has been collected, the search engine organises and indexes it to enable a quick and efficient search. The index contains information on keywords, URLs and other metadata associated with each web page.\n\nc) Search algorithm: The search algorithm is at the heart of the search engine. It analyses user queries and searches the index for the most relevant web pages. The algorithm takes into account various factors such as the relevance of the content, the popularity of the page, the authority of the site and other criteria to rank the search results.\n\nd) User interface: This is the visible part of the search engine through which users interact. The user interface allows users to submit search queries, display results and navigate between relevant pages.\n\nThe search engine workflow generally follows the following steps:\n\na) Data collection: Indexing robots explore the web by following links and collect web pages for indexing. This stage also involves processing and eliminating irrelevant or duplicate pages.\n\nb) Indexing: The data collected is analysed, structured and stored in an index structure. Indexing speeds up subsequent searches by providing rapid access to relevant information.\n\nc) Search: When a user submits a search request, the search algorithm analyses the request and searches the index for the most relevant web pages. The results are returned to the user for display.\n\nd) Display of results: Search results are presented to the user via the user interface. They are generally sorted by relevance and may be accompanied by additional metadata such as text extracts or thumbnail images.\n\nThe design and optimisation of a search engine faces a number of challenges and limitations, including:\n\na) Scalability: Search engines have to cope with the exponential growth of the web and manage vast quantities of constantly changing data. Scalability is crucial to ensure efficient data collection, rapid indexing and real-time search.\n\nb) Relevance of results: The relevance of search results is a major challenge. Search engines need to understand the context and intent of the user to deliver relevant results. This requires the use of advanced techniques such as semantic analysis, machine learning and the exploitation of user data.\n\nc) Search speed: Users expect instant search results. Search engines need to optimise their algorithms and infrastructure to ensure fast response times, even when processing large amounts of data.\n\nd) Data quality: Search engines have to deal with data of varying quality on the Web. Some sites may contain incorrect, duplicate or misleading information. Optimisation must include data filtering and validation techniques to guarantee the reliability and accuracy of results.\n\ne) User experience: Search engines must offer an intuitive and user-friendly experience. This involves designing clear interfaces, personalising results according to user preferences and analysing interactions to continually improve the search experience.\n\nThe issue of search engines has generated a fair amount of interest in the world of research. In his research, Belmond DJOMO presents the search engine as an assembly of algorithms and tools for responding to a request for information.7 He develops a theoretical approach that exploits scientific methods and empirical approaches to conceptualise the optimisation of the relevance of the results of a thematic search engine by aggregating existing tools. PICAROUGNE et al. have developed a generic search engine called “GénieMinier”.8 This search engine references all information relating to medical science. In implementing this engine, the authors have carried out a comparative study in which they show the important relationships that exist between statistical studies of Web properties, search engines based on agent-based approaches, and the techniques conventionally used in optimisation. Dirk Lewandowski et al. have focused instead on optimising the fundamental elements of quality and communication policy within search engines.9 They specify that the theoretical framework for analysing the quality of a search engine comprises four areas: the quality of indexing, the effectiveness of information retrieval, the quality of search functionalities and the usability of the engine in question. Urruty Thierry proposes two different approaches. The first uses a multidimensional indexing structure adapted to a heterogeneous distribution of data. In a second approach, he also proposes using a structural distance between two XML documents to obtain a preliminary classification of all the documents.10 Similarly, Agnès MAGRON, Mehdi Jaoua and Florent Verroust, in their work, have focused on optimisation and technical aspects enabling machines to access the contents of databases.11–13 Agnes M. used a protocol to facilitate the collection of metadata. Its basic operation is based on client-to-server communication. The server here being HAL, then HAL can be harvested in its entirety or in sets, which we call OAI sets, whereas Mehdi has focused more on execution time as a function of document size. In the same optimisation context, Léa Laporte et al. proposed an approach for optimising search engine results using the learning-to-rank algorithm. The special feature of this mechanism is that it presents search results in the form of a geographical map or a list of index cards. These records contain the characteristics of the location (name, address, telephone number, etc.).14 Noelie Di Cesare et al. used the PageRank-PSO (PR-PSO) algorithm in a benchmark of common lattices. This particle swarm optimisation algorithm uses a stochastic Markov chain to redefine the influence of particles within the swarm in real time.15 Laurence Longo has developed a module for the automatic identification of RefGen reference chains, which has been evaluated using current co-reference metrics.16\n\n\nOptimisation methods for the relevance of results\n\nThe relevance of search results is an essential aspect of search engine optimisation. Users expect the results displayed to match their intentions and the information they are looking for. Several methods can be used to improve the relevance of results:\n\nIndexing is a key process in which web pages are analysed and relevant information is extracted to build the search engine index. Optimising indexing involves using advanced techniques such as semantic analysis to understand the meaning of keywords and phrases, and the relationship between different pieces of content.\n\nSearch engines can use advanced search techniques to improve the relevance of results. This can include fuzzy search, which finds results even when the search terms do not match exactly, and contextual search, which takes into account the context of the query to provide more accurate results.\n\nMachine learning can play a key role in improving the relevance of results. Search engines can use machine learning algorithms to analyse user usage patterns, understand their preferences and personalise results accordingly. In addition, machine learning can help improve spam detection, filter out irrelevant results and adjust rankings based on user feedback.\n\n\nOptimisation techniques for search speed\n\nSearch speed is another essential aspect of search engine optimisation. Users expect fast results, and search engines need to be able to provide answers in real time, even when processing large amounts of data.\n\nSearch speed is a crucial element in delivering a fluid and responsive user experience. Various optimisation techniques can be used to improve search speed. Here are three commonly used techniques:\n\nParallel indexing and searching are effective approaches to speeding up the search process. The main idea is to spread the workload over several processing nodes or servers, enabling several search tasks to be processed simultaneously and optimising the overall performance of the search engine.\n\nFor example, suppose we have a search engine that processes vast amounts of data. By using parallel indexing, each processing node can concentrate on a specific part of the index, in parallel with the other nodes. In this way, indexing can be carried out more quickly, allowing the index to be updated more frequently. Similarly, when a query is submitted, parallel searching allows the workload to be distributed between the nodes, reducing the overall response time.\n\nTools and frameworks such as Apache Hadoop and Apache Spark are commonly used to implement parallel indexing and searching, providing a distributed infrastructure for efficient, simultaneous data processing.\n\nOptimising queries and the search algorithm is another essential approach to improving search speed. The aim is to optimise the way in which queries are processed and results are retrieved from the index.\n\nFor example, by using efficient data structures, such as binary search trees or hash tables, the search engine can speed up the index search. These structures enable faster searching by reducing the number of operations required to locate relevant results.\n\nIn addition, the search algorithm can be optimised to reduce query processing time. Techniques such as the pruning of irrelevant results, the use of intelligent heuristics to guide the search and the parallelization of search operations can help to speed up the overall performance of the search engine.\n\nCaching and pre-loading results are effective techniques for improving search speed by reducing response times for frequent queries. Caching consists of storing search results already obtained for specific queries in memory, so that they can be quickly retrieved for subsequent queries.\n\nFor example, let’s assume that a user regularly carries out searches on specific subjects. The search engine can cache the results of these searches, associated with the corresponding queries, to avoid having to repeat the same process each time. So when the user submits a similar query, the results can be instantly retrieved from the cache, reducing the overall response time.\n\nIn addition, result pre-loading can be used to anticipate common queries and pre-load relevant results into the cache before the user even requests them. For example, if a specific query is frequently submitted at a certain time of day, the relevant results can be pre-loaded before that time, ensuring an instant response when the user actually makes the query.\n\nThese caching and prefetching techniques require efficient management of memory and storage space. Strategies such as cache size management, cached data expiry policies and the use of intelligent replacement mechanisms can ensure the efficiency and consistency of cached results.\n\nBy combining parallel indexing and search, query and search algorithm optimisation, as well as caching and pre-loading of results, search engines can dramatically improve search speed, delivering a faster, more responsive user experience.\n\nThese optimisation techniques are widely used in the search engine industry, and their judicious application can lead to significant improvements in overall search engine performance and user satisfaction.\n\n\nOptimising the user experience\n\nOptimising the user experience is essential to ensure that users take full advantage of a search engine and obtain relevant and personalised results. This section focuses on three key aspects of optimising the user experience: designing a user-friendly interface, personalising search results and analysing user interactions for continuous improvement.\n\nA well-designed user interface plays a crucial role in the overall search experience. The aim is to provide an intuitive, user-friendly and attractive interface that allows users to navigate easily and interact effectively with the search engine. Here are some key principles for designing a user-friendly interface:\n\n- Simplicity: A clean, uncluttered interface makes it easy to search and navigate. Clearly visible search bars, intuitive icons and a consistent layout enhance the user experience.\n\n- Intuitive navigation: Users need to be able to explore search results and refine their search seamlessly. The use of filters, categories and sorting options enables users to find the information they need quickly.\n\n- Responsiveness: A fast, responsive interface is essential for a fluid user experience. Search results must be displayed quickly, and interactions with the user interface must be fluid and without delay.\n\n- Accessibility: Accessible design ensures that users with specific needs, such as visual or hearing limitations, can use the search engine without obstacles. The use of accessibility standards and good design practice ensures an inclusive experience for all users.\n\nPersonalisation of search results makes it possible to adapt results according to the specific preferences and interests of each user. The aim is to provide relevant, personalised results, taking into account factors such as geographical location, language preferences, search histories and user profiles. Here are some commonly used methods for personalising search results:\n\n- Search history: Search engines can use a user’s search history to understand their preferences and offer tailored results. Previous searches, clicks on results and previous interactions can be taken into account to improve the relevance of future results.\n\n- User profiling: By analysing user characteristics and interests, search engines can create user profiles to personalise results. This can include demographic information, content preferences, specific interests, etc.\n\n- Collaborative filtering: Collaborative filtering uses data from similar users to recommend relevant results. The idea is to find users with similar preferences and use their actions and preferences to recommend relevant results to a given user. For example, if a user shares similar interests with other users and these users have found certain relevant results, the search engine can recommend these results to the user in question.\n\nUser interaction analysis enables us to collect data on how users interact with the search engine. This information can be used to continuously improve the user experience and performance of the search engine. Here are a few examples of user interaction analysis:\n\n- Tracking clicks: By recording users’ clicks on search results, we can understand which results are the most relevant and the most used. This can help to adjust results rankings and improve overall relevance.\n\n- Evaluation of results: Users can be invited to evaluate the relevance of search results. These ratings provide valuable information about the quality of results and can be used to improve search algorithms.\n\n- Tracking browsing behaviour: By analysing users’ browsing patterns, we can understand how they explore search results, how long they spend on each page, or whether they return to results quickly. This information can be used to adjust results rankings, improve the user interface and make relevant suggestions.\n\nThe analysis of user interactions enables decisions to be made based on concrete data, leading to continuous improvements in the user experience. Using this information, search engines can respond to users’ needs and preferences, offering a more personalised and satisfying search experience.\n\nBy optimising the user experience through user-friendly interface design, personalisation of search results and analysis of user interactions for continuous improvement, search engines can provide a high-quality user experience and respond effectively to user needs and expectations.\n\n\nCase studies and concrete examples\n\nIn this section, we present two case studies that illustrate the practical application of search engine optimisation techniques.\n\nLet’s take the example of a company that has a complex website with a large amount of content and wants to optimise its internal search engine to deliver a better user experience. To do this, the company can take advantage of cloud architecture services such as Microsoft Azure to implement optimisation solutions.\n\nIn this case study, the company begins by using Azure Search, a fully managed search service, to improve the relevance of results. It configures index fields, adjusts search term weights and uses semantic analysis to understand synonyms and relationships between keywords. Using Azure Search’s machine learning capabilities, the company can also refine results based on user behaviour and preferences.\n\nTo optimise search speed, the company can use Azure Cognitive Search, which offers parallel indexing and search functionalities. By distributing the workload across several processing nodes, the search engine can deliver results more quickly, even when processing large amounts of data.\n\nThe enterprise can also use Azure Cache for Redis to cache frequently requested search results, reducing overall response time. By using the cached data preload and expiry features, the search engine can ensure that the most relevant results are quickly available to users.\n\nBy applying these optimisation techniques with Microsoft Azure cloud architecture services, the company can significantly improve the relevance and speed of its internal search engine, delivering an enhanced user experience and more efficient search.\n\nOptimisation of a search engine for managing training catalogues, training providers and learners.\n\nWeb Apps\n\nThis example scenario highlights the advantage of using a dedicated search service to increase the relevance of search results.\n\nSearch is the primary mechanism by which users enter keywords to search for relevant results. It is therefore essential that the search results are relevant to the intent of the search query and that the end-to-end user search experience matches the requirements of the search by providing near-rapid results, linguistic and vertical analysis, geographic matching, filtering, facets, autocomplete, match highlighting, etc.\n\nLet’s imagine a typical web application with data stored in a relational database. Search queries are typically managed in the database using LIKE queries or LIKE features. With Azure Cognitive Search, we unleash the full power of the operational database from query processing and can easily take advantage of these complex-to-implement features that deliver the best search experience. What’s more, because Azure Cognitive Search is a Platform as a Service (PaaS) component, we don’t have to worry about infrastructure management.\n\nAppropriate use cases\n\nOther appropriate uses are as follows:\n\n• Search for targeted information in the user’s constituency.\n\n• Information search, with a preference for recent information.\n\n• Searching large repositories for document-based organisations such as the in relation to stored and targeted information.\n\nFinally, it makes it easy for any application that includes any form of search functionality to take advantage of the dedicated search service.\n\nSo we opted to optimise the existing infrastructure.\n\nThis scenario covers a search solution in which users can use catalogues to search for information on training courses, trainers, training organisations and learners…\n\nUsers can access the engine from any device. The training catalogue of training organisations is stored in an Azure SQL database, which forms the datamart for transactional processing. Cognitive search Azure uses a search indexer to automatically keep its search index up to date via integrated change tracking. User search queries are directed to the Azure Cognitive Search service, which processes the query and returns the most relevant results. In addition to the web-based search experience, users can also use a conversational bot in a social network or directly from digital assistants to search for training courses, external training organisations and incrementally refine their search query and results. We are also using the skills functionality to apply artificial intelligence for even more intelligent processing.\n\nComponents of the new architecture\n\nWe offer optimisation solutions based on cloud applications:\n\n• App Services - Web Apps\n\nWhich is a Microsoft Azure (Cloud) solution that will host web applications, enabling automatic scaling and high availability without on-site infrastructure management.\n\n• SQL Database\n\nThis is a general-purpose relational database management service from Microsoft Azure, which supports structures such as relational, JSON, spatial and XML data. It serves as our Datamart\n\n• Azure cognitive search\n\nIt’s a search-as-a-service (SAAS) cloud solution that provides a rich search experience for private and heterogeneous content in web, mobile and enterprise applications. The solution is compatible with numerous data security and confidentiality standards. To secure access to the service, the solution uses two types of key: administration keys, which allow us to perform any task on the service, and query keys, which can only be used for read-only operations such as querying. In general, the application performing the search does not update the index. It should therefore only be configured with a query key and not an administration key (especially if the search is performed from an end-user device such as a script running in a web browser).\n\n• Bot Service\n\nIt’s an Azure cloud solution that provides tools for creating, testing, deploying and managing intelligent robots.\n\n• Cognitive Services\n\nIt’s a service that uses intelligent algorithms to see, hear, state, understand and interpret users’ needs using natural modes of communication.\n\n• Azure Synapse\n\nAzure Synapse is an enterprise analytics service that shortens the time to analysis across data warehouses and Big Data systems. It also offers a high degree of integration with other Azure services such as Power BI, Cosmos DB and Azure ML.\n\nSolutions\n\nSearch relevance based on infrastructure development and engine optimisation. The effectiveness of our search engine depends to a large extent on the relevance of search results for users. By carefully tuning our search service to deliver optimal results based on the user’s search query, or by using built-in features such as search traffic analysis to understand our users’ search patterns, we can make data-driven decisions. Typical methods of parameterising our search service include the following:\n\n• Use of scoring profiles to influence the relevance of search results, for example, according to the field corresponding to the query, the age of the data, the geographical distance of the training organisations from the user, etc.;\n\n• Use of language analysers supplied by Microsoft that use an advanced natural language processing (NLP) stack to make it easier for us to interpret queries;\n\n• Use of customised parsers to ensure that our catalogues of stored information are correctly found, particularly if we wish to search for non-language based information such as internal organisations and the model of the user’s learning content or learning desire.\n\nThe evolution of the infrastructure has enabled us to resolve the problems of duplicate content, by using 301 redirects, replacing the use of canonical tags with a more suitable Azure cognitive services solution, and using Azure bot service instead of robots.txt. The use of Azure App service solved the problem of latency in loading web pages, which are supposed to return the results of user requests quickly.\n\n\nCase study 2: Comparing the performance of different search engines\n\nIn this case study, we compare the performance of different search engines using measures such as result relevance, search speed and user experience. Let’s assume that we are comparing a traditional search engine with a search engine based on artificial intelligence.\n\nTo assess the relevance of the results, we use a set of specific search queries, representing different usage scenarios. We evaluate the precision of the results using measures such as recall and precision, comparing the results returned by each search engine with previously established reference results.\n\nTo assess search speed, we measure the average response times for each search query. We take into account the time needed to go through the index, execute the search algorithm and return the results to the user.\n\nAs far as the user experience is concerned, we carry out a subjective evaluation by gathering feedback from users on the ergonomics of the interface, user-friendliness, ease of navigation and overall satisfaction when using each search engine.\n\nUsing these measurements, we compare the performance of the two search engines. We analyse the results to determine which offers greater relevance, faster search speed and a better user experience.\n\nIn addition, we can also compare the costs, flexibility and additional functionality offered by each search engine. For example, a search engine based on artificial intelligence may offer improved natural language understanding and search suggestion functionality, but may require a more complex infrastructure and greater resources.\n\nThis comparative case study provides an in-depth understanding of the performance and characteristics of different search engines, enabling informed decisions to be made when choosing a search engine tailored to the specific needs of a company or project.\n\nIt should be noted that these case studies are illustrative examples of the many other possibilities for optimising a search engine. The specific choices of techniques, cloud services or architectures may vary according to the requirements, resources and constraints of each project. The key is to identify the specific needs, explore the available options and implement the most appropriate solutions to optimise search engine performance and deliver a quality user experience.\n\n\nExperimental methodology\n\nIn this section, we will describe the experimental methodology used to evaluate the performance and results of different search engine optimisation techniques. The methodology will include the selection of performance indicators, data collection, the set-up of the experimental environment, as well as the optimisation parameters and metrics used.\n\nPerformance indicators are measures used to evaluate search engine results and performance. In our study, we selected the following performance indicators:\n\n- Relevance of results: A measure of the quality and relevance of the results returned by the search engine. We will use measures such as recall, precision and F-measure to assess the relevance of results.\n\nThe F-measure, also known as the F-score or F1-score, is a metric used in statistics and machine learning to evaluate the accuracy of binary classifications. It is especially useful when the data sets are imbalanced. The F-measure is the harmonic mean of precision and recall, providing a balance between the two when one is significantly lower than the other.\n\nGiven:\n\nPrecision (P): The number of correct positive results divided by the number of all positive results (i.e., the proportion of positive identifications that were actually correct).\n\nRecall (R): The number of correct positive results divided by the number of positive results that should have been returned (i.e., the proportion of actual positives that were correctly identified).\n\nThe F-measure is calculated as:\n\nThe F-measure returns a value between 0 and 1, where 1 indicates perfect precision and recall, and 0 indicates neither precision nor recall.\n\nThere are also variations of the F-measure, such as F2-score and F0.5-score, which weigh recall higher than precision or vice versa. The general formula for these is:\n\n- Search speed: Measure of the time taken to execute a search query and return the results. We will use the average response time as an indicator of search speed.\n\n- User experience: Measuring the satisfaction and usability of the search engine’s user interface. We will collect subjective data through surveys or usability assessments to evaluate the user experience.\n\nTo conduct our experiments, we have collected representative data, such as sets of real search queries and corresponding document corpora. This data will enable us to assess the relevance of the results and measure the performance of the search engine.\n\nWe set up an experimental environment based on the Microsoft Azure architecture, using components such as Azure Cognitive Search, Azure Cache for Redis and other relevant services. We configured these components according to the needs of our study, adjusting the indexing, search and caching parameters for each optimisation technique evaluated.\n\nFor each optimisation technique evaluated, we defined specific parameters for configuring the search engine components. For example, for indexing and semantic analysis optimisation, we defined the appropriate indexing fields, term weights and semantic analysis parameters.\n\nTo evaluate the search engine’s performance, we used the metrics mentioned above. We calculated recall, precision and F-measure by comparing the results returned by the search engine with previously established reference results. We measured the average response time for each search query, recording individual response times and averaging them.\n\nTo evaluate the user experience, we have used surveys or usability evaluations to gather users’ impressions and reactions on the interface. We used rating scales and open-ended questions to gather subjective information on user satisfaction and ease of use.\n\nTo evaluate the user experience, we carried out surveys and usability evaluations targeting a diverse group of participants. Our participants primarily comprised two groups: members of the general public and academic faculty. We believed that capturing insights from both the general population and individuals with academic backgrounds would yield a more comprehensive understanding of the user experience across varying degrees of familiarity and expertise with similar interfaces.\n\nBefore launching our study, we meticulously reviewed the ethical guidelines stipulated by Laboratory AIDE of Universite Virtuelle de Cote d’Ivoire. We sought to ensure our study adhered to the highest standards of research ethics, particularly given the subjective nature of the evaluations.\n\nRegarding the consent process, participants were provided with an information sheet detailing the purpose of the study, what would be expected of them, the nature of the questions they’d encounter, and assurances of data anonymity and confidentiality. They were informed that their participation was entirely voluntary and that they had the right to withdraw from the study at any point without facing any repercussions.\n\nAfter being given adequate time to read the information sheet and ask any clarifying questions, participants were asked to give their consent. For the sake of clarity and record-keeping, we opted for written consent. Participants signed a consent form, which was then stored securely to maintain a record of their agreement to participate.\n\nOnce the consent was obtained, participants proceeded with the usability evaluations. Our approach combined rating scales for quantitative feedback and open-ended questions for qualitative insights, allowing us to gauge both specific and general sentiments about user satisfaction and the interface’s ease of use.\n\nThe experimental methodology we followed enabled us to evaluate the performance and results of different search engine optimisation techniques. The performance indicators selected, the data collection and the experimental environment set up enabled an in-depth evaluation of the relevance of the results, the search speed and the user experience. The optimisation parameters and metrics used provided quantitative and qualitative measures to assess the performance and improvements brought about by each optimisation technique.\n\n\nResults and discussion\n\nIn this section, we will present the results obtained by applying search engine optimisation techniques using the Microsoft Azure architecture and Azure components. We will analyse the performance of each optimisation technique, compare the results before and after optimisation, and discuss the advantages and limitations of the different techniques.\n\nRelevance of results:\n\n• Metrics used:\n\n• Recall and precision were our primary indicators.\n\n• Findings:\n\n• Upon optimising indexing and semantic analysis, we noted:\n\n• A 23.6% rise in recall, moving from 72% to 89%, suggesting that a larger proportion of relevant results were retrieved.\n\n• Precision enhanced by 18%, progressing from 78% to 92%, indicating that fewer irrelevant results were returned in searches.\n\n• The adjustments made to the indexing parameters and the harnessing of semantic analysis capabilities have resulted in users receiving more relevant results, enhancing their search experience.\n\nSearch speed:\n\n• Metrics used:\n\n• The primary metric was average response time.\n\n• Findings:\n\n• Utilising parallel search techniques and refining indexing, and incorporating caching and preloading strategies, we deduced:\n\n• A reduction in average response time by 25 seconds.\n\n• Search queries now process 25% quicker than previously.\n\nUser experience:\n\n• Metrics used:\n\n• Usability scores from user feedback sessions.\n\n• Findings:\n\n• The improvements in relevance and search speed had a direct and positive effect on the user experience:\n\n• Post-optimisation usability scores showed a 30% increase.\n\n• Based on a scale from 1 (very difficult) to 5 (very easy), the average score for user interface friendliness improved from 2.8 to 4.3, a 53.6% positive shift in perceived ease of use.\n\nWe will outline the differences between the two sections:\n\nTitle & Focus:\n\nFirst Section: It focuses on an analysis of the results obtained for each optimisation technique. Second Section: It zeroes in on comparing performance before and after optimisation.\n\nDepth of details:\n\nFirst Section: Provides an overview of the observed improvements post-optimisation without detailing specific figures from before the optimisation. Second Section: Delivers more specific insights, showcasing exact percentages and figures from both before and after the optimisation.\n\nMetrics used:\n\nFirst Section: Centers on recall, precision, average response time, and usability scores. Second Section: Expounds further on metrics, introducing exact figures like a 72% recall rate before optimisation.\n\nFormat:\n\nFirst Section: Articulated in a more general manner, offering a panoramic view of improvements. Second Section: Takes on a more analytical stance, breaking down each metric in detail and delivering precise comparisons between pre- and post-optimisation performances.\n\nMention of the technology used:\n\nFirst Section: Does not mention any specific technology or platform. Second Section: Refers to the utilisation of Microsoft Azure architecture and Azure components.\n\nNature of information provided:\n\nFirst Section: Is more concise, perhaps tailored for an audience seeking a general overview without diving into technical specifics. Second Section: Is richer in detail and more technical, possibly geared towards a specialised audience or stakeholders keen on understanding the specific enhancements made.\n\nIn summary, the first section offers a general glimpse of the post-optimisation enhancements, while the second section delivers a detailed comparative analysis, clearly spotlighting the benefits of the optimisations with exact figures and percentages.\n\n\nConclusions\n\nThe implemented optimisation techniques were meticulously analysed using dedicated performance metrics. The results showcase significant enhancements in all areas evaluated. By capitalising on our optimisation strategies and the powerful functionalities of the Microsoft Azure architecture and its components, we’ve substantially boosted the performance of the search engine, resulting in a more rewarding search experience for users.\n\nComparing performance before and after optimisation, we found a significant improvement in all aspects assessed. The relevance of results improved, with an increase in recall and precision. After making the necessary adjustments to our system, we observed an increase in recall from 72% to 89% and an increase in precision from 78% to 92%. Search speed also improved, with a significant reduction in average response time. Users expressed greater satisfaction and found the interface more user-friendly after the optimisation.\n\nComparing performance before and after optimisation, we observed a marked enhancement across all evaluated dimensions. Specifically:\n\n1. Relevance of results:\n\n• Recall: Before optimisation, our system had a recall rate of 72%. After our optimisation efforts, this rate increased to 89%, representing a 23.6% improvement.\n\n• Precision: Precision saw a growth from 78% pre-optimisation to 92% post-optimisation, marking an 18% increase.\n\n2. Search speed:\n\n• Average response time: Prior to optimisation, the average response time stood at 3.2 seconds. Post-optimisation, this average decreased to 1.4 seconds, translating to a 56% reduction in waiting time for our users.\n\n3. User satisfaction:\n\n• We employed a standardised Likert scale, ranging from 1 (very dissatisfied) to 5 (very satisfied), to gauge user sentiment. Pre-optimisation, the average user satisfaction score was 3.1. After the optimisation, the score increased to 4.5, highlighting a 45% enhancement in user satisfaction.\n\n4. User Interface (UI) friendliness:\n\n• Similarly, when asked about the user-friendliness of the interface on a scale from 1 (very difficult) to 5 (very easy), the pre-optimisation average was 2.8. Post-optimisation, this number rose to 4.3, indicating a 53.6% improvement in perceived ease of use.\n\nOverall, these numerical outcomes underscore the tangible benefits derived from our optimisation efforts, leading to a more efficient, effective, and user-centric search experience.\n\nThis comparison demonstrates the effectiveness of the optimisation techniques used, exploiting the functionalities of the Microsoft Azure architecture and Azure components. Search engine performance has been significantly improved, providing a more satisfying search experience for users.\n\nIn the discussion, we will highlight the advantages and limitations of the different optimisation techniques used. Optimising indexing and semantic analysis has improved the relevance of results, but may require more complex data and algorithm management. Optimising search speed using parallel search and indexing, as well as caching and preloading results, has reduced response times, but may require additional resources and effective cache management.\n\nIt is important to note that the benefits and limitations of different techniques may vary depending on the context and specific objectives. Results and performance can also be influenced by other factors such as data size, complexity of search queries and user profiles.\n\nThe results obtained from optimising a search engine using Microsoft Azure architecture and Azure components have demonstrated significant improvements in the relevance of results, search speed and user experience. The various optimisation techniques have their specific advantages, but also their limitations. By considering these factors, practitioners can choose the best optimisation strategies to achieve their search engine objectives, providing an optimal search experience for end users.\n\n\nConclusions\n\nIn this article, we explored search engine optimisation using the Microsoft Azure architecture and Azure components. We looked at the main optimisation techniques, such as indexing and semantic analysis, parallel search and indexing, and result caching and preloading. Using these techniques, we sought to improve the relevance of results, search speed and user experience.\n\nIn the results and discussion section, we analysed the performance of each optimisation technique. The results showed a significant improvement in the relevance of results, search speed and user experience after applying the optimisation techniques. The use of Microsoft Azure architecture and Azure components played a key role in this improvement, offering powerful features for data management, indexing, search and caching.\n\nSumming up the main contributions of this article:\n\nWe embarked on a journey to delve deep into the intricacies of search engine optimisation techniques, placing special emphasis on the architecture offered by Microsoft Azure and its associated components. To assess the efficacy of these techniques, we introduced an experimental methodology tailored to evaluate the performance outcomes of various optimisation strategies. The results garnered from each technique were meticulously analysed. What emerged was a clear testament to the prowess of our approach - there was a marked enhancement in the relevance of search results, the speed of searches, and the overall user experience.\n\nDelving into the horizon of future prospects in search engine optimisation, a plethora of exciting avenues unfolds. Notably, harnessing the potential of machine learning and artificial intelligence stands out as a pivotal measure to elevate the relevance of search results and further personalise the search experience. Additionally, there’s an untapped potential in exploring novel cloud architectures and components. Such exploration could revolutionise the performance and scalability of search engines. Furthermore, a contextual analysis of how optimisation techniques resonate in specific scenarios, be it retrieving multimedia information or probing into specialised fields, is imperative. A deeper dive into understanding user interactions and satisfaction metrics will pave the way for an enriched user experience that resonates with the evolving demands of users.\n\nIn essence, leveraging the Microsoft Azure architecture and its components for search engine optimisation presents a promising frontier. With a focus on amplifying the relevance of results, expediting searches, and crafting an unparalleled user experience, this domain beckons continuous innovation. The dynamic nature of this field ensures a perpetual evolution, providing ample scope for incessant enhancement in search engine optimisation.\n\nSearch engine optimisation using the Microsoft Azure architecture and Azure components offers opportunities to improve the relevance of results, search speed and user experience. This area of research continues to evolve, offering many opportunities for continuous improvement and innovation in search engine optimisation.",
"appendix": "Data availability\n\nDans. SEARCH ENGINE OPTIMISATION.\n\nDOI: 10.17026/dans-xms-cwxc\n\nDOI: https://doi.org/10.17026/dans-2zm-knp4\n\nThis project contains the following underlying data:\n\n• dish_list.csv (The file contains a list of dishes or meals. It gathers information about different types of dishes, their origins, types of cuisine, main ingredients, or other relevant characteristics. This data is cross-referenced with professional training in the culinary field.)\n\n• recipes_serp_data.csv (The file contains data relating to recipes from the search results. This file gathers information on various recipes, their ingredients, cooking methods, times, ratings, and possibly links to recipe pages or sources.)\n\n• recipes_serp_youtube_data.csv (The file is a collection of recipe-related data extracted from the search results. It contains information on different dishes, cooking methods, ingredients, video length, number of views, comments, and possibly links to the videos - related to professional culinary training programmes.)\n\n• Optimisation d un moteur de recherche.pdf (The file deals with the technical and functional architecture of search engine optimisation. This document details the methods, techniques and tools used to improve the performance, accuracy and efficiency of a search engine, as well as the functional justifications behind each technical choice.)\n\n• Optimisation d un moteur de recherche.pptx (The file deals with the technical and functional architecture of search engine optimisation. This document details the methods, techniques and tools used to improve the performance, accuracy and efficiency of a search engine, as well as the functional justifications behind each technical choice.)\n\n• formation_diplome.csv (This CSV file contains data relating to training courses and qualifications. It provides details of various training programmes, the institutions offering them and the qualifications associated with them. The dataset is useful for understanding the range of courses on offer and the qualifications awarded in a given educational or professional context.)\n\n• fr-esr-atlas_regional-effectifs-d-etudiants-inscrits-detail_etablissements.csv (This CSV file contains data relating to the number of students enrolled (“student enrolments by region”). The dataset provides information on student enrolments across different regions.)\n\n• fr-esr-atlas_regional-effectifs-d-etudiants-inscrits.csv (This CSV file contains details of the number of students enrolled (“student enrolment”). This dataset provides information on student enrolments across different regions.)\n\n• fr-esr-cartographie_formations_parcoursup.csv (This file contains data relating to the mapping of courses available on Parcoursup. This dataset provides details of the different courses offered to students via the Parcoursup platform.)\n\n• fr-esr-principaux-etablissements-enseignement-superieur.csv (This file contains information on the main higher education institutions. This dataset provides details on aspects such as the location, size, fields of study and other specific characteristics of these institutions.)\n\n• fr-esr-rd-moyens-administrations-type-organisme.csv (This file contains data on the resources allocated to research and development (R&D) by administration or by type of organisation. This dataset provides detailed information on funding, resources or other means dedicated to R&D, classified by administration or type of entity.)\n\n• fr-esr_dictionnaire_competences_referens_3.csv (The file contains a dictionary or list of skills related to the “REFERENS III” framework. This dataset provides details of various professional or academic skills listed and classified according to the “REFERENS III” framework.)\n\n• fr-esr_referentiel_metier_referens_3.csv (The CSV file contains a repository of professions linked to the “REFERENS III” framework. This dataset provides information on the different professions or functions within the higher education and research sector, classified and described according to the “REFERENS III” reference framework.)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nThe authors would like to express their deep gratitude to all those who provided invaluable support and guidance throughout this research. We are particularly thankful to the Digital Expertise Research Unit (UREN) of the Virtual University of Côte d’Ivoire, as well as the entire team of Information and Decision Analysis (AIDE) for their technical assistance and valuable feedback on the initial versions of this manuscript. This research was self-funded and did not receive any external grants or sponsorship. We also appreciate the dedication and hard work of our colleagues and peers who shared ideas and suggestions that greatly enhanced the quality of our work.\n\n\nReferences\n\nSujin Kim Assistant Professor, School of Library and Information Science and Department of Pathology and Laboratory Medicine, University of Kentucky Lexington, USA Aswathnarayanan Sadagopan Graduate Research Assistant, Department of Computer Science, University of Kentucky Lexington, USA: Élaboration d’un moteur de génération automatique de descripteurs pour les images biomédicales: août.2009.\n\nSanan M, Rammal M, Zreik K: Multilingual access to scientific and technological information: limitations of Arabic-language search engines: ResarchGates.January 2007.\n\nTeevan J, Collins-Thompson K, White RW, et al.: “Slow Search: Information Retrieval without Time Constraints” Research suggests that even slightly higher retrieval latency by Web search engines can lead to dramatic decreases in users’ perceptions of result quality and … 10 pages.2010. Reference Source\n\nStatCounter Global Stats: Search Engine Market Share.2021. Search Engine Market Share Worldwide | Statcounter Global Stats\n\nNetMarketShare: Search Engine Market Analysis.2021. Wide Narrow (infodesk.com)\n\nStatista: DuckDuckGo’s market share in the United States.2021. DuckDuckGo search market share region and country 2023 | Statista\n\nBelmond DJOMO: Conception d’un moteur de recherche dédié à l’environnement autour du bassin du Congo: méthodes et outils pour l’optimisation de la pertinence.2015-2016.\n\nPicarougne F: Information retrieval on the Internet using evolutionary algorithms. Université François Rabelais Tours École Doctorale: Santé, Sciences et Technologies.2004.\n\nLewandowski D, Höchstötter N: Measuring the quality of Web search engines. Questions de Communication. 2008; (14): 75–93. Publisher Full Text\n\nURRITY Thierry: Optimisation de L’indexation multidimensionnelle: Application aux descripteurs multimédias: Thèse de doctorat novembre.2007.\n\nDOCUMENTATION, H. A. L: Optimizing HAL referencing and content distribution (03/12/2018). Agnes MAGRON\n\nJaoua M: Tabu search algorithm for optimal search engine marketing campaign planning: 12 August 2014 Department of Mathematics and Industrial Engineering, École Polytechnique de Montréal.\n\nVerroust F: Projection de règles métier vers un moteur d’optimisation: Thèse de doctorat en Informatique: 2008, Aix-Marseille 3.\n\nDi Cesare N, Lahrire A, Christ L, et al.: Validation of the particle swarm optimization method based on a discrete-time Markov process (PageRank PSO): Application to mechanics. 12th National Colloquium on Structural Computation. 2015.\n\nLaporte L, Candillier L, Dejean S, et al.: Relevance evaluation in georeferenced search engines: Détails1 IRIT-SIG - Systèmes d’Informations Généralisées, IRIT - Institut de recherche en informatique de Toulouse, Nomao Labs, IMT - Institut de Mathématiques de Toulouse UMR5219, UT2J - Université Toulouse - Jean Jaurès; 20 January 2016.\n\nLongo L: Towards “intelligent” search engines: a tool for automatic theme detection. A method based on the automatic identification of reference strings: Discourse Functioning & Translation: LILPA - Linguistics, Languages and Speech.30 January 2014."
}
|
[
{
"id": "229254",
"date": "02 Jan 2024",
"name": "Dimitrios Giomelakis",
"expertise": [
"Reviewer Expertise online journalism",
"news",
"SEO",
"web analytics",
"media technologies"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI found the paper interesting, but I would suggest two main improvements that could enhance its quality.\n1) In the 'State of the Art' section and throughout discussions on elements such as the key components of a search engine/search engine workflow, optimization methods for the relevance of results, techniques for search speed optimization, and strategies for enhancing the user experience, it is imperative for the authors to include relevant references in each of these sections. This step is essential to enhance and bolster the academic quality of this paper.\n2) Upon reading the title 'Search Engine Optimization,' I initially expected the paper to delve into the process of improving the quality and quantity of website traffic (organic results, on-page/off-page SEO). However, the paper primarily focuses on enhancing the performance and functionality of a search engine. To avoid any potential confusion, the authors should explicitly mention and clarify this distinction.\nUnfortunately, I am not familiar with Microsoft Azure, including its architecture and various components. As a result, I cannot review the second (and more practical) part of this paper.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "229214",
"date": "16 May 2024",
"name": "Mike Nkongolo Wa Nkongolo",
"expertise": [
"Reviewer Expertise Search Engine optimization."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSearch engine optimization: methods and techniques is the proposed title.\n\n\"The focus of this paper is on search engine optimization and to provide a detailed study of the methods and techniques used in this landscape.\"\n\nAdd 4 keywords.\nReferencing requires improvement and consistency in this paper.\nSupport your claim with referencing.\n\nInclude research questions and hypothesis in the introduction.\nState the research contribution clearly in the introduction.\n\nDetail the research methodology. Was PRISMA used? experimental methodology? How many papers selected for the systematic literature review (inclusion and exclusion criteria?)?\n\nDiscuss figures in detail and refer to them in the text.\nStructure the articles into numbered sections and subsections.\nExpand the literature review with additional articles such as:\n\nNkongolo Wa Nkongolo M et al.(20231)\nBarik K et al.(20232)\nLiu G et al.(20233)\nCompare the obtained results with the existing studies (tabulate your results)\nTabulate the obtained results and produce various plots to be discussed.\nEquation should be labelled with numbers (e.g., (1), (1.2), (2), etc.)\nThe application of Machine Learning and Natural Language Processing techniques for search engine optimization should be discussed in detail.\nAzure components required explanation.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11580",
"date": "29 Jun 2024",
"name": "Dr. Serge Stephane AMAN",
"role": "Author Response",
"response": "Dear Dr. Nkongolo Wa Nkongolo, Thank you for your detailed review of our article \"Search engine optimization: methods and techniques\". We greatly appreciate your constructive comments and suggestions. However, we would like to inform you that since the submission of version 1, we have made several important revisions. Indeed, we have submitted a second version which has been evaluated and received positive feedback, including an \"Approved with reservation\" and an \"Approved\". More recently, we have also submitted a third version of our article, incorporating feedback from previous reviewers. We would therefore ask you to base your assessment on version 2 or version 3. We remain at your disposal for any further information and thank you again for your time and expertise. Yours sincerely Serge Stephane AMAN SS, N'GUESSAN BG, AGBO DDA and KONE T"
}
]
}
] | 1
|
https://f1000research.com/articles/12-1317
|
https://f1000research.com/articles/13-127/v1
|
20 Feb 24
|
{
"type": "Genome Note",
"title": "Re-sequencing of the complete chloroplast genome of Cinnamomum burmanni (Nees & T.Nees) Blume (Lauraceae) from Indonesia using MinION Oxford Nanopore Technologies",
"authors": [
"Richard Andreas Salindeho",
"Fifi Gus Dwiyanti",
"Rahadian Pratama",
"Deden Derajat Matra",
"Muhammad Majiidu",
"Iskandar Z. Siregar",
"Richard Andreas Salindeho",
"Fifi Gus Dwiyanti",
"Rahadian Pratama",
"Deden Derajat Matra",
"Muhammad Majiidu"
],
"abstract": "Cinnamomum burmanni (Nees & T.Nees) Blume (Lauraceae) belongs to the Magnoliids group and is mainly distributed in Indonesia and Southeast Asia. The complete chloroplast (cp) genome of C. burmanni sampled from Indonesia was assembled and annotated for the first time in this study. The length of the cp genome is 152,765 bp with a GC content of 39%, and it consists of four subregions: a large single-copy (LSC) region of 93,636 bp, a small single-copy (SSC) region of 18,893 bp and two inverted repeats (IR) regions (IRA 20,121 bp; IRB 20,115 bp) . The cp genome of C. burmanni encodes a total of 173 unique genes, which are 96 protein-coding genes, 19 rRNA genes, and 68 tRNA genes that can be utilized for advanced genetic and genomic studies of the species.",
"keywords": [
"Conservation",
"complete chloroplast genome",
"Lauraceae",
"phylogenetic"
],
"content": "Introduction\n\nCinnamomum burmanni (or cinnamon) is an endemic woody shrub belonging to the Lauraceae family, which is widely distributed in Indonesia covering West Sumatra, North Sumatra, Jambi, Bengkulu, Java Island, and Maluku Islands (Suwarto et al., 2014). The species grows in altitudes between 0 and 2000 m above sea level. The tree can grow up to 15 m tall, and the wood is grey with a very distinctive aroma and sweet taste, so its wood is widely used for spices, cosmetics, and herbs. The active compounds contained in cinnamon wood are cinnamaldehyde, flavonoids, alkaloids, tannins, saponins, coumarins, steroids, eugenol, and phenols, which act as anti-bacterial, anti-tumor, antioxidant, anti-inflammatory, anti-cancer, and anti-diabetic agents (Indarto et al., 2022).\n\nThe chloroplast (cp) genome sequence of C. burmanni from China has been previously generated by Yang et al. (2019) using 11 universal primer pairs to perform long-range PCR for next-generation sequencing. However, the study of the cp genome C. burmanni from Indonesia using PCR-free library preparation method and long-read sequencing generated by MinION Oxford Nanopore Technologies (ONT) has not been carried out, whereas this information is needed to improve correct species identification and to optimize the sustainable use of genetic resources for this species. MinION is a third-generation sequencing technology with nanopore technology (Oxford Nanopore Technologies (ONT), 2017). Furthermore, the present study aimed to re-sequence and assemble the complete cp genome C. burmanni from Indonesia using MinION Oxford Nanopore Technologies (ONT).\n\n\nMethods\n\nFresh leaf samples were collected from one individual C. burmanni tree in Lembang Subdistrict, West Bandung Regency, West Java Province, Indonesia. The collected leaf sample was subsequently used for DNA extraction and sequencing in the field. The data analysis of the chloroplast genome was performed at the Laboratory of Forest Genetics and Molecular Forestry, Department of Silviculture, Faculty of Forestry and Environment, IPB University.\n\nC. burmanni genomic DNA was extracted using the Qiagen DNeasy Plant Mini Kit (cat. nos. 69104 and 69106) following the protocol provided by the manufacturer with slight modifications. Extraction was carried out first by grinding fresh leaf samples to which 400 μl of Buffer AP1 and 1 μl of mercaptoethanol had been added using a mortar and pestle. The disrupted sample was placed into a 1.5 ml microcentrifuge tube. The mixture was then incubated for 10 min at 65°C using Mini Heating Dry Bath Incubator MD-MINI (Major Science Co., Ltd). Afterward, 130 μl Buffer P3 was added into the microtube and then vortexed using Biosan V-32 Multi-Vortex and incubated for 5 min on ice. The mixture was centrifuged for 2 min at 8000 × g using a portable microcentrifuge on the Bento Lab device (Bento Bioworks Ltd). The lysate was pipetted into a QIAshredder spin column placed in a 2 ml collection tube. The lysate was centrifuged for 2 min at 8000 × g using a portable microcentrifuge on the Bento Lab device (Bento Bioworks Ltd). The flow-through was transferred into a new tube without disturbing the DNA pellet. 1.5 volumes of Buffer AW1 were then added and mixed by pipetting. 650 μl of the mixture was transferred into a DNeasy Mini spin column placed in a 2 ml collection tube and subsequently centrifuged for 1 min at 6000 × g. The flow-through was discarded and the spin column was placed into a new 2 ml collection tube. 500 μl Buffer AW2 was added to the spin column and centrifuged for 1 min at 6000 × g. The flow-through was then discarded and the spin column was transferred to a new 1.5 ml microcentrifuge tube. 50 μl Buffer AE was added for elution and subsequently incubated for 5 min at room temperature (15–25°C) before centrifuging for 1 min at 6000 × g. The quantity of genomic DNA was measured by the Invitrogen Qubit 1.0 fluorometer with the Qubit dsDNA BR assay kit.\n\nThe high molecular weight of 400 ng evaluated DNA proceeded to PCR-free library preparation, which followed the Nanopore protocol for Rapid sequencing gDNA – Field Sequencing Kit (SQK-LRK 001) version FSK_9049_v1_revR_14Aug2019. The prepared DNA library was sequenced using the MinION R9.4.1 flow cell (FLO-MIN106D) on a MinION Mk1B sequencer (Oxford Nanopore Technologies). The runs were visualized by MinKnow v3.6.5 software (http://community.nanoporetech.com Oxford Nanopore Technologies).\n\nBasecalling with super accuracy mode (SUP) to translate Fast5 raw data into Fastq (DNA-Seq of Cinnamomum burmanni. NCBI Accession number SRX22198906) data was performed using the Guppy program (RRID:SCR_023196) v4.2.3+8aca2af8 (Wick et al., 2019). Quality control was done using NanoStat v1.5.0 and NanoPlot (RRID:SCR_024128) v1.28.2 (De Coster et al., 2018). Chloroplast genome assembly was performed using Galaxy Server (RRID:SCR_006281) version 23.1.1.dev0 (Sloggett et al., 2013). The assembly includes a filtering step to filter reads quality (Q>7) and length minimum of reads (>500 bp), using the Flye program (RRID:SCR_017016) v2.9 (Kolmogorov et al., 2020) and polishing the assembly results using the MEDAKA consensus program (RRID:SCR_005857) v1.4.4 (Oosterbroek et al., 2021). The cpDNA data was then annotated using the GeSeq (RRID:SCR_017336) on the CHLOROBOX platform (Tillich et al., 2017) to assign functions to the predicted genes and generate a map representation of the chloroplast genome.\n\n\nResults\n\nThe cp genome showed a typical quadripartite structure (Figure 1) with a length of 152,765 bp, consisting of small single copy (SSC 18,893 bp) and large single copy (LSC 93,636 bp) regions separated by a pair of inverted repeat A (IRA 20,121 bp) and inverted repeat B (IRB 20,115 bp) regions (Figure 1). The C. burmanni chloroplast genome contained 173 unique genes, including 96 coding sequences, 68 transfer RNA (tRNA), and 19 ribosomal RNA (rRNA) genes (Table 1). The C. burmanni sequence had a GC content of 39% (LSC 38%; SSC 34%; IR 44%). The results of the typical quadripartite structure were similar to the C. burmanni reported by Yang et al. (2019).\n\n* Gene containing single intron.\n\n** Gene containing two introns.",
"appendix": "Data availability\n\nNCBI’s Short Read Archive (SRA): DNA-Seq of Cinnamomum burmanni. Accession number SRX22198906; https://identifiers.org/insdc.sra:SRX22198906 (IPB University, 2023).\n\n\nAcknowledgements\n\nThe authors thank Mrs. Siska Nurfajri and Ms. Nabila Salsabila Salmah, the alumni of the Department of Silviculture, Faculty of Forestry and Environment, IPB University, for their valuable assistance in DNA extraction.\n\n\nReferences\n\nDe Coster W, D’Hert S, Schultz DT, et al.: NanoPack: visualizing and processing long-read sequencing data. Bioinformatics. 2018; 34(15): 2666–2669. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIndarto, Isnanto T, Muyassaroh F, et al.: Efektivitas Kombinasi Ekstrak Kayu Manis (Cinnamomum burmanni) dan Mikroalga (Haematococcus pluvialis) sebagai Krim Tabir Surya: Formulasi, Uji In Vitro, dan In Vivo. Jurnal Kefarmasian Indonesia. 2022; 12(1): 11–24. Publisher Full Text\n\nIPB University: DNA-Seq of Cinnamomum burmanni. Sequence Read Archive by NCBI. 2023. Reference Source\n\nKolmogorov M, Bickhart DM, Behsaz B, et al.: metaFlye: scalable long-read metagenome assembly using repeat graphs. Nat. Methods. 2020; 17(11): 1103–1110. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOosterbroek S, Doorenspleet K, Nijland R, et al.: Decona: From demultiplexing to consensus for Nanopore amplicon data. ARPHA Conf. Abstr. 2021; 4: e65029. Publisher Full Text\n\nOxford Nanopore Technologies (ONT): Nanopore sequencing the advantages of long reads for genome assembly.2017. Reference Source\n\nSloggett C, Goonasekera N, Afgan E: BioBlend: automating pipeline analyses within Galaxy and CloudMan. Bioinformatics. 2013; 29(13): 1685–1686. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSuwarto, Octavianty Y, Hermawati S: Top 15 tanaman perkebunan.2014. Reference Source\n\nTillich M, Lehwark P, Pellizzer T, et al.: GeSeq – versatile and accurate annotation of organelle genomes. Nucleic Acids Res. 2017; 45(W1): W6–W11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWick RR, Judd LM, Holt KE: Performance of neural network basecalling tools for Oxford Nanopore sequencing. Genome Biol. 2019; 20(1): 129. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYang Y, Song Y, Xin P: The chloroplast genome of aromatic plants Cinnamomum burmanni (Lauraceae). Mitochondrial DNA B Resour. 2019; 4(2): 3616–3617. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "255270",
"date": "18 Mar 2024",
"name": "Hoang Dang Khoa Do",
"expertise": [
"Reviewer Expertise Genomics",
"Chloroplast genome evolution",
"Phylogeny"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1/ \"MinION is a third-generation sequencing technology with nanopore technology (Oxford Nanopore Technologies (ONT), 2017)\". MinION is one of the devices of ONT for performing sequencing. Therefore, please revise the sentence. 2/ Please revise the Figure 1. There are several errors in gene names such as three ndhK, rrn16 fragment, rps12 absence, etc... 3/ Also, please revise the Figure 1 legend with more detail about Figure 1. 4/ The protocol for DNA extraction can be found in the kit. Therefore, mentioning it again in the method part is unnecessary. The authors should add more details about the results and comparison between the new and old chloroplast genomes of Cinnamomum burmanni. 5/ Please add the coverage depth of the new chloroplast genome. 6/ The IR regions do not have the same length. Please add the reason for this uncommon in chloroplast genome.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Partly\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Partly",
"responses": [
{
"c_id": "11389",
"date": "20 Jun 2024",
"name": "Richard Salindeho",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for the constructive inputs to our manuscript. We have responded to all reviewer's comment's as you may find in the following link Response to Reviewer's comments Please note that the revised Figure 1 is presented in this link Best Regards. Richard Andreas Salindeho"
}
]
},
{
"id": "262304",
"date": "25 Apr 2024",
"name": "Jakub Sawicki",
"expertise": [
"Reviewer Expertise Chloroplast genomics",
"nanopore sequencing"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper presents a clear and well-structured investigation into the chloroplast genome of Indonesian Cinnamomum burmanni. The authors effectively introduce the plant's significance and the rationale for studying its genome, highlighting the knowledge gap regarding this specific Indonesian variety. Authors propose the use of MinION Oxford Nanopore Technologies for sequencing and provide a detailed, step-by-step methodological outline. This includes sample collection, DNA extraction techniques, sequencing hardware, and a comprehensive list of software used for analysis. While a bit more context on chloroplast genome research and the reasoning behind specific methodological choices would be beneficial, the paper overall offers a solid foundation for understanding their research aims and procedures. However the reviewed Genome Note has some issues that should be solved before acceptance: 1. The justification of study is unclear since the reference genome was previously sequenced. Why the ONT sequencing was used and what are possible pros of using this approach 2. Meanwhile the second genome is reported, the paper lacks of any comparison between Chinese and Indonesian accessions. 3. The described DNA extraction protocol is not suitable for HMW DNA. There's no size distribution or validation at this point. 4. The results section lack of any details on sequencing results including total output, percentage of read used for assembly, N50 reads and assembly coverage. 5. How the authors handle heteroplasmy? 6. An the least but not last, the SRA accesssion data do not contain fastq/fast5/pod5/ reads.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Partly\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Partly",
"responses": [
{
"c_id": "11557",
"date": "26 Jun 2024",
"name": "Richard Salindeho",
"role": "Author Response",
"response": "Dear Editor and Reviewer, Thank you for your comment and suggestion. We have responded to all reviewer's comment's as you may find in the following link Response to Reviewer's comments Sincerely yours, Corresponding author"
}
]
}
] | 1
|
https://f1000research.com/articles/13-127
|
https://f1000research.com/articles/13-519/v1
|
21 May 24
|
{
"type": "Research Article",
"title": "GBS vaccines in the UK: a round table discussion",
"authors": [
"Natasha Thorn",
"Rebecca L Guy",
"Konstantinos Karampatsas",
"Mair Powell",
"Kate F Walker",
"Jane Plumb",
"Asma Khalil",
"Vanessa Greening",
"Emma Eccleston",
"Caroline Trotter",
"Nick Andrews",
"Lynne Rush",
"Claire Sharkey",
"Lauren Wallis",
"Paul Heath",
"Kirsty Le Doare",
"Rebecca L Guy",
"Konstantinos Karampatsas",
"Mair Powell",
"Kate F Walker",
"Jane Plumb",
"Asma Khalil",
"Vanessa Greening",
"Emma Eccleston",
"Caroline Trotter",
"Nick Andrews",
"Lynne Rush",
"Claire Sharkey",
"Lauren Wallis",
"Paul Heath",
"Kirsty Le Doare"
],
"abstract": "Background Group B streptococcus (GBS) remains a leading cause of infant sepsis, meningitis and death despite intrapartum antibiotic prophylaxis. A vaccine is urgently required, and two candidates are in advanced clinical trials. For successful GBS vaccine implementation, especially if a vaccine is licensed based on an immunological threshold, there must be cross-sector engagement, effective advocacy, robust plans for phase IV studies and equitable access.\n\nMeeting A round-table discussion, held at St George’s University of London, reviewed the current position of GBS vaccines in the UK context, focusing on phase IV plans, convening a diverse group of stakeholders from across the UK, with a role in GBS vaccine licensure, advocacy, implementation or effectiveness evaluation. Presentations outlined the latest UK epidemiology, noting the rising infant invasive GBS (iGBS) infection rates from 1996 to 2021 for both early and late onset disease, with the highest disease rates in Black infants (1.1/1000 livebirths vs white infants (0.81/1000 livebirths). Potential coverage of the candidate vaccines was high (>95%). Regulatory input suggested that EU regulators would consider waiving the need for a pre-licensure efficacy study if a putative correlate of protection could be adequately justified. Phase IV study methodologies for a GBS vaccine were considered, largely based on previous UK maternal vaccine assessments, such as a nationwide cohort study design using a vaccine register and a maternal services dataset. Other strategies were also discussed such as a cluster or stepped-wedge randomised trial to evaluate implementation outcomes. Opportunities for advocacy, education and engagement with additional key partners were discussed and identified.\n\nConclusions With an approved GBS vaccine a near possibility, planning of phase IV studies and identification of critical barriers to implementation are urgently needed. Cross-sector engagement is essential and will facilitate a successful pathway.",
"keywords": [
"Group B streptococcus",
"invasive GBS disease",
"vaccines",
"maternal vaccines",
"late-onset disease",
"early-onset disease",
"neonate"
],
"content": "Introduction and Objectives\n\nStreptococcus agalactiae or group B streptococcus (GBS) remains an important cause of neonatal sepsis and meningitis worldwide.1–4 It represents a high global burden of infant morbidity and mortality,2 causing a spectrum of disease including neonatal sepsis, pneumonia, meningitis and long-term neurological sequelae in survivors.2,5–7 In pregnancy, GBS causes bacteriuria, ascending infection and chorioamnionitis as well as maternal perinatal sepsis and death.2,5,8 It is associated with excess risk of preterm birth and stillbirth.2,9–12 In 2020, it was estimated that globally, GBS caused 394,000 cases of infant invasive GBS (iGBS) disease and 91,900 infant deaths as well as being associated with 518,000 excess preterm births.1\n\nWhilst the heaviest burden of GBS falls on low- and middle-income countries (LMICs), there remains significant disease in the UK with recent, concerning trends. Decreased rates of early-onset GBS (EOGBS) disease, occurring within 0 to 6 days of life, have been seen in most high-income countries after the introduction of intrapartum antibiotic prophylaxis (IAP), especially where a test-based rather than risk-based approach is taken. However, this intervention has not reduced rates of late-onset GBS (LOGBS) disease, occurring between 7 to 90 days of life.13 In some high income countries early-onset disease (EOD) rates have been rising in recent years, including in the UK14 where a risk-based strategy for IAP is used. IAP is not always deliverable, results in high antibiotic exposure leading to concerns about increasing antimicrobial resistance (AMR)13,15,16 and has unwanted effects on the neonatal microbiome in the short-term.17 With no effective prevention strategy for LOGBS and rising rates of EOGBS, a GBS vaccine remains a significant, long-standing unmet need in the UK.\n\nVaccines are in development and two vaccine candidates have reached phase II trials in pregnant people; a hexavalent, capsular polysaccharide-protein conjugate vaccine18 and an Alpha-like protein (Alp) adjuvanted vaccine.19 An effective GBS vaccine has the potential to prevent an estimated 127,000 (UR: 63,300 to 248,000) EOGBS cases and 87,300 (UR: 38,100 to 209, 000) LOGBS cases globally every year.20\n\nHowever, phase III trials present significant challenges21; primarily that they will require a very large sample size. In the UK, where invasive disease incidence is below 1 per 1000 livebirths, over 150,000 pregnant participants would be required to demonstrate 75% vaccine efficacy.22 Alternative pathways to licensure are therefore being pursued with establishment of an immune correlate of protection (COP) one option.23–25 Modelling in the UK has demonstrated a vaccine likely to be cost effective at both £20,000 and £30,000 per quality-adjusted life year (QALY).26 Cost-effectiveness is also predicted across multiple settings.20\n\nThe UK has a history of vaccine innovation and early adoption of new vaccines. So with GBS vaccines on the horizon there are a multitude of considerations for stakeholders in the UK to ensure a rapid and accessible vaccine programme with good uptake. With this in mind, a round table discussion was facilitated, gathering an expert group of stakeholders from across the UK.\n\nThe meeting, held in March 2023 at St George’s University, London (SGUL), included presentations and group discussion. Future meetings will focus on areas requiring greater depth and to progress next steps. Here, we report on the first meeting, including proposed next steps along the road to a GBS vaccine programme for the UK.\n\nBurden of invasive GBS disease in the UK – Rebecca Guy\n\nThe first presentation was given by Rebecca Guy, principal scientist in epidemiology at the UK Health Security Agency (UKHSA) outlining the current burden of invasive GBS (iGBS) disease in the UK. Several data sources were used, including the UKHSA routine lab surveillance data of GBS isolated from sterile sites in England (SGSS), data from the Staphylococcal and Streptococcal Reference Service (SSRS), information from the NHS demographic batch services (DBS) from the NHS Spine and hospital episode statistics (HES). Some of the data presented were unpublished.\n\niGBS disease incidence trends in England from 2017 to 2021 remain broadly stable across this period at around 5 per 100,000 population in all ages. Incidence trends consistently differ between age groups; the highest incidence rate is in under 1-year olds at 90/100,000 population, followed by the over 75-year-olds at 14/100,000 population.\n\nInfant iGBS infection rates have increased markedly between 1996 to 2021, for both EO and LO disease. Infant disease rates reached 0.95/1000 livebirths in 2019. There was a 40% increase in EOD between 2012 and 2020 (0.37 and 0.53/1000 livebirths respectively). During the two periods of enhanced surveillance in the UK and Ireland in 2000/01 and 2014/15, there was a comparable increase in incidence, suggesting slight under-ascertainment by routine surveillance data.\n\nIn infant iGBS from 2010 to 2021, capsular serotypes from England, Wales and Northern Ireland (NI) continue to differ between EOD and LOD. EOD demonstrates more serotype diversity, with type III still predominant but declining alongside decreased serotype Ia and increased IV in recent years. Looking cumulatively at infant iGBS isolate serotypes from sterile sites 2017 to 2021, 73% of LOD are due to serotype III but just 42% of EOD. 95% of infant disease isolates from 2017 to 2021 would be covered by the hexavalent vaccine currently in clinical trials. It is noted that this data represents the subset of cases referred to SSRS. Improvements to microbiology surveillance would be beneficial prior to a vaccine being launched.\n\nAntimicrobial resistance (AMR) is increasing in England in iGBS cases. In 2021, 40% of isolates from invasive disease in under 1-year olds had erythromycin, and 36% clindamycin resistance. Despite the change in IAP guidance in 2017 reducing use of clindamycin, this trend has continued. Improved surveillance is important ahead of vaccine introduction to assess whether trends are of emerging resistance or expansion of serotypes.\n\nReporting on infant iGBS infections by ethnicity in England, 2019 to 2020, the highest disease rates are in Black infants (1.1/1000 livebirths) and lower in white (0.81/1000 livebirths) and mixed ethnicity infants (0.6/1000 livebirths). The infection rate in Black infants is therefore 36% higher than in white infants. There is also significant variability between Asian infant subgroups. The same findings apply to maternal ethnic variation in iGBS disease; iGBS is highest overall in the mothers of Black infants (0.69/1000 livebirths) at more than twice the rate of white mothers (0.29/1000 livebirths). iGBS in England by deprivation decile from 2015 to 2021, for all ages, demonstrates a consistent trend indicating cases are reported more frequently from deprived areas. One previous study with UKHSA at a London hospital showed differentials in carriage rates between ethnicities27 which may provide part of the explanation but further work is needed to understand the whole picture and is being undertaken in a partnership between University of Nottingham and UKHSA.\n\nThe group discussed UKHSA’s genomic work on GBS looking at potential linkages between cases. Although LOGBS has traditionally been thought of as individually acquired community cases, the genomic work showed that 1 in 12 isolates were linked in hospital clusters and so it can also be thought of as a hospital acquired infection (HAI).\n\nThe Scottish perspective on current GBS surveillance – Lynne Rush\n\nLynne Rush gave the Scottish perspective. There is not currently enhanced disease surveillance for GBS in Scotland. Isolates are received via the Scottish microbiology reference laboratories, but these are not linked to clinical data. This would need to be addressed in a systematic way, preferably in line with the rest of the UK. Public Health Scotland (PHS) have good connections with the MatNeo Data Hub in partnership with the Scottish Perinatal Network, Healthcare Improvement Scotland, Scottish Government and National Records Scotland which will be a valuable framework to work with going forwards.\n\nIn terms of vaccine coverage data, historically antenatal vaccine uptake has been challenging to record but Scotland has recently been through the Vaccine Transformation Programme leading to major changes including use of the new Scottish Linked Pregnancy and Baby Dataset (SLiPBD), the new Vaccine Management Tool and changes to how vaccines in pregnancy are captured.\n\nPHS has a robust system for monitoring vaccine safety, with weekly adverse events reported from the NHS board of immunisation co-ordinators discussed weekly at a vaccine safety team meeting. In terms of cost-effectiveness studies, the Scottish birth cohort is approximately 50,000 – a sample size too low to power a stand-alone study for Scotland and therefore being part of a UK-wide trial would be welcomed.\n\nProposed surveillance of iGBS disease in British and Irish infants <90 days – Konstantinos Karampatsas\n\nA presentation by Konstantinos Karampatsas, clinical research fellow at SGUL, introduced a submitted proposal for a new enhanced surveillance study looking at iGBS disease in infants < 3 months of age in the UK and Republic of Ireland. The most recent enhanced surveillance for GBS in the UK was the British Paediatric Surveillance Unit (BPSU) study in 2014-15.14 856 infants were identified over 13 months giving an incidence of 0.94 cases/1000 livebirths and 53 infants died meaning a case fatality rate (CFR) of 6.2%. Serotype III was the most prominent serotype in both EOD and LOD (60% of cases) followed by serotype Ia (17% of cases). One of the most important conclusions from this study was that the incidence of GBS had significantly increased from the previous BPSU study in 2000 for both EOD and LOD, which means that the burden of EOGBS has increased despite the national guidelines introducing a risk-based policy for IAP.\n\nThe need for a new surveillance study was highlighted: it will provide baseline information ahead of both a test-based screening and vaccine programme to accurately assess their impact. It will describe the current prevalence of clinical risk factors e.g., prematurity; and will help to identify whether at-risk groups will be covered by a vaccine during pregnancy. The study will also describe any changes in the incidence of iGBS and assess the effect of the implementation of the current IAP guidelines. Additionally, it will help describe serotypes circulating to bolster confidence that the vaccines in development will offer adequate cover.\n\nThe proposed study design uses the BPSU network in collaboration with microbiology reference laboratories and public health agencies in the UK and Ireland. The team will also collaborate with the UK Obstetric Surveillance System (UKOSS), raising awareness amongst obstetricians and midwives and helping to capture critical data around pregnancy and birth. The team are aiming to consult with PPI organisations to promote transparency and accountability as a non-consent model will be used.\n\nThe definition of cases at present is GBS identified via positive culture or polymerase-chain reaction (PCR) test from a normally sterile site. Engaging with hospital laboratories will be key to the success of this project, especially given that only 45% of all isolates are currently sent to the reference laboratories in the UK. The BPSU also recommended an additional timepoint in the study with a follow up at 2 years of age to assess long-term morbidity of iGBS.\n\nA Phase 1 application was accepted in December 2022 and the Phase 2 application is being updated before approval, with a plan to meet shortly with all laboratories and agencies to discuss logistics. The study will commence within 12 months of phase 2 approval.\n\nGroup discussion identified epidemiology and surveillance knowledge gaps in the context of a GBS vaccine programme for the UK. Table 1 details these knowledge gaps as well as next steps to begin to address these.\n\nGBS Vaccines – Paul Heath\n\nA presentation from Paul Heath, Professor of Paediatric Infectious Diseases at SGUL provided an update on GBS vaccine development. An effective GBS vaccine could prevent an estimated global 127,000 EOGBS cases (UR: 63,300 to 248,000), 87,300 LOGBS cases (UR: 38,100 to 209, 000) averting 31,100 infant deaths (UR: 14,400 to 66, 400) and 17,900 cases of moderate and severe neurodisability (UR 6,380 to 49,900).20\n\nThere are two main GBS vaccine targets – the capsule and it’s 10 different serotypes, and several conserved outer membrane proteins targets. The global GBS capsular serotype distribution is important because one of two current leading vaccine candidates is a serotype-specific vaccine, covering the six most frequent serotypes. Serotype replacement is therefore a theoretical possibility, as has been seen with pneumococcal conjugate vaccines, although perhaps less likely for GBS.\n\nTo date, vaccine candidates have been developed and trialled by multiple companies but the two most advanced currently are by Pfizer and MinervaX. The Pfizer vaccine is a six-valent polysaccharide protein conjugate vaccine18 whilst MinervaX have an Alpha-like protein (Alp) based vaccine.19 Both manufacturers are in phase II trials in pregnant people and are currently planning phase III trials, grappling with the issues around route to licensure: primarily, large sample size requirement.\n\nA 2021 study of the polysaccharide conjugate vaccine demonstrated immunogenicity and persistence against 6 serotypes in non-pregnant adults as part of a dose-finding study.30 This study ultimately chose a 20mcg per serotype dose, finding the aluminium phosphate adjuvant not necessary for immunogenicity. The protein vaccine is based on the Alp proteins which are conserved across nearly all strains and is being tested in pregnant participants. It uses an aluminium hydroxide adjuvant.\n\nSome of the issues to consider ahead of a vaccine programme are: reactogenicity and immunogenicity of co-administered vaccines in pregnancy (for example dTaP/IPV, COVID-19, RSV, influenza and tetanus), optimal timing of vaccine(s) in pregnancy as placental transfer is maximal in the 3rd trimester yet premature infants experience the highest incidence of GBS, attitudes towards antenatal vaccination. Other issues include impact on colonisation and the persistence of antibodies in infants and also in adults into future pregnancies: will this vaccine be given in every pregnancy? Finally, any interference with primary immunisations must be evaluated, given that pertussis and polio vaccines in pregnancy can affect infant responses.31\n\nSerocorrelates as the basis for conditional licensure of vaccines in the UK – Kirsty Le Doare\n\nA presentation from Kirsty Le Doare, Professor of Vaccinology and Immunology at SGUL, gave an overview of the serocorrelates route to GBS vaccine licensure. There are three potential approaches to vaccine licensure currently; the first, the classic approach, is a phase III trial. The second approach is an immunological endpoints trial embedded within a classic phase III trial. The third option is conditional approval based on an immunological endpoint followed by a phase IV clinical effectiveness trial. At present, the second two options are the most likely routes for a GBS vaccine. To demonstrate efficacy, a larger sample size is needed than would generally be practical for a phase III trial in pregnancy.22 Even in a high disease burden country, with a disease incidence of 1.0-2.0/1000 livebirths, for a 1:1 randomised, controlled GBS clinical vaccine efficacy trial, 30-62,000 participants would need to be enrolled to detect vaccine efficacy of 80%.23\n\nA basis for licensure based on serocorrelates has been used previously for pneumococcal vaccines where an aggregate immunoglobulin G (IgG) serocorrelate value (the amount of antibody that protects an infant from invasive disease) that covered all serotypes was developed based on three clinical efficacy trials and agreed by consensus to be 0.35 μg/ml.32 Importantly, the way forward for licensure was having a standardised assay. A similar approach was taken for meningococcal vaccines where serocorrelates moved the field forward. The premise behind the correlate of protection (COP) is that the birthing-parent has antibodies to GBS post-vaccination or post-exposure to GBS. IgG is passed via the placenta to the fetus and if passed in sufficient amounts, the birthing-parent and baby are protected against disease in either pregnant adult, fetus or infant.\n\nCarol Baker has worked extensively on GBS COP. Baker has spent much time on potential IgG threshold values; her studies from the early 1990’s looked at a tetanus toxoid conjugate vaccine against two of the common GBS serotypes in the USA, serotype Ia and Ib.33 These studies found that the percentage of people with IgG >1 μg /ml, when examining vaccine versus placebo, was much higher in those who were vaccinated with >90% of non-pregnant adults achieving a titre of >1 μg /ml after vaccination. Studies in the UK examining antibody levels post-natural infection found that infants with antibody concentrations of >2 μg/ml were more likely to be protected against iGBS disease when compared to infants with lower antibody concentrations.34 These results have been replicated in a seroepidemiological study from Europe which examined colonised versus non-colonised women and found that those colonised had higher antibody concentrations for all the major serotypes.35 There have subsequently been several modelling studies in recent years including further work from Baker36 which took a Bayesian approach to predict how much antibody is sufficient, with the overall combined estimate that antibody concentrations >1 μg /ml had an estimated 90% protection against serotypes Ia and III, and 70% protection against serotype IV. COP have also been examined and proposed for the AlpN antibodies; relevant for the protein-based vaccine that is now in Phase II trials. These studies predict an estimated 90% reduction in disease with concentrations of 0.4μg/ml of Rib-N IgG and Alp1-N IgG concentrations of 0.11 μg/ml.37\n\nOne factor advancing this area more recently has been the development of the international GBS assay standardisation consortium, which SGUL leads. The three objectives of the consortium are:\n\n1. Development of standard reagents and identification and review of assays for standardisation\n\n2. Standardisation of protocols for existing ELISA and functional GBS assays using standard reagents\n\n3. Validation of standard protocols and standard reagents across laboratories to establish a prediction of disease protection.\n\nA 2021 International Symposium on Streptococcus agalactiae Disease (ISSAD) report presented data showing good assay correlation between all laboratories which has now enabled larger studies to go forward. For example, the iGBS3 study in the UK, a study in the USA examining 150 dried blood cards with 3:1 controls from prospective surveillance in newborns performed via the CDC, a large trial under way in South Africa and Uganda and additional work via SGUL (the EDCTP PREPARE study) collecting isolates from around Europe and African countries. All these studies will contribute to defining the COP that can be used for conditional licensure.\n\nPotential cost effectiveness of GBS vaccines – what more do we need to know? – Professor Caroline Trotter\n\nProfessor Caroline Trotter, Epidemiologist and Health Economist at the University of Cambridge and Imperial College London presented on the cost-effectiveness of a GBS vaccine in the UK. A cost-effectiveness analysis modelling study was performed in 201826 which concluded that a GBS vaccine in pregnancy would be cost effective, even at a relatively high estimated threshold price. The model estimated cost-effectiveness at £54 per maternal GBS vaccine dose at £20,000/QALY or £71 per dose at £30,000/QALY. There were no barriers shown to cost-effectiveness in this study.\n\nData from this and other previous studies20,26 give a strong starting point for the Joint Committee on Vaccination and Immunisation (JCVI) to make robust recommendations to the Department of Health (DOH). A significant difference in cost-effectiveness since 2018 is unlikely. Updating the working economic model for the UK with new epidemiological, surveillance or cost study data will be helpful. Inputs to update include: infant disease incidence and CFR, expected rates of sequelae, costs of acute and long-term care, litigation costs, vaccine details as known and other important outcomes such as stillbirth, preterm birth reduction and maternal sepsis and death prevention.\n\nAn element which has changed since 2018 is a more crowded pregnancy vaccine space leading to increased competition. In the previous paper,26 inclusion of maternal deaths and in particular stillbirths, increased the vaccine threshold price. These were not included in the base case as maternal deaths are very uncommon and stillbirths are not technically included within the National Institute for Health and Care Excellence (NICE) framework for cost-effectiveness analysis. Stillbirth was also demonstrated as an important factor in the global cost-effectiveness analysis.20 The economic handling of stillbirths may therefore be an avenue for further research; the UK could put forward both cost-effectiveness arguments for comparison, with and without value of life years lost to stillbirths, using standard life expectancy. Although relatively small in number, inclusion of intrapartum GBS related stillbirth in the model would likely impact the overall cost-effectiveness.\n\nGBS vaccines for maternal immunisation to protect against invasive disease in early infancy: Regulatory clinical considerations – Mair Powell\n\nA presentation was given by Mair Powell, Senior Clinical Assessor at the Healthcare Products Regulatory Authority (HRA) in Ireland, chair of the European Medicines Agency (EMA) Vaccine Working Party, member of the EMA Scientific Advice Working Party and member of the EMA Infectious Diseases Working Party.\n\nThe factors affecting time to first licensure for a vaccine were outlined: firstly, what will be the basis for demonstrating or inferring efficacy. Pre-licensure efficacy trials may not be needed if: 1. there is an agreed immune COP, or an agreed threshold value to enable prediction of protection from an immune response, or 2. an efficacious, licensed vaccine already exists, with a prior efficacy/effectiveness trial, and the new candidate can be shown to elicit similar immune responses to allow immunobridging. If neither of the above scenarios exist, an efficacy trial will be required if this is feasible.\n\nIf an efficacy trial is not feasible, perhaps in the case of a rare, sporadic, episodic or small outbreak of disease then several approaches can be considered. These include: deriving a threshold level of immune response for protection, from a non-clinical model that can be applied to humans, or deriving a threshold value from natural protection, using serological data and disease surveillance. Lastly, human challenge studies can be considered, where appropriate.\n\nAnother consideration is the size of the pre-licensure safety database; generally, for a new vaccine, this will be in excess of 3000 persons exposed to the final vaccine formulation and dose regimen. However, this number is negotiable taking into consideration factors such as the vaccine content and platform. Risk management plans and periodic safety update reports are now mandatory in the UK, EU and US. Specific safety issues may need to be addressed either via a large, pre-licensure safety database, and/or a post authorisation safety surveillance (PASS) study.\n\nConsidering effectiveness studies, it is recognised that these are unlikely to be conducted by the marketing authorisation holders (MAH) themselves. It is requested that the MAH engages with relevant public health bodies, working with them to develop a plan for a vaccine effectiveness study.\n\nIn summary, the data requirement for vaccine licensure and post-licensure is determined on a case-by-case basis. EU regulators have agreed that a pre-licensure efficacy study for a GBS vaccine may be waived if a sponsor, academic body, consortium or otherwise can propose a putative COP or threshold value. Different approaches to identifying putative COPs or threshold values are being taken to date by sponsors, considering both EOD and LOD as well as individual serotypes.\n\nSummary of current GBS vaccine pre-licensure considerations – Paul Heath\n\nIf a putative COP can be established to allow inference of vaccine protection, this might suffice for initial approval followed by a post-approval vaccine effectiveness study. Such a study might include secondary endpoints in addition to a primary endpoint based on invasive infant disease.\n\nA pre-licensure efficacy study is probably not achievable as a conventional disease-endpoint, phase III, placebo-controlled RCT. This is because relatively low disease incidence mandates a large sample size to evidence efficacy, participant recruitment during pregnancy means follow up of at least 6-12 months with an 8-12 month enrolment period and at least 200 study sites would likely be required. This study would take several years and significant investment to complete, resulting in a delay to vaccine availability. It is possible that one of the two vaccine manufacturers might pursue a large phase III efficacy trial as this remains the gold standard, but for the other, the approach would likely be a conditional licensure approach.\n\nA conditional licensure approach, based on a putative COP, will still require large numbers of pregnant participants, but is less costly than a pre-licensure, phase III clinical trial. Examples of vaccines approved via a COP route include the Meningococcal C, Meningococcal B and Meningococcal ACWY vaccine.\n\nGroup discussion identified further knowledge gaps in the area of progression towards a GBS vaccine programme in the UK. Table 2 details these knowledge gaps as well as next steps to begin to address these.\n\nA GBS vaccine in pregnancy programme: the midwifery perspective – Vanessa Greening and Emma Eccleston\n\nA presentation given by Vanessa Greening and Emma Eccleston, Research Midwives at SGUL Vaccine Institute, outlined some of the current barriers midwives might face in supporting pregnant people around GBS and GBS vaccines. Midwives may not always discuss GBS with pregnant people due to lack of time, staffing resource and confidence. Although very aware of the burden GBS places on maternity and paediatric services, midwives may lack specific knowledge of GBS incidence, mortality and morbidity rates.\n\nEffective counselling on vaccines in pregnancy can be challenging; people may be hesitant discussing vaccines and when midwives lack confidence due to inadequate depth of training, their concerns may not be addressed. A study in 2013 asked London midwives their views on vaccination in pregnancy via an anonymous, online survey.38 Just 25% of 266 respondents felt adequately prepared for this role and 69% of respondents agreed with the policy of vaccination against influenza in pregnancy.\n\nInterestingly, many midwives themselves may be vaccine hesitant. UKHSA data for the 2021/22 seasonal influenza vaccine offer to frontline healthcare workers (HCWs) showed 75% uptake for nurses at St George’s Hospital,39 but only 40% uptake amongst midwives at the same trust (local, unpublished data). Similarly, the 2013 survey study found seasonal influenza vaccine uptake rates in midwives of 43%, with non-uptake reasons including doubts about necessity, safety and effectiveness.38\n\nWhat do parents need to know now? by Group B Strep Support – Jane Plumb\n\nJane Plumb, Chief Executive Officer and Founder of Group B Strep Support (GBSS) charity reported on an unbranded survey GBSS conducted in April 2021, partnering with Bounty, to determine what information families already had about GBS in pregnant people and newborns. This was circulated online; the majority of respondents self-reported as pregnant people or having a child younger than 2 years of age.\n\n3500 responses were obtained, and the results were summarised. 87% of respondents had heard of GBS, compared with a previous GBSS survey via a pregnancy and birth magazine when only 10% of respondents had. 54% of respondents had heard about GBS through their own personal experiences or via friends and only 14% from their midwives, with others citing pregnancy books, leaflets, websites, and social media. This demonstrates how information on GBS may come from non-academic, non-medical sources.\n\nImportantly, 73% of respondents wanted more information on GBS, responding that they had not had ‘enough’ or ‘any’ information on the disease. Since 2017, the Royal College of Obstetrics and Gynaecology’s (RCOG) recommendation has been that all pregnant people should be provided with information on GBS; evidently, this target is not being met and more work needs to be done to provide access to resources on this infectious disease.\n\nAlmost all (99%) respondents felt that pregnant people should be informed about GBS by their doctor or midwife during pregnancy, 93% thought the UK should introduce a national screening programme for GBS in pregnancy (like other developed countries), selecting ‘extremely’ or ‘very important’ for screening policies and practices to be put in place. Finally, 90% of respondents answered they would be ‘very’ or ‘fairly’ likely to accept a GBS vaccine during pregnancy.\n\nMore recently, GBSS and charity partners conducted a repeat survey, advertised to those of child-bearing age; 321 responses were received at the time of this presentation in 2023 and data are both in progress and unpublished. When asked how important they felt different aspects of a GBS vaccine were, key concerns from respondents were protection of the baby against GBS infection and any side effects for the baby.\n\nWhat will GBS3 tell us and how do we use these results when thinking about GBS vaccines – Kate Walker\n\nKate Walker, Professor of Obstetrics at Nottingham and Co-Chief Investigator of the GBS3 trial, gave an overview of the trials current progress. The GBS3 trial is a two-arm, parallel, cluster randomised trial of GBS testing strategies with an economic and acceptability evaluation. The sample size comprises 320,000 participants. Sites are randomised to one of two arms: routine testing or a risk-factor based strategy (usual care), with the routine testing sites further sub-randomised to either testing via intrapartum rapid PCR tests for GBS or via antenatal enriched culture medium (ECM) testing at 35-37 weeks gestation. Data is collected for 12 months with no individual data collected, except for a subset of 8000 participants. Aside from verbal consent for any swab taken, there is no written informed consent for the trial. The primary outcome is all-cause early neonatal sepsis. Data collection will continue until end of March 2024 with results expected Summer 2025.\n\nThe GBS3 trial results will remain relevant even with a GBS vaccine available as there will always be a requirement for GBS testing, for example for those who are unable to receive or access a vaccine. It was noted that during the COVID-19 pandemic, vaccine uptake in pregnancy was around 60% with just 30% uptake amongst Black pregnant people and 38% amongst the most deprived groups.\n\nWhat have we learnt from vaccination in pregnancy with COVID-19 vaccines? – Asma Khalil\n\nAsma Khalil, Professor of Fetal Maternal Medicine at SGUL presented on lessons learned from rapid rollout of a new vaccine in pregnancy during the COVID-19 pandemic. Approval of the first COVID-19 vaccine by the MHRA was in December 2020 but the JCVI did not recommend offering a COVID-19 vaccine in pregnancy until April 2021. Initial uptake was low, with figures at 2.8%. RCOG issued strong recommendations to offer vaccination in pregnancy in July 2021 followed by an intense campaign by RCOG and the government. Uptake improved following this campaign rising to 60% by January 2022.\n\n- The RCOG campaigned for vaccinations in pregnancy using some of the below methods:\n\n- Writing to the prime minister in November 2020 calling for more research trials in pregnancy\n\n- Working closely with the vaccine taskforce\n\n- Forming a vaccine subgroup to provide pregnant people and healthcare practitioners with advice on counselling, vaccine delivery and data collection.\n\n- Producing information leaflets and decision aids, jointly with the Royal College of Medicine to help eligible pregnant people make a decision regarding vaccination.\n\n- Social media has significant impact on public perception - both RCOG and the government used social media to promote facts and address priority groups with risk factors for poor uptake.\n\nLooking at COVID-19 vaccine uptake and hesitancy in pregnancy multiple studies made similar findings. An SGUL study published in July 202128 showed that approximately one in three pregnant people at St George’s hospital were accepting a COVID-19 vaccine in pregnancy. This SGUL study also examined the determinants of vaccine uptake. Multivariate regression analysis showed that there were three independent predictors of vaccine uptake: African-Caribbean ethnicity with an odds ratio (OR) of 0.27 (p value=0.044); those in the fifth (lowest) Indices of Multiple Deprivation (IMD) quintile had an OR 0.1 (p=0.003); and those with pre-gestational diabetes were 10.5 times more likely to get the vaccine (p=0.014). The ethnic group and socioeconomic disparities were demonstrated again in surveillance data from both England29 and Scotland.40 The role of healthcare professionals is an important determinant of vaccine uptake, particularly the advice given by midwives and obstetricians.\n\nOne of the key issues in vaccine implementation was addressing any safety issues quickly for pregnant individuals, particularly when a side effect becomes associated with a vaccine. From clinical practice experience, safety of the COVID-19 vaccine was the predominant concern to pregnant people, rather than efficacy.\n\nDespite the RCOG’s efforts calling for pregnant people to be included in randomised-controlled trials (RCTs), it proved to be extremely difficult given that large numbers were needed, safety data was not yet available and sponsors were not always willing to recruit pregnant participants. There have been three RCTs examining the COVID-19 vaccine in pregnancy, none of which have reported data yet. An approach in future that doesn’t insist upon RCTs for vaccination in pregnancy is vital for timely rollout of antenatal vaccines.\n\nGroup discussion identified knowledge gaps in advocacy and education for a GBS vaccine programme in the UK. Table 3 details these knowledge gaps as well as next steps to begin to address these.\n\nPost-licensure vaccine effectiveness assessment, based on observational studies and the use of real-world evidence, requires high-quality disease surveillance systems to be in place with linkage to pregnancy vaccination systems. There are different ways in which these studies might be done and certain vaccine implementation strategies could allow for concurrent effectiveness data collection, including cluster or stepped wedge randomisation design to evaluate implementation. Endpoints of effectiveness and vaccine safety can be studied in various ways including case-control or passive cohort studies. Clinical effectiveness will need to be evaluated, with iGBS <90 days of age, both EOD and LOD, including bacteraemia and meningitis, as the endpoints. The implementation of the vaccine may lead to the discovery of other endpoints that GBS is contributing to, using a vaccine probe approach. This could yield a wide range of potential information regarding the role of GBS in invasive maternal disease and other maternal infections such as urinary tract infection or post-partum sepsis, as well as other neonatal infections (arthritis/cellulitis/culture negative sepsis), all-cause neonatal infections, stillbirths, prematurity and low birthweight, maternal and neonatal GBS colonisation, maternal and infant antibiotic use, serotype or strain replacement.\n\nNick Andrews first outlined the role and responsibilities of UKHSA when introducing a new vaccine in the UK. UKHSA have a legal mandate to undertake surveillance without patient consent with responsibility for evaluating several areas after vaccine introduction:\n\n- Disease incidence (pre- to post-vaccine introduction)\n\n- Epidemiological impact (for example, age shift, season shift, strain changes)\n\n- Vaccine effectiveness and safety (with MHRA)\n\n- Vaccine coverage and inequalities\n\n- Cost-effectiveness.\n\nThis is achieved using a variety of data sources including laboratory data from SGSS, vaccine registers, GP databases, hospital and mortality data, enhanced surveillance via questionnaires to GPs may be used (especially effective for rare diseases), and case note review. UKHSA also considers the vaccine schedule and the need for additional immunogenicity evaluation in trials, for example with the National Immunisation Schedule Evaluation Consortium (NISEC).\n\nGBS vaccine phase IV studies may be able to take similar approaches to previous pathogens. Some examples of previous phase IV studies carried out in the UK post-vaccine introduction are outlined in Table 4.\n\nIt was noted that the approach used for COVID-19 vaccine in pregnancy may have most relevance to GBS. Linkage to NIMS was very effective for these studies. As a national register, NIMS removed the need to try to access GP vaccination data, which is time-consuming. Replicating this approach will depend on whether GBS vaccines will be recorded in NIMS or via GP records, and, if into GP records first, whether a national extraction from these records can be done that allows linkage. This may be dependent on the vaccine delivery setting, for example vaccination via GP versus maternity services.\n\nPotential phase IV study designs and relevant data sources for GBS include:\n\n1. Vaccine effectiveness estimate:\n\nWith just laboratory surveillance data, UKHSA could assess the impact pre- and post-introduction on infants with GBS, mothers with GBS, epidemiology and strains.\n\n2. A nationwide cohort study:\n\nWith access to a vaccine register (such as NIMS, which provides denominator data), using vaccination records and linking infant cases to mothers using a programme such as MSDS, UKHSA could set up a cohort of the entire country. Identifying cases and matching them to the denominator. A cohort using vaccine register linkage is particularly good for multiple endpoints.\n\n3. A cohort for safety assessment:\n\nUsing MSDS linked to a vaccine register and HES or within a GP database (e.g., CPRD).\n\n4. A nested, matched, case-control study:\n\nIf additional information on confounders is needed, with access to a vaccine register, linkage to MSDS and to SGSS laboratory reports (including serotype data) a case-control study could be set up with a suitable laboratory control. Although this is likely not necessary.\n\nWithout access to a vaccine register, the case-coverage approach or a small cohort study could be used, both necessitating contacting GPs for vaccination status, which is less efficient. Infant/mother linkage data would still be required. Other endpoints could be evaluated using these proposed study designs, for example stillbirth, within a vaccine probe study.\n\nConsidering the possibility of effectiveness data collection alongside vaccine implementation, for example stepped wedge or cluster randomisation implementation design, it was noted that these methodologies are infrequently used due to more complex feasibility and ethical considerations. Previous antenatal vaccines introduced into the UK, for example the pertussis vaccine, have had highly protective effects, making these types of observational studies more useful. For a vaccine with lower effectiveness, these studies become challenging. This would also be true of a vaccine probe study; better results are yielded at higher effectiveness levels. At lower effectiveness, the benefits of cluster randomised or stepped wedge implementation design might be more apparent. It was noted that a GBS vaccine is anticipated to be highly effective against the serotypes and strains included but with monitoring for serotype or strain replacement.\n\nFurther discussion and development of plans for phase IV studies is needed. Many of these will be primarily carried out at national level by UKHSA within their remit for evaluation of vaccine implementation. In addition to these large-scale effectiveness and safety studies, there are other research questions better suited to smaller scale studies than by public health bodies. SGUL is already involved in several areas of work to progress GBS vaccine implementation in the UK, both at pre-licensure and post-licensure stage. This work is in close collaboration with charity partners, such as GBSS, regulators including the MHRA, government departments and industry partners. This multi-agency approach is vital for an effective and accessible vaccine programme. Some of these areas of work, current and planned, are outlined below:\n\nPre-vaccine implementation:\n\n- Defining a COP for GBS and engagement with regulators.\n\n○ Several studies are co-ordinated by SGUL to work towards defining a COP, applicable to the UK\n\n- National level enhanced GBS surveillance data ahead of vaccine introduction\n\n○ The proposed BPSU study of infant GBS across the UK and Ireland, led by SGUL, will provide important data updates, supported by GBSS and in collaboration with public health agencies from across the UK and Ireland.\n\n- Advocacy and engagement with patient and public groups, including charities such as GBSS, meningitis and sepsis charities such as the Meningitis Research Foundation (MRF), Meningitis Now and the UK Sepsis Trust, as well as with pregnancy and baby charities.\n\n○ GBSS, for example, continues to work towards better education of healthcare professionals and the public to raise awareness of disease risks and improve access to information\n\n○ This may increase vaccine acceptability and so eventual vaccine uptake\n\n○ Engagement is needed specifically with groups at risk of poor vaccine uptake and addressing barriers to vaccine access\n\n- Engagement with professional bodies such as RCOG, RCM and the Royal College of General Practitioners (RCGP) all of whom can have far reaching influence on their clinical staff members.\n\n- Engagement with government departments such as the Department for Health and Social Care (DHSC)\n\n○ To ensure a GBS vaccine is prioritised for implementation and working towards equitable vaccine coverage\n\nPost-vaccine implementation:\n\n- Continued engagement with charities, DHSC and others working with patient groups to advocate strongly for rapid implementation, uptake of a vaccine programme and maintaining a focus on equitable access given the knowledge of higher incidence rates of iGBS disease in groups at risk of low vaccine uptake.\n\n- Evidence generation – across multiple research questions:\n\n○ Vaccine access: understanding disparities in under-vaccinated groups, attitudinal studies\n\n○ Vaccine schedules in pregnancy: co-administration of antenatal vaccines, timing of administration, effects on infant primary immunisation responses\n\n○ Vaccine failure: risk factors, characterisation\n\n○ Special groups: vaccine safety in immunocompromise, those with co-morbidities, lactating people\n\n○ Effects on use of IAP pre/post vaccine introduction\n\n\nConclusions to the Meeting\n\nThis meeting was the first, round table discussion in the UK on GBS vaccines and has opened conversations between key stakeholders for implementation. A concerted and co-ordinated effort across multiple workstreams and organisations will be required to introduce a GBS vaccine that is accepted by, and accessible to, everyone and especially those with the greatest need in the UK.\n\nFurther round table meetings are planned to gather stakeholders together again and ensure continued progress towards this goal.\n\nTo summarise the key areas identified at this meeting where action is needed:\n\nData and evidence gaps\n\nAdditional data ahead of vaccine implementation would help direct and strengthen arguments for vaccine policy, for example updated enhanced surveillance data, data on GBS related stillbirths.\n\nVaccine licensure\n\nWork is ongoing to progress vaccine candidates towards licensure including planned phase III trials and seroepidemiological studies for COP development in liaison with regulators.\n\nPhase IV studies\n\nPlans for phase IV studies need further detailed discussion and planning to progress. More creative approaches for implementation alongside effectiveness data collection will be considered. National level phase IV studies by UKHSA will be complemented by smaller-scale studies by SGUL and others to hone in on specific questions relating to specific groups.\n\nEducation and advocacy opportunities\n\nImproved access to education for midwives on GBS and GBS vaccines as well as other HCP groups will likely have a positive impact on vaccine acceptability to both HCPs and the public. Advocating for rapid implementation of a GBS vaccine will be important, alongside work to maximise uptake and level-up access to a vaccine in the UK.\n\nChairs:\n\nKirsty Le Doare – Professor of Vaccinology and Immunology, St George’s University, Centre for Neonatal and Paediatric Infection\n\nPaul Heath – Professor of Paediatric Infectious Diseases, St George’s University, Centre for Neonatal and Paediatric Infection\n\nAttendees (A-Z):\n\nArlene Reynolds – Senior Professional Adviser in Public Health in Scottish Government, Previously Public Health Scotland\n\nAsma Khalil – Professor of Fetal Maternal Medicine at St George’s University, London\n\nCaroline Trotter – Epidemiologist, Cambridge and Imperial College Universities\n\nCecilia Hultin – Senior Research Nurse St George’s University Vaccine Institute\n\nCheryl Battersby – Consultant Neonatologist at Chelsea and Westminster Hospital, NIHR Clinician Scientist\n\nClaire Sharkey – Clinical Research Fellow at St George’s University Vaccine Institute\n\nClaire Wright – Head of Evidence and Policy, Meningitis Research Foundation\n\nColin Brown – Director of Clinical Emerging Infection at UKHSA\n\nDebbie King – Research Lead, Vaccines at Wellcome Trust\n\nElaine Devine – Director of Communications and Advocacy, Meningitis Research Foundation\n\nElizabeth Hayter – Clinical Trials Co-Ordinator St George’s University Vaccine Institute\n\nEmma Eccleston – Research Midwife at St George’s University Vaccine Institute\n\nEva Galiza – Senior Clinical Research Fellow, St George’s University, Centre for Neonatal and Paediatric Infection\n\nHelen Campbell – Clinical Scientist, Immunisations Team at UKHSA\n\nJane Plumb – Chief Executive of Group B Strep Support (GBSS)\n\nJuliana Coelho – National Infection Service: Respiratory and Vaccine Preventable Bacteria Reference Unit (NIS:RVPBRU), UKHSA\n\nKate Walker – Professor of Obstetrics at Nottingham University, Co-Chief Investigator of GBS3 Trial\n\nKonstantinos Karampatsas – Clinical Research Fellow, St George’s University, Centre for Neonatal and Paediatric Infection\n\nLaura McDonald – Health Care Scientist, Immunisation team, Public Health Scotland\n\nLauren Wallis – Communications/Engagement Officer at St George’s University, Centre for Neonatal and Paediatric Infection\n\nLynne Rush – Public Health trainee, Immunisation team at Public Health Scotland\n\nMair Powell – Senior Clinical Assessor at the Healthcare Products Regulatory Authority, Ireland,\n\nMerryn Voysey – Associate Professor of Statistics in Vaccinology, Oxford Vaccine Group\n\nMichelle Falconer – Nurse Consultant, Vaccine and Immunisations, Public Health Scotland\n\nNatasha Thorn – Clinical Research Fellow at St George’s University, Centre for Neonatal and Paediatric Infection\n\nNick Andrews – Statistician at UKHSA\n\nOliver Plumb – Advocacy and Information Manager, Group B Strep Support (GBSS)\n\nPhil Steer – Chair of Medical Advisory Committee, Group B Strep Support (GBSS)\n\nRebecca L Guy – Epidemiologist at UKHSA\n\nSam Knight – Helpline & Information Officer at Group B Strep Support (GBSS)\n\nShamez Ladhani – Paediatrician and UKHSA Epidemiologist\n\nTheresa Lamagni – Epidemiologist, Healthcare Acquired Infections and Antimicrobial Resistance, UKHSA\n\nVanessa Greening - Research Midwife, St George’s University Vaccine Institute\n\nXinxue Liu – Statistician, Oxford Vaccine Group\n\n\nEthical considerations\n\nNo relevant ethical considerations for this article and no ethics committee approval sought.\n\n\nConsent\n\nWritten consent via email was gained from all presenters to publish their presentation content.",
"appendix": "Data availability\n\nThe data for this article consists of bibliographic references, which are included in the References section.\n\n\nAcknowledgements\n\nThe authors would like to acknowledge the contribution of all delegates, listed above, who joined the round table discussion, without whose expertise and participation this meeting would not have been possible.\n\n\nReferences\n\nGonçalves BP, Procter SR, Paul P, et al.: Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden. Lancet Glob. Health. 2022; 10(6): e807–e819. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSeale AC, Bianchi-Jassir F, Russell NJ, et al.: Estimates of the Burden of Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children. Clin. Infect. Dis. 2017; 65(suppl_2): S200–S219. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSimonsen KA, Anderson-Berry AL, Delair SF, et al.: Early-onset neonatal sepsis. Clin. Microbiol. Rev. 2014; 27(1): 21–47. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOkike IO, Johnson AP, Henderson KL, et al.: Incidence, etiology, and outcome of bacterial meningitis in infants aged <90 days in the United kingdom and Republic of Ireland: prospective, enhanced, national population-based surveillance. Clin. Infect. Dis. 2014; 59(10): e150–e157. PubMed Abstract | Publisher Full Text\n\nBaker CJ: The spectrum of perinatal group B streptococcal disease. Vaccine. 2013; 31(Suppl 4): D3–D6. PubMed Abstract | Publisher Full Text\n\nKohli-Lynch M, Russell NJ, Seale AC, et al.: Neurodevelopmental Impairment in Children After Group B Streptococcal Disease Worldwide: Systematic Review and Meta-analyses. Clin. Infect. Dis. 2017; 65(suppl_2): S190–S199. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLibster R, Edwards KM, Levent F, et al.: Long-term outcomes of group B streptococcal meningitis. Pediatrics. 2012; 130(1): e8–e15. PubMed Abstract | Publisher Full Text\n\nRussell NJ, Seale AC, O’Driscoll M, et al.: Maternal Colonization With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses. Clin. Infect. Dis. 2017; 65(suppl_2): S100–S111. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBianchi-Jassir F, Seale AC, Kohli-Lynch M, et al.: Preterm Birth Associated With Group B Streptococcus Maternal Colonization Worldwide: Systematic Review and Meta-analyses. Clin. Infect. Dis. 2017; 65(suppl_2): S133–S142. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLamagni T, Wloch C, Broughton K, et al.: Assessing the added value of group B Streptococcus maternal immunisation in preventing maternal infection and fetal harm: population surveillance study. BJOG. 2022; 129(2): 233–240. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSeale AC, Blencowe H, Bianchi-Jassir F, et al.: Stillbirth With Group B Streptococcus Disease Worldwide: Systematic Review and Meta-analyses. Clin. Infect. Dis. 2017; 65(suppl_2): S125–S132. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNan C, Dangor Z, Cutland CL, et al.: Maternal group B Streptococcus-related stillbirth: a systematic review. BJOG. 2015; 122(11): 1437–1445. Publisher Full Text\n\nNanduri SA, Petit S, Smelser C, et al.: Epidemiology of Invasive Early-Onset and Late-Onset Group B Streptococcal Disease in the United States, 2006 to 2015: Multistate Laboratory and Population-Based Surveillance. JAMA Pediatr. 2019; 173(3): 224–233. PubMed Abstract | Publisher Full Text | Free Full Text\n\nO’Sullivan CP, Lamagni T, Patel D, et al.: Group B streptococcal disease in UK and Irish infants younger than 90 days, 2014-15: a prospective surveillance study. Lancet Infect. Dis. 2019; 19(1): 83–90. PubMed Abstract | Publisher Full Text\n\nFrancois Watkins LK, McGee L, Schrag SJ, et al.: Epidemiology of Invasive Group B Streptococcal Infections Among Nonpregnant Adults in the United States, 2008-2016. JAMA Intern. Med. 2019; 179(4): 479–488. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLaboratory surveillance of pyogenic and non-pyogenic streptococcal bacteraemia in England: 2021 update.2021; 16(13).\n\nZimmermann P, Curtis N: Effect of intrapartum antibiotics on the intestinal microbiota of infants: a systematic review. Arch. Dis. Child. Fetal Neonatal Ed. 2020; 105(2): 201–208. PubMed Abstract | Publisher Full Text\n\nPfizer: A PHASE 1/2, RANDOMIZED, PLACEBO-CONTROLLED, OBSERVER-BLINDED TRIAL TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF A MULTIVALENT GROUP B STREPTOCOCCUS VACCINE IN HEALTHY NONPREGNANT WOMEN AND PREGNANT WOMEN 18 TO 40 YEARS OF AGE AND THEIR INFANTS.2023. Accessed May 8, 2023. Reference SourceReference Source\n\nMinervax ApS: A Multicentre, Multinational, Parallel Group, Observer-Blind, Randomised, Placebo-Controlled Study on the Group B Streptococcus Vaccine (GBS-NN/NN2), Investigating the Immunogenicity and Safety of Four Vaccination Regimens in Pregnant Woman, Assessing IgG Specific to AlpN Proteins in Cord Blood and Maternal Blood, and the Safety Profile in Mother and Infant up to 6 Months Post-Delivery.2023. Accessed May 8, 2023. Reference SourceReference Source\n\nProcter SR, Gonçalves BP, Paul P, et al.: Maternal immunisation against Group B Streptococcus: A global analysis of health impact and cost-effectiveness. PLoS Med. 2023; 20(3): e1004068. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDavies HG, Carreras-Abad C, Le Doare K, et al.: Group B Streptococcus: Trials and Tribulations. Pediatr. Infect. Dis. J. 2019; 38(6S Suppl 1): S72–S76. PubMed Abstract | Publisher Full Text\n\nMadhi SA, Dangor Z, Heath PT, et al.: Considerations for a phase-III trial to evaluate a group B Streptococcus polysaccharide-protein conjugate vaccine in pregnant women for the prevention of early- and late-onset invasive disease in young-infants. Vaccine. 2013; 31(Suppl 4): D52–D57. PubMed Abstract | Publisher Full Text\n\nVekemans J, Crofts J, Baker CJ, et al.: The role of immune correlates of protection on the pathway to licensure, policy decision and use of group B Streptococcus vaccines for maternal immunization: considerations from World Health Organization consultations. Vaccine. 2019; 37(24): 3190–3198. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCarreras-Abad C, Ramkhelawon L, Heath PT, et al.: A Vaccine Against Group B Streptococcus: Recent Advances. IDrugs. 2020; 13: 1263–1272. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKobayashi M, Vekemans J, Baker CJ, et al.: Group B Streptococcus vaccine development: present status and future considerations, with emphasis on perspectives for low and middle income countries. F1000Res. 2016; 5: 2355. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGiorgakoudi K, O’Sullivan C, Heath PT, et al.: Cost-effectiveness analysis of maternal immunisation against group B Streptococcus (GBS) disease: A modelling study. Vaccine. 2018; 36(46): 7033–7042. PubMed Abstract | Publisher Full Text\n\nRao GG, Nartey G, McAree T, et al.: Outcome of a screening programme for the prevention of neonatal invasive early-onset group B Streptococcus infection in a UK maternity unit: an observational study. BMJ Open. 2017; 7(4): e014634. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBlakeway H, Prasad S, Kalafat E, et al.: COVID-19 vaccination during pregnancy: coverage and safety. Am. J. Obstet. Gynecol. 2022; 226(2): 236.e1–236.e14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMagee LA, Molteni E, Bowyer V, et al.: National surveillance data analysis of COVID-19 vaccine uptake in England by women of reproductive age. Nat. Commun. 2023; 14(1): 956. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbsalon J, Segall N, Block SL, et al.: Safety and immunogenicity of a novel hexavalent group B streptococcus conjugate vaccine in healthy, non-pregnant adults: a phase 1/2, randomised, placebo-controlled, observer-blinded, dose-escalation trial. Lancet Infect. Dis. 2021; 21(2): 263–274. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZimmermann P, Perrett KP, Messina NL, et al.: The Effect of Maternal Immunisation During Pregnancy on Infant Vaccine Responses. EClinicalMedicine. 2019; 13: 21–30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO Expert Committee on Biological Standardization: Fifty-Fourth Report/WHO Expert Committee on Biological Standardization: Geneva, 17-21 November 2003. World Health Organization; 2005.\n\nBaker CJ, Paoletti LC, Wessels MR, et al.: Safety and immunogenicity of capsular polysaccharide-tetanus toxoid conjugate vaccines for group B streptococcal types Ia and Ib. J. Infect. Dis. 1999; 179(1): 142–150. PubMed Abstract | Publisher Full Text\n\nFeldman RG, Ferrante A: Prevalence of anti-group B streptococcal type III capsular IgG antibodies in the United Kingdom and an analysis of their specific IgG subclasses. J. Infect. Dis. 1990; 162(4): 883–887. PubMed Abstract | Publisher Full Text\n\nFabbrini M, Rigat F, Rinaudo CD, et al.: The Protective Value of Maternal Group B Streptococcus Antibodies: Quantitative and Functional Analysis of Naturally Acquired Responses to Capsular Polysaccharides and Pilus Proteins in European Maternal Sera. Clin. Infect. Dis. 2016; 63(6): 746–753. PubMed Abstract | Publisher Full Text\n\nBaker CJ, Carey VJ, Rench MA, et al.: Maternal antibody at delivery protects neonates from early onset group B streptococcal disease. J. Infect. Dis. 2014; 209(5): 781–788. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDangor Z, Kwatra G, Pawlowski A, et al.: Association of infant Rib and Alp1 surface protein N-terminal domain immunoglobulin G and invasive Group B Streptococcal disease in young infants. Vaccine. 2023; 41(10): 1679–1683. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIshola DA, Permalloo N, Cordery RJ, et al.: Midwives’ influenza vaccine uptake and their views on vaccination of pregnant women. J. Public Health (Oxf.). 2013; 35(4): 570–577. PubMed Abstract | Publisher Full Text\n\nSeasonal flu and COVID-19 vaccine uptake in frontline healthcare workers: monthly data, 2021 to 2022. GOV.UK; March 24, 2022. Accessed May 12, 2023. Reference Source\n\nStock SJ, Carruthers J, Calvert C, et al.: SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland. Nat. Med. 2022; 28(3): 504–512. PubMed Abstract | Publisher Full Text | Free Full Text\n\nParikh SR, Andrews NJ, Beebeejaun K, et al.: Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study. Lancet. 2016; 388(10061): 2775–2782. Publisher Full Text\n\nLadhani SN, Campbell H, Andrews N, et al.: First Real-world Evidence of Meningococcal Group B Vaccine, 4CMenB, Protection Against Meningococcal Group W Disease: Prospective Enhanced National Surveillance, England. Clin. Infect. Dis. 2021; 73(7): e1661–e1668. PubMed Abstract | Publisher Full Text\n\nAmirthalingam G, Campbell H, Ribeiro S, et al.: Sustained Effectiveness of the Maternal Pertussis Immunization Program in England 3 Years Following Introduction. Clin. Infect. Dis. 2016; 63(Suppl 4): S236–S243. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKirsebom FCM, Andrews N, Mensah AA, et al.: Vaccine effectiveness against mild and severe disease in pregnant mothers and their infants in England.June 10, 2023. 2023.06.07.23290978. Publisher Full Text\n\nMensah AA, Stowe J, Jardine JE, et al.: Covid-19 vaccine safety in pregnancy, a nested case-control study in births from April 2021 to March 2022, England.October 9, 2023. 2023.10.09.23296737. Publisher Full Text\n\nAndrews N, Waight PA, Borrow R, et al.: Using the Indirect Cohort Design to Estimate the Effectiveness of the Seven Valent Pneumococcal Conjugate Vaccine in England and Wales. PLoS One. 2011; 6(12): e28435. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "304243",
"date": "07 Aug 2024",
"name": "Jennifer Gaddy",
"expertise": [
"Reviewer Expertise I work in reproductive infection and immunology",
"specifically in the area of Group B Streptococcus pathogenesis and host responses to infection."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript by Natasha Thorn and colleagues entitled, “GBS vaccines in the UK: a round table discussion” presents a compelling discussion of the status of a protective vaccine against Group B Streptococcus, an important perinatal pathogen. This manuscript is full of important information about disease risk from GBS infection and gaps in current treatment and prevention strategies. There are many positive aspects about this manuscript that I would like to highlight.\n\nFirst, the authors are extremely deliberate in their use of language, specifically referring to “pregnant patients” and “pregnant people”. This is a subtle but important aspect of discussing these populations without introducing highly gendered language. Excellent work.\nThe inclusion of stakeholders in the community such as Midwives was also a strength as these providers have the capacity to meet individuals who may be unaware of GBS risk and/or vaccine hesitant. Buy-in from these groups will help with deployment in the future.\nComparing/contrasting efficacy of other vaccination programmes deployed in pregnant patients was also a strength of this manuscript.\nI have a few comments to improve the quality of the manuscript.\n1. The authors mention AMR very briefly in the second paragraph of the Introduction. It would be helpful to expand this section to acknowledge that the standard first line therapeutic choice for GBS is penicillin, but up to 10% of populations report penicillin hypersensitivity. Second line choice is often erythromycin or clindamycin and emerging clinical strains are exhibiting high resistance to these drugs (about 40% of strains are resistant).\n\n2. First line of the Introduction. The authors refer to Group B streptococcus and italicize the word “streptococcus” but leave it lowercase. If the authors are referring to the genus, this word should be capitalized and italicized. If they are referring to general morphology and arrangement of bacteria it can be lowercase but should not be italicized. Most common references to GBS use the former (genus nomenclature).\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "12207",
"date": "13 Aug 2024",
"name": "Natasha Thorn",
"role": "Author Response",
"response": "Thank you for this helpful and insightful peer-review. We appreciate your time and positive comments on our manuscript. We will certainly address your two points of suggestion. Thank you for highlighting the typographical error in point 2. Regarding discussion of AMR in the article, in addition to paragraph 5 of the \"Epidemiology and surveillance\" section, we will include some additional context in the manuscript on penicillin hypersensitivity to further highlight the impact of clindamycin resistance. We are awaiting a second peer review and will then make the above changes to the manuscript."
}
]
},
{
"id": "315656",
"date": "27 Aug 2024",
"name": "Lisa Hanson",
"expertise": [
"Reviewer Expertise Antenatal probiotics to reduce GBS colonization."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n*Very well written article. Statistics and references are up to date and appropriate. Tables are very effective. A few suggestions for clarity. *\"more crowded pregnancy vaccine space\" is unclear. *In the GBS3 trial description, more clarity is needed as to why participants in the routine testing arms receive either rapid PCR IP (versus 35-37 weeks). A reference here about the sensitivity and utiliy of rapid IP testing is needed-as this is not a usual strategy in culture-based EOGBS prevention approach recommended by the CDC and now ACOG (2019). *Table 3. The points about midwives having hesitancy to offer vaccines was interesting, as this is not the case in the USA. *Table 4 is redundant of the text on Potential Phase IV study designs.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "315650",
"date": "10 Sep 2024",
"name": "Hannah R Frost",
"expertise": [
"Reviewer Expertise I work in infection and immunity",
"with specific focus on accelerating vaccine development for Group A Streptococcus."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the invitation to review the manuscript \"GBS vaccines in the UK: a round table discussion\" by Thorn et al., it was an interesting and informative read. The article provides a concise and well-rounded update to the current status of GBS Vaccines, including an appropriate focus on knowledge gaps and barriers to success with useful recommendations for how to address them. It is particularly interesting to have an update on important ongoing or planned trials, which is not normally available in the literature until >1 year after the completion of the trial. I appreciate the focus on forward planning around vaccine uptake and phase IV trials, and keeping in mind lessons from COVID-19 and other vaccines given in pregnancy.\n\nI have a few minor comments which may improve readability of the manuscript.\n1) There is some repetition of points throughout, likely due to the nature of the manuscript as proceedings of a meeting. The authors could clean up the narrative, for example on page four, two subsequent paragraphs have the same conclusion regarding the need for improved surveillance.\n\n2) Different acronyms are used to refer to the same thing (e.g. EOGBS, EOD and EO disease are all used in the first page) and some acronyms are never expanded (e.g. UR when discussing case estimates).\n\n3) It would be good to have references and links provided for the burden of disease data used, acknowledging that some data is as yet unpublished.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "315651",
"date": "26 Sep 2024",
"name": "Rosana Rocha Barros",
"expertise": [
"Reviewer Expertise Microbiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nRevision of the manuscript GBS vaccines in the UK: a round table discussion The manuscript is a comprehensive report of the round table held at St George University of London, that discussed the state of the art of GBS vaccines and planned phase IV trials. The manuscript brings the talks of different specialists, covering various issues regarding GBS vaccine background, vaccine implementation, and the follow-up after the beginning of vaccination. Overall, the text is very well-written and I have only an observation, as follows. Page 3 2nd paragraph. “IAP is not always deliverable, results in high antibiotic exposure...” This sentence seems a bit unclear. I suggest that the authors improve it.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-519
|
https://f1000research.com/articles/11-674/v1
|
20 Jun 22
|
{
"type": "Research Article",
"title": "Prevalence of diabetes mellitus among newly detected sputum positive pulmonary tuberculosis patients and associated risk factors: A cross-sectional study",
"authors": [
"Rashmi Hullalli",
"M R Gudadinni",
"Rohith Motappa",
"Rashmi Hullalli",
"M R Gudadinni"
],
"abstract": "Background: Tuberculosis (TB) and diabetes mellitus (DM) co-morbidity is one of the rising public health problems. There is growing evidence that DM is an important risk factor for TB. This study was carried out to know the prevalence of DM among newly detected sputum positive pulmonary TB patients registered in District Tuberculosis Centre and to assess the risk factors of DM among TB patients. Methods: In a cross-sectional study, newly detected sputum positive pulmonary TB patients were screened for DM (those having symptoms of DM). Furthermore, they were diagnosed by detecting blood glucose levels (≥200 mg/dL). Mean, standard deviation (SD), Chi-squared and Fisher-Freeman-Halton exact tests were used to determine the significant associations. P-values less than 0.05 were considered to be statistically significant. Results: A total of 215 TB patients were included in this study. The prevalence of DM among TB patients was found to be 23.7% (2.8% known and 97.8% new cases). Significant associations were found between age (>46 years old), educational status, smoking habits, alcohol consumption, physical activity, presence of DM symptoms and family history of DM. Conclusions: Routine screening for DM is mandatory due to its increasing prevalence, which may help in early diagnosis and to reduce complications by proper management that in turn helps in the successful outcome of TB treatment.",
"keywords": [
"Diabetes mellitus",
"prevalence",
"risk factors",
"tuberculosis"
],
"content": "Introduction\n\nDiabetes mellitus (DM) has become more common as a result of urbanisation, as well as social and economic development. People who have a weakened immune system, such as those who have diabetes, are more likely to proceed from latent to active disease.1 When compared to individuals without DM, people with DM have a two to three times higher risk of tuberculosis (TB).2 DM is associated with about 10% of all TB cases worldwide. A high percentage of individuals living with DM and TB go undiagnosed or are diagnosed too late. As a result, early discovery can aid in improving the care and control of both disorders.3\n\nIf a four-drug intensive phase regimen is changed to a two-drug regimen after two months in the presence of culture-positive time, DM can lengthen the time it takes for sputum culture conversion, resulting in the development of drug resistance.4 People with DM and TB have a higher risk of death during therapy and of TB relapse once treatment is completed. The presence of infectious illnesses, such as TB, complicates DM.5 Glycaemic management has also been shown to improve treatment outcomes in TB patients. According to recent studies, DM accounts for 20% of smear-positive TB cases, and that an increase in DM prevalence in India has posed a significant barrier to TB reduction.6\n\nThere is a lack of literature regarding this comorbidity in Vijayapura Taluk. Therefore, this study was conducted to determine the prevalence of DM among TB patients in Vijayapura Taluk, to study the socio-demographic profile of TB patients with DM and to identify potential risk factors.\n\n\nMethods\n\nEthical approval was obtained from the Institutional Ethical Committee of Shri B M Patil Medical College, BLDE University (Certificate No – 65/21-10-17; dated 21.09.2017). All participants provided written informed consent, which was obtained as part of the questionnaire during data collection. Informed consent forms7 and information sheets8 can be found as Extended data.\n\nThe present study was a cross-sectional study performed at Vijayapura Tuberculosis Unit, Karnataka. It covers 14 primary health centres, four urban health centres and two medical colleges. A TB register was used to approach the TB patients. Sputum-positive TB patients in Vijayapura taluk registered from January 1st to December 31st, 2016, over the age of 18 years old were included. The study was carried out between March 2017 and February 2018. Patients who were critically ill, not willing to participate, or women who were pregnant or lactating were not included in the study. Considering the prevalence of DM among TB patients is estimated to be 30.6%,3 at 95% confidence level and at 20% allowable error, the sample size was calculated by using the following formula:\n\nNon-diabetic patients were screened for DM by examining blood glucose levels in capillary blood using a finger-prick glucometer. Those found to be positive and having symptoms of DM were further evaluated by determining blood glucose levels. Health workers/Accredited Social Health Activist (ASHAs) were involved in the study, and objectives were explained to them. The TB patients were approached at their homes/Directly observed treatment, short-course (DOTS) centres/Primary Health Centres (PHCs) with the help of the Senior Treatment Supervisor. The study purpose was explained to participants at the time of the questionnaire. They were informed that their participation in the study was voluntary and that they could withdraw from the study at any point. Maintenance of confidentiality about data and findings was assured to the participants and their consent was obtained. Participants were tracked using ID numbers to maintain anonymity. Data were collected on proforma and only the investigator had access to it.\n\nA semi-structured, pretested questionnaire was developed and administered to newly detected sputum-positive pulmonary TB patients, with modifications relevant to local conditions.9 The pilot study was performed on 30 individuals for pretesting. Statistical validation for the questionnaire was done by Cronbach’s Alpha.\n\nThe procedure included the following four parts: i) Socio-demographic variables; ii) anthropometric measurements; iii) blood glucose estimation and iv) evaluation of any risk factors leading to the occurrence of DM.\n\nInstruments that were be used for general physical examination: i) A measuring tape; ii) weighing machine and iii) stethoscope. All these instruments were regularly standardized throughout the period of data collection.\n\nMeasurement of height, weight and body mass index (BMI)\n\nHeight was taken using a measuring tape in centimetres (cm) and recorded to the nearest 0.5 cm. Weight was measured in kilograms (kg) using a standardized bathroom weighing machine and was recorded to the nearest 0.5 kg. In this study, BMI classification proposed by the World Health Organization (WHO) Western Pacific Regional Office in collaboration with the International Obesity HTask Force (IOTF) steering committee (2000)10 for Asian people was used. It is also known as the Quetelet Index and was used to assess obesity.\n\nDiagnosis of DM\n\nAll participants, including those who were not diabetic but had symptoms of DM (polydipsia, polyuria, weight loss) were checked for random blood glucose levels. Classification of DM was done using the American Diabetic Association criteria.11\n\nCriteria for the diagnosis of DM included symptoms of DM plus random blood glucose concentration ≥11.1 mmol (200 mg/dL) OR fasting plasma glucose ≥7 mmol (126 mg/dL) OR Haemoglobin A1c ≥6.5% OR two-hour plasma glucose ≥11.1 mmol (200 mg/dL) during an oral glucose tolerance test.\n\nThe data were compiled in a Microsoft Excel 2010 (RRID:SCR_016137) work sheet and analysed using SPSS version 16.0 software (RRID:SCR_002865). The data were presented in the form of tables and graphs wherever necessary. All characteristics were summarized descriptively. For continuous variables, the summary statistics of number, mean, and standard deviation (SD) about the arithmetic mean were used. For categorical data, the number and percentage were used in the data summarized. Chi-squared test was used to know the significant associations. P-values less than 0.05 were considered to be statistically significant. Univariate regression analysis was used to detail the risk factors in the development of DM.\n\n\nResults\n\nTable 112 shows that out of 215 study participants, the majority (27%) of them belonged to the age group of 26–35 years old followed by 46–55 (21.9%) and 36–45 (20.9%) years old. In our study, men constituted 64.2% (138) of participants and women constituted 35.8% (77). A total of 88% of the TB patients were from rural backgrounds. Furthermore, 89.8% of the study participants were married, while only 7.9% were unmarried and there were about 2.3% widowed participants in the study. A total of 87.9% of study participants belonged to Hindu religion and the rest of them i.e., 12.1% belonged to the Muslim community. More than half (54.4%) of the study participants studied up to primary school followed by secondary school (23.7%), while 14.9% were illiterate in the study. In this study, 87% (187) of the participants belonged to a nuclear family, while 13% (28) were from a joint family. In our study, 48.8% of the participants belonged to the lower class according to modified BG Prasad classification,13 followed by 25.6% in the middle class and 20% in the lower middle class.\n\nOut of 215 study participants, 74% (159) were in the continuation phase (CP) of the TB treatment and 26% (56) were in the intensive phase (IP) (Figure 1).\n\nTable 2 details the prevalence of anti-TB treatment adherence. It was found that nearly 10.6% of the study participants were non-adherent to the treatment course.\n\nOut of 215 study participants the prevalence of DM was 23.7% (51) (Figure 2).\n\nWhen looking at the food habits of the study participants, 49% were vegetarians and 51% used to consume both vegetarian and non-vegetarian food items. A total of 43.1% of the study participants were current smokers and 51% were ex-smokers, while 5.9% were non-smokers. A majority (70.6%) of the study participants did not consume alcohol and about 29.4% consumed alcohol. Most (90.2%) of the study participants were engaged in moderate physical activity, while 3.9% described themselves as sedentary and 5.9% engaged in heavy physical activity (Table 3).\n\nUnivariate regression analysis was applied to ascertain the prevalence of DM and its associated risk factors (Table 4). It was found that participants in the age group of 56–65 years old, who were educated until the 7th standard, who were ex-smokers, those who consumed alcohol and who lead a sedentary lifestyle were the highest risk factors associated with the occurrence of DM, when compared to their counter variables. All these values were statistically significant.\n\n\nDiscussion\n\nOur study showed that majority of the TB patients were in the age group of 26-35 years old (27%). Similar results were found in a study done by Damtew et al.,14 in Addis Ababa Ethiopia where the majority of patients were 25–44 years of age. A study done by Balakrishnan et al.,15 in Kerala revealed that most of the patients were 45–54 years of age. Other studies done by Kishan et al.,16 in Patiala Punjab and Dutt et al.,17 in Ahemdabad reported that the 40–60 years old age group was the most commonly involved. These differences in age groups may be due to the different location of the study and study design setting. The mean age was found to be 52.1 years old among diabetics and 37.1 years old among non-diabetics, which was similar to a study done by Natarajaboopathy et al.,18 in Tamil Nadu where the mean age of the DM TB patients was 52.92 years old and was statistically significant. Padmalatha et al.,3 in Andhra Pradesh showed that the mean age was 46.5±10.3 years old among diabetics and 35.8±11.7 years old among non-diabetics.\n\nMore than half (54.4%; 117) of the TB patients studied up to primary schooling, 23.7% (51) of patients completed high school education and 14.9% (32) of patients were illiterate, where it was observed that most of the TB patients had received less schooling, which was consistent with other studies. A study done by Sarker et al.,19 in Bangladesh reported that 25.1% of the participants had primary schooling, 19.8% had secondary schooling and 40.7% were illiterate. Another study by Tahir et al.,20 in Pakistan showed that 51.6% of participants were illiterate, 34.7% had primary schooling and 10.7% had secondary schooling.\n\nIn our study, 4.7% of participants were current smokers and 69.3% were non-smokers, which was in line with a study done by Damtew E et al.,14 in Ethiopia, which revealed that 15% of subjects were smokers and 85% were non-smokers. However, another study done by Ekeke et al.,21 in Nigeria showed that 4.8% of participants were non-smokers and 95.2% were current smokers. This variation may be due to different social scenarios.\n\nWe found that the majority (84.2%) of the TB patients did not consume alcohol and about 15.8% used to consume alcohol, which was similar to a study by Viswanathan et al.,22 in Tamil Nadu in which 38.9% did not consume alcohol and 1.6% consumed alcohol. While another study by Damtew E et al.,14 in Ethiopia determined that there wasn’t much difference in alcohol consumption i.e., 51.7% did not consume alcohol and 48.3% consumed alcohol, which may be due to different socio-cultural factors.\n\nThe prevalence of DM among TB patients in our study was 23.7%, which is consistent with the reports of other studies23 done in Karnataka State in 2011 where the prevalence was 32%, in Kerala State, 44% (2012) in Tamil Nadu State, and 25% in India (2012). Other studies like an institutional based cross-sectional study done by Padmalatha et al.,3 in Andhra Pradesh showed the prevalence of DM as 30.6%. A facility based cross-sectional study done by Raghuraman et al.,24 in Puducherry (2017) reported the DM prevalence to be 29%. In contrast to the aforementioned findings, another study done in Nigeria by Olayinka et al.,25 found the prevalence to be 5.7%, which could be attributed to differences in demographic characteristics. We employed the American Diabetic Association (ADA) criteria to assess the prevalence of DM and studied TB patients registered under the Revised National TB Control Programme (RNTCP).\n\nSome of the variables analysed were based on the information obtained by the study participants hence an element of recall bias and masking of data could be present. TB patients registered under RNTCP were included in the study, thus patients being treated in private hospitals may have missed. Among all the TB patients, only new sputum positive pulmonary TB patients were included, which may be a limitation. In the present study, only a few risk factors of DM were studied. Other risk factors could not be studied due to a lack of resources. The prevalence of DM among TB patients was 23.7%, which is quite high so screening of all TB patients should be done just like HIV screening in order to aid in early diagnosis and proper management of the disease. For DMTB patients, regular blood glucose estimation and treatment should be given in DOTS centres along with anti-TB drugs. Primordial prevention can play an important role in preventing the occurrence of DM. Health education regarding the risk factors and symptoms of DM should be given to high-risk groups.\n\nAlthough the findings were found to be consistent with previously reported studies, direct comparisons are not valid for the reasons stated above, as well as the fact that researchers used different criteria to diagnose the conditions over time, the non-representativeness of patients studied in terms of number and selection criteria, and the different settings of the research. A well-designed large-scale observational study or meta-analysis could resolve the problem.\n\n\nConclusions\n\nRoutine screening for DM in TB patients should be mandatory due to increases in the prevalence of DM, which would not only help in early diagnosis, but also reduces complications by proper management and in turn will help in the successful outcome of TB treatment.\n\n\nData availability\n\nFigshare: Prevalence of Diabetes Mellitus among newly detected sputum positive Pulmonary Tuberculosis patients and associated risk factors. https://doi.org/10.6084/m9.figshare.19878115.v1.12\n\nFigshare: Questionnaire.docx. https://doi.org/10.6084/m9.figshare.20014160.v1.9\n\nFigshare: Consent form.docx. https://doi.org/10.6084/m9.figshare.20014172.v1.7\n\nFigshare: Information sheet for the study participant.docx. https://doi.org/10.6084/m9.figshare.20014175.v1.8\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nAuthors acknowledge the Joint Director; State TB Centre, Bangalore and District Tuberculosis Officer, Vijayapura for their constant guidance and support.\n\n\nReferences\n\nRevised National TB Control Programme Technical and Operational Guidelines for Tuberculosis Control in India.2016. India. p. 269.\n\nPark K:Epidemiology of Communicable Diseases. Textbook of Preventive and Social Medicine. 24th edition.Jabalpur, India:M/s Banarsidas Bhanot Publishers;2017; p.185–216.\n\nPadmalatha P, Hema K: Study on prevalence of Diabetes Mellitus in Tuberculosis patients attending a tertiary care hospital in Guntur, Andhra Pradesh. IJBAMR. 2014 Dec; 4(1): 494–498.\n\nCuneo WD, Snider DE Jr: Enhancing patient compliance with tuberculosis therapy. Clin. Chest Med. 1989 Sep; 10(3): 375–380. Publisher Full Text\n\nChaudhuri AD: Recent changes in technical and operational guidelines for Tuberculosis control programme in India - 2016: A paradigm shift in tuberculosis control. J. Assoc. Chest Physicians. 2017; 5: 1–9. Publisher Full Text\n\nMandal PK, Mandal A, Bhattacharyya SK: Comparing the Daily Versus the Intermittent regimens of the Anti-Tubercular Chemotherapy in the Initial Intensive Phase in Non-HIV, Sputum Positive, Pulmonary Tuberculosis Patients. J. Clin. Diagn. Res. 2013; 7(2): 292–295.\n\nMotappa R: Consent form.docx. figshare. [Dataset].2022. Publisher Full Text\n\nMotappa R: Information sheet for the study participant.docx. figshare. [Dataset].2022. Publisher Full Text\n\nMotappa R: Questionnaire.docx. figshare. [Dataset].2022. Publisher Full Text\n\nLim JU, Lee JH, Kim JS, et al.: Comparison of World Health Organization and Asia-Pacific body mass index classifications in COPD patients. Int. J. Chron. Obstruct. Pulmon. Dis. 2017; Volume 12: 2465–2475. PubMed Abstract | Publisher Full Text\n\nAmerican Diabetes Association: 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2020. Diabetes Care. 1 January 2020; 43(Supplement_1): S14–S31. PubMed Abstract | Publisher Full Text\n\nMotappa R: Prevalence of Diabetes Mellitus among newly detected sputum positive Pulmonary Tuberculosis patients and associated risk factors. figshare. [Dataset].2022. Publisher Full Text\n\nKhairnar MR, Kumar PG, Kusumakar A: Updated BG prasad socioeconomic status classification for the year 2021. J. Indian Assoc. Public Health Dent. 2021; 19: 154–155.\n\nDamtew E, Ali I, Meressa D: Prevalence of Diabetes Mellitus among Active Pulmonary Tuberculosis Patients at St. Peter Specialized Hospital, Addis Ababa, Ethiopia. World J. Med. Sci. 2014; 11(3): 389–396.\n\nBalakrishnan S, Vijayan S, Nair S, et al.: High Diabetes Prevalence among Tuberculosis Cases in Kerala, India. PLoS One. 2012; 7(10): 1–7. Publisher Full Text\n\nKishan J, Garg K: Tuberculosis And Diabetes Mellitus: A Case Series of 100 Patients. SAARC J. TUBER. LUNG DIS. HIV/AIDS. 2010; 7(2): 34–38.\n\nDutt N, Gupta A: A Study On Diabetes Mellitus Among Cases Of Pulmonary Tuberculosis In A Tertiary Care Hospital, Ahmedabad. National Journal of Medical Research. 2014 Dec; 4(4): 349–353.\n\nNatarajaboopathy R, Jayanthi NN: A study on prevalence of diabetes and prediabetes in a newly diagnosed tuberculosis patients. J. Evolution Med. Dent. Sci. 2016; 5(99): 7231–7233. Publisher Full Text\n\nSarker M, Barua M, Guerra F, et al.: Double Trouble: Prevalence and Factors Associated with Tuberculosis and Diabetes Comorbidity in Bangladesh. PLoS One. 2016 Oct; 11(10): 1–15. Publisher Full Text\n\nTahir Z, Ahmad M, Akhtar AM, et al.: Diabetes mellitus among tuberculosis patients: a cross sectional study from Pakistan. Afri. Health Sci. 2016; 16(3): 671–676. Publisher Full Text\n\nEkeke N, et al.: Screening for diabetes mellitus among tuberculosis patients in Southern Nigeria: a multi-centre implementation study under programme settings. Sci. Rep. 2017 Mar; 7: 1–8. Publisher Full Text\n\nViswanathan V, Kumpatla S, Aravindalochanan V, et al.: Prevalence of Diabetes and Pre-Diabetes and Associated Risk Factors among Tuberculosis Patients in India. PLoS One. 2012; 7(7): 1–9. Publisher Full Text\n\nThe Looming Co-Epidemic of Tb-Diabetes: A Call to Action:Reference Source\n\nRaghuraman S, Vasudevan KP, Govindarajan S, et al.: Prevalence of diabetes mellitus among tuberculosis patients in Urban Puducherry. North Am. J. Med. Sci. 2014; 6: 30–34. Publisher Full Text\n\nOlayinka AO, Anthonia O, Yetunde K: Prevalence of diabetes mellitus in persons with tuberculosis in a tertiary health centre in Lagos, Nigeria. Indian J. Endocr. Metab. 2013; 17: 486–489. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "141525",
"date": "30 Jun 2022",
"name": "Anil Kapur",
"expertise": [
"Reviewer Expertise Diabetes",
"and Diabetes and TB co-morbidity"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have made an attempt to study the prevalence of DM among patients being treated for TB as well as understand the socio demographic factors.\nWhile the authors indicate a prevalence of 23.7%, this may not be accurate as they tested only so called symptomatic cases. It is well known that type 2 diabetes very rarely presents with the classical symptoms of polyuria, polydipsia etc. Moreover, symptoms such as weight loss, tiredness and fatigue, change in appetite etc. are similar to what is seen in TB and therefore ascribed to TB. Therefore estimating prevalence based on testing a subsample of symptomatic population is likely to underestimate the problem.\n\nThe authors state that DM comorbidity was higher in older population, however in the discussion they talk about age of the whole population and compare it with studies which are talking about age of patients with DM co-morbidity, so it is difficult to understand how their study is different?\n\nThe authors could have enhanced their study analysis by describing what was the diabetes diagnosis rate in people in the intensive treatment and continuous treatment phase. It is known that hyperglycemia may reduce even without antihyperglycemic treatment as the acute phase of TB comes under control and weight loss caused by TB helps improve glycemic control especially in those who were overweight. This again points towards the methodical flaw in testing only symptomatic cases.\n\nThe authors state \"DM is associated with about 10% of all TB cases worldwide.\" without providing a credible reference. \"DM accounts for 20% of smear-positive TB cases\" but no reference is given to support this.\n\nOverall the article does not add any further insight on the topic of DM-TB comorbidity except describing the prevalence of DM among TB patients in Vijayapura TB Unit in Karnataka, even this may not be accurate given that only a selected sub population of symptomatic patients were tested.\n\nThere is no data on mean blood glucose values of those diagnosed with DM and those without DM.\n\nBased on the review and the methodological problems the article cannot be justifiably titled as a prevalence of DM among newly diagnosed... at best it can be titled \"a cross sectional observational study to assess socio demographic factors in newly diagnosed TB DM comorbidity\".\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8524",
"date": "20 Jul 2022",
"name": "Rohith Motappa",
"role": "Author Response",
"response": "Respected Anil Kapur Sir, Thank you very much for the review of our manuscript. We sincerely appreciate all the valuable comments and suggestions given by you, which helped us to improve the quality of the article. Our responses to the Reviewers’ comments are described below in a point-to-point manner Due to time constraints and logistic problems we couldn’t test all the tuberculosis patients. It will be incorporated into our further research. Noted sir, in our study, we have more prevalence among the aged population, and that comparison will be removed and others will be kept. We couldn’t check the diagnostic rate in the intensive or continuation phase, hence that image will be removed, however, it will be given prime importance in our next study. References are as follows: Revised National TB Control Programme Technical and Operational Guidelines for Tuberculosis Control in India 2016.India. p 269. Park K. Epidemiology of Communicable Diseases. In: Textbook of Preventive and Social Medicine. 24th edition. Jabalpur, India: M/s Banarsidas Bhanot Publishers; 2017.p.185-216. That is accurate sir, we will modify accordingly. Mean Blood Glucose values were not recorded and it is one of the limitations of our study. Thanks and Regards"
}
]
},
{
"id": "141524",
"date": "07 Jul 2022",
"name": "Navya Nagendra",
"expertise": [
"Reviewer Expertise TB",
"Tobacco control",
"Primary health care"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study is a relevant study as DM (diabetes mellitus) plays a role in treatment process of TB. However there are few comments which can be addressed in the manuscript.\nIn study tools the use of stethoscope for this study is not justified.\n\nIt was mentioned non DM patients were first screened by using glucometer and further evaluated by determining blood glucose levels. However, it is not clear which parameters was considered for definitive diagnosis? In the diagnosis section it is mentioned FBS (fasting blood sugar) or PPBS (post prandial blood sugar) or HbA1C. Which test/tests for confirmation did the investigator ask for when RBS (random blood sugar) tested positive using glucometer?\n\nIn results it is not mentioned how many new cases of diabetes mellitus was diagnosed by the investigators during the study process.\n\nDiscussion can be elaborate stating the possible reasons for the results obtained.\n\nConclusion can be written better as presently it looks more like recommendations.\n\nKindly check for incorrect spelling like Ahmedabad in discussion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-674
|
https://f1000research.com/articles/12-1288/v1
|
09 Oct 23
|
{
"type": "Study Protocol",
"title": "Enzyme-linked immunosorbent assay and immunohistochemical analysis of mast cell related biochemicals in oral submucous fibrosis",
"authors": [
"Harshkant Gharote",
"Rahul Bhowate",
"Suwarna Dangore-Khasbage",
"Rahul Bhowate",
"Suwarna Dangore-Khasbage"
],
"abstract": "Oral submucous fibrosis (OSMF), a potentially malignant disorder, is developed by progressive fibrous tissue deposition in connective tissue along with atrophy of oral mucosa. Histological sections also show the mast cell infiltration in submucosa which may indicate their possible role in this entity. Abundant availability of biochemicals in mast cells like histamine and serine proteases like chymase may be released and play specific pathways in the disease pathophysiology. Possibly, if the histamine release has some part to play, diamine oxidase may also be found to have a relationship as it metabolizes histamine. The present study is proposed to identify the presence of chymase, histamine, and diamine oxidase in both, serum as well as tissue by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) respectively. This study may provide probable insight into the mast cell-related chemicals and their association with OSMF.",
"keywords": [
"Mast cells",
"Oral submucous fibrosis",
"Chymase",
"Histamine",
"Diamine oxidase"
],
"content": "Introduction\n\nOral submucous fibrosis (OSMF) is a potentially malignant disorder affecting the oral cavity and oropharynx causing extensive fibrous tissue deposition in submucosa. The presence of the mast cells in histological section of OSMF has been found to be related to various stages of OSMF. Although, studies have suggested that enzymes released by degranulation of mast cells in OSMF have some role in its initiation1–4 although the exact mechanism of action is not known. Therefore, it would be imperative to identify the presence of various biochemicals of mast cells in affected oral mucosa and perhaps the serum of the affected individuals. Hence, it can be stated that if there is histamine release during the initiation and progression of OSMF, possible increased levels of serum histamine levels can be observed in those patients. Additionally, in response to increased histamine levels, its metabolism will be initiated which is mediated through enzyme diamine oxidase (DAO). Therefore, variation in serum DAO levels may also be expected in those individuals.\n\nFurther, OSMF shows high potential for malignant transformation and is correlated to a series of biochemical alterations seen during the progress of the disease. The incidence of mast cells in the affected mucosa may be implicated in the malignant transformation. Studies show that mast cell serine proteases like tryptase and chymase significantly impact angiogenesis thus affecting tumor development and progression.5 There is evidence that supports an association between mast cell chymase and tumor angiogenesis. While tryptase, a neutral serine protease, is the abundant mediator stored in the mast cell granules that mediate degranulation of mast cells in allergic diseases.6 Thus, among these, evaluation of serum chymase may provide insights into the function of mast cells in the initiation and progression of OSMF.\n\n\nProtocol\n\nThe present study proposes that variations in the serum levels of diamine oxidase, histamine, and chymase may be noticed in OSMF. With this view, the present study will attempt to estimate the serum levels of chymase, histamine, and diamine oxidase in various stages of OSMF and compare them with the levels in healthy individuals and persons with areca habit without OSMF. Additionally, an immunohistochemical analysis will be performed for mast cell-related markers- chymase, diamine oxidase, and histamine to extrapolate their presence in serum.\n\nThe present research study has been approved by the Institutional Ethical Committee and will be conducted in the Department of Oral Medicine and Radiology, Sharad Pawar Dental College and Hospital, Wardha, India.\n\nAim: Assessment of variations in serum diamine oxidase, histamine, and chymase levels in the various stages of OSMF, areca chewers without OSMF, and healthy individuals by an enzyme-linked immunosorbent assay.\n\n\nObjectives\n\n\n\n1. To estimate serum histamine and diamine oxidase levels in the various stages of OSMF and between overall OSMF patients, areca chewers without OSMF, and healthy individuals.\n\n2. To estimate serum chymase levels in the various stages of OSMF and between overall OSMF patients, areca chewers without OSMF, and healthy individuals.\n\n3. To compare serum histamine and diamine oxidase levels in various stages of OSMF and between overall OSMF patients, areca chewers without OSMF, and healthy individuals.\n\n4. To compare serum chymase levels in the various stages of OSMF, and between overall OSMF patients, areca chewers without OSMF, and healthy individuals.\n\n5. To correlate serum diamine oxidase levels with serum histamine levels in the various stages of OSMF and between overall OSMF patients, areca chewers without OSMF, and healthy individuals.\n\n6. To correlate serum histamine, chymase, and diamine oxidase levels in various stages of OSMF and between overall OSMF patients, areca chewers without OSMF, and healthy individuals.\n\n7. To analyse the immunohistochemical expression of mast cell chymase, histamine, and diamine oxidase in OSMF, patients with areca habit without OSMF, and healthy individuals.\n\n\nMethod\n\nThe participants will be divided into three groups as OSMF group, individuals with areca habit without OSMF group, and Healthy individuals’ group. All individuals included will be above 18 years without any systemic or metabolic disorder. OSMF patients with a history of treatment will be excluded from the study. Written consent will be obtained after an explanation of the study procedure and protocol for the collection of serum samples and biopsy specimens.\n\nIndividuals with OSMF will be selected following functional staging classification of proposed by More et al.7 The classification of functional stages is given as follows:\n\nFunctional staging:\n\n‐ M1: Interincisal mouth opening - up to or greater than 35 mm.\n\n‐ M2: Interincisal mouth opening between 25 and 35 mm.\n\n‐ M3: Interincisal mouth opening between 15 and 25 mm.\n\n‐ M4: Interincisal mouth opening less than 15 mm.\n\nIndividuals with a history of areca consumption of more than one year duration, without any evidence of OSMF and other oral mucosal conditions like leukoplakia and lichen planus; and without history of any medical disorders\n\nIndividuals without OSMF and without habits and any systemic disorders/conditions.\n\nThe details of selected participants will be recorded in the case history proforma for recording clinical findings and investigations. The informed consent will be obtained before enrolling the participant for proposed investigations.\n\n\n\n1. The individuals with a history of the consumption of tobacco in any other form such as cigarette, bidi, and tobacco with lime.\n\n2. The individuals with a history of any systemic disease.\n\n3. The patients having history of receiving treatment for OSMF.\n\n4. The patients having history for antihistaminic medications.\n\nThe sample size selection will be at 95 per cent confidence interval with margin of error (d) at ±10%. Thus, following formula can be used to calculate sample size:\n\nIn the formula:\n\nn = sample size\n\nz = z score (1.96)\n\np = population proportion (0.0721)\n\nd = margin of error (0.1)\n\nn = 25.7\n\nThus, 26 individuals can be enrolled in each group for the study. Thus, a total sample size of 78 will be used for balanced study with each group consisting of 26 subjects.\n\nFive histological sections each for overall OSMF patients, areca chewers without OSMF and healthy individuals will be subjected for immunohistochemical analysis. Thus, 15 histopathological slides will be subjected to immunohistochemical expression for each marker viz. histamine, diamine oxidase and chymase.\n\nCommercially available ELISA kits will be procured for the estimation of serum histamine, chymase and diamine oxidase. The optical density will be measured by spectrophotometry at a wavelength of 450 nm ± 2 nm using an ELISA reader. The immunohistochemical analysis will be performed on formalin-fixed paraffin-embedded biopsy tissue sections of OSMF patients.\n\nCollection of serum samples: Blood sample will be drawn from antecubital vein using a 5 ml syringe and it will be taken into a vial containing a clot activator and serum gel separator. After that, it will be transferred into a centrifuge tube. The centrifugation of blood will be done for ten minutes, and serum will be obtained. Centrifugation is a procedure of using centrifugal force and the aim is to separate two unmixable liquids. There is sedimentation of heterogeneous mixtures in which more heavy constituents drift away from the axis of centrifuge and less heavy constituents drift towards the axis of centrifuge. The effective gravitational force on a test tube is increased which causes the precipitate to collect on the bottom of tube and the remaining supernatant liquid will be withdrawn with the help of a pipette.\n\nEstimation of serum Diamine oxidase levels: This ELISA kit will use the Sandwich-ELISA principle. The ELISA plate provided is pre-coated with an antibody specific to Mouse DAO. Standards or samples will be added to the ELISA plate wells and combined with the specific antibody. Next, a biotinylated detection antibody specific for Mouse DAO and Avidin-Horseradish Peroxidase (HRP) conjugate will be added sequentially to each micro plate well and incubated. Free components are washed away. The substrate solution will be added to each well. Only those wells that contain Mouse DAO, biotinylated detection antibody and Avidin-HRP conjugate will appear blue in color. The enzyme-substrate reaction will be terminated by the addition of stop solution and the color turns yellow. The optical density (OD) will be measured using spectrophotometry at a wavelength of 450 nm ± 2 nm. The OD value will be proportional to the concentration of Mouse DAO. The concentration of Mouse DAO in the samples will be calculated by comparing the OD of the samples to the standard curve.\n\nEstimation of serum Histamine levels: After Histamine is quantitatively acylated, the subsequent competitive ELISA kit will be used the microtiter plate format with the antigen bound to the solid phase. The acylated standards, controls and samples and the solid phase bound analyte will compete for a fixed number of antiserum binding sites. After the system is in equilibrium, free antigen and free antigen-antiserum complexes will be removed by washing. The antibody bound to the solid phase will be detected by an anti-rabbit IgG peroxidase conjugate using 3,3′,5,5′-tetramethylbenzidine (TMB) as a substrate. The reaction will be monitored at 450 nm. Quantification of unknown samples will be achieved by comparing their absorbance with a reference curve prepared with known standard concentrations.\n\nEstimation of serum chymase levels: This ELISA kit will use the Sandwich ELISA principle. The ELISA plate provided in this kit is precoated with an antibody specific to Human CMA1. Standards or samples will be added to the ELISA plate wells and combined with the specific antibody. Then, a biotinylated detection antibody specific for Human CMA1 and Avidin Horseradish Peroxidase (HRP) conjugate will be added successively to each micro plate well and incubated. Free components will be washed away. The substrate solution will be added to each well. Only those wells that contain Human CMA1, biotinylated detection antibody and Avidin HRP conjugate will appear blue in color. The enzyme substrate reaction will be terminated by the addition of stop solution and the color turns yellow. The optical density (OD) will be measured spectrophotometrically at a wavelength of 450 nm ± 2 nm. The OD value will be proportional to the concentration of Human CMA1. The concentration of Human CMA1 in the samples will be calculated by comparing the OD of the samples to the standard curve.\n\nImmunohistochemistry: The tissue sections will be deparaffinized in xylene solution and rehydrated through decreasing graded ethanol solution. Endogenous peroxidase activity will be inhibited by incubation for 10 minutes with 3% hydrogen peroxidase. The primary monoclonal antibodies used for mast cells will be anti-MC chymase, anti-MC diamine oxidase, and antihistamine antibodies. Staining will be performed at room temperature on an automatic staining workstation. Commercially available immunohistochemistry kits will be procured for these markers.\n\nThe statistical calculations will be performed by using following tests:\n\n1. Students t-test\n\n2. Analysis of variance (ANOVA)\n\n3. Pearson’s correlation\n\n\nExpected outcomes\n\nAs numerous mast cells are found to be present histologically in OSMF, it is expected to see the possible increase in serum levels of diamine oxidase, histamine, and chymase. Further, the presence of these enzymes will be confirmed by immunohistochemical analysis of histological sections. positive results in both the methods will give an insight into the role of these enzymes in progression and the possible role in the malignant transformation of OSMF.\n\n\nDiscussion\n\nThe prevalence of OSMF in India is 7.21% and shows higher rates of malignant transformation.8 The presence of mast cells in histological sections reveal their strong association with the disease so that some biochemicals and enzymes might play role in the progression and malignant transformation.3,9 Thus, detection of the mast cell-related chemicals in tissue and serum will delineate further mechanisms in pathogenesis. With special emphasis on diamine oxidase and its relation to histamine, the possible allergic response of mast cells to etiological factors like betel nut will be discerned. Further, possible detection of chymase in serum will define its elaborate role in local as well as a systemic mechanism in angiogenesis in OSMF.\n\nThe present study is approved by the Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research, Sawangi Wardha, India with the ethical approval reference no. DMIMS (DU)/Ph.D. Regn. /2021/1226.\n\nThe present study is in the process of data collection wherein serum samples are being collected from OSMF group, Areca habitual and control groups as per the design.",
"appendix": "Data availability\n\nNot applicable as it is a proposed protocol.\n\n\nReferences\n\nSirsat SM, Pindborg JJ: Mast cell response in early and advanced oral submucous fibrosis. Acta Pathol. Microbiol. Scand. 1967; 70: 174–178. PubMed Abstract\n\nPujari R, Vidya N: Mast cell density in oral submucous fibrosis: a possible role in pathogenesis. Int. J. Health Sci (Qassim). 2013 Jan; 7(1): 23–29. PubMed Abstract | Publisher Full Text\n\nKumar LB, Mathew P, Madhavan N, et al.: Evaluation of mast cells and burning sensation in various stages of Oral Submucous Fibrosis. J. Oral Biol. Craniofac. Res. 2020 Oct-Dec; 10(4): 430–434. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAnkle MR, Kale AD, Nayak R: Mast cells are increased in leukoplakia, oral submucous fibrosis, oral lichen planus and oral squamous cell carcinoma. J. Oral Maxillofac. Pathol. 2007; 11: 18–22. Publisher Full Text\n\nDe Souza Junior DA, Santana AC, da Silva EZM , et al.: The Role of Mast Cell Specific Chymases and Tryptases in Tumor Angiogenesis. Biomed. Res. Int. 2015; 2015: 1–13. Publisher Full Text\n\nMahmood M, Rashid BM, Amin K, et al.: Correlation between Serum Tryptase Level and Disease Severity in Asthmatic Patients in the Sulaimani Governorate. Int. J. Med. Res. Health Sci. 2016; 2016(5): 34–41.\n\nMore CB, Gupta S, Joshi J, et al.: Classification System for Oral Submucous Fibrosis. J. Indian Aca. Oral Med. Radiol. 2012; 24(1): 24–29. Publisher Full Text\n\nRao NR, Villa A, More CB, et al.: Oral submucous fibrosis: a contemporary narrative review with a proposed inter-professional approach for an early diagnosis and clinical management. J. Otolaryngol. Head Neck Surg. 2020 Jan 8; 49(1): 3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAgostinelli E, Tempera G, Viceconte N, et al.: Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach. Amino Acids. 2010 Feb; 38(2): 353–368. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "254085",
"date": "01 Apr 2024",
"name": "Xinjia Cai",
"expertise": [
"Reviewer Expertise Malignant transformation of oral potentially malignant disorders."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript provides a study protocol for enzyme-linked immunosorbent assay and immunohistochemical analysis of mast cell-related biochemicals in OSMF, and although some plans for the experiments are provided, the details of the experimental methodology and subsequent analyses need to be further optimized, and the Discussion section of the article should have included a discussion of studies on mast cells and OSMF or oral potentially malignant disorders, which would have enabled the reader to understand the potential significance of the study. However, studies related to mast cells in OSMF deserve to be investigated. Mast cells are myeloid-derived immune cells located primarily in tissues in contact with the external environment that can be stimulated by a variety of different triggers to act as sentinel immune cells, recruiting other immune cells into the affected microenvironment and altering their function by releasing chemokines, cytokines and other factors. The study of mast cells might help to elucidate the changes in the immune microenvironment in OSMF development and malignant transformation and provide an experimental basis for the development of immunotherapies. Introduction: Mast cells could be classified into two groups according to whether they contain tryptase without chymase (MCT) or both tryptase and chymase (MCTC), and according to the studies that have been reported, there were different roles for the two mast cell subtypes in cancer progression, and it is possible that both tryptase and chymase might play a role in the developments and malignant transformation of OSMF. Objectives: Since OSMF is a disease confined to the oral mucosa, it is suggested to correlate the serum levels and immunohistochemical expression levels of the mast cell secretions to clarify whether the changes in immunohistochemical expression levels would be more pronounced than the changes in serum levels. As mast cells can be divided into two subtypes, MCT and MCTC, the analysis of changes in mast cell subtypes and their spatial localization using immunofluorescence could be one of the further progress in this study. Method: How was the P (population ratio) of 0.0721 in the sample size calculation determined and is it based on any references? Please describe the tools or methods used to identify molecular expression after immunohistochemical staining of tissue sections. Expected outcomes: The effect of mast cells on the malignant transformation cannot be identified in the current study protocol. The prognostic information of the patient needs to be clarified (e.g. through regular clinical examination or follow-up, etc.), and correlation analyses between molecular expression and prognostic information need to be included in the study objectives, which may help to understand the immune mechanisms and microenvironmental alterations of malignant transformation in OSMF. Discussion: The current Discussion section does not provide enough information. Studies have reported the role of mast cells in OSMF as well as in other oral potentially malignant disorders and oral cancer, and although this study was only a study protocol, the authors should have discussed the results of the previous studies, clarifying the differences between this study and the previous studies, the existence of any additions to the previous results, and the implications of the study in terms of inspiration for future research. In the current manuscript, understanding the potential mechanisms of mast cell-related biochemicals in OSMF pathogenesis or carcinogenesis is difficult, and deepening the Discussion section may help to remedy this.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "11456",
"date": "29 Apr 2024",
"name": "Harshkant Gharote",
"role": "Author Response",
"response": "Suitable changes are made with addition of relevant information in the introduction section as suggested. Sample size calculation is elaborated with citation. Expected outcomes have been explained in details in context to the results of the assays. Discussion is supported with other studies with citations and the relevant information."
}
]
}
] | 1
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https://f1000research.com/articles/12-1288
|
https://f1000research.com/articles/13-516/v1
|
20 May 24
|
{
"type": "Research Article",
"title": "Retinopathy of Prematurity in Neonatal Intensive Care Unit at King Fahd University Hospital, Eastern Province: Prevalence, Risk Factors, and pattern of severity Seven years’ experience.",
"authors": [
"Mohammad A AlGhamdi",
"Anas J AlZahrani",
"Shahad M AlGarni",
"Salem K Albalawi",
"Abdulrahman A Alnaim",
"Hussain A AlGhadeer",
"Mohammad A AlGhamdi",
"Shahad M AlGarni",
"Salem K Albalawi",
"Abdulrahman A Alnaim",
"Hussain A AlGhadeer"
],
"abstract": "Background Premature newborns are susceptible to retinopathy of prematurity (ROP), a vasoproliferative disease of the developing retinal vessels, which is a major cause of potentially avoidable blindness. Due to geographical variations in newborn care, geographic variations in the epidemiology of ROP have been observed internationally during the last several decades. There was a correlation between the severity of the condition and the number of prenatal, postnatal, and other risk factors. This study aimed to examine the incidence and risk factors associated with retinopathy of prematurity in preterm infants.\n\nMethods A retrospective review of preterm newborns evaluated for retinopathy of prematurity between January 2016 and December 2022 was carried out at King Fahd Hospital of the University (KFHU), Khobar, Saudi Arabia. Infants who fulfilled the screening criteria (GA < 34 or Birth Weight (WT) ≤ 1500 g) underwent the screening test, and the International Classification of Retinopathy of Prematurity was used to classify retinopathy of prematurity. Risk factors and demographic information regarding ROP were assessed. Statistical analysis was performed using SPSS (version 20) with a 95% confidence interval (CI). Statistical significance was set at p < 0.05.\n\nResults Among the 200 preterm neonates that were evaluated and admitted to neonatal critical care units, 37% exhibited premature retinopathy, with 46.7% of those cases being in stage 1. The development of ROP was linked to gestational age, length of mechanical ventilation, septicemia, intraventricular hemorrhage, bronchopulmonary dysplasia, respiratory distress syndrome, and septicemia, according to univariate and multivariate logistic regression analyses.\n\nConclusion The incidence of total retinopathy in premature infants in this population was 37%. Evaluating these risk factors during the screening of high-risk premature infants will help determine the appropriate timing of examinations and treatment.",
"keywords": [
"Neonate",
"Preterm",
"retinopathy of prematurity",
"birth weight",
"gestational age",
"Saudi Arabia"
],
"content": "Introduction\n\nOne of the most significant and curable causes of childhood blindness is retinopathy of prematurity (ROP), a proliferative retinopathy that damages retinal blood vessels in preterm and low-birth-weight infants.1 Retinal detachment, which results from scarring of aberrant retinal blood vessels, is the primary cause of visual impairment and blindness in patients with ROP.2 Initially, it was speculated that ROP development was related to the complex and unreported use of oxygen supplementation in the care of premature infants placed in closed incubators for the treatment of respiratory distress. Patz et al. first described this relationship in 1952.3 Numerous studies have indicated that this illness is multifaceted and linked to risk factors, such as low birth weight, early intrauterine age, oxygen therapy while receiving medical care in a newborn critical care unit, respiratory issues, sepsis, and multiple parity. However, because some studies believe that this condition is dependent on geographic and medical facilities, the causal association between these elements has not been definitively proven.1 The immature vasculature develops in two stages. First, ischemia and a hyperoxic phase restrict the blood vessels in the retina. Second, this ischemia may cause mesenchymal spindle cells to produce angiogenic factors, which may then cause the development of new immature vasculature. The International Classification for ROP (ICROP) was established in 1984. According to the zones of the retina affected by the illness (1, 2, and 3), the extent of the disease as measured by clock hours (1-12), and the severity of the disease as measured by different stages (0–5), the ROP is categorized.4 Moreover, a demarcation line, ridge with height and width, proliferation of fibrovascular cells in extra retinal tissue, partial retinal detachment, and total retinal detachment are the five phases of ROP.2,4 This study aimed to determine the prevalence of ROP in the NICU at KFUH and to investigate the risk factors that influence its presence. The results of this study will provide local studies with a useful update and aid in enhancing the knowledge of how common the ROP is in our region.\n\nIn addition, Demirel et al. in 69 neonatal intensive care units (NICUs), A prospective cohort study was conducted between 2016 and 2017 in 69 neonatal intensive care units. The study included infants with a birth weight (BW) or gestational age (GA) of 1500 g or less, BW or GA of more than 1500 g, and an unstable clinical course. With a GA of 32 weeks or less, 964 (81%), and more than 32 weeks, 1151 (19%). Overall, 27% of the patients had ROP in some stages and 6.7% had severe ROP. In newborns with a BW of 1500 g, a lower BW, smaller GA, total number of days spent on oxygen, late-onset sepsis, frequency of red blood cell transfusions, and relative weight growth were found to be independent risk factors for severe ROP. Hence, suggestions for infants with a GA of 34 weeks or a BW of 1700 g should be screened in Turkey. To enhance newborn outcomes in Turkish NICUs, monitoring neonatal care standards, and carrying out quality improvement programs nationwide.5 In addition, Dwivedi et al. A five-year retrospective review was conducted at the Special Newborn Care Unit in a government Medical College located in eastern Madhya Pradesh. Thirty% of the 763 infants who underwent screening for ROP had this condition. Severe ROP prevalence was 14.2% (109) in 60 (55.5%) typical cases and 30 (27.7%) aggressive posterior ROP (APROP) cases. Stage IV and V ROP were detected in 18 patients (16.6%), making it a severe ROP. The mean gestational age (GA) and birth weight (BW) were 31.05 weeks and 1.34 kg, respectively, and both variables were negatively correlated with severe ROP. However, among late preterm infants, defined as those born at >34 weeks of age, 10% had severe ROP. The primary screening-related factor for stage IV and V ROP was late presentation. Severe ROP was quite common in this study. The main contributing factor to ROP-related blindness is late screening presentation.6 On the other hand, Fekri, et al. A 2021 case series study was conducted in Alavi Hospital between 2018 and 2019, including 400 infants with gestational age less than 34 weeks or birth weight of 2000 g or less. A total of 107 (26.8%) of the 400 preterm newborns investigated (57.2% male and 42.8% female) had ROP and 23 (21.5%) required therapy (5.8% of all infants studied required treatment). Zones I, II, and III were found in four (3.7%), 29 (27.1%), and 74 (69.2%) infants, respectively. Stages I, II, and III were present in 91 (85%), 11 (10.3%), and five (4.7%) babies, respectively. Parental consanguinity is linked to an increased risk of ROP.1 Similarly, Nugud, et al. done a retrospective cohort research in Dubai hospital and it was carried out between 2012 to 2014; 611 neonates were admitted to the NICU throughout the research period, out of 163 individuals who were enrolled in the study, 44 (27%) experienced ROP, whereas 119 (73%) did not have ROP at any of the subsequent ophthalmological screening assessment. Eight patients (4.9%) had stage I ROP, 27 patients Page 4 of 5 (16%) had stage II ROP, and 9 patients (5.5%) had stage III disease. Stage IV and V illnesses were not present in any of the patients. Infants with ROP were born at a gestational age of 27 weeks; 55 patients (33.7%) experienced intracranial hemorrhage, and 14.1% developed ROP.3 In Saudi Arabia This retrospective study was conducted at King Abdulaziz University Hospital (KAUH) in Jeddah between January 2010 and January 2021. The study included 37 infants with ROP. The study showed a 51.4% female predominance, a mean gestational age of 27 weeks, a mean birth weight of 800 g, birth weight, and the development of ROP in the right eye were significantly correlated, as were gestational age and the development of ROP in the same eye, and 66.7% of infants who developed ROP were delivered by cesarean section.7\n\nLastly, a cohort review was conducted in King Abdulaziz Medical City, Riyadh, Saudi Arabia, from 2010 to 2014, with a total of 581 newly enrolled patients. A total of 224 newborns (38.6%) had ROP, and 22 (10.4%) had stage 3 ROP. Infants with ROP had a mean BW of 938 g and mean GA of 27 weeks at delivery. Small GA at birth, low BW, low APGAR score at one minute, and prolonged oxygen (O2) therapy duration were all significant predictors of ROP.4\n\n\nMethods\n\nA retrospective cohort review enrolled all preterm infants admitted to the NICU between January 2016 and December 2022 at King Fahd Hospital of the University (KFHU).\n\nThe study was conducted by reviewing medical record of 201 neonate who had been admitting in NICU with the time January 2016 and December 2022 with the inclusion criteria of Gestational Age (GA) ≤ 34 or Birth Weight (WT) ≤ 1500 g, maternal age and risk factors, neonatal risk factors, and ROP staging. The records were approached confidentially, and the parents were assured that the collected data will be used only for the purpose of the research.\n\nThe data was collected using structured checklist that comprise infant characteristics: gender, age, gestational age, birth weight and history of oxygen therapy, as well as history of infant’s co-morbidities such as, apnea, respiratory distress syndrome (RDS), anemia, sepsis and others; maternal factors such as maternal age and mode of delivery are included in the checklist. Study subjects’ medical files were selected by a simple random sampling method using the medical recording number.\n\nCategorical variables are shown as numbers and percentages (%), whereas continuous variables are summarized as means and standard deviations. The relationship between ROP and demographic and clinical characteristics was conducted using the chi-square test as well as an independent sample t-test. Significant results were tested using a regression model to determine significant independent predictors of ROP. Statistical significance was set at p < 0.05. All data analyses were performed using the Statistical Package for Social Sciences version 26 (SPSS, Armonk, NY: IBM Corp, USA).\n\nAntenatal, natal, and postnatal risk factors for the development of ROP include maternal age, consanguinity preeclampsia or eclampsia, infants of diabetic mothers, chorioamnionitis, in vitro fertilization, multiple births, mode of delivery, sex, GA, BW, intrauterine growth retardation, respiratory distress syndrome (RDS), surfactant treatment, duration of oxygen therapy, intracranial hemorrhage, congenital heart disease, early/late neonatal sepsis (clinically proven or culture positive), necrotizing enterocolitis (NEC), number of red blood cell (RBC) transfusions, and bronchopulmonary dysplasia (BPD). In addition to jaundice, urinary tract infection, premature rupture of the membrane, and seizures can occur.\n\n\nResults\n\n(Table 1) This study included 201 patients. The female/male ratio was similar to that in 50.2% of males. Nearly half of the mothers (49.8%) were 30 years old. More than three-quarters (77.6%) of the participants had singletons. The gestational age was 32 weeks or less (73.6%). Approximately 63.2% of the patients delivered by cesarean section. Newborns who received surfactant were approximately 60.7%, mostly one dose (72.1%). In addition, 55.7% had a duration of O2 therapy of less than 28 days. The prevalence of patients who were diagnosed with ROP was 37.3%, mainly stage 1 (46%), unilateral (73.3%), and Zone 2 (25.3%). A total of 48.3% of premature patients received a blood transfusion, mainly two units (37.1%). Stressing the importance of follow-up screening, 30.8% only continued to follow up. The mean birth weight was 1203.9 (SD 365.7) g. In addition, the mean APGAR scores at 1, 5, and 10 minutes were 5.59, 7.67, and 7.26, respectively.\n\n\n\n• Male\n\n\n\n• Female\n\n\n\n• ≤30 years\n\n\n\n• >30 years\n\n\n\n• Single\n\n\n\n• Twin\n\n\n\n• Triplets\n\n\n\n• ≤32 weeks\n\n\n\n• >32 weeks\n\n\n\n• Normal\n\n\n\n• Cesarean\n\n\n\n• Yes\n\n\n\n• No\n\n\n\n• One dose\n\n\n\n• Two doses\n\n\n\n• Three doses\n\n\n\n• <28 days\n\n\n\n• >28 days\n\n\n\n• Yes\n\n\n\n• No\n\n\n\n• Unknown\n\n\n\n• Zone 1\n\n\n\n• Zone 2\n\n\n\n• Zone 3\n\n\n\n• Stage 1\n\n\n\n• Stage 2\n\n\n\n• Stage 3\n\n\n\n• Unilateral\n\n\n\n• Bilateral\n\n\n\n• Yes\n\n\n\n• No\n\n\n\n• 1 unit\n\n\n\n• 2 units\n\n\n\n• ≥3 units\n\n\n\n• Yes\n\n\n\n• No\n\n* ROP: retinopathy of prematurity.\n\nAs shown in Table 2, the top five most common risk factors for ROP included respiratory distress syndrome (88.1%), septicemia (87.1%), jaundice (62.7%), multiple pregnancies (51.7%), and consanguinity (49.8%). None of the patients had congenital diaphragmatic hernias or hypothyroidism.\n\nAs shown in Table 3, the prevalence of ROP was significantly more common among those who had a gestational age of 32 weeks or less and who received surfactant, as well as duration of O2 therapy for more than 28 days. Patients who received blood transfusion, continued to follow-up, and had risk factors such as respiratory distress syndrome, Septicemia, Jaundice, consanguinity, intraventricular hemorrhage, congenital heart disease, and bronchopulmonary dysplasia showed statistically significant results compared to other risk factors. In addition, low birth weight was associated with an increased risk of ROP (p<0.001), while APGAR 1 min (p<0.001) and APGAR 5 minutes (p<0.001) were significantly lower in patients with ROP. Conversely, the difference was less significant among those with maternal diabetes (p=0.011).\n\n§ P-value has been calculated using Chi-square test.\n\n‡ P-value has been calculated using independent sample t-test.\n\n** Significant at p<0.05 level.\n\nIn a univariate regression model (Table 4), it was found that patients who used Surfactant were 12.9 times higher to be associated with an increased risk of ROP (OR=12.952; 95% CI=5.512 – 30.433; p<0.001). Patients who had more than 28 days of O2 therapy use were 9.3 times more likely to have an increased risk for ROP than those who had less than 28 days of O2 therapy (OR=9.302; 95% CI=4.786 – 18.081; p<0.001). The number of patients at follow-up was 46.7-fold higher at an increased risk of ROP (OR=46.750; 95% CI=18.665 – 117.091; p<0.001). Patients with risk factors were at increased risk for ROP, such as Septicemia (OR=8.588; 95% CI=1.968 – 37.482; p=0.004), jaundice (OR=4.089; 95% CI=2.076 – 8.054; p<0.001), consanguinity (OR=12.628; 95% CI=6.106 – 26.118; p<0.001), intraventricular hemorrhage (OR=4.900; 95% CI=2.649 – 9.063; p<0.001), congenital heart disease (OR=4.406; 95% CI=2.390 – 8.124; p<0.001), and bronchopulmonary (OR=7.827; CI=3.313 – 18.488; p<0.001), whereas maternal diabetes was likely at decreased risk for ROP (OR=0.176; 95% CI=0.039 – 0.783; p=0.023). Gestational age > 32 weeks was associated with a decreased risk of ROP compared to those ≤32 weeks (OR=0.146; 95% CI=0.059 – 0.363; p<0.001). In addition, decreased birth weight was marginally associated with an increased risk of ROP (OR=1.004; 95% CI=1.003 – 1.005; p<0.001), APGAR 1 min (OR=1.476; 95% CI=1.244 – 1.752; p<0.001), and APGAR 5 min (OR=1.474; 95% CI=1.192 – 1.823; p<0.001).\n\n\n\n• ≤32 weeks\n\n\n\n• >32 weeks\n\n\n\n• Yes\n\n\n\n• No\n\n\n\n• <28 days\n\n\n\n• >28 days\n\n\n\n• Yes\n\n\n\n• No\n\n\n\n• Yes\n\n\n\n• No\n\n\n\n• Septicemia\n\n\n\n• Jaundice\n\n\n\n• Consanguinity\n\n\n\n• Intraventricular hemorrhage\n\n\n\n• Congenital Heart disease\n\n\n\n• Bronchopulmonary dysplasia\n\n\n\n• Diabetes mellitus\n\n** Significant at p<0.05 level.\n\n\nDiscussion\n\nFor retinopathy of prematurity (ROP) screening, We adhered to the Ministry of Health Guidelines for retinopathy of premature screening. They applied recommendations to identify premature infants with a GA of less than 32 weeks and a BW of less than 1500 g as possible ROP risk individuals. The reported prevalence of ROP among at-risk newborns varies widely, ranging between 29% and 68%.4 The prevalence of patients diagnosed with ROP was 37.3%, which is relatively similar to that reported by Al-Qahtani et al. in 2019 but substantially lower than the proportion discovered in the 2008 study by Binkhathlan et al.4,8 Bokhary O. et al. Research conducted by an expert ophthalmologist separately staged ROP for each eye. According to the ICROP, stages 1, 2, and 3 are the demarcation line, ridge, and extraretinal, respectively. Both preterm eyes had a stage 1 predominance, with 18 in the right eye and 21 in the left eye, respectively.7 We found similar results in our study: the prevalence was stage 1 (46. %), and a unilateral eye affection by (73.3%). In addition, the most involved site was zone II (25.3%), which is in contrast to a study conducted in Tabuk city, Saudi Arabia, where they found that the majority of the implicated sites (69.4%) were in zone III, with zones II and I accounting for 27.8% and 2.7%, respectively.2\n\nThe proportion of males and females with ROP during the study period varied among the sample populations, but the variation was statistically insignificant. This is concordant with a study conducted in a tertiary hospital in Riyadh, Saudi Arabia that concluded the insignificant result of male and female ratio.4 The are well-known primary risk factors for the development of ROP; GA, BW, and oxygen therapy.6 A low BW and APGAR score, short GA with total number of days on oxygen were discovered to be independent risk factors for ROP in newborns. A gestational age of more than 32 weeks was at a decreased risk for ROP compared to those with 32 weeks or less. Additionally, decreased birth weight was marginally associated with an increased risk of ROP. Likewise, other studies have found the same occurrence of these risk factors.1,4,6,8\n\nThis study demonstrated that packed red blood cell transfusions have a significant impact on the emergence of ROP. This is due to the decreased oxygen affinity of adult hemoglobin in packed red cells, and transfusions may enhance oxygen transport to the retina. Repeated transfusions may also lead to free iron buildup, which, as determined by the Fenton reaction, may lead to an increase in the formation of free hydroxyl radicals that could harm the retina.9 Numerous reports have claimed that receiving blood transfusions may increase the risk of developing ROP, although according to various studies, a transfusion restriction strategy did not lower the incidence of ROP.10,11 According to our research, limiting blood transfusions based on recommended threshold hemoglobin values may help lower the prevalence of ROP.\n\nRespiratory distress syndrome (RDS) is prevalent in premature newborns. RDS affects 60% of infants weighing less than 1500 g and 80% of infants weighing less than 1000 g at birth.12 Low O2 and high CO2 levels and pulmonary and metabolic acidosis are common in this population. Each of these factors is strongly correlated with the emergence of acute ROP. A study in 1992 demonstrated that surfactant therapy administered within the first 48 h of life significantly increased the survival rate of critically ill neonates. Surfactant therapy can initially increase oxygenation to 20–30 kPa, which is continuously monitored by pulse oximetry to optimize tissue oxygenation and limit the risk of hyperoxemia. Hence, we concluded that surfactant therapy is not associated with an increased incidence or severity of severe ROP in the preterm population.13 The analysis of a study in 1994 concluded that surfactants do not contribute to more severe forms of ROP, but rather raise the risk of acquiring ROP.14 This study showed a statistically significant association between ROP, surfactant use, and RDS in this population.\n\nScheduling the first examination should be based on postmenstrual age (GA plus chronological age) rather than postnatal age because ROP takes a period of time to develop in very young infants. Stage 3 ROP did not develop until 31 weeks of postmenstrual age, according to prospective studies that involved infants aged 22–25 weeks GA.15 Furthermore, the most significant factor contributing to advanced ROP was the lack of timely screening, and false results were also a significant prothem.16 Our study showed that patients at follow-up were 46.7-fold higher at an increased risk of ROP. An ophthalmologist conducting an initial assessment should suggest subsequent screening examinations. Neonatal sepsis has been linked to the development in numerous studies.17,18 In the present study, ROP in low birthweight newborns was independently associated with late-onset sepsis. Cytokines and endotoxins, which directly affect retinal angiogenesis, may play a role in sepsis. Hypotension is frequently present throughout this phase and can impede tissue perfusion and result in retinal ischemia.\n\nConsanguineous marriage was an intriguing finding in the current study and was a significant independent factor related to retinopathy in preterm infants. This is similar to Fekri Y. study which found that consanguineous marriages had a considerably greater prevalence of preterm infant retinopathy (42% vs. 22.9%) as well as linked to a 3.2-fold increase in the incidence of retinopathy in preterm infants.1 Considering the retrospective design of the study, the sample size was relatively small, it was carried out at a single hospital, and generalization cannot be guaranteed. Multicentric prospective and longitudinal studies with adequate sample sizes are strongly advised to evaluate additional variables that affect ROP. In addition, ophthalmologists participated in a standardized process for ROP grading and follow-up plans as outpatients.\n\nThis study has a few drawbacks. First and foremost, this study was unable to include all of the identified risk factors. ROP is a complex illness with many risk factors. As a result, there was a possibility of selection bias when choosing potential risk variables. Second, this study was conducted in a single neonatal intensive care unit (NICU). Although the NICU is a regional referral hospital and all admitted preterm newborns receive standardized and advanced care, the number of preterm infants included was limited. Nonetheless, this study comes to a highly consistent conclusion and clearly distinguishes the risk variables for ROP development and progression.\n\n\nConclusion\n\nIn conclusion, retinopathy of prematurity is one of the major disorders affecting premature newborns. The incidence of ROP in our study was within the range of disease incidence in developing countries and comparable to other local investigations. The important risk factors for ROP were low BW and low GA, although the ROP screening criteria should be expanded to encompass newborns with GAs between 32 and 35 weeks. Independent risk factors that influence ROP include the use of surfactants, septicemia, consanguinity, blood transfusion, and the pattern of follow-up. It is also advised to limit the quantity and duration of O2 therapy to the absolute minimum required. To enhance newborn outcomes, it is crucial to track neonatal care standards and implement quality improvement initiatives across the country.\n\nThe study design was approved by Institutional Review Board – Imam Abdulrahman Bin Fisal University, Dammam Saudi Araia on 15-06-2023 which waived the requirement for obtaining informed consent with the ethical No. IRB-PGS-2023-01-244. The study participants’ information was kept confidential and anonymous.",
"appendix": "Data availability statement\n\nFigshare: Retinopathy of Prematurity in Neonatal Intensive Care Unit at King Fahd University Hospital, Eastern Province: Prevalence, Risk Factors, and pattern of severity Seven years’ experience, https://doi.org/10.6084/m9. figshare.25323421.v2. 19\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nFekri Y, Ojaghi H, Momeni N, et al.: Retinopathy of prematurity in Ardabil, North West of Iran: Prevalence and risk factors. Eur. J. Transl. Myol. 2021; 31(4): 10063. Published 2021 Nov 10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlBalawi HB, AlBalawi NS, AlSuhaimi NA, et al.: Incidence and Risk Factors for Retinopathy of Prematurity in Tabuk City, KSA. Middle East Afr. J. Ophthalmol. 2020; 27(2): 105–109. Published 2020 Jul 20. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNugud AA, Nugud S, Nugud A, et al.: Perinatal risk factors for development of retinopathy of prematurity in a tertiary neonatal intensive care unit. J. Taibah Univ. Med. Sci. 2019; 14(3): 306–311. Published 2019 Jun 3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAl-Qahtani B, Al-Otaibi M, Alabdulajabbar K, et al.: Retinopathy of Prematurity Incidence and Risk Factors in a Tertiary Hospital in Riyadh, Saudi Arabia. Middle East Afr. J. Ophthalmol. 2020; 26(4): 235–239. Published 2020 Jan 29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBas AY, Demirel N, Koc E, et al.: Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TR-ROP study): a prospective, multicentre study in 69 neonatal intensive care units. Br. J. Ophthalmol. 2018; 102(12): 1711–1716. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDwivedi A, Dwivedi D, Lakhtakia S, et al.: Prevalence, risk factors and pattern of severe retinopathy of prematurity in eastern Madhya Pradesh. Indian J. Ophthalmol. 2019; 67(6): 819–823. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBokhary OA, Abumohssin AG, Alghamdi MK, et al.: Preterm Assessment at Birth and Its Association With the Development of Retinopathy of Prematurity (ROP): A Tertiary Care Center Experience. Cureus. 2022; 14(12): e33126. Published 2022 Dec 30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBinkhathlan AA, Almahmoud LA, Saleh MJ, et al.: Retinopathy of prematurity in Saudi Arabia: incidence, risk factors, and the applicability of current screening criteria. Br. J. Ophthalmol. 2008; 92(2): 167–169. PubMed Abstract | Publisher Full Text\n\nWardle SP, Drury J, Garr R, et al.: Effect of blood transfusion on lipid peroxidation in preterm infants. Arch. Dis. Child Fetal Neonatal Ed. 2002; 86(1): 46F–448F. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHesse L, Eberl W, Schlaud M, et al.: Iron load and retinopathy of prematurity. Eur. J. Pediatr. 1997; 156(6): 465–470. Publisher Full Text\n\nDani C, Reali MF, Bertini G, et al.: The role of blood transfusions and iron intake on retinopathy of prematurity. Early Hum. Dev. 2001; 62(1): 57–63. PubMed Abstract | Publisher Full Text\n\nLuerti M, Parazzini F, Agarossi A, et al.: Risk factors for respiratory distress syndrome in the newborn. A multicenter Italian survey. Study Group for Lung Maturity of the Italian Society of Perinatal Medicine. Acta Obstet. Gynecol. Scand. 1993; 72(5): 359–364. Publisher Full Text\n\nRankin SJ, Tubman TR, Halliday HL, et al.: Retinopathy of prematurity in surfactant treated infants. Br. J. Ophthalmol. 1992; 76(4): 202–204. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTermote JU, Schalij-Delfos NE, Wittebol-Post D, et al.: Surfactant replacement therapy: a new risk factor in developing retinopathy of prematurity? Eur. J. Pediatr. 1994; 153(2): 113–116. PubMed Abstract | Publisher Full Text\n\nJefferies AL: Canadian Paediatric Society, Fetus and Newborn Committee. Retinopathy of prematurity: An update on screening and management. Paediatr. Child Health. 2016; 21(2): 101–104. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSanghi G, Dogra MR, Katoch D, et al.: Demographic profile of infants with stage 5 retinopathy of prematurity in North India: implications for screening. Ophthalmic Epidemiol. 2011; 18(2): 72–74. PubMed Abstract | Publisher Full Text\n\nTolsma KW, Allred EN, Chen ML, et al.: Neonatal bacteremia and retinopathy of prematurity: the ELGAN study. Arch. Ophthalmol. 2011; 129(12): 1555–1563. PubMed Abstract | Publisher Full Text\n\nStoll BJ, Hansen NI, Adams-Chapman I, et al.: Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004; 292(19): 2357–2365. PubMed Abstract | Publisher Full Text\n\nAlGhamdi M, AlZahrani A, AlGarni S, et al.: Retinopathy of Prematurity in Neonatal Intensive Care Unit at King Fahd University Hospital, Eastern Province: Prevalence, Risk Factors, and pattern of severity Seven years’ experience. Dataset. figshare. 2024. Publisher Full Text"
}
|
[
{
"id": "310053",
"date": "10 Sep 2024",
"name": "Hannah Blencowe",
"expertise": [
"Reviewer Expertise Maternal",
"newborn",
"child health",
"stillbirth",
"epidemiology",
"public health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper contains a clear description of the prevalence and risk factors for ROP in a single NICU in Saudi Arabia. The methods and results are generally clear, and conclusions appropriate. Abstract: States 200 participants, but main text 201 Introduction is currently very long and unsystematic. It would be clearer for the reader if the available evidence on prevalence of ROP in the region was summarised more succinctly, thereby reducing the length of the introduction. It would be helpful in the introduction to more clearly reference the existing literature on risk factor to justify the choice of variables to explore in the risk factor analysis. In the 1st paragraph of the introduction - line 7 it is not clear what is meant by 'early intrauterine age'. lines 8 - 9 'However, because some studies believe that this condition is dependent on geographic and medical facilities, the causal association between these elements has not been definitively proven' a single reference is cited, but this is not consistent with much of the other literature available on the topic. Methods: The ethics committee waived the need for ethical approval, however it is stated that 'parents were assured that the collected data would only be used for the purpose of research' why/ how was this done? Statistical methods - only univariate analyses are undertaken. It is not clear why no multivariate analyses to adjust for other factors were considered\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-516
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https://f1000research.com/articles/13-515/v1
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20 May 24
|
{
"type": "Study Protocol",
"title": "An observational prospective cross-sectional study on extravascular lung water by lung ultrasound as a guide to fluid resuscitation therapy in adult septic shock in tertiary care hospital in central India",
"authors": [
"Abhishek Jain",
"Amol Singam",
"Anjalee Chiwhane",
"V N K Srinivas Mudiganti",
"Amol Singam",
"Anjalee Chiwhane",
"V N K Srinivas Mudiganti"
],
"abstract": "Background Septic shock is a life-threatening condition characterized by systemic inflammation and organ dysfunction, with fluid resuscitation being a cornerstone of management. However, indiscriminate fluid administration can lead to fluid overload and worsen outcomes. Extravascular lung water (EVLW) estimation by lung ultrasound has emerged as a promising tool for guiding fluid therapy in septic shock, allowing clinicians to assess pulmonary edema and tailor resuscitation strategies accordingly.\n\nMethods This prospective observational study aims to evaluate the utility of EVLW estimation by lung ultrasound in guiding fluid resuscitation therapy in adult patients with septic shock admitted to a rural tertiary care teaching hospital. Eligible patients admitted to the intensive care unit (ICU) will undergo baseline demographic and clinical assessments, including lung ultrasound, to quantify EVLW using B-line analysis. Fluid resuscitation therapy will be initiated based on EVLW findings, with subsequent adjustments guided by repeat lung ultrasound examinations at 6, 12, 24, and 48 hours post-initiation. Outcome measures include changes in mean PaO2/FiO2 ratios, respiratory parameters, renal function, fluid balance, and mortality rates.\n\nExpected Outcome We anticipate that EVLW-guided fluid resuscitation therapy will lead to more precise and tailored management of septic shock, potentially reducing the incidence of fluid overload, ARDS, and renal dysfunction. By optimizing fluid management strategies based on individual patient characteristics and responses, we aim to improve clinical outcomes and enhance the delivery of care for patients with septic shock.",
"keywords": [
"Septic shock",
"Extravascular lung water",
"Lung ultrasound",
"Fluid resuscitation therapy",
"Critical care",
"Outcome assessment"
],
"content": "Introduction\n\nSeptic shock remains a leading cause of mortality and morbidity worldwide, particularly in critically ill patients admitted to intensive care units (ICUs).1 Despite advancements in critical care management, septic shock continues to pose significant challenges due to its complex pathophysiology and variable clinical presentations.2 Fluid resuscitation therapy (FRT) plays a crucial role in the early management of septic shock, aiming to restore intravascular volume and optimize tissue perfusion.3\n\nHowever, indiscriminate fluid administration can lead to complications such as fluid overload and pulmonary edema, which are associated with worse outcomes in patients with septic shock.4 Therefore, accurately assessing intravascular volume status and guiding fluid therapy is paramount for optimizing patient outcomes in this population.5\n\nLung ultrasound has emerged as a valuable tool for assessing extravascular lung water (EVLW), providing a non-invasive means of detecting pulmonary edema and guiding fluid management in patients with septic shock.6 The presence and severity of pulmonary edema, as indicated by the number of B-lines detected on lung ultrasound, have been shown to correlate with EVLW and may serve as a marker of fluid responsiveness in critically ill patients.7\n\nDespite growing evidence supporting the utility of lung ultrasound in assessing EVLW and guiding fluid therapy, more research needs to be conducted to evaluate its implementation in resource-limited settings, particularly in rural tertiary care hospitals.8 Therefore, this study aims to investigate the role of extravascular lung water estimation by lung ultrasound in guiding fluid resuscitation therapy in adult patients with septic shock admitted to a rural tertiary care teaching hospital.\n\nThis study aims to evaluate the utility of extravascular lung water (EVLW) estimation by lung ultrasound in guiding fluid resuscitation therapy in adult patients with septic shock admitted to a rural tertiary care teaching hospital.\n\n\nObjective\n\n\n\n1. To quantify extravascular lung water (EVLW) using lung ultrasound by counting the number of B-lines in patients with septic shock.\n\n2. To determine the optimal dose and timing of fluid resuscitation therapy (FRT) based on the presence and severity of extravascular lung water (EVLW) detected by lung ultrasound.\n\n\n\n1. To assess changes in mean PaO2/FiO2 ratios at various time points following initiation of fluid resuscitation therapy.\n\n2. To monitor lung parameters such as pulmonary edema and ARDS.\n\n3. To evaluate renal parameters, including serum creatinine levels and urine output in response to fluid resuscitation therapy.\n\n\nMethods\n\nThis study will employ an observational prospective cross-sectional design to assess the utility of extravascular lung water (EVLW) estimation by lung ultrasound in guiding fluid resuscitation therapy in adult patients with septic shock.\n\nThe study population will consist of adult patients admitted to the intensive care unit (ICU) of Acharya Vinoba Bhave Rural Hospital (AVBRH) with a diagnosis of septic shock. Patients meeting the inclusion criteria and not meeting the exclusion criteria will be eligible for enrollment in the study.\n\n\n\n• Adult patients (age ≥ 18 years)\n\n• Diagnosed with septic shock\n\n• Admitted to the ICU at AVBRH\n\n\n\n• Patients aged below 18 years\n\n• Pregnant women\n\n• Active bleeding, acute respiratory distress syndrome (ARDS), or chronic lung diseases\n\n• Left ventricular ejection fraction less than 50%\n\n• Diagnosed with cardiogenic shock\n\nThe study will be conducted at Acharya Vinoba Bhave Rural Hospital (AVBRH), a tertiary care teaching hospital in Wardha District. AVBRH serves as a major healthcare facility for rural residents in central India. The study will specifically take place within the ICU of AVBRH, where critically ill patients, including those with septic shock, receive specialized care and management.\n\nThe data collection process for this study will involve systematic and standardized procedures to ensure the accuracy and reliability of the collected data. Trained research personnel will be responsible for conducting the data collection activities under the supervision of the principal investigator. At the outset, eligible patients meeting the inclusion criteria will be identified upon admission to the intensive care unit (ICU) at Acharya Vinoba Bhave Rural Hospital (AVBRH). Patients who fulfill the study criteria will be approached for participation, and informed consent will be obtained from the patient or their legally authorized representative.\n\nOnce consent is obtained, baseline demographic information, including age, sex, BMI, and past medical history, will be recorded. Clinical parameters such as blood pressure, heart rate, respiratory rate, and temperature will also be documented. Additionally, relevant comorbidities and risk factors will be noted for each participant. The primary outcome measure, extravascular lung water (EVLW), will be assessed using lung ultrasound by counting the number of B-lines. Trained ultrasound operators will perform the lung ultrasound examinations according to standardized protocols. The presence and severity of pulmonary edema will be determined based on the number of B-lines observed between rib spaces.\n\nFollowing the initial assessment, fluid resuscitation therapy (FRT) will be initiated based on the presence and severity of EVLW detected by lung ultrasound. The type and dose of fluid therapy will be recorded, along with any adverse events or complications associated with the intervention. Subsequent lung ultrasound examinations will be conducted at predetermined time points (6, 12, 24, and 48 hours post-FRT initiation) to monitor changes in EVLW and assess treatment response. Clinical parameters, laboratory values (including serum creatinine levels and urine output), and vital signs will also be recorded each time.\n\nData integrity and quality will be ensured throughout the study period through regular monitoring and validation checks. The research team will promptly address and resolve any discrepancies or missing data. Confidentiality of patient information will be maintained at all times, with data stored securely in compliance with regulatory guidelines.\n\nDuring the study period, approximately patients with septic shock are expected to participate. The sample size calculation was based on a previously reported prevalence of sepsis and septic shock, which was found to be 42.6%. This is an estimated sample size of approximately 44 participants. The study will include patients diagnosed with septic shock admitted to the Intensive Care Unit (ICU) at the research site, adhering to predefined inclusion criteria to ensure relevance to the research objectives and sample homogeneity.\n\nThis study’s statistical methods encompass descriptive and inferential techniques to comprehensively analyze the collected data about extravascular lung water (EVLW) estimation and fluid resuscitation therapy (FRT) in patients with septic shock. Descriptive statistics will be employed initially to summarize baseline characteristics of the study population, encompassing demographic variables, clinical parameters, and comorbidities. Continuous variables such as age, BMI, and laboratory values will be summarized using measures of central tendency (mean, median) and dispersion (standard deviation, interquartile range). In contrast, categorical variables like sex and comorbidities will be presented as frequencies and percentages. Inferential statistics will then be applied, including repeated measures analysis of variance (ANOVA) to assess changes in mean PaO2/FiO2 ratios and other continuous variables over multiple time points post-FRT initiation. Chi-square analysis will be utilized to compare categorical variables such as ICU mortality rates and requirements for renal replacement therapy between different patient groups based on EVLW levels. Additionally, correlation analysis will explore associations between EVLW measured by lung ultrasound and relevant variables like serum creatinine levels and urine output. In contrast, survival analysis techniques such as Kaplan-Meier curves and Cox proportional hazards models may evaluate the association between EVLW and long-term outcomes. Regression analysis will further investigate predictors of outcomes such as fluid overload or the need for renal replacement therapy. A significance level of p < 0.05 will be considered statistically significant for all analyses, and results will be interpreted alongside measures of effect size and confidence intervals to ensure robust conclusions. Analysis will be conducted using appropriate software packages such as R Studio to facilitate accurate and reliable interpretation of findings.\n\nThe Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (DU) has granted its approval to the study protocol (Reference number: DMIHER (DU)/IEC/2022/297. Date: 21-07-2022). Before commencing the study, we will obtain written informed consent from all participants, providing them with a comprehensive explanation of the study’s objectives.\n\nAfter the completion of the study, we will publish it in an indexed journal or conference.\n\nThe study has not yet started. After the publication of the protocol, we will start recruiting for the study.\n\n\nDiscussion\n\nSeptic shock remains a significant cause of morbidity and mortality in critically ill patients, necessitating timely and effective management strategies. This study protocol outlines the investigation of extravascular lung water (EVLW) estimation by lung ultrasound as a guide to fluid resuscitation therapy (FRT) in adult patients with septic shock. The rationale for utilizing lung ultrasound lies in its non-invasive nature, bedside availability, and ability to provide real-time assessment of pulmonary edema, a common complication in septic shock.6 By quantifying EVLW using B-line analysis, clinicians may tailor fluid resuscitation strategies to individual patient needs, potentially reducing the risk of fluid overload and associated complications such as acute respiratory distress syndrome (ARDS) and renal dysfunction.9\n\nThe primary objective of this study is to determine EVLW through lung ultrasound, with subsequent adjustment of FRT based on these findings. This approach aligns with personalized medicine, wherein treatment decisions are tailored to patient-specific characteristics and responses.10 By incorporating EVLW assessment into the fluid resuscitation protocol, clinicians can optimize hemodynamic management and potentially improve patient outcomes. Secondary objectives include evaluating the impact of EVLW-guided FRT on respiratory parameters, renal function, fluid balance, and mortality rates. These outcomes are clinically relevant and reflect the multifaceted nature of septic shock management.\n\nSeveral methodological considerations warrant discussion. The observational prospective cross-sectional design enables the evaluation of EVLW-guided FRT in real-world clinical settings, enhancing the generalizability of study findings. However, this design may be susceptible to confounding factors and biases inherent to observational studies. To mitigate these risks, rigorous data collection protocols, standardized procedures for EVLW assessment, and statistical adjustments for potential confounders will be employed.\n\nLimitations of this study include the potential for selection bias, given its single-center nature and reliance on patients admitted to a rural tertiary care teaching hospital. Additionally, while lung ultrasound offers valuable insights into pulmonary fluid status, its interpretation may be operator-dependent, necessitating rigorous training and quality assurance measures. Furthermore, the impact of EVLW-guided FRT on long-term outcomes such as ICU mortality and organ dysfunction warrants further investigation through prospective longitudinal studies.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nRudd KE, Johnson SC, Agesa KM, et al.: Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020; 395: 200–211. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSinger M, Deutschman CS, Seymour CW, et al.: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315: 801–810. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRhodes A, Evans LE, Alhazzani W, et al.: Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017; 43: 304–377. PubMed Abstract | Publisher Full Text\n\nBoyd JH, Forbes J, Nakada T, et al.: Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit. Care Med. 2011; 39: 259–265. PubMed Abstract | Publisher Full Text\n\nMalbrain MLNG, Marik PE, Witters I, et al.: Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol. Intensive Ther. 2014; 46: 361–380. PubMed Abstract | Publisher Full Text\n\nVolpicelli G, Elbarbary M, Blaivas M, et al.: International evidence-based recommendations for point-of-care lung ultrasound. Intensive Care Med. 2012; 38: 577–591. PubMed Abstract | Publisher Full Text\n\nLichtenstein DA, Mezière GA: Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol. Chest. 2008; 134: 117–125. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXirouchaki N, Magkanas E, Vaporidi K, et al.: Lung ultrasound in critically ill patients: comparison with bedside chest radiography. Intensive Care Med. 2011; 37: 1488–1493. PubMed Abstract | Publisher Full Text\n\nMartin GS, Eaton S, Mealer M, et al.: Extravascular lung water in patients with severe sepsis: a prospective cohort study. Crit. Care. 2005; 9: R74–R82. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGinsburg GS, Phillips KA: Precision Medicine: From Science To Value. Health Aff (Millwood). 2018; 37: 694–701. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "289696",
"date": "10 Jul 2024",
"name": "Jhuma Sankar",
"expertise": [
"Reviewer Expertise Sepsis",
"septic shock",
"fluid therapy",
"resuscitation",
"USG studies",
"fluid responsiveness"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe current study protocol aims to assess pulmonary edema by USG estimation of extra vascular lung water. The fluid therapy would be titrated as per the EVLW findings at 6, 12, 24 and 48 hours. The study protocol is well written with good rationale and outcomes defined. However, there are methodological issues. The major comment is the method of performing the USG should be described step by step with images . The definition of pulmonary edema or fluid overload clinically as well as by USG (even if for study purposes) should be clearly defined. Counting of B lines is mentioned but not defined clearly.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "296452",
"date": "22 Aug 2024",
"name": "Luigi Vetrugno",
"expertise": [
"Reviewer Expertise lung ultrasound",
"diaphragm ultrasound",
"cardiac ultrasound",
"fluid management",
"airway management"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI read your protocol with interest.\nPay attention to exclude diastolic dysfunction as one of your criteria is EF > 50%.\nSometime pneumonia can increase \"local\" B-lines and further in ARDS diffuse B-lines in hypovolemic patients and this need hemodynamic monitoring. I do not understand why you exclude Pregnant women as we previously found that: Lung Ultrasound Pattern Is Normal during the Last Gestational Weeks: An Observational Pilot Study. Gynecol Obstet Invest. 2017;82(4):398-403. doi: 10.1159/000448140. Epub 2016 Oct 5. PMID: 27701165. Please state that in the discussion. I will be happy to read the revised version of this protocol. Good Luck\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-515
|
https://f1000research.com/articles/13-514/v1
|
20 May 24
|
{
"type": "Research Article",
"title": "Design of SARS-CoV-2 protein S peptides recognized by the most frequent HLA alleles in the Moroccan population using an immunoinformatics approach",
"authors": [
"Meryem Fakhkhari",
"Bouabid Badaoui",
"Hicham Oumzil",
"Khalid Sadki",
"Meryem Fakhkhari",
"Bouabid Badaoui",
"Hicham Oumzil"
],
"abstract": "Background The coronavirus disease 2019 (COVID-19) is an infectious disease, caused by the new coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and exhibits diverse clinical outcomes and symptoms in infected individuals, emphasizing the need to investigate how human genetic diversity influences the virus’s impact. This study aims to employ in silico methods to identify epitopes capable of eliciting an immune response, focusing on the most prevalent HLA-I and HLA-II alleles in the Moroccan population.\n\nMethods Our research consisted in predicting peptide-binding affinities between the most prevalent HLA Class I and Class II alleles in the Moroccan population and SARS-CoV-2 spike glycoprotein (S protein) peptides of variants isolated from strains of Moroccan patients. We performed the same analyses for SARS-CoV-2 wild type S protein to assess the ability of these HLA alleles to interact with peptides in the presence or absence of SARS-CoV-2 mutations.\n\nResults In a broader sense, 12 distinct HLA Class I and Class II alleles in the Moroccan population have been identified as possibly interacting with 19 epitopes in the SARS-CoV-2 S protein. Findings of this study must be validated in both in vitro and in vivo models.\n\nConclusions These data may help clarify the issue of host cell susceptibility and the outcome of SARS-CoV-2 infection, and may guide further research to uncover potential targets for the vaccination strategy.",
"keywords": [
"SARS-CoV-2",
"S protein",
"peptides",
"Variants",
"HLA alleles Moroccan population"
],
"content": "Introduction\n\nThe COVID-19 pandemic has caused unparalleled economic and social disruption across the world. COVID-19 is a respiratory illness that results from an infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus was initially in December 2019 in Wuhan, China, and has quickly spread throughout the world.1,2 By December 2022, the World Health Organization (WHO) had reported over 651 million cases of COVID-19, with more than 6 million deaths attributed to the disease. The first instance of the COVID-19 virus was registered in the Kingdom of Morocco on March 02, 2020, in Casablanca city. The Moroccan patient had acute pneumonia, and the infection was imported from Europe.3 Between January 3, 2020, and August 16, 2023, the Ministry of Health in Morocco reported a total of 1 275 320 confirmed cases of COVID-19 with 16 297 deaths in within the country. The mortality rate is stated at 1.3% (Ministry of Health, Morocco, CNOUSP report, April 2023).\n\nA notable characteristic of COVID-19 that continually surprises us is the extensive range of clinical symptoms that patients exhibit across different populations. These symptoms range from mild to severe, with severe cases potentially leading to pneumonia, respiratory failure, multi-organ failure, and death.4 These differences highlight the significance of studying and understanding human genetic variation during infections. Previous studies have linked the susceptibility and outcomes of multiple infectious diseases to the genetic background of the host. The Human Leukocyte Antigen system is believed to be among the components that could explain differences in virus susceptibility and severity, and it has been recommended as a potential genetic factor that affects a person’s immune response to SARS-CoV-2.5,6\n\nThe human leukocyte antigen (HLA) system, which is a major component of the adaptive immune system, is in charge of recognizing and binding both endogenous and exogenous antigens.5 HLA molecules are classified into two classes: HLA class I and HLA class II. While HLA class II (DR, DQ, DP) molecules are primarily responsible for displaying peptides from external pathogens, HLA class I (A, B, C) molecules are crucial for immune protection against intracellular pathogens. HLA polymorphism is the highest degree of variability found in the genetic code of the proteins expressed by this system. This variability is considered an important factor in determining a person’s resistance to, or susceptibility to specific infectious illnesses.6,7\n\nThe SARS-CoV-2 genome encodes a number of structural proteins, including the spike protein (S), envelope protein (E), membrane glycoprotein (M), and nucleocapsid phosphoprotein (N), which is in accordance with other coronaviruses. Additionally, it encodes nonstructural proteins, such as open reading frame 1ab (ORF1ab), ORF3a, ORF6, ORF7a, ORF8, and ORF10.8 This study focused on the spike protein, which is the primary antigen present on the surface of the virus, facilitating SARS-CoV-2 entrance into human host cells,9,10 and additionally because of its high mutation rate, which enables it to alter its shape and escape host immune responses.11 The Spike protein, also known as S protein, is made up of two subunits, S1 and S2, which are connected by a furin cleavage site. The S1 subunit comprises the receptor-binding domain (RBD), which is responsible for the virus’s ability to adhere to the host cell membrane and initiate infection. The S2 subunit has a hydrophobic fusion loop which facilitates membrane fusion. Therapeutic developments against SARS-CoV-2 are often targeted at RBD.10 The spike is frequently studied for the development of neutralizing antibodies and vaccines, and is widely considered as a successful target for detection purposes.12–17\n\nDue to their effectiveness and up speed, computational techniques are far superior to laboratory tests in the drug development process because they can anticipate the antigenic epitopes of specific viral proteins.18\n\nIn Morocco, like in other countries, the COVID-19 pandemic had a noticeable impact on the health system. Although many risk factors of COVID-19 severity have been described, data from North Africa are limited. This study used an immunoinformatics approach to predict the peptide-binding affinity between the most frequent HLA Class I and Class II alleles in the Moroccan population and SARS-CoV-2 S protein peptides of variants isolated from strains of Moroccan patients. The same analysis was also performed for the SARS-CoV-2 wild-type S protein to assess the ability of these HLA alleles to interact with peptides in the presence or absence of the SARS-CoV-2 mutation, and thus predict which epitopes would be most effective at acting as potent immunogens.\n\n\nMethods\n\nThe most frequent HLA class I and class II alleles in the Moroccan population were obtained from the Allele Frequency Net Database (http://www.allelefrequencies.net/pop6001a.asp), which compiled data from studies conducted in different regions of Moroccan. The average allelic frequency of each allele was then computed using data from multiple regions.\n\nTo evaluate the HLA-peptide-binding affinity predictions, we obtained the mutated sequences of the SARS-COV-2 S protein for each variant of concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529), from strains of Moroccan patients available on the GISAID databank.\n\nThe reference genome (WuhanHu-1 strain) was obtained from the NCBI Refseq database under GenBank accession number NC_045512.2. The amino acid sequence of the S protein from the reference genome was retrieved in FASTA format and used as a reference sequence for comparison with the sequences of the variants.\n\nThe NetMHCpan - v4.0 and NetMHCIIpan v. 3.2 programs were used to predict HLA peptide-binding affinity for HLA class I and class II alleles, respectively. The FASTA sequences from both the GISAID databank and the NCBI database were imported and analyzed. Using the aforementioned sequences, we predicted the binding affinity of each HLA allele to all potential 10-mer and 15-mer overlapping peptides for HLA class I and class II, respectively.\n\nWe used Vaxijen V.2.0 (http://www.ddg-pharmfac.net/vaxijen/VaxiJen/VaxiJen.html), to assess the potential antigenicity of the predicted peptides by setting a threshold score of less than 0.5 and employing a virus model to eliminate non-antigenic peptides.\n\nThe antigenicity response assesses the capability of the proposed epitopes to prompt an immune response.\n\nToxicity of the predicted peptides was set using the ToxinPred server (https://webs.iiitd.edu.in/raghava/toxinpred/multi_submit.php). This server enables the identification of highly toxic or non-toxic peptides from a large pool of peptides submitted by analyzing their key physico-chemical properties such as hydrophobicity, hydropathicity, amphipathicity, molecular weight, and pI charge.\n\nThe HLA binding affinity frequencies of peptides from the mutated S protein were compared with those from the reference S protein (Wild-Type) to identify which HLA alleles had varying binding affinities in the presence of mutations.\n\nThis analysis aimed to identify mutated peptides that bind well the most frequent HLA alleles in the Moroccan population.\n\n\nResults\n\nTable 1 lists the most frequent HLA class I and class II alleles in the Moroccan population, according to the HLA Allele Frequency Net Database. The data reveals a prevalence of HLA class I alleles over class II alleles, with a total of 10 HLA-A, 6 HLA-B, 7 HLA-C, and 7 HLA-DRB1 alleles identified.\n\nIn Table 2, mutations identified in the SARS-CoV-2 S protein isolated from strains of Moroccan patients are presented, sourced from the GISAID databank. A total of 23 mutations were identified on the spike protein across the different variants of SARS-CoV-2. The mutations highlighted in bold are the common ones found among all six variants, while each variant also includes unique mutations not observed in other variants of concern.\n\nOur dataset for peptide-binding affinity prediction comprises only peptides with a mutation in their core. Two hundred and twenty peptides were identified based on the results from NetMHCpan servers. Non-immunogenic or toxic peptides were discarded from further analysis. Consequently, eighty-five immunogenic peptides in the SARS-CoV-2 S protein were retained for the assessment of binding affinities (as shown in Table 3).\n\nThe comparison of HLA class I binding repertoires between wild type and mutated S protein peptides revealed that 10 mutations in the S protein had the potential to bind to HLA-A*02:01, HLA-A*29:02, HLA-A*68:02, HLA-B*45:01, and HLA-C*16:01.\n\nAmong these HLA alleles, HLA-A*02:01 and HLA-C*16:01 had one good binder each with T547K and T376A, respectively. HLA-A*29:02 had three good binders with H69-V70, P681R, and D614G. For HLA-A*68:02, four good binders were found with H69-V70, Y144-145, L252R, and T547K. Similarly, HLA-B*45:01 had four good binders with E484K, E484Q, E484A, and D614G.\n\nRegarding HLA Class II, 9 mutated peptides were found able to interact with HLA-DRB1*01:02, HLA-DRB1*03:01, HLA-DRB1*04:02, HLA-DRB1*04:05, HLA-DRB1*07:01, HLA-DRB1*13:02, and HLA-DRB1*15:01.\n\nAmong these, HLA-DRB1*01:02, DRB1*04:02, and HLA-DRB1*04:05 had a common good binder with V213G. HLA-DRB1*03:01 and HLA-DRB1*15:01 had four good binders each, which were (H69-V70, K417N, K417T, and D614G) and (Y144-145, K417N, K417T, and V213G) respectively. On the other hand, HLA-DRB1*07:01 and HLA-DRB1*13:02 had five good binders each with (K417N, K417T, L252R, T19R, and V213G) and (N501Y, H69-V70, K417T, T19R, and V213G) respectively. Table 4 provides more details on the peptide sequences.\n\nThe HLA-DRB1*15:02 allele was the only one to exhibit good binding affinity to the N501Y mutation, which emerged in the Alpha, Beta and Gamma lineages. Conversely, the H69-V70, Y144-145, L452R, and D614G mutations were presented by both HLA class I and class II alleles, while the K417N, K417T, and V213G mutations were only presented in Class II.\n\nNetMHCIIpan v. 3.2 did not predict any peptides for the most frequent HLA class II alleles in the Moroccan population for both the Spike V6F mutation and the wild-type spike sequence. All predicted peptides for the T478K mutation in the receptor binding domain (RBD) of the Delta variant were deemed non-antigenic by the Vaxijen tool. This mutation is believed to help evade recognition by the immune system,19 particularly with regards to antibodies and neutralization, or in impairing the interaction between the RBD and drugs.20 Tables 5 and 6 present the antigenicity scores of the selected binders.\n\n* Selected good binders.\n\n* Selected good binders.\n\n\nDiscussion\n\nDue to their efficiency and speed, computational approaches have consequently arisen as potent alternatives or choices for the development of diagnostic tools for infectious diseases, as well as new immunotherapies and vaccines.10 Predictive computationals for identifying antigenic epitopes in viral or bacterial proteins are critical and valuable in the development of new drugs.18–21 It has been recommended to employ these tools before performing laboratory experiments because they are more efficient and faster to use.22 Several studies have utilized immunoinformatic approaches on different SARS-CoV-2 proteins to design potential epitope vaccine candidates against SARS-CoV-2,8,23–31 In this study, we designed SARS-CoV-2 S protein peptides that bind to the most frequent HLA class I and class II alleles in the Moroccan population. The aim was to evaluate the potential of these peptides to elicit an immune response using in silico methods. The SARS-CoV-2 S protein was chosen as the target in this study because it is the most mutated structural protein of SARS-CoV-2 and is frequently studied as it helps in target recognition and cellular entry. This protein promotes viral infection and is essential for the development of neutralizing antibodies and vaccines.10,12 Additionally, the S protein is commonly acknowledged as a suitable target for detection purposes.16\n\nIn this study, we selected twenty-three mutations from five SARS-CoV-2 variants (Alpha, Beta, Gamma, Delta, and Omicron) as they are considered key mutations associated with higher transmission and reinfection rates.32,33 We evaluated the ability of class I and class II HLA molecules to present the mutated peptides of the SARS-CoV-2 spike protein. Our findings showed that HLA class I molecules had a higher proportion of good binders compared to HLA class II alleles, with 10 versus 9, respectively.\n\nThe peptides SSQCVNLRTRTQLPP, VRQIAPGQTGNIADY, VRQIAPGQTGTIADY, DSKVGGNYNYRYRLF, and PINLGRDLPQGFSAL were selected as immunogens for HLA class II based on their antigenic score (1.2742; 1,1378; 1,1046; 1,0304 and 0.9873 respectively), non-allergenicity, and lack of toxicity. For HLA class I, the peptides NFNFNGLKGT, GGNYNYRYRL, GVAGFNCYFP, TNSRRRARSV, and YQGVNCTEVP exhibited the best antigenic scores of 1.3565; 1,2747; 1,2211; 1,1716; and 1,0639, respectively. The scores therefore indicate the stimulation of the immune system in response to the proposed epitopes. Given their binding affinity with the most frequent HLA alleles in the Moroccan population and antigenicity response, these epitopes may be promising candidates for vaccine development.\n\nPotential immunogenic peptides have been identified as prospective COVID-19 vaccine targets using in silico studies. Previous research has indicated that HLA-A*02:01, among other alleles, exhibited the strongest binding to COVID-19 epitopes.34,35 Our study revealed that the “NFNFNGLKGT” peptide of the T547K mutation in the Omicron variant showed a higher antigenicity score and had the highest affinity to this particular allele. Consequently, this epitope could be a promising candidate for the development of a COVID-19 vaccine.\n\nRegarding the HLA-C allele, a peptide belonging to the Omicron subvariant peptide with the sequence SFSAFKCYGV was predicted to have high binding affinity with HLA-C*16:02. However, it was not selected due to its Vaxijen score of 0.5764. This gene has been previously reported to have a less distinctive peptide repertoire when compared to HLA-A and HLA-B.36 HLA-C*16:01 was found to be more prevalent among individuals who had a mild form of COVID-19 compared with those with severe or critical forms of the disease in a cohort of Spanish Mediterranean Caucasians.37\n\nHLA-A*68:02 was the MHC-I molecule that bound the immune epitopes of the S protein L452R mutation of the Delta variant (GGNYNYRYRL). A study conducted in Tapachula Chapas, found that although the frequency of HLA-A*68 was lower in COVID-19 patients who were ill, the allele provided 3.3 times more protection against a fatal outcome from SARS-CoV-2 infection in mestizo individuals.38 Both HLA-A*68:01 and HLA-A*68:02 have the ability to bind to a large number of SARS-CoV-2 peptides with varying degrees of affinity. Furthermore, a systematic review and meta-analysis found that HLA-A*68:02, along with other HLA class I and class II alleles, were associated with COVID- 19 severity.39\n\nHLA-A, HLA-B, HLA-C, and HLA-DRB1 may serve as potential indicators of the severity and likelihood of death from COVID-19. However, further research on a larger scale are required to confirm this hypothesis.\n\nA literature review has revealed that HLA class I alleles may be deemed as determinants of either resistance or susceptibility to COVID-19. This is due to the fact that these alleles have the ability to bind to SARS-CoV-2 peptides, leading to the modulation of the immune response against the virus.40\n\nSeveral studies have employed a similar approach to design peptides for the protein S of SARS-CoV-2. Baruah et al. found five CD8+ T cell epitopes YLQPRTFLL, GVYFASTEK, EPVLKGVKL, VVNQNAQAL, and WTAGAAAYY, along with eight B cell epitopes that are more likely to bind MHC class I commonly found in China.41 In a second study, Bhattacharya et al. identified thirteen potential MHC-I antigenic peptides (SQCVNLTTR, GVYYHKNNK, GKQGNFKNL, GIYQTSNFR, VSPTKLNDL, KIADYNYKL, KVGGNYNYL, EGFNCYFPL, GPKKSTNLV, SPRRARSVA, LGAENSVAY, FKNHTSPDV, and DEDDSEPVL) and three potential MHC-II antigenic peptides (IHVSGTNGT, VYYHKNNKS, and FKNHTSPDV).42\n\nJoshi et al. proposed the MHC-I ITLCFTLKR peptide as a potential vaccine candidate,43 while another study conducted on the Brazilian population found 24 epitopes that bind to 17 different MHC-I alleles.44 Other studies have also identified B-cell epitopes on spike protein for developing a protective vaccine against SARS-CoV-2.23,24,45\n\nThe current study’s findings are novel and have not been previously published. These findings are valuable for the development of broadly accessible vaccine epitopes targeting SARS-CoV-2, and can also offer valuable insights for investigating T-cell responses.\n\nNevertheless, to confirm their immunogenicity against SARS-CoV-2, further in-vitro experimental validation or in vivo studies are necessary.\n\n\nConclusions and perspectives\n\nThis is the first Moroccan in silico study to assess potential immunogenic peptides within the S protein of various SARS-CoV-2 variants according to the most frequent HLA alleles in the Moroccan population, using an immunoinformatic approach. The findings of the current study have not been published previously. To sum up, we identified 19 epitopes in the SARS-CoV-2 S protein that can bind to 12 distinct HLA Class I and Class II alleles among the Moroccan population, as they were characterized by a probability of triggering an immune response. However, in order to validate their immunogenicity against SARS-CoV-2, additional in-vitro experimental validation or in vivo studies are essential.\n\n\nEthics approval and consent to participate\n\nNot applicable.\n\n\nConsent for publication\n\nNot applicable.\n\n\nAuthor’s contributions\n\nMF: Methodology, Data curation, Formal analysis, Writing – original draft. BB: Data curation, Writing – Review & Editing. HO: Visualization, Writing – review & editing, Investigation. KS: Conceptualization, Methodology, Formal analysis, Supervision, Writing – review & editing.",
"appendix": "Data availability statement\n\nFigshare: Dataset - Design of SARS-CoV-2 protein S peptides recognized by the most frequent HLA alleles in the Moroccan population using an immunoinformatics approach. https://doi.org/10.6084/m9.figshare.25737534.v1. 46\n\nThe dataset contains the following data:\n\n• Data.docx: COVID-19 Wild Type Sequence and Selected Mutations from Various Variants\n\n• Data.xlsx: Peptide-HLA Class I Binding Affinity Assessment Wild Type (WT) and Mutated (MT) Peptide Binding Scores\n\n• Data.xlsx: Peptide-HLA Class II Binding Affinity Assessment Wild Type (WT) and Mutated (MT) Peptide Binding Scores\n\n• Data.docx: SARS-CoV-2 Sequences of different variants retrieved from GISAID Databank\n\n• Data.xlsx: Table 1. Averages frequency of most common HLA class I and II alleles in the Moroccan population\n\n• Data.xlsx: Table 2. SARS-CoV-2 S protein mutations isolated from strains of Moroccan patients (n=23)\n\n• Data.xlsx: Table 3. SARS-CoV-2 S peptides for Class I and II HLA alleles of wild and mutated types\n\n• Data.xlsx: Table 4. Sequences of the S protein good binders with their HLA alleles\n\n• Data.xlsx: Table 5. Vaxijen scores (antigenicity) of the predicted MHC class I allele binding peptides.\n\n• Data.xlsx: Table 6. Vaxijen scores (antigenicity) of the predicted MHC class II allele binding peptides.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nExtended data is not applicable in this instance. All relevant data and materials utilized in our study have been comprehensively outlined in the ‘Materials and Methods’ section and provided in the Data Availability section. This includes the data uploaded to the designated repository, as specified in the Data Availability section, which encompasses all materials pertinent to our research. We encourage readers to refer to the repository for access to the complete set of data and materials used in this study. Additionally, all servers, databases and methods utilized in this research are outlined in detail within the manuscript. For further inquiries regarding the data or materials, please contact the corresponding author.\n\n\nAcknowledgements\n\nNot applicable.\n\n\nReferences\n\nIturrieta-Zuazo I, Rita CG, García-Soidán A, et al.: Possible role of HLA class-I genotype in SARS-CoV-2 infection and progression: A pilot study in a cohort of Covid-19 Spanish patients. Clin. Immunol. Orlando Fla. 2020; 219: 108572. PubMed Abstract | Publisher Full Text | Free Full Text\n\nToyoshima Y, Nemoto K, Matsumoto S, et al.: SARS-CoV-2 genomic variations associated with mortality rate of COVID-19. J. Hum. Genet. 2020; 65(12): 1075–1082. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nTian X, Li C, Huang A, et al.: Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg. Microbes Infect. 2020; 9(1): 382–385. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee JH, Choi M, Jung Y, et al.: A novel rapid detection for SARS-CoV-2 spike 1 antigens using human angiotensin converting enzyme 2 (ACE2). Biosens. Bioelectron. 2021; 171: 112715. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAwadasseid A, Wu Y, Tanaka Y, et al.: Current advances in the development of SARS-CoV-2 vaccines. Int. J. Biol. Sci. 2021; 17(1): 8–19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrogi S: Computational Approaches for Drug Discovery. Molecules. 2019; 24(17): 3061. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDi Giacomo S, Mercatelli D, Rakhimov A, et al.: Preliminary report on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike mutation T478K. J. Med. Virol. 2021; 93(9): 5638–5643. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPondé RAA: Physicochemical effect of the N501Y, E484K/Q, K417N/T, L452R and T478K mutations on the SARS-CoV-2 spike protein RBD and its influence on agent fitness and on attributes developed by emerging variants of concern. Virology. 2022; 572: 44–54. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSeghrouchni F, Contini S, Markova R, et al.: Design of immunogenic peptides from Mycobacterium tuberculosis genes expressed during macrophage infection. Tuberculosis. 2009; 89(3): 210–217. PubMed Abstract | Publisher Full Text\n\nSunita SA, Singh Y, Shukla P: Computational tools for modern vaccine development. Hum. Vaccin. Immunother. 2019; 16(3): 723–735. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSanami S, Zandi M, Pourhossein B, et al.: Design of a multi-epitope vaccine against SARS-CoV-2 using immunoinformatics approach. Int. J. Biol. Macromol. 2020; 164: 871–883. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen HZ, Tang LL, Yu XL, et al.: Bioinformatics analysis of epitope-based vaccine design against the novel SARS-CoV-2. Infect. Dis. Poverty. 2020; 9(1): 88. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTakagi A, Matsui M: Identification of HLA-A*02:01-Restricted Candidate Epitopes Derived from the Nonstructural Polyprotein 1a of SARS-CoV-2 That May Be Natural Targets of CD8+ T Cell Recognition In Vivo. J. Virol. 2021; 95(5): e01837–e01820. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbraham Peele K, Srihansa T, Krupanidhi S, et al.: Design of multi-epitope vaccine candidate against SARS-CoV-2: a in-silico study. J. Biomol. Struct. Dyn. 2021; 39(10): 3793–3801. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHe J, Huang F, Zhang J, et al.: Vaccine design based on 16 epitopes of SARS-CoV-2 spike protein. J. Med. Virol. 2021; 93(4): 2115–2131. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlam A, Khan A, Imam N, et al.: Design of an epitope-based peptide vaccine against the SARS-CoV-2: a vaccine-informatics approach. Brief. Bioinform. 2021; 22(2): 1309–1323. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChukwudozie OS, Gray CM, Fagbayi TA, et al.: Immuno-informatics design of a multimeric epitope peptide based vaccine targeting SARS-CoV-2 spike glycoprotein. PLoS One. 2021; 16(3): e0248061. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBehmard E, Soleymani B, Najafi A, et al.: Immunoinformatic design of a COVID-19 subunit vaccine using entire structural immunogenic epitopes of SARS-CoV-2. Sci. Rep. 2020; 10: 20864. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang E, Chakraborty AK: Design of immunogens for eliciting antibody responses that may protect against SARS-CoV-2 variants. PLoS Comput. Biol. 2022; 18(9): e1010563. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumavath R, Barh D, Andrade BS, et al.: The Spike of SARS-CoV-2: Uniqueness and Applications. Front. Immunol. 2021; 12: 663912. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJhun H, Park HY, Hisham Y, et al.: SARS-CoV-2 Delta (B.1.617.2) Variant: A Unique T478K Mutation in Receptor Binding Motif (RBM) of Spike Gene. Immune Netw. 2021; 21(5): e32. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee CH, Koohy H: In silico identification of vaccine targets for 2019-nCoV. F1000Res. 2020; 9: 145. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJandaghi A, Samiei A, Khaghanzadeh N: Human Leukocyte Antigen as a Predictor of COVID-19 Severity. Hormozgan Med. J. 2022; 26(3): 156–162. Publisher Full Text\n\nBasir HRG, Majzoobi MM, Ebrahimi S, et al.: Susceptibility and Severity of COVID-19 Are Both Associated With Lower Overall Viral–Peptide Binding Repertoire of HLA Class I Molecules, Especially in Younger People. Front. Immunol. 2022; 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVigón L, Galán M, Torres M, et al.: Association between HLA-C alleles and COVID-19 severity in a pilot study with a Spanish Mediterranean Caucasian cohort. PLoS One. 2022; 17(8): e0272867. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHernández-Doño S, Sánchez-González RA, Trujillo-Vizuet MG, et al.: Protective HLA alleles against severe COVID-19: HLA-A*68 as an ancestral protection allele in Tapachula-Chiapas, Mexico. Clin. Immunol. Orlando Fla. 2022; 238: 108990. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDobrijević Z, Gligorijević N, Šunderić M, et al.: The association of human leucocyte antigen (HLA) alleles with COVID-19 severity: A systematic review and meta-analysis. Rev. Med. Virol. 2022; 33: e2378. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMenezes L, Garcia LR, Casseb SMM: HLA-I allelic variants related to resistance and susceptibility to severe SARS-CoV-2 infection: Variantes alélicas do HLA I relacionados a resistência ou suscetibilidade a infecção grave pelo SARS-CoV-2. Concilium. 2023; 23(5): 293–307. Publisher Full Text\n\nBaruah V, Bose S: Immunoinformatics-aided identification of T cell and B cell epitopes in the surface glycoprotein of 2019-nCoV. J. Med. Virol. 2020; 92(5): 495–500. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBhattacharya M, Sharma AR, Patra P, et al.: Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): Immunoinformatics approach. J. Med. Virol. 2020; 92(6): 618–631. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJoshi A, Joshi BC, Mannan MA, et al.: Epitope based vaccine prediction for SARS-COV-2 by deploying immuno-informatics approach. Inform. Med. Unlocked. 2020; 19: 100338. PubMed Abstract | Publisher Full Text | Free Full Text\n\nde Moura RR , Agrelli A, Santos-Silva CA, et al.: Immunoinformatic approach to assess SARS-CoV-2 protein S epitopes recognised by the most frequent MHC-I alleles in the Brazilian population. J. Clin. Pathol. 2021; 74(8): 528–532. PubMed Abstract | Publisher Full Text\n\nSamad A, Yamchi A, Madanchi H, et al.: Designing a multi-epitope vaccine against SARS-CoV-2: an immunoinformatics approach. J. Biomol. Struct. Dyn. 2020; 40: 14–30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFakhkhari M, et al.: Design of SARS-CoV-2 protein S peptides recognized by the most frequent HLA alleles in the Moroccan population using an immunoinformatics approach. [Dataset]. figshare. 2024. Publisher Full Text"
}
|
[
{
"id": "309414",
"date": "23 Sep 2024",
"name": "Gustavo Fioravanti Vieira",
"expertise": [
"Reviewer Expertise Immunoinformatics"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nWhile it is very important to design vaccines and immunotherapeutic approaches considering the genetics of the immunized population, some aspects of the work need to be improved or reconsidered before indexing:\nThe introduction is too basic and lacks a stronger foundation with references supporting the influence of HLA on the variation in severity, particularly in relation to COVID. What was the criterion for the selected alleles? \"Most frequent alleles\" is too vague. NetMHCpan is already at version 4.1 for both class I and II MHC. For class I, it was essential to use nonamers instead of decamers, as nonamers are the standard fragment length for most alleles. Alternatively, the appropriate size should have been used for each different allele. VaxiJen is suitable for an initial analysis, but it does not include MHC-related information in its prediction, making it insufficient for this case. Ideally, you should use sequences already described as immunogenic in IEDB. I didn’t understand why the toxicity of the peptides was assessed. Is the idea to administer them synthetically?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-514
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https://f1000research.com/articles/13-129/v1
|
22 Feb 24
|
{
"type": "Research Article",
"title": "Survival and predictors of adult patients admitted to intensive care unit in Yekatit 12 Hospitals, Addis Ababa, Ethiopia.",
"authors": [
"Esubalew Tesfahun",
"Mulat Bekele",
"Mulat Bekele"
],
"abstract": "Background In hospitals, one of the main service components is an intensive care unit (ICU) that provides aggressive therapy for critically ill and high-risk patients. The availability of ICU beds has been progressively growing in Africa, but many studies show that the ICU mortality rate is very high. However, many of those studies are only descriptive and focus on medical or surgical patients. This study includes patients from all wards except pediatrics.\n\nMethods A retrospective cohort study was carried out in the intensive care unit at Yekatit 12 Hospital, Ethiopia. The Kaplan-Meier method was used to describe the probability of survival in ICU stay. The Cox proportional hazard model was used for the multivariate analysis to determine the possible associations of predictor variables and to obtain the adjusted hazard ratios. A statistically significant association was declared at p <0.05 with a 95% confidence interval.\n\nResults The survival rate was 69.7% with a mortality rate of 30.3%. This study confirmed that the risk of mortality among ICU patients was the education status of the study participants, attending primary education was twice that of patients attending higher education with an adjusted hazard ratio (AHR) (AHR=2.097, 95% CI:1.081,4.067). Patients admitted to ICU because of shock were more than four times at risk of death compared to other causes (AHR= 4.51, 95% CI: 2.41, 8.45). The risk of mortality among ICU patients admitted because of brain injury was more than two times compared to other patients (AHR=2.77, 95% CI: 1.18, 6.47). Patients with respiratory failure were more than two times at risk of mortality (AHR=2.42, 95% CI: 1.19, 4.87).\n\nConclusions The survival of ICU patients was low. Formal education level, patients admitted for shock, brain injury, and respiratory failure were found to be significantly associated with the survival of ICU patients.",
"keywords": [
"Addis Ababa",
"Ethiopia",
"Intensive Care Unit",
"Survival Yekatit 12 hospital"
],
"content": "Introduction\n\nAn intensive care unit is also known as critical care designed for providing aggressive therapy by multidisciplinary and inter-professional specialties using state-of-the-art technology and both invasive and non-invasive monitoring for critically ill and high-risk patients.1,2 Intensive care units are essential components of the health care system; the units play a major role in recovering patients with multiple organ failures. As other aspects of healthcare in the developing world, intensive care faces the same challenges like resource scarcity to provide standard care. Intensive care faces an additional challenge in that it has often been deemed too costly or resource demanding.3,4\n\nPatients admitted to intensive care are critically ill at risk for chronic illness and intense suffering, characterized by longer hospital stay with high costs. Even though, a wide range of therapies focused on restoring mobility, body composition and function have been proposed but the prevalence of chronic critical illness remains high with high cost and substantial limitations of survivors5,6\n\nThe survival rate of patients in the critical care units depend on the existing use of infrastructure, the availability of skilled professionals, the presence of technological solutions, and advances in treatment approaches for critically ill patients in the ICU, such as invasive and non-invasive monitoring along with a better understanding of pathological and physiological behaviour in critically ill patients.7,8\n\nThe study conducted in the developing world on the global burden of critical illness adults confirmed that many critically ill patients are younger and have less co morbidity, critical care presents a remarkable occasion to provide important incremental benefit, this is much more than in the developed world.9\n\nMortality rate of patients in the intensive care unit in African countries (2013), albeit much higher than in high-income countries was, 30–50% and 8–20.9%, respectively.10 For better and cost-effective management and for a reduced mortality of patients admitted in intensive care, focus on identification of risk factors are needed.9 Many of the previous studies used descriptive study design and focused on medical or surgical patients. But this study includes patients from all wards except paediatrics and identifies predictor factors through analytical study design. The findings of the study generate evidence related to the survival rate and its predictors among adult patients admitted to the intensive care units used to minimizing the mortality rate of patients admitted in the ICU.\n\n\nMethods\n\nAn official letter was obtained from Africa Medical College department of Public Health in order to obtain ethical clearance from Addis Ababa Health Bureau and to get permission and cooperation from Addis Ababa Health Bureau and Yekatit 12 hospital. In order to conduct research in Yekatit 12 hospital, the hospital administrator requested the authors obtain ethical clearance from Addis Ababa Health Bureau. After the review of the proposal of this research, ethical clearance was obtained from Addis Ababa Health Bureau research review and ethics committee (reference number: AAHB/04/345/14). To ensure confidentiality, name and any other personal identities were not included during data collection in the data extraction sheet/data collection tools, any document in the raw data, and in writing the research findings. A consent form was signed by the registrar office of Yekatit 12 Hospital to use patient medical records as necessary. Before data extraction from the patient registration sheet, oral informed consent was obtained from all patients/healthy participants (or concerning deceased participants, consent was obtained from next of kin of the participants via phone communication). This is because data were extracted from the patient medical chart after patients were discharged. This made it difficult to access written consent from each patient. Oral informed consent was accepted by Addis Ababa Health Bureau research review and ethics committee.\n\nA retrospective cohort study of survival analysis was conducted by reviewing all eligible medical charts of ICU patients. A total of 438 patients admitted at Yekatit 12 Hospital Medical College ICU from March 15th, 2020 to March 15th, 2022 participated in this study. The follow-up with patients were done starting from admission up to discharge.\n\nThe sample size was determined by a double population proportion formula using Epi-Info version 7.0 statistical software with the following assumptions: Confidence Interval 95%, study Power=80% and one-to-to-one ratio based on a study conducted at Nigist Eleni Mohammed Memorial Hospital, Hosanna, Southern Ethiopia.11\n\nData was collected by well-trained nurse data collectors with a Bachelor of Science using a data extraction format. The data extraction format was developed by the authors by referring to the Global Health Care of the Critically Ill in Low-Resource Settings (recommended research instrument for low-resource setting) and edited as a local context to fit the research objective.3,7,12,13 The data extraction format was pretested on 5% of the samples. The inclusion criteria were all patients 18 years and above (because the clinical spectrum of disease for children is significantly different from adult illnesses) admitted to the ICU during March 15th, 2020 to March 15th, 2022. We excluded adult patient cards with incomplete medical record information. The study participants were selected using systematic random sampling techniques. For each patient, potential risk factors such as presence of comorbidities (diabetic mellitus, cardiovascular disorder, cancer, dyslipidemia, and neurologic disorder) and reason for admission (Sepsis, shock, trauma, brain injury) were extracted from the charts. The authors analyzed the first admission in a given year for patients who may have multiple ICU admissions within a year. The exit time was set as the earliest of either the death date or the ICU discharge date. The data extraction form Ref. 23 had three sections that cover socio-demographic characteristics, admission and discharge information, and survival of adult patients admitted in the ICU.\n\n\n\n• Survival rate: the number of ICU patients improved and discharged home or transferred to ward divided by the total number of admissions within the study period.\n\n• Length of stay: the period of stay in ICU from time of admission to time of discharge in days.\n\n• Socio-demographic characteristics: age, gender, educational status, marital status, occupation\n\n• Reason for admission: the reason for admission or entering the ICU ward.\n\nThe data was analyzed using SPSS version 23. The main outcome of this study was the survival status of patients admitted to ICU. The primary outcome measure was mortality during the ICU stay. To minimize information bias, the checklist was cross checked with the registers and cards. Baseline characteristics of patients at the time of ICU admission was reported as number and percentage for categorical variables and as mean and standard deviation (SD) for normally distributed continuous variables, or as the median and inter-quartile range (IQR) if not. A Kaplan-Meier curve was used to describe the probability of survival in ICU stay, thus the exit time was set as the earliest of either the death date or the ICU discharge date. Kaplan-Meier (KM) method was used to estimate overall survival (OS), while the Cox proportional hazard model was used for multivariate analysis to determine the possible associations of predictor variables, to control possible confounders and to obtain an adjusted hazard ratio at a p-value less than 0.05.\n\n\nResults\n\nA total of 438 adult ICU patients were included at all stage completing follow-up and analyzed in the study. The underlying data are publicly available.22 The mean age of the study participants was 44.34 (SD±17.7). More than half (237, (54.1%) of the study participants of the study were female. Most of the study participants (233, (53%) attended higher education. Married participants of this study constitute more than half (261, (61%) of the study population. The employed and unemployed participants of the study were 251 and 90, respectively. The mean time of follow-up was 4.15 days with minimum 1 and maximum 10 days respectively.\n\nThe main reasons for admission were sepsis (35, 8%), shock (63, 14.4%), trauma (23, 5.3%), brain injury (40, 9.1%), cardiovascular disorder (86, 19.6%), respiratory failure (79, 18%) and other cases (112, 25.6%). Some participants of the study were admitted with co-morbidity. Among the co-morbidities, the number of participants with a respiratory disorder was (89, 20.3%). A total of 128 participants (29.3%) suffered cardiovascular disorders. The rest of the co-morbidities included dyslipidaemia, cancer, neurological diseases, and diabetes mellitus (Table 1).\n\nThe total 438 ICU patients were followed for a total of 1816 person days (PD) of observation. The mean time of survival was 4.15 days with a minimum of one and maximum of 10 days.\n\nThe cumulative survival and mortality were 69.7% and 30.3%, respectively. The survival rate of ICU patients was 168 persons per 1000 person days (survival=168/1000PD, 95% CI: 0.15, 0.89). While the incidence of mortality or mortality rate of patients in the same hospital was 73 per 1000 person days (mortality= 73/1000PD, 95% CI: 0.073, 0.086) (Figure 1).\n\nThe finding of a multivariate analysis results confirmed that the risk of mortality among ICU patients attending primary education was twice that of patients attending higher education with an adjusted hazard ratio (AHR) (AHR=2.097, 95% CI:1.081,4.067). Patients who attended secondary education were more than one time at risk of suffering from mortality (AHR=1.79, 95% CI: 1.11, 2.88). Patients admitted to ICU because of shock were more than four times at risk of death compared to other causes (AHR=4.51, 95% CI: 2.41, 8.45). The risk of mortality among ICU patients admitted because of brain injury was more than two times compared to other patients (AHR=2.77, 95% CI: 1.18, 6.47). Patients with respiratory failure were more than two times at risk of mortality (AHR=2.42, 95% CI: 1.19, 4.87) (Table 2).\n\n* Statistically significant.\n\n\nDiscussion\n\nThis study assessed the survival and predictors of adult patients admitted to the intensive care unit of Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia. This study applied the standard sampling techniques which enabled the result to be generalized for the source population. Despite this fact the study has some limitations. This study used secondary data sources, and socio-economic factors like income were not included and restricted to adults in the age group >18 years. Because of this, the result may not be applicable to infants and children. This study reported that education levels and cause of admission were a predictor of survival status of ICU patients.\n\nAccording to this study, the survival of ICU patients was 69.7%, this result is comparable to the study conducted in Armed Forces General Teaching Hospital in Addis Ababa, Ethiopia, with the survival rate of 69.3% and the study done in Lilongwe, Malawi showed a mortality rate of 69.9%.14,15 But higher than the study conducted in India, the survival rate was 56.69%.16\n\nThe mortality rate of patients admitted in ICU in this study was 30.30%. This result is comparable with the study conducted in a hospital in India where the mortality rate was 31.3%. Tikur Anbessa Specialized Teaching Hospital, Addis Ababa, Ethiopia revealed that the mortality rate was 31.5% and Ugandan hospitals reported the mortality rate of 27.8%.14,17,18 However, the result of this study is higher than the study done at Tenwek Hospital in Kenya which reported that the mortality rate was 26.1% and Ayder Comprehensive Specialized hospital in Tigray, Ethiopia where the mortality rate was 27%.12,17 On the other hand, the result of this study is lower than the study conducted in Lilongwe, Malawi, which showed a mortality rate of 69.9%, a study in Istanbul which reported a mortality rate of 52.3% and a study done in St. Paul’s Hospital Millennium Medical College, Addis Ababa in Ethiopia which reported a greater mortality rate of ICU admitted patients than the current study which was 39%.15,16,19 These varations may be due to the diffence in the study period because as a result of technological development health care services delivery improved from time to time.\n\nThis study reported that lower education level was a predictor of survival status of ICU patients. According to the current study, ICU patients with lower level of education were two times at risk of mortality compared to their counter parts. There is supporting evidence of the study conducted on critical illness outcomes in USA.20 The proper utilization of the therapy (focused on restoring mobility, body composition, and function) prescribed by the physician may be linked with education level of the patients admitted in the ICU.\n\nAnother factor identified by this study was the cause of admission. Certain causes of admission were found to be contributing factors for the survival of ICU admitted patients. In this study, brain injury was significantly associated with the mortality of ICU admitted patients. As per the current study, ICU patients who were admitted because of brain injury were nearly three times at risk of mortality. This result was in line with a similar study finding in Uganda.13 The other predictor of survival in this study was shock. According to the current study, ICU patients admitted as a result of shock were more than four times at risk of death compared to other patients. This study report was similar to a study found in Jimma University Specialised Hospital in Ethiopia.21\n\n\nConclusions\n\nThe survival of ICU patients in Yekatit-12 medical college was low and the mortality rate was high as compared to other studies in Ethiopia. Primary education level, secondary education level, patients admitted for shock, patients admitted for brain injury, and patients admitted for respiratory failure were found to be significantly associated with survival of ICU patients in Yekatit-12 hospital medical college. The hospital managers should give attention to hospital intensive care units in terms of filling the units with professionals and the necessary equipment. On the other hand, the physician/clinicians have to take great care and help patients living with co-morbidity in ICU.\n\n\nAuthor contributions\n\nEsubalew Tesfahun: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Original Draft Preparation\n\nMulat Bekele: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Writing – Review & Editing",
"appendix": "Data availability\n\nZenodo: Raw data in SPSS Software. https://doi.org/10.5281/zenodo.8151987. 22\n\nThe project contains the following underlying data:\n\n- SPSS raw data. P - Copy.sav\n\nZenodo: Data extraction format. https://doi.org/10.5281/zenodo.8041793. 23\n\nThis project contains the following extended data:\n\n- Data extraction format 1.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nThe authors acknowledge Africa Medical College and Yekatit-12 medical college administrators and staff. In addition, we greatly appreciate the cooperation and support of all participants and are grateful to data collectors and supervisors.\n\n\nReferences\n\nBerthelsen P, Cronqvist M: Handbook of Critical and Intensive Care Medicine. Copenhagen: Scandinavica; 2010; p. 422.\n\nMarshall J, Bosco L, Adhikari K, et al.: What is an intensive care unit? A report of the task force of the World Federation of Societies of Intensive and Critical Care Medicine. J. Crit. Care. 2017; 37: 270–276. PubMed Abstract | Publisher Full Text\n\nRiviello E, Letchford S, Achieng L, et al.: Critical care in resource-poor settings: Lessons learned and future directions. Crit. Care Med. 2011; 39(4): 860–867. PubMed Abstract | Publisher Full Text\n\nBarrett M, Smith M: Utilization of Intensive Care Services: 2011-2014. Europe PMC. 2015; 15(6): 1–14.\n\nFranzosi O, Soranço G: Chronic critical illness: are we saving patients or creating victims? Rev. Bras. Ter. Intensiva. 2017; 29(1): 87–95. Publisher Full Text\n\nMaguire M, Carson S: Strategies to combat chronic critical illness. Curr. Opin. Crit. Care. 2016; 19(5): 480–487. Publisher Full Text\n\nMurthy S, Adhikari N: Global Health Global Health Care of the Critically Ill in Low-Resource Settings. Ann. Am. Thorac. Soc. 2013; 10(5): 509–513. Publisher Full Text\n\nZimmerman E, Kramer A, Knaus W, et al.: Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. BMC: Crit Care. 2013; 17(2): R81. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdhikari N, Fowler R, Bhagwanjee S, et al.: Critical care and the global burden of critical illness in adults. Lancet. 2010; 376: 1339–1346. Publisher Full Text\n\nICU Management and Practice: Challenges in Critical Care in Africa: Perspectives and Solutions. Health Management Org.; 2013; 12(4).\n\nMohammed S, Bedilu G, Tahir A: Factors affecting prolonged intensive care unit stay in Nigist Eleni Mohammed Memorial Hospital, Hosanna, Southern Ethiopia. Int. J. Med. Med. Sci. 2017; 9(9): 105–110. Publisher Full Text\n\nGidey K, Hailu A, Bayray A: Pattern and outcome of medical intensive care unit admissions to Ayder Comprehensive Specialized Hospital in Tigray, Ethiopia. Ethiop. Med. J. 2018; 56(1): 31–36.\n\nTowey R: Intensive care medicine in rular sub-saharan Africa. Amito J. 2017; 72: 181–189. Publisher Full Text\n\nSatinder G, Vanita A: A retrospective analysis of obstetric patient’s outcome in intensive care unit of a tertiary care center. J. Anaesthesiol. Clin. Pharmacol. 2014; 30(4): 502–507. Publisher Full Text\n\nGundo R, Lengu E, Maluwa A, et al.: An Audit of Admissions to Intensive Care Unit at Kamuzu Central Hospital in Malawi. Open J. Nurs. 2014; 04(8): 583–589. Publisher Full Text\n\nKamal A, Khatun W: An Analysis of First 300 ICU Patients at Rajshahi Medical College Hospital. TAJ J. Teach. Assoc. 2018; 25: 8–12. Publisher Full Text\n\nOngóndi M, Mwachiro M, Ranketi S: Predictors of Mortality in a Critical Care Unit in South Western Kenya. Afr. J. Online. 2016; 13(1): 3–6.\n\nSeyoum N, Biluts H, Zemenfes D, et al.: Morbidity and mortality among patients admitted to the Surgical Intensive Care Unit at Tikur Anbessa Specialized Teaching Hospit. Ethiop. Med. J. 2014; 52(2): 77–85. PubMed Abstract\n\nKedir S, Berhane A, Bayisa T: Admission Patterns and Outcomes in the Medical Intensive Care Unit of st. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia. Ethiop. Med. J. 2017; 55(1): 19–26. PubMed Abstract\n\nCheckley W, Martin G, Brown S, et al.: Structure, process and annual intensive care unit mortality across 69 Centers: United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study (USCIITG-CIOS). Crit. Care Med. 2015; 42(2): 344–356. Publisher Full Text\n\nSmith Z, Ayele Y, Mcdonald P: Outcomes in critical care delivery at Jimma University Specialised Hospital, Ethiopia. SAGE J. 2013; 41(3): 363–368. Publisher Full Text\n\nEsubalew T: Raw data in SPSS Software. [Data]. Zenodo. 2023. Publisher Full Text\n\nEsubalew T: Data extraction format. [Data]. Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "259469",
"date": "17 Apr 2024",
"name": "Cristina Granja",
"expertise": [
"Reviewer Expertise Critical Medicine and Anesthesiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to review the present manuscript. I read it with most interest and I would like to commend the authors for their effort. I think that it is very important that these kinds of studies are published, for the global community to understand the extension of the problem of survival with critically ill patients in developing countries and for the local authorities to be able to take some action.\nI would like to suggest some modifications/improvements throughout the manuscript:\nMETHODS 1) How many beds has the ICU? 2) How many patients were admitted in total to the ICU in the same period of time? 3) How many patients were excluded? Reasons for exclusion? 4) Please indicate detailed exclusion criteria\n\nRESULTS 5) Mean time of follow-up was 4,5 days with a maximum of 10 days - please clarify as it is not clear the reason for this time of follow-up 6) Shock corresponds to 14,4% of admissions - please specify what type of shock - Septic? Hypovolemic? Cardiogenic? 7) Cardiovascular disorder - please specify if it includes cardiogenic shock 8) Co-morbidities - please give a definition for each one\n\nDISCUSSION 9) Lower education and use of health services - lower education is more linked to the lack of the patient being able to recognize the severity of illness and the difficulty accessing health services, for reasons such as money constraints, remote areas, among others, and less linked to differences in treatment by health professionals - please add these issues on Discussion.\nThe all manuscript needs English editing.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11442",
"date": "20 May 2024",
"name": "Esubalew Tesfahun",
"role": "Author Response",
"response": "Reviewer comments 1) How many beds has the ICU? Accept and correct in the following section Authors response – Accept these comments and include in the following section Study design, settings, and participants A retrospective cohort study of survival analysis was conducted by reviewing all eligible medical charts of ICU patients. There were 45 number of beds in the ICU units. A total of 438 patients admitted at Yekatit 12 Hospital Medical College ICU from March 15th, 2020 to March 15th, 2022 participated in this study. The follow-up with patients were done starting from admission up to discharge. Reviewer comments 2)How many patients were admitted in total to the ICU in the same period of time? Accept these comments – Authors' response -There were 1234 adult patients were admitted in total to the ICU in the same period of time. 3)How many patients were excluded? Reasons for exclusion? Authors' response - We excluded 5 adult patient cards with incomplete medical record information. The above comments are accepted and included in the following section. Data collection procedure Data was collected by well-trained nurse data collectors with a Bachelor of Science using a data extraction format. The data extraction format was developed by the authors by referring to the Global Health Care of the Critically Ill in Low-Resource Settings (recommended research instrument for low-resource setting) and edited as a local context to fit the research objective.3,7,12,13 The data extraction format was pretested on 5% of the samples. The inclusion criteria were all patients 18 years and above (because the clinical spectrum of disease for children is significantly different from adult illnesses) admitted to the ICU from March 15th, 2020 to March 15th, 2022. There were 1234 adult patients admitted in total to the ICU in the same period of time. We excluded 5 adult patient cards with incomplete medical record information. Reviewer comments 4) Please indicate detailed exclusion criteria. Authors response - Indicated in the method section that is adult age less than 18 years and with incomplete medical record information. Reviewer comments RESULTS 5) Mean time of follow-up was 4,5 days with a maximum of 10 days - please clarify as it is not clear the reason for this time of follow-up. Authors response – Accept and corrected in the following section Socio-demographic characteristics The mean time of follow-up was 4.15 days with a minimum of 1 and maximum 10 days respectively (these days were the patients admitted and followed until discharged). Reviewer comments 6) Shock corresponds to 14,4% of admissions - please specify what type of shock - Septic? Hypovolemic? Cardiogenic? Authors' response – This data was not collected during the data collection time. Reviewer comments 7) Cardiovascular disorder - please specify if it includes cardiogenic shock Authors' response – this data was not collected during the data collection time. Reviewer comments 8) Co-morbidities - please give a definition for each one Authors response – This is not that much important for this study. Reviewer comments DISCUSSION 9) Lower education and use of health services - lower education is more linked to the lack of the patient being able to recognize the severity of illness and the difficulty accessing health services, for reasons such as money constraints, remote areas, among others, and less linked to differences in treatment by health professionals - please add these issues on Discussion. Authors' response – Accept these comments and include in the following section This study reported that lower education level was a predictor of the survival status of ICU patients. According to the current study, ICU patients with lower levels of education were two times at risk of mortality compared to their counterparts. There is supporting evidence of the study conducted on critical illness outcomes in USA (19). The proper utilization of the therapy (focused on restoring mobility, body composition, and function) prescribed by the physician may be linked with the education level of the patients admitted in the ICU. In addition, lower education is more linked to the lack of the patient being able to recognize the severity of illness and the difficulty accessing health services, for reasons such as money constraints, and remote areas, among others, and less linked to differences in treatment by health professionals."
}
]
},
{
"id": "252281",
"date": "31 May 2024",
"name": "Andrew Li",
"expertise": [
"Reviewer Expertise Sepsis",
"ICU",
"ILD"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study is a retrospective report of the performance of a single-centre Ethiopian ICU.\n\nThe authors demonstrated a mortality rate of 30.3%, with those having shock, respiratory failure and brain injury being at higher risk of death. Those who had poor education levels were also at higher risk of death.\nAfrica medical performance and even sepsis epidemiology in itself is hardly known (for example Ref 1). But the manuscript is quoting rather old papers on epidemiology and does not clearly demonstrate the lack of data. The papers quoted were in 2010-2013, but the study is being conducted in 2020-2022. The fact that they quoted single center studies from 2014 only. In a quick PubMed search, I already see quite a few much more updated references [Refer Ref 2,3,4]\n\n- Poor education level leads to low health literacy, leading to poor outcomes Ref [5]. - Patients with shock, respiratory failure and brain injury are not unexpected to have higher risk of death\nThere needs to be a unique slant which at present, the authors have not demonstrated.\nI believe a letter rather than a manuscript would be more ideal as there is a need to understand and be aware of such issues in African countries.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-129
|
https://f1000research.com/articles/13-513/v1
|
20 May 24
|
{
"type": "Study Protocol",
"title": "A prospective observational comparative study to compare the diagnostic efficacy of the Fenyo Lindberg scoring system and Yash scoring system in patients of acute appendicitis in tertiary care hospitals in central India",
"authors": [
"Dr Eeda Srinivasa Reddy",
"Dr. Darshana Tote",
"Dr. Darshana Tote"
],
"abstract": "Background Acute appendicitis is a typical surgical emergency requiring prompt and accurate diagnosis for timely intervention. This prospective observational comparative study aims to assess the diagnostic efficacy of two scoring systems, the Yash scoring system and the Fenyo-Lindberg scoring system, compared to the gold standard of histopathological diagnosis. The study is conducted at A.V.B.R.H., a tertiary care hospital in Central India, focusing on providing valuable insights into the comparative performance of these scoring systems in the local patient population.\n\nMethods The study adopts a prospective observational comparative design, enrolling clinically diagnosed cases of acute appendicitis from the outpatient and inpatient departments of the Surgery department at A.V.B.R.H. Patients willing to undergo surgery are included. At the same time, those with complicating factors or contraindications are excluded. Data collection involves thorough clinical evaluations, scoring system assessments, and comprehensive investigations, with histopathology as the reference standard. Statistical analyses include descriptive statistics, comparative analyses, primary outcome assessments, and regression analyses, ensuring a robust evaluation of the diagnostic efficacy of the scoring systems.\n\nExpected Outcome Anticipated outcomes include a comprehensive understanding of the diagnostic efficacy of the Yash and Fenyo-Lindberg scoring systems in acute appendicitis. The study aims to identify which scoring system demonstrates superior accuracy, sensitivity, and specificity, providing valuable information for clinical decision-making. The results will contribute to optimizing diagnostic protocols for acute appendicitis, potentially influencing patient management and surgical interventions. This study’s findings are expected to be relevant to the local setting and broader contexts, enhancing the knowledge surrounding acute appendicitis diagnosis.",
"keywords": [
"Acute Appendicitis",
"Diagnostic Efficacy",
"Scoring Systems",
"Histopathological Diagnosis",
"Comparative Study",
"Tertiary Care Hospital"
],
"content": "Introduction\n\nAcute appendicitis remains a typical surgical emergency globally, necessitating timely and accurate diagnosis for appropriate clinical management.1 While clinical evaluation plays a pivotal role in the diagnosis, scoring systems have been developed to aid in the stratification of patients and guide decision-making regarding surgical intervention. Among these, the Yash scoring system2 and the Fenyo-Lindberg scoring system3 have gained attention for their potential diagnostic efficacy. However, a comparative assessment of these scoring systems in acute appendicitis is essential to discern their strengths and limitations.\n\nThe Yash scoring system incorporates multiple clinical parameters, including migration of pain, nausea, and vomiting, anorexia, tenderness in the right iliac fossa, rebound tenderness, hyperesthesia in Sherren’s triangle, fever, elevated white blood cell count, and C-reactive protein levels, as well as ultrasonography results.2 On the other hand, the Fenyo-Lindberg scoring system encompasses components such as total leukocyte count, duration of pain, progression of pain, aggravation of pain by coughing, vomiting, migration of pain, rebound tenderness, rigidity of abdominal wall, and tenderness outside of the right lower quadrant.3 A critical evaluation comparing the diagnostic accuracy of these two scoring systems is imperative to inform clinical practice and enhance the precision of acute appendicitis diagnosis.\n\nThis prospective observational comparative study aims to systematically assess and compare the diagnostic efficacy of the Yash scoring system and the Fenyo-Lindberg scoring system in cases of acute appendicitis. The study design, inclusion criteria, and methodological details have been outlined to ensure the robustness and transparency of the investigation. Through this research endeavor, we seek to contribute valuable insights that may refine clinical decision-making processes in managing acute appendicitis.\n\nTo assess the diagnostic efficacy of the Yash scoring system and the Fenyo-Lindberg scoring system in cases of Acute Appendicitis.\n\nTo compare the diagnostic efficacy of the Yash scoring system and the Fenyo-Lindberg scoring system based on histopathological diagnosis of Acute Appendicitis.\n\n\n\n1. To evaluate cases of acute appendicitis using the Yash scoring system.\n\n2. To evaluate cases of acute appendicitis using the Fenyo-Lindberg scoring system.\n\n\nMethods\n\nStudy design: This study will utilize a prospective observational comparative study design.\n\nStudy population: The study will include all clinically diagnosed cases of acute appendicitis, encompassing all age groups and both sexes. Patients willing to give consent for surgery will be considered for inclusion.\n\nPlace of study: The study will be conducted at A.V.B.R.H. (Acharya Vinoba Bhave Rural Hospital), Sawangi, Wardha, a tertiary care hospital in Central India. The data collection will take place in the outpatient department and the inpatient department (I.P.D.) of the Surgery department at the mentioned hospital.\n\nThe research protocol got approval from the Datta Meghe Institute of Higher Education and Research (Deemed to be University) Institutional ethical committee in the meeting held on 11-07-2022 (approval date) with DMIMS (DU)/IEC/2022/28. All the participants will be educated about the research, and written and verbal informed consent will be obtained from all the participants before the intervention.\n\nInclusion criteria:\n\n1. Patients clinically diagnosed with acute appendicitis.\n\n2. All age groups and both sexes will be considered.\n\n3. Patients are willing and provide consent for surgery.\n\nExclusion criteria:\n\n1. Patients diagnosed with Appendicular perforation, peritonitis, appendicular mass, or appendicular abscess.\n\n2. Patients diagnosed with appendicitis who have a confirmed history of connective tissue dysfunction.\n\n3. Pregnant women.\n\n4. Patients who are unfit or unwilling for surgery or have an unsound mind.\n\nThe sample size for the study has been calculated to be 200 patients based on the formula:\n\nWhere:\n\n• α (alpha) = 0.05 (significance level, typically set at 0.05 for a 95% confidence level)\n\n• p (proportion) = 0.389 (the estimated proportion of surgical site infection in patients postoperatively as per the reference article)\n\n• d (estimated error) = 0.10 (10% margin of error)\n\nBy plugging in these values, get:\n\nThe study will begin by identifying and approaching patients clinically diagnosed with acute appendicitis at A.V.B.R.H. in Sawangi, Wardha, a tertiary care hospital in Central India. Informed consent will be obtained from patients willing to participate in the study. A thorough clinical evaluation involving history taking and physical examination will be conducted for each participant. The Yash scoring system and the Fenyo-Lindberg scoring system will be employed to assess the severity of acute appendicitis.\n\nNecessary investigations, including laboratory tests, imaging studies, and ultrasonography, will be performed to gather relevant data. Results from these investigations, such as white blood cell count, C-reactive protein levels, and imaging findings, will be recorded. Histopathology will be considered the gold standard for diagnosing acute appendicitis, and preoperative scores from the Yash and Fenyo-Lindberg scoring systems will be compared with histopathological findings.\n\nData collection will involve recording each participant’s demographic information, clinical findings, and scoring system results on a structured data collection form. Statistical methods, such as the chi-square test, mean, and standard deviation, will be utilized to analyze the relationship between variables. The sample size will be determined using the Cochran formula to ensure statistical validity.\n\nEthical considerations will be paramount throughout the study, with strict adherence to guidelines regarding patient confidentiality and the protection of participants’ rights. Quality control measures will be implemented to ensure the accuracy and reliability of collected data, with regular monitoring of the data collection process to address any issues promptly.\n\nThe study setting will encompass the outpatient and inpatient departments (I.P.D.) of the Surgery department at A.V.B.R.H., Sawangi, Wardha. Data analysis will involve using appropriate statistical tests to compare the diagnostic efficacy of the Yash and Fenyo-Lindberg scoring systems.\n\nComprehensive documentation of the study protocol, data collection procedures, and any deviations from the protocol will be maintained. The final step will involve preparing a detailed report summarizing the study findings, including comparisons of scoring systems and their diagnostic performance. Consideration will be given to publishing the results in a reputable medical journal to contribute to the existing body of knowledge. In conclusion, the study will draw insights based on its outcomes and provide recommendations for clinical practice or suggest avenues for further research.\n\nPrimary outcome: The primary outcome of this study is the diagnostic efficacy of acute appendicitis, as assessed by a comparison between the Yash scoring system and the Fenyo-Lindberg scoring system, with histopathological diagnosis serving as the gold standard. The primary focus is determining which scoring system demonstrates superior accuracy in diagnosing acute appendicitis.\n\nSecondary outcomes:\n\n1. Diagnostic performance of individual scoring components: Evaluate the performance of individual components within the Yash and Fenyo-Lindberg scoring systems. This assessment will provide insights into the specific criteria contributing most significantly to accurate diagnoses.4\n\n2. Comparison of sensitivity and specificity: Compare the sensitivity and specificity of the Yash and Fenyo-Lindberg scoring systems. Understanding the trade-off between sensitivity and specificity is crucial for practical clinical applications.\n\n3. Correlation with clinical presentation: Examine the correlation between the scoring systems and clinical presentations of acute appendicitis. This secondary outcome aims to assess the systems' ability to align with the diverse clinical manifestations of the condition.\n\n4. Impact on decision-making for surgery: Investigate how the utilization of each scoring system affects the decision-making process regarding surgical intervention. This secondary outcome explores the practical implications of the scoring systems on patient management.\n\n5. Exploratory analysis of patient subgroups: Perform exploratory analyses to assess the performance of the scoring systems within specific patient subgroups, such as different age categories or gender. This analysis aims to identify any variations in diagnostic efficacy across diverse patient populations.\n\nIn this prospective observational comparative study on acute appendicitis, a meticulous data management approach will be employed to ensure the accuracy and reliability of collected information. Structured data collection forms will be designed, encompassing various parameters such as demographic details, clinical findings, scoring system results, laboratory test outcomes, imaging findings, and histopathological results. Trained personnel will be responsible for accurate data entry, utilizing electronic tools to minimize errors, and implementing double-entry verification for critical data points. The collected data will be securely stored in password-protected databases, with regular backups to prevent loss and maintain data integrity. Continuous data cleaning procedures will be implemented to identify and rectify errors or inconsistencies, supported by validation checks during data entry. The study will prioritize participant confidentiality by using anonymized identifiers in datasets and limiting access to authorized personnel. An audit trail will be maintained to track any modifications to the dataset, ensuring transparency and accountability in data management. A comprehensive data analysis plan will be developed and aligned with the study objectives, and thorough documentation of the entire data management process will be maintained, including data dictionaries and any deviations from the initial plan. Clear communication channels and collaboration among team members will be established to address challenges and questions related to data collection and entry, ultimately contributing to the validity and reliability of the study findings.\n\nThe statistical analysis of this prospective observational comparative study on acute appendicitis will follow a comprehensive approach to derive meaningful insights from the collected data. Initially, descriptive statistics will be computed, including means and standard deviations for continuous variables and frequencies and percentages for categorical variables, to provide a clear overview of the study population. Comparative analyses, employing statistical tests like the chi-square test for categorical variables and t-tests or Mann-Whitney U tests for continuous variables, will be conducted to assess any differences in baseline characteristics between groups evaluated by the Yash and Fenyo-Lindberg scoring systems.\n\nMoving to the primary outcome, the diagnostic efficacy of each scoring system will be rigorously examined. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy will be compared with histopathological diagnosis. Receiver operating characteristic (ROC) curves will be constructed to visually compare the two scoring systems’ discriminatory ability.\n\nSecondary outcomes will undergo meticulous analysis, including the diagnostic performance of individual scoring components, a comparison of sensitivity and specificity, correlation with clinical presentation, impact on decision-making for surgery, and exploratory analyses of patient subgroups. Logistic regression will be considered to assess the independent contribution of individual components to overall diagnostic accuracy.\n\nTo ensure statistical power and precision, the sample size will be reassessed. Subgroup analyses based on relevant demographic factors will be explored to identify potential variations in diagnostic efficacy among different patient populations. Multivariable analyses will address confounding variables, and interactions between variables that may impact diagnostic performance will be carefully examined.\n\nThe analyses will be conducted using appropriate statistical software, such as R Studio Version 4.3.1, and the code and parameters used will be provided for reproducibility. To determine statistical significance, a predetermined significance level (e.g., 0.05) will be set for hypothesis testing. The statistical analysis results will be interpreted in alignment with the study objectives, offering valuable insights into the comparative diagnostic efficacy of the Yash and Fenyo-Lindberg scoring systems in the context of acute appendicitis.\n\nThe study still needs to be started.\n\n\nDiscussion\n\nAcute appendicitis is a typical surgical emergency, and accurate diagnosis is pivotal for timely and appropriate clinical management.5 This study protocol aims to prospectively compare the diagnostic efficacy of the Yash scoring system and the Fenyo-Lindberg scoring system in cases of acute appendicitis, shedding light on their respective roles in clinical practice.\n\nWith its comprehensive inclusion of clinical parameters and imaging results, the Yash scoring system has been advocated for its potential to enhance diagnostic accuracy.2 In contrast, the Fenyo-Lindberg scoring system focuses on clinical features, prioritizing simplicity in its approach.6 This study’s intention to compare these two scoring systems aligns with the need for evidence-based approaches to acute appendicitis diagnosis.\n\nOur findings will contribute to the ongoing discourse on refining diagnostic strategies for acute appendicitis. A study by Yash et al. demonstrated the utility of their scoring system in a specific population.2 The comparative aspect of our research will offer a broader perspective, potentially identifying nuances in diagnostic performance across diverse patient groups.\n\nHowever, this study has its limitations. The reliance on a single tertiary care hospital may limit the generalizability of our findings to other settings. Additionally, the study’s observational nature may introduce biases despite rigorous methodology. The potential impact of confounding variables, such as variations in disease presentation among different age groups, needs careful consideration during data analysis.\n\nConsidering these limitations, future research could explore the external validation of the identified scoring systems in different healthcare settings and patient populations. Furthermore, a long-term followup could assess the clinical outcomes of the diagnostic decisions guided by these scoring systems.\n\n\nEthics and consent\n\nThe research protocol got approval from the Datta Meghe Institute of Higher Education and Research (Deemed to be University) Institutional ethical committee in the meeting held on 11-07-2022 (approval date) with DMIMS (DU)/IEC/2022/28. All the participants will be educated about the research and written and verbal informed consent will be obtained from all the participants before the intervention.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nReporting guidelines\n\nName of repository: Zenodo\n\nZenodo: STROBE checklist for “A prospective observational comparative study to compare the diagnostic efficacy of the Fenyo Lindberg scoring system and Yash scoring system in patients of acute appendicitis in tertiary care hospitals in central India”, DOI: 10.5281/zenodo.10991859. 7\n\nURL: https://zenodo.org/records/10991859.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nEko FN, Ryb GE, Drager L, et al.: Ideal Timing of Surgery for Acute Uncomplicated Appendicitis. N. Am. J. Med. Sci. 2013; 5: 22–27. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDebnath J, Ram S, Balani S, et al.: Ultrasonography in Patients with Suspected Acute Appendicitis. Med. J. Armed Forces India. 2005; 61: 249–252. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFenyö G, Lindberg G, Blind P, et al.: Diagnostic decision support in suspected acute appendicitis: validation of a simplified scoring system. Eur. J. Surg. 1997; 163: 831–838. PubMed Abstract\n\nEnochsson L, Gudbjartsson T, Hellberg A, et al.: The Fenyö-Lindberg scoring system for appendicitis increases positive predictive value in fertile women--a prospective study in 455 patients randomized to either laparoscopic or open appendectomy. Surg. Endosc. 2004; 18: 1509–1513. Publisher Full Text\n\nJones MW, Lopez RA, Deppen JG: Appendicitis. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.\n\nLintula H, Kokki H, Pulkkinen J, et al.: Diagnostic score in acute appendicitis. Validation of a diagnostic score (Lintula score) for adults with suspected appendicitis. Langenbeck’s Arch. Surg. 2010; 395: 495–500. PubMed Abstract | Publisher Full Text\n\nReddy DES: STROBE checklist for “A prospective observational comparative study to compare the diagnostic efficacy of the Fenyo Lindberg scoring system and Yash scoring system in patients of acute appendicitis in tertiary care hospitals in central India”. Zenodo. 2024. Publisher Full Text"
}
|
[
{
"id": "302944",
"date": "16 Jul 2024",
"name": "kumar Hari Rajah",
"expertise": [
"Reviewer Expertise general surgery and gastroenterology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a study protocol for a prospective observational comparative study on the diagnostic efficacy of the Fenyo lindberg scoring system and the yash scoring system in patients with acute appendicitis. The inclusion and exclusion criteria are well defined, the statistical evaluation of the study results are also well presented. The comparison of the studies is well explained. I would like to point out that the yash scoring system included the ultrasound findings while the Fenyo Lindberg system is a pure clinical system with the addition of leukocytosis. This will provide a clear advantage when diagnosing a case of acute appendicitis. This may also affect the sensitivity and specificity of the scoring systems in diagnosing acute appendicitis. Normally when comparing scoring systems the parameters should be of the same characteristics ,like both scoring systems employ only clinical and laboratory parameters.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "302948",
"date": "06 Aug 2024",
"name": "Emad M Abdelrahman",
"expertise": [
"Reviewer Expertise general surgery",
"oncology surgery",
"plastic surgery",
"emergency and trauma"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the manuscript overall the topic is very important However, some points need to be clear in the abstract\n\nplease stick to the general rules for the sections background, aim, methods, results, conclusion in the introduction section, the hypothesis must be clear ( why the study was conducted) in the methods the assessment method for the scoring system must be clear for instance what was the cutoff value for the scoring system the main points of assessments were not described including the sensitivity, specificity, positive predictive value, negative predictive value and accuracy for the 5 main assessment points the results section must be clear and included in the discussion in comparison with other studies thank you\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-513
|
https://f1000research.com/articles/13-512/v1
|
20 May 24
|
{
"type": "Brief Report",
"title": "Quantification of 25-hydroxyvitamin D3 in dried blood spots as compared to plasma among Indian adults",
"authors": [
"Ashwini V Shete",
"Jyoti Sawant",
"Rajani Bagul",
"Ujjwala Ghule",
"Sarang S. Saluke",
"Christopher R. Sudfeld",
"Ashwini V Shete",
"Jyoti Sawant",
"Rajani Bagul",
"Ujjwala Ghule",
"Sarang S. Saluke"
],
"abstract": "Background Vitamin D may play an important role in later-life physical and cognitive health. Vitamin D status is standardly assessed in serum and plasma; however, collection, transport, and storage costs make large epidemiologic studies challenging. We assessed the agreement of 25-hydroxyvitamin D3 (25(OH)D3) quantification from dried blood spots (DBS) as compared to standard plasma assessment among older Indian adults.\n\nMethods A total of 58 adults over 45 years of age who resided in Pune, India were enrolled in the study from July 2020 to June 2021. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess 25(OH)D3 concentrations in paired plasma and DBS samples.\n\nResults Plasma and DBS 25(OH)D3 concentrations were highly correlated (Pearson’s correlation = 0.976). The median 25(OH)D3 concentration of the study population assessed by plasma was 14.6 ng/mL (Q1=12.0, Q3= 18.1) while the median concentration assessed in DBS was 12.8 ng/mL (Q1=11.0, Q3= 16.6). 25(OH)D3 concentrations measured from DBS were on average 6% (95% CI: 2-13%) lower than concentrations assessed by plasma across the observed 25(OH)D3 distribution.\n\nConclusions We found good agreement between 25(OH)D3 quantification between DBS and plasma and our findings indicate that DBS can be used in epidemiologic studies of vitamin D among Indian adults.",
"keywords": [
"Vitamin D",
"Calcifediol",
"Micronutrients",
"Dried Blood Spot Testing",
"Validation Study"
],
"content": "Introduction\n\nGlobally, it is estimated one billion people are vitamin D deficient (25(OH) D <20 ng/mL), while almost 50% of the global population is estimated to be vitamin D insufficient (25(OH) D 20-30 ng/mL).1 Dietary sources of vitamin D (e.g. fatty fish, milk, cheese, vitamin supplements) are not regularly consumed in most parts of the world and therefore exposure to sunlight is the primary source of vitamin D for most individuals globally.2 Older adults may be at greater risk of vitamin D deficiency due to decreased production of vitamin D in the skin, reductions in sun exposure and physical activity, decreased appetite, and changes in dietary habits.3 In India, studies have indicated that vitamin D deficiency is common among the general adult population; however, few studies have included population-based samples.4\n\nVitamin D status in humans is best indicated by 25-hydroxyvitamin D (25(OH)D), which is the total of the 25-hydroxy forms of 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3).5 Serum or plasma quantification of 25(OH) D are the standard biological specimens used in the assessment of vitamin D status.6 However, in large epidemiologic studies, collection and storage of plasma or serum are often not feasible due to the cost and logistic requirements of refrigeration after blood collection and cryogenic storage, particularly in resource-limited settings. As a result, dried blood spot (DBS) collection is becoming more common in epidemiologic studies to overcome these barriers. Prior studies have found that measurement of 25(OH) D from DBS with liquid chromatography-tandem mass spectrometry (LC-MS/MS) can yield valid and reliable results.7–13 However, older age may alter vitamin D binding protein levels and affinity influencing vitamin D level estimations in the elderly population.14\n\nWe conducted a study to evaluate the agreement of 25(OH)D3 assessment in DBS as compared to plasma concentrations among Indian adults over 45 years of age. The results of our study are intended to inform the ability to use DBS to assess vitamin D status in large population-based studies of vitamin D status among older adult populations in India.\n\n\nMethods\n\nThe study enrolled 58 adult participants over 45 years of age who resided in Pune, India. Participants were contacted for enrollment at ICMR-NARI Facility for Collaborative Clinical Research. The study enrolled participants from July 2020 to June 2021.\n\nEach participant had 4 mL of blood collected with a lavender top vacutainer (ethylenediaminetetraacetic acid (EDTA) anticoagulant). 50 μl Whole blood was spotted on predefined circles of Whatman 903 filter paper using a calibrated pipette. The DBS were air-dried and then stored at -20°C by placing them individually into a zip lock bag along with desiccants and a humidity indicator card. The blood sample was also centrifuged at 1500 g for 15 minutes to isolate plasma. The plasma samples were stored at -80°C until testing.\n\nThe study utilized D6-25-hydroxyvitamin D3 (IS) and 25-hydroxyvitamin D3 (25(OH)D3) from Sigma Aldrich (St. Louis, USA, catalog numbers H-074-1ML and 17938-1MG, respectively), HPLC grade methanol from J. T Bakers (Phillipsburg, NJ, USA, catalog number 8402.2500), formic acid from Sigma Aldrich (St. Louis, USA, catalog number F0507-100ML), acetonitrile from J. T Bakers (Phillipsburg, NJ, USA, catalog number 02-002-180), ammonium formate from Loba Chemie (Mumbai, India, catalog number 01210), and zinc sulfate pentahydrate from Thomas Baker (Mumbai, India, catalog number 169722). A set of 5 control samples with known target values of 25(OH)D3 were obtained from the DEQAS Vitamin D External Quality Assessment Scheme (London, UK, no catalog number).\n\nA stock solution of the standard, 25-hydroxycholecalciferol (25(OH)D3), was prepared in ethanol at a concentration of 1mg/mL. The standard was diluted to prepare liquid calibrators of concentrations of 5, 10, 20, 40, 60, 80, & 125 ng/mL and controls with the concentrations of 25, 50, and 100 ng/mL using 0.1%formic acid in methanol: water (80:20 v/v) as a diluent. DBS calibrators were prepared in artificial blood consisting of washed RBCs and phosphate buffer pH 6.5 (in water) mixed in 1:1 proportion. 50 μl of the spiked blood was spotted on Whatman filter paper number 903 to prepare standards of concentrations of 5, 10, 20, 40, 60,80, and 125 ng/mL. Controls were prepared similarly with concentrations of 25, 50, and 100 ng/mL.\n\nThe procedure for measuring 25(OH)D3 in plasma samples was as follows: 100 μL internal standard (50 ng in 100% methanol) was added to 100 μL of plasma samples and vortexed for 5 minutes. This was followed by the addition of 50 μL zinc sulfate pentahydrate (0.2 M) and 300 μL acetonitrile: methanol (70:30) with vortexing steps in between. The tubes were centrifuged for 10 minutes at 14000 rpm at 10°C. 200 μL supernatant was transferred to HPLC vials for analysis.\n\nTwo 6mm DBS punches were placed in Eppendorf tubes, to which 100 μL internal standard (50 ng in 100% methanol) was added and vortexed for 5 minutes. Thereafter 50 μL of zinc sulfate pentahydrate (0.2 M) and 300 μL acetonitrile: methanol (70:30) were added sequentially with vortexing steps after each addition. The tubes were centrifuged for 10 minutes at 14000rpm at 10°C and 200 μL supernatant was transferred to an HPLC vial for further analysis.\n\nThe system consisted of 4000 QTrap (A B Sciex) along with the Shimadzu LC 20AD LC System (Shimadzu Corporation, Singapore, no catalog number) with electrospray ionization (ESI) controlled by Analyst 1.4.2 software. (SCIEX, MA, USA, https://sciex.com/products/software/analyst-software, no catalog number). Copyright license was obtained for the Analyst 1.4.2 software. The following HPLC conditions were used:\n\n1. Column - Agilent Poroshell 120 EC-C18, (2.1×50 mm, 2.7-Micron particle size)\n\n2. Column temperature - 40°C\n\n3. Injection volume - 10 μl\n\n4. The mobile phase – A: Methanol and B: 10 mM Ammonium Formate in HPLC grade Water\n\n5. The mobile phase Composition – A: 90% and B: 10%. Isocratic flow.\n\n6. Flow rate – 0.4 mL/min\n\n7. Sample temperature – 5°C\n\nThe LC-MS/MS assay method was validated as per the guidelines for the bioanalytical method development and validation as well as CLSI C62 Liquid Chromatography-Mass Spectrometry Methods; Approved Guidelines.15,16 The LOQ (limit of quantitation) was set at 5 times the concentration of the LOD (Lower limit of Detection). The LOD was determined by the lowest concentration and its peak-to-peak signal to noise ratio which was required to be greater than 5. Linearity was determined by analyzing the standard graph for 25(OH)D3. Accuracy was determined by comparing the expected versus observed values for the in-house prepared control samples. The control samples were assayed on 5 consecutive days with 6 replicates per day for calculating inter-assay and intra-assay precision, respectively. Recovery was determined by spiking known amounts (5 and 100 ng/mL) of 25(OH)D3 in DBS samples and spiked concentration areas were compared with spiked blank extracted samples. Processed sample stability was assessed after storing the control samples on an autosampler tray at 5°C or benchtop at ambient temperature for 24 hours. Carryover was determined by analyzing the blank sample after the highest standard was measured.\n\nLinearity for plasma quantification and medians and interquartile ranges (IQRs) were presented for 25(OH)D3 concentrations for paired plasma and DBS assessments. A Pearson’s correlation was calculated and a Passing and Bablock analysis was conducted to compare plasma and DBS measurements. A Bland-Altman analysis was also conducted to estimate the mean bias and limits of agreement. Analyses were conducted with SAS version 9.3 and MedCalc version 20.027.\n\n\nResults\n\nPlasma 25(OH)D3 quantitation by LC-MS/MS method was validated first before proceeding to DBS validation. Retention time for 25(OH)D3 was observed to be 1.14 minutes. Plasma standards were linear between 5.0 to 125.0 ng/mL with r2 = 0.9988. Accuracy for the controls ranged from 95.02 to 101.3% and intra-assay precision varied from 5.0-6.4%. Vitamin D EQAS samples processed by LC-MS/MS method showed bias ranging from -3.32 to 3.26%.\n\nWe then performed LC-MS/MS method validation on DBS samples that were spiked with known 25(OH)D3 concentrations in artificial blood. The comparative results of plasma and DBS sample validation are presented in Table 1. DBS 25(OH)D3 standards showed good linearity over the working range from 5.0 to 125.0 ng/mL (r2 = 0.9967). Calibration curves for plasma and DBS standards are plotted in Figure 1. The peak-to-peak signal-to-noise ratio for 1 ng/mL standard was ~7. So LOD for the method was 1 ng/mL and the LOQ was 5 ng/mL. Accuracy for the analyte ranged from 100.50% to 113.75%. Intra-assay CVs varied from 5.13% to 13.39% and inter-assay CVs were 6.92% to 13.77% when measured using the in-house prepared QC samples. Recovery of 25(OH)D3 varied from 78.11-82.85% while the recovery of the internal standard was up to 90%. Retention time for 25(OH)D3 was observed to be 1.14 minutes. 25(OH)D3 was found to be stable after the QC samples were processed and left either on the autosampler tray at 5°C or benchtop at ambient temperature for 24 hours. No carryover was observed in the LCMS/MS analysis at a concentration of 100 ng/mL.\n\nWe then proceeded to compare human plasma and DBS samples from study participants. A total of 58 adults participated in the study of which 30 (51.7%) were male and 28 (48.3%) were female. The median age of study participants was 52 years (Q1 = 47, Q3 = 55). The median plasma 25(OH)D3 concentration of the study population was 14.6 ng/mL (Q1=12.0, Q3= 18.1, range = 8.0-33.6) while the median DBS 25(OH)D3 concentration was 12.8 ng/mL (Q1=11.0, Q3= 16.6, range = 7.7-31.9). Plasma and DBS 25(OH)D3 concentrations were highly correlated with a Pearson’s correlation of 0.976 (p<0.0001).\n\nFigure 2 presents a plot of the plasma and DBS 25(OH)D3 concentrations of study participants. The Passing and Bablock equation for the relationship between DBS and plasma concentrations in the study population was DBS 25(OH)D3 concentration (ng/mL) = -0.23 (95% CI: -0.98 to 0.66) + 0.94 × plasma 25(OH)D3 concentration (ng/mL) (95% CI: 0.87 to 0.98). There was no indication of non-linearity (p-value = 0.20). Therefore, 25(OH)D3 concentrations as assessed by DBS were on average 6% (95% CI: 2-13%) lower than concentrations assessed in plasma across the observed 25(OH)D3 distribution. Figure 3 presents the Bland-Altman plot. The mean bias ± standard error between plasma and DBS was 1.31 ± 0.16 ng/mL and the limits of agreement were -1.14 to +3.77 to ng/mL.\n\nBlue line indicates the Passing and Bablok regression equation with red dashed lines and shading indicating 95% confidence intervals. The identity line is presented as a green dashed line.\n\nDifference in concentrations between plasma and DBS (y-axis) plotted against mean of plasma and DBS measurements (x-axis).\n\n\nDiscussion\n\nOur study indicated satisfactory performance characteristics for the assessment of 25(OH)D3 in plasma and DBS samples using standards and spiked controls. Subsequently, among samples from Indian adults older than 45 years of age, we found a good agreement of measurement of 25(OH)D3 from DBS and plasma samples. We found that 25(OH)D3 concentrations in DBS samples were on average 6% (95% CI: 2-13%) lower than paired plasma samples. The difference was consistent across the observed range of 25(OH)D3 in plasma from 8-32 ng/mL.\n\nOur finding that 25(OH)D3 quantification in dried blood spots is a valid alternative to standard plasma assessment is in line with prior validation studies in other settings and populations.7–12 Further, most prior studies have also found that 25(OH)D3 assessed in DBS is systematically lower than serum or plasma concentrations.7,9,11,12 A study conducted among adults 22-48 years in India found that mean 25(OH)D3 concentrations were similar between DBS and serum and there was no difference in the classification of vitamin D sufficiency and insufficiency.9\n\nThe study had several limitations. First, we did not quantify 25(OH)D2 concentrations in the study population. Nevertheless, it is estimated that 25(OH)D3 accounts for the majority of the total 25(OH) D concentrations among adults in India and there is no current large-scale fortification with ergocalciferol (vitamin D2) in the country.9,12 Therefore, the assessment of 25(OH)D3 likely captures most of the variation in 25(OH) D concentrations in our study population. Second, we did not adjust for the hematocrit fraction. However, a prior study suggests that adjustment for hematocrit fraction in the normal range had minimal effect on DBS 25(OH)D3 quantification.13 Measurement of hematocrit in large populations studies may not be efficient in terms of resources for the potentially small increase in precision.\n\nOverall, we found good agreement between 25(OH)D3 quantification by LC-MS/MS in DBS as compared to standard plasma assessment. DBS assessment of 25(OH)D3 may help expand population-based vitamin D research in adult populations in India and other settings.\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by the National AIDS Research Institute Ethics Committee (Ref No. NARI-EC/2017-03, Approval date: 18 August 2020), Indian Council of Medical Research (Ref No. 54/17/Indo-foreign/Ger/17-NCD-II, Approval date: 9 October 2017), and the Harvard T. H. Chan School of Public Health Institutional Review Board (Ref. No. IRB17-0778, 8 June 2017). All participants provided written informed consent.",
"appendix": "Data availability statement\n\nFigshare: Vitamin D Validation – India, Sudfeld, Christopher (2024). Vitamin D Validation - India. figshare. Dataset. https://doi.org/10.6084/m9.figshare.25665483.v3. 17\n\nThis project contains the following underlying data:\n\n• vitd4222024.csv\n\nData are available under the terms of Creative Commons Zero (CC0) license.\n\n\nAcknowledgments\n\nWe would like to thank the participants who made this study possible.\n\n\nReferences\n\nLips P: Worldwide status of vitamin D nutrition. J. Steroid Biochem. Mol. Biol. 2010; 121(1-2): 297–300. Publisher Full Text\n\nPrentice A: Vitamin D deficiency: a global perspective. Nutr. Rev. 2008; 66(10 Suppl 2): S153–S164. Publisher Full Text\n\nAhmed T: Assessment and management of nutrition in older people and its importance to health. Clin. Interv. Aging. 2010; 5(1): 207–216.\n\nHilger J, Friedel A, Herr R, et al.: A systematic review of vitamin D status in populations worldwide. Br. J. Nutr. 2014; 111(01): 23–45. Publisher Full Text\n\nHolick MF: Vitamin D deficiency. N. Engl. J. Med. 2007; 357(3): 266–281. Publisher Full Text\n\nHolick MF: Vitamin D status: measurement, interpretation, and clinical application. Ann. Epidemiol. 2009; 19(2): 73–78. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHeath AK, Williamson EJ, Ebeling PR, et al.: Measurements of 25-hydroxyvitamin D concentrations in archived dried blood spots are reliable and accurately reflect those in plasma. J. Clin. Endocrinol. Metab. 2014; 99(9): 3319–3324. PubMed Abstract | Publisher Full Text\n\nKvaskoff D, Heath AK, Simila HA, et al.: Minimizing Matrix Effects for the Accurate Quantification of 25-Hydroxyvitamin D Metabolites in Dried Blood Spots by LC-MS/MS. Clin. Chem. 2016; 62(4): 639–646. PubMed Abstract | Publisher Full Text\n\nLote-Oke R, Pawar J, Kulkarni S, et al.: A LC-MS method for 25-hydroxy-vitamin D3 measurements from dried blood spots for an epidemiological survey in India. Sci. Rep. 2020; 10(1): 19873. PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan den Ouweland JM , Vogeser M, Bacher S: Vitamin D and metabolites measurement by tandem mass spectrometry. Rev. Endocr. Metab. Disord. 2013; 14(2): 159–184. Publisher Full Text\n\nMan PW, Heijboer AC, van der Meer IM , et al.: Agreement between measurement of 25-hydroxyvitamin D3 in dried blood spot samples and serum in a Chinese population in the Netherlands. J. Steroid Biochem. Mol. Biol. 2019; 195: 105472. PubMed Abstract | Publisher Full Text\n\nLarkin EK, Gebretsadik T, Koestner N, et al.: Agreement of blood spot card measurements of vitamin D levels with serum, whole blood specimen types and a dietary recall instrument. PLoS One. 2011; 6(1): e16602. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNewman MS, Brandon TR, Groves MN, et al.: A liquid chromatography/tandem mass spectrometry method for determination of 25-hydroxy vitamin D2 and 25-hydroxy vitamin D3 in dried blood spots: a potential adjunct to diabetes and cardiometabolic risk screening. J. Diabetes Sci. Technol. 2009; 3(1): 156–162. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSrikanth P, Chun RF, Hewison M, et al.: Associations of total and free 25OHD and 1,25(OH)2D with serum markers of inflammation in older men. Osteoporos. Int. 2016; 27(7): 2291–2300. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuidance for Industry, Bioanalytical Method Validation, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CMV).May 2001.\n\nCLSI: Liquid Chromatography-Mass Spectrometry Methods. 2nd ed.Clinical and Laboratory Standards Institute; 2022. CLSI guideline C62.\n\nSudfeld C: Vitamin D Validation - India. Dataset. figshare. 2024. Publisher Full Text"
}
|
[
{
"id": "300657",
"date": "13 Aug 2024",
"name": "Christopher T Sempos",
"expertise": [
"Reviewer Expertise Coordinator",
"Vitamin D Standardization Program"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: Object is to develop a dried blood spot (DBS) assay for the measurement of plasma 25(OH)D3 concentration that is accurate and precise compared to the Vitamin D Standardization Program (VDSP) standardized LC-MS/MS assay. That is, results from the LC-MS/MS assay can be interpreted as the \"True\" 25(OH)D concentration.\nComments: (1) P3, Chemicals and Reagents: The authors indicate that the that the LC-MS/MS produced results that were within -5% to +5% of the true 25(OH)D concentration of the DEQAS samples, As a result, the LC-MS/MS assay appears to be standardized according to criteria adopted the Vitamin D Standardization Program (VDSP) -- that is 25(OH)D3 measurements by the LC-MS/MS assay are the true concentration. If the authors reversed X and Y in Figure 2 the resulting regression equation could be used to standardize the DBS values to the true 25(OH)D concentration. I suggest that the make that change and then in the Discussion indicate the importance measuring the True 25(OH)D concentration for public health policy.\n(2) What do the authors mean when they write that \"...25(OH)D3 accounts for the majority of the total 25(OH)D among adults in India...\"? Even small quantifiable amounts of 25(OH)D2 can make an enormous difference when estimating the prevalence of low/deficient total 25(OH)D levels.\nFrom the National Indian Survey or other sources what are the 25(OH)D2 concentrations by age and sex. if this assay is to be used in the study of vitamin D in adults it needs to be established that 25(OH)D2 levels are close to nil in Indian adults.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "312373",
"date": "04 Sep 2024",
"name": "Katarzyna Dzik",
"expertise": [
"Reviewer Expertise neurodegeneration",
"vitamin D",
"exercise"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript entitled \"Quantification of 25-hydroxyvitamin D3 in dried....\" is well written and shows a simple yet important set of data presented in acceptable form. I have one major concern. In table 1. results show that the accuracy of DBS and plasma is different for 5 and 25 ng/mL concentrations. Also, there is very high CV% for DBS at 5 ng/mL concentration- 13.39. This results might impact the concentration corresponding to vitamin D deficiencies, therefore might be at the great importance. Please address this data in the discussion.\nMinor comments. 1. Please unify - over — in the description of LC-MS/MS conditions. It might be misleading and seems that the column temperature is minus 40℃.\n2. In the introduction the sentence „Dietary sources of vitamin D (…) are not regularly consumed in most parts of the world and therefore exposure to sunlight is the primary source of vitamin D for most individuals globally.” seems to be very misleading. The Authors cite a paper by Ann Pretice, however in the original paper by Ann Pretice we can find a sentence „The relative contributions of sunshine exposure and dietary intake to vitamin D supply and the achievement of adequacy in an individual, therefore, depend on many factors.” It would be better to avoid this sentence, or write more information to avoid misleading.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-512
|
https://f1000research.com/articles/13-506/v1
|
17 May 24
|
{
"type": "Research Article",
"title": "Negligible effects of read trimming on the accuracy of germline short variant calling in the human genome",
"authors": [
"Yury Barbitoff",
"Alexander Predeus"
],
"abstract": "Background Next generation sequencing (NGS) has become a standard tool in the molecular diagnostics of Mendelian disease, and the precision of such diagnostics is greatly affected by the accuracy of variant calling from sequencing data. Recently, we have comprehensively evaluated the performance of multiple variant calling pipelines. However, no systematic analysis of the effects of read trimming on variant discovery with modern variant calling software has yet been performed.\n\nMethods In this work, we systematically evaluated the effects of adapters on the performance of 8 variant calling and filtering methods using 14 standard reference Genome-in-a-Bottle (GIAB) samples. Variant calls were compared to the ground truth variant sets, and the effect of adapter trimming with different tools was assessed using major performance metrics (precision, recall, and F1 score).\n\nResults We show that adapter trimming has no effect on the accuracy of the best-performing variant callers (e.g., DeepVariant) on whole-genome sequencing (WGS) data. For whole-exome sequencing (WES) datasets subtle improvement of accuracy was observed in some of the samples. In high-coverage WES data (~200x mean coverage), adapter removal allowed for discovery of 2-4 additional true positive variants in only two out of seven datasets tested. Moreover, this effect was not dependent on the median insert size and proportion of adapter sequences in reads. Surprisingly, the effect of trimming on variant calling was reversed when moderate coverage (~80-100x) WES data was used. Finally, we show that some of the recently developed machine learning-based variant callers demonstrate greater dependence on the presence of adapters in reads.\n\nConclusions Taken together, our results indicate that adapter removal is unnecessary when calling germline variants, but suggest that preprocessing methods should be carefully chosen when developing and using machine learning-based variant analysis methods.",
"keywords": [
"variant calling",
"adapter trimming",
"benchmarking",
"DeepVariant",
"exome sequencing"
],
"content": "Introduction\n\nNext-generation sequencing (NGS) has rapidly transformed the field of genetics and genomics (reviewed in Goodwin et al., 2016). Besides all of its applications in basic and applied research, NGS is quickly becoming a standard tool in clinical practice of medical geneticists (Biesecker and Green, 2014). Despite the fact that NGS methods are widely used for rare disease diagnostics, the technology still has many important limitations. For example, commonly used second generation sequencing technologies based on short sequencing reads (e.g., Illumina or MGISEQ) are incapable of accessing certain regions of the human genome, such as regions with highly repetitive sequences and low mappability (Barbitoff et al., 2020; Ebbert et al., 2019). Our recent analysis showed that less than 90% of the coding genome sequence nucleotides could be considered high-confidence regions in which reliable variant calling is possible (Barbitoff et al., 2022). Furthermore, variant interpretation remains a major challenge, especially in the non-coding parts of the genome (Ellingford et al., 2022). Taken together, the aforementioned factors decrease the average rate of molecular diagnostics from NGS data (reviewed in Wright et al., 2018).\n\nBesides limitations associated with the technology itself, the choice of bioinformatic tools for data analysis may also greatly impact the diagnostic outcome. Recently, we have performed a systematic benchmark of state-of-the art variant calling pipelines (Barbitoff et al., 2022). The results suggested that most recent variant calling methods which make use of machine learning algorithms, such as DeepVariant (Poplin et al., 2018) perform substantially better compared to the widely used tools such as the Genome Analysis ToolKit (GATK) (RRID:SCR_001876) (McKenna et al., 2010; van der Auwera et al., 2013). Furthermore, we demonstrated that these solutions show no signs of being overfitted to the gold standard datasets. However, some machine learning (ML)-based approaches (e.g., GATK 2D CNN model or the Octopus random forest model) may produce puzzling results, for example, when facing substantial deviations in mean sequence coverage. These results suggest that careful choice of data preprocessing methods may become more critical for pipelines based on such variant callers.\n\nAdapter trimming is widely considered as one of the routine steps of the variant calling pipeline; however, it is frequently omitted due to the ability of the most common read aligners to soft-clip adapter bases during mapping. A recent study in bacteria showed that read trimming may even be detrimental (Bush, 2020). The question of the impact of adapters on variant calling in the human genome is especially relevant given the aforementioned sensitivity of certain ML-based variant calling methods to various properties of the data. Hence, in this study we analyzed the effects of read trimming on variant calling in the human genome by evaluating the performance of different variant calling pipelines on trimmed and untrimmed data. We demonstrate that the effects of adapter removal on variant caller performance is negligible, and, despite certain performance gains for individual methods, does not affect the overall performance differences between pipelines observed in our previous work.\n\n\nMethods\n\nWe acquired the sequencing data and gold standard sets of variants for the Genome In A Bottle (GIAB) v. 4.2 release as described in our previous work (Barbitoff et al., 2022). For the downsampling experiment, we used the seqtk tool (https://github.com/lh3/seqtk) to sample 40% of read pairs for each individual WES sample. For adapter trimming, we used fastp (RRID:SCR_016962) v. 0.23.2 (Chen et al., 2018), Trimmomatic (RRID:SCR_011848) v. 0.39 (Bolger et al., 2014), and BBduk (RRID:SCR_016969) v. 37.62. Only built-in databases of Illumina adapters were used for trimming. Trimming was performed in the palindromic mode.\n\nThe proportions of adapter bases and adapter-containing reads were calculated using a set of custom shell scripts using the raw and trimmed FASTQ files. We considered that all bases removed during trimming correspond to adapters, and any read that has shortened due to trimming contained adapter sequences.\n\nRaw or preprocessed reads were aligned onto the GRCh37.p13 human reference genome assembly using the BWA (RRID:SCR_010910) MEM v. 0.7.17-r1188 read alignment software (Li and Durbin, 2009). Mapped reads were converted to BAM and sorted by coordinate using samtools; duplicate reads were marked using the GATK MarkDuplicates tool. The resulting BAM file was used for variant calling with six different software tools: Clair3 v. 1.0.0 (Luo et al., 2020), DeepVariant v. 1.4.0 (Poplin et al., 2018). Freebayes (RRID:SCR_010761) v. 1.3.1 (Garrison and Marth, 2012), Genome Analysis ToolKit HaplotypeCaller v. 4.3.0 (DePristo et al., 2011), Octopus (RRID:SCR_024890) v. 0.7.4 (Cooke et al., 2021), and Strelka2 v. 2.9.10 (Kim et al., 2018). Variants called by Octopus were additionally filtered using the built-in random forest model. For GATK HaplotypeCaller (GATK-HC), an additional step of base quality score recalibration (BQSR) was performed, and variants were called with GATK-HC in the single-sample mode using the recalibrated BAM file. Raw GATK-HC VCF files were filtered using either the hard filtering method (with the recommended settings) or the CNNScoreVariants (Friedman et al., 2020) model (only 1D model was used due to generally low robustness of the 2D model (Barbitoff et al., 2022)). For both CNN models, different tranche values were tested, and SNP tranche value of 99.9 and indel tranche value of 99.5 were used as showing the best performance. For Strelka2, an additional pipeline step was performed to generate a list of candidate indel sites using Manta (Chen et al., 2016). For all tools, variant calling was limited to a set of CDS intervals containing flanking (150 bp up- and downstream) regions.\n\nBenchmarking of variant calling results was performed using the hap.py toolkit (Krusche et al., 2019). Analysis was restricted to CDS intervals only. For WES data, an additional BED file was used to limit the evaluation to targeted regions of the exome in the Agilent SureSelect v7 exome capture kit. A common set of high-confidence variant calling intervals was used to make all analyses (the set of intervals was constructed by merging GIAB v. 4.2 high-confidence regions for all seven samples included in the study (Barbitoff et al., 2022)).\n\nWhen evaluating the impact of read trimming on the variant calling accuracy, a value of each metric (precision, recall, F1 score) obtained using untrimmed data was subtracted from the corresponding metric value for the trimmed data. The number of affected variants was calculated by subtracting the number of true positive (TP) and false positive (FP) variants for the untrimmed data from the corresponding number obtained using the trimmed dataset.\n\n\nResults\n\nTo assess the effects of adapter removal on the efficiency of variant discovery we collected gold-standard WES and WGS datasets for the seven samples from the GIAB consortium - NA12878 (CEU), the Chinese trio, and the Ashkenazi trio (Barbitoff et al., 2022; Supplementary Table 1). We began by evaluating the overall presence of adapter sequences in these datasets. To this end, we calculated the percentage of bases corresponding to adapter sequences, as well as the proportion of reads containing adapters (see Methods for details). The analysis showed that, expectedly, adapters are present in higher levels in WES compared to WGS samples (Figure 1a). We also observed a substantial variation in the fraction of adapter bases and reads containing adapters among the WES samples - for example, the proportion of reads containing adapters varied from 8.1% to 35.2% (Figure 1a).\n\n(a) The proportion of bases removed during adapter trimming with fastp (Chen et al., 2018) (top) and the proportion of reads affected by this trimming (bottom) in WES and WGS data. (b) Boxplots of the differences in the benchmarking metrics (precision, recall, and F1 score) between trimmed and untrimmed data for SNPs and indels in WES and WGS. (c) A histogram showing the difference in the number of true positive variant calls (SNP, indel, and combined (denoted as “TOTAL”)) in WES (top) and WGS (bottom) data. (d) A scatterplot showing the correspondence between the fraction of adapter bases (shown in (a)) and the effect of adapter removal on precision (left) and recall (right). Only values for indel variants are shown. (e) Median difference in F1 score of SNP and indel discovery in WES data in 25bp-wide regions located at the indicated distance from the CDS boundary. Shaded area corresponds to the values observed for in-CDS variants. In (b-e), shown are the results obtained using the variant calling pipeline which showed best performance in our recent benchmark (Barbitoff et al., 2022) (BWA MEM + DeepVariant).\n\nWe next went on to evaluate the impact of adapter trimming on the results of variant calling with the best-performing variant calling pipeline identified in our earlier benchmark - a combination of the BWA MEM aligner (Li and Durbin, 2009) and the DeepVariant (Poplin et al., 2018) variant caller (Barbitoff et al., 2022). To this end, we ran this pipeline for raw FASTQ data for all samples, as well as on the same data preprocessed using the fastp method (Chen et al., 2018; 10.1093/bioinformatics/bty560). A comparison of benchmarking results (see Methods for details on benchmarking procedure) showed that adapter trimming had very limited effects on both precision and recall (Figure 1b). Consistently with the analysis of adapter proportion in reads, no performance difference was observed for the raw and trimmed WGS data, neither for SNP nor for indel variants. For WES data, no precision or recall gain was observed for the majority of the samples; however, a slight increase in precision and recall of indel calling was observed for the majority (four out of seven) datasets. Positive effects on recall, however, were observed in only two of the samples. Furthermore, when the total (SNPs and indels combined) number of true positive (TP) variants is considered, more TPs were discovered in two samples (two for HG002 and four - for HG006) (Figure 1c), while a decrease in the total TP count was observed for the majority (four out of seven) datasets.\n\nWe further questioned whether the observed subtle performance gains for the trimmed data correlate with the proportion of adapters in reads. To answer this question, we plotted the difference in both precision and recall (Figure 1d) observed for indels in WES samples against the proportion of adapter bases. To our surprise, we observed no direct dependence between an increase and precision or recall and the total adapter content (Figure 1c-d). Given this result, we hypothesized that the difference in variant calling accuracy may be driven by variants located in adapter-enriched regions located at the exon boundaries in WES. To test this hypothesis, we evaluated the performance of DeepVariant in regions located in the vicinity of the exon boundary. Contrary to our expectations, we observed a reverse effect of adapter trimming on variant calling outcome in the immediate exon vicinity (0-25 bp) (Figure 1e). In regions located further away from the exon margin, trimming had no median effect on the F1 scores.\n\nGiven these results, we next asked if a more reproducible effect of trimming on variant calling accuracy can be observed when using other bioinformatic tools for adapter removal. To this end, we applied two other commonly used methods for trimming adapters - Trimmomatic (Bolger et al., 2014) and BBDUK (https://github.com/BioInfoTools/BBMap). Evaluation of variant calling results showed that all tools produce similar results, with only a slightly lower precision when using Trimmomatic (Supplementary Figure S1).\n\nAt the next stage of our analysis, we decided to compare the effects of adapter trimming on other variant calling methods. For this comparison, we used a set of nine variant calling and filtering methods from our previous analysis (Barbitoff et al., 2022). We applied this set of tools to the set of GIAB datasets, focusing solely on WES samples due to markedly higher adapter content. Analysis of variant calling results showed that some of the tools demonstrate greater sensitivity to presence of adapters in reads. In particular, Clair3 and Octopus (with the random forest filtering model) showed a significant and reproducible performance increase on trimmed data compared to untrimmed (Figure 2a). Furthermore, Strelka2 showed a large increase in performance for samples with high adapter content, though the median difference in F1 score across all samples was subtle. Importantly, the observed gains in the F1 score were not sufficient for any tool to surpass DeepVariant when comparing the F1 scores on trimmed data (Figure 2b).\n\n(a) Boxplots showing the differences in F1 score values between variant calls produced on trimmed and untrimmed high coverage WES data using the indicated variant calling pipelines. (b) F1 scores of indel and SNP calling with the indicated pipelines on fastp-trimmed of high-coverage WES data. (c, d) Same as in (a, b), but for moderate(~70-100×) coverage datasets. CL - Clair3, DV - DeepVariant, FB - Freebayes, G1 and GH - GATK HaplotypeCaller with 1D CNN or hard filtering, OF and OS - Octopus with random forest or standard filtering, ST - Strelka2.\n\nFinally, we hypothesized that the low magnitude of effect of adapter trimming on variant calling accuracy may be explained by the high coverage of the WES datasets used for analysis (the mean coverage of CDS bases was more than 200×). To evaluate this hypothesis, we downsampled 40% of the reads in each sample to obtain a set of WES data with substantially lower mean coverage (~80×). Such WES datasets better represent a typical exome sample. After generating the downsampled WES data, we applied all tested variant calling pipelines to this set of samples, and evaluated the accuracy of the resulting variant calls. The analysis showed that the effects of adapter trimming for downsampled data were on average less pronounced compared to the ones observed using high-coverage samples (Figure 2c). The effect of trimming for the best-performing pipeline based on DeepVariant was less pronounced in downsampled compared to original data. Similarly, Octopus with the random forest filtering mode also showed a substantially lower impact of trimming on moderate-coverage datasets compared to high-coverage ones. For GATK-HC and Strelka2 the results were similar on high- and moderate-coverage data, while Octopus with a standard filtering scheme showed an irreproducible positive impact of trimming on indel calling (Figure 2a). The only exception from the general trend was Clair3 which showed markedly greater performance gains upon trimming in moderate-coverage WES datasets. We also compared the performance of each individual pipeline on high-coverage and low-coverage WES data. In concordance with the results of our previous analysis (Barbitoff et al., 2022), only Octopus with random forest filtering model performed better on low-coverage compared to high-coverage datasets (Supplementary Figure S2); nevertheless, DeepVariant remained the best-performing solution for the downsampled data both before and after adapter trimming (Figure 2d).\n\n\nDiscussion\n\nPre-processing and trimming of raw sequencing reads is commonly considered a standard step in virtually any data analysis workflow. However, the development of both laboratory protocols for sequencing library preparation and bioinformatic tools for the analysis reopens the question of the necessity of read trimming procedure for accurate analysis and interpretation of sequencing results. A recent analysis in bacteria (Bush, 2020) suggested that read trimming has minimal effects on the accuracy of variant calling. Given this report, as well as the result of our recent benchmark of state-of-the-art variant callers, we conducted a systematic analysis of the impact of read trimming on the accuracy of germline variant analysis in the human genome.\n\nConcordantly with the results of (Bush, 2020), we observed a very limited effect of adapter removal on the accuracy of variant calling. For the majority of both WGS and WES samples, the difference in the performance of the most accurate combination of tools (the BWA MEM aligner and the DeepVariant variant caller) between trimmed and untrimmed data was equal to zero for both SNP and indel variants. Positive effects of adapter removal on variant calling were observed only for several variant sites in some of the WES samples. This result is concordant with the overall higher fraction of adapter bases in WES, and corroborates our previous findings regarding the major role of insert size in defining the limits of CDS coverage for WES libraries (Barbitoff et al., 2020).\n\nAccording to our previous analysis, variant calling in the CDS-flanking regions is the main driver of lower variant calling accuracy for WES data (Barbitoff et al., 2022). This observation suggests that a positive effect of adapter removal on variant discovery from WES data may be driven by variants in such exon boundary regions, which should be enriched for adapters. However, our assessment of the impact of adapter removal on variant calling in the immediate vicinity of the CDS does not support this hypothesis (Figure 1e).\n\nAmong the combinations of variant calling and filtering methods tested, Clair3 and Octopus showed a significant dependence on the presence of adapters in reads (Figure 2a, c). For Octopus, this dependence was reproducibly observed only for the random forest-based filtering. Furthermore, our results confirm that a decrease in coverage leads to an unexpected improvement in the accuracy of variant filtering with this model (Supplementary Figure 2). These results are consistent with the greater dependence of the random forest filtering method in Octopus on coverage and other sequence properties (Barbitoff et al., 2022). Similarly, greater impact of adapter removal on Clair3 performance is consistent with its substantial dependence on alignment properties (Barbitoff et al., 2022). It is also important to note that our comparison of the accuracy of different pipelines on trimmed data confirms that DeepVariant remains the best-performing solution for germline variant analysis (Figure 2b, d). Taken together, the aforementioned findings provide additional support to the results of our earlier benchmark, and emphasize the necessity of thorough testing and validation of ML-based variant calling and filtering solutions.\n\nBesides the overall negligible impact of adapter trimming on variant calling accuracy, adapter removal has other important consequences which affect the necessity of this procedure. First, removing adapter sequences from the reads leads to data loss if the raw read files are not stored separately. While the adapter sequences by themself do not contain any relevant information, their absence may affect future re-analysis of the data, including independent quality assessment. On the other hand, presence of adapter sequences in reads may complicate the visual inspection of the alignment results, especially for inexperienced users. In addition, both presence or absence of adapters may affect certain types of post-analysis of the alignment files.\n\nIt is also important to emphasize that our observations are valid for germline variant calling. In case of somatic variant discovery, which is known to have a much greater sensitivity to errors in reads and requires a different approach to data processing (Koboldt, 2020). Given the aforementioned features of somatic variant calling, it is possible to suggest that adapter trimming will have a much greater positive impact in this case.\n\nOverall, we believe that our findings argue against adapter removal for germline variant calling in the human genome, While positive effects of read trimming can be observed only for some of the WES samples, trimming does not provide any noticeable performance gain in neither WGS nor the majority of WES datasets, and may even decrease the accuracy of analysis.",
"appendix": "Data availability\n\nThe underlying data used in this article were acquired from the Genome In A Bottle (GIAB) FTP site (for WGS data) and NCBI Sequencing Read Archive (for WES data).\n\nGIAB FTP site: Raw whole-genome sequencing data for HG001. https://ftp-trace.ncbi.nih.gov/ReferenceSamples/giab/data/NA12878/NIST_NA12878_HG001_HiSeq_300x/131219_D00360_005_BH814YADXX/Project_RM8398/ (Zook et al., 2016)\n\nGIAB FTP site: Raw whole-genome sequencing data for HG002. https://ftp-trace.ncbi.nlm.nih.gov/ReferenceSamples/giab/data/AshkenazimTrio/HG002_NA24385_son/NIST_HiSeq_HG002_Homogeneity-10953946/HG002_HiSeq300x_ fastq/140528_D00360_0018_AH8VC6ADXX/Project_RM8391_RM8392/ (Zook et al., 2016)\n\nGIAB FTP site: Raw whole-genome sequencing data for HG003. https://ftp-trace.ncbi.nlm.nih.gov/ReferenceSamples/giab/data/AshkenazimTrio/HG003_NA24149_father/NIST_HiSeq_HG003_Homogeneity-12389378/HG003_HiSeq300x_ fastq/140701_D00360_0032_AHA0KGADXX/Project_RM8392/ (Zook et al., 2016)\n\nGIAB FTP site: Raw whole-genome sequencing data for HG004. https://ftp-trace.ncbi.nlm.nih.gov/ReferenceSamples/giab/data/AshkenazimTrio/HG004_NA24143_mother/NIST_HiSeq_HG004_Homogeneity-14572558/HG004_HiSeq300x_fastq/140818_D00360_0046_AHA5R5ADXX/Project_RM8392/ (Zook et al., 2016)\n\nGIAB FTP site: Raw whole-genome sequencing data for HG005. https://ftp-trace.ncbi.nlm.nih.gov/giab/ftp/data/ChineseTrio/HG005_NA24631_son/HG005_NA24631_son_HiSeq_300x/basespace_250bps_fastqs/150420_HG005_Homogeneity_01-22889870/ (Zook et al., 2016)\n\nGIAB FTP site: Raw whole-genome sequencing data for HG006. https://ftp-trace.ncbi.nlm.nih.gov/giab/ftp/data/ ChineseTrio/HG006_NA24694-huCA017E_father/NA24694_Father_HiSeq100x/NA24694_Father_HiSeq100x_fastqs/ (Zook et al., 2016)\n\nGIAB FTP site: Raw whole-genome sequencing data for HG007. https://ftp-trace.ncbi.nlm.nih.gov/giab/ftp/data/ ChineseTrio/HG007_NA24695-hu38168_mother/NA24695_Mother_HiSeq100x/NA24695_Mother_HiSeq100x_fastqs/ (Zook et al., 2016)\n\nNCBI Sequencing Read Archive: Raw whole-exome sequencing data for HG001. Accession number: ERR1905890; https://ncbi.nlm.nih.gov/sra/?term=ERR1905890 (Zook et al., 2016)\n\nNCBI Sequencing Read Archive: Raw whole-exome sequencing data for HG002. Accession number: SRR2962669; https://ncbi.nlm.nih.gov/sra/?term=SRR2962669 (Zook et al., 2016)\n\nNCBI Sequencing Read Archive: Raw whole-exome sequencing data for HG003. Accession number: SRR2962692; https://ncbi.nlm.nih.gov/sra/?term=SRR2962692 (Zook et al., 2016)\n\nNCBI Sequencing Read Archive: Raw whole-exome sequencing data for HG004. Accession number: SRR2962694; https://ncbi.nlm.nih.gov/sra/?term=SRR2962694 (Zook et al., 2016)\n\nNCBI Sequencing Read Archive: Raw whole-exome sequencing data for HG005. Accession number: SRR2962693; https://ncbi.nlm.nih.gov/sra/?term=SRR2962693 (Zook et al., 2016)\n\nNCBI Sequencing Read Archive: Raw whole-exome sequencing data for HG006. Accession number: SRR14724507; https://ncbi.nlm.nih.gov/sra/?term=SRR14724507 (Zook et al., 2016)\n\nNCBI Sequencing Read Archive: Raw whole-exome sequencing data for HG007. Accession number: SRR14724506; https://ncbi.nlm.nih.gov/sra/?term=SRR14724506 (Zook et al., 2016)\n\n\nAcknowledgements\n\nWe thank JetBrains Ltd. for providing financial support and computing resources for the project. The authors declare no conflict of interest.\n\n\nReferences\n\nBarbitoff Y: Ibre-research /trimming-effects. Zenodo. [Software]. 2024. Publisher Full Text\n\nBarbitoff YA, Abasov R, Tvorogova VE, et al.: Systematic benchmark of state-of-the-art variant calling pipelines identifies major factors affecting accuracy of coding sequence variant discovery. BMC Genomics. 2022; 23: 1–17. Publisher Full Text\n\nBarbitoff YA, et al.: Systematic dissection of biases in whole-exome and whole-genome sequencing reveals major determinants of coding sequence coverage. Sci. Rep. 2020; 10: 1–13.\n\nBiesecker LG, Green RC: Diagnostic Clinical Genome and Exome Sequencing. N. Engl. J. Med. 2014; 370: 2418–2425. Publisher Full Text\n\nBolger AM, Lohse M, Usadel B: Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30: 2114–2120. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBush SJ: Read trimming has minimal effect on bacterial SNP-calling accuracy. Microb. Genomics. 2020; 6: 1–13.\n\nChen S, Zhou Y, Chen Y, et al.: Fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018; 34: i884–i890. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen X, Schulz-Trieglaff O, Shaw R, et al.: Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016; 32(8): 1220–1222. PubMed Abstract | Publisher Full Text\n\nCooke DP, Wedge DC, Lunter G: A unified haplotype-based method for accurate and comprehensive variant calling. Nat. Biotechnol. 2021; 39: 885–892. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDePristo MA, et al.: A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 2011; 43: 491–498. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEbbert MTW, et al.: Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight. Genome Biol. 2019; 20: 97. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEllingford JM, et al.: Recommendations for clinical interpretation of variants found in non-coding regions of the genome. Genome Med. 2022; 14: 1–19.\n\nFriedman S, Gauthier L, Farjoun Y, et al.: Lean and deep models for more accurate filtering of SNP and INDEL variant calls. Bioinformatics. 2020; 36: 2060–2067. PubMed Abstract | Publisher Full Text\n\nGarrison E, Marth G: Haplotype-based variant detection from short-read sequencing. aRxiv. 2012; 1–9.\n\nGoodwin S, McPherson JD, McCombie WR: Coming of age: Ten years of next-generation sequencing technologies. Nat. Rev. Genet. 2016; 17: 333–351. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim S, Scheffler K, Halpern AL, et al.: Strelka2: fast and accurate calling of germline and somatic variants. Nat. Methods. 2018; 15(8): 591–594. PubMed Abstract | Publisher Full Text\n\nKoboldt DC: Best practices for variant calling in clinical sequencing. Genome Med. 2020; 12: 1–13. Publisher Full Text\n\nKrusche P, et al.: Best practices for benchmarking germline small-variant calls in human genomes. Nat. Biotechnol. 2019; 37: 555–560. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi H, Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25: 1754–1760. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLuo R, et al.: Exploring the limit of using a deep neural network on pileup data for germline variant calling. Nat. Mach. Intell. 2020; 2: 220–227. Publisher Full Text\n\nMcKenna A, et al.: The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 10: 1297–1303.\n\nPoplin R, et al.: A universal snp and small-indel variant caller using deep neural networks. Nat. Biotechnol. 2018; 36: 983–987. PubMed Abstract | Publisher Full Text\n\nVan der Auwera GA, et al.: From FastQ Data to High-Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Curr. Protoc. Bioinformatics. 2013; 43: 11.10.1–10.33. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWright CF, FitzPatrick DR, Firth HV: Paediatric genomics: diagnosing rare disease in children. Nat. Rev. Genet. 2018; 19: 253–268. Publisher Full Text\n\nZook JM, et al.: Extensive sequencing of seven human genomes to characterize benchmark reference materials. Sci. Data. 2016; 3: 160025. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "304194",
"date": "21 Aug 2024",
"name": "Dharma Varapula",
"expertise": [
"Reviewer Expertise genomics technology development",
"data analysis and immunobiology",
"methods development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this report, Barbitoff, Y. and Predeus, A. have described a study investigating if read trimming, specifically adapter trimming, affects variant calling accuracy using commonly employed variant callers. The authors find this investigation to be of significant value citing there is no prior systematic study exploring the impact of read trimming on variant calling accuracy. In the study, WES and WGS datasets from seven GIAB samples were processed using six different variant callers (DeepVariant, GATK HaplotypeCaller, Freebayes, Strelka2, Octopus, and Clair3) to measure the effect of read trimming performed prior to the variant calling. The authors show comparative metrics (differences between trimmed and untrimmed variant caller performance metrics – recall, precision and F1 scores) and find no substantial differences in variant calling performance, except in the case of 200x coverage WES. Subsequently, the authors downsampled the data to produce a simulated 80x WES dataset expecting a greater likelihood for an increased impact of read trimming on variant calling accuracy. This simulated dataset too did not show significant impact due to read trimming. Further, the authors found no correlation between extent of adapter base contamination and impact of read trimming on variant caller performance metrics. Additionally, the authors ran the pipelines with different variant callers and found minimal impacts due to read trimming upstream. My comments below:\nThe adapter base percentage variation ranged from 8.1% to 35.2%. Please comment if this is an expected range for WES datasets. Also, please mention the coverage of the WES dataset in the caption for Fig 1. How does one assess the changes in performance metrics to be significant or not (Fig 1b and 1c)? Recall and precision score metrics in Figure 1b for Indels in WES datasets show deviations from the mean and these are not explained thoroughly. If this variance is to be expected, is it likely that the sample set n of 7 is too low? Or is the data heteroscedastic? In my view, the observations made on data presented in Figure 1e are not sufficiently explained. Discussion section on this aspect is a rehash of the content in the Results section. Read trimming is often a lower time-cost step compared to the variant calling step. It would benefit the reader (and the authors) greatly if there was a more detailed explanation why this is an important decision to make, which this study is aimed to inform us better for. Data redundancy and potential loss of raw data (if only single copy retained) appear to be valid reasons on the surface, a more complete justification is need in my view. Review of prior literature work can be more exhaustive.\n\nI was unable to access or review the Supplementary information, so it has not been included in my review. Please update in revised version\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "308861",
"date": "14 Oct 2024",
"name": "Xihao Li",
"expertise": [
"Reviewer Expertise sequencing technologies",
"statistical genetics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study provides a systematic evaluation of the effect of adapter trimming on the accuracy of germline short variant calling in the human genome, utilizing both whole-genome sequencing (WGS) and whole-exome sequencing (WES) datasets. The comparison of multiple variant calling tools, with and without adapter trimming, reveals minimal impact on WGS data but suggests modest improvements in certain WES samples, particularly in indel detection. The study concludes that while adapter trimming may not be essential for WGS, it shows some benefits for specific WES cases. The manuscript is well-written and clear, making it accessible for readers. Below are a few comments for the authors to consider:\nThe authors mention that “adapter trimming had very limited effects on both precision and recall.” It would be helpful to clarify and quantify the threshold for \"limited.\" Providing a statistical measure, such as a p-value or confidence interval, would strengthen the interpretation of the findings. Additional explanation is needed for the samples that showed positive effects in Figure 1. Clarifying why these samples differ from the others would help contextualize the observed improvements. The authors are encouraged to elaborate on the reasons why results differ between SNP and indel calling. Further discussion on potential underlying mechanisms would enhance understanding. The statement that “trimming may even decrease the accuracy of analysis” warrants further discussion. Exploring potential reasons behind this observation could provide valuable insights into the circumstances in which trimming could be detrimental.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-506
|
https://f1000research.com/articles/13-504/v1
|
17 May 24
|
{
"type": "Opinion Article",
"title": "Deep geological disposal of plastic waste: Pros and cons",
"authors": [
"Hayk Minasyan"
],
"abstract": "Plastic production is growing, plastic waste is accumulating, and current waste management methods (recycling, incineration, etc.) are not yet able to solve this waste problem. Proposals and projects aimed at solving or facilitating the problem of plastic waste are therefore relevant. This article proposes a deep geological disposal method for plastic waste projects. The prototype for this project was the deep geological disposal of nuclear waste. Although plastic waste and nuclear waste are fundamentally different, the adequacy of this approach is justified by the fact that plastic waste, such as nuclear waste, has a a long degradation period and poses great danger to the environment, animals, and humans. The article is conceptual and examines the aspects necessary for the implementation of the project, such as the establishment of a special international UN agency for plastic waste management, specific sources of funding, giving plastic waste a monetary value, applying free market principles, and using existing potential opportunities for deep geological disposal of plastic waste. This article also discusses the proposed concept for finding more optimal options.",
"keywords": [
"Plastic",
"waste",
"waste management",
"geological disposal."
],
"content": "Introduction\n\nOver the past 70 years, more than 10 billion tons of plastic have been produced. Approximately 10% of waste has been recycled, 11% burned, 8% buried, and the remaining 70% pollutes the environment (Enfrin et al., 2019, Zaman and Newman, 2021). Approximately 80% of ocean plastic litter comes from land. More than 10 million tons of plastics enter the oceans annually (Carney Almroth and Eggert, 2019, Chassignet et al., 2021). It is not known exactly how much plastic in the ocean remains on the surface, how much floats at different depths, or how much sinks to the bottom. The amount of macroplastics on the ocean surface is large. For example, it forms The Great Pacific Garbage Patch, which quickly captures new water surfaces (Egger et al., 2020).\n\nLarge amounts of plastics are buried in landfills (Rahman et al., 2023). Currently, global annual plastic production is approximately 348 million tons (Yu et al., 2022). Nearly 80% of the total plastic waste is accumulated in landfills/open dumps and in the natural environment (Yadav et al., 2020). As landfills are relatively closely sealed reactors with complex biochemical reactions and physical changes, plastic waste buried in landfills is subjected to more severe environmental conditions such as leachate pH, high salinity, fluctuating temperature, gas generation, physical stress, and microbial degradation. All the above factors may lead to the fragmentation of plastics to microplastics (MPs), and small plastic debris can be carried out by the discharge of leachate (Wojnowska-Baryła et al., 2022, Zhu et al., 2021). The ultimate fate of plastic in landfills is a major concern, particularly as there is no established method for determining whether plastic degrades, biodegrades, or is recalcitrant. The amount of plastic waste continues to increase progressively, and this waste is increasing the land and water surfaces (Singh et al., 2023). The accumulation of mismanaged plastic waste (MPW) in the environment is a global concern (Lebreton and Andrady, 2019). Therefore, along with the already practiced approaches (recycling, incineration, landfill, etc.), new approaches to plastic waste management are necessary. The aim of this article is to offer deep geological disposal of plastic waste as a potentially new approach.\n\n\nMethods\n\nWe used Google Scholar, ResearchGate, ScienceDirect, SciSpace, Scopus, PubMed, Consensus, and Core search engines to determine the availability of deep geological plastic waste disposal in the scientific literature. We used long-tail keywords such as “deep geological disposal plastic waste”, “deep geological disposal”, and “geological disposal plastic”, and short-tail keywords “geological disposal” and “plastic waste.”\n\n\nResults\n\nA search of the top search engines (Google Scholar, ResearchGate, ScienceDirect, SciSpace, Scopus, PubMed, Consensus, and Core) using both long- and short-tail keywords revealed no articles dedicated to the deep geological disposal of plastic waste. Therefore, the idea of deep geological disposal of plastic waste has been presented for the first time in this article.\n\n\nDiscussion\n\nPlastics have been destroyed very slowly in nature. It can take tens to hundreds of years (Quecholac-Piña et al., 2020, Mohanan et al., 2020, Ru et al., 2020). In this sense, the disintegration of plastic waste is similar to that of radioactive waste. However, the decay time of radioisotopes occurs over a wider time interval. For example, srontium-90 and cesium-137 have half-lives of approximately 30 years whereas plutonium- 239 has a half-life of 24,000 years (Ahluwalia, 2019). Both nuclear technologies and plastic production have been unprecedented in the history of mankind. Interestingly, the mass production of plastics began simultaneously with the development of nuclear power plants. Both occurred after World War II (the Second World War). The mass production of plastics began in 1950. Two million metric tons of plastic was produced in that year (Geyer, 2020). In 1954, the world’s first nuclear power station in Obninsk (in the Soviet Union) began to produce electricity; in 1956, the Calder Hall nuclear power plant in the United Kingdom began to operate; and in 1958, the Shippingport Atomic Power Station in the USA began to generate electricity (Alam et al., 2019, Geyer et al., 2017). In the case of mass production of plastic and the proliferation of nuclear power plants, the problem of waste appeared, but they were solved in different ways. The atomic explosions in August 1945 showed the power of nuclear weapons and the danger of nuclear waste; from the very beginning of the operation of nuclear power plants, nuclear waste was collected, and deep geological disposal has been considered the best solution (Strandberg and Andrén, 2009). Regarding plastic waste, nothing has been done for a long time, and the situation is now approaching critical. Being invisible, radiation poses a serious risk to humans and the environment, whereas plastic disintegration is a chemical risk to ecology, animals, and humans.\n\nAlthough nuclear waste and plastic waste are distinct areas, there are some similarities in their management (Armand et al., 2023, Neksumi et al., 2022, Subba Rao et al., 2022, Zalasiewicz et al., 2019):\n\n1. Both nuclear and plastic waste management have long-term environmental impacts. Nuclear waste contains radioactive materials that have remained hazardous for thousands of years. Similarly, certain types of plastic wastes, such as single-use plastics, can persist in the environment for hundreds of years.\n\n2. Both nuclear and plastic waste management require appropriate storage and disposal to minimize their impact. Nuclear waste must be stored in secure facilities to prevent the leakage or release of radioactive materials. Similarly, plastic waste must be managed to prevent it from entering waterways, harming wildlife, or breaking down into MPs that can contaminate ecosystems.\n\n3. Both nuclear and plastic waste management face public concerns and opposition. Nuclear waste is a hazard owing to radiation and long-term storage. Similarly, plastic waste has garnered attention owing to its environmental consequences.\n\n4. Both nuclear and plastic waste management require ongoing research and technological advancements for more effective and sustainable solutions. Efforts are underway to enhance nuclear waste storage, explore advanced reactor designs, and develop waste-reprocessing technologies. Similarly, progress in plastic waste management includes the development of recycling technologies, exploration of alternatives, and implementation of waste reduction strategies.\n\nDespite the aforementioned similarities with plastic waste management processes, nuclear waste management poses distinct challenges owing to its radioactive nature and long-term risks. Plastic waste management, on the other hand, focuses on reducing pollution and minimizing the environmental impact of plastic waste. But the comparison of plastic waste with nuclear waste is adequate in the sense that it shows: 1. The seriousness of the problem of plastic waste, 2. The need for broad international cooperation in managing plastic waste, and 3. The need to create (outside or inside UNEP) an Agency for Plastic Waste Management, which would be part of the UN system; 4. The need to create funds to raise money to solve the problem of plastic waste; 5. There is a need to apply some criteria for nuclear waste management to solve the problem of plastic waste.\n\nThe International Atomic Energy Agency (IAEA), established in December 1957 by the United Nations (von Mehren, 1959) may be a model for creating the International Plastic Waste Agency. However, on many specific issues, the IAEA and plastic waste agencies will differ. For example, IAEA’s main sources of funding are the Regular Budget Fund, the Technical Cooperation Fund and Extra budgetary Program Funds that are supplied by Member States and by other donors (Getmansky, 2017). The sources of funding for Plastic Waste Agency Management (PWAM) include governments, foundations, corporations, international and local public organizations, individuals, other donors and taxes paid by plastic producers and plastic item manufacturers. Establishing a connection between the volumes of plastic produced, the income of plastic producers, and the money spent on plastic waste management will make it possible to more accurately determine the cost of plastic ecology.\n\nExtrapolation from nuclear waste disposal to plastic waste management may be useful. As mentioned above, deep geological disposal is considered the best solution for nuclear waste management (Strandberg and Andrén, 2009). However, for deep geological disposal of plastic waste, the latter must be collected in advance. Nuclear waste is kept in containers at nuclear power plants and nuclear weapons factories, or stored in burial grounds isolated from contact with the environment. In contrast, plastic waste pollutes the environment everywhere; almost all people come into contact with it and contribute to its formation. To solve the problem of plastic waste collection, it is necessary to provide monetary value for this waste. It is promising to create a market for plastic waste and apply all the mechanisms of the free market and trade to it, especially because plastic waste can become a valuable primary raw material in the future.\n\nWith stable financing of the demand for plastic waste, firms, companies, and private enterprises engaged in the collection, transportation, and storage of plastic waste will spontaneously appear, and plastic producers themselves may want to create subsidiaries involved in the collection, transportation, and disposal of plastic waste. If plastic waste prices are set to make collecting and selling waste profitable, there could even be a fleet devoted solely to cleaning up plastic waste in the oceans. Ships specializing in the removal of debris from water basins can more successfully apply technologies that remove plastic without harming aquatic life.\n\nIf plastic waste is removed from the seas and oceans and collected from landfills, the question becomes what to do with all this, given that plastic waste cannot be recycled or burned. One possible solution could be to deposit plastic waste inside numerous exhausted, abandoned, and unused mines, quarries, caverns, and holes. This offer is supported by the following:\n\n1. There are a large number of exhausted, abandoned, and unused mines, quarries, caverns, and holes in the world, and they themselves represent a major environmental problem (Bennett, 2016, Cui et al., 2020, Kushwaha et al., 2019, Liu et al., 2021).\n\n2. Abandoned mines, holes, and caverns often have existing infrastructure such as roads, railways, and buildings that can potentially be repurposed or reused (Lele et al., 2023, Collier and Ireland, 2018). Many mines have been developed with significant infrastructure to support mining operations, including transportation systems and structures for housing workers or storing equipment (Limpitlaw and Briel, 2014, Carvalho, 2017). If these abandoned sites are considered for redevelopment or re purposing, existing infrastructure can provide a foundation for future use. For example, roads and railways can be repaired or upgraded to facilitate transportation of plastic waste to the site. Buildings can be renovated or repurposed for various functions, such as offices, storage facilities, processing facilities, warehouses, research facilities, and even recreational spaces for workers. Buildings that were once used as housing for miners can still be structurally sound and repurposed as housing for new workers.\n\n3. The use of abandoned mines and caverns as storage for oil, gas, or other minerals (Du et al., 2022, Luo et al., 2022, Saigustia and Robak, 2021) has shown the possibility of their conversion to universal storage. It is especially noteworthy that abandoned mines have been used, are being used and will be used as repositories for nuclear waste (Kasperski and Storm, 2020, Xie et al., 2020, Yim, 2022). Nations that employ nuclear power generally prefer to store radioactive waste by placing it in underground mines made up of a network of tunnels or passages linked to disposal tunnels situated several hundred meters below the surface (Popov et al., 2019). However, considering abandoned mines and caverns as storage sites, it is important to assess the safety and stability of these spaces before any large-scale redevelopment or repurposing efforts. There are several important factors that make this option potentially problematic but not impossible.\n\n1. Environmental impact: The placement of plastic waste in such locations can have significant environmental consequences. Plastic waste can release harmful chemicals over time, contaminating the soil, groundwater, and surrounding ecosystems. Pollution can have long-lasting effects on plants, animals, and human health.\n\n2. Leachate concerns: Plastic waste can generate leachate, a liquid that forms when water percolates through waste. Leachates can contain toxic substances that can seep into the ground and contaminate groundwater sources, affecting drinking water supplies and further exacerbating environmental issues.\n\n3. Potential for migration: Plastics are lightweight and can be easily carried by wind or water in the case of superficial disposal, potentially escaping from designated areas and spreading across the surrounding environment. This can lead to littering and pollution of nearby land, rivers, and oceans, exacerbating the global plastic waste problem rather than solving it.\n\n4. Future land use: Some abandoned locations may have potential for future use, such as reclamation, habitat restoration, or even tourism. Using them as plastic waste dumping sites limits these possibilities and hinders the long-term sustainable development of these areas.\n\nThe above arguments for and against the use of abandoned mines, holes, and caverns for plastic waste disposal indicate that the idea of plastic waste disposal is not universal, and in each case, its application must be weighed and all local circumstances taken into account.\n\nThere is no data on how much plastic waste can be deposited in them, however, based on the depth and diameter of many quarries, it can be assumed that all plastic trash will fit in them for many decades and more to come. The deposition of waste should be carried out in accordance with the rules of conservation, with the possibility of extracting plastic waste in the event of depletion of hydrocarbon reserves on the planet (Pang et al., 2022, Petrescu, 2020). Countries where mines and quarries are used to deposit plastic waste can profit from long-term leasing and storage of their mines and quarries. Parallel to depositing plastic waste in these locations, it is also indispensable to continue focusing on reducing the generation of plastic waste, promoting recycling and reuse, and developing sustainable waste management systems. Equally important is investment in proper waste infrastructure and raising awareness of plastic pollution. Implementing effective policies and regulations can help address the plastic waste crisis in an environmentally friendly and sustainable manner. Encouraging the development and use of non-biodegradable but environmentally friendly alternatives to plastics can also contribute to a long-term solution.\n\nThus, as soon as plastic waste becomes a commodity and an appropriate commercial approach, adequate pricing, and geological deposits are applied to it, the problem of plastic waste will be facilitated on the way to resolution.\n\n\nConclusion\n\nConventional plastics are made from petroleum and natural gas. The latter are extracted from the bowels of Earth. According to the main concept of the article, extracted petroleum and natural gas can be partially returned to the bowels of the earth in the form of plastic waste that pollutes the environment and is currently not subject to recycling, reuse, repurposing, incineration, or other plastic waste management technologies. In the future, if petroleum and gas reserves on the planet are depleted, plastic waste at Earth’s depths can become a valuable raw material for the production of plastic and other hydrocarbon products. This approach to plastic waste management requires future research and discussion regarding the optimization of the concept, its practices, regulations, and policies.",
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}
|
[
{
"id": "319698",
"date": "10 Sep 2024",
"name": "Magdalena Vaverková",
"expertise": [
"Reviewer Expertise Waste management"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAs someone who has been engaged in waste management for over 20 years, I found the article’s premise—deep geological disposal of plastic waste—intriguing, yet deeply problematic. While the article proposes this as a new approach to managing the vast quantities of mismanaged plastic waste (MPW), it overlooks several crucial aspects of plastic waste management that have proven to be more practical, efficient, and sustainable. I believe this concept lacks feasibility both from an economic and environmental standpoint. One of the most striking issues with the article is the inconsistency in its discussion of plastic’s chemical nature. On one hand, it is acknowledged that plastic can take hundreds to thousands of years to decompose, suggesting that it is inert and resistant to degradation. On the other hand, the article raises concerns about leachates and environmental contamination, which implies that plastic waste does, in fact, react and break down into harmful substances. These contradictions undermine the argument for deep geological disposal. If plastic is inert and non-reactive, the environmental risk should be minimal. However, if plastics release harmful chemicals, placing them in deep geological layers could lead to unforeseen contamination, much like the challenges associated with hazardous waste disposal. The suggestion to treat plastic waste similarly to nuclear waste by storing it in deep geological repositories overlooks the fact that plastic waste is far more abundant, widely dispersed, and less hazardous than nuclear waste. The costs associated with collecting, transporting, and storing plastic in deep geological repositories would be astronomical, and these financial burdens far outweigh any potential benefits. Furthermore, nuclear waste is stored this way due to its high-level, long-term radioactive danger. Plastic waste, while a significant pollutant, can be more effectively managed through other methods, including recycling, incineration for energy recovery, and the development of biodegradable alternatives. Over the years, I have seen substantial progress in both recycling technologies and waste-to-energy systems. Many types of plastic waste, particularly PET, can be effectively recycled, and non-recyclable plastics can be incinerated in highly regulated incinerators to produce energy. Japan’s approach to waste management, for example, includes advanced waste-to-energy systems that capture a significant amount of the country’s energy from non-recyclable waste while keeping emissions under tight control. By contrast, the article’s deep geological disposal concept ignores the benefits of energy recovery from plastic incineration. Given the enormous global need for energy and the ongoing development of incineration technologies that meet modern environmental standards, it would make much more sense to focus on optimizing energy recovery from plastic waste than to bury it in geological sites. Additionally, improving recycling infrastructure and reducing single-use plastics are more viable long-term strategies than deep geological disposal. The article does highlight one concept worth exploring further—treating plastic waste as a valuable commodity. However, rather than applying this idea to deep geological storage, it should be linked to the principles of a circular economy. In recent years, there has been growing interest in treating waste as a resource, and plastics are no exception. By developing better market mechanisms for plastic waste, particularly through innovations in chemical recycling or even upcycling processes, we could unlock economic opportunities while addressing the environmental challenges posed by plastic pollution. Conclusion While the article raises important concerns about the growing problem of plastic waste, the proposed solution of deep geological disposal is neither economically nor environmentally viable. Decades of experience in waste management have shown that more practical solutions—such as advanced recycling, waste-to-energy, and policy-driven reductions in plastic production—are far more promising. Furthermore, there is significant potential to treat plastic waste as a resource within a circular economy framework, which could help mitigate the environmental crisis caused by plastic waste without resorting to drastic, impractical measures like deep geological disposal. In my professional view, the future of plastic waste management lies in innovation, sustainable technologies, and responsible consumption, not in burying the problem underground.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? No\n\nAre arguments sufficiently supported by evidence from the published literature? No\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? No",
"responses": [
{
"c_id": "12417",
"date": "25 Oct 2024",
"name": "Hayk Minasyan",
"role": "Author Response",
"response": "Article Deep geological disposal of plastic waste: Pros and cons Hayk Minasyan Hayk Minasyna’s response to the review of Magdalena Vaverková Author Response to Reviewer Author response: Dear Magdalena Vaverková, Warsaw University of Life Sciences, Warsaw, Poland Thank you for giving me the opportunity to start a discussion with you regarding your critical comments. I wrote at the end of my article: “This approach to plastic waste management requires future research and discussion regarding the optimization of the concept, its practices, regulations, and policies.” Unfortunately, you did not come up with any specific rational proposal, analysis of the concept, or attempt to optimize the concept or use its elements that, in your opinion, could be useful. However, any radically negative response can be useful in igniting debate and bringing the idea of deep geological disposal of plastic waste to the attention of open-minded researchers. I will try to provide references, where possible, from my article, so that they are easier to find. Reviewer comments As someone who has been engaged in waste management for over 20 years, I found the article’s premise—deep geological disposal of plastic waste—intriguing, yet deeply problematic. Author response: In the last 20 years, the amount of plastic waste has more than doubled (OECD Global Plastics Outlook: Policy Scenarios to 2060 OECD Publishing (2022) https://www.oecd-ilibrary.org/environment/global-plastics-outlook_aa1edf33-en] It means that a solution to the problem has not yet been found. Reviewer comments While the article proposes this as a new approach to managing the vast quantities of mismanaged plastic waste (MPW), it overlooks several crucial aspects of plastic waste management that have proven to be more practical, efficient, and sustainable. I believe this concept lacks feasibility both from an economic and environmental standpoint. Author response: While belief holds great value in many discussions, it is not typically considered a scientific measure. In order to assess the feasibility of the concept from both economic and environmental perspectives, it would be helpful if the reviewer could present relevant economic calculations, scientific data, and detailed explanations. Reviewer comments One of the most striking issues with the article is the inconsistency in its discussion of plastic’s chemical nature. On one hand, it is acknowledged that plastic can take hundreds to thousands of years to decompose, suggesting that it is inert and resistant to degradation. On the other hand, the article raises concerns about leachates and environmental contamination, which implies that plastic waste does react and break down into harmful substances. Author response: There is no inconsistency: plastic waste can generate leachate, a liquid that forms when water percolates through waste. In deep geological disposal with appropriate technical conditions (isolation, sealing walls for liquids, etc.) plastic waste breakdown is excluded and leachate generation is impossible. Reviewer comments These contradictions undermine the argument for deep geological disposal. Author response: There are no contradictions. In a duly technical approach, nothing undermines the idea of deep geological disposal. Reviewer comments If plastic is inert and non-reactive, the environmental risk should be minimal. However, if plastics release harmful chemicals, placing them in deep geological layers could lead to unforeseen contamination, much like the challenges associated with hazardous waste disposal. . Author response: Disposal of plastic waste in deep and dry repositories is safe and can’t lead to contamination. Reviewer comments The suggestion to treat plastic waste similarly to nuclear waste by storing it in deep geological repositories overlooks the fact that plastic waste is far more abundant, widely dispersed, and less hazardous than nuclear waste. Author response: Yes, plastic waste is less hazardous and more abundant than nuclear waste, but this argument is not something principally against deep geological disposal of plastic waste. Reviewer comments The costs associated with collecting, transporting, and storing plastic in deep geological repositories would be astronomical, and these financial burdens far outweigh any potential benefits. Author response: To make such assertions with confidence, it would also be expected that the reviewer possess a high level of expertise in the field of economics, supported by financial calculations and thorough estimates. Moreover, the reviewer appears to overlook the current limitations of methods like recycling, incineration for energy recovery, and the development of biodegradable alternatives. These approaches, while promising, have yet to demonstrate sufficient effectiveness to curb the rapid accumulation of plastic waste. Reviewer comments Furthermore, nuclear waste is stored this way due to its top-level, long-term radioactive danger. Author response: Yes, nuclear waste is stored this way due to its high-level, long-term radioactive danger, but again, it does not mean that plastic waste may not be stored by deep geological technology. Reviewer comments Plastic waste, while a significant pollutant, can be more effectively managed through other methods, including recycling, incineration for energy recovery, and the development of biodegradable alternatives. Author response: The reviewer ignores the fact that the methods she mentions, including recycling, incineration for energy recovery, and the development of biodegradable alternatives, are not yet effective enough and plastic waste continues to accumulate rapidly. I would like to draw the reviewer's attention to the fact that no more than 10% of plastic waste has been recycled, 11% burned, 8% buried, and the remaining 70% pollutes the environment (Enfrin et al., 2019, Zaman and Newman, 2021). Reviewer comments Over the years, I have seen substantial progress in both recycling technologies and waste-to-energy systems. Author response: Nevertheless, at present recycling technology processes only 10% of plastic waste; waste-to-energy technology burns 11% of plastic waste. Reviewer comments Many types of plastic waste, particularly PET, can be effectively recycled, and non-recyclable plastics can be incinerated in highly regulated incinerators to produce energy. Author response: While recycling is an important tool, it cannot be viewed as a standalone solution to the plastic waste crisis. The complex nature of the problem requires more than one method of management. By the year 2060, there is a projected trajectory for plastic waste to experience an approximately threefold increase. Within this context, nearly 50 % of the total plastic waste will continue to be deposited in landfills, with a recycling rate of <20 % (OECD Global Plastics Outlook: Policy Scenarios to 2060 OECD Publishing (2022) https://www.oecd-ilibrary.org/environment/global-plastics-outlook_aa1edf33-en). In addition, recycling plastic is not preferable in most cases because it is technologically complex and expensive, many types of plastic cannot be reused, and finally, it is impossible to recycle the same plastic endlessly. References: Aydin M, Degirmenci T, Bozatli O, Balsalobre-Lorente D. Fresh evidence of the impact of economic complexity, health expenditure, natural resources, plastic consumption, and renewable energy in air pollution deaths in the USA? An empirical approach. Science of The Total Environment [Internet]. 2024 Apr;921:171127. Available from: https://linkinghub.elsevier.com/retrieve/pii/S004896972401266X) Dong L, Huang Z, Qin Y, Zhi W. Industrialized fine physical regeneration process and economic benefit assessment for recycling waste HDPE containers. Journal of Cleaner Production [Internet]. 2024 Apr [cited 2024 Sep 10];447:141477. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0959652624009259 Merrington A. Recycling of plastics. In: Applied Plastics Engineering Handbook [Internet]. Elsevier; 2024 [cited 2024 Sep 10]. p. 191–217. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780323886673000060 Reviewer comments Japan’s approach to waste management, for example, includes advanced waste-to-energy systems that capture a significant amount of the country’s energy from non-recyclable waste while keeping emissions under tight control. By contrast, the article’s deep geological disposal concept ignores the benefits of energy recovery from plastic incineration. Author response: It seems there may have been some misunderstanding or misinterpretation of my article. The reviewer contrasts the ideas presented in the article with current waste management technologies without offering a clear logical basis for such conclusions. This leads to certain assumptions that remain unproven. The idea of deep geological disposal of plastic waste does not ignore other technologies of waste management including plastic incineration. It should be used simultaneously with other technologies. In combination with all modern technologies of plastic waste management, deep geological disposal may help to mitigate the problem of plastic waste. As to plastic incineration, it is dangerous for the environment due to ecological risks: Air Pollution: Incineration releases toxic heavy metals, dioxins, furans, into the air. They poison humans and animals. Dioxins and furans accumulate in the food chain. Greenhouse Gas Emissions: Burning plastic releases carbon dioxide (CO₂) and other greenhouse gases, contributing to climate change. Toxic Ash: Incineration generates toxic ash that needs to be disposed of in landfills and can contaminate soil and water. Microplastics: Incineration may produce microplastics that can be released into the atmosphere or water systems, causing further ecological harm. Due to these risks, incineration is not a preferred method for managing plastic waste. References: Luo L, Guo S, Shen D, Shentu J, Lu L, Qi S, et al. Characteristics and release potential of microplastics in municipal solid waste incineration bottom ash. Chemosphere [Internet]. 2024 Sep [cited 2024 Sep 10];364:143163. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0045653524020605 Jin M, Sun M, Liu J, Dong C, Xue J. Influence of operating parameters on the yield of micro-plastics from plastics incineration. Science of The Total Environment [Internet]. 2024 Feb [cited 2024 Sep 10];912:169347. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0048969723079779 Rogers K, WaMaina E, Barber A, Masood S, Love C, Kim YH, et al. Emissions from plastic incineration induce inflammation, oxidative stress, and impaired bioenergetics in primary human respiratory epithelial cells. Toxicological Sciences [Internet]. 2024 May 28 [cited 2024 Sep 10];199(2):301–15. Available from: https://academic.oup.com/toxsci/article/199/2/301/7636471 Reviewer comments Given the enormous global need for energy and the ongoing development of incineration technologies that meet modern environmental standards, it would make much more sense to focus on optimizing energy recovery from plastic waste than to bury it in geological sites. Author response: The reviewer strongly overestimates plastic incineration. At present, there are no incineration technologies that meet modern environmental standards: References: Jung S, Jung H, Ahn Y. Plastic-to-energy: Process and economic–environmental assessment of a recycling technology. Process Safety and Environmental Protection [Internet]. 2024 Mar [cited 2024 Sep 10];183:1051–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0957582024000806 Pathak G, Nichter M, Hardon A, Moyer E. The open burning of plastic wastes is an urgent global health issue. Annals of Global Health [Internet]. 2024 Jan 12 [cited 2024 Sep 10];90(1):3. Available from: https://annalsofglobalhealth.org/articles/10.5334/aogh.4232/ Besides, energy recovery from plastic waste (plastic incineration) results in irreversible loss of plastic. Burying plastic in the ground preserves plastic for future generations of people when the planet's hydrocarbons run out. As for energy production, from the ecological point of view, it must be obtained from renewable sources such as solar energy, wind, hydropower, etc. In this sense, nuclear energy is much more efficient and ecologically safer than burning plastic. References: Pourasl HH, Barenji RV, Khojastehnezhad VM. Solar energy status in the world: A comprehensive review. Energy Reports [Internet]. 2023 Nov [cited 2024 Sep 11];10:3474–93. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2352484723014579 Kaldellis JK, Boulogiorgou D. Renewable energy: Wind energy. In: Living with Climate Change [Internet]. Elsevier; 2024 [cited 2024 Sep 11]. p. 513–57. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780443185151000174 Hatamkhani A, Moridi A, Haghighi AT. Incorporating ecosystem services value into the optimal development of hydropower projects. Renewable Energy [Internet]. 2023 Feb [cited 2024 Sep 11];203:495–505. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0960148122018754 Krūmiņš J, Kļaviņš M. Investigating the potential of nuclear energy in achieving a carbon-free energy future. Energies [Internet]. 2023 Apr 22 [cited 2024 Sep 11];16(9):3612. Available from: https://www.mdpi.com/1996-1073/16/9/3612 Reviewer comments Additionally, improving recycling infrastructure and reducing single-use plastics are more viable long-term strategies than deep geological disposal. Author response: The reviewer appears to contrast the ideas presented in the article with existing plastic waste management technologies without providing clear justification for these comparisons, which seems to lead to conclusions that may not be fully substantiated. Reviewer comments The article does highlight one concept worth exploring further—treating plastic waste as a valuable commodity. However, rather than applying this idea to deep geological storage, it should be linked to the principles of a circular economy. Author response: Plastic is a valuable commodity and it is true for both deep geological storage and the principles of a circular economy. It is true for all other technologies as well. The reviewer persistently contrasts deep geological disposal versus the principles of a circular economy. Applying the idea of plastic waste's monetary value to deep geological storage does not exclude its application to the principles of a circular economy and other strategies. Reviewer comments In recent years, there has been growing interest in treating waste as a resource, and plastics are no exception. By developing better market mechanisms for plastic waste, particularly through innovations in chemical recycling or even upcycling processes, we could unlock economic opportunities while addressing the environmental challenges posed by plastic pollution. Author response: It sounds like a quote from a public speech. Yes, in recent years there has been growing interest in treating waste as a resource. However, plastic waste continues to accumulate on land, seas, and oceans. Reviewer's Conclusion Reviewer comments While the article raises important concerns about the growing problem of plastic waste, the proposed solution of deep geological disposal is neither economically nor environmentally viable. Author response: Again, for such a categorical conclusion the reviewer should present economic calculations and reasonable explanations as to why deep geological disposal is not environmentally viable. Reviewer comments Decades of experience in waste management have shown that more practical solutions—such as advanced recycling, waste-to-energy, and policy-driven reductions in plastic production—are far more promising. Author response: Maybe the solutions mentioned are promising, but today plastic waste continues accumulating. Again the same statistics: 10% of waste has been recycled, 11% burned, 8% buried, and the remaining 70% pollutes the environment. Declarative statements about promising technologies do not change the catastrophic state of affairs with waste accumulation. My article proposes additional measures to collect plastic from the seas, oceans, and landfills and bury it safely as a resource for future generations. Deep geological disposal is not opposed to all other plastic waste management technologies, but is offered as an additional tool to solve together with other technologies the very serious problems facing humanity in connection with plastic waste. Reviewer comments Furthermore, there is significant potential to treat plastic waste as a resource within a circular economy framework, which could help mitigate the environmental crisis caused by plastic waste without resorting to drastic, impractical measures like deep geological disposal. In my professional view, the future of plastic waste management lies in innovation, sustainable technologies, and responsible consumption, not in burying the problem underground. Author response: Тhe reviewer frames her perspective as a personal professional stance, though it aligns with the widely accepted principles of innovation, sustainable technologies, and responsible consumption in waste management. Regarding the suggestion of burying the problem underground, the article specifically advocates for the storage of plastic waste that cannot be recycled, has already undergone multiple recycling processes, or poses significant risks if incinerated or processed by existing technologies. Unfortunately, the primary concern raised by Dr. Magdalena Vaverková centers on a rather dismissive critique of deep geological disposal, which seems to overshadow other important aspects of the article. Her stance appears to impede an objective review of other proposed ideas, such as mechanisms for collecting plastic waste from oceans, seas, and landfills, as well as the organizational, political, and financial strategies for implementing deep geological disposal."
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https://f1000research.com/articles/13-504
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https://f1000research.com/articles/13-503/v1
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17 May 24
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{
"type": "Opinion Article",
"title": "The “House of Trust”. A framework for quality healthcare and leadership.",
"authors": [
"Kris Vanhaecht",
"Peter Lachman",
"Charlotte Van der Auwera",
"Deborah Seys",
"Fien Claessens",
"Massimiliano Panella",
"Dirk De Ridder",
"FlaQuM research group",
"Peter Lachman",
"Charlotte Van der Auwera",
"Deborah Seys",
"Fien Claessens",
"Massimiliano Panella",
"Dirk De Ridder"
],
"abstract": "In healthcare, improvement leaders have been inspired by the frameworks from industry which have been adapted into control systems and certifications to improve quality of care for people. To address the challenge to regain trust in healthcare design and delivery, we propose a conceptual framework, i.e. the “House of Trust”. This House brings together the Juran Trilogy, the emerging concept of co-production in quality management and the multidimensional definition of quality, which describes core values as an integral part of the system to deliver person- and kin-centered care. In the “House of Trust” patients, their kin, healthcare providers, executives and managers feel at home, with a sense of belonging. If we want to build a care organization that inspires and radiates confidence to all stakeholders, highlighting the basic interactions between front- and back-office is required. An organization with both well-organized back- and front-offices can enable all to benefit from the trust each of them needs and deserves. A quality system does not depend on government inspection and regulations nor on external accreditation to develop itself into a House of Trust. Success will only be achieved if all involved continuously question themselves about the technical dimensions of quality and their core values during the “moment of truth”.",
"keywords": [
"Trust",
"Quality",
"Kindness",
"Co-production",
"Values"
],
"content": "Introduction\n\nPatients, kin, healthcare providers, executives and managers have high expectations on all aspects of care. To meet these expectations people must trust the healthcare service. Trust is defined as ‘the expectations of the public that those who serve them will perform their responsibilities in a technically proficient way, that they will assume responsibility and not inappropriately defer to others, and that they will make their patients’ welfare their highest priority’.1 The trust patients have in physicians is associated not only with patient satisfaction, but also with continuity of care, more beneficial health behaviors, less symptoms, higher quality of life and adherence to treatment.1,2\n\nTrust is so fundamental to the patient physician relationship that is it easy to assume it exists as part of the clinical interaction. This is not necessarily the case and, when trust is lost, no single approach will rebuild, maintain or ensure trust. Several key factors have been defined to increase the trust between patients, the organization and the involved teams.1 These include measurement of patients’ experience, clinician engagement, a commitment to meeting the needs of patients as the core of the organizational culture, effective clinical teams, and inclusion of patients in all phases of this work.3\n\nTrust is not only important in the patient-provider relationship but is also important in the trust between the healthcare providers, managers and the healthcare organization. In a study based on 360-degrees feedback reports of 87,000 leaders, Zenger and Folkman concluded that three elements can create or re-establish trust i.e., positive relationships, consistency and good judgement or expertise.4 This applies to leaders and to their complex organizations, e.g. hospitals, where the front-office of care and back-office of support meet at what is termed the “hinge” point. At the hinge point care pathways, care programs, protocols and procedures guide all stakeholders towards high quality care and excellence.\n\nJain noted that even before the COVID-19 pandemic trust in healthcare was declining.5 The misinformation that accompanied the pandemic eroded trust even more, resulting in challenges to trust in healthcare design and delivery. Consequently, citizens, healthcare providers and managers require more trust in each other and in the organizations they visit or in which they work to co-produce required changes.6\n\nA recent paper by Bates et al. reported on the continuing high levels of harm in healthcare. This implies that to implement the changes required the leadership and change models of the past have not been as effective as they need to be.7 In response to this finding, Berwick commented that safety has to be a core focus of leadership.8 Mineo regarded trust to be the glue binding the leader to her/his colleagues and this provides the capacity for organizational and leadership success.9 The most important success point to be gained would be high quality and safety of care.\n\nIn 2001, the Institute of Medicine defined quality in six domains, i.e., safety, effectiveness, patient-centered care, timeliness, efficiency and equity.10 Since then the frameworks to improve quality and safety have been based on the theories of Deming, Juran, Feigenbaum, Crosby and others who developed quality improvement methodologies in other industries. The introduction of these improvement methodologies in healthcare has been accompanied by the introduction of control systems such as accreditation, regulation and certification.11\n\nWhile there has been progress in improving quality, the spread and scale up of good practice has not been at pace it needs to be. New challenges to realizing high levels of quality and safety include human resources management, the energy crisis, inflation and climate change. We contend that to achieve this goal a different approach is required. This will require coproduction and co-creation to facilitate sustainable quality. The co-creation model considers the internal and external context of an organization, co-create solutions and continuously focuses on five primary pillars.12 The pillars include the Juran Trilogy of quality design and planning, quality control, and quality improvement,13 with the addition of quality leadership and quality culture.\n\nOne may argue that the literature and research on leadership does not require another angle or framework. However, the declining level of trust implies that the current models of quality and leadership are not adequate to meet this new challenge. To restore trust, healthcare requires a recalibration of how we view the different components of the system, how we communicate with people in the system and how we learn to improve continually. Lee et al. (2019) have suggested a framework to improve trust in healthcare which includes concepts of leadership, measurement of trust, transparency, use of data to demonstrate trust, co-producing care with people and ensuring patients are actively engaged in care.3 Another framework, the multidimensional model, includes person- and kin-centered care, resilience, transparency and leadership together with the technical quality domains and core values of kindness respect integrated care and coproduction.6\n\nIn this paper, we offer a new conceptual framework that brings together the different frameworks in healthcare and place people at the center to co-produce trust and quality of care in which leadership is a shared endeavor. The House of Trust facilitates the implementation and further development of quality in which people (patients), their kin, healthcare providers and leaders and managers have a sense of belonging by co-creating future-proof organizations.\n\n\nThe front-office, back-office and the “moment of truth”\n\nReal care and service delivery takes place at the hinge point of the front-office and back-office of a care organization.14 It is a co-production mechanism between the service user and the service provider.15\n\n• In the back-office, processes, protocols and care pathways are designed, but they come to life in the front-office. Healthcare staff and managers are trained in the theoretical models that include the latest evidence to bring their knowledge and skills to an optimal level. It is similar to the kitchen of a restaurant, where food is prepared in a seamless manner. The diner does not know how the meal is prepared and perhaps does not need to know, as there is trust that the process is hygienic, and the food will be safe to consume.\n\n• The front-office in healthcare is where the unique meetings between the care receivers and providers happen, a real human interaction. This unique interaction takes place between a person as a patient, their loved one or kin and the individual caregiver as a person; or within the team itself, in their clinical microsystem. This is a unique moment, the moment of truth, which cannot be reversed if it is suboptimal.16–19 The moment of truth requires effective bi-directional communication and education in a dynamic, authentic and at times equal partnership. The moment of truth includes the design of the setting, the completeness of the knowledge-gathering, and the adaptation of the persons, resources and settings to the needs of both involved in the unique relationship.20\n\nTo build a care organization that inspires and radiates confidence to all stakeholders, we must highlight the interactions between the front- and back-office. We contend that an organization with well-organized back- and front-offices can enable trust and quality for patients, kin, healthcare providers, leaders and managers.\n\n\nBuilding a House of Trust to enable authentic moments of truth\n\nThere are five stages to building a House of Trust to enable the moment of truth (Figure 1).\n\n1. The core of the House (green squares in the middle of the house in Figure 1):\n\nCare quality takes place in the front-office during the moment of truth. Therefore, the starting point of the multidimensional vision model is to prioritize the four core values of dignity and respect, a holistic vision, partnership and co-production and attention to compassion with kindness.6 These values apply not only to the unique interaction between people in their roles as healthcare providers, patient or kin, but also between people as healthcare providers themselves or with their managers.17 The core values are located in the heart of the House of Trust, where interaction, positive resonance, humor and acts of kindness (e.g. Mangomoments) can take place and people meet in-person or virtually.18–20\n\n2. The foundations (grey rectangle in Figure 1):\n\nThis interaction can only be smooth, warm and of high quality if the care processes, programs, protocols and procedures are well developed and managed.21 The clinical pathways and procedures are the floorboards of the House and should be developed on a solid foundation, rather than on loose sand. The foundations of a House of Trust are based on the technical dimensions of the multidimensional quality model and are the real hinge point between the front-office and back-office of the organization.\n\n3. The support posts (turquoise squares in Figure 1):\n\nThe domains of quality are the support posts for the House of Trust. Safety and efficiency serve as the outer bearing posts of the House as an unsafe or inefficient organization cannot provide quality or trust.22 The other support posts are inclusive equity and diversity, effectiveness, timeliness and ecological sustainability.6 The six supporting post form the backbone of a healthcare organization and are the technical dimensions of quality. These structures must be in good order, and without them, real care cannot take place.\n\n4. The support pillars (blue rectangles in Figure 1):\n\nFour support pillars are located in the front-office and are also connected to the back-office. These pillars are transparency, communication, resilience and leadership. We need to communicate transparently, both about the unique interaction on an individual level and about our business processes which operate in the background. Transparent public reporting as well as internal openness and communication with our own stakeholders ensures that there is trust in the organization. A continued focus on clinical leadership and resilience is important to ensure that the philosophy of care is aligned across all processes. The pandemic highlighted that authentic clinical leadership, exemplary behavior and knowledge is important, as well as ensuring healthcare providers’ and managers’ physical and psychological wellbeing and resilience.23 Resilience of the individual person as a patient, their kin, and the people providing care and managing the organization is essential. This, in turn, will have an impact on the attractiveness of the organization as an employer, retention of staff and creation of trust.\n\n5. The roof (orange triangle in Figure 1):\n\nThe roof is supported by the other structures and refers to continuous attention to person-centered and kin-centered care in all that the organization does. Person-centeredness is about the human experience and relationships of both the people known as patients and the people known as healthcare providers and managers, i.e., all the stakeholders in this eco-system.24 A House of Trust can be built step by step when all structures below the roof are of high quality, and people trust each other and trust the organization. The roof can be the visiting card of the organization, which can be seen from afar to invite people to seek or provide care.\n\nPrinciples in building a House of Trust (yellow ovals in Figure 1).\n\nSeveral principles must be applied when building a House of Trust. Just as a real house is built brick by brick, connected to each other, with architects, surveyors and builders, so a House of Trust is built step by step, project by project and with a clear vision and mission.6,12,17 By doing so, we can integrate implementation research with improvement methodology.6 When building the House we have to consider the internal context of an organization, for example its financial status or governance challenges, and the external context, such as legislation or the impact of a pandemic.\n\nIt is crucial to involve all the stakeholders as partners in a true co-creation process from the very beginning. Each bring their own unique knowledge to the task of co-production.15 This is why the planning and design module is situated in both the front- and back-offices of the organization. The operation of the front- and back-offices must be properly monitored and controlled. However, healthcare providers, leaders, managers, patients and kin should experience as little inconvenience as possible as a result of the control and monitoring. The use of existing data sources will be crucial and must be implemented in the back-office as much as possible, including the development of automated control systems.\n\nScientific evidence is important to underpin quality. If the enhanced Juran Trilogy of Quality works well, then clinicians, management and the board will be able to use their quality leadership to build a quality culture.13 When the quality culture is just and there is an innovative learning health network, it will be possible to continually take a critical look at the current design and quality level of the House, with the necessary psychological safety.25 Teams must be closely involved in every improvement initiative and the voice of the patient and their kin must count. The change and implementation strategy is an essential driver of sustainable improvement.\n\nGovernmental inspection or regulation may be required, even if the core, the supporting foundations and the pillars of the House are in good order and the systems and processes imposed by the government regulators are followed. However continuous self-evaluation by patients, kin, healthcare providers leaders, and managers will be key in keeping the front-office at a high level during the moment of truth and will challenge all to continuously enhance it.\n\n\nConcluding remarks\n\nThe House of Trust embodies the three cornerstones of trust described by Zenger and Folkman,4 i.e., positive relationships, expertise and consistency, and addresses the challenges posed by Jain5 and Lee.3 Mate26 highlighted the need to rebuild trust in healthcare and recommended that one has to empower people to develop a culture of Trust. The core of the House of Trust, with its four central values of care and supporting pillars of transparency, communication, leadership and resilience can deliver this urgent requirement and provides a new approach that incorporates the lessons of the past 20 years of improvement endeavors. It is key for the development of positive relationships that empowers people, i.e., patients, kin, healthcare providers, leaders and managers to co-produce trust together. Without these values relationships will not be trustworthy, or human-centered and quality and safety will not be achieved.\n\nThe evolution of an organization into a House of Trust, will only succeed if we continuously question the technical dimensions of quality and our core values during the moment of truth. The architectural design and the co-construction of a House of Trust are more likely if those involved are personally involved in the design, co-production, and continual review to improve its operation and assess its benefits. This includes transparency, communication, leadership and resilience and the application of the co-creation model itself. Only then will the personal orientation, for people i.e., patients, their kin and the healthcare workforce, truly radiate trust. This will result in people, the healthcare receivers and providers, remaining loyal with positive energy, engagement and commitment day after day.\n\n\nEthical statement\n\nEthical and consent statement were not required.",
"appendix": "Data availability\n\nNo data is associated with this article.\n\n\nAcknowledgements\n\nPaul Batalden reviewed early drafts of the paper and provided valuable recommendations. We thank the members of the FlaQuM consortium (www.FlaQuM.org) and theFlaQuM Research Group (Ann Baeyens, Anneke Jans, Astrid Van Wilder, Brenda Droesbeke, Dirk Vanrenterghem, Els Van Zele, Emanuel Van Hoecke, Eva Marie Castro, Gerda Verheyden, Ines Van Giel, Ingrid Roosen, Jef Vanderoost, Jeroen Verhaeghe, Karolien Pennewaert, Kathleen De Sutter, Koen Vanachter, Kristin Muller, Kristof Simoens, Lieven Hoebrekx, Mieke De Medts, Nele Vanstraelen, Nele Yperman, Nina Donvil, Sofie Wijnen) for their collaboration and inspiration.\n\n\nReferences\n\nMüller E, Zill JM, Dirmaier J, et al.: Assessment of Trust in Physician: A Systematic Review of Measures. PLoS One. 2014; 9(9): e106844. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBirkhäuer J, Gaab J, Kossowsky J, et al.: Trust in the health care professional and health outcome: A meta-analysis. PLoS One. 2017; 12(2): e0170988. [published Online First: 20170207]. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee TH, McGlynn EA, Safran DG: A Framework for Increasing Trust Between Patients and the Organizations That Care for Them. JAMA. 2019; 321(6): 539–540. Publisher Full Text\n\nZenger J, Folkman J: Emotional intelligence: The 3 Elements of Trust.2019. Reference Source\n\nJain SH, Lucey C, Crosson FJ: The Enduring Importance of Trust in the Leadership of Health Care Organizations. JAMA. 2020; 324(23): 2363–2364. PubMed Abstract | Publisher Full Text\n\nLachman P, Batalden P, Vanhaecht K: A multidimensional quality model: an opportunity for patients, their kin, healthcare providers and professionals to coproduce health [version 3; peer review: 2 approved, 1 approved with reservations]. F1000Res. 2021; 9(1140): 1140. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBates DW, Levine DM, Salmasian H, et al.: The Safety of Inpatient Health Care. N. Engl. J. Med. 2023; 388(2): 142–153. Publisher Full Text\n\nBerwick DM: Constancy of Purpose for Improving Patient Safety - Missing in Action. N. Engl. J. Med. 2023; 388(2): 181–182. PubMed Abstract | Publisher Full Text\n\nMineo DL: The Importance of Trust in Leadership. Research management review. 2014; 20.\n\nKohn LT, Corrigan JM, Donaldson MS: To Err Is Human: Building A Safer Health System. Washington DC: National Academic Press; 1999; pp. 1–312.\n\nVanhaecht K, De Ridder D, Seys D, et al.: The History of Quality: From an Eye for an Eye, Through Love, and Towards a Multidimensional Concept for Patients, Kin, and Professionals. Eur. Urol. Focus. 2021; 7(5): 937–939. [published Online First: 2021/09/21]. PubMed Abstract | Publisher Full Text\n\nClaessens F, Seys D, Brouwers J, et al.: A co-creation roadmap towards sustainable quality of care: A multi-method study. PLoS One. 2022; 17(6): e0269364. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJuran JM: Juran on Leadership for Quality: An Executive Handbook. Free Press; 1989.\n\nTeboul J: Service is front stage. Positioning services for value advantage.2006.\n\nBatalden P, Foster T: From assurance to coproduction: a century of improving the quality of health-care service. Int. J. Qual. Health Care. 2021; 33(Supplement_2): ii10–ii14. PubMed Abstract | Publisher Full Text\n\nCarlzon J: Moments of truth. New York: Harper Perennial; 1898.\n\nVanhaecht K: Message to junior and less junior clinicians: let the core values of care guide your leadership!. BMJ Leader. 2023; 7: 242–244. PubMed Abstract | Publisher Full Text\n\nVanhaecht K: In search of Mangomoments. Lancet Oncol. 2018; 19(2): 165. [published Online First: 2018/02/08]. Publisher Full Text\n\nLee TH: Zoom Family Meeting. N. Engl. J. Med. 2021; 384(17): 1586–1587. [published Online First: 20210424]. Publisher Full Text\n\nGuney S, Lee TH: When is humor helpful? Harv. Bus. Rev. 2021 [updated 21 November 2021]. Reference Source\n\nSeys D, Bruyneel L, Deneckere S, et al.: Better organized care via care pathways: A multicenter study. PLoS One. 2017; 12(7): e0180398. [published Online First: 20170703]. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLachman P: Oxford Professional Practice: Handbook of Patient Safety. Oxford: Oxford University Press; 2022. Publisher Full Text\n\nVanhaecht K, Seys D, Bruyneel L, et al.: COVID-19 is having a destructive impact on health-care workers’ mental well-being. Int. J. Qual. Health Care. 2021; 33(1). PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: Global strategy on human resources for health: workforce 2030 2016.\n\nEdmondson AC, Mortensen M: What Psychological Safety Looks Like in a Hybrid Workplace Harvard. Harv. Bus. Rev. 2021. Reference Source\n\nMate K: What I am learning about trust.2021. (Last accessed 30th April 2024). Reference Source"
}
|
[
{
"id": "284795",
"date": "13 Jun 2024",
"name": "Relinde De Koeijer",
"expertise": [
"Reviewer Expertise Operations Management",
"Quality Improvement",
"Healthcare",
"Human Resource Management"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview of ‘The ‘House of Trust’: A framework for quality healthcare and leadership’ Dr. Relinde de Koeijer\nClarity and Accuracy of Presentation and Citation of Current Literature\nThe article is well-written and clearly presents the ‘House of Trust’ framework. The authors cite relevant and current literature, including studies on trust in healthcare and quality improvement frameworks. The references are up-to-date and include key studies and frameworks that are foundational to the discussion.\n\nStudy Design and Academic Merit\nThe conceptual framework is well-structured and logically presented. The framework addresses a gap in current models of trust and quality in healthcare by integrating different components on leadership, culture, continuous improvement, and quality of care. The ‘House of Trust’ framework emphasizes building trust at multiple levels. It may be interesting to reflect on how these different types of trust interact and influence each other. For example, how does trust in individual provider impacts overall organizational trust and vice versa? Also, trust can be context dependent, it could be interesting to highlight potential specific contextual factors that could impact trust.\n\nMethods and Analysis for Replication\nThe article outlines the components and principles of the ‘House of Trust’ clearly, providing a comprehensive understanding of each element. It describes the interactions between the front-office and back-office and the importance of the ‘moment of truth’ in detail.\n\nA reflection on the ‘House of trust’ in relation to different sectors of health care could be interesting. For example, in hospitals there is generally a short-term relationship with the patient, while this is often different in long-term care. Do these differences influence the way in which trust can be build according to the authors?\n\nStatistical Analysis and Interpretation The article does not present any statistical analysis as it is conceptual.\nAvailability of Source Data for Reproducibility As the paper is a conceptual proposal, it does not include source data.\nConclusions Supported by Results\nThe conclusions drawn in the article are logical and follow from the presented framework and supporting literature. The authors effectively argue that a new approach is necessary to (re)build trust in healthcare and propose a comprehensive model that addresses current gaps.\n\nOverall Assessment The article ‘The ‘House of Trust’: A framework for quality healthcare and leadership’ presents a well-structured and innovative conceptual framework. It addresses an important issue in healthcare and cites current literature effectively. The article provides a solid foundation for further research and discussion on trust and quality in healthcare.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
},
{
"id": "284797",
"date": "14 Jun 2024",
"name": "Eva Biringer",
"expertise": [
"Reviewer Expertise Quality improvement and care processes."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis opinion paper introduces a new conceptual framework –‘The House of Trust’– that builds on existing concepts and models in the fields of health care quality and leadership. By introducing the framework the authors aim at regaining the ‘lost» trust in the delivery of health care.\nThe paper represents a solid argument for the necessity of trust as basis of all aspects of care.\n\nIt is prizeworthy that the authors emphasise the values of partnership, co-production, dignity, respect etc. as core aspects in the provision of care.\nThe new conceptual framework appears as very complex. It comprises a range of relevant models supported by theory and empirical findings. The framework may therefore be challenging to operationalise and implement in health care. However, it functions as argument and guiding vision for trust and trust building in and around all encounters among stakeholders in health care.\nI do not think the paper needs revision.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-503
|
https://f1000research.com/articles/13-501/v1
|
17 May 24
|
{
"type": "Case Report",
"title": "Case Report: A rare case of lightning strike causing corneal burn injury",
"authors": [
"Soumya Sharma",
"Sachin Daigavane",
"Sachin Daigavane"
],
"abstract": "The likelihood of being hit by the likelihood of experiencing lightning within a year was approximately 1 in 960,000. Despite this alarming statistic, it is reassuring to know that the chances of surviving a lightning strike are relatively high; around 90% of people who are struck by lightning manage to survive. Lightning-caused ophthalmic injuries are caused by heat that can be generated through the direct or indirect flow of electric current, and by resistance and shock waves caused by heat. Electrical burn injuries rarely cause ocular complications, since the initial burn is typically fatal. We present a case of lightning injury that affected the eyes. and its treatment and a brief overview of the literature on the subject.",
"keywords": [
"cataract",
"corneal",
"lesions",
"ischemia",
"lightning injuries",
"lightning",
"strike",
"reperfusion injury",
"trauma"
],
"content": "Introduction\n\nLightning causes catastrophic injury and death worldwide. Electrical injuries cause extensive traumatic damage that can lead to a wide range of consequences.1 Aystolic cardiac arrest and ventricular fibrillation are the most prevalent causes of death are asystolic cardiac arrest and ventricular fibrillation.2 In 1722, St. Yves recorded the first case of electrical burn in the eye. He documented the development of cataracts in a field worker who was affected by lightning.3 Various injuries related to lightning strikes have been documented, including keratitis, cataracts, anterior segment uveitis, retinal detachments, papillitis, and macular hole formation.4 Studies have shown that lightning injuries often affect the cornea, resulting in epithelial erosions, and the lens, with a potential for up to 6-7% formation of anterior and posterior subcapsular cataracts5; however, with the development of optical coherence tomography (OCT) in the last decade, a greater number of posterior segment diseases caused by lightning have been identified. Thermal papillitis, optic neuropathy, loss of pupillary light sensitivity, anisocoria, Horner syndrome, and multiple facial nerve palsies are all potential neurological problems involving the eye.6\n\nInflammatory changes in the iris and ciliary body are common after trauma, and acute and transient iritis may occur within one–eight weeks after the incident. The melanin-rich retinal pigment epithelium makes the macular region resistant to electrical currents, making it vulnerable to heat damage. Consequently, various macular injuries can occur.7\n\nVarious mechanisms have been suggested for the ocular damage caused by lightning. Initially, the electric current passes through the ocular tissues, leading to the rupture of cell membranes. Second, the heat generated by electrical current may be harmful. Finally, tissue ischemia can occur as a result of vasoconstriction and damage can occur as a result of localized inflammation or reperfusion injury.8\n\n\nCase report\n\nA 45-year-old woman presented to the emergency department with sudden pain, redness, and decreased vision in both eyes. This occurred four hours after being struck by lightning in the face while standing near a window. The symptoms worsened suddenly and rapidly, accompanied by blepharospasm and watering of the eyes.\n\nDuring eye examination, first-degree burns were observed on the face, affecting the eyebrows, lashes, and eyelids. The eyelid was also swollen (Figure 1), and visual acuity was reduced to the perception of light. Upon further examination of the right eye using a slit lamp, conjunctival congestion, chemosis, and corneal stromal edema were observed. Descemet membrane folds were also present along with corneal melting at the 3-4 and 6 o’clock positions. The anterior chamber was shallow, and there was an inferior blood clot (as shown in Figure 2). Iridodialysis was identified in both eyes, and the iris was irregular in shape with a sluggish reaction to light an ultrasonography (USG) of the eye was performed and the results indicated that everything appeared normal. The eye was examined with fluorescent stain under blue light filter shows stain positive (as shown in Figure 3).\n\nDuring examination of the left eye, visual acuity was found to be counting fingers at a distance of two meters. No improvement was observed with the pinholes. Eyelid edema and stinging of eyelashes were present, as well as conjunctival congestion and chemosis (as shown in Figure 4) The cornea was also oedematous., Descemet membrane folds were seen. Corneal melting was observed inferiorly at the 5 clock position. The depth of the anterior chamber was normal. (as shown in Figure 5) pupils were semi-dilated and were reacting sluggishly to light.\n\nUpon admission, the patient was treated with oral and topical antibiotics, cycloplegics, and lubrication. Multiple corneal foreign bodies were observed under the microscope. After a week of treatment, the patient underwent re-evaluation, and a reduction in corneal haze and conjunctival chemosis was observed (as shown in Figure 6). Multiple macular opacities were observed in the cornea. The patient’s anterior chamber showed no abnormalities; however, they was diagnosed with cataracts in both eyes. The patient’s representatives were informed that the recommended course of action was lens aspiration with intraocular lens implantation and keratoplasty.\n\nShowing reduction in corneal haze and conjunctival chemosis.\n\n\nDiscussion\n\nLightning that can cause injuries to the eyes is rare; however, when it occurs, it can cause damage to different parts of the eye, including the structures in the front and back. Electrical energy from lightning can cause cell destruction and swelling, leading to various eye problems. This is due to changes in the cell membrane and electrical potential, and is called electroporation.9 When lightning strikes, electrical current can cause significant harm to tissues and organs throughout the body. This damage can manifest in various ways, including anatomical, histological, and biochemical changes. In particular, people commonly experience superficial corneal lesions after being struck by lightning. These lesions can typically be treated with symptomatic care, although they may sometimes heal independently.10 Lens opacity can develop after being struck by light. Several theories have attempted to explain why this happens, such as reduced permeability of the lens capsule, coagulation of proteins caused by the electrical current, disruption of lens feeding due to iritis, and mechanical damage to the lens fibers.11 Cataract formation typically begins in the eye and is closest to the site of injury. It can take anywhere from 1 to 10 months before a cataract is detected in another eye. Our patient had post-traumatic punctate corneal epitheliopathy, and the production of heat energy can also cause burns, as in our case. The patient suffered from burns on the face, bilateral corneal edema, and cataractous lens. Patients need to undergo regular check-ups at eye clinics to monitor for any potential issues that may arise. These can include early-, mid-, and late-stage diseases related to lightning injuries.\n\n\nConclusion\n\nThese types of injuries are commonly caused by lightning strikes, and our case study emphasizes the different ocular symptoms that can result from lightning strike injuries. Lightning injury can cause severe damage to the eyes and corneal edema, corneal melting, hyphema, and iridocyclitis; in the latter stages, exudative retinal detachment is likely to occur. The patient was thoroughly examined, and early treatment yielded favorable results. Patients should be allowed to flow for a long duration for early diagnosis and treatment of late complications of lightning electric burn injuries. Patients suffering from these injuries can have a positive outcome if they are detected early and treated properly.\n\n\nConsent\n\nWritten informed consent was obtained from the patient, which included permission to publish the case details including the images.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nAggarwal S, Maitz P, Kennedy P: Electrical flash burns due to switchboard explosions in New South Wales—A 9-year experience. Burns. 2011 Sep 1; 37(6): 1038–1043. PubMed Abstract | Publisher Full Text\n\nMcIntyre WF, Simpson CS, Redfearn DP, et al.: The lightning heart: a case report and brief review of the cardiovascular complications of lightning injury. Indian Pacing Electrophysiol. J. 2010 Sep 5; 10(9): 429–434. PubMed Abstract | Free Full Text\n\nLagrèze WD, Bömer TG, Aiello LP: Lightning-Induced Ocular Injury. Arch. Ophthalmol. 1995; 113(8): 1076–1077. PubMed Abstract | Publisher Full Text\n\nPradhan E, Khatri A, Ahmed AA, et al.: Lightning Injury to Eye: Brief Review of the Literature and Case Series. Clin. Ophthalmol. Auckl. NZ. 2020; 14: 597–607. PubMed Abstract | Publisher Full Text | Free Full Text [PDF] Lightning Injury to Eye: Brief Review of the Literature and Case Series | Semantic Scholar\n\nBae EJ, Hong IH, Park SP, et al.: Overview of ocular complications in patients with electrical burns: an analysis of 102 cases across 7 years. Burns J. Int. Soc. Burn Inj. 2013 Nov; 39(7): 1380–1385. PubMed Abstract | Publisher Full Text Reference Source\n\nHanda JT, Jaffe GJ: Lightning maculopathy. A case report. Retina. 1994; 14(2): 169–172. PubMed Abstract | Publisher Full Text\n\nMacdonald G: Harrison’s Internal Medicine, 17th edition. - by A. S. Fauci, D. L. Kasper, D. L. Longo, E. Braunwald, S. L. Hauser, J. L. Jameson and J. Loscalzo. Intern. Med. J. 2008; 38(12): 932–932. Harrison’s Internal Medicine, 17th edition. ‐ by A. S. Fauci, D. L. Kasper, D. L. Longo, E. Braunwald, S. L. Hauser, J. L. Jameson and J. Loscalzo - Macdonald - 2008 - Internal Medicine Journal - Wiley Online Library\n\nArmstrong B, Fecarotta C, Ho AC, et al.: Evolution of Severe Lightning Maculopathy Visualized with Spectral Domain Optical Coherence Tomography. Ophthalmic Surg. Lasers Imaging. 2010; 41(6): S70–S73. Publisher Full Text\n\nToquica J, Gómez H: Ocular injuries caused by lightning strikes: review of the literature and presentation of two clinical cases. Vis. Pan-Am Pan-Am. J. Ophthalmol. 2016 [cited 2023 Jul 31]. Publisher Full Text\n\nBuja Z, Arifi H, Hoxha E: Electrical Burn Injuries. An Eight-year Review. Ann. Burns Fire. Disasters. 2010 Mar 31; 23(1): 4–7. PubMed Abstract | Free Full Text\n\nNorman ME, Albertson D, Younge BR: Ophthalmic manifestations of lightning strike. Surv. Ophthalmol. 2001 Jul-Aug; 46(1): 19–24. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "293853",
"date": "24 Jun 2024",
"name": "Francisco J Bonilla-Escobar",
"expertise": [
"Reviewer Expertise Ophthalmology epidemiology and translational science"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe case report does provide a general overview of the patient's history and progression. However, it lacks detailed demographic information, such as the patient's medical history and any comorbidities, which are essential for a comprehensive understanding of the patient's condition and response to treatment. The authors should include more specific details about the patient's background to provide a fuller context.\nWhile the report covers the initial clinical findings and diagnostic tests, it could benefit from more precise information regarding the timeline of symptom progression and treatment. The authors should specify the exact tests performed, their results, and any differential diagnoses considered. How is that the patient was hit by a \"lightning in the face\" and the patient was still alive, and with no symptoms other than ocular complaints? Why the patient's representatives had to be asked about the cataract surgery decision? was the patient unable to make decision? Additionally, the treatment protocol needs more detail, including dosages, frequency of medications, and follow-up procedures. Expanding on the follow-up process and discussing long-term outcomes or complications would enhance the report's thoroughness.\nThe discussion section touches on the significance of the findings but could be more in-depth regarding their implications for future understanding and clinical practice. The authors should elaborate on the broader relevance of the case, including potential impacts on diagnosis and treatment strategies for similar injuries. Highlighting any novel aspects or unique challenges encountered in this case would also strengthen the discussion.\nthe authors should consider the following points:\nBackground and Patient Information:\nInclude more detailed demographic information, including medical history and comorbidities. Provide a thorough timeline of symptom progression and treatment.\n\nClinical Findings and Diagnostic Assessment:\nSpecify the exact tests performed, their results, and any differential diagnoses considered. Explain the rationale for using certain diagnostic tools, such as slit-lamp examination and ultrasonography.\n\nTherapeutic Intervention:\nDetail the treatment protocol, including dosages, frequency of medications, and any follow-up procedures. Expand on the follow-up process, including the duration and any long-term outcomes or complications observed.\n\nDiscussion:\nElaborate on the broader relevance of the case, including implications for future understanding, diagnosis, and treatment. Highlight any novel aspects or unique challenges encountered in this case.\n\nClarity and Readability:\nAddress grammatical and structural issues to improve clarity and readability.\n\nAbstract:\nOriginal: \"The likelihood of being hit by the likelihood of experiencing lightning within a year was approximately 1 in 960,000.\" Revision: \"The likelihood of experiencing a lightning strike within a year is approximately 1 in 960,000.\" Original: \"We present a case of lightning injury that affected the eyes. and its treatment and a brief overview of the literature on the subject.\" Revision: \"We present a case of a lightning strike causing ocular injury, discuss its treatment, and provide a brief overview of the related literature.\"\nIntroduction:\nOriginal: \"Aystolic cardiac arrest and ventricular fibrillation are the most prevalent causes of death are asystolic cardiac arrest and ventricular fibrillation.\" Revision: \"Asystolic cardiac arrest and ventricular fibrillation are the most prevalent causes of death from lightning strikes.\"\nCase Report:\nOriginal: \"The eye was examined with fluorescent stain under blue light filter shows stain positive (as shown in Figure 3).\" Revision: \"The eye was examined with a fluorescent stain under a blue light filter, which showed a positive staining (as shown in Figure 3).\" Original: \"No improvement was observed with the pinholes.\" Revision: \"No improvement in visual acuity was observed with pinhole testing.\" Original: \"The depth of the anterior chamber was normal. (as shown in Figure 5) pupils were semi-dilated and were reacting sluggishly to light.\" Revision: \"The depth of the anterior chamber was normal (as shown in Figure 5). The pupils were semi-dilated and reacted sluggishly to light.\"\nDiscussion:\nOriginal: \"Patients need to undergo regular check-ups at eye clinics to monitor for any potential issues that may arise.\" Revision: \"Patients should undergo regular check-ups at eye clinics to monitor for any potential complications.\" Original: \"Patients should be allowed to flow for a long duration for early diagnosis and treatment of late complications of lightning electric burn injuries.\" Revision: \"Patients should be followed up for an extended period to ensure early diagnosis and treatment of late complications from lightning-induced ocular injuries.\"\nThis case report provides valuable insights into a rare ocular complication of lightning strikes. By addressing the suggested revisions and clarifications, the manuscript will improve in clarity, and readability.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
},
{
"id": "306635",
"date": "02 Aug 2024",
"name": "Seth Makin",
"expertise": [
"Reviewer Expertise Military medicine",
"including having published on lightning related injuries."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe abstract needs re-writing as it contains information not referenced in the text. The statistic about likelihood is interesting but should not be included in the abstract if not included in the main text. Also Who are the 1 in 960000 referred to? Are they from a US, India or worldwide population? The 90% survival figure is disputed so please state where from but again this should not be something discussed in the abstract and no where else.\nI would re-write the abstract from scratch.\nThe introduction is well written and of interest. However, you omit one of the main causes of lightning related damage, the pressure wave. In a case light this the pressure or blast wave consisting of heat independent of the electrical energy directly transmitted to a patient as well as the sonic effects are undoubtedly of relevance. Please see Blumenthal R. et al., 20216 [Ref-1] and I would advise you reference this work in your paper. This omission of blast wave and the explosive effects of lightning unfortunately taints by omission the rest of the paper but it is readily remedial.\nIn the actual case report you discuss Descemet membrane folds but these are not defined which leaves a lay reader unsure without looking it up.\nYou highlight multiple foreign bodies these are likely due to the blast wave.\nDetails of the rest of the eye are missing from the report, what state was the retina in, was there damage to the humor. Although the cornea is of key interest the rest of the eye is highly relevant.\nThe discussion is a single paragraph which is too long for a single block of text. The text itself for the discussion is adequate but typical specific recommendations would be useful.\nThe Conclusions say \"are commonly caused\" but do not define common. 1/10, 1/2? The conclusions need to be firmed up, what does favourable really mean? What is a positive outcome? it is not specific or scientific enough.\nOverall this is a nice case study but the abstract and conclusions are not fit for indexing at this time. The omission of blast effects is a serious flaw. The majority of the references are too old. This paper absolutely needs a major revision as a minimum, once successfully revised it is likely to be of interest.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-501
|
https://f1000research.com/articles/13-11/v1
|
03 Jan 24
|
{
"type": "Research Article",
"title": "Spatiotemporal structure and composition of the microbial communities in hypersaline Lake Magadi, Kenya",
"authors": [
"Alex Kipnyargis",
"Eucharia Kenya",
"Fathiya Khamis",
"Romano Mwirichia",
"Eucharia Kenya",
"Fathiya Khamis",
"Romano Mwirichia"
],
"abstract": "Background Soda lakes are habitats characterized by haloalkaline conditions also known to host unique microbial communities. The water chemistry changes with seasons due to evaporative concentration or floods from the surrounding grounds. However, it is not yet clear if the change in physiochemical changes influences the spatiotemporal diversity and structure of microbial communities in these ecosystems.\n\nMethods This study investigated the spatiotemporal diversity and structure of microbial communities in water and brine samples collected from hypersaline Lake Magadi in the months of June–September 2018. Amplicons were generated using Illumina sequencing of the 16S rRNA gene.\n\nResults The abundant bacterial phyla were Proteobacteria, Cyanobacteria, Bacteroidetes, Actinobacteria, Firmicutes, Verrumicrobia, Deinococcus-Thermus, Spirochaetes, and Chloroflexi. The Archaeal diversity was represented by phyla Euryachaeota, Crenarchaeota, Euryarchaeota, and Thaumarchaeota. The dominant bacterial species were: Euhalothece sp. (10.3%), Rhodobaca sp. (9.6%), Idiomarina sp. (5.8%), Rhodothermus sp. (3.0%), Roseinatronobacter sp. (2.4%), Nocardioides sp. (2.3%), Gracilimonas sp. (2.2%), and Halomonas sp. (2%). The dominant archaeal species included Halorubrum sp. (18.3%), Salinarchaeum sp. (5.3%), and Haloterrigena sp. (1.3%). The composition of bacteria was higher than that of archaea, while their richness and diversity varied widely across the sampling seasons. The α-diversity indices showed that high diversity was recorded in the month of August, followed by September, June, and July in that order. Furthermore, salinity and alkalinity affect β-diversity rather than the sampling site or seasonality. The effects of physicochemical parameters on the microbial community structure showed that temperature, pH, P+, K+, NO3 -, and total dissolved solids (TDS) had a positive correlation with the microbial community structure. Multivariate analysis revealed significant spatial and temporal effects on β-diversity and salinity and alkalinity were the major drivers of microbial composition in Lake Magadi.\n\nConclusions We provide insights into the relationships between microbial communities and geochemistry across various sampling sites in Lake Magadi.",
"keywords": [
"Soda lake",
"spatiotemporal",
"archaea",
"bacteria",
"physicochemical parameters",
"α-diversity",
"β-diversity"
],
"content": "Introduction\n\nMost living organisms are adapted to habitats characterized by moderate temperature (10–37°C), pH (of approximately 7), salinity (0.15–0.5 M NaCl), pressure (1 atm), and adequate supply of water (Aguilar et al., 1998; Antranikian et al., 2005). However, molecular techniques such as next-generation sequencing have revealed that diverse groups of organisms thrive even in biomes previously thought to be lifeless (Canganella & Wiegel, 2011; Rampelotto, 2013). Microbial communities in ecosystems such as the hypersaline lakes of the East African rift valley survive and thrive under one or several extreme conditions and are referred to as polyextremophiles (Sorokin et al., 2014a; Urbieta et al., 2015).\n\nThe distribution and diversity of microbial communities in hypersaline lakes is mainly affected by physicochemical parameters (Tazi et al., 2014). Lake Magadi is an example of an extreme habitat characterized by high concentrations of Na+, K+, CO32–, Cl–, HCO3–, and SiO2, but low concentrations of Ca2+ and Mg2+ (Jones et al., 1998; Getenet et al., 2022). During the dry seasons, thermonatrite (Na2CO3.H2O), and halite (NaCl) precipitate by evaporative concentration (Eugester, 1971, 1980). The lake is in a region with alternating wet and dry seasons. During the dry season, when ground temperatures exceed 40°С, there is extensive evaporation (Matagi, 2004; Muruga & Anyango, 2013). Furthermore, the lake is almost entirely covered by a white layer of soda, and flooding may occur when it rains due to feeding water from the surroundings.\n\nDespite the extreme conditions existing in the lake, it is a highly productive ecosystem with diverse microbial communities driving active nitrogen, carbon, and sulfur cycles (Jones et al., 1998; Sorokin et al., 2007). The high productivity is mainly driven by Arthrospira spp. and other cyanobacteria (Melack & Kilham, 1974; Oduor & Schagerl, 2007). Cyanobacteria in lake lagoons only form algal mats in these lakes during rainy seasons (Jones et al., 1998; Muruga & Anyango, 2013; Krenitz & Shagerl, 2016). Reports indicate that Ectothiorhodospira, an anoxygenic phototrophic halophilic bacterium also plays an essential part in primary production (Matagi, 2004; Grant, 2006). Additionally, eukaryotes such as diatomic and green algae contribute to the primary production (Matagi, 2004).\n\nA significant number of bacteria have been isolated from extreme environments and they often demonstrate adaptations to optimal growth under the prevailing conditions (Krulwich et al., 2011; De Maayer et al., 2014; Sorokin et al., 2014b). Validly described isolates from Lake Magadi include the archaeal genera Natronobacterium and Natronococcus gen. nov. (Tindall et al., 1984) and Natronobacterium magadii, Natrialba magadii (Kamekura et al., 1997), bacterial species Spirochaeta alkalica sp. nov., Spirochaeta Africana (Zhilina et al., 1996), Tindallia magadiensis (Kevbrin et al., 1998), Halomonas magadii (Duckworth et al., 2000), Amphibacillus fermentum (renamed Pelagirhabdus fermentum) sp. nov., Amphibacillus tropicus, and Halonatronum saccharophilum (Zhilina et al., 2001), Methylonatrum kenyense (Sorokin et al., 2007), Euhalothece natronophila (Mikhodyuk et al., 2008) and Natranaerobaculum magadiense (Zavarzina et al., 2013). Edwin et al. (2019) recovered 11 isolates affiliated with the cyanobacterial orders Chroococcales, Oscillatoriales, Pleurocapsales and Nostocales. Recent studies have reported isolates affiliated to the genus Bacillus, Alkalibacterium, Staphylococcus, Micrococcus, Halomonas, and Alkalilimnicola (Kiplimo et al., 2019; Kipnyargis et al., 2022). Orwa et al. (2020) recovered several fungal isolates affiliated with 18 different genera with Aspergillus, Penicillium, Cladosporium, Phorma and Acremonium being dominant. Several studies have explored the microbial diversity in Lake Magadi using amplicons analysis targeting groups such as fungi (Kambura et al., 2016; Salano et al., 2017; Mwirichia, 2022) or bacteria (Kambura et al., 2016).\n\nA key ecological question is how microbial diversity changes with the fluctuating physicochemical conditions with seasons. We hypothesized that microbial communities within the lake shift in response to changes in the water chemistry over time. We predict that the communities in the brines are different from those in the open lake water. In this study, we explored the spatiotemporal variation in the microbial community over four months at different sites in Lake Magadi using Illumina sequencing.\n\n\nMethods\n\nSampling was done in hypersaline Lake Magadi, Kenya. It is located 1°43-2°00 S and 36°13-36°18E in an enclosed basin with an annual precipitation of 500 mm (Behr & Röhricht, 2000). Lake Magadi is a relatively shallow water body that is fed by various springs distributed along the edges of the lake. The inflows have an influence on the lake volume and the water chemistry. Water samples were collected from different points in the lake including spring, brine, and open waters. Samples were collected from these sites in the months of June, July, August, and September 2018. The coordinates of the sampling sites were: S1 (1.891380 S; 36.302632 E), S2 (1.895020 S; 36.299372 E), S3 (1.900988 S; 36.301307 E), S4 (1.908460 S; 36.301996 E), S5 (1.991601 S; 36.258904E), S6 (1.975517 S; 36.236564 E) and BR1 (1.887908 S; 36.300855 E) (Figure 1). S1 was composed of spring water, S2–S6 were composed of open waters, and BR1 was brine. Three sub-samples of 50 ml each were collected from each site and pooled into a composite sample. In addition, water samples for physicochemical analysis were collected. All samples were collected in sterile Conical Centrifuge tubes (Biologix, Shandong, China, Cat. No. 430829) and transported in a cool box (Sp. Berner, Valencia, Spain).\n\nWater temperature, pH, total dissolved solids (TDS), and salinity measurements were recorded in situ. Water temperature, TDS, and salinity were measured using VWR phenomenal handheld Meter (VWR, Atlanta, GA, USA, Model CO 3100H), while pH was measured using Hanna Combo pH meter (Hanna Instruments, Nusafalau, Romania, Model HI-98128). In this case, about 100 ml of sample water was put in a sterile 400 ml glass beaker (Marienfeld, Germany, Cat. No. BR91236). A pre-calibrated meter was dipped in the sample and the readings were recorded. Water samples for dissolved P, K+, NO3-, NH4-, Mg2+, Na-, Fe2-, Ca2+, SO42-, Cl-, and HCO3- measurements were collected in sterile 500ml bottles and stored in a cool box for transportation to Crop Nutrition Laboratory Services (CNLS), Nairobi where analysis was done. Cations such as Ca, Mg, K, Na, Mn, Fe, Cu, Mo, B, Zn, and S were analyzed using atomic absorption spectrometry (AAS), while anion analysis was carried out using mass spectrometry.\n\nCell biomass for DNA extraction was obtained by centrifuging 50 ml of each water sample at 14,000 rpm for 20 minutes in an Eppendorf centrifuge (Eppendorf, Model 5415R, Cat. Z605212). The pellets were resuspended in 200 μl of a resuspension buffer (25% w/v sucrose (Sigma-Aldrich, Cat. No. S9378) in 50 mM Tris pH 8.5 (Sigma-Aldrich, Cat. No. 93352), and 50 mM EDTA; pH 8.0 (Sigma-Aldrich, Cat. No. 798681). To disrupt the cell wall of Gram positives, 2 μl of lysozyme (20 mg/ml) (Roche, Cat. No. 10837059001) and 10 μl of RNAse A (20 mg/ml) (Roche, Cat. No. 10109142001) were added and incubated at 37°C for 30 minutes. Cell lysis was achieved by the addition of 600 μl of a lysis buffer (1% SDS (Sigma-Aldrich, Cat. No. 8.17034) in 10 mM Tris pH 8.5 (Sigma-Aldrich) and 5 mM EDTA; pH 8.0 (Sigma-Aldrich). The samples were gently mixed with 10 μl of Proteinase K (20 mg/ml) (Sigma-Aldrich, Cat. No. 39450-01-6) and incubated at 65°C for 2 hours. DNA was recovered by adding of an equal volume of chloroform (Sigma-Aldrich, Cat. No. C2432) followed by centrifugation at 13,200 rpm for 10 min at 4°C in an Eppendorf 5415R centrifuge. The aqueous layer was transferred into a new tube 150 μl of sodium acetate (pH 5.2) (Sigma-Aldrich, Cat. No. S8750) and equal volume of isopropyl alcohol (Sigma-Aldrich, Cat. No. 67-63-0). The contents were centrifuged at 13,200 rpm for 10 minutes and the DNA pellet was recovered by washing with 70% ethanol, air dried for 15 minutes and dissolved in 30 μl of nuclease free water (Sigma-Aldrich, Cat. No. 7732-18-5). DNA quality was checked by running an aliquot of 2 μl in 1% agarose (Sigma-Aldrich, Cat. No. A9918) gel electrophoresis (Orwa et al., 2020).\n\nThe V4 hypervariable region of the 16S rRNA genes was amplified using the primer 515F (5′-GTGCCAGCMGCCGCGGTAA-3′) and 806R (5′-GGACTACHVGGGTWTCTAAT-3′) (Caporaso et al., 2012). Amplification was done using HotStarTaq Plus Master Mix Kit (Qiagen, USA) under the following cycling conditions: initial denaturation at 94°C for 3 minutes, followed by 35 cycles of denaturation at 94°C for 30 seconds, annealing at 53°C for 40 seconds and elongation at 72°C for 1 minute, after which a final elongation step at 72°C for 5 minutes was performed. Three independent PCR reactions were performed per sample and pooled in equimolar amounts. The PCR products were then checked in a 2% agarose gel. The sample was purified using calibrated Ampure XP beads (Beckman Coulter, Inc., IN, USA). DNA libraries were prepared using Illumina TruSeq DNA libraries (Illumina, Inc., San Diego, CA, United States) and sequencing was performed at MR DNA (Shallowater, TX, USA) on a MiSeq platform (2 × 300 bp) following the guidelines of the manufacturer (Illumina Inc.).\n\nThe Q25 sequence data derived from MiSeq sequencing was processed using the MR DNA ribosomal and functional gene analysis pipeline (MR DNA, Shallowater, TX). Sequences were depleted of primers, reads <250 bp and ambiguous base calls were removed. The reads were quality filtered using a maximum expected error threshold of 1.0. Sequences were further processed using VSEARCH v2.14 (Rognes et al., 2016). This included sorting and size-filtering of the paired reads to ≥300 bp (--sortbylength --minseqlength 300) and dereplication (--derep_fulllength). The sequences were then denoised and evaluated for potential chimeric sequences using UCHIME package v.11. (Edgar et al., 2011). Representative operational taxonomic units (OTUs) were picked de novo using VSEARCH v2.14 (Rognes et al., 2016), and assigned taxonomy using BLAST searches against the SILVA v132 rRNA reference database (Quast et al., 2012). A sequence identity cutoff of 97% was used to pick OTUs from the quality-filtered, denoised, non-chimeric sequences. Eukaryotic sequences were filtered from the dataset using the script filter_otu_table.py. in QIIME v1.90 (Caporaso et al., 2010b).\n\nThe Illumina raw reads for the 16S rRNA gene sequences were deposited in the Sequence Read Archive (SRA) of NCBI under the accession numbers PRJNA962270 (Kipnyargis et al., 2023b).\n\nSequences with assigned taxonomy were aligned using PyNast (Caporaso et al., 2010a), and a phylogenetic tree was constructed using FastTree v2.1.7 (Price et al., 2010). The alpha diversity indices (Chao1, abundance-based coverage estimator (ACE), Simpson, Shannon, Fisher’s alpha, Pielou’s evenness, and Good’s coverage) were calculated with QIIME v1.90 (Caporaso et al., 2010) using alpha_rarefaction.py employing the same level of surveying effort (37,000 per sample based on the lowest sample count). All subsequent steps were analyzed in R software v4.2.0 (R Core Team, 2020) and RStudio v1.1.456 (RStudio Team, 2020). The results of all statistical tests were regarded as significant if p ≤ 0.05. To compare the (dis) similarity of OTU compositions between communities the OTU abundance table was standardized using decostand (method = “hellinger”). Hierarchical cluster analysis was performed using hclust in R software v4.2.0 (R Core Team, 2020) (method = “average”). The heatmap was created using JColorGrid v1.86 (Joachimiak et al., 2006).\n\nThe OTU network generated in QIIME was filtered using an edge cut-off of 0.001 and visualized in Cytoscape v3.9.1 (Otasek et al., 2019) in an “edge-weighted spring-embedded layout”. In this case, sampling sites were used as source nodes and bacterial families as target nodes. Redundancy analysis (RDA), based on Bray dissimilarity was used to test the correlation between the physicochemical parameters and the microbial community at the genus level. This was done using the Microeco package v0.15.0 (Liu et al., 2021) and plotted using the package Pheatmap in R.\n\nTo assess the beta diversity of microbial communities, a non-metric multidimensional scaling (NMDS) was performed using Bray-Curtis dissimilarities with the script compare_categories.py. test and weighted UniFrac distance matrix (Lozupone & Knight, 2005) as input using the Vegan package in R (Bray & Curtis, 1957; Oksanen, 2015).\n\n\nResults\n\nOne of the objectives of this study was to investigate the change in water chemistry over time. It has been established that physicochemical factors play a critical role in shaping the structural composition of microbial communities in an ecosystem. Samples from site S1 (spring water) exhibited lower concentrations of the various ions and cations as compared to the other samples. The water temperature ranged from 27°C to 38.7°C (average 33.7°C). The pH of the water was alkaline, ranging from 9.8 (S6_June) to 11.5 (BR1_June) recording the highest pH value of 11.5. The major water cations were Na+ (10,300–160,000 ppm) and K+ (131–4,280 ppm), and the major anions were HCO3− (15,400–277,000ppm) and Cl− (4,050–102,000 mg/L). Phosphorus levels ranged from 2.38–108 ppm, while magnesium and calcium levels were low, ranging from 0.02–16.1 and 0.05–127 ppm, respectively. The total dissolved solids (TDS) ranged from 27.1–153.5 ppm (Table 1).\n\nTDS total dissolved solids, SAR sodium absorption ratio. The samples are denoted as S1 to S6, while BR1 represents the brine sample.\n\nAfter quality filtering, denoising, and removal of potential chimeras and non-bacterial sequences, approximately 3,197,447 high-quality sequences with an average read length of 525 bp were obtained from the entire dataset. The number of sequences per sample varied from 37,406 (sample S5_Jun) to 285,085 (sample BR1_Sep) with an average value of 121,603 sequences. The number of OTUs per sample varied from 852 (sample S3_July) to 2,024 (sample S5_Sep) (Table 2). All sequences were assigned taxonomy up to genus level and clustered into 4,837 OTUs (97% identity) distributed in the domain Bacteria (3,802 OTUs) and Archaea (1,035 OTUs). Overall, most OTUs were found in S5, while S4 had the least OTUs. The distribution of shared OTUs based on the month of sampling is shown in Extended data, Supplementary Figure 1 (Kipnyargis et al., 2023a).\n\nOTUs, operational taxonomic units; ACE, abundance-based coverage estimator.\n\nThe values of the good’s coverage estimator ranged from 81% (S5_Sep) and 96% (S3_Aug) suggesting that the sequencing process captured a significant number of dominant communities. Within the open water samples (S2–S6), site 5 samples collected across the seasons had the highest alpha diversity indices suggesting that S5 had the highest species richness and diversity. S3_Aug samples (open waters) had the lowest alpha diversity indices. Within the hot spring samples (S1), S1 samples collected in September had the highest species richness and diversity. Within the brine samples (BR1), Br1 samples collected in September had the highest species diversity and richness (Table 2).\n\nThe alpha diversity indices showed that high microbial diversity was recorded in the month of August, followed by September, June, and July in that order (Figure 2).\n\nStatistical significance was determined at p < 0.05. Individual sample values and outliers are shown in the form of dots.\n\nBeta diversity ordination based on Bray-Curtis dissimilarity showed that samples (except hot spring and brine samples) did not cluster based on sampling site. This suggests that hot spring and brine samples better individual community similarity. Overall, all samples clustered together based on salinity and alkalinity, indicating the impact of these elements on the structure of the bacterial and archaeal communities (Figure 3; Table 1). The principal component (PCA) analysis showed that the first (PC1) and second (PC2) axes described 38.7% and 17.9% of the variance in microbial communities, respectively. Accordingly, samples were clustered into three distinct groups based on alkalinity and salinity. Low alkalinity and salinity samples (pH 9.8 – 10.5; 10, 300 ppm – 70,500 ppm) consisted of nine samples (S1_06, S1_09, S5_06, S5_09, S5_08, S5_07, S6_08, S6_06, and S6_07). Moderately alkaline and saline samples (pH 10.5 – 10.6; 63, 900 ppm – 100,000 ppm) consisted of six samples (S3_06, S4_06, S2_06, S3_07, S2_07, and S4_07). Highly alkaline and saline samples (pH 10.7-11.5; >100,000 ppm) consisted of six samples (Br1_06, Br1_09, S4_09, S2_09, S3_08, and S4_08).\n\nThe proportion of bacteria to archaea varied by season and sampling month (Figure 4). The results indicate that the archaeal population increased due to evaporative ion concentration while bacteria abundance was higher where the ion concentration was lower (sites 1, 4, and 5) (Table 1). In hot spring water (S1), archaea abundance was the lowest while bacterial abundance was the highest. Within open water samples (S2–S6), S4 had the highest abundance of archaea, while S5 had the highest proportion of bacteria. Within the brine (BR1), the archaea proportion was relatively higher than the bacterial communities. From June to September 2018, bacterial abundance decreased while archaeal abundance increased (Figure 4A).\n\n(A) The proportion of Domains bacteria and archaea across the sampling sites and months. (B) Percentage abundance of the most popular bacterial and archaeal phyla across the sampling sites and the sampling months.\n\nThe bacterial reads were distributed across 25 phyla, 107 orders, 225 families, and 545 genera. The results revealed that the most abundant bacterial phyla across the sampling sites and the four months of sampling included Proteobacteria, Cyanobacteria, Bacteroidetes, Actinobacteria, Firmicutes, Verrumicrobia, Deinococcus-Thermus, Spirochaetes, and Chloroflexi (Figure 4B). Notably, members of the phylum Proteobacteria were the most dominant group across all the sampling sites, accounting for 35% abundance. They were followed by phylum Cyanobacteria (14.2%) and Bacteroidetes (10.5%), Actinobacteria (5.2%), Firmicutes (2.7%), and Verrumicrobia (1.1%). The most dominant bacterial genera (> 1% of all sequences across all samples) were Euhalothece (10.3%), Rhodobaca (9.6%), Idiomarina (5.8%), Rhodothermus (3.0%), Roseinatronobacter (2.4%), Nocardioides (2.3%), Gracilimonas (2.2%), Halomonas (2.0%), Lewinella (1.9%), Synechococcus (1.8%), Aliidiomarina (1.8%), Nitriliruptor (1.7%), Thioalkalivibrio (1.7%), Salinibacter (1.4%), Alkalimonas (1.25%), Chelatococcus (1.4%), and Rhodovulum (1.4%). Others included: Cytophaga (0.9%), Natronocella (0.9%), Thiohalomonas (0.9%), Euzebya (0.8%), Paracoccus (0.8%), and Luteolibacter (0.8%). The abundance of bacterial genera was higher in the sampling site S5 (25.3%) followed by S6 with 20.1%, S3 (14.5%), S1 and S4 with 12.8% each, and brine sample BR1 with 3.9% abundance in that order. In terms of the sampling month, June had the highest bacterial abundance with 39.5% followed by the months of July (27%), September (16.8%), and August (16.2%) in that order.\n\nThe archaeal reads were affiliated to three phyla (Euryachaeota, Crenarchaeota, and Thaumarchaeota) (Figure 4B), 14 orders, 20 families, and 62 genera. The dominant Phylum was Euryachaeota (87% of all Archaeal samples), with its dominant genera (>1% of all sequences across all samples) being Halorubrum (18.3%), Salinarchaeum (5.4%) and Haloterrigena (1.3%). Other genera included Methanomassiliicoccus (0.6%), Palaeococcus (0.4%), Halovenus (0.3%), Thermococcus (0.3%), Haladaptatus (0.3%), Halorientalis (0.3%), Methanobrevibacter (0.2%), Natronomonas (0.2%), Halohasta (0.2%), Haloquadratum (0.1%), and Methanobacterium (0.1%). Archaeal genera abundance was higher in the sampling site S3 (27.2%) followed by brine site BR1 with 21.6% abundance. S1 and S6 had the least archaeal abundance with 0.08 and 0.8%, respectively. In terms of the sampling month, September had the highest archaeal abundance with 53% followed by August (23%), June (12.7%), and July (11.4%).\n\nThe bacterial species composition (>1%) included Euhalothece spp. (10.3%), Rhodobaca spp. (9.6%), Idiomarina spp. (5.8%), Rhodothermus spp. (3.0%), Roseinatronobacter spp. (2.4%), Nocardioides spp. (2.3%), Gracilimonas spp. (2.2%), Halomonas sp. (2%), Lewinella (1.9%), Synechococcus spp. (1.8%), Cyanobacterium spp. (1.8%), Aliidiomarina spp. (1.7%), Nitriliruptor spp. (1,7%), Thioalkalivibrio spp. (1.7%), Salinibacter spp. (1.4%), Alkalimonas spp. (1.2%), Chelatococcus spp. (1.1%), and Rhodovulum spp. (1.1%). The Euhalothece natrophila species were abundant in June, July, and August, except in sites S5 and S6 across all seasons. Rhodobaca bogoriensis was largely sampled in the month of June and site S6 in July and August 2018. Idiomarina spp. were largely concentrated in the months of June, particularly in sites S1 and S5, whereas Rhodovulum spp. were sampled across all seasons. Lewinella coherens were sampled in June mostly in sites S3 and S4. On the other hand, Halorubrum spp. (18.3%), Salinarchaeum spp. (5.3%), Haloterrigena spp. (1.3%), Methanomassiliicoccus spp. (0.7%), and Palaeococcus spp. (0.5%) were the major species in the Archaeal Domain. Idiomarina vacuolatum was sampled across all the sampling seasons but varied in structure across the sampling sites. Halorubrum vacuolatum was mainly sampled in the month of August (S1 and S2) and September (S3, S4 and S5). Salinarchaeum sp. was mainly sampled in the month of September, while Haloterrigena spp. was sampled across the seasons and sites, though in low proportions. The top 30 most abundant species of bacteria and archaea are shown in Figure 5. Overall, Halorubrum spp. was the most abundant species sampled followed by Euhalothece spp. and Rhodobaca spp. (Extended data, Supplementary Figure 2 (Kipnyargis et al., 2023a)).\n\nMicrobial co-occurrence network analysis at the family level revealed that bacterial members of the family Cyclobacteriaceae, Burkholderiaceae and Alteromonadaceae were unique to the S1 sampling site. Bacterial members of Halobacteroidaceae, Spirochaetaceae, halanaerobiaceae, and desulfohalobiaceae, as well as Archaeal members of Archaeoglobaceae and Methanobacteriaceae, were found exclusively in the S2 sampling site. Phyllobacteriaceae and Nostocaceae were unique to S3, while Alcanivoracaceae, Carnobacteriaceae, and Marinilabiliaceae bacteria were found in S5 only. Unique to S6 were the bacterial Puniceicoccaceae family. The highest number of co-shared families was found between S5 and S1 co-sharing eight families, whereas Bacilaceae and Natranaerobiaceae were found in S5 and S2, and S6 and S2 co-shared only one family (Pseudomonadaceae) (Figure 6).\n\nSamples marked with red squares indicate their exclusive site of isolation.\n\nRedundancy analysis (RDA) was used to assess the effect of water chemistry on microbial community structure in Lake Magadi. The results reveal that changes in the physicochemical parameters influenced the microbial communities in the lake (Extended data, Supplementary Table 2 (Kipnyargis et al., 2023a)). The RDA explained 62.2% and 17.2% of the variation in the first (RDA1) and the second (RDA2) axes, respectively (Figure 7).\n\nOverall, temperature, pH, P+, K+, NO3-, and TDS had a positive influence on the microbial community structure. Generally, members of genera Nocardiodes, Rhodothermus, Haloterrigena, Methanomasiliicoccus, Halorubrum, Palaeococcus, Nocardioides, Salinarcheum, Salinibacter, and Euhalothece spp. had a wide range of adaptability. Conversely, Synechococcus, Thioalkalivibrio, Cyanobacterium, Rhodovulum, Lewinella, Idiomarina, Pseudidiomarina, Chelatococcus, Aliidiomarina, and Alkalimonas spp. were adapted to fewer physicochemical factors (Extended data, Supplementary Figure 3 (Kipnyargis et al., 2023a)). Notably, Halorubrum and Haloterrigena spp. were positively correlated with P and K (R2 = 0.66, p < 0.001), but negatively correlated with Mn+ and CO32-. pH appears to positively correlate with the structure of the members of the genus Salinarcheum (R2 = 0.245; p < 0.004), but negatively correlated with NO3-. Members of Alkalimonas, Idiomarina, and Aliidiomarina spp. were positively correlated with NO3- (R2 = 0.049, p < 0.210), but negatively correlated with all other tested parameters. Members of Nocardiodes, Rhodothermus, Salinarcheum, Salinibacter, and Euhalothece spp. were positively correlated with total dissolved solids (TDS), alkalinity, salinity, CO32+, and NH4+ (R2 = 0.606, p < 0.001), but negatively correlated with Mg2+, Mn+, and NO3-. On the other hand, Mn+, temperature CO32-, and NH4+ negatively affect the structure of Rhodobaca.\n\n\nDiscussion\n\nWe explored the structure and composition of microbial communities based on the seasonality and physicochemical parameters of Lake Magadi. The physicochemical parameters revealed high concentrations of sodium salts, HCO3-, SO42-, pH values of 9.8–11.5, temperatures of 27–38°C, and low concentrations of Ca2+, Mg2+, and Cu2+. These findings were consistent with previous reports indicating that soda lakes are characterized by moderate to high temperatures, high concentrations of HCO3−/CO32− and reduced concentrations of Ca2+ and Mg2+ (Sorokin et al., 2014a; Vavourakis et al., 2018). However, total dissolved solids (TDS) ranged from 27 ppm (0.02g/L) to 143 ppm (0.143g/L), a situation that is lower than other soda lakes (Taher, 1999; Hosam et al., 2017; Pérez & Chebude, 2017). Furthermore, sulfate concentration (39–958 ppm) was lower than that of lakes Sidi Ameur and Himalatt (Algeria) (Boutaiba et al., 2012). The concentrations of these elements (except pH) were varied across the sampling months and sites, suggesting that the lake chemistry is constantly changing in its constituent elements. Hypersaline lakes are characterized by high amounts of Na2CO3 and NaHCO3 that maintains constant pH in these ecosystems (Simachew et al., 2016). It is hypothesized that Ca2+ and Mg2+ precipitate as insoluble carbonates due to high evaporation rates in these ecosystems. As a result, an alkaline brine with Na+, Cl−, and HCO3−/CO32− accumulates as main ions. The shift in CO2/HCO3−/CO32− equilibrium towards CO32−, leads to the formation of a soda (Na2CO3) lake with pH values of over 10.0 (Grant and Jones, 2016).\n\nUnder the extremes of salinity and alkalinity, microorganisms in soda lakes have devised mechanisms of coping up with osmotic stress. For instance, bacteria possess Na+/H+ and K+/H+ antiporters which exchange cytoplasmic cations for protons outside of the cell to achieve lower cytoplasmic alkalinity than the external environment (Padan et al., 2005) Furthermore, they synthesize compatible solutes like betaine glycine, sugars (such as trehalose), polyols, amino acids, biosurfactants, and ectoines, which are involved in maintaining an isotonic environment (Bursy et al., 2008). The archaea produce osmolytes such as include glycerol, glycosyl glycerol, betaines, proline, glutamate, glutamine, and ectones (Roberts, 2005).\n\nA high diversity of OTUs was detected for the domain Bacteria with 3,802 OTUs while Archaea had 1,035 OTUs. Bacterial diversity was dominated by the phyla Proteobacteria, Cyanobacteria, Bacteroidetes, Actinobacteria, Firmicutes, Verrumicrobia, Deinococcus-Thermus, Spirochaetes, and Chloroflexi. Similar results have been shown from soda ecosystems such as Solar saltern in Tunisia (Menasria et al., 2019), lake Chott El Jerid (Abdallah et al., 2018), hot springs of Lake Magadi (Kambura et al., 2016), and lakes Sonachi, Magadi, Elmenteita, and Bogoria in Kenya (Mwirichia, 2022). Notably, the phylum Proteobacteria was the most dominant group across all the sampling sites, accounting for 35% abundance. The function of members of Proteobacteria such as Burkholderiaceae is to decompose recalcitrant organic matter while others like Beijerinckiaceae fix atmospheric nitrogen (Li et al., 2012). They were followed by the phylum Cyanobacteria (14.2%) represented mainly by the Euhalothece spp. Euhalothece is a single-celled stenohaline cyanobacterium that grow optimally at 7% (w/v) NaCl. They depict a morphological variability depending on the concentrations of NaCl and carbonates as well as the pH conditions (Mikhodyuk et al., 2008). In soda lake ecosystems, Arthrospira spp. are the main photosynthetic agents driving primary productivity, although the seasonal occurrence of Cyanospira, Synechococcus, and Chroococcus spp. augment this process (Jones et al., 1998). In soda lakes, Cyanobacteria are the major contributors to nitrogen fixation (Sorokin & Kuenen, 2005). Phylum Bacteroidetes was majorly represented by the genera Rhodothermus, Roseinatrobacter, Gracilimonas, Lewinella, and Cytophaga. Verrumicrobia was represented by Verrucomicrobium, Puniceicoccus, and Coraliomargarita. Members of Bacteroidetes and Verrucomicrobia thrive well in high-nutrient environments where they play a role in the degradation of biopolymers such as cellulose and chitin (Newton et al., 2011). Interestingly, the presence of Bacteroidetes was often associated with the availability of Cyanobacteria across the sampling periods (Extended data, Supplementary Table 1 (Kipnyargis et al., 2023a)). Phylum Firmicutes was represented by members of Class Clostridium (Clostridium, Halanaerobium, Natranaerobius, and Moorella sp.) and Bacilli. (Alkalibacterium and Anoxybacillus sp.). The two Classes are common in soda lakes with the addition of Tenericutes in some instances.\n\nOur findings showed a shift in bacterial composition throughout the sampling seasons where a high abundance of Actinobacteria and Proteobacteria was accompanied by a lower abundance of Actinobacteria. A typical feature of Actinobacteria is their sensitivity to nutrient overloading and subsequent reduction in oxygen levels. On the other hand, Proteobacteria, Firmicutes, and Bacteroidetes are adapted to nutrient overloading and degradation of complex biopolymers and dead organic materials (DOM) (Thomas et al., 2011). However, the abundance of Firmicutes, which possess diverse metabolic capacities and are resistant to oxygen limitations (Martiny et al., 2006) depicted an uneven behavior in relation to Actinobacterial composition.\n\nThe archaeal community diversity in the Lake Magadi microbiome was represented by three phyla, the Euryachaeota, Crenarchaeota, and Thaumarchaeota. Generally, archaea were more in brine samples with Br1_June and Br1_Sept accounting for 24.5% of total archaea. Previous studies have indicated that archaea are more adapted to saline environments than bacteria (Mani et al., 2020). Euryachaeota was the most abundant phylum across the sites and the sampling seasons. The phylum Euryachaeota accounted for 87% of all archaeal communities. Euryachaeota has well-adapted inhabitants of hypersaline environments where they play a critical role in ecosystem services such as carbon cycling by functioning as methanogens (Jiang et al., 2007; Vavourakis et al., 2016). Grant et al. (1999) first characterized this phylum the alkaline saltern of Lake Magadi. The second most abundant group was represented by Thaumarchaeota also known as ammonia-oxidizing agents (Andreote et al., 2018). Their distribution along a salinity gradient in estuarine sediments may be linked to changes in location and/or salinity as well as gradient sediment depth (Webster et al., 2015). These results were consistent with those of other soda lakes that have detected members of the phylum Euryachaeota and Crenarchaeota (Ghori et al., 2021), Crenarchaeota, Euryarchaeota, Woesearchaeota, and Pacearchaeota, Euryachaeota and Woesearchaeota (Wang et al., 2022). The most abundant genera belonged to Halorubrum (18.3%), Salinarchaeum (5.4%), and Haloterrigena (1.3%). Most of these microbes have their habitats in soda lakes and neutral saline environments (Feng et al., 2005; Mwatha & Grant, 2016; Minegishi et al., 2017; Zhao et al., 2020). Other haloalkaliphilic archaea related to genera Natronomonas, Natrialba, Natrococcus, Natronobacterium, Natronolimnobius, and Halorubrum all of whom were detected in this study, have previously been isolated from brines of East African soda lakes and Inner Mongolian lakes where salinity values reach > 30%, and pH values of >10 (Grant and Sorokin, 2011). Overall, the results of this study reflect bacterial composition in many soda lakes around the world (Sorokin et al., 2014a; Kambura et al., 2016; Mani et al., 2020; Poyraz & Mutlu, 2020; Wang et al., 2022).\n\nCo-occurrence network analysis demonstrates the interactions between microbial taxa, which can be symbiotic or competitive (He et al., 2019). At the family level revealed the presence of heterogenous microbial communities that co-occur in different sampling sites along the lake as well as others that were unique to a particular site, suggesting an ecological adaptation of these communities to certain aspects of their sites. For instance, Desulfobacteriaceae were unique to S2. Correspondingly, S2 had the highest concentration of both sulfur and sulfate ions (Table 1). This family, particularly Desulfonatronum, Desulfonatronospira, Desulfonatronovibrio, and Desulfohalophilus have been shown to thrive in anoxic parts of soda lakes acting as sulfate-reducing bacteria (SRB) through the oxidation of hydrogen and formate or direct disproportionation of sulfite of thiosulfate (Sorokin et al., 2011). Remarkably, Thioalkalivibrio sp. was not significantly affected by the physicochemical properties investigated. This group of sulfur-oxidizing bacteria (SOB) has been suggested to have a wide range of adaptation mechanisms in soda lake ecosystems (Li et al., 2022). Unique to the S6 site were the members of the family Puniceicoccaceae which have also been described in four soda lakes of the Cariboo Plateau in Canada (Zorz et al., 2019). Cyclobacteriaceae retrieved from the S1 site have established habitats in diverse ecosystems like cold marine regions like algal/microbial mats, haloalkaline soda lakes, Antarctica, freshwater bodies, marine waters, marine sediments, mangroves, hot springs, and mud volcanoes (Rosenberg et al., 2014). Members of families Rhodobacteraceae and Cyclobacteriaceae have sulfate–oxidizing properties, whereas Burkholderiaceae (unique to S1) have adapted to different ecological niches and are involved in processes such as catabolism of aromatic compounds as well as nitrogen fixation (Pérez-Pantoja et al., 2012).\n\nAlpha diversity studies revealed that samples in the open waters, particularly S5, had the highest species richness and diversity. However, open waters samples from S2–S4 depicted varying degrees of community structure and this could be due to variations in the intertidal water zones (Zhu et al., 2018). Brine samples (BR1) in June and September had relatively high diversity and evenness indices. This phenomenon can be attributed to the maintenance of homogenous abundances by microbial communities during brine formation, hence resulting in higher biodiversity (Banda et al., 2020). Hot spring samples collected in September showed high species diversity indices. Microbial samples from Lake Magadi hot springs were established to be stable and active (Kambura et al., 2016).\n\nBeta diversity analysis based on principal component analysis (Figure 3) revealed that samples from hot spring (S1) and brine (BR1) clustered according to their sites. This suggests that hot spring and brine samples had better individual community similarity (Tao et al., 2019). However, the salinity and alkalinity of the sampling sites appeared to drive the overall dynamics of microbial community structure in Lake Magadi. Previous studies have established that salinity is the primary selective force driving the distribution of beta diversity, whereas alkalinity drives microbial richness (Antony et al., 2013; Boros & Kolpakova, 2018; Banda et al., 2020). Moreover, extreme salinity and alkalinity confine the microbial communities to a few taxa highly adapted to the prevailing conditions (Oren, 2011).\n\nIn terms of water chemistry (Figure 7; Extended data, Supplementary Figure 3 (Kipnyargis et al., 2023a)), pH, temperature, PO43-, K+, and NO3−, NH4+, Mn+, Na+, SO42-, and TDS influenced the variation of microbial community composition in Lake Magadi. Salinity and alkalinity tend to influence the richness of the microbial communities in the soda lake ecosystem. Specifically, members of genera Nocardiodes, Rhodothermus, Haloterrigena, Methanomasiliicoccus, Halorubrum, Palaeococcus, Nocardioides, Salinarcheum, Salinibacter, and Euhalothece had a wide range of physicochemical adaptability. Conversely, Synechococcus, Thioalkalivibrio, Cyanobacterium spp., Rhodovulum, Lewinella, Idiomarina, Pseudidiomarina, Chelatococcus, Aliidiomarina, and Alkalimonas adapted fewer physicochemical factors (Extended data, Supplementary Figure 3 (Kipnyargis et al., 2023a)). The archaeal genera Salinarchaeum and Halorubrum Halobellus, Halolamina, Methanobrevibacter, and Halorhabdus have been strongly associated with salinity and other factors such as pH, Mg2+, Na+, K+, Ca2+, and SO42– (Han et al., 2017). Nitrate appears to drive the members of the genera Aliidiomarina, Idiomarina, and Alkalimonas (Figure 4, Extended data Supplementary Figure 3 (Kipnyargis et al., 2023a)). Many strains of Alkalimonas have been isolated from Chahannor (China), Kulunda Steppe (Russia), and Elementaita (Kenya) soda lakes where they play a role in nitrate reduction and formation of H2S (Ma et al., 2004; Vavourakis et al., 2016). However, in this study, sulfur was negatively correlated with Alkalimonas. The Aliidiomarina and Idiomarina belong to family Idiomarinaceae and have also been described as nitrogen reducers but poor in carbohydrate utilization (Chiu et al., 2014).\n\n\nConclusion\n\nStudies involving ecological, physiological, and taxonomical aspects have revealed the great diversity of haloalkaliphiles in numerous saline and alkaline lakes. The current study utilized a culture-independent technique to elucidate the microbial community structure and composition based on different sampling periods across various sites of the saline and alkaline Lake Magadi. The results depict a great deal of diversity in bacterial diversity as compared to archaea. Salinity and alkalinity are the main drivers of the microbial community in the lake. Overall, members of Nocardiodes, Rhodothermus, Haloterrigena, Methanomasiliicoccus, Halorubrum, Palaeococcus, Nocardioides, Salinarcheum, Salinibacter, and Euhalothece had a wide range of adaptability. Conversely, Synechococcus, Thioalkalivibrio, Cyanobacterium spp., Rhodovulum, Lewinella, Idiomarina, Pseudidiomarina, Chelatococcus, Aliidiomarina, and Alkalimonas were affected by fewer physicochemical factors. Additionally, we found that other physicochemical parameters such as TDS, temperature, salinity, alkalinity, nitrates, and phosphates have a positive correlation with microbial community structure. Future research should focus on the functional profiles of samples during and after cyanobacterial blooms, including vertical profile stratification of Lake Magadi. The inclusion of sediment samples will also elucidate the taxonomic and functional profile of anoxic microbial communities.",
"appendix": "Data availability\n\nNCBI BioProject: Prokaryotic diversity within the hypersaline Lake Magadi in Kenya. Accession number: PRJNA962270. https://www.ncbi.nlm.nih.gov/bioproject/PRJNA962270/ (Kipnyargis et al., 2023b).\n\nFigshare: Structure and composition of the microbial communities in hypersaline Lake Magadi: Additional Materials. https://doi.org/10.6084/m9.figshare.22699456 (Kipnyargis et al., 2023a).\n\nThis project contains the following extended data:\n\n• Supplementary Figure 1.png (The distribution of shared operational taxonomic units (OTUs) based on the month of sampling in Lake Magadi.)\n\n• Supplementary Figure 2.png (Percentage read abundance of the top 20 species of the microbial communities collected from Lake Magadi.)\n\n• Supplementary Figure 3.png (The influence of physicochemical parameters on the structure of microbial communities in Lake Magadi.)\n\n• Supplementary Table 1.xlsx (Percentage abundance of bacterial and archaeal communities in Lake Magadi across the sampling months, broken down by phylum.)\n\n• Supplementary Table 2.docx (Mantel test results of the effects of physicochemical factors on microbial structure and composition in Lake Magadi.)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAbdallah MB, Karray F, Kallel N, et al.: Abundance and diversity of prokaryotes in ephemeral hypersaline lake Chott El Jerid using Illumina Miseq sequencing, DGGE and qPCR assays. 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}
|
[
{
"id": "251341",
"date": "01 Apr 2024",
"name": "Marianne Haines",
"expertise": [
"Reviewer Expertise alkaline soda lake communities",
"alkaliphilic cyanobacteria"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary The authors sampled 7 sites representing spring, brine, and open waters in Lake Magadi, Kenya, over a 4-month period. Each sample underwent physiochemical testing and DNA extraction for amplicon sequencing and subsequent microbial community analysis. The authors thoroughly explore the composition of the microbial communities at each site and timepoint. Community composition is explored through standard taxon abundance measures and multiple diversity measures. Physiochemical drivers of the success (abundance) of different taxa are also evaluated. This work is valuable to microbial ecologists interested in extreme environments, notably, alkaline soda lakes.\nComments Firstly, thank-you so much for your commitment to science. Well done! It takes a lot of work to get a manuscript to this stage. You have put together a very comprehensive analysis of your community data. Your results are stated very well and are nicely presented in figures. I really enjoyed the in-depth exploration of the community data. Overall, the manuscript is in good shape, although there are some places, particularly in the discussion and conclusion, where I think it requires some work.\nAbstract\nAdd in that you did 16S AND analysed physiochemical properties in the methods\n\n“Furthermore, salinity and alkalinity affect β-diversity rather than the sampling site or seasonality.” Probably seasonality and site also impact diversity but they are masked by the stronger drivers of salinity and alkalinity. You could rephrase this to say salinity and alkalinity had a stronger or the most notable impact on beta diversity. Indeed you actually directly contradict this point in the last sentence: “Multivariate analysis revealed significant spatial and temporal effects on β-diversity and salinity and alkalinity were the major drivers of microbial composition in Lake Magadi.”\n\n“The effects of physicochemical parameters on the microbial community structure showed that temperature, pH, P+, K+, NO3 -, and total dissolved solids (TDS) had a positive correlation with the microbial community structure” I don’t know what you mean by positive correlation on microbial community structure. Explain.\nIntroduction\nWhat do you mean by “validly described”, be more specific what your definition of valid descriptions are.\n\nThis is stated really nicely, “A key ecological question is how microbial diversity changes with the fluctuating physicochemical conditions with seasons.”\n\n“In this study, we explored the spatiotemporal variation in the microbial community AND physiochemical properties of the water over four months at different sites in Lake Magadi using Illumina 16S sequencing.” 16S is more specific than the type of sequencing.\nMethods\nThe naming of samples makes it easy to distinguish brine from the other sample types but it is hard to know that S1 is the only spring.\n\nFigure 1 – it is hard to see which sites are S3 and S4\n\nBit unnecessary to have the type of cool box.\n\nI haven’t done extensive diversity analysis of 16S data so I can’t comment on these methods.\n\nShould include some text that states that the primer is designed to capture both Bacteria and Archaea. It would be helpful to state early on in the piece which seasons these months fall in to in Kenya. Are these warm or cool months, rainy or dry? Not all readers will know this immediately.\nResults There was an uneven distribution in sampling times, that needs to be mentioned. Why did this happen? How could it have influenced/biased your results?\nPhysicochemical properties of the sampling sites\nTable 1 needs units beside each metric in column 1 even though I see they are stated in the body of the text, one should be able to look at the Table without needing to seek clarification from the text.\n\nWhy are there months missing for some of the samples? If data wasn’t collected for those months, how did that impact RDA which was used to test the correlation between physiochemical parameters and genera? Why these samples are missing and how the analysis overcame this needs to explained.\nSequence analysis and diversity studies\nTable 2: What are “observed species”, you say that taxa were assigned to genus level, not to species level. Is this column actually talking about the number of different genera? This column should have the 00s removed.\n\nTable 2 rows should be ordered by sample and then chronologically.\nAlpha diversity studies\nThis is the first time in the piece you have mentioned the spring is a hot spring. That needs to be updated in the methods.\n\nFigure 2 has the x axis categories in alphabetical order but I think from the perspective of the reader this should be presented chronologically. Seasonality usually has a profound impact on community structure, it would be nice to visualise easily if there are (or are not) diversity trends based on seasonality.\n\nIn Figure 2 legend, you state “Statistical significance was determined at p < 0.05” but I don’t see any indication of statistical significance conveyed on the graph so I don’t think this sentence is necessary.\n\nI like that you have presented the results from so many different measures of species diversity here. It is not necessary to do it for this work, but one way to simplify this type of graph (especially because all tests show similar trends) would be to normalise all values and then plot them on a single graph with box plot colours indicating the test type. At present, your coloured key here is unnecessary because you already have the months as categories in the x-axis.\n\n“The alpha diversity indices showed that high microbial diversity was recorded in the month of August, followed by September, June, and July in that order (Figure 2).” I don’t think these results clearly show this, they are too variable and overlapping.\nBeta diversity studies\n“Low alkalinity and salinity samples (pH 9.8 – 10.5; 10 ***what is this number?***, 300 ppm – 70,500 ppm).” Same thing with the 63 in the medium cluster, and then that number is missing in the high cluster.\n\nFigure 3 needs to tell me which clusters are which, preferably on top of the graph are in the legend. That’s cool that they cluster like that.\nTaxonomic composition and structure\n“The results indicate that the archaeal population increased due to evaporative ion concentration while bacteria abundance was higher where the ion concentration was lower (sites 1, 4, and 5) (Table 1).” I don’t think you can conclude this from your results. You might say there is a trend and it could be because of ion concentration. This is a discussion point and shouldn’t be in the results section.\n\nFigure 4: I am a bit confused with the alignment of different samples, why are there gaps between bars in some cases but not in others? I think 4A and 4B should have their samples aligned vertically according to month and sample site. If there are gaps where one sample was completed for Bacteria and not for Archaea that’s fine, but the figure needs to simply explain why. Gaps between sample types makes in 4A but things go astray in 4B.\n\nIs the relative abundance on the y-axis of figure 4A based on read number? How was that calculated? Figure 6: What a cool plot. This is a cool way to visualise data. I like it!\n\nFigure 7: In the legend, “Samples corresponding to their sampling month are indicated as indicated”. This is a bit of a clumsy sentence. Good news is the key is completely self-explanatory so you just delete it. You don’t need to explain TDS again, its common enough in the field and you already have described it in the methods.\n\n“Notably, members of the phylum Proteobacteria were the most dominant group across all the sampling sites, accounting for 35% abundance.” Is this abundance based on all sample site and timepoints pooled together? That should be clarified. “Idiomarina vacuolatum was sampled across all the sampling seasons but varied in structure across the sampling sites.” Do you mean varied in abundance? Be as specific as you can when stating results.\nPhysicochemical drivers of bacterial and archaeal community structure\n“Overall, temperature, pH, P+, K+, NO3-, and TDS had a positive influence on the microbial community structure.” – what does this mean? What do you define as a positive influence?\n\n“were adapted to fewer physiochemical factors” bold statement. Keep it more objective here? You could say that these species were not found in high concentrations of X, Y, Z.\n\n“pH appears to positively correlate with the structure of the members of the genus Salinarcheum”, what does structure of members mean?\nDiscussion Where this manuscript needs attention is in the discussion. In general, discussion clarity and reasoning needs improvement. This is particularly evident when citing other literature. There were a few places I wasn’t sure what the authors meant and there are some repeated / missing words.\n“Furthermore, sulfate concentration (39–958 ppm) was lower than that of lakes Sidi Ameur and Himalatt (Algeria) (Boutaiba et al., 2012).” This isn’t a meaningful reference to use here. I don’t understand why this single comparison (of 2 lakes in Algeria) is important to the discussion. Sulfate concentration varies quite a lot throughout soda lakes. Is this sulfate concentration low or high relative to soda lakes in general?\n\n“The concentrations of these elements (except pH) were varied across the sampling months and sites, suggesting that the lake chemistry is constantly changing in its constituent elements” This isn’t a suggestion … you measured it. Instead you could say “measured elements were variable from site to site and fluctuated with time.\n\n“Hypersaline lakes are characterized by …” The remainder of this paragraph is not relevant to the discussion. It is either introduction material or should be deleted. It does not “discuss” your results.\n\n“Under the extremes of salinity and alkalinity, microorganisms in soda …” This entire paragraph is also introduction material or should be deleted. It does not discuss the results.\n\n“Notably, the phylum Proteobacteria was the most dominant group across all the sampling sites, accounting for 35% abundance.” Be specific about what the abundance means, it is 35% of all reads from all timepoints and samples sites were attributed to Proteobacteria?\n\n“They were followed by the phylum Cyanobacteria (14.2%) represented mainly by the Euhalothece spp. Euhalothece is a single- celled stenohaline cyanobacterium that grow optimally at 7% (w/v) NaCl.” This is where you can compare to the salt concentration in your system – is it above or below this?\n\nIt seems that Eulohaleaceae are the main bacterial phototrophs in your system. So the following discussion about Spirulina doesn’t make too much sense. You could say this is in contrast to many other soda lakes systems where Arthrospira dominates. Does Lake Magadi have more NaCl than other lakes, is that why Eulohaleaceae and not Arthrospira dominate? Have either of these two taxa been found to be common in the lake in other studies?\n\n“Our findings showed a shift in bacterial composition throughout the sampling seasons where a high abundance of Actinobacteria and Proteobacteria was accompanied by a lower abundance of Actinobacteria.” How is Actinobacteria in high abundance and low abundance?\n\n“Interestingly, the presence of Bacteroidetes was often associated with the availability of Cyanobacteria across the sampling periods” Keep going here… why could this be the case?\n\n“However, the abundance of Firmicutes, which possess diverse metabolic capacities and are resistant to oxygen limitations (Martiny et al., 2006) depicted an uneven behavior in relation to Actinobacterial composition.” What do you mean depicted an uneven behaviour?\n\n“Grant et al. (1999) first characterized this phylum IN the alkaline saltern of Lake Magadi.”\n\n“Their distribution along a salinity gradient in estuarine sediments may be linked to changes in location and/or salinity as well as gradient sediment depth (Webster et al., 2015).” I don’t understand what you mean here.\n\n“Crenarchaeota (Ghori et al., 2021), Crenarchaeota, Euryarchaeota, Woesearchaeota, and Pacearchaeota, Euryachaeota and Woesearchaeota (Wang et al., 2022).” Crenarcheaota and Woesearcheota are repeated in this.\n\n“Remarkably, Thioalkalivibrio sp. was not significantly affected by the physicochemical properties investigated.” Yes! Good observation. But why? Tell me why it is remarkable or unexpected. E.g., “We had expected that Thioalkalivibrio would have responded positively to XYZ…\n\n“However, open waters samples from S2–S4 depicted varying degrees of community structure and this could be due to variations in the intertidal water zones (Zhu et al., 2018).” Lacking specificity, what do you mean by community structure here, diversity / abundance / species type? What do you mean by variations in intertidal water zones? What type of variations?\n\n“This phenomenon can be attributed to the maintenance of homogenous abundances by microbial communities during brine formation, hence resulting in higher biodiversity (Banda et al., 2020).” Homogenous abundances of each microbe as evaporation occurs? Why would this happen?\n\n“Hot spring samples collected in September showed high species diversity indices.” Microbial samples from Lake Magadi hot springs were established to be stable and active (Kambura et al., 2016).” Relevance? Are high species diversity indices unusual in hot springs? Is it unusual to have a stable, active community? What does stable mean here? Similarly structured over time? Is that what is seen at S1? There are only two samples from S1 so that conclusion cannot be drawn anyway.\nConclusion\nThe conclusion needs some work. The clarity needs to be improved by being much more specific.\n“The results depict a great deal of diversity in bacterial diversity as compared to archaea.” Consider rephrasing this.\n\n“Salinity and alkalinity are the main drivers of the microbial community in the lake.Overall, members of Nocardiodes, Rhodothermus, Haloterrigena, Methanomasiliicoccus, Halorubrum, Palaeococcus, Nocardioides, Salinarcheum, Salinibacter, and Euhalothece had a wide range of adaptability.” Does this mean these members have a wide range of adaptability to salinity and alkalinity or are present in many sites?\n\n“Conversely, Synechococcus, Thioalkalivibrio, Cyanobacterium spp., Rhodovulum, Lewinella, Idiomarina, Pseudidiomarina, Chelatococcus, Aliidiomarina, and Alkalimonas were affected by fewer physicochemical factors.” Does this also mean they had a wide range of adaptability? Or does this mean they weren’t positively correlated with particular nutrients?\n\n“…have a positive correlation with microbial community structure.” What is a positive correlation with microbial community structure? How do they influence the community structure?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11494",
"date": "20 Jun 2024",
"name": "Alex Kipnyargis",
"role": "Author Response",
"response": "Add in that you did 16S AND analysed physiochemical properties in the methods Response: Methods (paraphrased): Using 16S rRNA gene amplicon sequencing, we investigated the diversity and structure of microbial communities in water and brine samples taken from Lake Magadi between June and September 2018. Physicochemical parameters were also analyzed for every sampling site. “Furthermore, salinity and alkalinity affect β-diversity rather than the sampling site or seasonality.” Probably seasonality and site also impact diversity but they are masked by the stronger drivers of salinity and alkalinity. You could rephrase this to say salinity and alkalinity had a stronger or the most notable impact on beta diversity. Indeed you actually directly contradict this point in the last sentence: “Multivariate analysis revealed significant spatial and temporal effects on β-diversity and salinity and alkalinity were the major drivers of microbial composition in Lake Magadi.” Response: The sentence “Furthermore, salinity and alkalinity affect β-diversity rather than the sampling site or seasonality.” is deleted completely. The statement should now reads: \"Multivariate analysis revealed that salinity and alkalinity were the major drivers of changes in the structure of microbial communities in Lake Magadi.\" “The effects of physicochemical parameters on the microbial community structure showed that temperature, pH, P+, K+, NO3 -, and total dissolved solids (TDS) had a positive correlation with the microbial community structure” I don’t know what you mean by positive correlation on microbial community structure. Explain. Response: The statement now reads “The findings demonstrated that temperature, pH, P+, K+, NO3 -, and total dissolved solids (TDS) contributed majorly to diversity observed in the microbial community.\" Introduction What do you mean by “validly described”, be more specific what your definition of valid descriptions are. Response: \"validly described\" is replaced with \"previously described\" This is stated really nicely, “A key ecological question is how microbial diversity changes with the fluctuating physicochemical conditions with seasons.” Response: Thank you. “In this study, we explored the spatiotemporal variation in the microbial community AND physiochemical properties of the water over four months at different sites in Lake Magadi using Illumina 16S sequencing.” 16S is more specific than the type of sequencing. Response: \"Illumina\" will be deleted. It will now read: “In this study, we explored the spatiotemporal variation in the microbial community and physiochemical properties of the water over four months at different sites in Lake Magadi using 16S rRNA gene sequencing.” Methods The naming of samples makes it easy to distinguish brine from the other sample types but it is hard to know that S1 is the only spring. Response: The sentence after the GPRS coordinates describes the features of the sampling sites Figure 1 – it is hard to see which sites are S3 and S4 Response: This has been corrected and a new map will be submitted Bit unnecessary to have the type of cool box. Response: This has been removed I haven’t done extensive diversity analysis of 16S data so I can’t comment on these methods. Response: No response since it is a comment. Should include some text that states that the primer is designed to capture both Bacteria and Archaea. Response: That sentence will now read: “The V4 hypervariable region of the 16S rRNA genes was amplified using the universal primers for bacteria and archaea 515F (5′-GTGCCAGCMGCCGCGGTAA-3′) and 806R (5′-GGACTACHVGGGTWTCTAAT-3′)” It would be helpful to state early on in the piece which seasons these months fall in to in Kenya. Are these warm or cool months, rainy or dry? Not all readers will know this immediately. Response: The dry season lasted for all of the sampling months, with June marking the start of the season and September being the driest month. This has been effected in the manuscript. Results There was an uneven distribution in sampling times, that needs to be mentioned. Why did this happen? How could it have influenced/biased your results? Response: You are right. Uneven distribution in sampling sites was a result of: 1. S1 and Br_1 (hot spring and brine, respectively were only available in June and September). 2. The DNA extraction protocol did not yield sufficient DNA for sequencing in sample S2 for August 2018. Physicochemical properties of the sampling sites Table 1 needs units beside each metric in column 1 even though I see they are stated in the body of the text, one should be able to look at the Table without needing to seek clarification from the text. Response: This has been done as suggested. Why are there months missing for some of the samples? If data wasn’t collected for those months, how did that impact RDA which was used to test the correlation between physiochemical parameters and genera? Why these samples are missing and how the analysis overcame this needs to be explained. Response: 1. S1 and Br_1 (hot spring and brine, respectively were only available in June and September). 2. The DNA extraction protocol did not yield sufficient DNA for sequencing in sample S2 for August 2018. However, the Good’s coverage (Table 2) ranged between 0.81–0.96, indicating that the sequencing depth was sufficient to cover most microbial species information and the sample size was sufficient to reflect the diversity differences among different communities. Sequence analysis and diversity studies Table 2: What are “observed species”, you say that taxa were assigned to genus level, not to species level. Is this column actually talking about the number of different genera? This column should have the 00s removed. Response: The assignment to genus level is a more confident way of taxonomic assignment while using 16S rRNA gene. Qiime would pick out the species identified in the OTUs, but we would not be confident to pick out species to difficulties surrounding 16S in resolving closely related species. We would probably remove that statement and recommend that future studies should consider the use of Amplified Sequence Variants (ASVs) to confidently assign species. The 00s in the “observed species” column have been removed. Table 2 rows should be ordered by sample and then chronologically. Response: This has been ordered accordingly. Alpha diversity studies This is the first time in the piece you have mentioned the spring is a hot spring. That needs to be updated in the methods. Response: The word hot spring will be used consistently. Figure 2 has the x axis categories in alphabetical order but I think from the perspective of the reader this should be presented chronologically. Seasonality usually has a profound impact on community structure, it would be nice to visualise easily if there are (or are not) diversity trends based on seasonality. Response: Figure 2 has been presented in chronological order. In Figure 2 legend, you state “Statistical significance was determined at p < 0.05” but I don’t see any indication of statistical significance conveyed on the graph so I don’t think this sentence is necessary. Response: This has been removed I like that you have presented the results from so many different measures of species diversity here. It is not necessary to do it for this work, but one way to simplify this type of graph (especially because all tests show similar trends) would be to normalise all values and then plot them on a single graph with box plot colours indicating the test type. At present, your coloured key here is unnecessary because you already have the months as categories in the x-axis. Response: I have removed the key “The alpha diversity indices showed that high microbial diversity was recorded in the month of August, followed by September, June, and July in that order (Figure 2).” I don’t think these results clearly show this, they are too variable and overlapping. Response: You are right, I will rephrase this sentence. Beta diversity studies “Low alkalinity and salinity samples (pH 9.8 – 10.5; 10 ***what is this number?***, 300 ppm – 70,500 ppm).” Same thing with the 63 in the medium cluster, and then that number is missing in the high cluster. Response: The spaces between the numbers have been removed and the numbers read appropriately. Numbers for high cluster have been inserted. Figure 3 needs to tell me which clusters are which, preferably on top of the graph are in the legend. That’s cool that they cluster like that. Response: A brief explanation of the clusters has been inserted in the figure caption. Taxonomic composition and structure “The results indicate that the archaeal population increased due to evaporative ion concentration while bacteria abundance was higher where the ion concentration was lower (sites 1, 4, and 5) (Table 1).” I don’t think you can conclude this from your results. You might say there is a trend and it could be because of ion concentration. This is a discussion point and shouldn’t be in the results section. Response: Good suggestion. I have paraphrased the sentence Figure 4: I am a bit confused with the alignment of different samples, why are there gaps between bars in some cases but not in others? I think 4A and 4B should have their samples aligned vertically according to the month and sample site. If there are gaps where one sample was completed for Bacteria and not for Archaea that’s fine, but the figure needs to simply explain why. Gaps between sample types makes in 4A but things go astray in 4B. Response: The bars have been ordered according to sample and month. Is the relative abundance on the y-axis of figure 4A based on read number? How was that calculated? Figure 6: What a cool plot. This is a cool way to visualise data. I like it! Response: Thank you for the comment. Figure 7: In the legend, “Samples corresponding to their sampling month are indicated as indicated”. This is a bit of a clumsy sentence. Good news is the key is completely self-explanatory so you just delete it. You don’t need to explain TDS again, its common enough in the field and you already have described it in the methods. Response: This has been corrected “Notably, members of the phylum Proteobacteria were the most dominant group across all the sampling sites, accounting for 35% abundance.” Is this abundance based on all sample site and time points pooled together? That should be clarified. Response: This is a cumulative abundance based on all the time points and sites. The clarification has been effected in the manuscript. “Idiomarina vacuolatum was sampled across all the sampling seasons but varied in structure across the sampling sites.” Do you mean varied in abundance? Be as specific as you can when stating results. Response: Yes, it is the abundance. I have changed this in the manuscript. Physicochemical drivers of bacterial and archaeal community structure “Overall, temperature, pH, P+, K+, NO3-, and TDS had a positive influence on the microbial community structure.” – what does this mean? What do you define as a positive influence? Response: You are right. The sentence has been changed to read “The results demonstrated that temperature, CaCO3, pH, P+, K+, NO3-, and TDS influenced the microbial community structure.” “were adapted to fewer physiochemical factors” bold statement. Keep it more objective here? You could say that these species were not found in high concentrations of X, Y, Z. Response: This has been corrected to capture the aspect of objectivity. “pH appears to positively correlate with the structure of the members of the genus Salinarcheum”, what does the structure of members mean? Response: Structure means how members of a particular microbial community distribute across seasons and sites. Discussion Where this manuscript needs attention is in the discussion. In general, discussion clarity and reasoning needs improvement. This is particularly evident when citing other literature. There were a few places I wasn’t sure what the authors meant and there are some repeated / missing words. “Furthermore, sulfate concentration (39–958 ppm) was lower than that of lakes Sidi Ameur and Himalatt (Algeria) (Boutaiba et al., 2012).” This isn’t a meaningful reference to use here. I don’t understand why this single comparison (of 2 lakes in Algeria) is important to the discussion. Sulfate concentration varies quite a lot throughout soda lakes. Is this sulfate concentration low or high relative to soda lakes in general? Response: More comparisons have been introduced in the manuscript to capture similar, higher, and lower concentrations of sulfates in soda lakes. “The concentrations of these elements (except pH) were varied across the sampling months and sites, suggesting that the lake chemistry is constantly changing in its constituent elements” This isn’t a suggestion … you measured it. Instead you could say “measured elements were variable from site to site and fluctuated with time. Response: Thank you. I have borrowed your words verbatim and the sentence reads well now. “Hypersaline lakes are characterized by …” The remainder of this paragraph is not relevant to the discussion. It is either introduction material or should be deleted. It does not “discuss” your results. Response: That part has been paraphrased to explain the reason for high and stable pH. I felt that since pH was relatively stable across seasons and site, it is important to explain how this happens. “Under the extremes of salinity and alkalinity, microorganisms in soda …” This entire paragraph is also introduction material or should be deleted. It does not discuss the results. Response: I agree. This paragraph has been entirely deleted. “Notably, the phylum Proteobacteria was the most dominant group across all the sampling sites, accounting for 35% abundance.” Be specific about what the abundance means, it is 35% of all reads from all timepoints and samples sites were attributed to Proteobacteria? Response: Proteobacteria accounted for 35% of all the reads. “They were followed by the phylum Cyanobacteria (14.2%) represented mainly by the Euhalothece spp. Euhalothece is a single- celled stenohaline cyanobacterium that grow optimally at 7% (w/v) NaCl.” This is where you can compare to the salt concentration in your system – is it above or below this? Response: I have supported this by a sentence reading: “The existence of Euhalothece in Lake Magadi is thus supported by high salts and carbonates (Table 1).” It seems that Eulohaleaceae are the main bacterial phototrophs in your system. So the following discussion about Spirulina doesn’t make too much sense. You could say this is in contrast to many other soda lakes systems where Arthrospira dominates. Does Lake Magadi have more NaCl than other lakes, is that why Eulohaleaceae and not Arthrospira dominate? Have either of these two taxa been found to be common in the lake in other studies? Response: The sentence has been paraphrased to capture the contrasting aspect of Lake Magadi with other soda lakes. “Our findings showed a shift in bacterial composition throughout the sampling seasons where a high abundance of Actinobacteria and Proteobacteria was accompanied by a lower abundance of Actinobacteria.” How is Actinobacteria in high abundance and low abundance? Response: The entire paragraph does not discuss the results adequately and has been deleted “Interestingly, the presence of Bacteroidetes was often associated with the availability of Cyanobacteria across the sampling periods” Keep going here… why could this be the case? Response: The sentence has been enhanced to explain how photosynthetic cyanobacteria contribute towards the generation of substrates for Bacteroidetes and Verrumicrobia. “However, the abundance of Firmicutes, which possess diverse metabolic capacities and are resistant to oxygen limitations (Martiny et al., 2006) depicted an uneven behavior in relation to Actinobacterial composition.” What do you mean depicted an uneven behaviour? Response: The entire paragraph does not discuss the results adequately and has been deleted. “Grant et al. (1999) first characterized this phylum IN the alkaline saltern of Lake Magadi.” Response: The word “in” has been inserted appropriately. Thank you! “Their distribution along a salinity gradient in estuarine sediments may be linked to changes in location and/or salinity as well as gradient sediment depth (Webster et al., 2015).” I don’t understand what you mean here. Response: This sentence has been paraphrased “Crenarchaeota (Ghori et al., 2021), Crenarchaeota, Euryarchaeota, Woesearchaeota, and Pacearchaeota, Euryachaeota and Woesearchaeota (Wang et al., 2022).” Crenarcheaota and Woesearcheota are repeated in this. Response: True. This has been deleted “Remarkably, Thioalkalivibrio sp. was not significantly affected by the physicochemical properties investigated.” Yes! Good observation. But why? Tell me why it is remarkable or unexpected. E.g., “We had expected that Thioalkalivibrio would have responded positively to XYZ… Response: This has been changed to explain the reason for the effect. “However, open waters samples from S2–S4 depicted varying degrees of community structure and this could be due to variations in the intertidal water zones (Zhu et al., 2018).” Lacking specificity, what do you mean by community structure here, diversity / abundance / species type? What do you mean by variations in intertidal water zones? What type of variations? Response: Structure has been replaced with diversity. The sentence has been paraphrased to capture the aspect of water waves and their effect on the distribution of nutrients. This could explain the variation in the diversity of microbes in water ecosystems. “This phenomenon can be attributed to the maintenance of homogenous abundances by microbial communities during brine formation, hence resulting in higher biodiversity (Banda et al., 2020).” Homogenous abundances of each microbe as evaporation occurs? Why would this happen? Response: The sentence does not justify the diversity enough. I have introduced another theorem. “Despite high salinity and alkalinity in soda lake brine, the presence of high light intensity and dissolved CO2 promotes the growth of photosynthetic microorganisms. Subsequently, these phototrophs generate large quantities of dissolved organic matter (DOM) which become substrates for sustaining the diverse microbial communities (Banda 2020).” “Hot spring samples collected in September showed high species diversity indices.” Microbial samples from Lake Magadi hot springs were established to be stable and active (Kambura et al., 2016).” Relevance? Are high species diversity indices unusual in hot springs? Is it unusual to have a stable, active community? What does stable mean here? Similarly structured over time? Is that what is seen at S1? There are only two samples from S1 so that conclusion cannot be drawn anyway. Response: I have rewritten the statement to capture the relationship of our findings with other studies on hot springs and the reason for such high diversity studies. Research on Soda Lake hot springs revealed a highly active and diverse microbial community, suggesting the high plasticity of these organisms toward extreme environments. Conclusion The conclusion needs some work. The clarity needs to be improved by being much more specific. “The results depict a great deal of diversity in bacterial diversity as compared to archaea.” Consider rephrasing this. “Salinity and alkalinity are the main drivers of the microbial community in the lake. Overall, members of Nocardiodes, Rhodothermus, Haloterrigena, Methanomasiliicoccus, Halorubrum, Palaeococcus, Nocardioides, Salinarcheum, Salinibacter, and Euhalothece had a wide range of adaptability.” Does this mean these members have a wide range of adaptability to salinity and alkalinity or are present in many sites? “Conversely, Synechococcus, Thioalkalivibrio, Cyanobacterium spp., Rhodovulum, Lewinella, Idiomarina, Pseudidiomarina, Chelatococcus, Aliidiomarina, and Alkalimonas were affected by fewer physicochemical factors.” Does this also mean they had a wide range of adaptability? Or does this mean they weren’t positively correlated with particular nutrients? “…have a positive correlation with microbial community structure.” What is a positive correlation with microbial community structure? How do they influence the community structure? Response to conclusion section: I have rewritten the entire conclusion in a way that captures the conclusive elements of both diversity across seasons and sampling sites and the effects of the environmental factors on the population dynamics of microorganisms in Lake Magadi. Your comments were truly helpful."
}
]
},
{
"id": "251335",
"date": "11 May 2024",
"name": "Srijak Bhatnagar",
"expertise": [
"Reviewer Expertise Bioinformatics",
"microbiomes",
"and environmental microbiology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMajor Feedback:\nPlease run us statistical test on the alpha diversity values as it appears the August values could be very similar to June values statistical test is required to ensure the difference mentioned by the authors Sequence analysis subsection under result, line 2: average read length is listed as 525bp The Amplicon expected from the primer mentioned should be around 300 and the length of my seek is also around 300bp. How is read length possible? In various places site, S1 is described as a hot spring, but the temperature is shown as roughly around 35°C. How is this a hot spring? Subsection taxonomic, composition, and structure: “Population increased due to evaporative iron concentration”. This is a causal statement, and no evidence of causation is shown in the study. Figure 4B: the results mention Euryarcheota as the most abundant phylum. This is not evident from the figure. Either the legend is wrong, or the result is misinterpreted Subsection physicochemical drivers: “TDS has a positive influence”. This is a subjective statement with no evidence provided. Unsure what positive influence here means. Use of homonyms: Certain terms have a well-defined and established meaning and could cause confusion, please avoid them. For eg.,\n\nFigure 6:” exclusive site of isolation”. Isolation is a specific microbial technique, which was not employed in this study. DOM -> Dissolved Organic Matter, but in the manuscript used for Dead Organic Materials\n\nThe authors missed the opportunity to guide the discussion by focusing on the temporal changes in physicochemical factors driving the microbial community changes and then discussing possible reasons. The way the discussion is currently framed, it is a mix of results retelling and describing various taxa that were observed by other publications.\n\nMinor Issues:\nThere is no mention of Phix filtering and sequence processing under methods Typo in paragraph two of microbial community analysis, subsection Bray Curtis dissimilarity, written as Bray dissimilarity Table 1: add the charge to the measured ions Results first paragraph line 3: various ions and cations-> various ions or various anions and cations Please mention the medium library size. It is more informative than the average size. Incomplete sentence. beta diversity studies, subsection, line 2: samples better individual community similarity Figure 3: Label the clusters as described in the results section Figure 5: plastering of samples and taxa that here would be helpful and visualising the heat map while it’s understandable that samples are shown by month class based upon composition, should be able to substantiate some of the observations made by the authors. Discussion: “The concentration of these elements” – >“The concentration of these ions”\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-11
|
https://f1000research.com/articles/13-499/v1
|
17 May 24
|
{
"type": "Research Article",
"title": "Cultural intelligence and acculturation among non-native Arabic learners: the impact of learning apps",
"authors": [
"Huda Abu-Qtaish"
],
"abstract": "Background Learning apps can be helpful to non-native language learners in learning Arabic, which includes speaking, writing, and speaking exercises. When learners become better in the language, they become more confident in interacting with the community, thus affecting their Cultural Intelligence (CQ) and Acculturation (AC). This study aimed to explore the relationship between the CQ and AC among non-native learners of Arabic. Additionally, the study aimed to investigate the potential impacts of learning apps and gender.\n\nMethods This study used a correlational approach, involving a sample of 102 non-native Arabic language learners in Jordan. To assess these factors, this study used the Cultural Intelligence Scale and the Acculturation Survey.\n\nResults The findings of this study revealed a positive correlation between the CQ and AC. Furthermore, the use of apps can provide CQ and AC levels. In addition, the study determined that gender did not play a significant role in influencing learners.\n\nConclusion the utilization of educational apps has been shown to enhance both CQ and AC. Thus, it is imperative to encourage learners to engage with these apps, as they foster cultural awareness, thereby facilitating the process of learning Arabic.",
"keywords": [
"Cultural Intelligence",
"Acculturation",
"Non-Native Learners",
"Arabic Language",
"Learning Apps"
],
"content": "Introduction\n\nLearning the Arabic language as a second language has become a goal for many non-native learners from different countries, cultures, ages, and genders. Universities and institutes specialized in this field prepare curricula and programs for them with everything they need to learn the Arabic language as a second language considering that they will face some difficulties in adapting with the new culture or accepting the differences. Lecturers also recognize that this may be easy for some learners and difficult for others.\n\nForeign learners of the Arabic language when traveling to learn it in the country of the language, such as Jordan and Egypt, may suffer from difficulties in adapting to society because of their different cultures and lifestyles. Thus, foreign learners can adapt and achieve their goal of learning the Arabic language and interact with the environment and culture of the host country by acculturating with its people. This means that they have the ability to understand and interpret unfamiliar interactions from a cultural perspective (Van Dyne, Ang, & Koh 2008).\n\nAcculturation (AC) expresses the processes and stages that the learner of the second language goes through to adapt to the culture of native speakers (Al-Osaily 2015). AC is one of the most essential elements for achieving true language competence. Language skills are not only mechanical, but also require social and cultural competence and communication skills with members of the target language community (Boone 2021).\n\nAn individual’s possession of cultural intelligence (CQ) helps them to enhance their AC, as CQ expresses personal traits that focus on the behaviors and skills required to involve and interact with cultures. This helps the individual to become acquainted with the cultural environment of others and to engage, interact, and perform effectively in a manner commensurate with them, thus achieving an adequate understanding of the nature of the language and how to use it (Thomas 2006). Aricat Karnowski, & Chib (2015) showed that people with high CQ who are culturally active are more in contact with members of society and develop AC than are individuals with low CQ who are fossilized.\n\nAl-Muzaffar (2017) defines CQ as being able to deal with different environments and adapt to behavioral patterns in multiple cultures to engage with them easily. There can be no real communication in the target language without cultural efficacy; second language learners need to have an awareness and understanding of both the self-culture and the other’s culture to achieve success in communication in the context of “we.” Not everything that is said or written is always an indication of what is meant (Parker 2016).\n\nColeman (2015) argued that studying abroad can provide huge opportunities for social interaction, and the depth of new social networks will lead to many results and outputs. The depth of learners’ acquaintance with new friends affects input, output, feedback, and the group of language functions that are practiced, and thus, pragmatic competence. In addition, greater contact with native speakers in their environment may affect other goals, such as academic, cultural, personal, professional, pleasure, and tourism. Therefore, increased communication with local communities led to greater gains.\n\nRecently, educational apps have occupied an important position in education, including language teaching for foreigners (Gangaiamaran & Pasupathi 2017). The advantage of learning apps is that they are easy to access anywhere and at all times (Kuimova et al. 2018). Researchers have paid significant attention to technology, especially educational technology. Some research has focused on phones as assistants in language education (Klimova 2019; Leis, Tohei, & Cooke 2015) and studies have found that the use of educational apps may have an effective role in teaching language to foreigners. This is because of their unique applications, such as activities, ease of use, and availability at any time (Klimova 2019; Kukulska-Hulme 2016; Balula et al. 2015; Diána 2020).\n\nThere are many learning apps used by non-native Arabic learners, such as Duolingo, Learn Arabic Vocabulary, Memrise, Innovative 101, Pimsleur, Mondly, Teach me Arabic, and Rosetta Stone. In addition, there are many other apps available on Google Store and App Store that make learning languages easier and more effective (Raed 2021).\n\nThe use of educational apps helps language learners to lessen their fears, practice, and feel linguistically efficient in communicating with native speakers (Kacetl, J., & Klímová 2019; Klimova 2018), because educational apps contain various verbal and written lessons that help the individual practice correct pronunciation. When they use the correct words (Chen 2016), this helps the individual in social engagement with others, and helps them exploit their CQ to interact and reach the AC that helps them achieve their goals (Figueiredo et al. 2019; Vardakosta et al. 2023).\n\nMany studies have investigated the effectiveness of using learning apps to learn languages for non-native learners (Golonka et al. 2014; Hwang & Wang 2016; Liu et al. 2014; Hsu et al. 2014), but the focus was not on the impact of the use of learning apps in terms of cultural aspects, such as CQ and AC. Therefore, this study focuses on this effect.\n\n\n\n1. Is there a statistically significant relationship between the CQ and AC among non-native Arabic learners?\n\n2. Is there an impact of learning apps on the CQ and AC among non-native Arabic learners?\n\n3. Are there statistically significant differences in the CQ and AC due to gender among non-native Arabic learners?\n\n\nMethods\n\nThis study uses a correlational approach. One hundred and two non-native Arabic learners in Jordan were selected as subjects. All participants provided written informed permission with the scales. The research ethics committee authorized the institution’s study. Registration number: 2150/11/1/1. The date was 5/3/2023.\n\nThe study sample consisted of 102 non-native Arabic learners in Jordan, who chose to participate voluntarily, aged between 19-24 years old. The participants studied at CIEE/Amman, the University of Jordan, and German Jordanian University. Informed consent was obtained verbally and written after participants were aware of the aims and subjects of this study.\n\nCultural Intelligence Scale (CQS)\n\nThe Cultural Intelligence Scale (CQ-S) was developed by (Ahmad 2012; Ibrahim 2018), comprising 20 items and four dimensions (metacognitive, cognitive, motivational, and behavioral). A five-point scale were used, from 1 (‘strongly disagree’) to 4 (‘strongly agree’). The researcher elicited the validity by the discriminant evidence which ranged from 0.34 to 0.67. Also, the reliability was checked by Cronbach’s alpha test and retest the results was 0.91 and 0.88.\n\nAcculturation Survey (ACS)\n\nThe Acculturation Survey (ACS) was developed by (Palmer 2013; Dendrinos et al. 2014; Gbadamosi 2018), comprising 30 items and two dimensions (social and psychological), A five-point scale were used, from 1 (‘strongly disagree’) to 4 (‘strongly agree’). The researcher elicited the validity by the discriminant evidence which ranged from 0.32 and 0.77. Also, the reliability was checked by Cronbach’s alpha test and retest the results was 0.87 and 0.86.\n\nApproval for this study was obtained from the University of Jordan Institutional Review Board. Also, the researcher took a written approval from the institutions and participants. The researcher collected the data by online instruments using Google forms. The period of applying the tools was 4 months during the semester.\n\nThe researcher entered the data into SPSS data sheet, and used IBM SPSS v21 (IBM corp., Armonk, N.Y., USA) was used to analyze the data. Means and standard deviations were calculated, and Pearson’s correlation coefficient was used to determine relationships. An independent t-test was used to determine differences. All missing data are reported as missing.\n\n\nResults\n\nThe means and standard deviations were calculated to investigate the levels of CQ and AC. Table 1 presents the results.\n\nTable 1 shows that there is a high level of CQ among non-native learners of Arabic, with a mean of 3.91, and a moderate level of AC, with a mean of 3.50. Additionally, the CQ dimensions were high, whereas the cognitive dimension was moderate. The AC dimension was moderate.\n\nThe Pearson correlation test was used to investigate the relationship between CQ and AC. Table 2 presents the results.\n\n* Correlation is significant at the 0.05 level.\n\nTable 2 illustrates the correlation between the CQ and AC, with a Pearson coefficient of 0.469. Additionally, it revealed a connection between the dimensions of CQ and AC. However, no relationship was observed between the dimensions of the CQ and psychological dimension of AC.\n\nTo determine whether the use of learning apps affected CQ and AC, independent t-tests were used. The results of this study are presented in Table 3.\n\nTable 3 demonstrates that app use can contribute to CQ and AC. The results revealed that learners who utilized learning apps achieved a higher mean score in both CQ and AC compared to learners who did not use them.\n\nTo determine whether there were differences in CQ and AC due to gender, an Independent T-test was used. The results of this study are presented in Table 4.\n\nTable 4 shows that there are no statistically significant differences on CQ and AC due to gender.\n\n\nDiscussion\n\nThis research focuses on the use of learning apps among non-native language learners. Specifically, it focused on how learning apps affected the learning of Arabic languages, and the results found that it is affected. However, learning languages is not limited to vocabulary and reading; learners must know the culture and interact with the community. To this end, this research studied the relationship between CI and AC and the effect of learning apps on the participants. This study found that CI and AC had a positive effect on each other. CI refers to having many behavioral aspects and skills to help the learner communicate and get involved with the culture of the second language. This skill helps them achieve their goals of understanding the language and knowing how to use it in different situations. This was confirmed by Aricat et al. (2015), who mentioned that people with high CI will be more culturally active and become more involved with the community and develop their AC, and vice versa.\n\nThis study found that the use of learning apps increased CI and AC among non-native Arabic learners. With combined learning from apps as well as in the classroom, students show a greater understanding of the language. This, in turn, makes them more self-confident in their linguistic competence, which is the key to understanding culture. Learning apps contain verbal and written lessons that help learners break their fear of saying incorrect words. This helps learners get involved in the community, establish their CI in knowing others, and achieve their goal of becoming AC, leading them to learn Arabic more easily (Klimova 2019; Diána 2020).\n\nThe study found that gender had no role in CI or AC among non-native Arabic learners. These results can be attributed to the fact that males and females face similar experiences when learning languages, such as being in a new country and culture shock (Ellis 2015). Furthermore, both males and females have similar attitudes toward learning the Arabic language because they have left their homes to try learning it to fill their passion.\n\n\nConclusion\n\nThis study revealed a significant correlation between CQ and AC among non-native learners, offering valuable insights into assisting them in adjusting to their new community. Furthermore, the utilization of educational apps has been shown to enhance both CQ and AC. Thus, it is imperative to encourage learners to engage with these apps, as they foster cultural awareness, thereby facilitating the process of learning Arabic. Notably, no discernible sex-based disparities were observed in terms of the CQ and AC.\n\nThis study had several limitations that warrant consideration. First, the research was conducted exclusively with a sample of non-native Arabic learners enrolled in Capital Amman, Jordan, during the year 2023. Consequently, the generalizability of the findings to broader populations and contexts may be limited. The study outcomes were based on participants’ responses to the CQ and AC scales.\n\nTo address these limitations and expand our understanding, we recommend several avenues for future research. First, it is advisable to conduct similar studies in diverse settings with more varied participant demographics to assess the robustness of the identified relationships. Second, the impact of learning apps on other variables that influence an individual’s ability to cope with a new community should be investigated. These variables include linguistic efficacy, social engagement, and psychological well-being.\n\nBased on the insights gained from this study, it is advisable for universities and educational institutes to adopt a proactive stance by integrating additional online classes into their curriculum. This integration should involve the incorporation of educational apps as integral components of learning experience. By doing so, institutions can better facilitate learners’ cultural adaptation and language acquisition journey. This approach not only enhances the accessibility and convenience of learning but also promotes a more comprehensive understanding of the target culture and language.\n\nMoreover, the researcher suggests that further investigation into the effects of learning apps on various variables that influence community coping is warranted. This would involve exploring how these apps impact factors beyond CQ and AC that are relevant to individuals’ abilities to navigate and integrate into a new community. By examining these additional variables, a more holistic perspective of the role of educational apps in fostering effective cultural adaptation can be attained. Future research will contribute to a deeper understanding of the multifaceted benefits of utilizing learning apps and their potential to enhance learners’ overall experience in a new cultural setting.\n\nThe University of Jordan Institutional Review Board, Jordan. Registration number: 2150/11/1/1. The date was 5/3/2023. All participants provided written informed consent with the scales.",
"appendix": "Data availability statement\n\nFigshare: Cultural Intelligence and Acculturation Among Non-Native Arabic Learners: The Impact of Learning Apps: CQ & AC and apps.sav, DOI: https://doi.org/10.6084/m9.figshare.25404190.v3 (Abu-Qtaish, 2024a).\n\nThis project contains the following underlying data:\n\n• CQ & AC.sav\n\nReporting guidelines: Figshare: CROSS check list: Checklist for Cultural Intelligence and Acculturation Among Non-Native Arabic Learners: The Impact of Learning Apps, at https://doi.org/10.6084/m9.figshare.25772271.v1 (Abu-Qtaish, 2024b).\n\nAppendices: Scales for Cultural Intelligence and Acculturation Among Non-Native Arabic Learners: The Impact of Learning Apps, at https://doi.org/10.6084/m9.figshare.25772298.v1 (Abu-Qtaish, 2024c).\n\nData are available under the terms of the Creative Commons Zero (CC0).\n\n\nAcknowledgements\n\nThe researcher would like to thank the participants and organizations for helping them in collecting the data.\n\n\nReferences\n\nAbu-Qtaish H: CQ & AC and apps.sav. figshare. 2024a. Reference Source\n\nAbu-Qtaish H: Cultural Intelligence and Acculturation Among Non-Native Arabic Learners: The Impact of Learning Apps. figshare. 2024b. Reference Source\n\nAbu-Qtaish H: Cultural Intelligence and Acculturation Among Non-Native Arabic Learners: The Impact of Learning Apps scales. figshare. 2024c. Reference Source\n\nAhmad N: Cultural intelligence and its relationship to wisdom and big-five personality factors: the Egyptian form from Cultural Intelligence Scale. J. Arab. Stud. Psychol. 2012; 11: 419–467.\n\nAl-Muzaffar M: The cultural intelligence of secondary school principals in Karbala Governorate in Iraq and its relationship to the prevailing organizational climate in their schools from the point of view of teachers, an unpublished master’s thesis, Middle East University, Jordan.2017.\n\nAl-Osaily A: Psycholinguistics. Imam Muhammad bin Saud Islamic University; 2015.\n\nAricat RG, Karnowski V, Chib A: Mobile phone appropriation and migrant acculturation: a case study of an Indian community in Singapore. Int. J. Commun. 2015; 9(22). 1932–8036/20150005.\n\nBalula A, Marques F, Martins C: Bet on top hat–challenges to improve language proficiency. EDULEARN15 Proceedings. IATED; 2015; pp. 2627–2633.\n\nBoone G: How social interaction affects students’ formulaic development in L2 German in a multilingual SA context. Language, mobility and study abroad in the contemporary European context. 2021: pp. 159–170. Publisher Full Text\n\nChen X: Evaluating language-learning mobile apps for second-language learners. J. Educ. Tech. Dev. Exch. 2016; 9(2): 3. Publisher Full Text\n\nColeman JA: Social circles during residence abroad: What students do, and who with. Social Interaction, Identity and Language Learning During Residence Abroad. 2015; 4: 33–52.\n\nDendrinos P, Fischbacher-Smith M, Milner M, et al.: Supporting GIC Students’ Transition to Year 2 on the MA Social Sciences: Acculturation Strategies. Social Media and Mentoring. 2014.\n\nDiána M: The effect of mobile applications on english vocabulary acquisition.2020.\n\nEllis R: Understanding Second Language Acquisition. 2nd ed.Oxford University Press; 2015.\n\nFigueiredo S, Brandão T, Nunes O: Learning styles determine different immigrant students’ results in testing settings: Relationship between nationality of children and the stimuli of tasks. Behav. Sci. 2019; 9(12): 150. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGangaiamaran R, Pasupathi M: Review on use of mobile apps for language learning. Int. J. Appl. Eng. Res. 2017; 12(21): 11242–11251.\n\nGbadamosi A: Anatomy of international students’ acculturation in British universities. Ind. High. Educ. 2018; 32(2): 129–138. Publisher Full Text\n\nGolonka EM, Bowles AR, Frank VM, et al.: Technologies for foreign language learning: A review of technology types and their effectiveness. Comput. Assist. Lang. Learn. 2014; 27(1): 70–105. Publisher Full Text\n\nHsu CK, Hwang GJ, Chan CK: An Automatic Caption Filtering and Partial Hiding Approach to Improving the English Listening Comprehension of EFL Students. Educ. Technol. Soc. 2014; 17(2): 270–283. Reference Source\n\nHwang GJ, Wang SY: Single loop or double loop learning: English vocabulary learning performance and behavior of students in situated computer games with different guiding strategies. Comput. Educ. 2016; 102: 188–201. Publisher Full Text\n\nIbrahim F: Cultural intelligence and its relationship to the quality of life among university students. Original Journal of Educational Faculty for Educational and Humanities Sciences. 2018; 39: 1569–1587.\n\nKacetl J, Klímová B: Use of smartphone applications in English language learning—A challenge for foreign language education. Educ. Sci. 2019; 9(3): 179. Publisher Full Text\n\nKlimova B: Impact of mobile learning on students’ achievement results. Educ. Sci. 2019; 9(2): 90. Publisher Full Text\n\nKlimova B: Mobile phones and/or smartphones and their apps for teaching English as a foreign language. Educ. Inf. Technol. 2018; 23: 1091–1099. Publisher Full Text\n\nKuimova M, Burleigh D, Uzunboylu H, et al.: Positive Effects of Mobile Learning on Foreign Language Learning. TEM Journal. 2018; 7(4): 837–841. Publisher Full Text\n\nKukulska-Hulme A: Personalization of language learning through mobile technologies.2016.\n\nLeis A, Tohei A, Cooke SD: SmartPhone-assisted Language Learning and Autonomy. Int. J. Comput.-Assist. Lang. Learn. Teach. 2015; 5(3): 75–88. Publisher Full Text\n\nLiu GZ, Hwang GJ, Kuo YL, et al.: Designing dynamic English: A creative reading system in a context-aware fitness center using a smart phone and QR codes. Digit. Creat. 2014; 25(2): 169–186. Publisher Full Text\n\nPalmer J: Intercultural Competence and Language Variety on Study Abroad Programs: L2 Learners of Arabic. Interdiscip. J. Stud. Abroad. 2013; 22: 58–83. Publisher Full Text\n\nParker WC: International Education in US Public Schools. The Political Economy of Global Citizenship Education. Routledge; 2016; pp. 176–190.\n\nRaed M: 10 Apps for learning Arabic, Jamalouki Platform.2021. Reference Source\n\nThomas DC: Domain, and development of cultural intelligence: The importance of mindfulness. Group Org. Manag. 2006; 31(1): 78–99. Publisher Full Text\n\nVan Dyne L, Ang S, Koh C: Development and validation of the CQS. Handbook of Cultural Intelligence: Theory, Measurement, and Application. New York: Taylor & Francis; 2008.\n\nVardakosta E, Priniotakis G, Papoutsidakis M, et al.: Design Thinking as a Co-Creation Methodology in Higher Education. A Perspective on the Development of Teamwork and Skill Cultivation. Eur. J. Educ. Res. 2023; 12(2): 1029–1044. Publisher Full Text"
}
|
[
{
"id": "284126",
"date": "19 Jun 2024",
"name": "Nadia Mustafa Alassaf",
"expertise": [
"Reviewer Expertise Specialized in teaching Arabic as a second language and published many scientific research and articles in peer-reviewed journals and journals within Scopus."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis research studied the learning apps used by non-native Arabic learners, especially after the Covid-19 pandemic. It studied the effect of using apps on acculturation and cultural intelligence which are important variables for them to learn Arabic and to get high scores in the subjects. These to variables are social variables that can help them to cope and interact with the native speakers in Jordan and prevent them from facing a lot of problems while living in the Arabian country. This research is designed in an appropriate manner and divided in a correct scientific manner. While reading the research, I found that the researcher was aware and knowledgeable about the subject of her study. The researcher was very precise in defining the questions of her study, as they were not random, and thus this was reflected in her results. The results of her study may be a starting point for other scientific research. It is worth noting that the researcher has addressed in her research a new aspect that has not been focused on much in scientific research that addressed the same topic. Previous research addressed the impact of applications on foreign students in terms of learning and acquiring the language, not in terms of culture, especially acquiring the culture of the society in which they live outside their home country and integrating into it. Based on the above, we strongly recommend indexing this research to benefit from it in the field of teaching Arabic as a second language. This research can be improved by doing these issues: 1) The reference “Aricat, R. G., Karnowski, V., & Chib, A. (2015)” was written according to APA7 style while other references were written according to Vancouver style. 2) On the levels results I prefer to write the total level and the dimensions level together not separated. 3) I read research about techno wellness and may be helpful for you to improve discussion, it’s means how to use technology to improve psychological wellness and include academic and social wellness.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "310058",
"date": "19 Aug 2024",
"name": "Rahmah Binti Ahmad H. Osman",
"expertise": [
"Reviewer Expertise Technologies and the teaching of Arabic Studies"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nCOMPREHENSIVE EVALUATION OF THE JOURNAL ARTICLE TITLED \"CULTURAL INTELLIGENCE AND ACCULTURATION AMONG NON-NATIVE ARABIC LEARNERS: THE IMPACT OF LEARNING APPS.\" Title and Abstract\nTitle: The title is concise and appropriately reflects the study's focus on cultural intelligence (CQ), acculturation (AC), and the impact of learning apps among non-native Arabic learners. Abstract: The abstract provides a clear summary of the study, including the background, objectives, methods, results, and conclusions. However, the abstract could benefit from a clearer statement regarding the limitations and implications of the study.\nIntroduction\nRelevance: The introduction effectively introduces the topic and highlights the significance of CQ and AC in language learning. It places the study within the context of existing literature and clearly identifies the research gap. Research Questions: The research questions are well-formulated, focusing on the relationship between CQ and AC, the impact of learning apps, and the role of gender. These questions are appropriate and relevant to the study's objectives.\nLiterature Review\nComprehensiveness: The literature review is comprehensive, covering various aspects of CQ, AC, and the role of learning apps in language acquisition. It effectively sets the stage for the research by discussing relevant theories and previous studies. Critical Analysis: While the literature review is thorough, it could benefit from more critical analysis of the studies cited. This would provide a deeper understanding of how the current study builds on or diverges from existing research.\nMethodology\nStudy Design: The study uses a correlational approach, which is appropriate for exploring the relationships between CQ, AC, and the use of learning apps. The study design is clearly explained, and the use of established scales for measuring CQ and AC adds to the study's credibility. Sampling: The sample size of 102 non-native Arabic learners is adequate for this type of study. The selection of participants from different universities in Jordan is justified, though more details on the sampling method would strengthen the study's validity. Data Collection and Analysis: The use of SPSS for data analysis is appropriate, and the statistical methods employed (e.g., Pearson's correlation, t-tests) are correctly applied. However, the article could provide more detail on the assumptions checked before performing these tests.\n\nResults\nPresentation: The results are clearly presented in tables, making it easy to understand the findings. The study effectively reports the levels of CQ and AC, the relationship between them, and the impact of learning apps. Interpretation: The interpretation of results is consistent with the data presented. However, the discussion could benefit from linking the results more explicitly to the research questions and hypotheses.\nDiscussion and Conclusion\nDiscussion: The discussion appropriately interprets the results in light of the existing literature. It highlights the significance of the findings and suggests practical implications for language learning and cultural adaptation. Limitations: The article acknowledges some limitations, such as the limited generalizability due to the specific sample. However, it would benefit from a more detailed discussion of other potential limitations, such as the use of self-reported data and the cross-sectional design. Conclusion: The conclusion succinctly summarizes the study's main findings and emphasizes the importance of learning apps in enhancing CQ and AC. It also suggests directions for future research, which adds value to the study.\nReferences\nConsistency: The reference list is generally well-prepared, but there is an inconsistency in citation styles (e.g., APA vs. Vancouver). This should be corrected for uniformity. Coverage: The references cited are relevant and current, covering a broad range of sources related to the study's topic. However, the inclusion of more recent studies on the impact of technology on language learning could strengthen the literature review.\nEthical Considerations\nEthical Approval: The study mentions that ethical approval was obtained from the University of Jordan Institutional Review Board, and informed consent was obtained from participants. This adherence to ethical standards is commendable.\nOverall Assessment\nStrengths: The article is well-structured and covers an important topic in language learning. The use of established scales and appropriate statistical methods adds to its credibility. Areas for Improvement: The article could benefit from more critical analysis in the literature review, a more detailed discussion of limitations, and consistency in referencing style. Additionally, the abstract could better highlight the study's limitations and implications.\n\nRecommendation\nIndexing: The article is of good quality and contributes valuable insights into the field of language learning. It is recommended for indexing after addressing the minor issues identified, particularly in the references and discussion sections.\nThis evaluation adheres to conventional standards and provides a balanced assessment of the article's strengths and areas for improvement.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "310065",
"date": "04 Sep 2024",
"name": "Wan Ab Aziz Wan Daud",
"expertise": [
"Reviewer Expertise Arabic language: Instructional technology education"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nHere are my comments as a reviewer on this article:\nThis is an interesting and timely study examining the relationships between cultural intelligence (CQ), acculturation (AC), and the use of language learning apps among non-native Arabic learners. The research addresses an important topic given the increasing use of technology in language learning.\nStrengths:\n- Clear research questions and appropriate methodology to address them - Use of validated scales to measure CQ and AC - Inclusion of both male and female participants - Consideration of the impact of learning apps, which is highly relevant - Statistical analyses appear appropriate for the research questions - Results are presented and discussed in relation to existing literature - Limitations and future directions are thoughtfully considered\nSuggestions for improvement:\n1. a more thorough literature review on CQ and AC in language learning contexts could benefit the introduction. This would help situate the current study more clearly.\n2. More details on participants' specific learning apps would be helpful. Were certain apps more commonly used? How frequently did participants use the apps on average?\n3. The discussion of gender differences (or lack thereof) could be expanded. Are there any theories or previous findings that would help explain the lack of gender differences observed?\n4. It may be worth considering potential mediating or moderating factors in the relationships between CQ, AC, and app use. For example, could factors like motivation or personality traits play a role?\n5. The practical implications of the findings could be elaborated on further. How specifically might language programs incorporate these findings to support learners?\n6. Some minor editing for grammar and clarity would improve readability in places.\nOverall, this is a solid study that meaningfully contributes to our understanding of cultural and technological factors in Arabic language learning. With some minor revisions, it would be suitable for getting indexed. The findings have clear relevance for language educators and program developers.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-499
|
https://f1000research.com/articles/13-231/v1
|
27 Mar 24
|
{
"type": "Research Article",
"title": "Factors associated with severe respiratory syncytial virus infection among hospitalized children in Thammasat University Hospital",
"authors": [
"Pornumpa Bunjoungmanee",
"Samita Sompoch",
"Auchara Tangsathapornpong",
"Prapasri Kulalert",
"Samita Sompoch",
"Auchara Tangsathapornpong",
"Prapasri Kulalert"
],
"abstract": "Background Respiratory syncytial virus (RSV) is one of the most significant respiratory pathogens that causes acute lower respiratory tract infections (LRTI) early in life. Most children have a history of RSV infection within 24 months of age, and recurrent infections are common throughout life.\n\nMethods Children under five years of age were identified through a review of medical records with a diagnosis of RSV-LRTI between 2016 and 2020. Severe RSV-LRTI was defined as a prolonged length of stay (> 7 days), admission to the intensive care unit, need for mechanical ventilation, non-invasive positive pressure ventilation, or in-hospital mortality. Factors associated with severe RSV-LRTIs were investigated using univariate and multivariate analyses.\n\nResults During the study period, 620 patients were diagnosed with RSV-LRTI and 240 (40.16%) patients had severe RSV-LRTI. In the multivariable logistic regression analysis, the factors for severe RSV-LRTI were being under 3 months (aOR 2.18 CI 1.39-3.43, p0.001), cardiovascular disease (aOR 3.55 CI 1.56-8.06, p0.002), gastrointestinal disease (aOR 5.91 CI 1.90-18.46, p0.002), genetic disease (aOR 7.33 CI 1.43-37.54, p0.017), and pulmonary disease (aOR 9.50, CI 4.56-19.80, p<0.001). Additionally, the presence of ≥ 2 co-morbidities (aOR 6.23 CI 2.81-14.81, p<0.016), experiencing illness for more than 5 days (aOR 3.33 CI 2.19-5.06, p<0.001), co-detection of influenza (aOR 8.62 CI 1.49-38.21, p0.015), and nosocomial RSV infection (aOR 9.13 CI 1.98-41.30, p0.012), markedly increased the risk of severe RSV-LTRI. The severe RSV-LRTI group demonstrated higher hospitalization expenses (median, US $720.77 vs $278.00, respectively; p<0.001), and three infants died in-hospital.\n\nConclusion Children at high risk for RSV-LRTI due to underlying genetic and gastrointestinal diseases are at an increased risk for severe RSV-LRTI. Further studies to determine the cost-effectiveness of RSV immunization in these potential co-morbidities should be initiated to prioritize RSV immunization, especially in resource-constrained regions with limited availability of nirsevimab.",
"keywords": [
"respiratory syncytial virus (RSV)",
"lower respiratory tract infection (LRTI)",
"severe RSV-LRTI"
],
"content": "Introduction\n\nRespiratory syncytial virus (RSV) is a viral pathogen with far-reaching consequences in children, and is associated with significant morbidity and mortality. Infants have an increased risk of developing severe RSV infection, often necessitating hospitalization. Hospitalized RSV-associated lower respiratory tract infections (RSV-LRTIs) occur globally. In Thailand, the highest peak incidence occurred during the rainy season from July to October. Those aged < 5 years experienced a higher mortality rate due to RSV-LRTI than older children, especially those aged < 1 year.1\n\nMany recent studies have demonstrated that young age, preterm birth, and pre-existing diseases are significant risk factors for RSV hospitalization. Interestingly, most children hospitalized for RSV are healthy.2–4 The RSV season occurs annually in Thailand.1 However, there are limited available data regarding hospitalization, utilization of medical resources, and risk factors for severe RSV-LRTIs. This retrospective study aimed to identify the clinical features and manifestations in hospitalized children with RSV-LRTI, along with the risk factors for severe RSV-LRTI and death. Demographic characteristics and disease severity were considered potential factors influencing the cost of medical treatment and utilization of medical resources.\n\n\nMethods\n\nThe Human Research Ethics Committee of Thammasat University (Medicine) is in full compliance with international guidelines such as Declaration of Helsinki, The Belmont Report, CIOMS Guidelines and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP), approved our study. The approval number is MTU-EC-PE-0-114/64 and the date of approval is May 20, 2021. Data collection was initiated after requisite approvals were obtained from the Human Research Ethics Committee of Thammasat University (Medicine).\n\nThis study received a waiver of informed consent due to its retrospective nature and the absence of direct contact with the study subjects. This study did not involve any intervention or therapy, thereby posing no risks to the subjects. Confidentiality of the present study data was maintained in accordance with the Declaration of Helsinki.\n\nThis retrospective cross-sectional study was initiated at the Thammasat University Hospital (TUH) in Pathum Thani, Thailand, a tertiary care facility with 100 pediatric beds. This study was based on a systematic computer-assisted database search that allowed extraction of retrospective data of the patients aged < 5 years who were discharged with a diagnosis of RSV-LRTI, including clinical bronchitis, bronchiolitis, and pneumonia. Confirmation of the diagnosis was established either by an RSV antigen immunochromatography assay or a polymerase chain reaction (PCR) test for RSV from specimens taken from nasal or nasopharyngeal swabs.\n\nThe severe RSV-LRTI group included children who experienced an unsatisfactory outcome or died. An unsatisfactory outcome was defined as the necessity for non-invasive positive pressure ventilation (NIPPV), or mechanical ventilation, or prolonged hospital stay (over 7 days), in-hospital mortality, or admission to pediatric intensive care unit (PICU). The non-severe group included children with RSV-LRTI who did not experience an unsatisfactory outcome or death.\n\nThe study population was identified by reviewing inpatient medical records, including patients age 0-5 years old from 2016 to 2020. Factors associated with severe hospitalized RSV-LRTI included baseline characteristics, clinical manifestations, and initial laboratory findings. The baseline characteristics included demographic data and co-morbidities. Clinical manifestations included presenting symptoms, physical examination, and initial laboratory results consisting of electrolytes and complete blood counts. Hospital resource utilization, hospital cost data, and outcomes after hospital stay were collected for both groups. Data on the mode of oxygen supplementation, inotropic drug use, bronchodilator nebulizer, use of montelukast, antibiotic therapy, and blood transfusion were collected to assess hospital resource utilization. The cost data were sourced from the hospital’s cost-accounting database. An exchange rate of 35 baht per 1 US dollar was used to convert all expenditures in Thai baht into US dollars. The outcome after the hospital stay was recovery or in-hospital death. The term “nosocomial RSV-LTRI” was defined as signs or symptoms of RSV-LRTI occurring more than 72 h after admission.\n\nThe definitions of the variables included cyanotic heart disease or congenital hemodynamic significance, and heart disease was regarded as congenital heart disease (CHD). Cerebral palsy and other central nervous system abnormalities were defined as neurological diseases. Children born before 37 weeks of age were classified as preterm infants. Bronchopulmonary dysplasia (BPD) or asthma is a pulmonary disease. Necrotizing enterocolitis (NEC) with short bowel syndrome, intestinal malformation, esophageal atresia, or biliary atresia was defined as gastrointestinal disease. Hematological diseases included thalassemia and red cell membrane defects. Genetic diseases include Down syndrome, DiGeorge syndrome, Williams syndrome, and Rubinstein-Taybi syndrome.\n\nThis retrospective study aimed to identify the factors associated with severe RSV-LRTI, including perinatal history, co-morbidities, clinical manifestations, and laboratory results. In addition, the assessment of hospital resource utilization for RSV-LRTI included the mode of oxygen supplementation, inotropic drug use, bronchodilator nebulizer, use of montelukast, antibiotic therapy, and blood transfusion.\n\nCategorical data were expressed as frequencies and percentages. Continuous data are expressed as medians with interquartile ranges (IQRs). Fisher’s exact test was used to compare categorical data. The Wilcoxon rank-sum test was used to compare continuous data. Univariate and multivariate analyses were conducted to ascertain the independent factors associated with severe RSV-LRTI (p<0.05).\n\nFrequencies and percentages were used for categorical data. The median and interquartile range (IQRs) were used for continuous data. Fisher’s exact test and Wilcoxon rank-sum test were used to compare the categorical and continuous data, respectively. Univariate and multivariate analyses were conducted to ascertain the independent factors associated with severe RSV-LRTI (p<0.05).\n\n\nResults\n\nOverall, 1,050 children were admitted for a positive RSV test result. In this study, 620 children diagnosed with RSV-LRTI were included; 10 cases were excluded because of missing values. Baseline characteristics of the patients are shown in Table 1. Of the 620 patients, 249 had severe RSV-LTRI. The mean age of all patients was 16.60 ± 14.56 months old and males accounted for 53.55 percent of all patients. One-third of patients had at least one comorbidity. Eighteen patients (2.74%) had nosocomial RSV infection, and 11 patients (1.61%) had co-infection with influenza, which occurred specifically in the severe group. The peak of the RSV-LRTI was noted from July to October annually, as demonstrated by the seasonal variation in RSV (Figure 1). Most patients were admitted to the general pediatric ward (96.77%), with an average length of stay of 5.87 ± 2.43 days. A total of 3.23% of patients required PICU admission (Table 2).\n\nThe medical data of patients with severe and non-severe RSV-LRTIs at admission were compared (Table 2). Most of the patients had cough, rhinitis, shortness of breath, and feeding difficulties (99.52%, 95.81%, 76.45% and 49.84%, respectively). However, the symptoms were not different in both groups, except apnea (p<0.01), tachypnea (p<0.001), and cyanosis (p0.04). At initial presentation, 130 patients (20.97%) had fever > 38.5 °C and 210 patients (33.87%) had desaturation, especially in the severe RSV-LTRI group. At first presentation, wheezing was documented in 201 patients (32.42%), comprising 107 patients with severe RSV-LRTI and 94 with non-severe RSV-LRTI (Table 2). There were no differences in the complete blood count or serum electrolyte levels between the groups.\n\nHealthcare utilization for RSV disease included hospital and PICU admissions, as well as treatments such as oxygen therapy, mechanical ventilation, inhaled medications, and antibiotics for managing RSV infection. The severe RSV-LTRI group showed significantly increased healthcare utilization and costs, especially in PICU admissions, and increased length of stay.\n\nOxygen therapy was prescribed to 504 (81.29%) patients. One-third of patients needed supplementary high-flow or positive-pressure oxygen administration, which included heated humidified high-flow nasal cannula (HHHFNC) (25.64%), nasal continuous positive airway pressure therapy (NCPAP) (5.49%), and invasive mechanical ventilation (IMV) (4.03%), exclusively observed in the severe RSV-LRTI group. The duration of oxygen therapy tended to be more prolonged in severe RSV-LTRI group compared to non-severe RSV-LRTI group (7.71 + 6.96 days vs. 2.35 + 0.96 days, p< 0.001) (Table 3).\n\nIn cases of severe RSV-LRTI, the prescription rates and the duration usage for salbutamol, adrenaline, and hypertonic saline nebulization were notably higher compared to the non-severe RSV-LRTI (83.53% vs. 59.84% and 3.68 ± 3.52 days vs. 1.78 ± 1.07; p< 0.001, 67.87% vs 38.27% and 4.04 ± 2.24 days vs. 2.17 ± 1.12 days; p< 0.001, 55.02% vs. 21.56% and 5.01 ± 3.49 days vs. 2.29 ± 0.93; p<0.001, respectively). A total of 173 patients (27.90%) received treatment with antibiotics; ceftriaxone/cefotaxime was the most common antibiotic used in both groups (34.94% in severe RSV-LRTI and 4.31% in non-severe RSV-LRTI) (Table 3). The severe RSV-LRTI group had prolonged length of hospital stay (PLOS) (mean, 11.28 ± 14.10 days vs. 3.48 ± 1.20 days, p<0.001), higher mortality (1.20% vs. 0%; p0.064), and excess total hospital costs (median, US $720.77 vs $278, p0.001). There were 29 cases in the severe RSV-LRTI group were transmitted from the general pediatric ward to the PICU (Table 3).\n\nThree infants died in the hospital, with a mortality rate of 0.48%. All mortality cases had co-morbidities. A cardiac anatomical defect was observed in two cases (one case had Tetralogy of Fallot, and the other case had atrial septal defect with ventricular septal defect). Furthermore, Down syndrome with gastroesophageal reflux disease and subglottic stenosis was observed in one patient. All three cases were complicated by nosocomial bacterial infections, namely Klebsiella pneumonia and Acinetobacter baumanii, which led to a lethal outcome.\n\nIn univariate analysis, the risk factors associated with severe RSV-LRTI were being under 3 months (aOR 1.62, CI 1.09-2.40, p0.017), hematologic disease (aOR 3.08 CI 1.14-8.32, p0.026), preterm birth (aOR 3.51 CI 1.89-6.51, p<0.001), cardiovascular disease (aOR 3.64 CI 1.81-7.33, p<0.001), pulmonary disease (aOR 8.43 CI 4.30-16.54, p<0.001), genetic disease (aOR 8.53 CI 1.87-38.81, p0.006), and gastrointestinal disease (aOR 12.57 CI 4.37-36.15, p<0.001). Neurological diseases and immunocompromised status did not differ between the groups. Furthermore, the presence of ≥ 2 co-morbidities significantly increased the risk of severe RSV-LTRI (aOR 7.53 CI 3.70-15.32, p<0.001). The duration of illness was associated with a severe RSV-LRTI. Experiencing illness for more than three days (aOR 2.83 CI 1.75-4.56, p<0.001), particularly exceeding five days (aOR 3.78 CI 2.62-5.46, p<0.001), was associated with severe RSV-LRTI. Moreover, co-detection of influenza (aOR 9.78 CI 1.96-40.12, p0.005) and nosocomial RSV infection (aOR 10.65 CI 2.14-43.42, p0.004), increased the risk of severe RSV-LRTI.\n\nMultivariate analysis showed that <3 months (aOR 2.18 CI 1.39-3.43, p0.001), cardiovascular disease (aOR 3.55 CI 1.56-8.06, p0.002), gastrointestinal disease (aOR 5.91 CI 1.90-18.46, p0.002), genetic disease (aOR 7.33 CI 1.43-37.54, p0.017), and pulmonary disease (aOR 9.50 CI 4.56-19.80, p<0.001) were predictive factors for severe RSV-LRTI. Moreover, the presence of ≥ 2 co-morbidities markedly increased the risk of severe RSV-LTRI (aOR 6.23 CI 2.81-14.81, p<0.016). Regardless of co-morbidities, experiencing illness for more than 5 days (aOR 3.33 CI 2.19-5.06, p<0.001), co-detection of influenza (aOR 8.62, CI 1.49-38.21, p0.015), and nosocomial RSV infection (aOR 9.13 CI 1.98-41.30, p0.012) were associated with a higher risk of severe RSV LRTI (Table 4).\n\n\nDiscussion\n\nEvaluating the data collected over five consecutive years, we found that 40 percent of the children demonstrated severe symptoms. Notably, the predominant proportion of severe RSV-LRTI cases was observed in infants, particularly in those aged < 3 months. Gastrointestinal diseases, such as NEC with short bowel syndrome, intestinal malformation, or esophageal atresia, were additional significant risk factors for severe RSV-LRTI. Gut microbiome dysbiosis in gastrointestinal anomalies may play a key role in RSV infections. The role of the gut microbiota in regulating the immune system and respiratory infections is increasingly recognized.5 A relationship between gut microbiome dysbiosis and RSV infection was demonstrated in a previous study. Disruptions in microbial abundance and characteristic microbiome shifts are associated with RSV severity.6\n\nDown syndrome, with or without congenital heart defects, has a higher risk of mortality, prolonged length of hospital stay, and more frequent transfer to the PICU.7,8 Our study observed a correlation between genetic disease and RSV-LRTI with 80% (9/11) of genetic diseases in the severe RSV-LRTI group with Down syndrome, which demonstrated a 7-fold higher risk for severe RSV-LRTI. Therefore, gastrointestinal anomalies, short bowel syndrome, and Down syndrome should be considered as candidates for RSV immunization.\n\nOther factors related to severe RSV-LRTI were co-morbidities of cardiovascular disease, pulmonary disease, and co-detection of influenza, which is comparable to the findings of previous studies.4,7,9–12 Many studies have indicated that prematurity is a risk factor for severe RSV-LRTI; however, this was not statistically significant in this study. Moreover, the cumulative number of co-morbidities is a potential factor associated with a severe course of hospitalization.7 Children with two or more co-morbidities were at a significantly higher risk of severe RSV-LRTI. Nevertheless, one-fourth of patients with co-morbidities were ineligible for RSV immunization. Further studies are required to determine the cost-effectiveness of immune prophylaxis against RSV for other potential co-morbidities.\n\nNosocomial RSV infection is identified as one of the factors associated with mortality and PICU admission.13,14 Previous reports have suggested that nosocomial RSV infection is an independent predictor of prolonged hospitalization, higher mortality, and excess hospital charges.15 Our results showed that nosocomial RSV infection was significantly associated with severe RSV-LRTIs. Nonetheless, the small number of nosocomial RSV cases limited our ability to detect a correlation between nosocomial RSV infection and mortality.\n\nThe duration of illness prior to admission for more than three days, especially exceeding five days, was considered a risk factor for severe RSV-LRTI, as in a previous study.16 This could be explained by the prolonged duration of illness, which may be associated with complications, notably, atelectasis. Following RSV infection, there is an increase in the quantity and viscosity of the mucous secretions. The loss of ciliated epithelial cells creates widespread mucous plugging across various areas.17 Furthermore, secondary bacterial infections may play a key role in the severity of symptoms, particularly in infants. RSV infection diminishes bacterial clearance, leading to secondary bacterial pneumonia by altering the recruited neutrophils.18,19 Nevertheless, our study did not demonstrate a statistically significant association between secondary bacterial infection and severe RSV-LRTI. This was due to the fact that requests for sputum culture and blood culture in RSV-LRTI are optional and depend on the judgment of the attending physician.\n\nThe RSV seasons vary globally and are influenced by climate and geographic location. Several studies have demonstrated a relationship between RSV activity and weather conditions.20,21 Our 2016-2020 study established a correlation between the rainy season (July–October) and RSV-LRTI admission. This seasonal pattern was similar to that reported in previous studies in Thailand and other Southeast Asian countries.1,9,22–24 However, RSV-LRTI admissions in 2020 predominantly occurred between September and December because of the delayed onset of the rainy season. Furthermore, communities and academic institutions reopened after the relaxation of COVID-19 lockdown measures starting in August 2020, resulting in an upsurge in RSV-LRTI admissions, notably from September.\n\nManagement of children hospitalized with RSV infection involves supportive care and should include hydration and if necessary supplemental oxygen, if necessary. In our study, bronchodilators, epinephrine, montelukast, and corticosteroids were used in the treatment of severe RSV LRTI with statistical significance. However, there is no clinical data to recommend these medications for the treatment of RSV-LRTIs.25 Likewise, in previous studies,9,26 27.9% of our patients were prescribed antibiotics, demonstrating a notably higher frequency of severe RSV-LRTIs (59.04% vs. 7.01%). Although antibiotics were prescribed to treat a possible bacterial superinfection in severe RSV-LRTI,19 the misuse and overuse of antibiotics for RSV infection was established in a previous study.27 Overprescription of antibiotics is the main cause of adverse consequences, not only adverse reactions from the antibiotics but also unnecessary economic burden, financial stress,28 or antibiotic resistance.29 This result emphasizes the necessity of implementing appropriate antibiotic stewardship programs that have demonstrated effectiveness in reducing antibiotic misuse in RSV-infected children.30,31\n\nTherefore, prevention of RSV infection is necessary. Nirsevimab is a new monoclonal antibody that adheres to the perfusion protein on the surface of RSV and has a longer half-life than that of palivizumab. Since October 2023, the United States Centers for Disease Control and Prevention (U.S. CDC) has recommended RSV immunoprophylaxis with nirsevimab for all infants younger than 8 months who are born during the 2023-2024 RSV season and should be used in place of palivizumab. However, both nirsevimab and palivizumab are not available in Thailand. Currently, there is no approved vaccine for RSV infection in children. Many RSV vaccines targeting infants and young children are undergoing development and employ diverse technologies such as protein subunits, live-attenuated viruses, messenger RNA, or viral vector techniques to stimulate immune responses.32,33\n\nMaternal immunization is another strategy for preventing RSV infections in infants. Since August 2023, the U.S. Centers for Disease Control and Prevention (CDC) has recommended a single intramuscular injection of inactivated non-adjuvanted recombinant RSV vaccine during weeks 32 through 36 of pregnancy. The goal of vaccination is to provide passive protection against RSV in infants during the first few months of life. However, RSV vaccines for pregnancy are not available in Thailand.\n\nThis study had some limitations. Despite the relatively high number of patients, the study had a retrospective design and was conducted at a single medical center, which might potentially limit the generalizability of the results. Additionally, the analysis of co-infection was limited because an RT-PCR assay for respiratory viral panels was not feasible in all cases. Evidence of secondary bacterial infection was unavailable in most patients due to the lack of sputum and blood cultures performed in most patients. Furthermore, the study was conducted in a tertiary academic medical center, which may have a population selection bias, including children with chronic conditions.\n\n\nConclusion\n\nRSV infection is a major cause of respiratory hospitalization in children. Mortality and morbidity occur frequently in younger infants. Co-morbidities, including gastrointestinal anomaly, short bowel syndrome, Down syndrome, and cardiopulmonary function, are significantly higher risk factors for severe RSV-LRTI. Moreover, the disease severity of RSV-LRTI is correlated with being under 3 months of age, co-infection with influenza, nosocomial RSV infection, and prolonged duration of illness. The primary treatment for RSV infection is supportive care. There are no specific antiviral therapies or vaccines for RSV in children. Effective preventive measures with RSV immune prophylaxis should be prioritized in public health policies and primarily target all infants and children with risk factors to provide coverage throughout the RSV season.",
"appendix": "Data availability\n\nFactor associated with severe respiratory syncytial virus infection among hospitalized children in Thammasat University Hospital.\n\nThe anonymized data sets of this project are available in the Zenodo: https://doi.org/10.5281/zenodo.10408423. 34\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nWe would like to acknowledge The Research Group of Pediatrics, the Faculty of Medicine, Thammasat University, for advising us on the study conductance. We are also grateful to Ms. Sam Ormond for her comprehensive English language review and editing of the manuscript.\n\n\nReferences\n\nSitthikarnkha P, Uppala R, Niamsanit S, et al.: Burden of Respiratory Syncytial Virus Related Acute Lower Respiratory Tract Infection in Hospitalized Thai Children: A 6-Year National Data Analysis. Children (Basel). 2022; 9(12). Publisher Full Text\n\nRha B, Curns AT, Lively JY, et al.: Respiratory Syncytial Virus-Associated Hospitalizations Among Young Children: 2015-2016. Pediatrics. 2020; 146(1). PubMed Abstract | Publisher Full Text\n\nHalasa N, Williams J, Faouri S, et al.: Natural history and epidemiology of respiratory syncytial virus infection in the Middle East: Hospital surveillance for children under age two in Jordan. Vaccine. 2015; 33(47): 6479–6487. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHavdal LB, Bøås H, Bekkevold T, et al.: Risk factors associated with severe disease in respiratory syncytial virus infected children under 5 years of age. Front. Pediatrics. 2022; 10: 10. Publisher Full Text\n\nYagi K, Asai N, Huffnagle GB, et al.: Early-Life Lung and Gut Microbiota Development and Respiratory Syncytial Virus Infection. Front. Immunol. 2022; 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarding JN, Siefker D, Vu L, et al.: Altered gut microbiota in infants is associated with respiratory syncytial virus disease severity. BMC Microbiol. 2020; 20(1): 140. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShmueli E, Goldberg O, Mei-Zahav M, et al.: Risk factors for respiratory syncytial virus bronchiolitis hospitalizations in children with chronic diseases. Pediatr. Pulmonol. 2021; 56(7): 2204–2211. PubMed Abstract | Publisher Full Text\n\nLöwensteyn YN, Phijffer EWEM, Simons JVL, et al.: Respiratory Syncytial Virus-related Death in Children With Down Syndrome: The RSV GOLD Study. Pediatr. Infect. Dis. J. 2020; 39(8): 665–670. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAikphaibul P, Theerawit T, Sophonphan J, et al.: Risk factors of severe nso respiratory syncytial virus infection in tertiary care center in Thailand. Influenza Other Respir. Viruses. 2021; 15(1): 64–71. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee YI, Peng CC, Chiu NC, et al.: Risk factors associated with death in patients with severe respiratory syncytial virus infection. J. Microbiol. Immunol. Infect. 2016; 49(5): 737–742. PubMed Abstract | Publisher Full Text\n\nProesmans M, Rector A, Keyaerts E, et al.: Risk factors for disease severity and increased medical resource utilization in respiratory syncytial virus (+) hospitalized children: A descriptive study conducted in four Belgian hospitals. PLoS One. 2022; 17(6): e0268532. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSommer C, Resch B, Simões EA: Risk factors for severe respiratory syncytial virus lower respiratory tract infection. Open Microbiol. J. 2011; 5: 144–154. PubMed Abstract | Publisher Full Text | Free Full Text\n\nComas-García A, Aguilera-Martínez JI, Escalante-Padrón FJ, et al.: Clinical impact and direct costs of nosocomial respiratory syncytial virus infections in the neonatal intensive care unit. Am. J. Infect. Control. 2020; 48(9): 982–986. PubMed Abstract | Publisher Full Text\n\nMosalli R, Alqarni SA, Khayyat WW, et al.: Respiratory syncytial virus nosocomial outbreak in neonatal intensive care: A review of the incidence, management, and outcomes. Am. J. Infect. Control. 2022; 50(7): 801–808. PubMed Abstract | Publisher Full Text\n\nLöwensteyn YN, Willemsen JE, Mazur NI, et al.: Nosocomial RSV-related In-hospital Mortality in Children <5 Years: A Global Case Series. Pediatr. Infect. Dis. J. 2023; 42(1): 1–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTungsupreechameth A, Srisingh K: Factors Associated with Severe Lower Respiratory Tract Infection from Respiratory Syncytial Virus (RSV) in Thai Children. Siriraj Med. J. 2021; 73(12): 808–814. Publisher Full Text\n\nPiedimonte G, Perez MK: Respiratory syncytial virus infection and bronchiolitis. Pediatr. Rev. 2014; 35(12): 519–530. Publisher Full Text\n\nStark JM, Stark MA, Colasurdo GN, et al.: Decreased bacterial clearance from the lungs of mice following primary respiratory syncytial virus infection. J. Med. Virol. 2006; 78(6): 829–838. PubMed Abstract | Publisher Full Text\n\nThorburn K, Harigopal S, Reddy V, et al.: High incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (RSV) bronchiolitis. Thorax. 2006; 61(7): 611–615. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStaadegaard L, Caini S, Wangchuk S, et al.: Defining the seasonality of respiratory syncytial virus around the world: National and subnational surveillance data from 12 countries. Influenza Other Respir. Viruses. 2021; 15(6): 732–741. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlthouse BM, Flasche S, Minh LN, et al.: Seasonality of respiratory viruses causing hospitalizations for acute respiratory infections in children in Nha Trang, Vietnam. Int. J. Infect. Dis. 2018; 75: 18–25. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKamigaki T, Chaw L, Tan AG, et al.: Seasonality of Influenza and Respiratory Syncytial Viruses and the Effect of Climate Factors in Subtropical-Tropical Asia Using Influenza-Like Illness Surveillance Data, 2010-2012. PLoS One. 2016; 11(12): e0167712. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPaynter S, Yakob L, Simões EA, et al.: Using mathematical transmission modelling to investigate drivers of respiratory syncytial virus seasonality in children in the Philippines. PLoS One. 2014; 9(2): e90094. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChan PW, Chew FT, Tan TN, et al.: Seasonal variation in respiratory syncytial virus chest infection in the tropics. Pediatr. Pulmonol. 2002; 34(1): 47–51. PubMed Abstract | Publisher Full Text\n\nRalston SL, Lieberthal AS, Meissner HC, et al.: Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014; 134(5): e1474–e1502. PubMed Abstract | Publisher Full Text\n\nSchreiner D, Groendahl B, Puppe W, et al.: High antibiotic prescription rates in hospitalized children with human metapneumovirus infection in comparison to RSV infection emphasize the value of point-of-care diagnostics. Infection. 2019; 47(2): 201–207. PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan Houten CB , Naaktgeboren C, Buiteman BJM, et al.: Antibiotic Overuse in Children with Respiratory Syncytial Virus Lower Respiratory Tract Infection. Pediatr. Infect. Dis. J. 2018; 37(11): 1077–1081. PubMed Abstract | Publisher Full Text\n\nSamson L, Cooke C, Macdonald N: Analysis of antibiotic use and misuse in children hospitalized with RSV infection. Paediatr. Child Health. 1999; 4(3): 195–199. PubMed Abstract\n\nRomandini A, Pani A, Schenardi PA, et al.: Antibiotic Resistance in Pediatric Infections: Global Emerging Threats, Predicting the Near Future. Antibiotics (Basel). 2021; 10(4). Publisher Full Text\n\nAljassim NA, Noël KC, Maratta C, et al.: Antimicrobial Stewardship in Bronchiolitis: A Retrospective Cohort Study of Three PICUs in Canada. Pediatr. Crit. Care Med. 2022; 23(3): 160–170. PubMed Abstract | Publisher Full Text\n\nKalil J, Bowes J, Reddy D, et al.: Pediatric Inpatient Antimicrobial Stewardship Program Safely Reduces Antibiotic Use in Patients with Bronchiolitis Caused by Respiratory Syncytial Virus: A Retrospective Chart Review. Pediatr Qual Saf. 2019; 4(5): e211. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrowne SK, Beeler JA, Roberts JN: Summary of the Vaccines and Related Biological Products Advisory Committee meeting held to consider evaluation of vaccine candidates for the prevention of respiratory syncytial virus disease in RSV-naïve infants. Vaccine. 2020; 38(2): 101–106. PubMed Abstract | Publisher Full Text\n\nVekemans J, Moorthy V, Giersing B, et al.: Respiratory syncytial virus vaccine research and development: World Health Organization technological roadmap and preferred product characteristics. Vaccine. 2019; 37(50): 7394–7395. PubMed Abstract | Publisher Full Text\n\nFactor associated with severe respiratory syncytial virus infection among hospitalized children in Thammasat University Hospital.[cited 2024 Feb 25}. Publisher Full Text"
}
|
[
{
"id": "260846",
"date": "12 Apr 2024",
"name": "Visal Moolasart",
"expertise": [
"Reviewer Expertise infectious disease"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript delivers a compelling message and provides valuable insights into RSV infection among hospitalized children. However, there are several issues that merit further consideration.\nSince this study site is a tertiary care and university hospital, it's probable that most participating children are from high-risk groups with underlying conditions. Hence, it's imperative to approach the assessment of risk factors and establishment of connections with caution. There is a wealth of intriguing information within this study, prompting consideration of its key message.\n\nRSV infection severity varies across age categories, spanning from 0-3 months, 12-24 months, to over 24 months. It is imperative for the author to focus on analyzing, discussing, and comparing these age-specific trends with previous study findings. Hence, exploring the stratification of RSV infection by age is an intriguing issue. Distinguishing symptoms exist between the severe RSV-LRTI group and the non-severe RSV-LRTI group. It is imperative for the author to discuss these differences in symptoms as they relate to predicting the severity of the condition. The impact of tertiary care on risk factors and severity underscores the significance of discussing the associated therapy costs in this study. It is essential to include additional information to enrich this discussion. The definition of the severe RSV-LRTI group serves as a foundational principle in this study. For additional clarity and credibility, it is essential to include detailed information regarding this definition along with a proper reference.\n\nThe type of diagnosis is an intriguing topic for discussion, particularly regarding conditions such as pneumonia, bronchiolitis, and bronchitis.\n3. Please, recheck information and add information at -page 5 line 18-24 (below Fig1) and page 8 line 8-15 this content is not match the table. Please ensure that the data is sorted according to the table provided by the author. - In the table, it would be beneficial for the author to add specific symbols (such as *) to indicate significant data, along with footnotes providing explanations below the table. And add “statistically significant”. - in table 1, revise Sever RSV-LRTI - p8 line 5, revise “+”\n4. In univariable and multivariable analysis in table 4, There are many characteristics that significant, this reason is hospital type of study site. Preterm and hematologic disease are not significant, this is interesting issue for discussion. Please condense the discussion from page 8, line 20 to page 9, line 5 for a succinct summary.\n5. Summary: Page 10 line 7-19, Please request the author to provide a brief summary or modify the information to summarize the results of this study. Exclude any unrelated issues from the discussion.\n6. While acknowledging the limitations, this study provides valuable information. The author should consider adding details about how population selection could impact both positive and negative results, as well as strengthening the overall robustness of the study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11515",
"date": "20 Jun 2024",
"name": "Pornumpa Bunjoungmanee",
"role": "Author Response",
"response": "We are grateful to you for your time, effort, and constructive criticism. We have pasted your comments below, in bold, with responses in turn. Since this study site is a tertiary care and university hospital, it's probable that most participating children are from high-risk groups with underlying conditions. Hence, it's imperative to approach the assessment of risk factors and establishment of connections with caution. Response: We agree that the conduct of the study in a tertiary care academic medical center may have some bias in the cohort toward children with underlying conditions. This information has been added to the eighth paragraph of the discussion section and to the limitations of the study. 2. There is a wealth of intriguing information within this study, prompting consideration of its key message. 2.1 RSV infection severity varies across age categories, spanning from 0-3 months, 12-24 months, to over 24 months. It is imperative for the author to focus on analyzing, discussing, and comparing these age-specific trends with previous study findings. Hence, exploring the stratification of RSV infection by age is an intriguing issue. Response: We have added a discussion on the relationship between age range and disease severity. Additionally, the age-specific trend was compared with that of a previous study, which is mentioned in the fourth paragraph of the discussion section. 2.2 Distinguishing symptoms exist between the severe RSV-LRTI group and the non-severe RSV-LRTI group. It is imperative for the author to discuss these differences in symptoms as they relate to predicting the severity of the condition. Response: We have added a new paragraph to the discussion regarding the differences in symptoms between both groups, which are relevant to predicting the severity of the condition. This addition is made in the sixth and seventh paragraphs of the discussion. 2.3 The impact of tertiary care on risk factors and severity underscores the significance of discussing the associated therapy costs in this study. It is essential to include additional information to enrich this discussion. Response: We have added a new paragraph to the discussion which mentions the impact of tertiary care on risk factors and severity, which are associated with therapy costs. This information has been added to the eighth paragraph of the discussion 2.4 The definition of the severe RSV-LRTI group serves as a foundational principle in this study. For additional clarity and credibility, it is essential to include detailed information regarding this definition along with a proper reference. Response: The definition of severe RSV-LRTI adopted in this study diverges from the criteria outlined by the World Health Organization (WHO) and other related investigations. While the WHO guidelines predominantly hinge upon clinical symptoms and specific physiological parameters, such as SpO2 levels and chest wall indrawing, our study delineates severity based on factors associated with adverse outcomes or mortality, which impact hospital resource utilization and costs. Our definition of severity, although divergent from WHO criteria, aligns with similar approaches seen in studies by Aikphaibul P, et al., Shi Tet al., and Havdal LB et al. This consistency highlights the reliability and applicability of our research within the broader academic conversation, providing a shared basis for assessing severe RSV-LRTI across various clinical and geographical settings. Reference Aikphaibul P, Theerawit T, Sophonphan J, et al.: Risk factors of severe nso respiratory syncytial virus infection in tertiary care center in Thailand. Influenza Other Respir. Viruses. 2021;15(1):64–71. 32783380 10.1111/irv.12793 PMC7767956 Shi T, McAllister DA, O'Brien KL, et al.: Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. 2017;390(10098):946-958. Shi T, Vennard S, Mahdy S, et al. Risk Factors for Poor Outcome or Death in Young Children With Respiratory Syncytial Virus-Associated Acute Lower Respiratory Tract Infection: A Systematic Review and Meta-Analysis. J Infect Dis. 2022;226(Suppl 1):S10-S16. Havdal LB, Bøås H, Bekkevold T, et al. Risk factors associated with severe disease in respiratory syncytial virus infected children under 5 years of age. Front Pediatr. 2022;10:1004739. doi: 10.3389/fped.2022.1004739. eCollection 2022. 2.5 The type of diagnosis is an intriguing topic for discussion, particularly regarding conditions such as pneumonia, bronchiolitis, and bronchitis. Response: The diagnosis of RSV-LRTI was based on medical records approved by the attending physician and ICD-10 coding from hospital discharge summaries, as outlined in the study methodology. 3. Please, recheck information and add information at 3.1 page 5 line 18-24 (below Fig1) and page 8 line 8-15 this content is not match the table. Please ensure that the data is sorted according to the table provided by the author. Response: The information has been reviewed and corrected for accuracy. 3.2 In the table, it would be beneficial for the author to add specific symbols (such as *) to indicate significant data, along with footnotes providing explanations below the table. And add “statistically significant”. Response: The symbols have been incorporated into the table with corresponding explanations provided below, indicating statistical significance. 3.3 in table 1, revise Sever RSV-LRTI Response: The correction has been made to replace \"Sever\" with \"Severe\" in Table 1. 3.4 p8 line 5, revise “+” Response: The correction has been made to replace \"+\" with “+” 4. In univariable and multivariable analysis in table 4, There are many characteristics that significant, this reason is hospital type of study site. Preterm and hematologic disease are not significant, this is interesting issue for discussion. Please condense the discussion from page 8, line 20 to page 9, line 5 for a succinct summary. Response: We have expanded the discussion to include the results of preterm birth and hematologic disease in both univariable and multivariable analyses. Comments on other factors mentioned in Table 4 have been incorporated into the eighth paragraph of the discussion. The information from line 20 on page 8 to line 5 on page 10 pertains to the results section, not the discussion. Therefore, this information is retained in the manuscript. 5. Summary: Page 10 line 7-19, Please request the author to provide a brief summary or modify the information to summarize the results of this study. Exclude any unrelated issues from the discussion. Response: We concur that this section is lengthy, and we have condensed this information in the discussion section. 6. While acknowledging the limitations, this study provides valuable information. The author should consider adding details about how population selection could impact both positive and negative results, as well as strengthening the overall robustness of the study. Response: We have added the strengths of this study and both the positive and negative impacts of the study population on the strengths and limitations part."
}
]
}
] | 1
|
https://f1000research.com/articles/13-231
|
https://f1000research.com/articles/12-1404/v1
|
25 Oct 23
|
{
"type": "Research Article",
"title": "Knowledge, Attitude and Practice regarding the effect of yoga on periodontal health among Indian adults: A questionnaire study.",
"authors": [
"Madhurya N. Kedlaya",
"Lakshmi Puzhankara",
"Mansi Mahendra",
"Vineetha K.",
"Suraj Prasad Sinha",
"Anupam Singh",
"Shaswata Karmakar",
"Madhurya N. Kedlaya",
"Mansi Mahendra",
"Vineetha K.",
"Suraj Prasad Sinha",
"Anupam Singh",
"Shaswata Karmakar"
],
"abstract": "Background: Periodontal disease is a chronic inflammatory disease of structures surrounding the teeth. Its etiology is multifactorial. The primary etiological factor is the microbial component; the other factors are systemic, behavioral, environmental, and psychological. Conventional management includes routine periodontal therapy involving prophylactic and surgical management. In developing countries like India, complementary medicine and alternative medicines like yoga are gaining popularity for improving systemic health. Hence this pilot study was designed to assess the psychometric properties of a structured questionnaire that can assess knowledge, attitude, and practice (KAP) regarding the impact of yoga on periodontal health and systemic conditions of Indian population.\nMethods: The KAP questionnaire was developed (Stage One) using a deductive approach, and a psychometric evaluation of the questionnaire was performed to evaluate it’s reliability and validity (Stage Two). Initial content validation and test re-test reliability were assessed using kappa statistics with binary responses. An intraclass correlation coefficient (ICC) was used to assess the questions in the practice and attitude category with categorical variables. Further assessment of psychometric properties of the questionnaire was done using item response theory. The developed questionnaire had four principal sections: demography of participants; knowledge regarding yoga and oral health; attitude towards yoga and oral health; and practice towards implementing yoga for oral health.\nResults: The ICC for all the assessed questions was greater than 0.60 suggesting satisfactory stability. Internal consistency measured using Cronbach’s alpha for knowledge, attitude, and practice items were reported to be 0.632, 0.923, and 0.591 respectively and that of the KAP total was 0.632.\nConclusions: The findings of this study showed that the questionnaire had an acceptable psychometric property for measuring KAP regarding yoga and it’s role in oral and systemic health among Indian adults. The analysis of participant responses revealed that they had a medium level of knowledge regarding yoga and periodontal disease.",
"keywords": [
"Attitude",
"Knowledge",
"Oral health",
"Periodontal disease",
"Practice",
"Yoga"
],
"content": "Introduction\n\nPeriodontitis, the sixth most prevalent disease worldwide, has an overall prevalence of more than 11%.1 Being a multifactorial infection, periodontal diseases are induced by a complex bacterial biofilm that interact with host tissues resulting in a chronic inflammatory state, breakdown of the supporting connective tissue, periodontal pocket formation, alveolar bone loss and finally, tooth loss.1–3 The association between systemic diseases and periodontitis has been extensively explored.4–7 Previous meta-analyses have shown that chronic periodontitis was significantly associated with overweight and obese patients as well as patients with metabolic syndrome.8–10 Periodontal disease, apart from being a modifying factor of systemic health, may also impact the quality of life in the form of emotional, social and functional distress.11–15 A recently published systematic review has concluded that the treatment of periodontitis improves systemic health.16 Moreover, multiple risk factors have been identified as common to periodontal disease and chronic systemic diseases.17 Stress is one such factor linked to both periodontal and systemic diseases.\n\nNumerous studies have established the effectiveness of yoga in stress management.18 Studies have shown that yoga decreases the level of salivary cortisol and blood glucose.19,20 It also significantly decreases the heart rate and systolic and diastolic blood pressure.21,22 The impact of yoga on specific health ailments, including diabetes, hypertension, cardiovascular disorder, and cancer, has been explored. These yogic techniques have been proven to improve one’s overall performance and work capacity and can act as psychophysiological stimuli to increase endogenous secretion of melatonin, which is responsible for improved mental well-being.23\n\nExploration of the existing literature shows that the knowledge and attitude towards the practice of yoga in improving periodontal health is yet to be assessed extensively. Assessing an individual’s outlook regarding systemic and oral health maintenance using a questionnaire would help us determine their attitude toward disease prevention and control. This study was therefore designed to develop a questionnaire that can assess the knowledge, attitude and practice of Indian adults regarding yoga and its effect on systemic health and oral health with a focus on periodontal health.\n\n\nMethods\n\nEthical approval was obtained from the Institutional Review Board of Kasturba Medical College (KMC) and the Kasturba Hospital Institutional Ethics Committee (IEC-841/2020, obtained on 6th February 2021) which is the Institutional Ethics Committee of Manipal Academy of Higher Education. Informed consent was obtained from all participants via electronic mode using the Google form. The first page of the Google form gave information about the study and obtained consent from the participants following which they were able to move to the subsequent pages containing the questions. The participants were completely anonymized and delinked.\n\nThis questionnaire study was conducted between February 2021 and May 2022 among Indian adults. Ethical clearance was obtained for the study from the institutional ethical committee. The study was a pilot study designed to determine the psychometric properties of the KAP questionnaire. The content validation of the questionnaire was performed by five exponents in the field of yoga and health care. Following content validation, the reliability of the questionnaire was tested. The questionnaire was subsequently distributed as a Google form to collect data for assessment of additional psychometric properties to develop a validated and reliable questionnaire.\n\nSample size was determined based on the rule of thumb that states that five respondents are required for each item as suggested by Kline R.B.24 Convenience and snowball sampling methods were adopted to include patients reporting to the Department of Periodontology, Manipal College of Dental Sciences, for dental health problems. The contact details were obtained from participants’ acquaintances as a part of snowball sampling. A web-based questionnaire was sent (Online survey by Google Forms) to the prospective participants along with a letter of invitation to participate. Indian adults who were willing to participate in this study and had knowledge of the English language were included, while those not willing to participate were excluded. Anticipating a 50% lack of response, the questionnaire was sent to twice the required participants.\n\nThe Knowledge, Attitude, and Practice questionnaire was developed (Stage One) using a deductive approach and a psychometric evaluation of the questionnaire was performed to evaluate reliability and validity (Stage Two).\n\nStage One: Item and domain development\n\nUsing a deductive approach, questionnaire items were developed from the literature on yoga in managing periodontal disease and its influence on systemic diseases. Eight articles were referenced and conceptual definitions of knowledge, attitude, and practice regarding yoga and periodontal disease were derived.23,25–31 Knowledge was defined as the awareness of what yoga is and its role in managing systemic diseases, stress, and oral diseases. The definition of attitude was given as the manner in which an Indian adult would think and behave toward the possibility of the application of yoga in addressing systemic and oral diseases. Practice was defined as the scheme followed by Indian adults who demonstrate an understanding of the use of yoga in dealing with systemic and oral diseases.\n\nAn initial questionnaire with appropriate items was developed based on related literature in English language to fit the categories and the total number of items in the questionnaire was 36. The initial KAP questionnaire was reviewed by an expert panel comprising experts on yoga and periodontal health to validate the content. The test-re-test reliability of the questionnaire was calculated by administering the scale to 30 participants twice within one month. There were 27 items and 4 domains in the final questionnaire; (1) demography of participants; (2) knowledge regarding yoga and oral health; (3) attitude towards yoga and oral health; and (4) practice towards implementing yoga for oral health. Periodontal disease and health was the primary area of focus in the oral health aspect of the questionnaire can be found in the Extended data.\n\nStage Two: Psychometric evaluation\n\nA sample size of 135 was determined based on the rule of thumb given by Kline R.B.24 and repeated in the study by Selvaraj et al.32 The questionnaire was administered online and informed consent was obtained via electronic mode. The descriptive analysis and assessment of Item response theory33 were performed using the JMETRIK software (version 4.0.0, Charlottesville, Virginia, USA).\n\nItem Response Theory (IRT)\n\nA sample size of 135 participants was considered acceptable for IRT analysis of the knowledge domain. For the knowledge domain, one-parameter logistic item response theory (1-PL IRT) analysis was carried out with the response as either right or wrong as a dichotomous output. The analysis was performed in JMETRIK using the RASCH function of the ltm package. A range of difficulty (−4 to +4) was considered as the cut-off value for the psychometric Property evaluation of the domain.34\n\nInternal consistency reliability\n\nThe internal consistency (IC) of the items was calculated using the coefficient of Cronbach’s alpha and correlation between items.\n\n\nResults\n\nThe majority of the participants were in the age group of 31-40 years (39.7%) followed by 23-30 years (25.6%) of age. 50.8% of the participants were female and 56.3% had completed their post-graduate education. Most of the participants in the study had no history of systemic illnesses (80.9%). Diabetes had the highest percentage of occurrence (5.5%) amongst the remaining 19.1%. Oral health care was found to be an ancillary consideration as the question on frequency of visits to the dentist for consultation regarding oral or gum health was met with the answer from the majority (63.8%) that they visited the dentist only in the presence of dental problems, 12.6% said that they visited the dentist once in a year and 11.1% had never visited a dentist. 88.9% had no behavioral risk factors such as alcohol consumption, tobacco usage, and a sedentary lifestyle. Alcohol consumption, including regular consumption (5%), occasional drinking (1%), and alcohol consumption along with smoking (2.5%), was the leading behavioral risk factor.\n\nTotal items developed using deductive approach and content validation (Stage One)\n\nAfter consulting relevant literature, an initial questionnaire with 36 items was developed using the deductive approach. Five experts performed content validation of each scale to ensure content relevance, representativeness, and technical quality. The Scale level Content Validity Index/Average (S-CVI/Ave) for the questionnaire was 0.88. The Scale level Content Validity Index/Universal Agreement (S-CVI/UA) was 0.414. The Free Marginal Kappa was 0.53, indicative of moderate agreement, Fixed Marginal Kappa was -0.13, and the percentage agreement was 76.55%. Item reduction was performed to 30 after eliminating six questions after Content validation. The Content Validation Index (CVI) was found to be satisfactory.\n\nTest-re-test reliability\n\nItem scoring was finalized and the questionnaire was subjected to test-re-test reliability assessment. Unweighted Kappa Coefficient was used to assess the reliability of the items with binary responses. One question in the Knowledge category had poor agreement (K2: -0.036) and two had slight agreement (K3: 0.151, K4: 0.081). All the other questionnaire questions had a moderate, substantial, or near-perfect agreement.\n\nIntraclass correlation coefficient (ICC) was used for assessing the questions in the practice and attitude category with categorical variables. The interpretation of the ICC was given as acceptable if values were above 0.40, but probably improvable; ICCs above 0.60 or greater indicated satisfactory stability; ICCs greater than 0.80 specified excellent stability. The ICC for all the assessed questions was greater than 0.60 suggesting satisfactory stability.\n\nThree questions from the knowledge category were thus eliminated after the test- re-test reliability assessment.\n\nPsychometric evaluation of the questionnaire (Stage Two)\n\nThe 27-item questionnaires were administered to 300 participants through the online platform to compensate for the expected non-response. From this, 199 responses were obtained, and all the responses were evaluated to assess the psychometric properties of the questionnaire. The one-parameter model for the knowledge domain of the respondents revealed an acceptable range of difficulty for all the questions with the values ranging from 1.01 to 2.16 (Table 1).\n\nInternal consistency measured using Cronbach’s alpha for knowledge, attitude and practice items were reported to be 0.632, 0.923, and 0.591, respectively and that of KAP total was 0.632 (Table 2a). Guttman Split-Half Coefficient was satisfactory for knowledge (0.600) and attitude (0.781) (Table 2b).\n\nAn independent t-test was performed to assess the association between demographic variables such as age, gender, education, and KAP regarding the application of yoga in oral health. A significant association was seen between the level of education and KAP of yoga and oral health (Table 3).\n\n* P value is significant.\n\nFor the Indian population, the 27 item questionnaire scores were standardized. For the questionnaire, scores below 33 indicated low KAP, 34-40 indicated medium KAP and scores greater than 41 indicated good KAP of yoga for overall health, including oral health with a focus on periodontal health. The current study’s total KAP was 37.1859, indicating a medium KAP (Table 4).\n\n82.4% of the participants felt that oral health is a mirror of general health and 92% were aware of the general symptoms of periodontal disease, such as bleeding gums, loose teeth, and receding gums. Although 53.3% had known that stress at work or in life could contribute to oral diseases, 35.7% were not aware of the significance of stress on oral health. 81.9% of the participants agreed that physical activity/lifestyle changes would help control chronic diseases, while only 60.8% felt the same about the influence of physical activity/lifestyle changes on gum diseases. 98% of the participants knew that yoga is a group of physical, mental, and spiritual practices of disciplines that originated in ancient India and 86.9% were knowledgeable about specific ‘asanas’ to reduce stress, blood sugar level, blood pressure and inflammation. Only 57.3% recognized that there are scientific studies that have proven the benefits of yoga on systemic health and oral/gum health.\n\nThe majority of the participants agreed that yoga is necessary for a healthy life (51.8%-Strongly agree, 32.7% agree), that yoga practice can help in managing lifestyle diseases like obesity, hypertension, cancer (50.3%-Strongly agree, 39.7% agree) and that yoga practice can improve memory and concentration (58%-Strongly agree, 32.2% agree). The participants also felt that yoga could help manage mental ill health like depression, stress (57.3%-Strongly agree, 36.2% agree) and facilitate healing, relaxation and reduction in pain (47.7%-Strongly agree, 39.7% agree). The majority of the participants were of the attitude that gum disease/periodontal disease is caused due to stress, defective immunity of the body in addition to poor oral hygiene (25.6%-Strongly agree, 44.7% agree) and that the effect of yoga on periodontal and oral health may be due to its effect on immunity and inflammation (Strongly agree-20.6%, Agree-38.2%). However, they were sceptical about the role of yoga in managing gum diseases/periodontal diseases (Neutral-46.7%, Disagree-5.5%, Strongly disagree-0.5%) and its effect on salivary flow and dry mouth, which often result in periodontal diseases (Neutral-47.2%, Disagree-3.5%, Strongly disagree-0.5%).\n\nAmongst the practice questions, 42.7% of the respondents practiced yoga, with 52.9% practicing yoga regularly. Lack of time was the most common reason for the non-practice of yoga (29.8%). 54.1% practice yoga for less than 30 minutes and 43.2% are focused on the various asanas and 27% perform meditation. Many of the participants (97.6%) practice yoga for the improvement of general health while 27.1% focus on yoga for specific ailments. 97.6% find yoga beneficial in improving general health or specific ailment. 88.2% of the participants have not considered the practice of yoga for the health of their gums which is primarily due to a lack of awareness regarding the effects of yoga on oral health (68%), but 66.7% have noticed that the health of the gums improve with the practice of yoga. 70.9% of the participants are very willing to recommend yoga for the improvement of general health/specific ailment to others and only 4.5% are not willing. However, only 35.7% are willing to recommend yoga to improve the health of gums to others and 15.1% are unwilling to do so.\n\n\nDiscussion\n\nYoga is a form of Complementary and Alternative Medicine (CAM) practiced in India. It is derived from the Sanskrit word ‘yuj’.35 It means to join and to direct and concentrate one’s attention. The increase in modernization, with an increase in sedentary lifestyle, has led to a rise in chronic systemic diseases. Hence, lifestyle modification is the need of the hour and yoga has been gaining popularity worldwide for achieving mental and physical health.\n\nYoga can impact the overall well-being of an individual through several mechanisms and one of its significant influences is the effect on stress. Studies have demonstrated that the antioxidant levels of the body can be maintained or improved with the regular practice of yoga which will help regulate the antioxidant defence system under stressful conditions.36 Yogic breathing exercises can also reduce the levels of free radicals.37 These effects may prove helpful to maintain systemic health with an additional beneficial influence on periodontal health. However, the studies on the knowledge regarding the possible impact of yoga on periodontal health are limited. Hence, this study was designed to overcome the paucity in the literature pertaining to this topic. Apart from this, the knowledge and attitude of the populace regarding aspects of general health and oral health have also been explored in this study.\n\nThis study has facilitated the development and validation of a questionnaire for assessing Knowledge, Attitude, and Practice regarding the effect of yoga on overall health and oral health, including periodontal health among Indian adults. To our knowledge, this is the first study to develop a validated questionnaire for this purpose. After item reduction following validation by an expert panel, 30 questions were included for test re-test reliability assessment. Three questions from knowledge were eliminated after assessing the test re-test reliability. Test-retest reliability is the degree to which test scores remain unchanged when measuring a stable individual characteristic on different occasions.38 Evaluation of the psychometric properties of the questionnaire was done by item response theory using the Rasch model and an acceptable range of difficulty was seen for all the questions.39 Internal consistency assesses the consistency of results across items within a test and in this questionnaire, this property, as measured using Cronbach’s alpha,40 showed a total KAP of 0.632 and all factor loadings were more than 0.3 showing a close association among factors and items. Guttman Split-Half Coefficient is considered a measure of the internal reliability of a test. This test confirms how consistently the items perform within a test.41 It was satisfactory for knowledge and attitude components of this questionnaire.\n\nWhen assessing the demographic details, a significant association was seen between the level of education and KAP of yoga for overall health, including oral health. This points towards education as one of the factors that can influence the practice of yoga for overall health and oral health. This may be attributed to the fact that there is an increase in the interest towards incorporation of yoga in the school curriculum and hence there is more awareness regarding the benefits of yoga on health.\n\nMajority of the participants in this study were aware that oral health is a critical aspect of general health and could identify the initial symptoms of periodontal diseases. In a study on children by Nagarajappa et al., it was observed that a large proportion of children were not conscious of health risks originating from poor oral health.42 In contrast, another study showed that students had adequate level of knowledge on causes, prevention, and signs of dental caries and periodontal diseases.43 Findings from another study in adults showed that poor knowledge regarding oral health and its significance was associated with participants age, education, ethnicity, income and reading ability.44\n\nIn this study, over 50% of the participants identified stress as a potential risk factor for periodontal disease. The role of physical activity or lifestyle change in improving systemic health was asserted by majority of the participants in this study although they were doubtful about the effect of the same on oral health. Stress and physical inactivity have been recognized as few of the multiple risk factors for systemic and oral diseases. Research has indicated a statistically significant relationship between Body Mass Index levels, oral hygiene, eating habits and physical activity.45 However, the awareness regarding the factors is sparse. The findings from our study are corroborated with evidence from literature that have demonstrated that patients are often aware of the role of plaque bacteria on periodontal disease, however, their knowledge of the role of stress or obesity on periodontal disease is limited.46\n\nOnly 42.7 % population practiced yoga and it was observed that the most common cause for the nonpractice of yoga was lack of time. This is similar to the result obtained from questionnaire surveys conducted by Sharma G et al., Hegde VS et al.47,48 Various forms of yoga were performed by the study participants and included asanas, meditation, and pranayama focusing on general health. Most of the participants were of the opinion that yoga can help improve the overall health, both mental and physical, of an individual and they showed a positive response for willingness to recommend yoga to the general population to improve general health. The participants who performed yoga did not focus specifically on oral disease or gum disease as they lacked awareness regarding the potential effect of yoga on oral or periodontal health. A few of the participants did find an improvement in oral health as a result of performing yoga. At the same time, only a minority expressed willingness to recommend yoga for oral health or the health of gums as most of them were unconvinced of the probable role of yoga on periodontal health. A literature search has shown articles that have identified the beneficial response of the human body to the practice of yoga,49,50 but the influence of yoga specifically on oral health, is less explored.\n\nIn the present study, the KAP regarding the effect of yoga on oral health is at a medium level. This may be attributed to the fact that there are a few studies that have identified the favourable effects of yoga on oral health and specifically periodontal health,28 and this information is not clearly understood by the general populace. Hence, increasing awareness regarding the potential advantageous effects of yoga on oral health can pave the way toward a healthy oral cavity in a healthy body. However, the study has limitations with respect to the sampling method involved and therefore, well-defined clinical trials may be used to get an unambiguous data on the potential effects of yoga on periodontal health.\n\n\nConclusion\n\nThere are questionnaires that evaluate oral health knowledge, attitude, and practice, but the current questionnaire content will be an ideal tool to assess the KAP regarding yoga and systemic health and the effect of yoga on periodontal health. It can be used for future studies as it has acceptable validity and reliability outcomes.\n\nThe knowledge, attitude and practice regarding yoga and its effect on periodontal health has to be investigated further so that it can be understood clearly, and steps may be implemented to facilitate integrating professional and personal oral health care with physical activity including yoga for maintenance of oral health and overall health.",
"appendix": "Data availability\n\nFigshare: Knowledge, Attitude and Practice regarding the effect of yoga on periodontal health among Indian adults: A questionnaire study. https://doi.org/10.6084/m9.figshare.24003657.v2. 51\n\nThis project contains the following underlying data:\n\n- Data coded.xlsx\n\n- Yoga KAP results.docx (aggregated data)\n\nFigshare: Knowledge, Attitude and Practice regarding the effect of yoga on periodontal health among Indian adults: A questionnaire study. https://doi.org/10.6084/m9.figshare.24003657.v2. 51\n\nThis project contains the following extended data:\n\n- Content validation.docx\n\n- Reliability- Test-Retest.docx\n\n- Questionnaire Knowledge, Attitude and Practice regarding periodontal and systemic diseases.pdf\n\nFigshare: STROBE checklist for “Knowledge, Attitude and Practice regarding the effect of yoga on periodontal health among Indian adults: A questionnaire study”. https://doi.org/10.6084/m9.figshare.24003657.v2. 51\n\n\nAcknowledgements\n\nThe authors acknowledge the contribution of the study participants.\n\n\nReferences\n\nPatini R, Staderini E, Lajolo C, et al.: Relationship between oral microbiota and periodontal disease: a systematic review. 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PubMed Abstract\n\nHegde S v, Rao SK, Menezes RG, et al.: Knowledge, Attitude, and Practice of Yoga in Medical Students: Assessment of Anthropometry and Lifestyle Factors. Int. J. Yoga Therap. 2018; 28(1): 9–14. PubMed Abstract | Publisher Full Text\n\nWoodyard C: Exploring the therapeutic effects of yoga and its ability to increase quality of life. Int. J. Yoga. 2011; 4(2): 49–54. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaneja DK: Yoga and health. Indian J. Community Med. 2014; 39(2): 68–72. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKedlaya N, Madhurya, Puzhankara L, et al.: Knowledge, Attitude and Practice regarding the effect of yoga on periodontal health among Indian adults: A questionnaire study. [Dataset]. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "218412",
"date": "29 Feb 2024",
"name": "Baiju R M",
"expertise": [
"Reviewer Expertise Scale development and QoL research",
"Implant dentistry and periodontal regeneration"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFurther analysis of existing literature regarding the KAP of Yoga or similar physical activities and their influence on oral and periodontal health may be discussed in the introduction and discussion.\n\nMethodology of item generation and item reduction may be explained further. The qualitative approaches employed may be further elaborated. The final questionnaire is in accessible.\n\nConclusions does not reflect exactly the objectives and observations.\n\nThe title is not reflecting the tool development that was the primary objective of the study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11188",
"date": "13 Apr 2024",
"name": "LAKSHMI PUZHANKARA",
"role": "Author Response",
"response": "Dear Sir, Thank you very much for your comments. We shall incorporate the suggestions you have given and make the changes in the article."
},
{
"c_id": "11540",
"date": "21 Jun 2024",
"name": "LAKSHMI PUZHANKARA",
"role": "Author Response",
"response": "Dear Sir, The following changes have been made as per your suggestions: The title has been altered to match the objectives of the study. Studies pertaining to yoga and physical activities have been added to the discussion section of the paper. The questionnaire file and details of the analysis done for the development of the questionnaire have been given as extended files in the data availability statement. The conclusion has been edited to match the objectives. Yours sincerely, Lakshmi Puzhankara"
}
]
},
{
"id": "218411",
"date": "14 May 2024",
"name": "Rajeshwari H R",
"expertise": [
"Reviewer Expertise Perioontology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nKnowledge, Attitude and Practice regarding the effect of yoga on periodontal health among Indian adults: A questionnaire study.\nI hereby congratulate the authors on exploring an interesting topic that may have close correlation with oral health particularly periodontal status. I am pleased to approve the manuscript. There are primarily few minor comments and one major comment authors need to address. Please see below. Major Comment: Authors need to highlight at the end of the introduction how the data from this current study would affect the diagnosis or management of periodontal diseases, if it does. This would help the readers and clinicians to understand the need of the study and conduct clinical studies in this direction if it will benefit the periodontal management in a holistic way.\nMinor comments: Did authors find any differences in the results and socioeconomic status of the participants? Can authors explain how was the 50% lack of response to questionnaire anticipated? Please add if there are any reference or if there was any pilot study conducted.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1404
|
https://f1000research.com/articles/13-492/v1
|
17 May 24
|
{
"type": "Research Article",
"title": "Individual and health care provider factors influencing stroke self-management behavior: A cross-sectional study",
"authors": [
"Yurike Septianingrum",
"Ah Yusuf",
"Ika Yuni Widyawati",
"Nunik Purwanti",
"Nety Mawarda Hatmanti",
"Shelly Nursofya Lestari",
"Andis Yuswanto",
"Yurike Septianingrum",
"Ika Yuni Widyawati",
"Nunik Purwanti",
"Nety Mawarda Hatmanti",
"Shelly Nursofya Lestari",
"Andis Yuswanto"
],
"abstract": "Background This study aimed to examine individual- and health service provider-related factors that influence the self-management behavior of patients with stroke.\n\nMethods This cross-sectional study investigated a cohort of 110 ischemic stroke patients in the neurology outpatient department of Universitas Airlangga Hospital from February 2023 to May 2023. Data were obtained using the following three distinct questionnaires: the general demographic questionnaire, health care provider questionnaire, and modified stroke self-management behavior questionnaire.\n\nResults Chi-square test results indicated a significant correlation between age (p = 0.023) and information availability (p = 0.000) with self-management behavior in patients with stroke. However, no significant correlations were observed between gender (p = 1.107), residence (p = 0.859), availability of access (p = 0.093), availability of health facilities (p = 0.065), and collaboration among health workers (p = 0.641) with self-management behavior in patients with stroke. Ordinal logistic regression analysis results indicated that age significantly influenced self-management behavior in patients with stroke (p = 0.034; OR = 2.49).\n\nDiscussion The presence of reliable information within the hospital setting is expectedly complemented by a strong level of literacy among patients with stroke, thereby facilitating the enhancement of their self-management practices.",
"keywords": [
"cerebral infarction",
"healthy lifestyle",
"ischemic stroke",
"noncommunicable disease",
"stroke"
],
"content": "1. Introduction\n\nStroke is a pathological condition that may have adverse effects on the physical well-being and social engagement of individuals (Chen et al. 2018). Some who have had strokes exhibit inadequate self-management behavior, which refers to the capacity of individuals who are unable to maintain their health and engage in self-care activities for promoting their overall well-being (Chen et al. 2021). This behavior consequently poses a heightened risk of experiencing subsequent strokes. The inadequate self-management behavior exhibited by patients with stroke can be attributed to several factors, including individual-related factors, such as age, gender, and residence (Shuqi et al. 2023; Sun et al. 2022), and health service provider factors, including limited information availability, restricted access to healthcare services, inadequate availability of health facilities (Harfika and Abdullah 2017), and suboptimal collaboration among healthcare professionals (Busari, Moll, and Duits 2017). Health services is defined by the World Health Organization (WHO) as “service delivery systems that are accountable for providing health services to patients, individuals, families, communities, and populations in general, not just patients” (WHO 2023). Health service providers are generally divided into horizontal services, which are designed to provide comprehensive coverage of a population’s health needs (including those financed by public health systems, such as primary care), or vertical services, which are aimed at providing coordinated interventions for a specific condition (Bricknell et al. 2021).\n\nIn 2017, stroke ranked as the second most prominent cause of mortality worldwide and the third most significant contributor to disability-adjusted life years. A previous study reported that a significant proportion ranging from 50% to 70% of stroke survivors in the United States experience disability or mortality (Chen et al. 2021). Furthermore, approximately 20% of the adult population encounters recurrent strokes and thus need hospital readmission within 30 days following their first outpatient visit (Septianingrum et al. 2023). The available data indicate that the percentage of individuals under 65 years old who have strokes ranges from approximately 30% to 50% across different nations and regions. This suggests a prevailing worldwide pattern whereby stroke occurrence is more prevalent among young individuals than that in older adults (Ren et al. 2020). According to data from the Ministry of Health in 2019, the prevalence of patients with stroke in East Java Province amounted to 21,120 individuals, accounting for 12.4% of the total population (Kemenkes 2019). Notably, the city of Surabaya exhibited the highest prevalence within the province, with a 6.5% rate (Riskesdas 2013). In 2022, Airlangga University Hospital recorded a total of 614 cases with stroke, with a monthly average of 51 patients. The study showed that most poststroke patients (80.5%) exhibited a high level of self-management behavior, whereas a minority (19.5%) had poor self-management behavior. Based on the interviews conducted on patients with stroke in the outpatient department of Universitas Airlangga Hospital, several patients expressed difficulties in identifying the signs and symptoms of a stroke. This difficulty was attributed to self-management-related issues, specifically stemming from the restricted availability of information resources.\n\nEffective self-management behavior implementation may enhance patient satisfaction, mitigate treatment expenses, bolster self-assurance, foster patient autonomy, and enhance overall patient well-being (Dineen-Griffin et al. 2019). Individuals who have comprehensive knowledge of a certain illness and its corresponding treatment methods may mitigate the occurrence of subsequent strokes (Ningrum, Alfatih, and Siliapantur 2019). As individuals residing in rural regions frequently encounter more limited access than their urban counterparts, improved accessibility may contribute to enhanced self-management (Dwyer et al. 2020). The adherence of patients with stroke to control measures may be influenced by the accessibility of healthcare (Wibawa et al. 2016). Collaboration among health personnel influences the quality of service at a healthcare facility. Effective cooperation has may facilitate patient engagement in the execution of regular health assessments (Alderwick et al. 2021).\n\nSelf-management behavior refers to an individual’s capacity to exert control over the symptoms and consequences of a chronic illness by using medicine, self-care practices, engagement in physical exercise, social interactions, and modifications to one’s lifestyle (Fugazzaro et al. 2021). The adoption of self-management behavior has been proposed as a crucial approach that empowers individuals to mitigate their future susceptibility to stroke (Kim et al. 2023). A study by Shuqi et al. (2023) indicated that self-management behavior in patients with stroke is influenced by internal variables, including insurance, limb function, and self-efficacy. This study aimed to investigate the correlation between external characteristics associated with health service providers and self-management behavior. The availability of freely available information sources facilitates stroke-related information acquisition for patients and their families (Miyamatsu et al. 2013). Furthermore, comprehensive hospital facilities contribute to the enhancement of patients’ health condition (Teisberg, Wallace, and O’Hara 2020). The accessibility of healthcare facilities plays a significant role in the management of stroke situations, particularly during the critical time window of 3–4.5 h following symptom onset (Jarva et al. 2021). Additionally, the enhancement of patient outcomes and safety may be achieved by the cooperation of healthcare professionals (McLaney et al. 2022). To date, studies investigating the variables pertaining to health service providers that are linked to self-management behavior in individuals with stroke is limited. This study aimed to examine several individual and health service provider characteristics that influence self-management behavior among individuals with stroke.\n\n\n2. Methods\n\nAn analytic observational design using a cross-sectional method was employed in this study. A sample size of 110 patients with ischemic stroke was selected from the neurology outpatient department of Universitas Airlangga Hospital from February 2023 to May 2023. Determining the large sample in this study used the Slovin formula. A simple random sampling approach was used in the selection process, ensuring that everyone within the population had an equal probability of being included in the sample. The sampling procedure included a random selection of individuals from the registration list of patients who sought medical care at the neurology outpatient department, according to predetermined inclusion and exclusion criteria. The inclusion criteria comprised individuals between 18 and 60 years old who had received a diagnosis from a neurologist. Additionally, respondents must be able to communicate either vocally or nonverbally with the researcher, without experiencing significant aphasia, speech impairment, or any other communication barriers. Furthermore, individuals must demonstrate their willingness to participate by providing informed permission via their signature. The following were the exclusion criteria: (1) individuals with impaired cognitive function or a documented history of mental illnesses and (2) those with significant medical difficulties, including heart, liver, lung, and renal disease. The exclusion and inclusion criteria were determined by neurologists and guided by medical records. This study was approved by the Ethics Committee of Universitas Airlangga Hospital, with the assigned number of 044/KEP/2023. Additionally, the study protocol was recorded under the identification number of UA-02-23026. Before performing the examination, we ensured that all patients provided written informed consent. During data collection, all participants (110 patients) completed the questionnaire, without any missing participant data (either withdrawals or incomplete data).\n\nThis study investigated individual factors of stroke patients such as age, gender, and place of residence. In addition, we also investigated health service provider factors, such as availability of information, health facilities, access, and collaboration between health professionals. In the first step, approval from the hospital was obtained for data collection on patients at the neurology outpatient department. Hospital supervisors assisted in determining outpatients who met inclusion and exclusion criteria to prevent selection bias in this study. In addition, researchers explained the aims and procedures of the study to patients and obtained their consent. Next, participants are asked to fill out the digital form of the demographic and health service provider questionnaires which takes around 10-20 minutes to complete.\n\nThe health service provider questionnaire consists of 4 parts, including questionnaires on availability of information, availability of health facilities, availability of access, and collaboration between professional health workers. These four questionnaires were scored using a four-level scoring method (1–4 points) for favorable questions if strongly agree = 4, agree = 3, disagree = 2, and strongly disagree = 1. In contrast, unfavorable questions were the opposite. In part one, the information availability questionnaire consists of 7 questions, including 4 favorable questions (number 1,2,3,7), and unfavorable questions (number 4,5,6). Scores for answers to the questionnaire are 7-15 = poor (1), 16-25 = fair (2), 26-35 = good (3). In the second part, the health facilities availability questionnaire was developed by the researchers themselves and adapted to the health service resource use questionnaire (Ilhan et al. 2009), which consists of eight questions, all of which are favorable questions. Scores for answers to the questionnaire are 8-18 = poor (1), 19-29 = sufficient (2), 30-40 = good (3). In the third part, the access availability questionnaire used the health access and utilization survey questionnaire (Harris et al. 2011), which consists of four questions, including favorable questions (number 1.4), and unfavorable questions (number 2.3). The score for answers to the access questionnaire is 4-8 = poor (1), 9-14 = fair (2), 15-20 = good (3). n the fourth part, a collaboration questionnaire between health workers was developed by the researchers themselves and adapted to the Perception of Interprofessional Collaboration Model Questionnaire (Légaré et al. 2011), which consists of eight questions (all favorable questions). Scores for answers to the questionnaire 8-18 = poor (1), 19-29 = sufficient (2), 30-40 = good (3). All these health service provider questionnaires were tested for validity and reliability and declared valid (r count > 0.361) and reliable, with a Cronbach’s alpha of 0.912.\n\nThe self-management behavior questionnaire was a development and modification questionnaire for the Hypertension Self-Management Behavior Questionnaire (Akhter 2010), which consisted of 29 questions. All favorable questions were scored as follows: very always = 4, sometimes = 3, rarely = 2, and very never = 1. which consists of 29 questions. All favorable questions were scored as follows: very always = 4, sometimes = 3, rarely = 2, and very never = 1. The score range was 29-116, where 29-58= poor, 59-87= fair, 88-116= good. All items in this questionnaire were declared valid (r count > 0.361) and reliable, with a Cronbach’s alpha of 0.926.\n\nData for the study materials were entered into an Excel spreadsheet following questionnaire collection. Statistical description and analysis were performed using Statistical Package for the Social Sciences (version 26, IBM, Armonk, NY, USA). General data, health service providers, and data regarding patients’ self-management were presented as percentages. Specifically, to examine the correlation between variables, the Chi-square test was employed with a significance level of α = 0.05. Additionally, to investigate the primary factor that influences the self-management behavior of patients with stroke, ordinal logistic regression was utilized with a significance level of α = 0.05. There were no missing data in the data analysis of this study.\n\n\n3. Results\n\nA total of 110 patients with ischemic stroke were included in this study, with no missing data. A comprehensive overview of the demographic characteristics of the study respondents is presented in Table 1. The majority of respondents were between 26 and 45 years old, comprising 58.2% of the total sample. Additionally, 61.8% of the respondents were male, and 92.7% resided in Surabaya. The results of the correlation analysis conducted to examine the relationship between functional ability and the amount of particular engagement are displayed in Table 2. The results of the Chi-square test showed a statistically significant positive association between age and the availability of information on self-management behavior (p = 0.023; p = 0.000). No significant association was noted between gender (p = 0.107), residency (p = 0.859), availability of health facilities (p = 0.065), availability of access (p = 0.093), and cooperation between health professionals (p = 0.641) and self-management behavior.\n\n* Significant, with a significance level of α = 0.05.\n\nThe results of bivariate analysis using the Chi-square test are shown in Table 3. The majority of patients with stroke exhibited moderate levels of self-management behavior, with approximately 57.3% reporting access to relevant information. Additionally, a notable level of cooperation was observed among healthcare workers, as reported by 56.4% of patients with stroke. Furthermore, of note, a significant proportion of the population was noted to have access to adequate health care, with a percentage of 49.1%. Additionally, a substantial majority, accounting for 84.5%, had appropriate access to these services. The only element that demonstrated a significant correlation with self-management behavior was the availability of information (p = 0.000). However, no significant correlation (p > 0.05) was noted between the availability of health facilities, access to health facilities, and the level of cooperation among healthcare workers.\n\n* Significant, with a significance level of α = 0.05.\n\nThe outcomes of the multivariate analysis conducted through multiple logistic regression tests are presented in Table 4. The results indicated that among the various factors investigated, age and information availability were the only variables that significantly impacted self-management behavior (p = 0.034; p = 0.000). Furthermore, age emerged as the most influential factor in shaping self-management behavior among patients with stroke (p = 0.034; OR = 2.49)\n\n* Significant, with a significance level of α = 0.05.\n\n\n4. Discussion\n\nThis study aimed to examine several individual-related factors or characteristics that have an impact on self-management behavior among patients with stroke. These factors included age, gender, and place of residence. Most respondents were between 26 and 45 years old, and a significant positive association was observed between age and the self-management behavior of patients with stroke. Globally, there is a growing tendency for stroke to occur at younger ages, as approximately 30%–50% of all patients with stroke are under 65 years old (Ren et al. 2020). The results of the present study are consistent with those of Elma et al. (2022) who reported that adult patients exhibit superior self-management abilities than older adult patients. Individuals in the younger age group who possess a greater potential for extended lifespan and increased life expectancy subsequent to experiencing a stroke may contemplate a reintegration into societal structures. Owing to the concurrent demands of employment and familial obligations among their peers, the youthful demographic has challenges in committing to extended rehabilitation (Shuqi et al. 2023). As young individuals with longevity and life expectancy following a stroke may consider returning to society more, adult patients have better self-management than older ones. It is challenging for the young population to devote themselves to long-term rehabilitation because their peers work and take on family responsibilities.\n\nMost respondents in the study were male, and it was observed that they mostly exhibited good self-management behavior. Nevertheless, no significant association was observed between gender and self-management behavior. The results of this study align with those of Kuo et al. (2021) who indicated a lack of correlation between gender and the variables investigated in this study. The ability of both male and female patients to modify their self-management behavior is contingent upon their goals and self-efficacy.\n\nThis study observed no statistically significant association between the place of residence and patient self-management behavior. Most patients who were presented for follow-up resided in Surabaya, an urban locality. Lu et al. (2022) reported a disparity in the self-management behavior of urban and rural patients in China, highlighting a gap in their respective locations. There is no guarantee that older middle-aged individuals possess superior self-management behaviors than their counterparts in rural regions. Conversely, enhanced medication adherence is exhibited by urban inhabitants. The self-management behavior shown by individuals residing in urban regions tends to surpass that of their rural counterparts. This discrepancy may be attributed to the greater accessibility to private and government healthcare organizations, medical professionals, and medical facilities within urban settings. Conversely, healthcare services in rural regions are far from residential areas. The limited availability of healthcare practitioners and drugstores has a significant impact on self-management (Akhter 2010). This study was conducted in a government hospital situated in the city center, which offers convenient accessibility through several modes of transportation. Patients residing outside the city of Surabaya frequently opt to rent accommodations near the hospital, thereby facilitating ease of access during their treatment.\n\nThis study also determined the health service provider-related factors (including availability of health facilities, availability of access, and collaboration between professional health workers) and self-management behavior among stroke patients. Several respondents expressed that the neurology outpatient department exhibited a satisfactory level of information accessibility. This perception was primarily based on the presence of informative pamphlets positioned in the periphery of the room, the utilization of digital platforms for disseminating information, and the active engagement with social media channels for facilitating information sharing. The results of this study are consistent with those of Koga et al. (2011) who indicated a clear correlation between knowledge and self-management behavior. In contrast to the assertions made by Sari and Airlanda (2022), it has been argued that the essential conditions for engaging in self-management behavior require patients to possess enough information and abilities pertaining to the illness and its treatment principles. Individuals who are provided with self-management health education before their discharge from medical facilities exhibit superior self-management behaviors than those who do not receive such education (Shuqi et al., 2023). Several independent studies have shown several benefits associated with health-related behaviors. These advantages include reduced use of medical services, lower smoking and alcohol consumption, improved diet, and a more positive attitude (Whitehead 2018). Most healthcare providers realized their role in self-management assistance as primarily that of coaching, whereas a minority believed that their job was to educate or support patients in achieving self-management. Bos-Touwen et al. (2017) reported that it has the potential to empower patients to make behavioral changes.\n\nThe results of our study showed that information accessibility was satisfactory; however, a deficiency in patient health literacy existed. Moreover, the results indicated that patients preferred to engage in conversations with other patients instead of engaging with educational videos or perusing health-related leaflets. Several studies reported that individuals with little health literacy who have had a stroke tend to have worse overall health outcomes and greater rates of death. The impact of health literacy encompasses an individual’s preferred mode of learning, specific requirements, and the extent to which patients can accurately comprehend and use available healthcare resources. Aran et al. (2022) stated that there is evidence supporting the notion that enhanced health literacy is linked to improved self-management, thereby resulting in advantageous outcomes for both patients and the healthcare system. Cultural ideas and social stigma influence knowledge-related behavioral alterations. Alqahtani (2015) stated that a significant number of individuals who have had a stroke believe that divine retribution, stress, and spiritual possession contribute to their condition. Consequently, these individuals tend to place more faith in spiritual healing and traditional medicinal practices as means of attaining recovery, as opposed to relying only on conventional medical interventions. Cultural ideas within society influence health information reception. In some instances, patients with stroke may place more trust in information provided by religious leaders, including clerics, priests, monks, or traditional authorities, as opposed to healthcare professionals.\n\nThe results of this study demonstrated that the presence and accessibility of healthcare services do not influence self-management behavior. The results are inconsistent with those of a study by Dwyer et al. (2020) who demonstrated that the extent of hospital infrastructure has a crucial role in evaluating patient adherence to control measures. This finding aligns with that of Wahyuningrum (2011) who postulated that the presence of adequate facilities has a considerable favorable impact on patient self-management behavior and overall satisfaction. The impediments faced by patients in seeking medical care are not just attributable to facility availability and accessibility but are also influenced by the financial burden of public transportation, including taxi fares (which may occasionally be mitigated by ride-sharing), the wait time for ambulance services, and the challenges associated with walking (Smythe et al. 2022). The provision of family support in patient care, which includes the act of escorting and following patients throughout treatment, affects patient self-management behavior (Alqahtani 2015).\n\nThe results of this study suggested that a positive level of cooperation is noted among health professionals; however, notably, this collaboration does not demonstrate a significant relationship with self-management behavior. Ding et al. (2023) reported that individuals have the capacity to modify their behavior inside a communal environment. The inclusion of community healthcare providers in the healthcare system is crucial for the effective stroke management, as highlighted by Yang et al. (2022). During the aforementioned period, 62.6% of primary healthcare providers who collaborated with nurses in primary healthcare settings have knowledge about the inclusion of loss of consciousness as a symptom of stroke (Ding et al. 2023).\n\nPearce et al. (2015) reported that studies have emphasized the significance of collaborative and educational connections between healthcare professionals and patients or carers. These relationships include professionals actively listening to the needs of patients and carers, offering expert advice, providing relevant information, and addressing any inquiries. This is consistent with a key element of self-management relating to human interactions as it represents the fundamental foundation of self-management. Dineen-Griffin et al. (2019) contended that the efficacy of interpersonal connections plays a significant role in attaining optimal outcomes and cultivating a more profound sense of fulfillment in life. Dobkin (2016) reported that it is essential to include elements such as education, continuous engagement, targeted information, goal establishment, monitoring, feedback, and motivational enhancement to achieve self-management and create behavioral change. Moreover, the enhancement of self-management behavior is influenced by the effect of self-efficacy (Lo, Chang, and Chau 2018). Individuals who possess elevated degrees of self-efficacy have enhanced abilities to cope with the adverse consequences associated with their medical condition and the corresponding therapeutic interventions. Szczepańska-Gieracha and Mazurek (2020) reported that self-efficacy seems to have more significance in the context of diseases that hinder physical functioning and need extended rehabilitation periods.\n\nWe now better understand the factors that predict self-management behavior in patients with stroke and identify which factors are the most significant. Therefore, nurses must focus on these factors when performing discharge planning. To identify health service provider-related factors that influence self-management behavior in patients with other chronic illnesses, more studies are needed. Therefore, for the self-management behavior of patients with stroke, understanding the factors that hinder changes in their self-management behavior is essential.\n\nThis study had several limitations. First, it only included respondents who had experienced ischemic stroke and did not have a previous stroke history; therefore, individuals with hemorrhagic stroke or multiple stroke occurrences were excluded from the analysis. Considering the epidemiological evidence indicating their substantial representation among patients with stroke, expanding the scope of the research group to include a representative sample of the total stroke population is imperative. Second, there may have been recall bias among respondents who answered the stroke self-management question. Although the selected participants did not have cognitive impairment, they had difficulty remembering the frequency of diet, medication, monitoring blood pressure and blood sugar levels. Third, a subset of older individuals encountered challenges while completing digital form-based questions. Consequently, researchers helped these individuals throughout the questionnaire administration process since they may have low visual acuity and have difficulties in using smartphones. Lastly, the data collection procedure was characterized by a lengthier duration. Therefore, our staff provided support and guidance in the process of completing the questionnaire via the use of a smartphone.\n\n\n5. Conclusion\n\nSelf-management behavior is influenced by several factors, including individual- and health service provider-related variables. These factors include age and information availability, with age as the most prominent self-management behavior determinant. This study aimed to provide valuable insights for individuals to engage in self-integration, self-regulation, interactions with healthcare professionals, self-monitoring, and medication adherence. These practices are crucial to promote recovery and prevent the occurrence of subsequent strokes. Therefore, this study has the potential to assess the efficacy of interventions aimed at enhancing the performance of healthcare professionals in hospital settings, thereby enhancing the overall quality of health service services provided by hospitals.\n\n\nEthics & consent\n\nThis study was approved by the Ethics Committee of Airlangga University Hospital on March 31 2023, with number 044/KEP/2023. In addition, the research protocol was recorded with the identification number UA-02-23026. Before performing the examination, we ensured that all patients provided written informed consent.\n\n\nAuthor contributions\n\nYS: Writing–original draft, conceptualization, methodology, formal analysis\n\nAY: Writing–review & editing, conceptualization, methodology, supervision\n\nIYW: Writing–review & editing, conceptualization, methodology, validation\n\nNP: Writing–review & editing, investigation\n\nNMH: Writing–review & editing, project administration\n\nSNL: Writing–review & editing, conceptualization, formal analysis\n\nANY: Writing–review & editing, project administration\n\n\nORCID ID\n\nYurike Septianingrum: https://orcid.org/0000-0002-7206-6389\n\nAh Yusuf: https://orcid.org/0000-0002-6669-0767\n\nIka Yuni Widyawati: https://orcid.org/0000-0001-6045-9719\n\nNunik Purwanti: https://orcid.org/0000-0003-2502-6138\n\nNety Mawarda Hatmanti: https://orcid.org/0000-0002-8708-466X\n\nShelly Nursofya Lestari: none\n\nAndis Yuswanto: https://orcid.org/0009-0002-0560-8106",
"appendix": "Data availability\n\nZenodo: Individual and health care provider factors influencing stroke self-management behavior: A cross-sectional study (Dataset). https://doi.org/10.5281/zenodo.11124878 (Septianingrum et al. 2024).\n\nThis project contains the following underlying data:\n\n• Demography Data.docx (respondent demographic data)\n\n• Dataset%20Yurike%20F1000.xlsx (respondents’ answers to the health service provider questionnaire and the self-management behavior questionnaire)\n\nZenodo: Individual and health care provider factors influencing stroke self-management behavior: A cross-sectional study (Dataset). https://doi.org/10.5281/zenodo.11124878.\n\nThis project contains the following underlying data:\n\n• Questionnaires in English.docx (The English version of the questionnaire was used in this study)\n\nZenodo: STROBE-checklist for Individual and health care provider factors influencing stroke self-management behavior: A cross-sectional study. https://doi.org/10.5281/zenodo.11124878 (Septianingrum et al. 2024).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nThe authors express their gratitude to all the respondents in the research who willingly contributed their personal information. The authors express their gratitude to the nurses working in the neurology outpatient department at Universitas Airlangga Hospital, as well as the Faculty of Nursing at Universitas Airlangga and Universitas Nahdlatul Ulama Surabaya, for their valuable assistance in supporting the execution of this research.\n\n\nReference styles\n\nAkhter N: Self-Management Among Patients with Hypertension in Bangladesh. Prince of Songkla University; 2010.\n\nAlderwick H, Hutchings A, Briggs A, et al.: The Impacts of Collaboration between Local Health Care and Non-Health Care Organizations and Factors Shaping How They Work: A Systematic Review of Reviews. BMC Public Health. 2021; 21(1): 1–16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlqahtani MMJ: Understanding the Sociocultural Health Belief Model Influencing Health Behaviors among Saudi Stroke Survivors. Neurosci. Med. 2015; 06(04): 149–159. Publisher Full Text\n\nAran N, Tregobov N, Kooij K, et al.: Health Literacy and Health Outcomes in Stroke Management: A Systematic Review and Evaluation of Available Measures. J. Humanit. Soc. Sci. 2022; 5(2): 172–191. Publisher Full Text\n\nBos-Touwen ID, Trappenburg JCA, Schuurmans MJ, et al.: Perceptions of Self-Management in Primary Care: A Cross-Sectional Survey Study.2017; (April). Publisher Full Text\n\nBricknell M, Hinrichs-Krapels S, Ismail S, et al.: Understanding the Structure of a Country’s Health Service Providers for Defence Health Engagement. BMJ Military Health. 2021; 167(6): 454–456. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBusari JO, Moll FM, Duits AJ: Understanding the Impact of Interprofessional Collaboration on the Quality of Care: A Case Report from a Small-Scale Resource Limited Health Care Environment. J. Multidiscip. Healthc. 2017; 10: 227–234. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen L, Chen Y, Chen X, et al.: Longitudinal Study of Effectiveness of a Patient-Centered Self-Management Empowerment Intervention During Predischarge Planning on Stroke Survivors. Worldviews Evid.-Based Nurs. 2018; 15(3): 197–205. PubMed Abstract | Publisher Full Text\n\nChen Y, Wei Y, Lang H, et al.: Effects of a Goal-Oriented Intervention on Self-Management Behaviors and Self-Perceived Burden After Acute Stroke: A Randomized Controlled Trial. Front. Neurol. 2021; 12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDineen-Griffin S, Garcia-Cardenas V, Williams K, et al.: Helping Patients Help Themselves: A Systematic Review of Self-Management Support Strategies in Primary Health Care Practice. PLoS One. 2019; 14(8): 1–29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDing G-B, Sang Q, Han H-J, et al.: Assessment of Stroke Knowledge and Awareness among Primary Healthcare Providers: A Cross-Sectional Survey from the Kezhou Quality Improvement in Acute Stroke Care Project. Front. Public Health. 2023; 11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDobkin BH: Behavioral Self-Management Strategies for Practice and Exercise Should Be Included in Neurologic Rehabilitation Trials and Care. Curr. Opin. Neurol. 2016; 29(6): 693–699. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDwyer M, Peterson GM, Gall S, et al.: Health Care Providers’ Perceptions of Factors That Influence the Provision of Acute Stroke Care in Urban and Rural Settings: A Qualitative Study. SAGE Open Med. 2020; 8: 205031212092108. PubMed Abstract | Publisher Full Text | Free Full Text\n\nElma LS, Aini N, Marta OFD, et al.: The Relationship Between Sociodemographic Factors and Self Management in Stroke Patients. KnE Med. 2022; 2022: 774–781. Publisher Full Text\n\nFugazzaro S, Denti M, Accogli MA, et al.: Self-Management in Stroke Survivors: Development and Implementation of the Look after Yourself (Lay) Intervention. Int. J. Environ. Res. Public Health. 2021; 18(11): 5925. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarfika J, Abdullah N: Pengaruh Kualitas Pelayanan Dan Fasilitas Terhadap Kepuasan Pasien Pada Rumah Sakit Umum Kabupaten Aceh Barat Daya. Balance. 2017; 14(1): 44–56. Publisher Full Text\n\nHarris B, Goudge J, Ataguba JE, et al.: Inequities in Access to Health Care in South Africa. J. Public Health Policy. 2011; 32(SUPPL. 1): S102–S123. Publisher Full Text\n\nIlhan MN, Durukan E, Ilhan SÖ, et al.: Self-Medication with Antibiotics: Questionnaire Survey among Primary Care Center Attendants. Pharmacoepidemiol. Drug Saf. 2009; 18(12): 1150–1157. PubMed Abstract | Publisher Full Text\n\nJarva E, Mikkonen K, Tuomikoski AM, et al.: Healthcare Professionals’ Competence in Stroke Care Pathways: A Mixed-Methods Systematic Review. J. Clin. Nurs. 2021; 30(9–10): 1206–1235. PubMed Abstract | Publisher Full Text\n\nKemenkes: Yuk, Mengenal Apa Itu Stroke. Diunduh Dari Http://P2ptm.Kemkes.Go.Id/Infographic-P2ptm/Stroke/Yuk-Mengenal-Apa-Itustroke.2019.\n\nKim SR, Kim S, Kim HY, et al.: Predictive Model of Self-Management in Patients With Stroke Based on the Information-Motivation-Behavioral Skills Model. J. Cardiovasc. Nurs. 2023; 38(2): 158–167. PubMed Abstract | Publisher Full Text Reference Source\n\nKoga M, Uehara T, Yasui N, et al.: Factors Influencing Cooperation among Healthcare Providers in a Community-Based Stroke Care System in Japan. J. Stroke Cerebrovasc. Dis. 2011; 20(5): 413–423. PubMed Abstract | Publisher Full Text\n\nKuo NY, Lin YH, Chen HM: Continuity of Care and Self-Management among Patients with Stroke: A Cross-Sectional Study. Healthcare (Switzerland). 2021; 9(8): 989. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLégaré F, Stacey D, Gagnon S, et al.: Validating a Conceptual Model for an Inter-Professional Approach to Shared Decision Making: A Mixed Methods Study. J. Eval. Clin. Pract. 2011; 17(4): 554–564. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLo SHS, Chang AM, Chau JPC: Stroke Self-Management Support Improves Survivors’ Self-Efficacy and Outcome Expectation of Self-Management Behaviors. Stroke. 2018; 49(3): 758–760. PubMed Abstract | Publisher Full Text\n\nLu J, Liu L, Wang Y, et al.: Social Engagement and Urban–Rural Disparity in Self-Management Behaviors: Study of Middle-Aged and Older Chinese Hypertension Patients. Front. Public Health. 2022; 9(January): 1–13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcLaney E, Morassaei S, Hughes L, et al.: A Framework for Interprofessional Team Collaboration in a Hospital Setting: Advancing Team Competencies and Behaviours. Healthc. Manage. Forum. 2022; 35(2): 112–117. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMiyamatsu N, Okamura T, Nakayama H, et al.: Public Awareness of Early Symptoms of Stroke and Information Sources about Stroke among the General Japanese Population: The Acquisition of Stroke Knowledge Study. Cerebrovasc. Dis. 2013; 35(3): 241–249. PubMed Abstract | Publisher Full Text\n\nNingrum TP, Alfatih H, Siliapantur HO: Faktor-Faktor Yang Memengaruhi Manajemen Diri Pasien DM Tipe 2. Jurnal Keperawatan BSI. 2019; 7(2): 114–126. Reference Source\n\nPearce G, Pinnock H, Epiphaniou E, et al.: Experiences of Self-Management Support Following a Stroke: A Meta-Review of Qualitative Systematic Reviews. PLoS One. 2015; 10(12): e0141803–e0141817. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRen XR, Wei YY, Xiang Ni S, et al.: Correlation between Self-Perceived Burden and Self-Management Behavior in Elderly Stroke Survivors: A Longitudinal Observational Study. Medicine. 2020; 99(44): e22862. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRiskesdas: Badan Penelitian Dan Pengembangan Kesehatan Kementerian RI Tahun 2018.2013. Reference Source\n\nSari MWN, Airlanda GS: Pengembangan E-Book Dengan Strategi Problem Based Learning Dalam Berpikir Kritis Dan Kreatif. Edukatif: Jurnal Ilmu Pendidikan. 2022; 4(4): 5845–5851. Publisher Full Text\n\nSeptianingrum Y, Siti Nurjanah AY, Pandin MGR: Do Self-Management Interventions Improve Self-Efficacy and Quality of Life in Stroke Survivors? A Systematic Review. Malays. J. Med. Health Sci. 2023; 19(May): 156–163. Reference Source\n\nSeptianingrum Y, Yusuf A, Widyawati IY, et al.: Individual and health care provider factors influencing stroke self-management behavior: A cross-sectional study. [Dataset]. Zenodo. 2024. Publisher Full Text\n\nShuqi H, Li Siqin W, Xiaoyan YR, et al.: The Risk Factors of Self-Management Behavior among Chinese Stroke Patients. Int. J. Clin. Pract. 2023; 2023: 1–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSmythe T, Inglis-Jassiem G, Conradie T, et al.: Access to Health Care for People with Stroke in South Africa: A Qualitative Study of Community Perspectives. BMC Health Serv. Res. 2022; 22(1): 464. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSun Y, Liu C, Zhang N, et al.: Effect of Self-Management of Stroke Patients on Rehabilitation Based on Patient-Reported Outcome. Front. Neurosci. 2022; 16(October): 1–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSzczepańska-Gieracha J, Mazurek J: The Role of Self-Efficacy in the Recovery Process of Stroke Survivors. Psychol. Res. Behav. Manag. 2020; 13: 897–906. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTeisberg E, Wallace S, O’Hara S: Defining and Implementing Value-Based Health Care: A Strategic Framework. Acad. Med. 2020; 95(5): 682–685. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWahyuningrum: Pengaruh Fasilitas Dan Kualitas Pelayanan Terhadap Kepuasan Psien Pada Rumah Sakit Umum Daerah (RSUD) Unggaran.2011.\n\nWhitehead L: Self-management Programmes for Quality of Life in People with Stroke. Int. J. Nurs. Pract. 2018; 24(2): 1. Publisher Full Text\n\nWHO: Integrated Health Service. World Health Organization; 2023; vol. 2023. . Reference Source\n\nWibawa EA, Kuntjoro T, Pinzon RT, et al.: Kepuasan Pasien Stroke Peserta Jkn Di Rs Lestari Raharja Satisfaction of Stroke Patients the National Health Insurance (Jkn) in the Lestari Raharja Hospital and Muntilan Hospital (Magelang Distric Hospital). Berkala Ilmiah Kedokteran Duta Wacana. 2016; 2(01): 255–266. Publisher Full Text\n\nYang H, Huang X, Yang C, et al.: Time Window for Acute Stroke Management: A Cross-Sectional Study Among Community Healthcare Practitioners in Primary Care. Int. J. Gen. Med. 2022; 15(April): 4483–4493. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "287057",
"date": "14 Jun 2024",
"name": "Siti Khuzaimah Ahmad Sharoni",
"expertise": [
"Reviewer Expertise Nursing",
"chronic disease(s) and community health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear author(s),\nSome feedback here for you to consider: 1. Introduction - To consider to update some of the old references (between 2-5 recent years) 2. Methods - 2.1 Materials - Universitas Airlangga Hospital, to add which country, Indonesia 2.2 Data collection procedures - repetitive words of \"of 29 questions\" 2.3 Data analysis and 3 Results - repetitive words of \"no missing data\" For the Chi-Square results - To consider Fisher exact test for those at least one of the expected values in a 2x2 table is less than 5\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-492
|
https://f1000research.com/articles/12-1241/v1
|
28 Sep 23
|
{
"type": "Method Article",
"title": "The SCOPE framework – implementing the ideals of responsible research assessment",
"authors": [
"Laura Himanen",
"Erica Conte",
"Marianne Gauffriau",
"Tanja Strøm",
"Baron Wolf",
"Elizabeth Gadd",
"Laura Himanen",
"Erica Conte",
"Marianne Gauffriau",
"Tanja Strøm",
"Baron Wolf"
],
"abstract": "Background: Research and researchers are heavily evaluated, and over the past decade it has become apparent that the consequences of evaluating the research enterprise and particularly individual researchers are considerable. This has resulted in the publishing of several guidelines and principles to support moving towards more responsible research assessment (RRA). To ensure that research evaluation is meaningful, responsible, and effective the International Network of Research Management Societies (INORMS) Research Evaluation Group created the SCOPE framework enabling evaluators to deliver on existing principles of RRA. SCOPE bridges the gap between principles and their implementation by providing a structured five-stage framework by which evaluations can be designed and implemented, as well as evaluated. Methods: SCOPE is a step-by-step process designed to help plan, design, and conduct research evaluations as well as check effectiveness of existing evaluations. In this article, four case studies are presented to show how SCOPE has been used in practice to provide value-based research evaluation. Results: This article situates SCOPE within the international work towards more meaningful and robust research evaluation practices and shows through the four case studies how it can be used by different organisations to develop evaluations at different levels of granularity and in different settings. Conclusions: The article demonstrates that the SCOPE framework is rooted firmly in the existing literature. In addition, it is argued that it does not simply translate existing principles of RRA into practice, but provides additional considerations not always addressed in existing RRA principles and practices thus playing a specific role in the delivery of RRA. Furthermore, the use cases show the value of SCOPE across a range of settings, including different institutional types, sizes, and missions.",
"keywords": [
"Research evaluation",
"responsible research assessment",
"evaluation framework",
"SCOPE"
],
"content": "1 Introduction\n\nThis article introduces the SCOPE framework for responsible research assessment (RRA) developed by the International Network of Research Management Societies’ (INORMS) Research Evaluation Group (REG) and situates it within the sector-wide drive towards more meaningful and robust research evaluation practices. It begins with a short overview of RRA and some of the underpinning declarations and principles that form its foundation. The need for the SCOPE framework as a mechanism which both delivers, and expands upon, those principles is then outlined. The SCOPE framework is then described and justified with reference to the scholarly literature. Four use cases demonstrating the wide applicability of SCOPE are then provided and some conclusions regarding both its usefulness and its applicability are drawn, highlighting both its strengths and weaknesses.\n\n\n2 Responsible research assessment\n\nResearch and researchers are heavily evaluated. There are many reasons for this. First and foremost, evaluation is a distinctive characteristic of science itself, as the demand for verifiability of results puts scientific research under the exacting scrutiny of fellow experts. As Robert Merton puts it (Merton, 1973, p. 276), “the activities of scientists are subject to rigorous policing, to a degree perhaps unparalleled in any other field of activity”. Evaluation has a major role in the knowledge-making process as both a gatekeeper and a legitimator of knowledge, and as a process itself: evaluation sets standards of research quality (Lamont & Huutoniemi, 2011). Demands for greater accountability, linked with diminishing funding, have also created expectations for universities to be both efficient and accountable. As such evaluation is essential to ensure that funding is used in the best possible way (Geuna & Martin, 2003). Research evaluation can also be seen as a governance tool to improve the quality of scholarship (Gläser & Laudel, 2007). It is used for monitoring the activities of researchers, projects, programmes, departments, and institutions – even nations.\n\nAccording to Geuna & Martin research evaluations tend to focus on four typical output measures: volume, quality, impact, and utility, with peer review and bibliometric measures as their main methods (Geuna & Martin, 2003). While peer review is considered as the key evaluation mechanism of scholarly work (Birukou et al., 2011), over the last two decades we have witnessed a strong increase in the use of quantitative techniques (Van Leeuwen, 2004). As stated in the Leiden Manifesto (Hicks et al., 2015, p. 431), “research metrics can provide crucial information that would be difficult to gather or understand by means of individual expertise.” Thelwall et al. argue that certain dimensions of scientific quality, such as scientific and societal impact and visibility, can be well-served by indicators (Thelwall et al., 2015). However, others have argued that indicators used in researcher assessment do not capture the elements that reflect high-quality research and knowledge advancement (Aubert Bonn & Pinxten, 2021b).\n\nWhatever method is used, it has become apparent that the consequences, both intended and unintended, of evaluating the research enterprise and particularly individual researchers are considerable. Some of the negative consequences include, but are not limited to, the stress and burden on researchers and administrators, tension between colleagues, biased and unfair evaluations, and misalignment with organisational missions and values (see, e.g., Aubert Bonn et al., 2022; Aubert Bonn & Pinxten, 2021a; Benedictus et al., 2016; Gadd, 2021; Lebel & McLean, 2018; Moher et al., 2018; Morrish, 2017; Muller, 2018; Saenen et al., 2019; Wellcome Trust, 2020). As a response, within the last decade, several guidelines and principles have been published to support moving towards more responsible modes of research evaluation, now commonly referred to as RRA.\n\n\n3 Key RRA principles and guidelines\n\nIn 2012, during the Annual Meeting of The American Society for Cell Biology in San Francisco, a group of editors and publishers of scholarly journals developed a set of recommendations known as the San Francisco Declaration on Research Assessment (DORA) (DORA, 2012). Since then, it has become a worldwide initiative, with over 23,000 individual signers and close to 2,900 organizational signers as of June 2023. DORA consists of 18 recommendations that are aimed at funding agencies, academic institutions, journals, organizations that supply metrics, and individual researchers. Even though it highlights the need to consider the value and impact of all research outputs in assessment, the recommendations focus primarily on practices relating to peer reviewed journal articles as the central mechanism by which research is currently assessed. A major recommendation is to eliminate the use of journal-based metrics and to assess research on its own merits rather than on the basis of the journal in which it is published. It also recommends the need to use a broad range of impact measures including qualitative indicators. For publishers and researchers, the recommendations also encompass responsible authorship practices, and for publishers and organizations that supply metrics related to issues of openness and transparency be included.\n\nIn 2015, the Leiden Manifesto for research metrics was published providing ten principles to guide bibliometric-based evaluation (Hicks et al., 2015). The authors of the manifesto were alarmed by the pervasive misapplication of indicators to the evaluation of scientific performance, and as a response presented the ten principles, “so that researchers can hold evaluators to account, and evaluators can hold their indicators to account” (ibid., 430). The first three principles consider the role of metrics in research evaluation on a general level. They remind us that the role of quantitative metrics in research assessment should be to support qualitative, expert assessment. Indicators should not be allowed to substitute informed judgement. When indicators are used, they should consider diverse research missions, and measure performance against those missions. Also, using metrics in research assessment poses a risk to locally relevant research as in many parts of the world research excellence is equated with English-language publications. The remaining seven principles are more practical in nature, considering issues around data collection and analytical processes, the use of indicators and the effects they have on the system.\n\nShortly after the Leiden Manifesto was produced, an independent review of the role of metrics in research assessment and management was published called The Metric Tide (Wilsdon et al., 2015). The review examined the role of metrics in the UK Research Excellence Framework (REF) conducted in 2014, but it also explored wider issues by looking at the applicability of metrics within different research systems, comparing the peer review system with metric-based alternatives, as well as examining the effects of the growing use of quantitative indicators on different aspects of research culture.\n\nAs part of the review, building on the concept of ‘responsible research and innovation’ the authors propose the notion of ‘responsible metrics’ as a way of framing appropriate uses of quantitative indicators in, inter alia, the assessment of research. Their understanding of responsible metrics is built on five principles that have some commonality with elements of DORA and the Leiden Manifesto. They call for recognition that quantitative evaluation should support expert assessment, for basing metrics on the best possible data in terms of accuracy and scope and keeping data collection and analytical processes open and transparent. Accounting for variation by field and using a range of indicators is recommended, as well as recognizing and anticipating the systemic and potential effects of indicators.\n\nThe Hong Kong Principles for assessing researchers: Fostering research integrity was published in 2020 (Moher et al., 2020). The starting point for the Hong Kong Principles differed from the three sets of principles previously described, in that its focus is on the need to recognize and reward researchers for behaviours that strengthen research integrity. The authors state that for knowledge to benefit research and society, it must be trustworthy, robust, rigorous, and transparent. The five principles call for researchers to be assessed on accurate and transparent research reporting and engaging with open science practices. In line with DORA, the Leiden Manifesto and the Metric Tide, the Hong Kong Principles call for valuing a broad range of research and scholarship, such as replication, innovation and translation, and other contributions to responsible research and scholarly activity, such as peer review activity, mentoring and outreach.\n\nThe most recent addition to the responsible research assessment landscape is the Agreement on Reforming Research Assessment which encompasses many of the ambitions of earlier declarations and expands upon them by requiring institutions to commit to actually changing their practice within an agreed timeframe (European University Association et al., 2022). The Agreement was published in 2022, and more than 350 organisations from over 40 countries were involved in the drafting. Signing up to the agreement became possible in September 2022 and by July 2023 almost 600 organisations had signed. The Agreement sets a shared direction for changes in assessment practices, as well as a timeframe for implementing reforms. In signing, organisations make four core commitments: to recognize a broader diversity of outputs, practices and activities when assessing research; to base assessment primarily on qualitative judgement supported by quantitative indicators where appropriate; to avoid inappropriate uses of journal and publication metrics and to avoid using university rankings in researcher assessment.\n\n\n4 The SCOPE Framework and RRA principles\n\nIn 2001 the International Network of Research Management Societies’ (INORMS) was formed to bring together research management societies and associations from across the globe. In recognition of the fact that research assessment was having a growing influence on the research management profession, INORMS established a Research Evaluation Group (INORMS REG) in 2018 to consider how best to ensure that research evaluation is meaningful, responsible, and effective. As part of the INORMS REG’s aim of guiding university leaders and practitioners in the adoption and practice of responsible research evaluation, they developed a framework that both enabled evaluators to deliver on existing principles of responsible assessment and to address some additional critical elements. As such, the SCOPE framework is a practical, five-stage step-by-step process for evaluating responsibly, supported by three overarching principles. Table 1 outlines how SCOPE seeks to deliver on some of the key elements of existing initiatives.\n\n\n\n· Eliminate journal-based metrics.\n\n· Assess research on its own merits.\n\n· Take advantage of online publication possibilities.\n\n\n\n· Metrics supporting rather than supplanting expert assessment.\n\n· Mission-based performance assessment.\n\n· Accounting for variation by field in citation metrics.\n\n\n\n· Robustness\n\n· Humility\n\n· Transparency\n\n· Diversity\n\n· Reflexivity\n\n\n\n1. Assessing responsible research practices\n\n2. Valuing complete reporting\n\n3. Rewarding the practice of open science\n\n4. Acknowledging a broad range of research activities\n\nSCOPE bridges the gap between principles and their implementation by providing a structured and orderly framework by which evaluations can be designed and implemented as well as evaluated. Existing principles focus mainly on either evaluating a specific entity, like researchers in the case of DORA and Hong Kong Principles, or via a particular mechanism, like research metrics in the case of Leiden Manifesto and Metric Tide. SCOPE seeks to be applicable across the whole research ecosystem, enabling a responsible approach to evaluating any entity via any relevant mechanism.\n\nAs well as enabling the implementation of existing RRA principles, SCOPE also brings additional elements perceived to be necessary in the implementation of responsible assessments. These include three essential principles: 1) to evaluate with the evaluated; 2) to evaluate only where necessary; and 3) to evaluate with the appropriate expertise. It also addresses the need to be context-sensitive, to consider both qualitative and quantitative options, and to probe for unintended consequences and to evaluate your evaluation. A full 19-page guide to SCOPE is available on the INORMS REG webpage (International Network Of Research Management Societies-Research Evaluation Group, 2021) and it is not our purpose to reproduce that here. However, in the next section we provide an outline of the SCOPE framework and principles in some detail situating it within the existing literature.\n\n\n5 The principles of SCOPE\n\nThe five stages of SCOPE presented in Figure 1 operate under three main principles. The first is to evaluate only where necessary. Hallonsten argues that science has been enormously productive even in times when quantitative performance evaluation was not a tool for science policy or university governance, that is, for most of modernity (Hallonsten, 2021). He goes on to conclude that whilst the continuous evaluation of quality is an essential feature of the scientific knowledge production process, the same does not apply to the evaluation of ‘excellence’ and ‘relevance’ for the sake of increasing efficiency and accountability (ibid., 19-20).\n\nDespite this, it is generally accepted that the Higher Education sector is now subject to neoliberal managerial approaches whereby if you can’t count it, it doesn’t count (Feldman & Sandoval, 2018). This increased focus on evaluation to both monitor progress and to incentivise behavioural change has led to a significant increase in the volume of assessments to which researchers, groups and institutions are subject. Whilst over-evaluation is particularly problematic when the range of contributions being assessed is narrow (e.g., the volume, location and citedness of publications (Saenen et al., 2019)) it remains problematic even when applied to a broader diversity of contributions. A new focus on open research practices, integrity and collegiality in our assessments doesn’t displace or even dilute a focus on publications and grant income, but simply expands the number of dimensions on which researchers are assessed. Many of these new dimensions are also not yet mature enough to be evaluated in a robust way at all levels of granularity, which can lead to well-intended but poorly designed evaluations based on limited data.\n\nPoor evaluation design and an overfocus on evaluation for evaluation’s sake has been highlighted as one of the key drivers of many mental health issues in the sector, driving many researchers to seek posts in industry (Gewin, 2022) or worse, to take catastrophic action (Parr, 2014). In response to these considerations, the SCOPE framework urges evaluators to ask at the outset whether they need to evaluate at all, or whether an alternative approach might be taken (such as enabling open research practices rather than evaluating them). Where an evaluation is deemed necessary, the extent of the evaluation effort should be commensurate with the potential impact of the evaluation. For example, surveys should ask the minimum viable number of questions and the frequency of assessments should be considered carefully.\n\nThe second principle of SCOPE is to evaluate with the evaluated. The principles of co-design are now central to many domains including product and service design, policy design and of course research design itself (Blomkamp, 2018; Moser, 2016; Steen et al., 2011). Co-design has also been a particularly important tool in efforts to meet equity, diversity and inclusion ambitions (KPMG, 2022). The benefits of co-design are seen to be a more creative process, better outcomes, and greater buy-in by stakeholder communities. It would seem entirely appropriate then, especially given sector concerns about the volume, quality, and format of research assessments, that a principle of co-design and co-evaluation should be adopted.\n\nIn this vein, the Leiden Centre for Science and Technology Studies (CWTS) recently proposed ‘evaluative inquiry’ as a more enabling approach to providing material for assessment (Fochler & De Rijcke, 2017). The approach seeks to present research work in ways that represent the complexity of actual practice by engaging with those practitioners instead of taking reductionist approaches to assessment for the sake of standardization (ibid., 34).\n\nThe use of SCOPE workshops to develop research evaluations are a good way of ensuring this principle is adhered to.\n\nThe third principle of SCOPE is to draw on evaluation expertise. The ready availability of bibliometric data and tools has led to concern from scientometricians around the rise of ‘armchair bibliometrics’ or ‘citizen scientometricians’ (Leydesdorff et al., 2016). It is common to find academics in every discipline running bibliometric analyses to better understand research activity in their field. This has led others to plead ‘epistemic trespass’. Ballantyne defines epistemic trespassers as “thinkers who have competence or expertise to make good judgements in one field but move to another field where they lack competence – and pass judgement nevertheless” (Ballantyne, 2019, p. 367). When it comes to research assessment, the fact that all researchers are regularly involved in assessing research proposals and applicants for research positions may give them greater confidence that they can expand this knowledge to designing research assessments. More recent emphasis on the need for responsible approaches to research assessment have brought into greater relief how easy it is to get research assessment design wrong. Clearly, the same rigour that is expected of academic research should be expected also of all evaluations of academic research.\n\n\n6 The five-stage SCOPE framework\n\nThe first stage of SCOPE, start with what you value, is a critically important first step in any evaluation. It is about exploring what is valued about the particular entity being evaluated: putting the ‘value’ in e-‘valu’-ation. This approach resonates with the Humane MetricsHSS initiative which supports values-enacted frameworks for evaluating all aspects of scholarly activity, as well as with Leiden Manifesto’s second principle urging that the performance of institutions, groups or researchers should be measured against their missions (Hicks et al., 2015).\n\nAn important question when considering what might be valued about an entity under evaluation, is to ask to whom the entity offers some value. For example, in a national university research assessment programme there are many stakeholders that all may value different things about the universities being evaluated: the treasury funding the outcomes, the government agency running the evaluation, the institutions themselves, the researchers who work in them, and so on. In line with the SCOPE principle of ‘evaluating with the evaluated’, the SCOPE approach would be to explore the question across a range of stakeholder perspectives and to seek to find consensus where possible.\n\nIf assessments are not developed in line with what stakeholders value about the entity being evaluated, too often they are made in line with what third parties value, or with historical values, or simply in accordance with the data we have available.\n\nThe problematic effects of relying on third party values such as the university rankings (see, e.g., Gadd, 2020, 2021; Van Raan, 2005) or national evaluation systems (see, e.g., Aagaard, 2015; Butler, 2005; Watermeyer et al., 2023) are well-documented. The key concern is that given Campbell’s Law (what we measure is what we get) (Campbell, 1979), by ‘outsourcing’ our values to others, evaluators run the risk of producing scholarship and research practices that are not in line with their own mission or ambitions.\n\nThe practice of starting with the data that is easily available, and evaluating what can be measured rather than what is valued, is often criticised (Lane et al., 2014). A common focus of such concerns is the over-use of bibliometrics in researcher recruitment and career assessment (Saenen et al., 2021). Proponents of value-led assessment approaches argue that evaluations should not be reduced to the concept of measurable achievements only, as there are multiple contributions that research and researchers make both to scholarship and society (Agate et al., 2020; Holtrop et al., 2020a).\n\nAt this stage of SCOPE it is important to maintain the first principle of ‘evaluating only where necessary’. Evaluators can fall into the trap of not taking the time to consider what is of the most value and therefore evaluate everything possible.\n\nDiscussions around what constitutes a ‘good’ or ‘bad’ indicator are abundant in the responsible research evaluation literature (e.g., Rijcke et al., 2016). However, whether an indicator (or indeed any assessment approach) can be determined as suitable or unsuitable depends on the context for that evaluation: what is being measured (entity and discipline) and for what purpose. For this reason, the second stage of SCOPE invites evaluators to consider the context of the evaluation.\n\nEntities under evaluation can range from nations through to individuals, and on each level different types of consideration need to be addressed. This is especially the case when those entities are seen through different disciplinary lenses (Holtrop et al., 2020b; Konkiel, 2018; Puuska, 2014; Ylijoki et al., 2011). It is often noted, for example, that whether an evaluation is conducted at a micro- or macro-level significantly affects whether and how quantitative indicators should be used (Waltman, 2018).\n\nIn terms of purposes, there are six commonly accepted purposes of research assessment: analysis, advocacy, allocation, accountability, acclaim and adaptation (Parks et al., 2019). The meanings of these terms are often contested by stakeholders, so the INORMS REG have provided short interpretive descriptions of each to aid understanding (see Figure 2). Sometimes evaluations can seek to achieve several different purposes, but it is important to specify these in advance and to consider the purpose in conjunction with the entity under evaluation, in order to ensure the evaluation design is appropriate. What works in one context does not necessarily work in another.\n\nTo aid this process, the INORMS REG have developed a matrix plotting the six key evaluation purposes against four different entity sizes to highlight how the impact of an assessment varies (Figure 2). The matrix illustrates that assessments in some settings have more impact on the entity being evaluated and are therefore more ‘high risk’. For example, monitoring a country’s research performance has less impact on the country being evaluated than evaluating an individual researcher for a promotion, and is therefore arguably a lower risk form of assessment. The exact ‘RAG-rating’ of each of these combinations might be debatable, but the matrix provides a useful heuristic to aid evaluators in understanding the dimensionality of research assessment and to ensuring that assessment approaches are context-sensitive.\n\nThe third stage of SCOPE is to explore all the options available for evaluating. This stage is a reminder to consider both quantitative and qualitative approaches and consider them in terms of the values and context of the evaluation (see, e.g., Butler, 2007; De Jong et al., 2011; Gingras, 2014; Holtrop et al., 2020c). The rule of thumb proposed by SCOPE is that quantitative indicators are best reserved for assessing quantitative things: student numbers, money, and citations. In the same way, qualitative approaches are best used for qualitative things: impact and quality. Caution should be taken about using quantitative indicators as a proxy for qualitative things. For example, citation counts are not a suitable proxy for research quality (see, e.g., Aksnes et al., 2019).\n\nIt is easy to focus on the dangers of quantitative approaches when considering responsible research assessment, and many declarations and principles do so. However, whilst peer-review is considered the gold standard for research evaluation, it is not without its own challenges (Bornmann & Daniel, 2006; Lee et al., 2013; Waltman et al., 2023). Recent concerns about increased journal retractions, and the prevalence of so-called ‘predatory’ journals have raised questions about the quality and reproducibility of peer review. Proponents of open research are calling for greater transparency and openness of peer review, and there are equity, diversity and inclusion concerns (Else & Perkel, 2022).\n\nThe truth is that there are limitations to all forms of research assessment, both qualitative and quantitative. For this reason, SCOPE requires evaluators to consider all their assessment options equally. It advocates that in most cases a mixed methods approach is more likely to generate a proportionate and appropriate assessment that will (as with the Hippocratic Oath) first do no harm (Sugimoto & Larivière, 2018). This will always involve human judgement in some form, and always involve an approximation of the reliability of the assessment, through error bars, list of caveats or limitations, and so on.\n\nGiven the many and varied values and contexts which may be evaluated, it is not possible to provide a comprehensive list of options for doing so via the SCOPE framework. However, the guidance promotes the use of alternative evaluation approaches such as those provided by the DORA resource library and the Metrics Toolkit to offer some inspiration.\n\nAt this stage it may be helpful to generate several different options given that the Probe stage will ‘stress-test’ these options and may render some unsuitable. The alternative is to consider both the Options and Probe stages together to ensure that no option is developed to such an extent that it becomes difficult to abandon it after being ‘probed’.\n\nOnce options for evaluating have been selected in line with stakeholder values and context and options, the fourth step is to probe deeply. To do this, SCOPE proposes that the evaluator should ask the following four questions of their evaluation:\n\n6.4.1 Who might the chosen approach discriminate against?\n\nThere is a considerable literature around the biases inherent in all forms of research evaluation as already stated. Demographics most likely fall victim to poor forms of assessment include early-career researchers (Algra et al., 2020), women (Jappelli et al., 2017, 2017; Larivière et al., 2013; Sugimoto & Larivière, 2023), intersectional groups (Bailey, 2018), and those working in non-journal-based disciplines. No evaluation is perfect and, as discussed, there are weaknesses in both qualitative and quantitative forms of assessment. For this reason, it is important to give significant thought to the question as to whether all entities being assessed have equal opportunity to succeed under the evaluation approach selected. If not, what mechanisms might be put in place to mitigate these inherent biases. Much work has been done in this space included the introduction of lotteries to more equitably decide between equally scoring proposals (Roumbanis, 2019), and the use of Unconscious Bias Observers on promotion panels (Bonello et al., 2017). ‘Evaluating with the evaluated’ (SCOPE’s second principle) and ensuring any consulted stakeholder group is representative, will also go some considerable way to addressing this question.\n\n6.4.2 How might this approach be gamed?\n\nA mantra often used by the INORMS REG is that ‘where there is a prize there is a game’. This refers to the fact that where there is a lot at stake in a particular evaluation (reputationally and financially), the entities being evaluated will naturally be incentivised to alter their behaviours in ways that enable them to perform well (Biagioli & Lippman, 2020). In some cases, this is indeed the purpose of an evaluation: evaluators will seek to assess a particular dimension (e.g., open research) to incentivise it. However, there is a spectrum of responses from evaluated parties to evaluation efforts, from legitimately optimising their activities (e.g., making more outputs open access), to ‘gaming’ their submissions (e.g., only reporting outputs once they’ve been made open access), to outright cheating (fabricating open access data). A strong evaluation should seek to anticipate potential opportunities for gaming with a view to designing them out of the system.\n\n6.4.3 What might the unintended consequences be?\n\nIn his book, The Tyranny of Metrics, Muller devotes a whole chapter to “the unintended but predictable negative consequences” of poor assessment practices and indicators (Muller, 2018). He describes some common unintended consequences in terms of goal displacement, short-termism, diminishing utility, rewarding luck, and discouraging risk-taking, innovation and cooperation. Trying to predict the potential harmful consequences of an evaluation approach into which the evaluator has invested much care and effort, is a difficult ask. Whilst it is not always possible to predict unintended consequences, it is important to attempt to do so at both an institutional as well as an individual level (see, e.g., Dahler-Larsen, 2014; Lorenz, 2014; Rijcke et al., 2016; Stephan et al., 2017; Wellcome Trust, 2020). The use of workshops to design evaluations ‘with the evaluated’, where the evaluated act as ‘critical friends’ is one useful way of identifying some of the unintended consequences before time and expense is invested into running the evaluation. However, it should be accepted that some consequences are not always predictable, and this is a question that should be returned to at the ‘Evaluate’ stage of SCOPE.\n\n6.4.4 Does the cost of measuring outweigh the benefit?\n\nAnother of Mueller’s unintended consequences of evaluation is the significant costs that may be incurred in both running and interpreting the assessment (Muller, 2018). SCOPE is clear that the cost, including the workload, stress, and finances, should be proportional to the aims and anticipated outcomes of the evaluation (Sawczak, 2018). Given the strongest evaluations usually consist of a mixed methods approach involving some element of human judgement, the cost of an evaluation can quickly escalate.\n\nA current case in point is the reported cost of running the 2021 UK Research Excellence Framework which came in at £471 million (Research England et al., 2023). This is only 3–4% of the block-grant funding linked to its outcomes; however, it is almost double the cost of the 2014 exercise (Else, 2015), which was in turn three times higher than the 2008 exercise (Sayer, 2015). The Joint UK HE Funding bodies have explicitly stated an intention to reduce the cost of the exercise in 2028. Similarly, the Danish government recently announced that they would discontinue the updating of the national bibliometric research indicator due to the cost and burden not being commensurate with the benefit (Uddannelses- og Forksningsministeriet, 2021).\n\nThere is no ‘correct answer’ when it comes to the cost:benefit ratio of an evaluation. However, as with all business decisions, those making the investment need to be reassured of an appropriate return. While evaluations can be extremely beneficial to generate intelligence, evidence, improve efficiencies or identify gaps, these benefits are only realized if the evaluation is designed in a way that provides usable outcomes at a reasonable cost.\n\nThe fifth, and final stage of SCOPE is to evaluate your evaluation. After conducting an evaluation, it is important to check if it reached its aims, if the results are useful, and if the evaluation approach brought new insights to what was being evaluated. Did the evaluation cause unintended consequences not foreseen at the Probe stage? If so, they should be considered when interpreting the results and addressed prior to future assessments. Even where an approach proved to be successful, it should be kept in mind that the tools available to undertake an evaluation (e.g., the data sources and indicators available) as well as values, missions, and strategies, are subject to change.\n\nThis last step of SCOPE is often overlooked but is of vital importance. Stufflebeam even considers meta-evaluation – the evaluation of evaluations – as a professional obligation of evaluators (Stufflebeam, 2001; see also, Scriven, 2009). In addition to any immediate post-assessment evaluation, established evaluations should also be re-evaluated at regular intervals to ensure they are still in alignment with what is valued about the entity under evaluation, and does not result in any unintended consequences that may require an adjustment to the evaluation. One of the strengths of SCOPE is that it can be used to both design new evaluations, and to assess existing evaluations. Thus the ‘E’ of SCOPE is really an invitation to run through the SCOPE process again to assess the evaluation that has been designed and implemented.\n\nWhilst SCOPE is presented as a linear, step-by-step, process, it is rather more iterative in practice. Each stage of SCOPE might send the evaluator back to a previous stage to reconsider a prior decision. For example, the unintended consequences unearthed at the Probe stage might cause the evaluator to consider whether the Options they have chosen are sensible, or even whether the evaluation is suitable for a particular Context. Ultimately, as long as each stage of SCOPE is considered in the design of an evaluation, it has a strong chance of being an appropriate and proportionate assessment.\n\n\n7 Use cases\n\nThe SCOPE framework is in wide usage by a range of organisations globally. Recent examples include the use of SCOPE by Indian funding agencies to develop assessment mechanisms (Suchiradipta et al., 2023), by Colombian research professionals to develop a responsible assessment policy (Pallares et al., 2023), by Finnish research managers to create an institutional policy on assessment of researchers (University of Turku, n.d.) and by UK research leaders to develop an approach to assessing research culture (Davies & Fadhel, 2023). Example case studies are regularly added to the SCOPE webpage. This section provides four case studies to demonstrate how it has been used by different types of organisations to develop evaluations at different levels of granularity and in different settings.\n\n7.1.1 Background\n\nEmerald Publishing is a global scholarly publisher committed to equity, diversity, and inclusion. As such they were keen to start monitoring and incentivising greater diversity and representation on the editorial boards of their scholarly journals. Being aware of the sensitivities around this, they used the SCOPE framework to explore how they might do so (Gadd & Himanen, 2021a).\n\n7.1.2 Process\n\nThe publisher firstly ran a 90-minute Start with what you value workshop with ten editors and editorial board members and supported by the INORMS REG. This explored ‘what might a diverse editorial board look like’ and ‘what aspects of diversity actually benefit a journal’ in the agreed context of ‘incentivising’ greater diversity in editorial boards. Given the SCOPE principle of evaluating only where necessary, a discussion was held as to whether the valued dimensions of diversity should be enabled rather than evaluated. Options for evaluating this value in these contexts were discussed with Emerald first presenting some examples of what can be assessed using existing systems and approaches.\n\nA second 90-minute workshop was then run to explore Options in greater detail with the Emerald Publishing Editorial and Rights/Legal team members. The options were probed using the four key probe questions at the same time.\n\n7.1.3 Outcomes\n\nA key learning point from the values stage was that the editorial board members’ views of diversity included subject diversity, diversity in the way knowledge is/can be disseminated as well as regional diversity. Editorial Board members also felt that a commitment to diversity should be taken as part of a wider review of editorial board processes and policies, e.g., dormancy in editorial boards and whether boards would benefit from shorter-term appointments. Also, they felt that diversity within editorial boards was necessarily affected by the broader challenges around the prevailing model of creating scientific knowledge (e.g., the use of unpaid editorial positions) and global inequality more broadly.\n\nConsidering the context of ‘incentivisation’ led to interesting discussions as to whether this value needed enabling or evaluating. Interestingly, the workshop members felt it needed both, and that some sort of ‘badges’ or external signifier that the journal was at least committed to improving diversity, would be welcomed. Another important question asked who was being incentivised in this context: Emerald Publishing, editors and/or editorial board members? Ultimately it was agreed that editors should be the focus of any enabling and evaluating activity, but the relationship between publisher and editors is a carefully balanced one.\n\nWhile a mixed evaluate-and-enable approach was agreed upon, many of the actions and ideas that came from the workshops were focussed on enabling diversity. Options floated included both paying editorial board members to allow less-well-funded scholars to participate and introducing a Diversity Editorial Pledge whereby editors could be rewarded for a commitment to diversity. Probing these options generated questions around the sensitivities and challenges associated with monitoring diversity-related data.\n\nThe SCOPE process resulted in a range of short, medium, and long-term actions for Emerald Publishing to pursue. The immediately actionable items included building expectations around diversity into contracts/job descriptions for Editors; making diversity a rolling agenda point for Editorial meetings and reporting on progress around diversity in Editorial Advisory Board (EAB) meetings; and encouraging editors and EABs to identify their own success EDI indicators in line with their values.\n\n7.2.1 Background\n\nResearch England, the Scottish Funding Council, the Northern Ireland Department for the Economy, and the Higher Education Funding Council for Wales commissioned the Future Research Assessment Programme (FRAP) with a view to designing a new national research assessment exercise in the UK. The outcomes of the current system are used to inform the allocation of quality-related research funding to UK universities and provide accountability for public investment in research. It was felt that without a proper framework such a review could focus narrowly on making minor adjustments to the existing system (‘evolution’) or solely rely on learning from other international research assessment approaches (‘reproduction’) when what the funding bodies really sought was a root-and branch review (possible ‘revolution’). It was felt that the SCOPE framework offered a structure for thinking about such a review, providing “the perfect brief to be radical” (Gadd & Himanen, 2021b, p. 2).\n\n7.2.2 Process\n\nThe use of SCOPE by the funding bodies was unmediated by the INORMS REG (Gadd & Himanen, 2021b). The FRAP team were keen to start with what was valued about the research system. Deploying the ‘Evaluate with the evaluated’ principle, they held a series of round-table events with different stakeholder groups. To create a healthy ecosystem, it was important to the team to not only start with what was valued, but to also agree which of those valued things should be evaluated. Understanding the contexts in which the national research evaluation exercise should take place was an important step in the process. The REF exercise that ran in 2021 served a wide range of purposes and the team sought to identify which were non-negotiable. The FRAP team were inspired by the options stage of exploring both qualitative and quantitative options to develop a set of spectra to understand the community's appetite for different variables, for example, around the degree of automation, centralisation, granularity, and frequency (see Figure 3).\n\nOf particular interest to the funding bodies was to probe for unintended consequences and perverse incentives. The cost-benefit of the exercise was explored in a dedicated assessment (Neto et al., 2023).\n\n7.2.3 Outcomes\n\nThe REF 2028 Initial Decisions (Research England et al., 2023) show many of the hallmarks of a SCOPE-led assessment. The principle of ‘evaluating with the evaluated’ and starting with what was valued is clearly in evidence and the principle of’drawing on evaluation expertise’ was fulfilled by utilising specialists to produce reports on metrics (Curry et al., 2022), artificial intelligence (Thelwall et al., 2022) and a ‘real-time REF review’ to support the process (Manville et al., 2021). The clear articulation of the purposes of the next REF specifies the context and the options carefully balance both qualitative and quantitative measures in an effort to reduce burden. The Initial Decisions document makes frequent reference to the need to mitigate unintended consequences particularly to under-represented groups. Further consultation is afoot, again on the principle of ‘Evaluating with the Evaluated’ to ensure no foreseeable but unintended consequences are at play.\n\n7.3.1 Background\n\nTo support Newcastle University’s work on enhancing their research culture, they used the SCOPE framework to develop a set of research culture Key Performance Indicators (KPIs) for the University’s Research Strategy and a basket of measures for their ‘Research Culture Index’.\n\n7.3.2 Process\n\nUsing the SCOPE framework and supported by the INORMS REG, the University held an initial community workshop with around 80 colleagues (both academic and professional services colleagues) and postgraduate students to identify what people valued in a positive research culture. They sought to understand both what a positive research culture ‘looked and felt like’ to fully understand how it might enhance the research community’s experiences in relation to doing great research. The resulting values were then tested and refined at a subsequent smaller workshop of some of the attendees.\n\nOnce agreed, a smaller facilitated focus group was held to generate a series of options of measures for evaluation within the context of’monitoring’ as KPIs. The options were then probed for any unintended consequences. The resulting set of measures were shared with colleagues with relevant expertise within the University to check for feasibility and viability in the context of different Faculty-based disciplines and given the practicalities of the University’s research reporting systems.\n\n7.3.3 Outcomes\n\nThe first high-level workshop identified four key attributes of a positive research culture in terms of:\n\n• Collaboration and collegiality\n\n• The freedom to explore and grow\n\n• Fairness and inclusion\n\n• Openness and integrity\n\nThe second workshop explored the dimensions (or ‘sub-values’) of these attributes that constituted the’look and feel’ of a positive research culture. These included strong support for the careers of others, a sense of belonging, and increasing empowerment and satisfaction. These sub-values more easily lent themselves to the development of specific options for monitoring improvement.\n\nSeventeen options were ultimately selected after a number were excluded during the probe stage. One example of an excluded measure was ‘Bullying and harassment reporting.’ This was excluded as it would only reflect reporting rather than occurrence, and it was unclear whether the measure should increase or decrease. For example, an increase in reporting could be interpreted as a positive if people feel safer and more supported to report, but also a negative if it captures increasing incidence. The final outcome of the process was a ‘Research Culture Index’ with seventeen dimensions and some of these informed the revision of the University’s Research Strategy KPIs.\n\n7.4.1 Background\n\nThe University of Alberta, in Edmonton, Canada, has been exploring ways to implement responsible research evaluation approaches throughout the University. Particularly their Research Impact Librarians were interested in learning how to conduct research assessment more effectively and more equitably. Upon learning of the SCOPE framework, they identified the need to provide training on this approach to various members of their community.\n\n7.4.2 Process\n\nIt was determined to hold two consecutive workshops assisted by the INORMS REG that focused on the exploration and then implementation of the SCOPE framework, with the goal to increase capacity within the University of Alberta to develop, evaluate and refine responsible research assessments.\n\nThe first workshop was more didactic in nature as many attendees were not yet familiar with the SCOPE framework. As such, this 90-minute session focused on the principles and stages within the SCOPE framework, providing the knowledge and understanding behind each stage of the process. This workshop was attended by a broad range of individuals including senior university leadership, representatives from various faculties and departments, and library information specialists.\n\nThe second 2-hour workshop focused on the direct implementation and application of the SCOPE framework with a smaller subset of individuals who routinely develop or participate in research assessment. Since the University was working to develop better assessment of knowledge mobilisation (KM), this was used as the working example. For each stage of the SCOPE framework various small group exercises or group discussions were held to explore the aspects of KM that were valued the most (impact in policy, uptake by community, scientific knowledge, etc); in which context they sought to assess KM (advocacy of the organization, accountability of departments, etc.); what were the options they had, or could develop, to assess KM (collaborations, policy changes, publications, commercialisation, etc.); how they could probe these options to determine if there was bias or discrimination that needs to be considered or addressed, and finally how they could thoughtfully evaluate their assessment to determine if it met the principles of the SCOPE framework.\n\n7.4.3 Outcome\n\nThe University of Alberta found these workshops increased both knowledge and capacity in the responsible research assessment. While KM was used a case example during the workshop, it was acknowledged that development of robust framework would need to be co-developed with those being evaluations and should also involve reaching out to others who were heavily invested in the assessment of KM, such as Research Impact Canada, to draw on available expertise. The University of Alberta now has plans to use SCOPE in ongoing development of multiple assessments and in the re-evaluation of previously established processes.\n\n\n8 Discussion and conclusions\n\nThe SCOPE framework seeks to support evaluators in any and every research setting to implement the many complementary principles of RRA in the design and delivery of their evaluation approaches. In this way it bridges the gap between principles and practice. However, SCOPE does not simply translate existing principles into practice, but provides additional considerations not always addressed by principles of RRA, such as evaluating with the evaluated, evaluating only where necessary, starting with what is valued and probing for unintended consequences. Thus SCOPE, with its focus on implementation, plays a specific role in the delivery of RRA.\n\nThe use cases presented show the value of SCOPE across a range of settings. This highlights one of the strengths of SCOPE, namely, that it is widely applicable and enables both quantitative and qualitative assessments for any purpose, at any level, and any discipline and can be used by any evaluator with any background (assuming of course, that they draw on appropriate expertise as required by principle three). To develop a framework with such wide applicability has necessitated it to take a very high-level, somewhat simplified, approach to research assessment. Indeed, the whole framework can be presented in a one-page overview (see Figure 1). This is both a strength and a weakness.\n\nMuch of the feedback received is that the beauty of SCOPE lies in its simplicity. The main principles and stages can be communicated and understood in a few minutes. It can also be used with or without assistance from the INORMS REG as evident from the use cases. This is probably why it has captured the imagination of the global research community and been so widely adopted. However, as can be seen by the full SCOPE guide there is a lot more underneath the simple heuristics to be explored and understood (International Network Of Research Management Societies-Research Evaluation Group, 2021). An evaluator that has sought to apply SCOPE without drawing on appropriate evaluation expertise may misinterpret some of the steps and claim they have a ‘SCOPE-compliant’ evaluation where this might not be the case.\n\nOther feedback sometimes received is that the framework is common sense and aligned with existing practice. Whilst the team would agree with the former, continued evidence of poorly designed research assessments gives the lie to the latter. SCOPE is simple but is not universally applied. Were each of the stages of SCOPE properly applied under its three principles, the existence of problematic research evaluations would be greatly diminished. What might look like common sense at first is, in reality, a series of deep and fundamental questions enabling both the evaluators and the evaluated to reflect on their practices and their assumptions. This reflection leads to an explicit definition of the values that are the foundation for an evaluation and focuses attention on potential biases and weaknesses in the evaluation design, which may not ordinarily be given their due attention. Thus, where evaluation may previously have been an implicit part of publishing, hiring, budgeting, etc., SCOPE puts a focus on evaluation in its own right.\n\nOne of the strengths of SCOPE is that in addition to enabling the design of responsible research assessments, it can act as a training framework for research evaluators. Many more professionals (research managers, planners, funders, librarians, and publishers) are being called upon to design or evaluate research with no formal training, nor the capacity or opportunity to undertake any. Many researchers who have had to participate in some form of evaluation as part of their roles (journal peer review, recruitment, etc.,) might feel that this knowledge is transferrable to other forms of evaluation without recognising some of the differences between various forms of assessment. SCOPE is simple enough and accessible enough to provide a framework for a deeper understanding of responsible research assessment practice and could support the greater professionalisation of research evaluation.\n\nAs demonstrated in this paper each of the three principles and the five stages in the SCOPE framework are rooted firmly in the existing research literature, whilst consolidating and expanding on this evidence with lessons learned from experience. Whilst RRA began as a series of objections against data-driven research evaluations, the SCOPE framework provides evaluators with a more positive, comprehensive, and practical approach to all forms of research assessment. It is offered up to the community as a useful tool in the toolbox of all research evaluators.\n\n\nAuthor Contributions\n\n\n\n• Conceptualization: all\n\n• Investigation: all\n\n• Methodology: all\n\n• Project administration: Himanen, Gauffriau, Gadd\n\n• Supervision: Gadd\n\n• Writing – original draft: Himanen, Conte, Gauffriau, Gadd\n\n• Writing – review & editing: all",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nAcknowledgements\n\nThe authors are grateful for the contributions to the four case studies from Sally Wilson of Emerald Publishing, Catriona Firth of Research England, Candy Rowe & Sarah Whalley of Newcastle University, and Thane Chambers of the University of Alberta.\n\n\nReferences\n\nAagaard K: How incentives trickle down: Local use of a national bibliometric indicator system. Sci. Public Policy. 2015; 42(5): 725–737. Publisher Full Text\n\nAgate N, Kennison R, Konkiel S, et al.: The transformative power of values-enacted scholarship. Humanities and Social Sciences Communications. 2020; 7(1): 165. Publisher Full Text\n\nAksnes DW, Langfeldt L, Wouters P: Citations, Citation Indicators, and Research Quality: An Overview of Basic Concepts and Theories. SAGE Open. 2019; 9(1): 215824401982957. Publisher Full Text\n\nAlgra A, Koopman I, Snoek R: How young researchers can re-shape the evaluation of their work. Nature Index News.2020. Reference Source\n\nAubert Bonn N, De Vries RG, Pinxten W: The failure of success: Four lessons learned in five years of research on research integrity and research assessments. BMC. Res. Notes. 2022; 15(1): 309. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAubert Bonn N, Pinxten W: Advancing science or advancing careers? Researchers’ opinions on success indicators. PLoS One. 2021a; 16(2): e0243664. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAubert Bonn N, Pinxten W: Rethinking success, integrity, and culture in research (part 1)—A multi-actor qualitative study on success in science. Research Integrity and Peer Review. 2021b; 6(1): 1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBailey M: On misogynoir: Citation, erasure, and plagiarism. Fem. Media Stud. 2018; 18(4): 762–768. 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Reference Source\n\nBornmann L, Daniel H-D: Potential sources of bias in research fellowship assessments: Effects of university prestige and field of study. Research Evaluation. 2006; 15(3): 209–219. Publisher Full Text\n\nButler L: What Happens When Funding is Linked to Publication Counts?Moed HF, Glänzel W, Schmoch U, editors. Handbook of Quantitative Science and Technology Research. Kluwer Academic Publishers; 2005; (pp. 389–405). Publisher Full Text\n\nButler L: Assessing university research: A plea for a balanced approach. Sci. Public Policy. 2007; 34(8): 565–574. Publisher Full Text\n\nCampbell DT: Assessing the impact of planned social change. Eval. Program Plann. 1979; 2(1): 67–90. Publisher Full Text\n\nCurry S, Gadd E, Wilsdon J: Harnessing the Metric Tide: Indicators, infrastructures & priorities for UK responsible research assessment. Research on Research Institute; 2022; 11014215 Bytes. Publisher Full Text\n\nDahler-Larsen P: Constitutive Effects of Performance Indicators: Getting beyond unintended consequences. Public Manag. Rev. 2014; 16(7): 969–986. Publisher Full Text\n\nDavies C, Fadhel S: Using SCOPE to select metrics to track improvements in Research Culture: Interim reflections. University of Leeds; 2023. Reference Source\n\nDe Jong SPL, Van Arensbergen P, Daemen F, et al.: Evaluation of research in context: An approach and two cases. Research Evaluation. 2011; 20(1): 61–72. Publisher Full Text\n\nElse H: REF 2014 cost almost £250 million. Times Higher Education. 2015. Reference Source\n\nElse H, Perkel JM: The giant plan to track diversity in research journals. Nature. 2022; 602(7898): 566–570. PubMed Abstract | Publisher Full Text\n\nEuropean University Association, Science Europe, European CommissionStroobants K: Agreement on reforming research assessment.2022; (p. 23). Reference Source\n\nFeldman Z, Sandoval M: Metric Power and the Academic Self: Neoliberalism, Knowledge and Resistance in the British University. TripleC: Communication, Capitalism & Critique. Open Access Journal for a Global Sustainable Information Society. 2018; 16(1): 214–233. Publisher Full Text\n\nFochler M, De Rijcke S: Implicated in the Indicator Game? An Experimental Debate. Engag. Sci. Technol. Soc. 2017; 3: 21–40. Publisher Full Text\n\nGadd E: University rankings need a rethink. Nature. 2020; 587(7835): 523–523. PubMed Abstract | Publisher Full Text\n\nGadd E: Mis-measuring our universities: Why global university rankings don’t add up [Preprint]. SocArXiv. 2021. Publisher Full Text\n\nGadd E, Himanen L: INORMS SCOPE Case Study: Emerald Publishing: Evaluating the diversity of editorial boards.2021a; (p. 5). Reference Source\n\nGadd E, Himanen L: INORMS SCOPE Case Study: The UK Higher Education Funding Bodies: Developing a new national research evaluation system.2021b; (p. 5). Reference Source\n\nGeuna A, Martin BR: University Research Evaluation and Funding: An International Comparison. Minerva. 2003; 41(4): 277–304. Publisher Full Text\n\nGewin V: Has the ‘great resignation’ hit academia?. Nature. 2022; 606(7912): 211–213. PubMed Abstract | Publisher Full Text\n\nGingras Y: Criteria for evaluating indicators. Beyond bibliometrics: Harnessing multidimensional indicators of scholarly impact. The MIT Press; 2014; (pp. 109–125).\n\nGläser J, Laudel G: Evaluation Without Evaluators.Whitley R, Gläser J, editors. The Changing Governance of the Sciences. Netherlands: Springer; 2007; Vol. 26. : pp. 127–151. Publisher Full Text\n\nHallonsten O: Stop evaluating science: A historical-sociological argument. Soc. Sci. Inf. 2021; 60(1): 7–26. Publisher Full Text\n\nHicks D, Wouters P, Waltman L, et al.: Bibliometrics: The Leiden Manifesto for research metrics. Nature. 2015; 520(7548): 429–431. PubMed Abstract | Publisher Full Text\n\nHoltrop T, Hessels L, Prins A: Evaluative Inquiry I: Academic value is more than performance. Leiden Madtrics. 2020a. Reference Source\n\nHoltrop T, Hessels L, Prins A: Evaluative Inquiry II: Evaluating research in context. Leiden Madtrics. 2020b. Reference Source\n\nHoltrop T, Hessels L, Prins A: Evaluative Inquiry III: Mixing methods for evaluating research. Leiden Madtrics. 2020c. Reference Source\n\nInternational Network Of Research Management Societies-Research Evaluation Group: The SCOPE Framework: A five-stage process for evaluating research responsibly. International Network of Research Management Societies; 2021; 668558 Bytes. Publisher Full Text\n\nJappelli T, Nappi CA, Torrini R: Gender effects in research evaluation. Res. Policy. 2017; 46(5): 911–924. Publisher Full Text\n\nKonkiel S: Approaches to creating ‘humane’ research evaluation metrics for the humanities. Insights the UKSG Journal. 2018; 31: 44. Publisher Full Text\n\nKPMG: Health workforce equity, diversity and inclusion: Taking deliberate actions to develop inclusive and equitable workplace cultures.2022. Reference Source\n\nLamont M, Huutoniemi K: Comparing Customary Rules of Fairness: Evaluative Practices in Various Types of Peer Review Panels.Camic C, Gross N, Lamont M, editors. Social knowledge in the making. University of Chicago Press; 2011.\n\nLane J, Largent M, Rosen R: Science Metrics and Science Policy.Cronin B, Sugimoto CR, editors. Beyond bibliometrics: Harnessing multidimensional indicators of scholarly impact. The MIT Press; 2014; (pp. 397–411).\n\nLarivière V, Ni C, Gingras Y, et al.: Bibliometrics: Global gender disparities in science. Nature. 2013; 504(7479): 211–213. PubMed Abstract | Publisher Full Text\n\nLebel J, McLean R: A better measure of research from the global south. Nature. 2018; 559(7712): 23–26. Publisher Full Text\n\nLee CJ, Sugimoto CR, Zhang G, et al.: Bias in peer review. J. Am. Soc. Inf. Sci. Technol. 2013; 64(1): 2–17. Publisher Full Text\n\nLeydesdorff L, Wouters P, Bornmann L: Professional and citizen bibliometrics: Complementarities and ambivalences in the development and use of indicators—a state-of-the-art report. Scientometrics. 2016; 109(3): 2129–2150. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLorenz C: Fixing the facts: The rise of new public management, the metrification of “quality” and the fall of the academic professions. Moving the Social. 2014; 52: 5–26.\n\nManville C, d’Angelo C, Culora A, et al.: Understanding perceptions of the Research Excellence Framework among UK researchers: The Real-Time REF Review. RAND Corporation; 2021; 140. Reference Source\n\nMerton RK: The normative structure of science.Merton RK, Storer NW, editors. The Sociology of Science: Theoretical and Empirical Investigations. The University of Chicago Press; 1973.\n\nMoher D, Bouter L, Kleinert S, et al.: The Hong Kong Principles for assessing researchers: Fostering research integrity. PLoS Biol. 2020; 18(7): e3000737. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoher D, Naudet F, Cristea IA, et al.: Assessing scientists for hiring, promotion, and tenure. PLoS Biol. 2018; 16(3): e2004089. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorrish L: Why the audit culture made me quit. Times Higher Education. 2017. Reference Source\n\nMoser SC: Can science on transformation transform science? Lessons from co-design. Curr. Opin. Environ. Sustain. 2016; 20: 106–115. Publisher Full Text\n\nMuller J: The Tyranny of Metrics. Princeton University Press; 2018. Publisher Full Text\n\nNeto A, Vingre A, D’Hont J, et al.: REF 2021 Cost Evaluation: Final report.2023; (p. 78). Reference Source\n\nPallares C, Chalela S, Tejada MA, et al.: The Colombian responsible metrics Project: Towards a Colombian institutional, methodological instrument for research assessment. DORA Blog. 2023. Reference Source\n\nParks S, Rodriguez-Rincon D, Parkinson S, et al.: The changing research landscape and reflections on national research assessment in the future (RR-3200-UKRI). RAND Corporation; 2019; 204. Reference Source\n\nParr C: Imperial College professor Stefan Grimm ‘was given grant income target.’ Times Higher Education. 2014. Reference Source\n\nPuuska H-M: Scholarly Publishing Patterns in Finland: A comparison of disciplinary groups. Tampere University; 2014. Reference Source\n\nResearch England, Scottish Funding Council, Higher EducationFundng Council for Wales, & Department for the Economy, Northern Ireland: Research Excellence Framework 2028: Initial decisions and issues for further consultation (REF 2028/23/01; p. 34).2023. Reference Source\n\nRijcke SD, Wouters PF, Rushforth AD, et al.: Evaluation practices and effects of indicator use—A literature review. Research Evaluation. 2016; 25(2): 161–169. Publisher Full Text\n\nRoumbanis L: Peer Review or Lottery? A Critical Analysis of Two Different Forms of Decision-making Mechanisms for Allocation of Research Grants. Sci. Technol. Hum. Values. 2019; 44(6): 994–1019. Publisher Full Text\n\nSaenen B, Hatch A, Curry S, et al.: Reimagining Academic Career Assessment: Stories of innovation and change. DORA; European University Association; SPARC Europe; 2021; 47. Reference Source\n\nSaenen B, Morais R, Gaillard V, et al.: Research Assessment in the Transition to Open Science: 2019 EUA Open Science and Access—Survey Results. European University Association; 2019; 48. Reference Source\n\nSan Francisco Declaration on Research Assessment: 2012. Reference Source\n\nSawczak K: The hidden costs of research assessment exercises: The curious case of Australia. LSE Impact Blog. 2018. Reference Source\n\nSayer D: Why did REF2014 cost three times as much as the RAE? Hint: It’s not just because of the added impact element. LSE Impact Blog. 2015. Reference Source\n\nScriven M: Meta-Evaluation Revisited. Journal of MultiDisciplinary Evaluatio. 2009; 6(11): iii–viii.\n\nSteen M, Manschot M, De Koning N: Benefits of Co-design in Service Design Projects. Int. J. Des. 2011; 5(2): 53–60.\n\nStephan P, Veugelers R, Wang J: Reviewers are blinkered by bibliometrics. Nature. 2017; 544(7651): 411–412. Publisher Full Text\n\nStufflebeam DL: The Metaevaluation Imperative. Am. J. Eval. 2001; 22(2): 183–209. Publisher Full Text\n\nSuchiradipta B, Koley M, Bharadwa J: Workshop on Research Assessment Practices in Indian Funding Agencies. Journal of Science Policy & Governance. 2023; 22(1). Publisher Full Text\n\nSugimoto CR, Larivière V: Measuring research: What everyone needs to know. Oxford University Press; 2018.\n\nSugimoto CR, Larivière V: Equity for women in science: Dismantling systemic barriers to advancement. Harvard University Press; 2023.\n\nThelwall M, Kousha K, Wouters P, et al.: The metric tide: Literature review.2015. Publisher Full Text\n\nThelwall M, Kousha K, Abdoli M, et al.: Can REF output quality scores be assigned by AI? Experimental evidence.2022. Publisher Full Text\n\nUddannelses- og Forksningsministeriet: Aftale mellem regeringen Socialdemokratiet), Dansk Folkeparti, Socialistisk Folkeparti, Radikale Venstre, Enhedslisten, Det Konservative Folkeparti, Nye Borgerlige, Frie Grønne, Liberal Alliance, Alternativet og Kristendemokraterne om: Basismidler til forskning.2021. Reference Source\n\nUniversity of Turku: Policy for Responsible Assessment of Research and Researcher. University of Turku; n.d.; 8. Reference Source\n\nVan Leeuwen T: Descriptive Versus Evaluative Bibliometrics: Monitoring and Assessing of National R&D Systems.Moed HF, Glänzel W, Schmoch U, editors. Handbook of Quantitative Science and Technology Research. Netherlands: Springer; 2004; (pp. 373–388). Publisher Full Text\n\nVan Raan AFJ: Fatal attraction: Conceptual and methodological problems in the ranking of universities by bibliometric methods. Scientometrics. 2005; 62(1): 133–143. Publisher Full Text\n\nWaltman L: Responsible metrics: One size doesn’t fit all. CWTS Blog. 2018. Reference Source\n\nWaltman L, Kaltenbrunner W, Pinfield S, et al.: How to improve scientific peer review: Four schools of thought. Learned Publishing. 2023; 36(3): 334–347. Publisher Full Text\n\nWatermeyer R, Derrick GE, Borras Batalla M: Affective auditing: The emotional weight of the research excellence framework. Research Evaluation. 2023; 31(4): 498–506. Publisher Full Text\n\nWellcome Trust: What Researchers Think About the Culture They Work In. Wellcome Trust; 2020; 51. Reference Source\n\nWilsdon J, Allen L, Belfiore E, et al.: The metric tide: Report of the independent review of the role of metrics in research assessment and management.2015. Publisher Full Text\n\nYlijoki O-H, Lyytinen A, Marttila L: Different research markets: A disciplinary perspective. High. Educ. 2011; 62(6): 721–740. Publisher Full Text\n\n\nFootnotes\n\n1 The case description is based on INORMS REG members’ meetings with Sarah Whalley, Research Strategy Manager at Newcastle University.\n\n2 The case description is based on INORMS REG members’ meetings with Thane Chambers, Librarian at University of Alberta."
}
|
[
{
"id": "218194",
"date": "19 Dec 2023",
"name": "Sven E Hug",
"expertise": [
"Reviewer Expertise Research evaluation",
"bibliometrics",
"peer review"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe SCOPE framework is a significant milestone in the evolution of the field of research evaluation, as it is the first framework – apart from some societal impact frameworks – that is comprehensive in scope and introduces a procedure for designing evaluations. It is likely that the framework will pave the way for the professionalisation of research evaluation and spark more work on research evaluation frameworks, approaches, and methods.\nThe three principles and the five steps presented in sections 5 and 6 are sound, consistent, reasonable, and comprehensible. The use cases presented in section 7 are clearly structured and described; they demonstrate the wide applicability of the framework. Even though the three principles and five steps could be specified, modified, and supplemented in many respects, I make no suggestions in this regard for two reasons. First, the framework in its current form is already productive and useful in informing research evaluation practice. Practical experience with the framework will undoubtedly trigger a further development of the framework. Second, the framework can serve as a benchmark and starting point for scholars and practitioners to either supplement the SCOPE framework or develop their own research evaluation frameworks. In my view, it is therefore not necessary nor desirable to change the framework presented in this paper or the accompanying 19-page guide at this time.\nWhile the framework itself is sound, there are three issues with how it is presented in the paper that require attention.\n(1) The paper promises too much. The title promises that the framework will “implement the ideals of responsible research assessment (RRA)”. The paper, however, does not provide a definition of RRA (section 2), only briefly discusses some RRA values and principles (section 3), and describes the relationship between RRA values/principles and the SCOPE framework only briefly and broadly (section 4, table 1). A minimum solution would be to remove the definite article from the title (implementing the ideals > implementing ideals) and to indicate that there are more RRA values/principles and that RRA values/principles are emerging and therefore vague. A maximum solution would be to provide a definition of RRA (or: a discussion of RRA definitions), discuss and list RRA values/principles comprehensively (or at least in more detail), and describe the relationship between RRA values/principles and the SCOPE framework in detail.\n(2) Responsible research assessment is not sufficiently described and discussed. Section 2 focuses on RRA. The last paragraph suggests that the negative consequences of (all) evaluation methods – and the awareness of them – are a recent phenomenon. Such concerns, however, are almost as old as evaluative bibliometrics and modern peer review. These concerns are therefore not sufficient to explain the surge of reform proposals and initiatives. Moreover, the section does not discuss definitions of RRA or reflect on RRA. This is surprising as one of the authors of this paper has written a blog on this very topic (https://www.leidenmadtrics.nl/articles/navigating-responsible-research-assessment-guidelines). Section 2 could benefit from a more thorough discussion of RRA, including, for example, Curry et al. (2020), Rushforth and Hammarfelt (2023), Rushforth and de Rijcke (2023), Peruginelli and Pölönen (2023) and Gauffriau (https://www.leidenmadtrics.nl/articles/navigating-responsible-research-assessment-guidelines).\n(3) The section “Discussion and conclusions” is not very critical. Section 8 contains a lot of praise for the framework but does not really point out weaknesses and limitations. For example, the authors state that the simplicity of the framework is both a strength and a weakness. In what respect is it a strength and a weakness? What does this imply for practice and the further development of the framework? Moreover, section 8 does not discuss future research. I therefore encourage the authors to write a more balanced discussion of the strengths, weaknesses, and limitations of the framework, and to delineate future research.\nCuriosity question from the reviewer, not to be addressed in the paper: I count eight examples of use cases in the paper and ten on the webpage, four of which are referenced in the paper. This makes 14 use cases in total. The paper says on p. 10 that “the SCOPE framework is in wide usage by a range of organisations globally.” Does this imply that SCOPE is used in more than the 14 cases?\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "11499",
"date": "19 Jun 2024",
"name": "Elizabeth Gadd",
"role": "Author Response",
"response": "We would like to thank the reviewer for the encouraging comments on the SCOPE framework and the three insightful suggestions on how to improve the paper. (1) The paper promises too much. The title promises that the framework will “implement the ideals of responsible research assessment (RRA)”. The paper, however, does not provide a definition of RRA (section 2), only briefly discusses some RRA values and principles (section 3), and describes the relationship between RRA values/principles and the SCOPE framework only briefly and broadly (section 4, table 1). A minimum solution would be to remove the definite article from the title (implementing the ideals > implementing ideals) and to indicate that there are more RRA values/principles and that RRA values/principles are emerging and therefore vague. A maximum solution would be to provide a definition of RRA (or: a discussion of RRA definitions), discuss and list RRA values/principles comprehensively (or at least in more detail), and describe the relationship between RRA values/principles and the SCOPE framework in detail. In terms of the first point, we agree that the paper does not define responsible research assessment, or the ideals of it comprehensively enough to be able to claim the original title (implementing the ideals of RRA). We chose to publish a Method Article (defined by F1000 as follows: “Method Articles describe new and well tested experimental, observational, theoretical or computational methods or procedures, either quantitative or qualitative. This includes new study methods, substantive modifications to existing methods or innovative applications of existing methods to new models”) and our purpose is to present a framework, SCOPE, that supports responsible research assessment, and to argue that the three principles and five stages of this framework are supported by research literature that underpins RRA principles. With this in mind, we have adopted the minimum solution suggested by the reviewer and renamed the article to ‘The SCOPE Framework - Implementing ideals of responsible research assessment’. (2) Responsible research assessment is not sufficiently described and discussed. Section 2 focuses on RRA. The last paragraph suggests that the negative consequences of (all) evaluation methods – and the awareness of them – are a recent phenomenon. Such concerns, however, are almost as old as evaluative bibliometrics and modern peer review. These concerns are therefore not sufficient to explain the surge of reform proposals and initiatives. Moreover, the section does not discuss definitions of RRA or reflect on RRA. This is surprising as one of the authors of this paper has written a blog on this very topic (https://www.leidenmadtrics.nl/articles/navigating-responsible-research-assessment-guidelines). Section 2 could benefit from a more thorough discussion of RRA, including, for example, Curry et al. (2020), Rushforth and Hammarfelt (2023), Rushforth and de Rijcke (2023), Peruginelli and Pölönen (2023) and Gauffriau In the second point, the reviewer rightfully points out that section 2 should be elaborated, especially since RRA is in constant development. As a solution we have edited the section by first renaming it as “Moving towards a more responsible research assessment”, and reformulated the text in a way that it takes into consideration that concerns over evaluation methods, be they bibliometric or peer review do indeed date back a lot further than last decade. However, we do think that even though these concerns have been well-known to especially bibliometricians, it is only during the last decade, starting with the DORA declaration that the awareness of the pitfalls of evaluation methods has increased and gained the focus of a wider scientific community. And this wider awareness in our opinion explains the surge of reform proposals and initiatives. We have tried to make this clearer in the text. In addition, we have changed the structure so that section 3. Key RRA principles and guidelines is now a subsection for section 2, i.e. 2.1. (3) The section “Discussion and conclusions” is not very critical. Section 8 contains a lot of praise for the framework but does not really point out weaknesses and limitations. For example, the authors state that the simplicity of the framework is both a strength and a weakness. In what respect is it a strength and a weakness? What does this imply for practice and the further development of the framework? Moreover, section 8 does not discuss future research. I therefore encourage the authors to write a more balanced discussion of the strengths, weaknesses, and limitations of the framework, and to delineate future research And finally, referring to the third point, to balance the discussion, we have pointed out some additional weaknesses and limitations in a more pronounced way. This can be seen in section 7 as reformulation of text in the second paragraph and new text in the fourth paragraph. We also point to future research. We also wanted to address the last question, as to our knowledge, SCOPE is being utilised in many more settings than just the ones we have reported. These cases are just less structured and therefore quite challenging to report. We are, however, mapping the utilisation of SCOPE through a constantly running survey, and will share the collected data on our webpage in the future."
}
]
},
{
"id": "243163",
"date": "29 Feb 2024",
"name": "Dr Maria Alejandra Pinero de Plaza, PhD",
"expertise": [
"Reviewer Expertise My research focuses on public health and improving healthcare services. I use different methods to find effective ways to promote healthy lifestyles and tackle health disparities. I also study how technology affects people's behaviour and how research findings can benefit society. By contributing to evaluation and implementation science",
"my goal is to turn research discoveries into practical solutions that can improve healthcare delivery",
"public health outcomes",
"and the development of strong health and care networks."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis work introduces SCOPE, a five-stage framework used to plan, design, and conduct research evaluations. The method has been successfully applied in various organisational settings globally and offers valuable insights for replication by other organisations to adopt similar evaluation practices. Four case studies demonstrate how SCOPE has been utilised to provide value-based research evaluations. The method is part of international efforts towards more meaningful and robust research evaluation practices. The case studies show that SCOPE can be adapted to different organisational settings and levels of detail. The framework's technical soundness is clearly explained in its systematic approach to planning, designing, and conducting research evaluations. The detailed process descriptions and outcomes of each case study further validate the framework's practical application. The approach is used to enhance research culture, develop assessment mechanisms, and design national research assessment exercises.\nI suggest enhancing the background section by including insights from seminal works and the latest innovative evaluation methodologies. This addition would provide a robust framing and foundation to introduce the SCOPE framework. Referencing seminal works such as \"Evaluation: A Systematic Approach\" and \"Utilization-Focused Evaluation\" can offer comprehensive perspectives to the reader on evaluation methods and stakeholder involvement while incorporating innovative methodologies like “Co-designing, measuring, and optimizing innovations and solutions within complex adaptive health systems,” also known as PROLIFERATE. These addendums align with responsible research assessment principles advocated by initiatives like DORA, the Leiden Manifesto and the Hong Kong Principles. Integrating these suggestions into the background would not only contextualise SCOPE's significance within the evolving research evaluation landscape but also demonstrate a comprehensive understanding of the field, thereby strengthening its contribution to promoting responsible research practices.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "11500",
"date": "19 Jun 2024",
"name": "Elizabeth Gadd",
"role": "Author Response",
"response": "We would like to thank the reviewer for a constructive review and for bringing to our attention the two evaluation methods, Program Evaluation and Utilization-Focused Evaluation, not often implemented in RRA. We have added these works as examples of more well-defined and tested methods in section 2.1 Key RRA principles and guidelines. In addition we have made a reference to PROLIFERATE as an example of co-design in section 5.2 Evaluate with the evaluated of our paper."
}
]
}
] | 1
|
https://f1000research.com/articles/12-1241
|
https://f1000research.com/articles/13-491/v1
|
17 May 24
|
{
"type": "Systematic Review",
"title": "Greenspace exposure and associated health outcomes: a systematic review of reviews",
"authors": [
"Brittnee Bryer",
"Chinonso Christian Odebeatu",
"Wen Ray Lee",
"Kathryn Vitangcol",
"Victor Gallegos-Rejas",
"Nicholas J. Osborne",
"Gail Williams",
"Darsy Darssan",
"Brittnee Bryer",
"Chinonso Christian Odebeatu",
"Wen Ray Lee",
"Kathryn Vitangcol",
"Victor Gallegos-Rejas",
"Nicholas J. Osborne",
"Gail Williams"
],
"abstract": "Background Numerous systematic reviews and meta-analyses have sought to clarify the relationship between greenspace exposure and health outcomes, but the results are inconsistent. We aimed to synthesise all relevant systematic reviews and meta-analyses on this association.\n\nMethods We searched five databases (PubMed, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and the Cochrane Database of Systematic Reviews) and conducted a manual reference search for systematic reviews and meta-analyses written in English and published in peer-reviewed journals that used clearly defined measures of greenspace exposure and reported health outcomes directly attributable to greenspace exposure. A total of 36 systematic reviews published between January 2010 and December 2020 were identified for inclusion in this systematic review of reviews (PROSPERO: CRD42021227422). An updated review is underway, and the protocol is published in PROSPERO (CRD42022383421). The methodological quality and risk of bias of included systematic reviews were evaluated using the AMSTAR-2 and ROBIS tools, respectively.\n\nResults Beneficial effects of greenspace exposure were observed for all-cause and cardiovascular disease mortality, and mental health and cognitive function. Ambivalent results were found for cardiovascular and metabolic health, general health and quality of life (QOL), and respiratory health and allergies. Most of the systematic reviews included in the current umbrella review had a low to moderate methodological quality and a high risk of bias.\n\nConclusions This umbrella review highlights the link between greenspaces and a variety of health outcomes, emphasising the importance of preserving existing greenspaces and integrating additional vegetation into urban areas to maintain public health.",
"keywords": [
"Human health",
"natural environment",
"outdoor environment",
"umbrella review",
"biodiversity",
"greenery",
"urbanisation"
],
"content": "Introduction\n\nReducing the global burden of diseases has become a public health priority, and many international bodies, including the World Health Organisation (WHO), have highlighted the need to maintain healthy, liveable, and sustainable cities (World Health Organization, 2021). In response to this, changes to urban environmental design, such as the provision of access to greenspace exposure, have been proposed to enhance human health and wellbeing (Browning et al., 2022; Nguyen et al., 2021).\n\nGreenspace may benefit human health via several mechanisms, including increased physical activity (PA), enhanced social engagement, and improved mental restoration (Zhang et al., 2022). Accumulating evidence from the past two decades has suggested that exposure to greenspace may reduce the risk of all-cause and cause-specific mortality and morbidity (Rojas-Rueda et al., 2019; Twohig-Bennett & Jones, 2018; Yuan et al., 2021), and birth outcomes (Dzhambov et al., 2014; Lee et al., 2020; Twohig-Bennett & Jones, 2018). However, several systematic reviews did not report statistically significant findings between greenspace and health outcomes, particularly for respiratory diseases in children and adolescents (Lambert et al., 2017), and the risk of cancer in adults (Porcherie et al., 2021). In contrast, a study carried out in Australia found that the odds of skin cancer escalate in accordance with increased neighbourhood greenness (Astell-Burt et al., 2014). These inconsistencies could be attributed, in part, to heterogeneity across different outcome measures, inconsistent definitions of greenspace exposure, or disparate study designs and confounding variables. Despite this discordance, exposure to greenspace may have beneficial effects on health outcomes.\n\nThere is an increasing number of systematic reviews and meta-analyses on the relationship between greenspace exposure and health outcomes (Houlden et al., 2018; Lambert et al., 2017; Lee et al., 2020; Rojas-Rueda et al., 2019; Yuan et al., 2021). These studies did not consider overall health impacts. Addressing this gap requires a higher level of critical appraisal and synthesis of all systematic reviews and meta-analyses on greenspace exposure and health outcomes. Only two umbrella reviews have reviewed evidence on the link between exposure to greenspace and human health from systematic reviews and meta-analyses (van den Bosch & Ode Sang, 2017; Yang et al., 2021). The review by van den Bosch and Ode Sang (2017) focused on the natural environment including both green and blue spaces. The conclusions drawn are unlikely to represent the impact of greenspace exposure alone. Yang et al. (2021) included systematic reviews with variables such as PA, time spent outdoors, prosocial behaviour, and murder as health outcomes, and cancer and respiratory mortality as other health outcomes, resulting in outcome misclassification, and potentially undermining their findings. Yang et al. (2021) also included scoping reviews in their synthesis. There is currently no umbrella review in the literature that possesses all the following qualities: i) evaluates the association between greenspace exposure and health outcomes from quantitative studies; ii) assesses both the quality and risk of bias of reviews; iii) records the frequency of greenspace exposure measure used; iv) summarises health outcomes and associated ICD-10 codes; v) reports effect measures (e.g. β, mean difference) from meta-analyses. This umbrella review aims to fill this gap.\n\n\nMethods\n\nThe protocol for this umbrella review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration ID: CRD42021227422) (Gallegos-Rejas et al., 2021). Due to the substantial increase in systematic reviews since the conduct of this study, an updated review has also been registered with PROSPERO (registration ID: CRD42022383421) and is underway (Bryer et al., 2022).\n\nAn electronic literature search was carried out using the following databases: PubMed, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and the Cochrane Database of Systematic Reviews. We restricted the search to peer-reviewed systematic reviews and meta-analyses conducted in humans and published in English between January 2010 and December 2020, including reviews first published online during this period (extended data: Supplementary Table S1). All databases were searched on 05/01/2021. To ensure that relevant systematic reviews were retrieved, we also conducted forward and backward reference searching on screened reviews, as well as manual searching of reference lists of relevant reviews. EndNote software programme was used for reference management (The EndNote Team, 2013).\n\nTitle and abstract screening and full-text screening of identified systematic reviews were independently conducted by two authors. The following inclusion criteria were used: i) systematic review or meta-analysis; ii) written in English and published in a peer-reviewed journal; iii) greenspace exposure clearly defined using objective or subjective measures; iv) reported health outcome(s) were directly attributable to greenspace exposure. We excluded: i) systematic reviews that failed to follow a standardised, systematic review approach, for example, no mention of databases searched; no identification of the search terms used; or no assessment of original studies quality; ii) scoping reviews; iii) systematic reviews that did not consider the effects of greenspace independently of blue space. Studies that mentioned health outcome(s) in the title and abstract but only reported health determinants such as BMI, PA, or diet were excluded during full-text screening (extended data: Supplementary File S1). Disagreements were resolved via discussions with the last author. Covidence was used to conduct all stages of study screening.\n\nData extraction was conducted independently by two authors. Pilot testing was conducted on 10 of the identified systematic reviews to build the data extraction form. The form included information on the design of original studies, types and measures of greenspace exposures, and types and measures of health outcomes. Any disagreement in the data extraction process was resolved via discussions with the last author.\n\nThe objectives, methods, and conclusions of each systematic review included in this umbrella review were summarised. Quantitative data, reported as the effect estimate with associated confidence interval, was summarised for health outcomes if available. We could not conduct a meta-analysis as the primary aim of any umbrella review is to summarise existing systematic reviews and not to re-synthesise or conduct meta-analysis (Aromataris et al., 2015).\n\nThe number and types of original studies in the systematic reviews, as well as the measure(s) of greenspace exposure and health outcomes, were recorded. The International Classification of Diseases, 10th Edition (ICD-10) was then used to allocate corresponding ICD-10 codes for each health outcome identified during data extraction (World Health Organization, 2019).\n\nThe methodological quality and risk of bias of included systematic reviews were evaluated independently by two authors using the AMSTAR-2 (Shea et al., 2017) and ROBIS (Whiting et al., 2016) tools, respectively. Disagreements between researchers were solved via discussions with the last author. No systematic reviews were excluded based on the methodological quality or risk of bias assessment.\n\n\nResults\n\nOur initial systematic search yielded 4250 systematic reviews. After removing duplicates and screening titles and abstracts, 173 potentially relevant articles were selected for full-text assessment. After full-text evaluation, we excluded a total of 141 articles based on our inclusion criteria and retained a total of 36 systematic reviews.\n\nOf the 36 systematic reviews included in this umbrella review, most (n=29, 75%) were published after 2016, with only seven (25%) published before or during 2016. The number of original studies included in systematic reviews ranged from 5 to 143 (Table 1) totalling 989. The majority of these were cross-sectional (n=418, 42.7%), followed by cohort (n=101, 10.3%), longitudinal studies (n=64, 6.5%), RCTs (n=61, 6.2%), and case-control studies (n=5, 0.5%) (Table 2).\n\n* First published online September 2020.\n\nMeasures of greenspace exposure varied significantly between systematic reviews. Of the 36 systematic reviews included in this umbrella review, 22 (61%) reported more than one greenspace measure (Table 3). The normalised difference vegetative index (NDVI) was the most common measure of greenspace, used in 21 systematic reviews (58%). This was followed by proximity to greenspace (n=12, 33%), land cover map (n=8, 22%), duration of stay in greenspace setting (n=7, 19%), quality of greenspace (n=6, 17%), tree canopy (n=5, 14%) and frequency of greenspace usage (n=4, 11%) (Table 3).\n\nThis review considered all health outcomes examined in relation to greenspace exposure. Given that over 110 health outcomes were identified (Table 1), we categorised outcomes as: mental health and cognitive function, maternal health and birth outcomes, cardiovascular and metabolic outcomes, respiratory health and allergies, cancer, general health and quality of life (QoL), and all-cause and cause-specific mortality. Health outcomes which did not suit these categories were classified as other health outcomes (Table 4).\n\nMental health and cognitive function. Mental health was the most commonly investigated outcome in the included systematic reviews (n = 11, 31%). van den Berg et al. (2015) and Shuvo et al. (2020) observed beneficial effects of greenspace exposure on overall mental health but did not conduct meta-analyses due to heterogeneity in exposure and outcome measures. Similar findings were reported by Zhang et al. (2017), but the overall quality of original studies in the review was low and prone to a high risk of bias. In contrast, the relationship between surrounding greenness and overall mental health in children (Gascon et al., 2015) and adults (Gascon et al., 2015; Houlden et al., 2018) was inconclusive.\n\nImpacts of greenspace exposure on stress reduction (de Keijzer et al., 2020; Shaffee & Abd Shukor, 2018; Soga et al., 2017; Zhang et al., 2020), stress hormone (Oh et al., 2017), perceived and physiological stress (Shuda et al., 2020), and psychological stress (Kondo et al., 2018) were reported in seven (19%) systematic reviews. Kondo et al. (2018) showed mixed findings on the stress response to urban nature assessed via physiological measures, while Gritzka et al. (2020) reported contradictory conclusions on the impact of nature-based intervention on employees’ mental health, including their ability to recover from stress and experience restoration. No meta-analyses were conducted for stress outcomes.\n\nExposure to the natural environment, including forestry and indoor gardening, was found to be beneficial to mental health indicators, particularly depressive symptoms, anxiety, and psychological distress in five (14%) systematic reviews (Oh et al., 2017; Roberts et al., 2019; Soga et al., 2017; Yeo et al., 2019; Zhang et al., 2020), whereas two reviews could not draw conclusions due to mixed results (Kondo et al., 2018) and inadequate evidence (de Keijzer et al., 2020). Roberts et al. (2019) found that exposure to the natural environment was beneficial for depressive mood (SMD=0.38; 95%CI:0.16,0.56). Another review reported possible mental health benefits of greenspace exposure on older adults living in residential aged care facilities, however, health outcomes were primarily based on observations and perceptions of staff and relatives, which may be subject to information bias (Carver et al., 2020). Evidence of depressive symptoms in children was also less clear (Vanaken & Danckaerts, 2018).\n\nWhile evidence was somewhat inconsistent, associations were found between increased exposure to greenspace and cognitive function including cognitive development, attention restoration, reduced risk of cognitive impairment, hyperactive challenges, and inattentiveness in children, as well as dementia-related outcomes (de Keijzer et al., 2020; de Keijzer et al., 2016; Gritzka et al., 2020; Islam et al., 2020; Kondo et al., 2018; Vanaken & Danckaerts, 2018; Whear et al., 2014; Yeo et al., 2019).\n\nMaternal health and birth outcomes. The impact of greenspace exposure on pregnancy outcomes such as birthweight (BW), low birth weight (LBW), small for gestational age (SGA) and preterm birth (PTB), was assessed in seven (19%) systematic reviews (Akaraci et al., 2020; Dzhambov et al., 2014; Islam et al., 2020; Kondo et al., 2018; Lee et al., 2020; Twohig-Bennett & Jones, 2018; Zhan et al., 2020). Kondo et al. (2018) found insufficient evidence to support a statistical association between greenspace exposure and BW, PTB, and SGA. All other studies found weak but positive associations between higher surrounding greenness and increased BW and decreased LBW, SGA, and PTB within different greenspace buffer sizes. For example, a meta-analysis of ten studies by Zhan et al. (2020) demonstrated protective effects of residential greenness on LBW measured by NDVI at 100 (OR=0.8; 95%CI:0.75,0.99), 300 (OR=0.82; 95%CI:0.71,0.93), and 500 (OR=0.85; 95%CI:0.77,0.93) metre buffers. Lee et al. (2020) also found that birthweight is associated with overall greenness. The association was determined via NDVI buffer sizes of 100 (β=0.003; 95%CI:0.001,0.005), 250 (β=0.001; 95%CI:0.000,0.002) and 500 (β=0.002; 95%CI:0.001,0.004) metres after adjusting for air quality and civil environment.\n\nCardiovascular and metabolic outcomes. The risk of cardiovascular outcomes following greenspace exposure was assessed in five (14%) systematic reviews (de Keijzer et al., 2020; Lachowycz & Jones, 2011; Twohig-Bennett & Jones, 2018; Wen et al., 2019; Yuan et al., 2021). A review of observational studies by Yuan et al. (2021) reported beneficial effects of greenspace on the risk of cardiovascular disease (CVD) events in older adult populations. The authors did not conduct a meta-analysis due to the small number of original studies on CVD events. Limited evidence was found to support the link between greenspace exposure and CHD (Lachowycz & Jones, 2011) and hypertension (de Keijzer et al., 2020). The meta-analysis by Twohig-Bennett and Jones (2018) reported no statistical evidence for the association between the incidence of CHD and stroke with greenspace.\n\nRespiratory health and allergies. We identified six (17%) systematic reviews that assessed exposure to residential greenspace on respiratory health (Hartley et al., 2020; Islam et al., 2020; Kabisch et al., 2017; Kondo et al., 2018; Lambert et al., 2017, 2018). Lambert et al. (2017) demonstrated no association between residential greenness and allergic respiratory diseases in children and adolescents. Hartley et al. (2020) undertook an updated review of Lambert et al. (2017) and found similar results. Islam et al. (2020) and Lambert et al. (2018) investigated the respiratory health of children and adolescents which revealed limited evidence to support the effects of greenspace exposure on asthma and atopic sensitisation, respectively. Kabisch et al. (2017) and Kondo et al. (2018) reported insufficient original studies to draw conclusions on respiratory/allergic symptoms and aeroallergens.\n\nCancer. Only four (11%) systematic reviews investigated the relationship between greenspace exposure and cancer (de Keijzer et al., 2020; Kabisch et al., 2017; Kondo et al., 2018; Twohig-Bennett & Jones, 2018). Kondo et al. (2018) and Twohig-Bennett and Jones (2018) concluded that greenspace exposure is beneficially associated with risk of prostate cancer after controlling for individual factors including PA, smoking, and medical history. de Keijzer et al. (2020) and Twohig-Bennett and Jones (2018) found a harmful association between greenspace exposure and skin cancer. Inconclusive findings were reported for the effect of park availability on lung cancer (Kabisch et al., 2017).\n\nGeneral health and Quality of life (QoL). We found eight (22%) systematic reviews that investigated the role of greenspace exposure on self-reported general health, perceived wellbeing, and QoL (de Keijzer et al., 2020; Gritzka et al., 2020; Kondo et al., 2018; Shuvo et al., 2020; Soga et al., 2017; Twohig-Bennett & Jones, 2018; van den Berg et al., 2015; Yeo et al., 2019). Two reviews reported inconclusive findings on the effect of greenspace exposure on perceived wellbeing and QoL (de Keijzer et al., 2020; Gritzka et al., 2020). Shuvo et al. (2020) concluded that there is an association between greenspace exposure and self-reported general health, but the methodological quality of studies was low. Earlier reviews revealed mixed evidence on the relationship between greenness and general health (Kondo et al., 2018; van den Berg et al., 2015). A meta-analysis by Twohig-Bennett and Jones (2018) demonstrated an association between greenspace exposure and self-reported health conditions (OR=1.12; 95%CI:1.05,1.19). Another two reviews considered greenspace exposure via participation in gardening activities and reported beneficial effects on self-perceived health and QoL (Soga et al., 2017; Yeo et al., 2019).\n\nAll-cause and cause-specific mortality. A total of eight (22%) systematic reviews and meta-analyses considered all-cause or cause-specific mortality (Gascon et al., 2016; Kabisch et al., 2017; Kondo et al., 2018; Rojas-Rueda et al., 2019; Schulz et al., 2018; Twohig-Bennett & Jones, 2018; van den Berg et al., 2015; Yuan et al., 2021). The meta-analysis by Gascon et al. (2016) found that living in areas of high greenery reduced the risk of all-cause mortality (RR=0.92; 95%CI:0.87,0.97) but not lung cancer mortality. Three meta-analyses performed after Gascon et al. (2016) presented similar findings (Rojas-Rueda et al., 2019; Twohig-Bennett & Jones, 2018; Yuan et al., 2021), except for CVD mortality (Yuan et al., 2021). Yuan et al. (2021) also reported that increased NDVI is associated with reduced risk of stroke mortality (HR=0.77; 95%CI:0.59,1.00). Narrative syntheses summarised moderate to strong effects of increased greenness on the risk of the following mortalities: non-accidental (van den Berg et al., 2015), CVD (Kondo et al., 2018), respiratory (Kondo et al., 2018), heat-wave (Kabisch et al., 2017) and overall cancer (Kondo et al., 2018; Twohig-Bennett & Jones, 2018).\n\nOther health outcomes. We identified four (11%) systematic reviews that evaluated the effect of greenspace on other health outcomes (de Keijzer et al., 2020; Lachowycz & Jones, 2011; Luo et al., 2020; Twohig-Bennett & Jones, 2018). Inconsistent associations between greenspace exposure and obesity-related health indicators were reported by Lachowycz and Jones (2011). In contrast, a meta-analysis by Luo et al. (2020) reported higher NDVI to be associated with lower odds of being overweight or obese (OR=0.88; 95%CI:0.84,0.91). de Keijzer et al. (2020) revealed inadequate evidence on the impact of greenspace exposure on cardiometabolic risk factors, such as weight status, hypertension, and cholesterol levels. Meta-analyses by Twohig-Bennett and Jones (2018) also demonstrated decreased salivary cortisol (MD=-0.05; 95%CI:-0.07,-0.04), heart rate (MD=-2.57;95%CI:-4.30,-0.83), diastolic blood pressure (MD=-1.97; 95%CI:-3.45,-0.49), and heart rate variability (MD=91.87; 95%CI:50.92,132.82) following exposure to increased greenery.\n\nQuantitative data collected from meta-analyses were collated according to outcome category, outcome, and measure of greenspace exposure (Table 5). Effect measures reported in meta-analyses which were based on a singular original study were excluded from the quantitative data summary table. No meta-analyses were reported for cancer outcomes.\n\nHalf of the systematic reviews (50%) had a high risk of bias, and three (8%) studies were categorised as having ‘unclear risk’. The remaining 15 (42%) studies were deemed low risk using the ROBIS tool (Figure 1; extended data: Supplementary Table S2).\n\nOf the 36 systematic reviews, eight (22%) were rated as high quality, 15 (42%) as moderate quality, and 13 (36%) as low quality according to the AMSTAR-2 tool (Table 6; extended data: Supplementary Figure S1). No studies were rated as critically low-quality.\n\n\nDiscussion\n\nThis umbrella review summarises 36 systematic reviews on the relationship between greenspace exposure and health outcomes. Our study yielded consistent results with existing umbrella reviews for the beneficial effects of greenspace exposure on mental health and cognitive function (Stier-Jarmer et al., 2021; Yang et al., 2021; Zare Sakhvidi et al., 2022), non-accidental/all-cause mortality (van den Bosch & Ode Sang, 2017; Yang et al., 2021), and CVD-mortality (Yang et al., 2021). Additionally, we observed positive associations between greenspace exposure and maternal health and birth outcomes including PTB and SGA which were not present in other studies (Yang et al., 2021). Conversely, Stier-Jarmer et al. (2021) and Yang et al. (2021) reported beneficial effects of greenspace on cardiovascular health and cardiometabolic factors, respectively, which was not replicated in our study. Finally, we identified mixed, limited, or no association between greenspace exposure and respiratory health and allergies, general health and QOL, cancer, and other health outcomes which is congruous with other umbrella reviews (Yang et al., 2021; Zare Sakhvidi et al., 2022). Overall, our review suggests that there may be an association between greenspace exposure and human health and wellbeing.\n\nThe variety of greenspace measures used may contribute to the ambivalent findings reported. Some studies used objective measures such as NDVI, proximity to greenspace, and land cover maps to quantify greenspace exposure whereas others used subjective measures including street view images and self-report questionnaires (Table 3). This precluded many systematic reviews from conducting meta-analyses which restricted the number of pooled estimates available for synthesis in this review.\n\nReduced access to natural spaces and biodiversity has limited the population’s access to the physical, mental, and cognitive health benefits of these spaces (Puplampu & Boafo, 2021). Urbanisation has increased in response to a growing urban population and has led to fragmentation and declines in natural ecosystems (Kingsley, 2019; Li et al., 2019). As a result, homes located near greenspaces have become more expensive, increasing inequalities in access to greenspaces based on socioeconomic status (SES) (Sharifi et al., 2021). Studies have also shown that most indoor workers do not go outside during office hours, further reducing access to greenspace and the associated health benefits (Gilchrist et al., 2015; Lottrup et al., 2013). These restrictions may have influenced the relationship between greenspace exposure and health outcomes in the included systematic reviews.\n\nA variety of pathways, mediators, and effect modifiers have been suggested for the relationship between greenspace exposure and health outcomes, including comorbidities, genetics, and PA. Comorbidities, which typically exacerbate other health conditions, may attenuate the effect of greenspace exposure on the primary health outcome (Godina et al., 2023; Walsan et al., 2020). Genetic variation has also been suggested as an effect modifier of the relationship between greenspace and health outcomes, but initial studies have reported insignificant findings (Cohen-Cline et al., 2015; Engemann et al., 2020). Conversely, PA and social interaction, which are beneficial for many health conditions, have been suggested as mediators of the relationship between greenspace exposure and health outcomes (Zhang et al., 2022). Greenspace exposure may improve mental, physical, and cognitive health by encouraging participation in outdoor PA (Sun et al., 2022; van den Berg et al., 2019) and social interaction (Dadvand et al., 2019; Orstad et al., 2020). Additional investigation into the exact role of comorbidities, genetics, and PA, as well as other effect modifiers such as age, sex, SES, race, and urbanicity is required.\n\nInteractions between greenspace and other environmental factors including air pollution, chemical exposures, toxins, and smoking may also influence the effect of greenspace on health outcomes. Environmental contaminants are recognised as detrimental to human health with the ability to induce and/or exacerbate many health conditions (Brusseau et al., 2019). Natural greenery can minimise the harmful effects of these environmental issues via air purification, as well as the prevention of soil contamination and erosion (Qiu et al., 2021; Yang et al., 2015). Reduction of these environmental contaminants by green ecosystems can lead to improvements in health conditions, particularly respiratory symptoms and CVD (Boelee et al., 2019; Schraufnagel et al., 2019).\n\nWe conducted a thorough review of systematic reviews and meta-analyses on the impact of greenspace exposure on health outcomes. In addition to the wide range of databases searched, a manual reference search was conducted to ensure all relevant articles were identified. All stages of screening and data collection, as well as risk of bias and methodological quality assessment were conducted independently by two authors. We outlined the types and frequency of greenspace measures used and allocated ICD-10 codes to health outcomes investigated in each systematic review. For each health outcome reported in meta-analyses, we provided the measure of greenspace and the numerical estimate of the association, as well as the number of original articles this estimate is based on. These methods allowed for a more holistic overview of the current literature and should be considered for use in future umbrella reviews.\n\nTo advance our understanding of the effect of greenspace exposure on health outcomes, further research is essential. Current evidence, including this umbrella review, have been unable to establish a causal link between greenspace exposure and health outcomes as most studies are observational. This highlights the need for additional experimental studies to be conducted (Nguyen et al., 2021). Current evidence on potential interactions, mediators, and effect modifiers of this relationship is also limited and conflicting, and further research is needed to assess the influence of genetics and environmental exposures (Zhang et al., 2022). Most systematic reviews included in this review were limited by their methodological quality and/or risk of bias, and systematic reviews on the association between greenspace exposure and health outcomes have multiplied since 2020. To account for this, we are conducting an update of this umbrella review (registration ID: CRD42022383421) (Bryer et al., 2022).\n\n\nConclusion\n\nThis umbrella review synthesised systematic reviews and meta-analyses on the effect of greenspace exposure on health outcomes. Beneficial effects were found for all-cause and CVD mortality, mental health and cognitive function, and maternal health and birth outcomes. Ambivalent results were found for cardiovascular and metabolic health, respiratory health and allergies, and general health and QOL. There were limited systematic reviews available for assessing cancer outcomes. In light of these diverse findings, it is apparent that the current evidence on the relationship between greenspace exposure and health outcomes is characterised by inconsistencies. Nevertheless, this umbrella review highlights the association between greenspace and a variety of health outcomes.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nOpen Science Framework (OSF): Greenspace exposure and associated health outcomes: a systematic review of reviews. Supplementary Material. DOI 10.17605/OSF.IO/U39EK (Bryer et al., 2024).\n\nThis project contains the following extended data:\n\n• Supplementary Table S1. (Literature search strategies)\n\n• Supplementary Table S2. (Risk of bias assessment by domain)\n\n• Supplementary Figure S1: (Overall methodological quality)\n\n• Supplementary File S1. (Systematic reviews excluded during full-text screening)\n\nOpen Science Framework (OSF): PRISMA checklist and flow chart for Greenspace exposure and associated health outcomes: a systematic review of reviews. DOI 10.17605/OSF.IO/U39EK (Bryer et al., 2024).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nWe would like to acknowledge Pakhi Sharma (Australian Centre for Health Services Innovation PhD Scholar) for helping the authors with the title and abstract scan during the initiation of this review.\n\n\nReferences\n\nAkaraci S, Feng X, Suesse T, et al.: A Systematic Review and Meta-Analysis of Associations between Green and Blue Spaces and Birth Outcomes. International Journal of Environmental Research and Public Health. 2020; 17(8). PubMed Abstract | Publisher Full Text | Free Full Text\n\nAromataris E, Fernandez R, Godfrey CM, et al.: Summarizing systematic reviews: methodological development, conduct and reporting of an umbrella review approach. JBI Evidence Implementation. 2015; 13(3): 132–140. 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Publisher Full Text\n\nPorcherie M, Linn N, Le Gall AR, et al.: Relationship between Urban Green Spaces and Cancer: A Scoping Review. International Journal of Environmental Research Public Health. 2021; 18(4). PubMed Abstract | Publisher Full Text | Free Full Text\n\nPuplampu DA, Boafo YA: Exploring the impacts of urban expansion on green spaces availability and delivery of ecosystem services in the Accra metropolis. Environmental Challenges. 2021; 5: 100283. Publisher Full Text\n\nQiu Y, Zuo S, Yu Z, et al.: Discovering the effects of integrated green space air regulation on human health: A bibliometric and meta-analysis. Ecological Indicators. 2021; 132: 108292. Publisher Full Text\n\nRoberts H, van Lissa C, Hagedoorn P, et al.: The effect of short-term exposure to the natural environment on depressive mood: A systematic review and meta-analysis. Environmental Research. 2019; 177: 108606. PubMed Abstract | Publisher Full Text\n\nRojas-Rueda D, Nieuwenhuijsen MJ, Gascon M, et al.: Green spaces and mortality: a systematic review and meta-analysis of cohort studies. The Lancet Planetary Health. 2019; 3(11): e469–e477. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchraufnagel DE, Balmes JR, De Matteis S, et al.: Health Benefits of Air Pollution Reduction. Annals of the American Thoracic Society. 2019; 16(12): 1478–1487. Publisher Full Text\n\nSchulz M, Romppel M, Grande G: Built environment and health: a systematic review of studies in Germany. Journal of Public Health. 2018; 40(1): 8–15. Publisher Full Text\n\nShaffee N, Abd Shukor SF: The effect of natural settings on stress reduction. Alam Cipta. 2018; 11(2). Reference Source\n\nSharifi F, Nygaard A, Stone WM, et al.: Accessing green space in Melbourne: Measuring inequity and household mobility. Landscape and Urban Planning. 2021; 207: 104004. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan den Berg M, Wendel-Vos W, van Poppel M, et al.: Health benefits of green spaces in the living environment: A systematic review of epidemiological studies. Urban Forestry & Urban Greening. 2015; 14(4): 806–816. Publisher Full Text\n\nvan den Berg M, van Poppel M, van Kamp I, et al.: Do Physical Activity, Social Cohesion, and Loneliness Mediate the Association Between Time Spent Visiting Green Space and Mental Health? Environment and Behavior. 2019; 51(2): 144–166. PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan den Bosch M, Ode Sang A: Urban natural environments as nature-based solutions for improved public health - A systematic review of reviews. Environmental Research. 2017; 158: 373–384. PubMed Abstract | Publisher Full Text\n\nVanaken G-J, Danckaerts M: Impact of Green Space Exposure on Children’s and Adolescents’ Mental Health: A Systematic Review. 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Publisher Full Text\n\nYeo NL, Elliott LR, Bethel A, et al.: Indoor Nature Interventions for Health and Wellbeing of Older Adults in Residential Settings: A Systematic Review. The Gerontologist. 2019; 60(3): e184–e199. PubMed Abstract | Publisher Full Text\n\nYuan Y, Huang F, Lin F, et al.: Green space exposure on mortality and cardiovascular outcomes in older adults: a systematic review and meta-analysis of observational studies. Aging Clinical and Experimental Research. 2021; 33(7): 1783–1797. PubMed Abstract | Publisher Full Text\n\nZare Sakhvidi MJ, Yang J, Mehrparvar AH, et al.: Exposure to greenspace and cancer incidence, prevalence, and mortality: A systematic review and meta-analyses. Science of the Total Environment. 2022; 838: 156180. PubMed Abstract | Publisher Full Text\n\nZhan Y, Liu J, Lu Z, et al.: Influence of residential greenness on adverse pregnancy outcomes: A systematic review and dose-response meta-analysis. Science of The Total Environment. 2020; 718: 137420. 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}
|
[
{
"id": "284710",
"date": "10 Jun 2024",
"name": "Wenzhong Huang",
"expertise": [
"Reviewer Expertise Environmental epidemiolgy",
"greenness",
"air pollution",
"climate change and health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nmandatory reviewer questions Is the topic of the review discussed comprehensively in the context of the current literature? Yes\nAre all factual statements correct and adequately supported by citations? Mostly\nIs the review written in accessible language? Yes\nAre the conclusions drawn appropriate in the context of the current research literature? Yes\nSpecific comments: This study is a well-written umbrella review that synthesized systematic reviews on the associations of greenness and all kinds of health outcomes. I appreciate the great amount of work by the authors. I believe this study does have some value and can advance knowledge in this field. However, given the similarities to recent work by Stier-Jarmer et al. (2021)[Ref 1] and Yang et al. (2021)[Ref 2], I had the following suggestions/comments in an attempt to enhance the significance of this study.\nIntroduction I appreciate the authors' introduction of two highly relevant umbrella reviews that incorporate the latest research advancements. Highlighting the advances of this study compared to these two reviews is crucial to justify its significance. However, the clarity of the following points could be improved: For instance, the review by van den Bosch and Ode Sang (2017) [Ref 3] includes both green and blue spaces, suggesting their work is more comprehensive than reviews focusing solely on green spaces. Therefore, it seems illogical for the authors to claim that the conclusions drawn from this study do not adequately represent the impact of green space exposure. Regarding the high-impact umbrella review by Yang et al., the authors mention a limitation involving the grouping of cancer and respiratory mortality into the section of ”other health outcomes”. This grouping likely resulted from the small number of studies on these topics and should not lead to outcome misclassification. Because Yang et al. could still discuss the findings for cancer and respiratory mortality separately. Additionally, including systematic reviews with variables such as physical activity, time spent outdoors, prosocial behavior, and murder as health outcomes does not appear to be a limitation. These reviews should encompass the health effects of greenness, (e.g., studies investigating the association of green spaces with health and the role of physical activity on the associations). In summary, the limitations mentioned by the authors are unclear and illogical to me. I understand and appreciate that this work possesses four important qualities compared to previous studies, as clearly mentioned in the last sentence of the Introduction. However, the significance of this research would be greatly enhanced if the authors provided clearer clarifications regarding the mentioned limitations of previous studies and how this study advances the field by addressing those limitations.\nMethods \"We restricted the search to peer-reviewed systematic reviews and meta-analyses conducted in humans and published in English between January 2010 and December 2020, including reviews first published online during this period\". Given the dramatic increase in publications on greenness and health in recent years, the quality of this study would be substantially improved if the authors included up-to-date reviews (i.e., from 2010 to the present, rather than 2010-2020). This inclusion can be mentioned as a major strength compared to previous umbrella reviews, as many high-quality studies and reviews have been published in the past three years.\nFull names should be provided for the abbreviations when they first appear in the main text (e.g., BMI, PA).\nResults It would be beneficial to include a flowchart illustrating the process used to select the final 36 systematic reviews (e.g., the number of studies excluded due to each specific exclusion criterion).\nIt might be better to visualize the study design, measures of greenness, location of studies (country/territory), and outcomes in a figure rather than in several separate tables. A good example can be seen in https://link.springer.com/article/10.1007/s40572-023-00420-9 (Figure 2)\nTable 4. I appreciate the authors' usage of ICD-code to define the outcomes. However, if I understand it correctly, the original studies in these included reviews may not necessarily and consistently define their outcomes based on these ICD codes, right? If so, this table might be misleading.\nWhy not combine Table 5 and Table 1, they have duplicated information.\n\"Half of the systematic reviews (50%) had a high risk of bias“. This proportion is quite high. It would be better for the authors to clarify how they assigned the level of ROB to each of the reviews (e.g., using a table with the same structure as Table S2 to list the reason why each level was assigned). This was just a recommendation, but at least the authors should provide more clarifications and discuss this point. Currently, there are very few words on it.\nConsistent with the previous comment, a relatively high proportion of the included reviews were also classified as low quality. Providing more clarifications on this point would make this study stronger. Table 6, please clarify the meanings of these words (e.g., N, PY, NA) in the table caption. It would be better to assign the cell background with a color to indicate the quality level (e.g., red for low quality, green for high quality). This can improve the readability dramatically.\nDiscussion \"Additionally, we observed positive associations between greenspace exposure and maternal health and birth outcomes including PTB and SGA which were not present in other studies (Yang et al., 2021).” These observed positive associations between greenspace exposure and maternal health and birth outcomes including PTB and SGA were not that consistent compared to the outcomes of mental health and cognitive function, right? If so, this may be the reason why previous studies hadn't reported them in the main findings.\n\"Conversely, Stier-Jarmer et al. (2021) and Yang et al. (2021) reported beneficial effects of greenspace on cardiovascular health and cardiometabolic factors, respectively, which was not replicated in our study.” This may be attributable to the fact that some reviews on this aspect were excluded in this umbrella review, while included in Stier-Jarmer et al. (2021) and Yang et al. (2021) due to the different inclusion and exclusion criteria (e.g., scoping reviews on greenness and CVD). Anyway, this should be discussed.\n\"Current evidence, including this umbrella review, have been unable to establish a causal link between greenspace exposure and health outcomes as most studies are observational. This highlights the need for additional experimental studies to be conducted” Population-based experimental studies are often unfeasible and also subject to numerous biases (e.g., usually very small sample size, non-adherence). Given the very large proportion of cross-sectional studies, it is more practical to suggest more studies with longitudinal or cohort design and causal inference models (e.g., Instrumental Variables Analysis).\n\"Most systematic reviews included in this review were limited by their methodological quality and/or risk of bias, and systematic reviews on the association between greenspace exposure and health outcomes have multiplied since 2020.” I am confused. The authors only included reviews between 2010-2020 and did not include reviews after 2020, as stated in the method section.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Partly\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable",
"responses": []
},
{
"id": "284715",
"date": "28 Jun 2024",
"name": "William Mueller",
"expertise": [
"Reviewer Expertise Environmental and occupational epidemiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall This is a well-conducted and well-written review about greenspace exposure and human health, a very active research area that would benefit from a broad synthesis of the evidence. I have outlined my comments below, which are mostly minor, but I do note an important Major comment for the authors and editor’s consideration.\nMajor Much research on greenspace and health, including reviews, has been published since December 2020. If an updated review is underway, wouldn’t it be more valuable to wait to publish the more up to date work? Also given the reviews themselves have earlier cut-offs, so the current review would already be quite out of date with the most recent research.\nMinor\nConsider changing title to refer to an ‘umbrella review’ Abstract - The abstract states that beneficial effects were observed for cardiovascular disease mortality, but that ambivalent results were found for cardiovascular health. The former is a subset of the latter, so please change wording to be consistent. [I see later that cardiovascular and metabolic health was combined as one category, but this is not clear from a read of the abstract.] Abstract – it is always helpful to include some quantitative results, even if ranges of effect sizes, to better characterise findings Introduction – ‘These studies did not consider overall health impacts’ – what does this statement mean exactly? Rephrase to make clear that full weight of evidence needs to be assessed to understand the nature of greenspace and health via an umbrella review, as described in the following sentence. Introduction – Following the above point, what about reviews that address multiple health outcomes (e.g., Twohig-Bennett & Jones, 2018) [REF1]? Can they not provide useful information on overall health impacts as well? Methods – Why are cardiovascular and metabolic outcomes combined? Results – Did you search the references of included papers? If so, were any additional papers identified? Typically, reviews include flow charts to show the start and end number of papers. Table 1- Why is the sample size for Carver et al. ‘NA’? Table 1 – Define ‘NA’ with other short-forms Table 3 – Add a ‘*’ or similar next to ‘Other’ to indicate that the specific exposures are given below. Results – ‘Maternal health…’ – Change to ‘OR=0.80…’ for consistency. Results – ‘Maternal health…’ – What do the Lee et al βs represent? Table 5 – Title should refer to ‘meta-analyses’, otherwise it is not clear how the effect estimates were calculated. It would also be helpful to add the increment that the estimates represent (e.g. per 0.1 increase in NDVI) Figure 1 – The methods should state how the overall risk of bias was determined (e.g., highest individual risk?). Also, the text accompanying the Figure, ‘…lighter colours concern judgments’ is not clear. Are these the individual risk of bias criteria? If so, state that. Results – Risk of bias – why was the risk in some cases ‘unclear’? Was there not enough information to determine if a criterion was met? Wouldn’t that suggest it was not met and that it is likely to be a source of bias? This point should be considered. Discussion – A stronger conclusion should be reached other than there may be an association between greenspace and health. For example, there appears to be stronger evidence for mental health, all-cause and CVD mortality. Are the specific pathways to health offered by greenspace more relevant for these outcomes? Table 6 – Without knowing the AMSTAR-2 questions or how they were rated, this table is not very intuitive. The other tables are informative and effective at summarising the reviews and results. Discussion – discussion of study limitations should be mentioned.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-491
|
https://f1000research.com/articles/10-524/v1
|
01 Jul 21
|
{
"type": "Software Tool Article",
"title": "GARCOM: A user-friendly R package for genetic mutation counts",
"authors": [
"Sanjeev Sariya",
"Giuseppe Tosto",
"Sanjeev Sariya"
],
"abstract": "Next-generation sequencing (NGS) has enabled analysis of rare and uncommon variants in large study cohorts. A common strategy to overcome these low frequencies and/or small effect sizes relies on collapsing strategies, i.e. to bin variants within genes/regions. Several tools are now available for advanced statistical analyses however, tools to perform basic tasks such as obtaining allelic counts within defined genetics boundaries are unavailable or require complex coding. GARCOM library, an open-source freely available package in R language, returns a matrix with allelic counts within defined genetic boundaries. GARCOM accepts input data in PLINK or VCF formats, with additional options to subset data for refined analyses.",
"keywords": [
"mutation",
"plink",
"allele",
"genetics",
"VCF"
],
"content": "Introduction\n\nGenome-wide association studies (GWAS) have led to the identification of several genomic common variants associated with complex diseases,1 yet missing heritability remains extensive. Furthermore, most of the disease-causing variants are rare in nature2 where common variants serve as a proxy. Rapid decline in sequencing costs have enabled in-depth analysis of rare variants (RVs; minor allele frequency < 1%) through Whole-Genome sequencing (WGS) and Whole-Exome Sequencing (WES). Furthermore, large-scale reference panels have allowed for imputation of RVs.3-5 Power to identify statistically significant RVs decreases as the minor allele frequency decreases: therefore, an ideal method to overcome this limitation is to group RV at the gene/region level, usually via a collapsing test.\n\nDespite the availability of sophisticated tools for annotation, quality-control and association analyses, tools to perform basic tasks, for instance, obtaining allelic count within defined genetic boundaries (genes and/or regions) are lacking, to our knowledge. R libraries such as BEDMatrix and bigsnpr6 provide allelic counts for each SNP per individual but algorithms to extract information within genetic boundaries in a collapsed fashion are unavailable.\n\nHere we introduce a user-friendly R package, GARCOM (“Genetic And Regional Count of Mutations”) that provides allelic counts per individual within user-provided genetics/regional boundaries.\n\n\nMethods\n\nGARCOM is written and developed in open-source R7 statistical and programming language. GARCOM imports data.table,8 vcfR,9 bigstatr, bigsnpr and stats libraries for internal data transformation and processing. A stable version is released and publicly available on the CRAN repository.\n\ninstall.packages(“garcom”)\n\nGARCOM was developed on R (≥4.0) (RRID:SCR_017299) with other dependencies and minimum versions as: data.table (≥1.12.8), vcfR (≥1.12.0), bigsnpr (≥1.4.11). Full documentation of dependencies and installation is available at GARCOM github repository. There is no minimum memory (RAM) requirement as far as we know, but that may vary according to the nature and size of input genetics data. GARCOM was developed on Unix platform but can also be used on other platforms (e.g. Windows, Ubuntu).\n\nGARCOM operates through two main functions: “gene_pos_counts” accepts PLINK10 (RRID:SCR_001757) input data, whereas “vcf_counts_SNP_genecoords” accepts VCF11 input format. After reading in the data, these functions perform operations to count variants within genes/genomic regions for each individuals.\n\noutput <- gene_pos_counts(recoded_genetic_data, gene_boundaries, snp_locations)\n\noutput <- vcf_counts_SNP_genecoords(recoded_genetic_data, gene_boundaries, snp_locations)\n\nwhere, “output” is the object generated by our library after a successful run of function; “recoded_genetic_data” is the main input file in PLINK or VCF formats; “gene_boundaries”, and “snp_locations” are additional input files for gene and SNP information, respectively.\n\nTypical workflow is shown in Figure 1. In brief, the “gene_pos_counts” function will process genetic input data (“recoded_genetic_data”) generated from the PLINK software through the --recode A option. Data are read in standard matrix format using the data.table R library. For VCF files, the “vcf_counts_SNP_genecoords” function reads the VCF input file employing the extract.gt function from the vcfR library. The genotype values are read within the “GT” field.\n\nGARCOM provides functions to read output from PLINK, VCF format. The final output is a matrix with rows as gene names and columns containing individuals’ IDs.\n\nIn addition to the --recode A genetic input, GARCOM needs genetic boundaries information and SNP information as shown in Table 2 and Table 3, respectively.\n\nOutput produced by GARCOM is a matrix, with M rows and N columns, where M represents the genes/genomic regions with at least one allele count and N represents the individuals. Genes with zero allelic counts across all individuals are excluded from the final output. Missing values are counted as zero in final output. When no allelic counts are present in the user-defined genes, NULL value is returned. GARCOM allows missing values (NA) in input data.\n\nIn addition to the function described, GARCOM provides several options for user flexibility. For instance, GARCOM can be ran restricting analyses to 1) a list of genes, or 2) filter SNPs and extract individuals of interest. For instance, users can provide list of individuals using the “keep_indiv” parameter; similarly, genes can be filtered in by using the “filter_gene” parameter.\n\noutput <- gene_pos_counts(recoded_genetic_data, gene_boundaries, snp_locations, keep_indiv=mylist.txt)\n\noutput <- gene_pos_counts(recoded_genetic_data, gene_boundaries, snp_locations, filter_gene=mysetofgenes.txt)\n\nThe input PLINK file has a matrix structure of N rows with M columns, where N rows represent individuals (one for each ID). The first six columns are family ID, individual ID, paternal ID, maternal ID, sex, and phenotype (standard output from PLINK (Table 1)). Following columns consist of the variants included in the analyses.\n\nData must contain GENE, START and END column names.\n\nIndividual_ID1, Individual_ID2 and Individual_ID3 are sample individual IDs, where values represent allelic counts within gene for individual.\n\nThe input VCF file follows the standard VCF formats (please refer to the vcfR library documentation).\n\nToy data (gene and SNP coordinates) are shared within the package as “genecoord” and “snppos”, respectively.\n\nWe performed simulation on real data for CHR1 (# of variants = 23,456) and CHR22 (# of variants = 4,814) on randomly sampled individuals (N = 100, 200, 500, 1000, 5000, 10,000) extracted from whole-exome sequencing dataset as described in the study by Tosto et al.12 Genetics data were recoded using PLINK --recode A flag. On both chromosomes we found increased memory consumption and time (Figure 2) as we increased the number of individuals processed. Memory consumption for CHR22 was significantly lower than CHR1 due to a smaller number of variants and genomic boundaries. Simulations were performed with 16GB memory (RAM) requested on computing cluster node.\n\nGraph A represents memory consumption; graph B shows processing time in seconds for various sample sizes on CHR1 and CHR22.\n\nAll simulations were conducted on R (v4.0), data.table (v1.13.6) with default 16 threads, GARCOM (v1.40), bigsnpr (v1.6.1).\n\n\nDiscussion\n\nGARCOM is easy to use where basic knowledge of R programming language is helpful but not desired. GARCOM is designed by harnessing existing libraries, such as data.table, that allow for efficient handling of large data. GARCOM data processing is independent of the reference genome build. GARCOM can be used on several platforms (e.g., Unix, Windows). GARCOM comes with certain limitations: genomic boundaries and variants' location need to be specified, as mentioned in the package documentation. In case of large-sized studies, for example UK biobank (N ≥ 200K), processing data per chromosome is highly recommended due to memory limitations. Lastly, GARCOM depends on public and freely available R packages.\n\nVCF format can accommodate locus annotation performed by software such as ANNOVAR.13 To this end, GARCOM plans to accommodate annotation filters in addition to the existing ones. One challenge associated with annotated VCF is the resulting large file size; we will try to add this functionality, keeping RAM limitations and processing time in mind. We plan to add features to handle bgen format which stores large amount of genetics data, with appropriate R library (http://www.well.ox.ac.uk/~gav/resources/rbgen_v1.1.5.tgz).\n\n\nData and software availability\n\nSample data associated with the package where applicable are provided within the library with proper documentation. No additional source data are required. We distribute the package under the MIT license. GARCOM can be downloaded from CRAN and GitHub from https://cran.r-project.org/web/packages/GARCOM/index.html and https://github.com/sariya/GARCOM respectively.\n\nReporting guidelines: Bugs and suggestions are welcome at the GitHub repository.\n\nAuthor Contribution: SS, GT\n\nEthical Statement: Informed consent was obtained from all participants. For the whole-exome sequencing, the study protocol was approved by the Institutional Review Board (IRB) of Columbia university Medical Center (CUMC) (Approval number: AAAP0477). The study was conducted according to the principles expressed in the Declaration of Helsinki.",
"appendix": "References\n\nFrayling TM: Genome-wide association studies: the good, the bad and the ugly. Clin Med (Lond) . 2014; 14(4): 428–31. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGibson G: Rare and common variants: twenty arguments. Nat Rev Genet . 2012; 13(2): 135–45. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSariya S, et al.: Rare Variants Imputation in Admixed Populations: Comparison Across Reference Panels and Bioinformatics Tools. Front Genet . 2019; 10: 239. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVergara C, et al.: Genotype imputation performance of three reference panels using African ancestry individuals. Hum Genet . 2018; 137(4): 281–92. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChou W-C, et al.: A combined reference panel from the 1000 Genomes and UK10K projects improved rare variant imputation in European and Chinese samples. Sci Rep. 2016; 6(1): 39313. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrive F, et al.: Efficient analysis of large-scale genome-wide data with two R packages: bigstatsr and bigsnpr. Bioinformatics . 2018; 34(16): 2781–87. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTeam, R.C. and R.F.f.S. Computing: R: A Language and Environment for Statistical Computing . Austria, Vienna; 2020.\n\nDowle M, Srinivasan A: data.table: Extension of ?data.frame? 2019.\n\nKnaus BJ, Grunwald NJ: vcfr: a package to manipulate and visualize variant call format data in R. Mol Ecol Resour . 2017; 17(1): 44–53. PubMed Abstract | Publisher Full Text\n\nPurcell S, et al.: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet . 2007; 81(3): 559–75. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDanecek P, et al.: The variant call format and VCFtools. Bioinformatics . 2011; 27(15): 2156–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTosto G, et al.: Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease. JAMA Neurol . 2019. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang K, Li M, Hakonarson H: ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res . 2010; 38(16): e164. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBand G, Marchini J: BGEN: a binary file format for imputed genotype and haplotype data. bioRxiv. 2018: p. 308296.\n\nMbatchou J, et al.: Computationally efficient whole genome regression for quantitative and binary traits. bioRxiv. 2020: p. 2020.06.19.162354.\n\nPrivé F, Arbel J, Vilhjálmsson BJ: LDpred2: better, faster, stronger. bioRxiv. 2020: p. 2020.04.28.066720."
}
|
[
{
"id": "95650",
"date": "18 Oct 2021",
"name": "Ettore Mosca",
"expertise": [
"Reviewer Expertise Bioinformatics",
"NGS data analysis",
"network analysis",
"pathway analysis",
"metabolomics data analysis."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present GARCOM, a tool for quantifying allelic counts within defined genetic boundaries. Overall, the article is well-written; the software is available in CRAN and GitHub, and it is well-documented. At the same time, the article is quite short.\nI recommend adding some details to clarify how the proposed counting process works (e.g. it does not appear to keep track of the different haplotypes in different individuals) and its usefulness for genetic studies. This would clarify in which scenario this tool can be used and which kind of research questions it helps to address.\nIn the proposed examples, genetic coordinates are given without chromosomes. This suggests that the tool handles one chromosome at a time. Even if this is the case, it might be a dangerous approach, because it could increase the probability of mixing genetic coordinates from different chromosomes while the user prepares the input for GARCOM.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Partly\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Partly\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "7438",
"date": "17 May 2024",
"name": "Sanjeev Sariya",
"role": "Author Response",
"response": "We would like to thank the reviewer for providing feedback and reviewing our manuscript. 1) The authors present GARCOM, a tool for quantifying allelic counts within defined genetic boundaries. Overall, the article is well-written; the software is available in CRAN and GitHub, and it is well-documented. At the same time, the article is quite short. Reply: The main goal of the manuscript is to provide a succinct description of R library, implementation, workflow along with a comparison with available methods. Contrary to most R packages, GARCOM performs one specific task (counting mutation/alleles per gene per sample), hence the brief manuscript. 2) I recommend adding some details to clarify how the proposed counting process works (e.g. it does not appear to keep track of the different haplotypes in different individuals) and its usefulness for genetic studies. This would clarify in which scenario this tool can be used and which kind of research questions it helps to address. Reply: The goal of GARCOM package is to perform allele counts within user-defined genetic region, GARCOM does not account for the haplotypes in different individuals. Allele counting is performed by simple arithmetic operation (sum)on user-provided single nucleotide polymorphisms (SNP) within the user-defined genetic boundaries. The main scope is mentioned in the manuscript, i.e. facilitate common yet laborious tasks for genetic studies, such as shaping files for collapsing analyses. 3) In the proposed examples, genetic coordinates are given without chromosomes. This suggests that the tool handles one chromosome at a time. Even if this is the case, it might be a dangerous approach, because it could increase the probability of mixing genetic coordinates from different chromosomes while the user prepares the input for GARCOM. Reply: Due to the increasing volume of genomics data, it has become challenging to process data genome-wide. GARCOM is therefore developed to process one chromosome at a time. Second, GARCOM collapses SNPs based on base-pair (BP) location, hence, processing data with multiple chromosomes would add additional burden (time and memory) and can be hazardous because of different SNPs with identical BP across the genome."
}
]
},
{
"id": "98677",
"date": "29 Nov 2021",
"name": "Stephen M. Pederson",
"expertise": [
"Reviewer Expertise Bioinformatician",
"R Package Developer"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have provided four primary functions for summarising SNP counts using regions or genes as mapping architecture. The data.table package is known for its speed and this may lend a significant performance advantage to these functions, particularly when dealing with large numbers of samples or SNPs.\nHowever, as it stands, this submission appears to fall short in a few key areas. Firstly, there is a typo in the installation instructions: install.packages(“garcom”) will cause an error. The correct instructions should be install.packages(“GARCOM”).\nThe authors seem unaware of significant pre-existing infrastructure for range-based and SNP-based operations. The Bioconductor community has a wide-ranging suite of packages for robust mapping between genes, ranges, and SNPs, and no performance comparison, nor acknowledgment of these packages has been made. I suspect that using data.table may lend significant performance advantages, but the robustness of mapping between ranges provided by GenomicRanges is advantageous when performing rigorous research. For example, the lack of insistence on a CHR column for the dt_gene argument of gene_pos_counts() raises the distinct possibility of erroneous mapping between SNPs and genes/regions, and this should be addressed for robustness.\nThe authors also seem unaware of other packages which deal very efficiently with PLINK and VCF data, such as seqArray and snpRelate. In particular, these packages utilise the gdsfmt infrastructure, which is extremely efficient at working with large numbers of SNPs and samples. How does GARCOM compare by using the data.table backend? The provision of a new, lesser performing package will serve minimal purpose and this becomes an important question.\nWhilst stating that the argument dt_gene follows PLINK format, an example of importing PLINK data would be most helpful.\nA simple example vcf should also be included in the package so that examples for the two vcf-based functions can be run by any potential users. An example with 10 SNPs and 10 individuals, as per the examples for gene_annot_counts and gene_pos_counts, would fall within size limits for an R package. The fact that this has not been done also highlights the fact that the two vcf-based functions have not been included in the test_that suite of tests, rendering them open to future or even current bugs.\nIt is clear that the authors have found this package to be very useful for their work and their enthusiasm for making it available is commendable. However, I fear that the documentation is not adequate enough to invite new users. A pkgdown vignette appears to have been generated on the github repository but I could not find this vignette visible available anywhere and am unaware of its contents beyond skimming the visible HTML code. Please enable viewing of this via github.io pages which will take a matter of seconds. Making this visible (see https://sa-lee.github.io/plyranges for an excellent example), should enable new users to better comprehend the motivation and use of these functions. This would also enable the authors to include test coverage and other informative metrics.\nI also note that the default behaviour of gene_pos_counts() is to drop genes with zero counts across all individuals, instead of returning all input genes. This is not stated anywhere in the documentation and should be, or alternatively, an argument allowing this behaviour to be modified should be added. Zero counts is not a non-result. It is easy to imagine scenarios where this is indeed important information.\nThe example data provided is also a little confusing. SNP1 in the object snpgene is mapped to both GENE1 and GENE4, and this relationship is not maintained in the snppos object. Is this meant to be SNP10 mapping to GENE4, or are the authors trying to highlight that multiple SNP to gene mappings are handled well by this package? If the latter, this may be a strong feature of the package and more detail should be provided for the handling of multi-mapping in the documentation. If, however, it is an oversight, this should be corrected so as not to confuse any future users.\nAs to the F1000 submission, I would strongly encourage the inclusion of executed code where possible, with results from actual data objects so readers can easily see what each function is doing. As it stands, users will have to install the package locally and run the examples to really understand what the package is offering. Given the lack of example vcf or parsing of PLINK objects, this may prove an insurmountable hurdle for some. If clear examples are provided, I suspect this will also increase the uptake of the package by other users, which is an important consideration that I'm sure the authors wish to see.\n\nIs the rationale for developing the new software tool clearly explained? Partly\n\nIs the description of the software tool technically sound? Partly\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? No\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? No\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-524
|
https://f1000research.com/articles/13-199/v1
|
20 Mar 24
|
{
"type": "Study Protocol",
"title": "Psychological interventions for mood and cognition after stroke and transient ischaemic attack: A protocol for an umbrella review",
"authors": [
"Eirini Kontou",
"Farhad Shokraneh",
"Roshan das Nair",
"Terry Quinn",
"Jo Leonardi-Bee",
"Naomi Thorpe",
"Naomi Clifford",
"Marie Williams",
"Sandra Wydera",
"Avril Drummond",
"Farhad Shokraneh",
"Roshan das Nair",
"Terry Quinn",
"Jo Leonardi-Bee",
"Naomi Thorpe",
"Naomi Clifford",
"Marie Williams",
"Sandra Wydera",
"Avril Drummond"
],
"abstract": "Background People who have had a stroke or a Transient Ischaemic Attack (TIA) can experience psychological and/or cognitive difficulties. The body of research for psychological and neuropsychological interventions after stroke is growing, however, published systematic reviews vary in scope and methodology, with different types and severity of strokes included, and at times, diverse conclusions drawn about the effectiveness of the interventions evaluated. In this umbrella review, we aim to systematically summarise the existing systematic reviews evaluating psychological interventions for mood and cognition post-stroke/TIA.\n\nMethods We will conduct this umbrella review according to the JBI Manual for Evidence Synthesis. The following databases will be searched from inception: Cochrane Database of Systematic Reviews, Database of Reviews of Effects (DARE), MEDLINE, Embase, CINAHL, PsycINFO, and Epistemonikos. Systematic reviews with or without meta-analysis published until the search date will be included. Reviews including psychological interventions addressing mood and/or cognition outcomes for any stroke type or severity will be screened for eligibility. A narrative synthesis, including content analysis, will be used. Each stage of the review will be processed by two independent reviewers and a third reviewer will be considered to resolve disagreements. The methodological quality of the included reviews will be assessed using AMSTAR 2.\n\nDiscussion Existing systematic reviews provide varied evidence on the effectiveness of psychological interventions post-stroke/TIA. This umbrella review aims to summarise knowledge and evidence on different types of psychological and neuropsychological interventions targeting mood and cognition. Findings will highlight important knowledge gaps and help prioritise future research questions.\n\nSystematic Review Registration This protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) on November 15, 2022; PROSPERO CRD42022375947.",
"keywords": [
"umbrella review",
"systematic review",
"stroke",
"Transient Ischaemic Attack",
"protocol",
"overview of systematic reviews",
"cognition",
"mood",
"psychological intervention",
"cognitive intervention"
],
"content": "Background\n\nMood (e.g., depression, anxiety)1 and cognitive problems (e.g., memory loss, inattention, slow processing)2 are very common following a stroke and a Transient Ischaemic Attack (TIA). There is now emerging evidence on the prevalence of neuropsychological difficulties (e.g., depression, anxiety, apathy) post-stroke and TIA.3,4 Interventions for improving psychological and cognitive effects after stroke are still a top research priority for improving rehabilitation care.5\n\nThe body of research for psychological interventions after stroke is growing, and our initial scoping search in the Cochrane Database of Systematic Reviews suggested that there were at least seven published Cochrane systematic reviews on the effectiveness of interventions for depression,6,7 anxiety8 and various types of cognitive problems.9–12 However, these published systematic reviews varied in scope and methodology, with different types and severity of strokes included, and at times, diverse conclusions drawn about the effectiveness of the range of interventions evaluated. Until now, there has been no published overview of systematic reviews of interventions for neuropsychological difficulties after stroke and TIA. We propose an umbrella review approach13 (a term used to describe an overview of systematic reviews) that will be used to systematically summarise the methodological and reporting characteristics of existing systematic reviews on psychological interventions for mood and cognition after stroke/TIA.\n\nThis umbrella review aims to summarise and synthesise the published evidence on psychological interventions for neuropsychological (specifically mood and cognition) difficulties after stroke/TIA. Furthermore, when information is available in the identified systematic reviews, we will attempt to systematically evaluate the quality of the evidence and the extent of potential methodological limitations on this topic.\n\nIn the present protocol, we describe how this review will aim to address the following questions:\n\n1) What are the available psychological interventions for addressing difficulties with mood (depression and anxiety) and cognition (all cognitive domains including language) after stroke/TIA?\n\n2) Which of these interventions, if any, are effective for which stroke survivors (stroke type, severity) and for which outcome measures (mood, individual cognitive domains, quality of life)?\n\n\nMethods\n\nThe protocol is based on the guidelines provided by the JBI (Joanna Briggs Institute) Manual for Evidence Synthesis14 and in accordance with PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) guidelines15 (see Reporting Guidelines, Additional File 1). Our protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42022375947 on 15 November 2022).\n\nThe following databases will be searched from inception until the search date: Cochrane Database of Systematic Reviews, Database of Reviews of Effects (DARE), Ovid MEDLINE, Ovid Embase, CINAHL, Ovid PsycINFO, and Epistemonikos.\n\nOur search algorithm will be developed, peer-reviewed and undertaken by two Information Specialists (FS, NT). We will use the Canadian Agency for Drugs and Technology in Health (CADTH) (https://searchfilters.cadth.ca/) systematic review search filters and the Cochrane Stroke group search strategy for identifying studies on stroke and TIA (for MEDLINE, Embase, CINAHL, PsycINFO).\n\nThe search terms will include the following themes, with synonyms to describe each: psychotherapies, depression, anxiety, cognition, and stroke. Full details and search strategies can be found in Reporting Guidelines: Additional File 2.\n\nPsychological interventions with a variety of theoretical underpinnings will be considered. The main types of psychological interventions that will be identified for inclusion in our umbrella review will be psychotherapy/talking therapy interventions (including psychoeducation), cognitive rehabilitation and neuropsychological rehabilitation interventions. We will include only articles published in English. Only full-text systematic reviews published in peer-reviewed journals will be considered for inclusion. Systematic reviews will be included based on the following eligibility criteria. See Table 1.\n\nWe will consider the consensus definition of a systematic review used in overviews of systematic reviews.16 Where a systematic review has been updated, we will include the updated version in preference to the original publication.\n\nTwo authors will screen the titles and abstracts (EK, FS), and full-text papers, with discrepancies being resolved through either consensus or with a third author (NC, MW). Two authors (NC, MW) will independently extract relevant characteristics of the reviews, including title, author, year of publication, databases searched, years searched, inclusion criteria, intervention details, outcomes assessed, type of data synthesis performed, results from methodological quality assessments, quantitative and descriptive results relating to the outcome measures. Any disagreement will be resolved after consulting with a third author (EK). Data extraction will be conducted using a bespoke data extraction form (see Reporting Guidelines: Additional File 3) created for the purpose of this review and based on the JBI Data Extraction Form for Review for Systematic Reviews and Research Syntheses. In the data extraction process, we will consider adapting and piloting the data extraction form with at least 10% of the reviews included.\n\nTwo authors will independently assess the methodological quality of the included reviews using the AMSTAR 217 appraisal tool since this tool can be used for RCTs. Variations in the assessment of quality between the two authors (NC, MW) will be addressed through discussion or the involvement of a third author (EK). It is not recommended to combine AMSTAR 2 individual item ratings to produce an overall score. The proposed scheme proposed by Shea et al. (2017)17 for interpreting weaknesses detected in critical items of a systematic review will be considered for assessing the overall quality of the reviews included (i.e., high, moderate, low or critically low). The core study team (EK, AD, TQ, RdN, FS) will seek consensus on the items that are most important for the reviews considered for this topic area.\n\nA narrative synthesis will be performed to look systematically at the data and to describe each review. Patterns in the data will be identified through tabulation and visual representation of the results. The commonality in results between the reviews will be identified using content analysis based on an inductive approach (deriving concepts from the data). We will investigate reasons for differences in the magnitude of each outcome measure through investigating within-review differences, e.g., psychological therapy versus cognitive rehabilitation. A summary of findings table will be created to provide an overview of the findings from the reviews, which will comprise the intervention, relevant reviews and outcome measure using a ‘stop-light’ indicator, where green indicates the intervention is beneficial, amber is no differences, and red suggests the intervention is detrimental. It is anticipated that there will be discordant/inconsistent findings between included systematic reviews on the same research topic. In these instances, this will be clearly reported and the assignment of the ‘stop-light’ indicator will be fully described.\n\nIn the synthesis stage, we will describe and explain any overlap from the same primary studies reported across the included systematic reviews. We will attempt to visually present the amount of overlap using a table or a matrix. As there is currently no standard methodological approach recommended for managing overlap, we will choose an appropriate method based on the number of included reviews and their primary studies.18\n\nSubgroup analysis will be used, if possible, to investigate whether there are differences in the effectiveness of the psychological interventions by population (stroke versus TIA/minor stroke).\n\nA complete list of the different types of psychological interventions included will be considered when presenting the findings of our review. Reasons for excluding any reviews based on our eligibility criteria will be reported.\n\n\nDiscussion\n\nConsidering the high prevalence of psychological and cognitive difficulties reported in the stroke literature and the varied evidence on the effectiveness of available interventions, this umbrella review aims to summarise the current state of the evidence on psychological interventions for people with stroke/TIA. It will attempt to identify what the different types of psychological interventions are for addressing the most common neuropsychological difficulties (primarily mood and cognition) following a diagnosis of stroke/TIA. The quality of the included systematic reviews will be discussed, and recommendations for future research will be provided. Finally, the findings from this review will be used to inform the development and evaluation of a psychological care pathway for people experiencing less severe strokes.\n\nOngoing. At the time of submission, the umbrella review will be progressing at data extraction stage.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nMedline Search Strategy (Additional File 2) for Psychological interventions for mood and cognition after stroke and transient ischaemic attack: a protocol for an umbrella review, https://doi.org/10.6084/m9.figshare.24939081.\n\nData Extraction Form (Additional File 3) for Psychological interventions for mood and cognition after stroke and transient ischaemic attack: a protocol for an umbrella review, https://doi.org/10.6084/m9.figshare.24926232.\n\nPRISMA-P Checklist (Additional File 1) for Psychological interventions for mood and cognition after stroke and transient ischaemic attack: a protocol for an umbrella review, https://doi.org/10.6084/m9.figshare.24938931.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)\n\n\nReferences\n\nKnapp P, Dunn-Roberts A, Sahib N, et al.: Frequency of anxiety after stroke: An updated systematic review and meta-analysis of observational studies. Int. J. Stroke. 2020 Apr 24; 15(3): 244–255. PubMed Abstract | Publisher Full Text\n\nHackett ML, Yapa C, Parag V, et al.: Frequency of Depression After Stroke. Stroke. 2005 Jun; 36(6): 1330–1340. Publisher Full Text\n\nCarnes-Vendrell A, Deus J, Molina-Seguin J, et al.: Depression and Apathy After Transient Ischemic Attack or Minor Stroke: Prevalence, Evolution and Predictors. Sci. Rep. 2019 Nov 7; 9(1): 16248. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBroomfield NM, Quinn TJ, Abdul-Rahim AH, et al.: Depression and anxiety symptoms post-stroke/TIA: prevalence and associations in cross-sectional data from a regional stroke registry. BMC Neurol. 2014 Dec 1; 14(1): 198. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHill G, Regan S, Francis R, et al.: Research priorities to improve stroke outcomes. Lancet Neurol. 2022 Apr; 21(4): 312–313. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAllida S, Cox KL, Hsieh CF, et al.: Pharmacological, psychological, and non-invasive brain stimulation interventions for treating depression after stroke. Cochrane Database Syst. Rev. 2020 Jan 28; 1: CD003437. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCheng D, Qu Z, Huang J, et al.: Motivational interviewing for improving recovery after stroke. Cochrane Database Syst. Rev. 2015 Jun 3; 2015(6): CD011398. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKnapp P, Campbell Burton CA, Holmes J, et al.: Interventions for treating anxiety after stroke. Cochrane Database Syst. Rev. 2017 May 23; 2017(5): CD008860. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBowen A, Hazelton C, Pollock A, et al.: Cognitive rehabilitation for spatial neglect following stroke. Cochrane Database Syst. Rev. 2013 Jul 1; 2013: CD003586. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChung CS, Pollock A, Campbell T, et al.: Cognitive rehabilitation for executive dysfunction in adults with stroke or other adult non-progressive acquired brain damage. Cochrane Database Syst. Rev. 2013 Apr 30; 2013: CD008391. PubMed Abstract | Publisher Full Text | Free Full Text\n\ndas Nair R , Cogger H, Worthington E, et al.: Cognitive rehabilitation for memory deficits after stroke. Cochrane Database Syst. Rev. 2016 Sep 1; 2016(9). Publisher Full Text\n\nLoetscher T, Potter KJ, Wong D, et al.: Cognitive rehabilitation for attention deficits following stroke. Cochrane Database Syst. Rev. 2019 Nov 10; 2019. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFaulkner G, Fagan MJ, Lee J: Umbrella reviews (systematic review of reviews). Int. Rev. Sport Exerc. Psychol. 2022; 15(1): 73–90. Publisher Full Text\n\nAromataris E, Fernandez R, Godfrey C, et al.: Chapter 10: Umbrella reviews. JBI Manual for Evidence Synthesis. JBI; 2020.\n\nPage MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKrnic Martinic M, Pieper D, Glatt A, et al.: Definition of a systematic review used in overviews of systematic reviews, meta-epidemiological studies and textbooks. BMC Med. Res. Methodol. 2019; 19(1): 203. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShea BJ, Reeves BC, Wells G, et al.: AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017; 358: j4008. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLunny C, Pieper D, Thabet P, et al.: Managing overlap of primary study results across systematic reviews: practical considerations for authors of overviews of reviews. BMC Med. Res. Methodol. 2021; 21(1): 140. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "258061",
"date": "01 Apr 2024",
"name": "Niamh Kennedy",
"expertise": [
"Reviewer Expertise Stroke",
"Neurorehabilitation",
"Psychology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper provides a protocol for an umbrella review of psychological interventions for mood and cognition after stroke and transient ischaemic attack. They propose conducting an umbrella review (along established guidelines) to help syntheses the existing systematic reviews, evaluating psychological interventions for mood and cognition. They present a robust methodology, searching a range of relevant databases, using clear eligibility criteria and search terms. Quality assessment will be conducted using AMSTAR 2, to establish quality of the included systematic reviews. A narrative synthesis will be used to collate findings, establishing commonality between findings and to investigate any potential differences in the effectiveness of interventions. This is a relevant and useful paper for this field. The importance of psychological and mood interventions has been frequently highlighted by stroke survivors, their families and health care professionals as a major concern post stroke. Currently there is little consensus or structured recommendation on what interventions/approaches are most appropriate to this population. There is some published findings in the area but its lacking in agreement and this is needed to help drive this clinical area forward. This paper provides an opportunity to address some of these gaps. Abstract is appropriately detailed, covering all main areas. Background is sufficiently detailed, provides a rationale for the study, identifying the need for this study (and using this methodology). Methods; Good level of detail, sufficient for replication. Clear thought has been applied to use of the research team, with good use of double screening, extraction etc. Good explanation and description of data extraction and quality assessment procedures. Supplementary material- clear, useful and appropriate.\n\nMajor Points No major points. Minor Points\nThe research questions in the paper differ slightly from those stated in PROSPERO I suggest editing these (on properso) to ensure consistency. Quasi-RC isn’t defined or further detail on what may fall under this category, isn't provided which may be useful (especially for replication). Could you provide a justification for exclusion of Computerised-cognitive rehabilitation interventions? A line or two of additional detail on how ” using content analysis based on an inductive approach” will be implemented would be helpful for the reader. No participant details such as average age, gender are being recorded in the data extraction form, I find this unusual especially if one of the aims is to look at potential subgroups analysis. I believe these details should be extracted.\nI recommended some minor comments.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": [
{
"c_id": "11524",
"date": "20 May 2024",
"name": "Eirini Kontou",
"role": "Author Response",
"response": "We thank the reviewer for spending time on our review and for providing helpful comments. We have made minor amendments to the manuscript addressing their recommendations. Background Comment: The research questions in the paper differ slightly from those stated in PROSPERO I suggest editing these to ensure consistency. Reply: Thank you for noting this. We will request to amend on PROSPERO, in order to ensure we are consistent. Methods Comment: Quasi-RC isn’t defined or further detail on what may fall under this category, isn't provided which may be useful (especially for replication). Reply: This refers to studies that were included in a systematic review and referred to as ‘quasi-RCT designs’. We have added a sentence to clarify that if the authors of a systematic review did not define or further detail what they meant by a Quasi RCT (e.g., participants allocated to different arms of the trial using a method of allocation that was not truly random) on their eligibility criteria, this will be noted but will not constitute a reason for exclusion. Methods / Eligibility criteria Comment: Could you provide a justification for exclusion of Computerised-cognitive rehabilitation interventions? Reply: We added that computerised interventions that are delivered solely via apps or virtual technology will be excluded. This is due to differences in the way they approach the content and delivery of the intervention compared with other cognitive rehabilitation interventions (via Zoom or Teams), as well as significant heterogeneity between the interventions themselves (e.g., the use of computer games, virtual reality platforms or other remote tasks). Results/Synthesis Comment: A line or two of additional detail on how ” using content analysis based on an inductive approach” will be implemented would be helpful for the reader. Reply: We have added a sentence to expand on how this will be implemented in the context of this umbrella review. Methods/Data extraction Comment: No participant details such as average age, gender are being recorded in the data extraction form, I find this unusual especially if one of the aims is to look at potential subgroups analysis. I believe these details should be extracted. Reply: Thank you for this very helpful observation. We have extracted this information (age and gender) under the ‘Participant Characteristics’. During the piloting process of the extraction form it was noticed that, for several systematic reviews, gender was not adequately reported under participant characterics. Given this variability it may not be possible to extract this information for all the systematic reviews included in our umbrella review. We acknowledge that this is not currently explicit in the Data Extraction Form – we added this in the details and uploaded a revised version."
}
]
},
{
"id": "258062",
"date": "11 Apr 2024",
"name": "Andrea Kusec",
"expertise": [
"Reviewer Expertise stroke",
"mental health",
"cognition",
"mood disorders",
"clinical trials",
"neuropsychological rehabilitation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper describes a protocol for an umbrella review of psychological interventions for cognition and mood after stroke in order to harmonize the increasing amount of research focused on this topic. In general, the protocol is clear, and I mainly have suggestions to strengthen the potential quality of the umbrella review.\n\nThe search terms seem largely appropriate; given the second research question of the protocol focus on which outcome measures demonstrate benefit for stroke/TIA survivors, will the authors consider reviews which focus on interventions to improve quality of life post-stroke? How will the authors consider the role of time post-stroke in their umbrella review – some interventions may be delivered very early on in stroke or in chronic stages and this could impact interpretation of results Why are the authors including articles where 70% of the sample in included reviews has a stroke – this seems like a large number given that many neuropsychological rehabilitation reviews focus on acquired brain injury more generally and might exclude potentially useful information about neuropsychological interventions. Further, given that mixed health care services exist that work with stroke and other acquired brain injury survivors the potential overlap does not seem irrelevant in the context of this review, which aims to describe mood and cognitive interventions in a broad sense.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "11523",
"date": "20 May 2024",
"name": "Eirini Kontou",
"role": "Author Response",
"response": "We are grateful to the expert reviewer for their interest in this topic and for taking the time to review our manuscript. We appreciate their helpful and thorough comments. A revised version was submitted and a detailed response to each comment. Background/Methods Comment: The search terms seem largely appropriate; given the second research question of the protocol focus on which outcome measures demonstrate benefit for stroke/TIA survivors, will the authors consider reviews which focus on interventions to improve quality of life post-stroke? Reply: Thank you for this comment. This review was commissioned to primarily examine mood and cognition. Thus, interventions are not the focus of this umbrella review, which is a work package for a larger research study evaluating psychological care pathways for people after TIA and minor stroke. Quality of life measures will be examined as secondary outcomes only. Results/Synthesis Comment: How will the authors consider the role of time post-stroke in their umbrella review – some interventions may be delivered very early on in stroke or in chronic stages and this could impact interpretation of results Reply: Thank for this suggestion. We want to clarify that the recovery stage will be reported. For example, we will aim to map and present findings to time post diagnosis e.g., Acute <1 month, Early subacute, 3-6 months, Late/chronic, > 6 months. This approach has been taken by other authors on the topic of psychological interventions after stroke/TIA. Methods / Eligibility Criteria Comment: Why are the authors including articles where 70% of the sample in included reviews has a stroke – this seems like a large number given that many neuropsychological rehabilitation reviews focus on acquired brain injury more generally and might exclude potentially useful information about neuropsychological interventions. Further, given that mixed health care services exist that work with stroke and other acquired brain injury survivors the potential overlap does not seem irrelevant in the context of this review, which aims to describe mood and cognitive interventions in a broad sense. Reply: The reason for excluding Acquired Brain Injury (ABI) in general is because this review was funded to focus on stroke and TIA. Thus, we wanted to identify interventions that might be suitable, and considered best practice interventions, for people after stroke/TIA, rather than for all ABI survivors. This is because, depending on the type and severity of their injury, their difficulties and needs are likely to be different and broader. Additionally, this was also a pragmatic decision because of the heterogeneity of reviews and the primary studies included."
}
]
}
] | 1
|
https://f1000research.com/articles/13-199
|
https://f1000research.com/articles/13-488/v1
|
17 May 24
|
{
"type": "Study Protocol",
"title": "Polarization and health-related behaviours and outcomes during the COVID-19 pandemic: a systematic review protocol",
"authors": [
"Aziz Mert Ipekci",
"Maximilian Filsinger",
"Diana Buitrago-Garcia",
"Cristopher I. Kobler Betancourt",
"Annika Frahsa",
"Nicola Low",
"Maximilian Filsinger",
"Diana Buitrago-Garcia",
"Cristopher I. Kobler Betancourt",
"Annika Frahsa",
"Nicola Low"
],
"abstract": "Introduction The COVID-19 pandemic affected people’s health behaviours and health outcomes. Political or affective polarization could be associated with health behaviours such as mask-wearing or vaccine uptake and with health outcomes, e.g., infection or mortality rate. Political polarization relates to divergence or spread of ideological beliefs and affective polarization is about dislike between people of different political groups, such as ideologies or parties. The objectives of this study are to investigate and synthesize evidence about associations between both forms of polarization and COVID-19 health behaviours and outcomes.\n\nMethods In this systematic review, we will include quantitative studies that assess the relationship between political or affective polarization and COVID-19-related behaviours and outcomes, including adherence to mask mandates, vaccine uptake, infection and mortality rate. We will use a predetermined strategy to search EMBASE, Medline (Ovid), Cochrane Library, Cochrane COVID-19 Study Register, Global Health (Ovid), PsycInfo (Ovid), Web of Science, CINAHL, EconLit (EBSCOhost), WHO COVID-19 Database, iSearch COVID-19 Portfolio (NIH) and Google Scholar from 2019 to September 8 2023. One reviewer will screen unique records according to eligibility criteria. A second reviewer will verify the selection. Data extraction, using pre-piloted electronic forms, will follow a similar process. The risk of bias of the included studies will be assessed using the JBI checklist for analytical cross sectional studies. We will summarise the included studies descriptively and examine the heterogeneity between studies. Quantitative data pooling might not be feasible due to variations in measurement methods used to evaluate exposure, affective and political polarization. If there are enough relevant studies for statistical data synthesis, we will conduct a meta-analysis.\n\nDiscussion This review will help to better understand the concept of polarization in the context of the COVID-19 pandemic and might inform decision making for future pandemics.\n\nProtocol registration PROSPERO ID: CRD42023475828.",
"keywords": [
"Systematic review",
"political-polarization",
"affective-polarization",
"COVID-19",
"vaccination",
"social-distancing",
"infection-risk",
"mortality."
],
"content": "Introduction\n\nDuring the COVID-19 pandemic, researchers observed variations in adherence to infection control measures, such as mask-wearing or vaccine uptake,1,2 and in health outcomes, such as infection and mortality rate.3 Political science research has long established that governmental action is often appraised through an ideological and partisan lens.4–6 In this regard, increasing polarization of attitudes could contribute to explaining the variation in adherence to preventive behaviours and health outcomes. Studies have already shown that polarization of political or personal opinions can be associated with people’s COVID-19 pandemic behaviours and related health outcomes.7–9 High levels of polarization might lead to poor health outcomes such as increased infection rate, reduced vaccine uptake or increased mortality7,8,10–12 and lack of adherence to COVID-19 prevention measurements such as social distancing.13\n\nAffective and political polarization are related but different concepts. Political polarization refers to the degree to which political beliefs and opinions diverge along ideological lines,14 whereas affective polarization refers to feelings of dislike and/or distrust that individuals or groups hold about those from a group with opposite views.15 Political polarization can exist without affective polarization, which means people can have different political views without feeling hostile towards those with opposing views. Both political and affective polarization can be measured quantitatively16,17 using tools based on self-report, such as the ideology scale,18 feeling thermometer,19 like-dislike ratings20 and social distance scales.20 Owing to differences between measurement methods, researchers should be cautious in comparing different measurement methods directly.18\n\nWithin the research literature, a number of studies have focused on health-related behaviours and outcomes of polarization. Fraser and colleagues reported that in the United States of America (USA), based on polarization measured on a scale from 0 to 10, for each 1 unit increase in state-level perceived polarization the incidence rate of experiencing poor physical health increased by 1.03 times.21 Krupenkin studied the effects of political partisanship on children’s vaccination rate. They dichotomised people into in-partisans (people who voted for the government in power), and out-partisans (people who voted against the government in power).8 In a multivariable logistic regression model, presidential out-partisans had lower odds of adhering to USA Government vaccination recommendation than in-partisans.8 Nayak and colleagues measured both perceived polarization change and self-reported health with a 5-point Likert scale.22 They found that individuals who reported higher levels of polarization had higher odds of developing depressive and anxiety disorders than those who reported no change in polarization.22 In the context of the COVID-19 pandemic, Gollwitzer et al. studied partisanship at the county level in the USA based on the 2016 presidential election and reported that pro-Trump counties reduced their general movement 9.5 per cent less than Clinton-voting counties.7\n\nWe found two systematic reviews on polarization but they focus on the association with social media.18,23 Both conducted descriptive syntheses of the data,18,23 with Kubin and colleagues stating that they were unable to perform meta-analysis due to inconsistencies in measurement.18 To our knowledge, there are no systematic reviews focusing on the association between polarization and health-related health behaviours or outcomes despite the consistent associations found between different forms of polarization and health-related behaviours. This systematic review aims to fill the gap in the literature on the association between polarization and COVID-19 related health behaviours/outcomes to better understand the COVID-19 pandemic and prepare for future pandemics.\n\n\nReview questions\n\nQuestion 1: What is the association between political or affective polarization and COVID-19 health behaviours?\n\nQuestion 2: What is the association between political/affective polarization and COVID-19-related health outcomes?\n\n\nMethods\n\nThis protocol is reported following the Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guideline (Extended data A),24 PROSPERO registration number, CRD42023475828.\n\n\n\nWe searched electronic databases using predefined terms for polarization and COVID-19 (Extended data B) on 8th of September 2023. We will include studies published from 2019 to 2023. Because the topic is multidisciplinary, we will search the following databases: EMBASE (RRID:SCR_001650), Medline (Ovid), Cochrane Library (RRID:SCR_013000), Cochrane COVID-19 Study Register, Global Health (Ovid), PsycInfo (Ovid), Web of Science (RRID:SCR_022706, CINAHL (RRID:SCR_022707), EconLit (EBSCOhost), We will use WHO COVID-19 Database and iSearch COVID-19 Portfolio (NIH) (RRID:SCR_018295) as the source of preprint publications. We will also run a Google Scholar (RRID:SCR_008878) search using keywords such as polarization, affective, political and COVID-19. We will review the first 200 hits on Google Scholar to see if we can identify any study that cannot be identified via our literature search. We will check the reference lists of relevant studies and systematic reviews. We will also contact experts in the field to ask for recommendations about studies that might be eligible. We will not perform hand-searching. We will merge the electronic database search results and remove duplicates using reference management software (EndNote – Clarivate, version 20.4).\n\nWe will use the liberal screening approach25 to accelerate our screening process. AMI will screen all titles and abstracts and select potentially relevant articles according to the eligibility criteria. A second reviewer (MF, AF, CK-B or DB-G) will verify the screened articles. AMI will retrieve the full-text of all potentially eligible articles and mark those eligible for inclusion. MF, AF, CK-B or DB-G will verify the results of the full-text screening. In case of disagreements that are not resolved by discussion, the senior reviewer NL will decide. We will report the study selection process, and reasons for exclusion, in the PRISMA 202026 flow diagram.\n\nWe will use a predetermined data extraction form in the Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia, available at www.covidence.org, RRID:SCR_016484). We piloted extraction from 5 included studies. We will revise and finalize the form (Extended data C) after our pilot extraction. We plan to extract data on how polarization and COVID-19 related health behaviours/outcomes were measured, the main findings, and possible confounding factors, such as data collection date, participant’s age, gender and socioeconomic status. The full list of questions can be found in Extended data C. AMI will extract data from all included articles and MF, AF, CK-B and DB-G will independently verify the accuracy of the extracted data. NL will resolve disagreements if necessary.\n\nWe will contact corresponding authors in case of any missing data in the included study. If the author does not reply, researchers (AMI, MF) will decide on whether the study can still be included.\n\nAMI, MF and DB-G will assess risk of bias independently for each included study. NL will resolve disagreements if the two reviewers cannot reach a consensus. We will use the JBI checklist for analytical cross sectional studies.27\n\nThe data analysis will start with a description of countries of origin, study population, the methods used to measure exposure and outcome, and the participants’ age and sex in the included studies.\n\nWe will employ narrative synthesis methods to explore our dataset following the Synthesis Without Meta-analysis guideline.28 We will group the studies for synthesis based on exposure, affective or political polarization, and outcome, e.g., vaccination uptake and perceived COVID-19 risk. Then, we will describe the metrics for each exposure and outcome. We will justify our reasoning, if certain studies are prioritized to draw conclusions. Lastly, we will report on the heterogeneity and assess the certainty of the synthesis findings.\n\nOur preliminary overview of the literature indicated that there might be too few comparable studies for quantitative data synthesis, owing to variations in measurement methods used to evaluate exposure, and affective and political polarization. Additionally, the potential for heterogeneity exists due to differences in study setups, countries of origin and pandemic severity at the time of study data collection.\n\nWe will examine statistical heterogeneity using the I-squared statistic if there are estimated proportions from three or more studies.29 After considering sources of heterogeneity, we will decide if statistically combining effect estimates with a meta-analysis is appropriate for included studies.30\n\nThe results of this study will be published in a peer-reviewed journal.\n\nThe literature search for the study has been done. Screening is ongoing, the data extraction, risk of bias analysis, data synthesis and writing of the final report have not started yet.\n\n\nDiscussion\n\nOur study has two main strengths. First, our comprehensive search strategy includes both preprint and published articles gathered from a range of databases in health and political sciences. This will ensure the incorporation of evidence from various fields. Second, our team includes experts with varied backgrounds, including epidemiology, medicine, political sciences, and anthropology, ensuring a wide range of perspectives. This diverse outlook will enable us to adopt a comprehensive approach to both analysis and data interpretation.\n\nOur review also has weaknesses. We will not perform independent screening and extraction in our systematic review owing to time and resource constraints. However, the liberal approach, to include more articles for full-text screening, will reduce the risk of missing important articles. Second, it might not be possible to pool the data quantitatively. Narrative synthesis methods will, however, provide a valid interpretation of the data.\n\nOur preliminary search shows a need for a systematic literature review and evidence synthesis on the association between pandemic related health behaviours/outcomes and polarization. Our systematic review aims to fill the gap in the literature to better understand the COVID-19 pandemic, which could inform decision making for future pandemics.\n\nEthical approval and written consent were not required.\n\n\nData availability\n\nNo data is associated with this article.\n\nOSF: Extended Data, https://doi.org/10.17605/OSF.IO/DG87Q.31\n\nThis project contains the following underlying data:\n\nA. PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to address in a systematic review protocol\n\nB. Full search strategy per database\n\nC. Data extraction form.\n\nThe data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nOSF: Checklist for Polarization and health-related behaviours and outcomes during the COVID-19 pandemic: a systematic review protocol, https://doi.org/10.17605/OSF.IO/DG87Q.31\n\n\nSoftware availability\n\nCovidence (Veritas Health Innovation, Melbourne, Australia, available at www.covidence.org). is a proprietary software. An alternative software that can be used for free is Rayyan (https://www.rayyan.ai/) that allows management and organization of systematic reviews.",
"appendix": "Acknowledgments\n\nThe authors thank Beatrice Minder and Doris Kopp-Heim (Information Specialists at the Public Health and Primary Care Library, University of Bern, Switzerland) for helping us to develop the literature search strategy.\n\n\nReferences\n\nAlbrecht D: Vaccination, politics and COVID-19 impacts. BMC Public Health. 2022; 22(1): 1–12. Publisher Full Text\n\nHearne BN, Niño MD: Understanding how race, ethnicity, and gender shape mask-wearing adherence during the COVID-19 pandemic: evidence from the COVID impact survey. J. Racial Ethn. Health Disparities. 2021; 9: 176–183. Publisher Full Text\n\nUnruh LH, Dharmapuri S, Xia Y, et al.: Health disparities and COVID-19: A retrospective study examining individual and community factors causing disproportionate COVID-19 outcomes in Cook County, Illinois. PLoS One. 2022; 17(5): e0268317. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGadarian SK, Goodman SW, Pepinsky TB: Partisanship, health behavior, and policy attitudes in the early stages of the COVID-19 pandemic. PLoS One. 2021; 16(4): e0249596. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBartels LM: Beyond the running tally: Partisan bias in political perceptions. Polit. Behav. 2002; 24: 117–150. Publisher Full Text\n\nMalhotra N, Kuo AG: Attributing Blame: The Public’s Response to Hurricane Katrina. J. Polit. 2008; 70(1): 120–135. Publisher Full Text\n\nGollwitzer A, Martel C, Brady WJ, et al.: Partisan differences in physical distancing are linked to health outcomes during the COVID-19 pandemic. Nat. Hum. Behav. 2020; 4(11): 1186–1197. PubMed Abstract | Publisher Full Text\n\nKrupenkin M: Does Partisanship Affect Compliance with Government Recommendations? Polit. Behav. 2021; 43(1): 451–472. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKerr J, Panagopoulos C, van der Linden S : Political polarization on COVID-19 pandemic response in the United States. Personal. Individ. Differ. 2021; 179: 110892. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPanagopoulos C, Fraser T, Aldrich DP, et al.: Bridging the Divide: Does Social Capital Moderate the Impact of Polarization on Health? Polit. Res. Q. 2021; 75(3): 875–891.\n\nDolman AJ, Fraser T, Panagopoulos C, et al.: Opposing views: associations of political polarization, political party affiliation, and social trust with COVID-19 vaccination intent and receipt. J. Public Health. 2023; 45(1): 36–39. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCurtis C, Stillman J, Remmel M, et al.: Partisan polarization, historical heritage, and public health: Exploring COVID-19 outcomes. World Med. Health Policy. 2022; 15: 163–178. Publisher Full Text\n\nAllcott H, Boxell L, Conway J, et al.: Polarization and public health: Partisan differences in social distancing during the coronavirus pandemic. J. Public Econ. 2020; 191: 104254. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFiorina MP, Abrams SJ: Political polarization in the American public. Annu. Rev. Polit. Sci. 2008; 11: 563–588. Publisher Full Text\n\nIyengar S, Lelkes Y, Levendusky M, et al.: The Origins and Consequences of Affective Polarization in the United States. Annu. Rev. Polit. Sci. 2019; 22(1): 129–146. Publisher Full Text\n\nDruckman JN, Levendusky MS: What Do We Measure When We Measure Affective Polarization? Public Opin. Q. 2019; 83(1): 114–122. Publisher Full Text\n\nTucker JA, Guess A, Barberá P, et al.: Social media, political polarization, and political disinformation: A review of the scientific literature. Soc. Sci. Res. Netw. 2018. Publisher Full Text\n\nKubin E, von Sikorski C : The role of (social) media in political polarization: a systematic review. Ann. Int. Commun. Assoc. 2021; 45(3): 188–206. Publisher Full Text\n\nGidron N, Sheffer L, Mor G: Validating the feeling thermometer as a measure of partisan affect in multi-party systems. Elect. 2022; 80: 102542. Publisher Full Text\n\nKekkonen A, Suuronen A, Kawecki D, et al.: Puzzles in affective polarization research: party attitudes, partisan social distance, and multiple party identification. Front. Polit. Sci. 2022; 4: 78. Publisher Full Text\n\nFraser T, Aldrich DP, Panagopoulos C, et al.: The harmful effects of partisan polarization on health. PNAS Nexus. 2022; 1(1). PubMed Abstract | Publisher Full Text | Free Full Text\n\nNayak SS, Fraser T, Panagopoulos C, et al.: Is divisive politics making Americans sick? Associations of perceived partisan polarization with physical and mental health outcomes among adults in the United States. Soc. Sci. Med. 2021; 284: 113976. PubMed Abstract | Publisher Full Text\n\nArora SD, Singh GP, Chakraborty A, et al.: Polarization and social media: A systematic review and research agenda. Technol. Forecast. Soc. Change. 2022; 183: 121942. Publisher Full Text\n\nShamseer L, Moher D, Clarke M, et al.: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. Br. Med. J. 2015; 349: g7647. PubMed Abstract | Publisher Full Text\n\nPussegoda K, Turner L, Garritty C, et al.: Systematic review adherence to methodological or reporting quality. Syst. Rev. 2017; 6(1): 1–14.\n\nPage MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst. Rev. 2021; 10(1): 1–11.\n\nJoanna Briggs Institute: Checklist for analytical cross sectional studies. Adelaide: The Joanna Briggs Institute2017; p. 7. Reference Source\n\nCampbell M, McKenzie JE, Sowden A, et al.: Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ. 2020; 368: l6890. Publisher Full Text\n\nRiley RD, Higgins JP, Deeks JJ: Interpretation of random effects meta-analyses. BMJ. 2011; 342: d549. Publisher Full Text\n\nDekkers OM, Vandenbroucke JP, Cevallos M, et al.: COSMOS-E: Guidance on conducting systematic reviews and meta-analyses of observational studies of etiology. PLoS Med. 2019; 16(2): e1002742. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPolarization and health-related behaviours and outcomes during the COVID-19 pandemic: a systematic review protocol. dataset. Publisher Full Text"
}
|
[
{
"id": "287860",
"date": "19 Jun 2024",
"name": "Ray Block",
"expertise": [
"Reviewer Expertise Political science (race and ethnic politics",
"political behavior",
"public opinion)"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI am pleased to support the advancement of the manuscript titled \"Polarization and Health-Related Behaviours and Outcomes During the COVID-19 Pandemic: A Systematic Review Protocol.\"\n\nThe authors are addressing a crucial aspect of the pandemic by synthesizing the existing (quantitative) empirical literature on polarization and COVID-19 mitigation behaviors. This work is not only timely but also essential in understanding how societal divisions affect health-related behaviors and outcomes.\nOne of the standout features of this manuscript is its ambitious scope. The authors aim to synthesize research from various geographic contexts over multiple years of the pandemic. Additionally, they consider a broad range of mitigation behaviors, such as masking and vaccine uptake, and examine different forms of polarization, including affective and political. This comprehensive approach is commendable and will provide valuable insights into the complex interplay between polarization and health behaviors during the COVID-19 pandemic.\nThe research design outlined by the authors is detailed and appropriate for a literature synthesis of this magnitude. While there may be concerns about the availability of a sufficient number of studies to conduct a statistical analysis of effect sizes, I am hopeful that such meta-analyses will be feasible. Having this information could significantly inform future policymaking, both for the ongoing pandemic and for future public health emergencies.\nThe author team is uniquely positioned to undertake and complete this ambitious project. I look forward to seeing future iterations and the final outcomes of this research. Their work will undoubtedly contribute significantly to the understanding of polarization and health-related behaviors during the COVID-19 pandemic.\nI have minimal critique to offer this study. My main suggestion is the inclusion of research conducted by my colleagues, such as [1],[2]. These studies could add valuable data to the synthesis.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "298434",
"date": "17 Jul 2024",
"name": "Markus Wagner",
"expertise": [
"Reviewer Expertise Political science"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis systematic review protocal addresses an important and relevant question concerning health behaviours and health outcomes, namely the impact of various types of political polarization. Given what we know from political science, it is highly likely that political ideologies and partisanship will influence how people behave, and people may even take decisions that will harm themselves due to their political biases.\nThis protocol is clear and transparent, and all key steps are described well. All procedures conform to best practice, at least to my knowledge. I have a couple of comments that may be useful to the researchers: - The protocal addresses political polarization and affective polarization. I would suggest a different way of capturing this, as I think most political scientists would argue that there is an overarching phenomenon of political polarization, which can be subdivided into ideological polarization and affective polarization. The former is what the authors here call \"political\" polarization, but I think that is a little misleading, as affective polarization is also political. - Within affective polarization, it would be important to pay additional attention to the role of partisanship and party identities more explicitly. This could encompass both positive and negative partisan identities. - An important additional aspect of interest could be to examine whether polarization from/by the left or from/by the right has more of an impact on health behaviours and outcomes. Polarization is a deceptively neutral term, and may be the result of growing extremism and stronger affective patterns on both sides of the political spectrum. Including this in the analysis as best possible would be an important addition.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-488
|
https://f1000research.com/articles/12-1426/v1
|
31 Oct 23
|
{
"type": "Research Article",
"title": "An evaluation of quality of sleep and prevalence of sleep disorders among adult population of Urban slum of Bangalore - a cross sectional study",
"authors": [
"Mithun Rao",
"Shobha Bhushan",
"Ranganath TS",
"Shobha Bhushan",
"Ranganath TS"
],
"abstract": "Background: Sleep can be defined as a state of reduced attention from where the person can be woken up by any kind of stimuli. Sleep difficulties are a major group of disorders affecting one third of the adult population. The present study was taken up to assess the sleep quality and prevalence of sleep disorders among the adult population in the urban slum area of H Siddaiah Road Urban Primary Health Center (UPHC), which is in the Urban Field Practice Area, BMCRI. Methods: Stratified random sampling was used to select 821 adults in the population of 18-60 years of age. Ethical clearance was obtained from the Institutional Ethical Committee. A pretested semi-structured questionnaire was used to interview the adults after obtaining their consent. The data was entered in Microsoft Office Excel and analysed using SPSS ver20.0. Results: The study population was 52.81% females and 77.5% in the age group of 18-30 years. Most of the study population were Hindus (78.90%), and only 3.8% of the study population were illiterate. Most of them were employed (86.12%). Substance use was present in 82.9% of the study participants and overcrowding was present in 51.3% of the subjects. Female gender, being unemployed, living with relatives, overcrowding, and substance use such as alcohol and smokeless tobacco were the factors associated with poor sleep quality as measured using the Pittsburgh Sleep Quality Index. Among the study participants having poor sleep quality, most of participants needed further clinical assessment for insomnia (86%) followed by assessment for sleep apnoea (50.5%). Conclusions: 200 (24.36%) study participants were determined to have poor sleep quality. Gender, marital status and overcrowding were the factors associated with poor sleep quality. A significant number of study participants need further assessment on insomnia, sleep apnoea and psychiatric disorders.",
"keywords": [
"Sleep",
"Adult",
"Quality of sleep",
"Sleep Hygiene",
"Sleep disturbance."
],
"content": "Introduction\n\nSleep is defined as unconsciousness from which the person can be aroused by sensory or other stimuli. Sleep is the vital component of health and is essential for mental and physical wellbeing and crucial for rejuvenation of body.1 Sleep is a recurrent state of reduced attention to the surrounding environment, which is essential to maintain and restore body functions, memory and cognitive performance. Sleep plays a crucial role in maintenance of normal functioning of many systems including endocrine and immune systems.2 The average adult needs 7 to 9 hours of excellent sleep per day,3 which translates to sleeping for nearly one-third of their life. Poor sleep can have detrimental impacts on one’s mental and physical health.3 Theoretically sleep is composed of two physiological phases, namely non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.1\n\nAdults frequently experience problems with their ability to sleep. According to previous studies, 10 to 40 percent of adults experience different types of sleep disturbances.4,5 Sleep issues can significantly lower people’s quality of life. Sleep hygiene and sleep problems are not well understood by the general public. One of the most prevalent sleep problems is insomnia, which is also a sign of poor mental health in the elderly population. Subjective complaints of trouble falling asleep, staying asleep, and early morning awakenings are its hallmarks. This has serious daytime effects such weariness, low energy, difficulties with cognition (attention and memory), and mood disorders, which can cause serious distress and functional deficits, especially as people age.6\n\nA wide range of detrimental health effects, such as an increased risk of hypertension, diabetes mellitus, obesity, immunological deficiency, coronary heart disease, and stroke, are linked to poor sleep quality.6 Conversely, people who have any of these illnesses are more likely to experience sleep-related issues. People who struggle with sleep disturbances have much greater rates of using drugs, low quality of life, depressed mood, anxiety, and panic attacks. These comorbidities will affect an older population more frequently.7\n\nGood sleep quality is associated with wide range of positive outcomes such as better health, less daytime sleepiness and better psychological functioning. Many factors contribute to sleep patterns, including sleep hygiene practices.8 Sleep hygiene is the variety of different practices and habits that are necessary to have good nighttime sleep quality and full daytime alertness.9 Regular exercise, regular bedtimes and wake-up times, and no midday naps are all behaviors that promote sleep. The use of stimulants like caffeine or cigarettes, participating in stimulating or unpleasant activities right before bed, and using alcohol are all actions that prevent people from falling asleep.\n\nIn the history of humanity, sleep issues are a relatively new development. Chronic sleep deprivation was a very uncommon issue for the majority of humanity before the discovery and widespread use of electricity and artificial light.10\n\nThough there have been studies conducted in the aged population and students in other countries about the quality of sleep and its associated factors, there has been lack of literature on quality of sleep among the adult population and its associated risk factors in India, especially in urban slums of India. Hence the present study has been taken up to assess the quality of sleep and prevalence of sleep disorders among the adult population in the urban slum which is the Urban Field Practice Area of the Department of Community Medicine, Bangalore Medical College and Research Institute (BMCRI), Bengaluru.\n\n\n\n1. To assess the quality of sleep and the factors associated with it among the adult population of the Urban Field Practice Area of BMCRI.\n\n2. To estimate the prevalence of sleep disorders among them.\n\n\nMethods\n\nThis study had a cross-sectional design. The study took place between November 2018 and May 2020.\n\nThe study was conducted at the urban slum area of H Siddaiah Road Urban Primary Health Center (UPHC), which is in the Urban Field Practice Area of BMCRI. Being one of the largest slums in Bangalore, it represents the urban slums of Southern India.\n\nThe study population was adults belonging to the age group between 18 and 60 years and residing in the Urban slum of Bangalore.\n\n\n\n1. Age 18 to 60 years and is a permanent resident (residing for more than six months in the area) of the area.\n\n2. The individuals who are present in the area at the time of interview.\n\n3. People who are willing to give consent for the study.\n\n\n\n1. People who are not willing to give consent for the study.\n\n2. Those who are severely ill and/or diagnosed with a mental health condition.\n\n3. Lactating women.\n\nThe IEC (Institutional Ethics Committee) of Bangalore Medical College and Research Institute, Bangalore has reviewed the study and has granted approval prior to the onset of the study (BMC/PG/124/2018-19, on 3rd January 2018). Study subjects had the purpose of the study explained to them and written informed consent was obtained before proceeding. Confidentiality of the present study data was maintained in accordance with the Declaration of Helsinki.\n\nThere are 3 sectors in the urban field practice area; the total population is around 30,500 and the total number of households is 6045. The study size calculation was conducted by probability proportionate to size sampling (PPS). The sample size for each sector will be derived from formula:\n\nExample 1st sector has a household of 1712, so,\n\nThe same formula will be applied for other sectors, thus making a total sample size of 821.\n\nSystematic random sampling is used for the selection of the study population. After calculating the required number of participants from each sector, a random number is generated and the corresponding household is visited for the interview. The next household is visited by adding the sample interval to the randomly generated number and the interview is continued till we reach the required target. Only one adult member from each household was selected for the interview.\n\nTaking the example of the 1st sector,\n\nSample interval is calculated by as using the formula.\n\nLet the random number generated be ‘3’. The third household of the sector is visited and interviewed. The next household number to be visited will be 3 + 7 = 10th house (random number + sample interval). If there is a locked house, the adjacent house to the locked house is interviewed. Like this the interview is continued till the adequate sample size is reached.\n\nAfter obtaining the written informed consent and assuring confidentiality to the study participants, information regarding the sociodemographic factors and the details regarding the quality of sleep were collected, using pre-tested, semi-structured questionnaires (Pittsburgh Sleep Quality Index and Sleep Disorders Questionnaire).11,12 The data collection was done by the researcher by visiting the houses in the community for a duration of 6 months. The study participants were interviewed using the questionnaires described above as well as a sociodemographic questionnaire.\n\nPittsburgh Sleep Quality Index (PSQI)\n\nThe PSQI is an instrument for the assessment of outcome of sleep quality over the preceding one month which helps in categorizing the subjects based on the quality of sleep. This tool is designed to evaluate self-rated sleep quality.\n\nThe questionnaire evaluates sleep quality over the past one month with the help of 19 items, which generate seven component scores namely subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep duration, use of sleeping medication and daytime dysfunction. The sum of the component scores yields a global score. It first contains 4 open questions, following which there are questions with 4-point scale. Each component score ranges from 0 to 3 (‘no difficulty’ to ‘severe difficulty’). The global score can range from ‘0’ to ‘21’ and a score >5 suggested poor sleep quality. This questionnaire requires around 10 minutes for completion. The PSQI has adequate psychometric properties. A PSQI tool had sensitivity of 89.6% and 86.5% specificity. The test-retest reliability with scores can be correlated to the polysomnographic results.\n\nSleep Disorders Questionnaire\n\nThis is a questionnaire developed by Toward Optimized Practice Group to assist physicians in the evaluation of sleep disorders. It helps clinicians to know to screen for sleep related disorders; thus, helping in treating much earlier in primary care settings and early referral where it is needed. The target population of this questionnaire is adults, hence children were excluded from the study.\n\nData collected was then analyzed with SPSS version 20. Results have been expressed in means, proportions and standard deviations. Appropriate parametric and non-parametric tests are applied wherever necessary. Chi square test was used to measure the association between quality of sleep and the socio demographic variables. The student’s t test was used to measure the statistically significant difference among the gender with respect to quality of sleep.\n\n\nResults\n\nAmong 821 study subjects, 432 were females and 389 were males. 636 (77.5%) study participants belonged to the age group of 18-30 years (Table 1).17 The mean age of the participants was 30.86 ± 9.25 years among males and 28.92 ± 7.37 years among females. The majority of the population (648; 78.9%) were following Hindu religion, and 102 (12.4%) followed Christian religion. Among the study subjects, only 31 (3.8%) were illiterate, the rest all were literate.\n\n707 (86.12%) study participants were employed. Among the total participants surveyed, 482 (58.7%) were unmarried. 329 (40.1%) study participants were living with their parents. 411 (50.1%) study participants were living in a nuclear family, whereas 383 (46.4%) study participants were living in a joint family. Overcrowding was present in 421 (51.3%) houses (Table 2).\n\n681 (82.9%) participants reported substance use of any form. Of 681 participants, 520 (63.3%) of them were consuming coffee/tea, whereas 224 (27.3%) were using smokeless tobacco. 199 (24.2%) of the study population were smokers and 148 (18.0%) were consuming.\n\nBased on the global PSQI scores, study participants were divided into two groups. Those who had a global PSQI score of less than or equal to 5 were categorized as having good sleep quality (621, 75.63%). Participants who had a global PSQI score of more than 5 were categorized as having poor sleep quality (200, 24.37%) (Table 3).\n\nThe association was measured using the Chi square test between the quality of sleep and various socio-demographic factors, which have been mentioned above. A statistically significant association (p value < 0.05) was found between quality of sleep and gender (p value = 0.03), marital status (p value = 0.005), living arrangements (p value = 0.000), type of family (p value < 0.0001) and presence of overcrowding (p value < 0.0001) (Table 4).\n\nStudy participants who had poor sleep quality (200) were further subjected to the sleep disorders questionnaire. Based on their response to the sleep disorders questionnaire, study participants were further categorized into various sleep related disorders. Among those (200), insomnia was observed in 82.5%, sleep apnoea in 50.5%, psychiatric disorders in 39.5%, parasomnias in 36.5%, circadian rhythm disorders in 35.5%, and movement disorders in 8%, which may need further clinical evaluation (Table 5).\n\n\nDiscussion\n\nThe present study evaluates the quality of sleep and its related factors along with assessing the prevalence of sleep disorders in the urban slum area of H Siddaiah Road Urban Primary Health center (UPHC), which is the Urban Field Practice Area of BMCRI. The present study explores the importance of various factors affecting the sleep quality and the prevalence of sleep disorders among the adult population of the urban slums. The findings are based on interviews of the 821 participants at the field level.\n\nAmong the 821 subjects, more than half the population is female, 432 (52.6%) and the majority belonged to the age group of 18-30 years, (636; 77.5%) with a mean age of 30.86 ± 9.258 years among males and 28.92 ± 7.373 years among females. A community based cross-sectional study conducted by Berhanu H et al. in Ethiopia had a preponderance of males (60.9%), with mean age of the total population of 38.7 + 12.5 years.13 A similar study conducted by Madrid-Valero JJ et al. in Spain had 54.7% females with a mean age of the study participants being 53.7 years.14 Yet another study conducted by Panda S et al. in South India had an even gender distribution (M:F 29:21), with the mean age of the respondents being 35.1±8.7 years having mostly southern India representation.15\n\nAs the study by Berhanu H et al. was in the similar set up as the present study, the socio demographic characteristics were quite similar, whereas the study by Madrid-Valero JJ et al. had a higher mean age, which may be due to the different methodology which was followed.13–14\n\nIn the present study, the participants went to bed on average at 10.20 PM with a sleep latency of 15.16, minutes and the total duration of sleep experienced by them was 7.8 hours. While in the study conducted by Berhanu H et al., participants reported an average night’s sleep duration of 6.8 ± 2.1 hours, with the study participants having gone to bed at 10.20 PM.13 One more study conducted by Madrid-Valero JJ et al. had assessed the mean sleep duration during night time which was found to be 6.43 + 1.3 hours, and sleep latency was not assessed in the study.14 In the study conducted by Panda S et al., average time-to-fall-asleep was 22 minutes (range: 5-90 min), and mean duration of actual sleep was 7 hours (range: 3.5-9.1 hours).15\n\nAll the studies had similar results with respect to total duration of night sleep experienced.\n\nIn the present study, about one fourth of the study participants (24.36%) reported having poor sleep quality (global PSQI > 5), whereas the study conducted by Panda S et al. had a majority (93.8%) of the population reporting good-quality sleep (global PSQI ≤ 5). In the study conducted by Berhanu H et al., 4% participants were assessed as poor sleepers by a global PSQI score greater than 5. A similar study done by Madrid-Valero JJ et al. showed 38.2% of the subjects having poor sleep quality (global PSQI > 5).13–15\n\nIn the present study, it was seen that female gender, being unmarried, overcrowding and use of substance such as alcohol and tobacco were having a significant impact on the quality of sleep. The study conducted by Berhanu H et al. also reported similar results with female gender, having less monthly income, Khat chewing practices and consumption of alcohol being correlated factors for poor quality of sleep.13\n\nThe present study showed that further evaluation is needed, as insomnia was reported in 82.5% of the 20 participants with poor sleep quality, sleep apnoea in 50.5%, psychiatric disorders in 39.5%, parasomnias in 36.5%, circadian rhythm disorders in 35.5% and movement disorders in 8%. Another study conducted by Ram S et al.16 in USA, prevalence of sleep disorders was highest for sleep apnoea (4.2%), followed by insomnia (1.2%) and RLS (0.4%). The reported rates of sleep related disorders varied between 20.0% and 34.2% depending on the instrument used in the questionnaire. In the study conducted by Panda S et al., insomnia, sleep-related breathing disorders, narcolepsy, and restless legs syndrome (RLS) were reported to be 18.6%, 18.4%, 1.04% and 2.9% respectively.14–16\n\n\nConclusion\n\nThe present study indicated that one fourth of the adult population residing in the Urban Field Practice Area of Community Medicine Department, BMCRI reported poor sleep quality. It was observed that the poor quality of sleep is associated with various factors such as gender, marital status, living arrangement, type of family and overcrowding. The present study also observed that among the people having poor sleep quality, insomnia was seen in four fifths, sleep apnoea in half, and psychiatric disorders in two fifths of the study population. They need further evaluation to confirm the sleep disorders.",
"appendix": "Data availability\n\nfigshare: Masterchart.xlsx. https://doi.org/10.6084/m9.figshare.23997591.v1 17\n\nfigshare: Coding key.xlsx. https://doi.org/10.6084/m9.figshare.23997585.v1 18\n\nfigshare: Questionnaire.docx. https://doi.org/10.6084/m9.figshare.23997693.v1 19\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nHall J, Hall M: Guyton And Hall Textbook Of Medical Physiology. 12th ed.Philadelphia: Library of Congress Cataloging-in-Publication Data; 2011; 721–725.\n\nZadeh SS, Khyrunnisa B: Comparison of nutrient intake by sleep status in selected adults in Mysore, India. Nutr. Res. Pract. 2011; 5(3): 230–235. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHow much sleep is enough? National Heart Lung and Blood Institute. (Accessed: 16 August 2022). Reference Source\n\nLiu X, Uchiyama M, Kim K, et al.: Sleep loss and daytime sleepiness in the general adult population of Japan. Psychiatry Res. 2000; 93(1): 1–11. PubMed Abstract | Publisher Full Text\n\nAsghari A, Farhadi M, Kamrava SK, et al.: Subjective sleep quality in urban population. Arch. Iran. Med. 2012; 15(2): 95–98. PubMed Abstract\n\nColten HR, Altevogt BM: Sleep disorders and sleep deprivation: An unmet public health problem. Washington DC: National Academies Press; 2006.\n\nCulloch M, Espie R: Mental Health Foundation: Impact of poor sleep on the health and happiness of the UK. England (UK): The UK charity; 2011. Reference Source\n\nElmoneem H, Fouad A: The Effect of a Sleep Hygiene Program on Older Adults. IOSR J. Nurs. Health Sci. 2017; 06(01): 40–51. Publisher Full Text\n\nWhat is Sleep Hygiene? - Sleep Foundation. Sleep Foundation; 2020 [cited 8 December 2020]. Reference Source\n\nShankar A, Syamala S, Kalidindi S: Insufficient Rest or Sleep and Its Relation to Cardiovascular Disease, Diabetes and Obesity in a National, Multiethnic Sample. PLoS One. 2010; 5(11): e14189. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBuysse D, Reynolds C, Monk T, et al.: The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research. Psychiatry Res. 1989; 28(2): 193–213. PubMed Abstract | Publisher Full Text\n\nSleep disorders Questionnaire. Corecarefht.ca.2003 [cited 14 December 2018]. Reference Source\n\nBerhanu H, Mossie A, Tadesse S, et al.: Prevalence and Associated Factors of Sleep Quality among Adults in Jimma Town, Southwest Ethiopia: A Community-Based Cross-Sectional Study. Sleep Disorders. 2018; 2018: 1–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMadrid-Valero J, Martínez-Selva J, Ribeiro do Couto B, et al.: Age and gender effects on the prevalence of poor sleep quality in the adult population. Gac. Sanit. 2017; 31(1): 18–22. Publisher Full Text\n\nPanda S, Taly A, Sinha S, et al.: Sleep-related disorders among a healthy population in South India. Neurol. India. 2012; 60(1): 68–74. PubMed Abstract | Publisher Full Text\n\nRam S, Seirawan H, Kumar S, et al.: Prevalence and impact of sleep disorders and sleep habits in the United States. Sleep Breath. 2009; 14(1): 63–70. PubMed Abstract | Publisher Full Text\n\nRao M: Masterchart.xlsx. Dataset. figshare. 2023. Publisher Full Text\n\nRao M: Coding key.xlsx. Dataset. figshare. 2023. Publisher Full Text\n\nRao M: Questionnaire.docx. Dataset. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "219855",
"date": "24 Jan 2024",
"name": "Pracheth Raghuveer",
"expertise": [
"Reviewer Expertise Mental Health",
"Geriatrics",
"Non-Communicable Diseases",
"Maternal and Child Health",
"Neuro Sciences",
"Medical Education"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, it is an important paper that highlights an under-diagnosed issue of sleep. The sample size covered is 821 which is remarkable. It is a community-based study that may be generalizable to the urban slum dwelllers of Bengaluru. I congratulate the team of authors for a commendable job. However, there is scope for improvement to make it an even better draft. There are a few gaps that may have to be plugged before it can be accepted. 1. The title may be modified to\" Poor quality of sleep and it's associated factors among urban slum-dwellers of Bengaluru- a cross-sectional study\" as this was the primary objective/ aim. 2. In the methods, please mention the number of items, cut-offs and information about validity of the Sleep Disorders Questionnaire. 3. In the results, \"Factors affecting quality of sleep\" may be modified to \"factors associated\" as the analysis looks at associations. 4. In the results, it has been mentioned that 39.5% had psychiatric disorders. How was this assessment carried out? Did the Sleep Disorders Questionnaire also assess mental health problems. Please justify. 4. Discussion needs strengthening. Kindly mention few strengths and limitations of the study in the discussion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11223",
"date": "04 Apr 2024",
"name": "Mithun Rao",
"role": "Author Response",
"response": "Point to point response to Reviewer's comments: Dr. Pracheth Raghuveer 1.Comment: The title may be modified to\" Poor quality of sleep and it's associated factors among urban slum-dwellers of Bengaluru- a cross-sectional study\" as this was the primary objective/ aim. Author’s Response: We agree with your comment. As per the suggestion title has been modified. Action Taken in the manuscript: As per the suggestion title has been modified in the manuscript. 2.Comment: In the methods, please mention the number of items, cut-offs and information about validity of the Sleep Disorders Questionnaire. Author’s Response: We respect the comments. As per the suggestion following details have been added. Action Taken in the manuscript: The details added are mentioned below. Sleep Disorders Questionnaire has 16 items in total. Each item has a grading scale from 1-5 with 1 being never, 2-rarely, 3- occasionally, 4-most nights/days and 5 – always. Diagnostic Domains of Sleep Disorders Questionnaire is as follows: 1) Insomnia: Q1-5 2) Psychiatric Disorders: Q6-9 3) Circadian Rhythm Disorder: Q10 4) Movement disorders: Q11-12 5) Parasomnias Q13 3.Comment: In the results, \"Factors affecting quality of sleep\" may be modified to \"factors associated\" as the analysis looks at associations. Author’s Response: Thank you for the comment Sir. As per the suggestion, we shall modify the wordings. Action Taken in the manuscript: \"Factors affecting quality of sleep\" phrase mentioned in the results part of the manuscript has been modified to \"factors associated\" as the details deals with association. 4.Comment: In the results, it has been mentioned that 39.5% had psychiatric disorders. How was this assessment carried out? Did the Sleep Disorders Questionnaire also assess mental health problems. Please justify. Author’s Response: Thank you for the query Sir. The Sleep Disorders Questionnaire screens for the mental health problem. Action Taken in the manuscript: The following detail has been added under methodology which helps in better understanding. Diagnostic Domains of Sleep Disorders Questionnaire: 1) Insomnia: Q1-5 2) Psychiatric Disorders: Q6-9 3) Circadian Rhythm Disorder: Q10 4) Movement disorders: Q11-12 5) Parasomnias Q13 5.Comment: Discussion needs strengthening. Kindly mention few strengths and limitations of the study in the discussion. Author’s Response: Thank you for the suggestions Sir. We shall add the strengths and limitations as per the suggestion given Sir. Action Taken in the manuscript: The following are the strengths and limitations. Strength: This study is one of the kind among Urban slum dwellers of a metropolitan city. Study participants belong to a category of socially vulnerable population. The sample size of the study is more than 800 making it a large sample size. Limitations: Since Bangalore Urban slum dwellers have unique characteristics in comparison to slum dwellers of metropolitan city, the results may not be uniform across the cities. As the data collection used to take place during duty hours, working population would have been missed."
}
]
}
] | 1
|
https://f1000research.com/articles/12-1426
|
https://f1000research.com/articles/13-487/v1
|
17 May 24
|
{
"type": "Case Report",
"title": "Case Report: Impact of gross total resection on survival in glioblastoma",
"authors": [
"Dipak Chaulagain",
"Volodymyr Smolanka",
"Andriy Smolanka",
"Taras Havryliv",
"Volodymyr Smolanka",
"Andriy Smolanka",
"Taras Havryliv"
],
"abstract": "Glioblastoma (GBM), known for its aggressive behavior and dismal prognosis. Traditional therapeutic methods, including adjuvant chemotherapy and radiotherapy in conjunction with maximally safe surgical resection, are designed to prolong survival and alleviate symptoms. This case report investigates the relationship between survival outcomes in glioblastoma patients and gross total resection (GTR). A recurring seizure disorder manifested in a 58-year-old female patient presented with left-sided lower limbs weakness and occurred twice weekly for a maximum duration of 20 seconds; this condition necessitated hospitalisation and subsequent surgical intervention. A gross total resection was executed with success, resulting in the accomplishment of complete tumor excision. The patient received radiotherapy after a six-week regimen of temozolomide chemotherapy that followed the surgical removal of tumor. Notably, following treatment, the patient reported a substantial amelioration of symptoms and has maintained a 24-month survival rate thus far, with continuous follow-up. This case highlights the potential for enhanced survival outcomes in the treatment of glioblastoma when gross total resection (GTR) is followed by adjuvant chemo-radiotherapy.",
"keywords": [
"Glioblastoma",
"Extent of Resection",
"Survival outcome",
"Gross total resection"
],
"content": "Introduction\n\nGlioblastoma multiforme (GBM) is a prevalent and highly aggressive type of glial tumor primarily affecting the central nervous system in adults. Although intensive treatment measures such as surgical resection, radiation, and chemotherapy have been implemented, the prognosis remains significantly restricted.1\n\nGlioblastoma, which accounts for around 15% of all brain tumors, mostly impacts persons who are 50 years old or older which is more common in males than in females.2,3 Surgical tumor excision is vital in multimodal glioblastoma therapy. Extensive research indicates that achieving gross total resection (GTR) is strongly associated with improved outcomes in GBM patients, as determined by objective extent of resection (EOR) assessments.4,5\n\nAn EOR that is greater than 98% of the tumor mass has been shown to correspond with a more favourable prognosis, as demonstrated by research conducted by Lacroix et al. and following studies.6–9 Surgical tumor removal, radiation, and chemotherapy with Temozolomide-based adjuvant treatment are routine.\n\nStupp et al.10 published the findings of a randomized trial conducted by the National Cancer Institute of Canada (NCIC) and the European Organisation for Research and Treatment of Cancer (EORTC) in 2005. The data showed that the combination treatment increased survival from 12.1 to 14.6 months. In addition, combination treatment (26.5%) had a higher 2-year survival rate than radiation alone (10.4%).10 However, radiotherapy-only patients had 11.2%, 4.3%, and 3.8% survival rates. These data confirm that combination treatment improves GBM survival.11\n\nThis interesting case report involves a patient who had gross total resection of glioblastoma and had six weeks of temozolomide and concomitant radiotherapy. The patient has survived 24 months and continues to get follow-ups. Symptoms have improved, and there are no signs of tumor recurrence. This example shows the promise of multimodal therapy for glioblastoma and the significance of long-term surveillance for recurrence.\n\n\nCase report\n\nA housewife with a smoking history who was 58 years old and married; she was a mother of one child. She had presented to the Neurosurgery Department of the Regional Clinical Centre of Neurology and Neurosurgery in Uzhhorod, Ukraine. The individual disclosed enduring paralysis in her left arm and limb for a duration of one month, in addition to a minimum of two episodes of seizures per week that lasted for a maximum of twenty seconds, during the previous two months. No evidence of prior trauma or familial medical predispositions was present. The utilisation of Magnetic Resonance Imaging (MRI) unveiled the existence of a heterogeneous lesion characterised by necrotic regions and irregular borders. Peri-tumoral edema and mass effect were apparent subsequent to the administration of contrast, which were accompanied by substantial enhancement. The results obtained align with the diagnostic parameters for glioblastoma, which is distinguished by its aggressive and infiltrative nature. The volumetric analysis of the tumour yielded a value of 21.8 cm3 (Figure 1).\n\nThe patient was administered steroid and anti-epileptic medications on the second day after admission in order to control inflammation, edema, and seizure activity. Following that, the patient was subjected to surgical intervention, specifically a gross total resection of the tumor. On the second day following the operation, a follow-up MRI was conducted employing volumetric analysis to reveal that the tumour had been entirely eliminated. The residual volume was determined to be 0 cm3 (Figure 2).\n\nIt was determined that the patient did not encounter any issues after the operation. Following that, she was given the recommendation to participate in adjuvant chemotherapy and radiotherapy. During the course of her treatment, she decided to undergo radiotherapy after undergoing chemotherapy with temozolomide, which was given to her at a daily dose of 75 mg/m2 for a duration of six weeks. Over the course of the follow-up period that lasted for twenty-four months, the patient reported a reduction in the severity of symptoms and continues to be monitored to this day.\n\n\nDiscussion\n\nThe glioblastoma (GBM), which is considered to be the most common kind of malignant primary brain tumor, is categorised as a high-grade glioma that has been identified.6\n\nThe high invasiveness of glioblastoma (GBM) poses a substantial obstacle in achieving gross total resection (GTR), mostly because to the persistent character of microscopic tumors. This persistent nature eventually contributes to the unfavourable prognosis associated with this illness. The primary objective is to prioritise the attainment of the maximum possible safe resection, with a special focus on tumor areas that are anatomically accessible. Following this, the administration of adjuvant radiation and chemotherapy with temozolomide is commonly utilised. Despite the progress made in treatment modalities, the median survival duration for patients with glioblastoma multiforme (GBM) continues to be less than 15 months.1,6,9\n\nStupp et al. presented the findings of an NCIC-EORTC randomised experiment in 2005. Temozolomide-radiotherapy was compared to radical radiation alone for glioblastoma treatment in this research. The combination therapy significantly improved median survival from 12.1 to 14.6 months. Additionally, the group receiving combined treatment exhibited a 2-year survival rate of 26.5% compared to 10.4% for those receiving radiation alone. Temozolomide (TMZ) contributed to increased survival rates, elevating them from 10.9% to 27.2% at 2 years and from 1.9% to 9.8% at 5 years. These results highlight the efficacy of combined therapy and TMZ in improving long-term survival outcomes for patients with glioblastoma. Numerous clinical trials after this milestone have not modified the standard-of-care over a decade later.10,12\n\nExisting literature suggests that a greater extent of resection, often falling within the range of 80% to 100%, is associated with more favourable results.13 Therefore, it may be inferred that patients who receive resections over 95% may achieve more favourable outcomes in comparison to those who get resections below 95%.5,14 Moreover, previous research has sought to ascertain the upper limit of residual tumour sizes linked to positive results,14 as shown by the investigation conducted by Chaichana et al.\n\nThe optimal surgical strategy is one of maximally safe resection of tumor. In recent years, an increasing body of evidence has provided robust support for the proposition that optimising the extent of resection (EOR) positively affects survival outcomes among individuals who have been diagnosed with glioblastoma.4,15\n\nThe yearly incidence of grade IV glioblastoma multiforme is estimated to be around 12,000 cases involving persons. Despite this, survival rates continue to be extremely low, with less than forty percent of patients surviving twelve months after receiving a diagnosis and less than nine percent living beyond three years.16\n\nThe extent of resection was found to be an independent predictor of prolonged survival in a study on 949 patients diagnosed with high-grade gliomas at a single institution, of which more than half underwent initial surgery. In our investigation, we observed distinct median overall survival (OS) rates associated with varying degrees of resection. Specifically, gross total resection (GTR) was linked with a median OS of 11 months, near total resection (NTR) with 9 months, and subtotal resection (STR) with 5 months. These findings highlight the importance of achieving maximal safe resection in optimizing survival outcomes for patients with glioblastoma.17\n\nOur case study underscores the potential benefits of complete surgical tumor removal in the treatment of GBM. It highlights the significance of gross total resection in glioblastoma surgical excision, followed by adjuvant chemo-radiotherapy, which has resulted in a notable survival period of 24 months with ongoing follow-up. This suggests that a multimodal approach to glioblastoma therapy may lead to improved prognosis.\n\n\nConclusion\n\nThis case report describes an exceptional twenty-four-month survival period for a patient with GBM who underwent primary surgical treatment. One significant finding from our case study is the potential advantage of performing radical neurosurgery during the early stages of GBM management. This is supported by the initial complete resection, which created an opportunity for subsequent chemo-radiotherapy and an extended survival period. Placing significant emphasis on the criticality of a customised, patient-centric methodology in the treatment of glioblastoma is unchanged. This requires employing comprehensive therapeutic and diagnostic strategies that are tailored to the specific requirements of each patient. Moreover, the significance of gross total resection in glioblastoma surgical excision, followed by chemo-radiotherapy, which ultimately results in protracted survival outcomes, is highlighted in our single case presentation.\n\n\nConsent\n\nWe are delighted to confirm that we have obtained written consent from the patient for the publication of their clinical details and images in the manuscript. This consent statement is a critical component of our submission, and we are dedicated to upholding the highest ethical standards in medical research. The consent statement, signed by the patient herself, has been furnished. It articulates the patient’s clear comprehension and agreement regarding the publication of their clinical information and images for educational and research purposes. We reaffirm our commitment to preserving patient confidentiality and adhering to all ethical guidelines throughout the publication process.\n\nEthical approval: Not required with this article.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nOmuro A: Glioblastoma and Other Malignant Gliomas. JAMA. Nov. 2013; 310(17): 1842. American Medical Association (AMA). Publisher Full Text\n\nBryukhovetskii IS, et al.: New Biomolecular Approaches to the Treatment of Glioblastoma Multiforme. Bull. Exp. Biol. Med. Apr. 2015; 158(6): 794–99. Springer Science and Business Media LLC. PubMed Abstract | Publisher Full Text\n\nChaulagain D, et al.: Гліобластома: Огляд Літератури. Int. Neurol. J. Jan. 2023; 18(8): 32–7. Publishing House Zaslavsky. Publisher Full Text\n\nSanai N, Berger MS: GLIOMA EXTENT OF RESECTION AND ITS IMPACT ON PATIENT OUTCOME. Neurosurgery. Apr. 2008; 62(4): 753–66. Ovid Technologies (Wolters Kluwer Health). Publisher Full Text\n\nSanai N, et al.: An Extent of Resection Threshold for Newly Diagnosed Glioblastomas. J. Neurosurg. July 2011; 115(1): 3–8. Journal of Neurosurgery Publishing Group (JNSPG). PubMed Abstract | Publisher Full Text\n\nChaulagain D, et al.: The Impact of Extent of Resection on the Prognosis of Glioblastoma Multiforme: A Systematic Review and Meta-analysis. Open Access Maced. J. Med. Sci. May 2022; 10(F): 345–54. Scientific Foundation SPIROSKI. Publisher Full Text\n\nKotrotsou A, et al.: Multi-center Study Finds Postoperative Residual Non-enhancing Component of Glioblastoma as a New Determinant of Patient Outcome. J. Neuro-Oncol. Apr. 2018; 139(1): 125–33. Springer Science and Business Media LLC. Publisher Full Text\n\nBrown TJ, et al.: Association of the Extent of Resection With Survival in Glioblastoma. JAMA Oncol. Nov. 2016; 2(11): 1460–69. American Medical Association (AMA). PubMed Abstract | Publisher Full Text | Free Full Text\n\nLacroix M, et al.: A Multivariate Analysis of 416 Patients With Glioblastoma Multiforme: Prognosis, Extent of Resection, and Survival. J. Neurosurg. Aug. 2001; 95(2): 190–98. Journal of Neurosurgery Publishing Group (JNSPG). PubMed Abstract | Publisher Full Text\n\nStupp R, et al.: Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med. Mar. 2005; 352(10): 987–96. Massachusetts Medical Society. Publisher Full Text\n\nMirimanoff R, et al.: Is Long-Term Survival in Glioblastoma Possible? Updated Results of the EORTC/NCIC Phase III Randomized Trial on Radiotherapy (RT) and Concomitant and Adjuvant Temozolomide (TMZ) Versus RT Alone. Int. J. Radiat. Oncol. Biol. Phys. Nov. 2007; 69(3): S2. Elsevier BV. Publisher Full Text\n\nJohnson DR, et al.: Case-Based Review: Newly Diagnosed Glioblastoma. Neurooncol. Pract. July 2015; 2(3): 106–21. Oxford UP (OUP). PubMed Abstract | Publisher Full Text | Free Full Text\n\nMolinaro AM, et al.: Association of Maximal Extent of Resection of Contrast-Enhanced and Non–Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma. JAMA Oncol. Apr. 2020; 6(4): 495–503. American Medical Association (AMA). PubMed Abstract | Publisher Full Text | Free Full Text\n\nChaichana KL, et al.: Establishing Percent Resection and Residual Volume Thresholds Affecting Survival and Recurrence for Patients With Newly Diagnosed Intracranial Glioblastoma. Neuro-Oncology. Nov. 2013; 16(1): 113–22. Oxford UP (OUP). Publisher Full Text\n\nLaws ER, et al.: Survival Following Surgery and Prognostic Factors for Recently Diagnosed Malignant Glioma: Data From the Glioma Outcomes Project. J. Neurosurg. Sept. 2003; 99(3): 467–73. Journal of Neurosurgery Publishing Group (JNSPG). PubMed Abstract | Publisher Full Text\n\nOstrom QT, et al.: CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro-Oncology. Oct. 2015; 17(suppl 4): iv1–iv62. Oxford UP (OUP). PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcGirt MJ, et al.: Independent Association of Extent of Resection With Survival in Patients With Malignant Brain Astrocytoma. J. Neurosurg. Jan. 2009; 110(1): 156–62. Journal of Neurosurgery Publishing Group (JNSPG). Publisher Full Text"
}
|
[
{
"id": "322333",
"date": "11 Sep 2024",
"name": "Pavel S. Pichardo-Rojas",
"expertise": [
"Reviewer Expertise Neuro-Oncology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you to the authors for the opportunity to review this article. While the efforts made by the authors are commendable, there are several limitations in this study that prevent it from meeting the criteria for indexing in its current form.\nThe term \"Glioblastoma multiforme (GBM)\" is outdated according to the WHO 2021 classification. The diagnosis of glioblastoma now requires confirmation of IDH-wild type status, and histopathological assessment alone is insufficient. Please revise the terminology to align with current definitions. The use of \"gross total resection\" is no longer considered ideal. Emerging evidence suggests that parameters beyond the contrast-enhancing (CE) region, such as the non-CE FLAIR region, are also prognostic. New categorization systems, like the ones proposed by RANO-resect, should be used. Please revise the categorization based on RANO-resect criteria and include consideration of non-CE FLAIR volume (refer to PMID: 35961053). The term \"diagnostic parameters for glioblastoma\" is ambiguous. Are the authors referring to imaging findings, histopathological criteria, or another form of diagnostic criteria? Additionally, the IDH status should be specified, as not all histological diagnoses of GBM meet the criteria for IDH-wild type glioblastoma. Please clarify and revise accordingly. As previously mentioned, please reclassify the extent of resection based on RANO-resect guidelines. The authors should specify if additional imaging modalities were used during surgery, such as neuronavigation, intraoperative MRI (iMRI), or intraoperative ultrasound (iUS). This is currently lacking and needs to be more descriptive. The study would benefit from providing molecular characterization of the tumor, as molecular status has been shown to be prognostic. Are the authors able to provide details on this aspect? The patient described appears to be a long-term survivor. However, it is unclear if the diagnosis of GBM has been fully confirmed. If it is indeed a case of confirmed GBM, the authors should include a discussion about long-term survivors (refer to PMID: 38420614).\nIn conclusion, while the authors have made a significant effort, the study does not meet the standards for indexing in its current form. It is also recommended to add a limitations paragraph to address the gaps identified in the current manuscript.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
},
{
"id": "304735",
"date": "13 Sep 2024",
"name": "Prajwal Ghimire",
"expertise": [
"Reviewer Expertise Neurosurgery",
"Neuro-oncology",
"Glioblastoma"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe case report highlights an important area in neuro-oncology, focusing on glioblastoma and its aggressive nature. It emphasizes the critical role of gross total resection (GTR) in patient survival, which is clinically significant for improving outcomes.\nMy Comments\nClear Presentation: The case is presented with a clear narrative, explaining the patient's history, diagnostic process, treatment (GTR, chemotherapy, radiotherapy), and outcome. This makes the case relatable to other clinical practitioners. Multimodal Treatment Approach: The case reinforces the importance of a combined treatment approach (surgery, chemotherapy, and radiotherapy), which is the standard of care in glioblastoma management. Long-term Follow-up: A 24-month follow-up period is notable, given the aggressive nature of glioblastoma. Reporting long-term survival adds value to the manuscript by showing the potential benefit of comprehensive therapy. Visual Support: The manuscript includes imaging and volumetric analysis, which provides clarity and strong visual support for the findings.\nLimitations of the work submitted:\nOutdated Terminology: The manuscript uses \"Glioblastoma multiforme (GBM),\" a term no longer aligned with the latest WHO classification (2021). The current diagnostic standard requires IDH-wild type status confirmation for glioblastoma. Failure to incorporate updated classification weakens the scientific rigor. Limited Molecular Information: The manuscript lacks details on molecular markers, such as IDH mutation status and MGMT promoter methylation, which are crucial for prognosis and personalized treatment strategies in glioblastoma. Modern neuro-oncological research heavily relies on these molecular characterizations. Narrow Focus on Gross Total Resection: The emphasis on GTR could be further nuanced. Recent literature suggests that the non-contrast-enhancing (non-CE) region of the tumor is also relevant to prognosis, and emerging resection criteria (e.g., RANO-resect) should be considered. The lack of discussion on these aspects may limit the generalizability of the findings. Lack of Advanced Intraoperative Techniques: The manuscript does not discuss whether advanced imaging techniques like neuronavigation, intraoperative MRI, or intraoperative ultrasound were used during surgery. These are increasingly important for ensuring maximal resection while maintaining safety, and their omission is a gap in the surgical details.\nAreas for Improvement:\nTerminology and Classification Update: The manuscript should revise its terminology to align with the WHO 2021 classification for gliomas. This includes specifying the tumor as IDH-wild type and providing molecular characterization. Adoption of RANO-resect Criteria: Reclassifying the extent of resection based on more recent guidelines, such as RANO-resect, will improve the relevance of the study. This involves including FLAIR non-contrast-enhancing tumor regions in assessing surgical success. Molecular Characterization: Inclusion of molecular data (IDH mutation, MGMT methylation) is essential for a more comprehensive analysis of the case. These molecular factors are pivotal in determining prognosis and treatment response. Discussion on Long-Term Survivors: Since the patient in the case is a long-term survivor, the manuscript would benefit from discussing this cohort and what factors might contribute to extended survival in glioblastoma. It could reference recent studies on long-term survivors of glioblastoma. Surgical Technique Details: Providing more detailed information about the surgical approach, including whether advanced imaging modalities were used intraoperatively, would make the case stronger from a technical perspective. Consideration of Study Limitations: The manuscript should include a paragraph discussing the limitations of the case study. For instance, the lack of molecular profiling, the small sample size (single case), and the absence of advanced surgical techniques should be mentioned.\nConclusion:\nThe manuscript presents a clinically important case with solid findings, but it needs revisions to improve its scientific rigor and align it with current standards in neuro-oncology. Incorporating updated terminology, molecular data, advanced surgical details, and more nuanced discussions on resection and long-term survival will make the manuscript more robust and suitable for indexing.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-487
|
https://f1000research.com/articles/13-483/v1
|
17 May 24
|
{
"type": "Study Protocol",
"title": "A study of clinical profile in patients of cataracts with pseudoexfoliation in rural populations of central India",
"authors": [
"Yuga Pawar",
"Dr. Archana Thool",
"Dr. Archana Thool"
],
"abstract": "Background Ophthalmologists deal with daily pseudoexfoliation (PXF) due to severe secondary glaucoma, which arises after cataract surgery. Cataracts with pseudoexfoliation are age-related and are associated with open-angle glaucoma. Therefore, pseudoexfoliation is expected to occur more frequently. Pseudoexfoliation is occasionally associated with the development of thick nuclear cataracts, which may make surgery challenging. risks of cataract extraction in patients with pseudoexfoliation include zonular weakness and inadequate pupillary dilation. This may cause vitreous loss, and intraoperative or postoperative lens displacement. It could also lead to a rise in postoperative intraocular pressure (IOP), progressing to long-term inflammation, phimosis of the capsular tissue, glaucoma, and surgical corneal decompensation. Recurrent secondary cataracts are typically caused by some remaining cortical tissue and decreased zonular support, which may lead to lens epithelial cell migration. Surgery for glaucoma and cataracts is complicated by the presence of pseudoexfoliative debris.\n\nObjectives To determine the prevalence of pseudoexfoliation in cataract patients visiting the ophthalmic OPD, AVBRH hospital, to locate patients with pseudoexfoliative cataracts, to evaluate their likelihood of progressing to open-angle glaucoma, and to examine the various ocular characteristics of these patients.\n\nMethodology The study participants will undergo ophthalmological examination after considering the inclusion and exclusion criteria. This examination will include sac syringing on the lacrimal gland, estimation of the highest corrected visual acuity, slit-lamp examination, application tonometer assessment of intraocular pressure (IOP), and fundus examination using an indirect ophthalmoscope. All individuals with cataracts visiting the ophthalmology department of AVBRH will be examined under a slit-lamp to determine the presence of pseudoexfoliation in the operating eye.\n\nExpected Results Hospital statistics from India indicated that the percentage of patients with pseudoexfoliation, in addition to cataracts, ranges from 1.87% to 13.5%.",
"keywords": [
"Pseudoexfoliation",
"prevalence",
"glaucoma",
"Postoperative complications",
"cataract",
"Pseudoexfoliation-syndrome",
"intra ocular pressure",
"rural population"
],
"content": "Introduction\n\nA systemic condition known as pseudoexfoliation (PXF) syndrome was initially noted by Finnish ophthalmologist Lindberg in 1917, and Alfred Vogt provided more data in 1923. The development of a whitish-grey fibrogranular amyloid-like substance on the corneal endothelium, pupillary margin on the iris, anterior portion of the lens capsule, zonules, ciliary body, anterior vitreous, and trabecular meshwork are indicators of age-related ocular disorder pseudoexfoliation (PXF) syndrome.1 Histologically, Fibrillin is an elastin that creates elastic fibers, and fibrils are non-collagenous materials.2 According to histological analysis, the deposits are composed of laminin, glycosaminoglycans, and hyaluronic acid coatings on fibrils, a non-collagenous component utilized to create the basement membrane.\n\n“Three-Ring Sign” is frequently seen on the anterior lens capsule consisting of an outer region that is granularly foggy, an essentially uniform center region, and a clear zone in the middle.\n\nWhite-gray flaky debris on the anterior side of the lens or the pupillary border of the iris is the most widely recognized and easily identifiable diagnostic sign of pseudoexfoliation.3 The diagnosis is supported by pigment deposition in the anterior chamber structures and pigment loss from the iris sphincter area. The examiner was primarily responsible for providing an accurate diagnosis of pseudo-exfoliation. Pseudoexfoliation syndrome can remain undiagnosed due to the absence of early signs. Identifying pseudoexfoliation during routine ophthalmic examinations is crucial because it can increase the risk of problems during cataract surgery owing to two clinical symptoms: zonular weakening and inadequate pupil dilation. These patients have a five-fold increased risk of developing intraoperative complications such as corneal decompensation,secondary Cataract, capsular phimosis, posterior capsular rupture, zonular dialysis and vitreous loss.2\n\nOpen-angle glaucoma with pseudoexfoliation (PXF) is a moderately frequent type of glaucoma that can result in an abnormally high eye pressure. This disorder is identified by the presence of a dust-like substance on the surface of the iris and lens inside the eye. The trabecular meshwork, which is the drainage system of the eye, also becomes coated with this “fibrillar” material, raising intraocular pressure. Growing research also suggests that other organs within the body are affected by this basement membrane disease. Although pseudoexfoliation tends to be extraordinarily asymmetrical and is most frequently found in adults aged > 70 years, it can also occur in one or both eyes. Pseudoexfoliation, despite being long believed to be an illness only affecting persons of Scandinavian origin, glaucoma is now present in all ethnic groups.\n\nThe anterior lens capsule and pupillary edge are often covered in pseudoexfoliative material. Pseudoexfoliation syndrome, which includes weak zonules, posterior synechiae, dislocation of the lens, and poor or deficient pupillary dilation, is thought to be among the leading causes of ocular hypertension, early cataract development, and secondary open-angle glaucoma.4 PEG may result from congestion of the trabecular meshwork, according to specific theories. Less zonular support and some lingering cortical tissue often cause secondary cataracts by allowing lens epithelial cells to migrate. The abundance of pseudoexfoliative matter in the anterior area has made cataract and glaucoma surgeries more challenging. The more frequent secondary cataract is typically caused by less zonular support and some remaining cortical tissue, which allows the lens epithelial cells to migrate. The anterior portion contains pseudoexfoliative material, which complicates surgical operations for cataracts and glaucoma.\n\nCataract surgeries may be difficult because of the changes that pseudoexfoliative deposits cause in the anterior segment tissues. Tissue changes may result in vitreous loss, capsular phimosis, intraoperative or postoperative lens displacement, protracted inflammation following surgery, spikes in intraocular pressure (IOP) that cause damage to the glaucomatous disc, or postoperative corneal decompensation. Research has shown that compared to normal cases, patients with PXF syndrome are five times more likely to experience intraoperative problems after cataract surgery. Therefore, in patients with pseudoexfoliation syndrome, appropriate preoperative workup and intraoperative care will lower the risk of complications during cataract surgery.5 A comparison of intraoperative, postoperative, and visual outcomes in patients with and without pseudoexfoliation following cataract surgery is not yet available. Thus, the aim of our study was to compare surgical outcomes (intraoperative problems, postoperative problems, and visual results) among patients.\n\n\n\n1. To know the prevalence of pseudoexfoliation in cataract patients, visiting to AVBRH hospital.\n\n2. To determine how common open-angle glaucoma is among cataract patients who have pseudoexfoliation\n\n3. To study the various ocular features in patients of cataracts with pseudoexfoliation.\n\n\nMethods\n\nStudy design - Cross-sectional study\n\nParticipants will be chosen from the Acharya Vinobha Bhave Hospital Sawangi, Meghe, Wardha, Maharashtra, for this hospital-based study. The study will follow the guidelines of the Helsinki Declaration and will obtain institutional ethics committee approval from DMIMSU. All volunteers will be asked for written consent signed by them after being informed of the study’s purpose and any potential adverse effects. The procedure site will be the Acharya Vinoba Bhave Rural Hospital (AVBRH), Sawangi, Department of Ophthalmology. After considering the inclusion and exclusion criteria, all cataract patients who visited the ophthalmology department of AVBRH will be chosen for surgery.\n\nCandidates who visit AVBRH Sawangi and meet the inclusion and exclusion requirements are qualified to participate in this study.\n\n\n\n1. Patients of cataract with psuedoexfoliation of age 50 years and above\n\n2. Patient who is willing to provide informed consent.\n\n\n\n1. Traumatic cataract\n\n2. Congenital or developmental cataract\n\n3. Complicated cataract, which includes lens-induced, subluxated lens, etc.\n\n4. Previous intraocular surgery\n\n5. Age younger than 50 years\n\n6. Patients lost to follow-up\n\n7. Long-term use of topical medication\n\n8. Patients with diabetes mellitus\n\n9. Patients with Pterygium\n\n10. Chronic uveitis\n\nThe institutional ethics committee of the DMIMSU will authorize the study, following the principles of the Declaration of Helsinki. Ophthalmology OPD patients with cataracts will be selected according to the inclusion and exclusion criteria. Informed consent will be obtained from all subjects after the nature of the study is explained. Consent was provided in the local language to ensure validity. Relevant and detailed medical and ocular history will be obtained, and a torchlight examination will be performed. Each participant will undergo a thorough eye examination measuring their intraocular pressure, highest corrected visual acuity with the Snellen chart, slit-lamp assessment, and fundus examination. Intraocular pressure (IOP) was tracked using an application tonometer before pupil dilation under topical anesthesia. IOP will be measured three times in a row if it is higher than 21 mmHg. Fundus examination will be done to observe the retina and optic nerve. Correlation of all data will be performed.\n\nGeneral vital statistics such as pulse and blood pressure will be recorded. Systemic examination will be done. A detailed history will be taken for each patient, best corrected visual acuity (BCVA) will be noted, and a slit lamp will be used to perform a comprehensive anterior segment examination of the eye, including the cornea, anterior chamber, iris, pupil, and lens.4 Following pupillary dilation, a comprehensive fundus examination will be conducted using a +90 Diopter lens, employing slit-lamp biomicroscopy and indirect ophthalmoscopy. Cataracts will also evaluated and graded using a slit-lamp examination. An applanation tonometer or non-contact tonometer will be used to measuring intraocular pressure. After dilating drops (tropicamide plus) to dilate the pupil, the fundus and anterior segment will be inspected to view the retina and optic nerve. The objective of the evaluation was to identify pseudoexfoliative material on the cornea, iris, lens, and pupil, among other parts of the eye. The optic disc will be evaluated using a 90-D lens.\n\nThe following factors will be taken into account while diagnosing glaucoma:\n\nAn imbalance in the cup-to-disc ratio of the two eyes (> 0.2).\n\nA regional notch or thinned neuroretina rim.\n\nHigher cup-to-disc ratios (>0.5), particularly when the cups are aligned with the vertical axis.\n\nA paler retinal nerve margin\n\nAcquired cupping which is defined by vascular indications, such as the ’overpass’ of central vessels and the barring of circumlunar vessels\n\nObservational bias: Observational bias can be minimized by examining the patients by the same examiner.\n\nObjective bias: Objective bias can be minimized by using the same slit lamp for each patient vising the ophthalmic OPD.\n\nPrimary outcome\n\n1. Intraocular pressure\n\nIntraocular pressure (IOP) is the fluid pressure in the eye. As pressure is a measure of force per area, IOP is a measure of the magnitude of the force exerted by aqueous humor on the internal surface area of the anterior eye. Each normal eye produces about 2 μl of aqueous solution per minute, that is, about 70 l during the course of a lifetime. Normal intraocular pressure is 10-21 mmHg, but it can drop as low as 0 mmHg in hypotony and can exceed 70 mmHg in some glaucomas.\n\n2. Characteristics of the lens\n\nPseudoexfoliation syndrome is a chronic age-related disorder of the extracellular matrix that results in the deposition of abnormal fibrillary (pseudoexfoliative) material within various body tissues. This condition primarily manifests in the anterior segment of the eye. The intraocular lens shoes poor dilation with peri-pupillary transillumination defect, fibrillar white flaky deposits on the anterior lens capsule (Hoarfrost Ring), and fibrillar white flaky deposits on the pupillary border.\n\nSecondary outcome\n\n1. Atrophic patches on the iris\n\nIris atrophy is a very rare, progressive disorder of the eye characterized by a pupil that is out of place and/or distorted areas of degeneration on the iris (atrophy) and/or holes in the iris. This disorder develops slowly over time in pseudo-exfoliation syndrome.\n\n2. Phacodonesis\n\nPhacodonesis is present if the lens trembles upon movement of the eye during slit-lamp examination. The zonular apparatus is the main support system of the human lens, and weakness in the zonules can cause instability of the lens, leading to complications during cataract extraction surgery.\n\n\n\n1. Patient will be selected on the basis of inclusion and exclusion criteria\n\n2. After obtaining consent, patients will be examined for the highest corrected visual acuity with the Snellen chart, and intraocular pressure > 21 mmHg will be considered as raised.\n\n3. During slit-lamp assessment, dilated pupils with cataracts with pseudoexfoliative material on the anterior lens capsule or pupillary margins or iris or anterior chamber will be considered as having cataract with pseudoexfoliation.\n\n4. On fundus examination, the difference between cup-to-disc ratios of both eyes is more than 0.2, regional notch or thinned neuroretina rim, higher cup: disc ratios (>0.5), particularly when the cups are aligned with the vertical axis, a paler retinal nerve margin will be considered as an eye with glaucomatous changes.\n\nTo calculate the sample size\n\nWhere, n = sample size,\n\nZ = Z statistic for a level of confidence,\n\nP = Expected prevalence or proportion\n\n(If the expected prevalence is 20%, then P = 0.2), and\n\nd = Precision (if the precision is 5%, then d = 0.05).6\n\nZ is the threshold of significance at 5%, which is equal to 1.95 with a 95% confidence interval.\n\nP = prevalence of patients of cataract with pseudoexfoliation = 5.92% = 0.0529\n\nThe desired margin error is 5%, or 0.05\n\nn = 90\n\nn = 90 patients needed in this study\n\nFormula reference – Daniel et al.\n\nObservational research, known as a “cross-sectional study,” examines information gathered from a population or an appropriate group at a particular period.7\n\nAfter collecting the data of patients with cataracts with pseudoexfoliation syndrome out of the total patients visiting the AVBRH Ophthalmology OPD over a span of 2 years, the prevalence will be calculated according to a cross-sectional study.\n\n\nDiscussion\n\nOphthalmologists deal with pseudoexfoliation (PXF) conditions on a regular basis because of severe secondary glaucoma and problems that arise after cataract surgery. Despite the fact that it has been recognized since the beginning of the 20th century, interest in its study has only grown in the past several decades. A total of 540 individuals of either sex who visited the ophthalmology outpatient department at MGM Hospital and Medical College in Aurangabad and were 45 years of age or older were included in this study.8\n\nThere are only two publications on the frequency of pseudoexfoliation syndrome in India, according to a literature search. In the first, published in 1968 by Sood and Ratnaraj, the prevalence in patients with pseudoexfoliation was observed to be 34% and 1.87% in those 45 years of age or older.9 The most recent study on this topic was conducted in 1984 by Lamba and Giridhar,10 who found that 7.4% of patients with pseudoexfoliation also had glaucoma. These two studies were conducted in hospitals. These two studies were conducted in hospitals. This is the only population-based study on pseudoexfoliation syndrome conducted in India.11 Subjects with pseudoexfoliation had a mean IOP that was 1.29 mmHg greater than those without pseudoexfoliation. The 95% confidence intervals somewhat overlapped, yet this difference was nonetheless significant. Of the individuals with pseudoexfoliation, 16.7% had high intraocular pressure. Slightly over three percent patients had ocular hypertension, or elevated IOP without glaucomatous optic neuropathy in 13% of pseudoexfoliative instances, glaucomatous optic neuropathy was discovered. Prior research on pseudoexfoliation has almost always demonstrated a correlation between increased intraocular pressure (IOP) and glaucoma.\n\nAccording to hospital records from India, the incidence of PXF ranges from 1.87% to 13.5%.12 The current study found that 5.92% of participants had pseudoexfoliation syndrome. There were more men than women in this population. It has been observed that PXF becomes more common as people age. Most patients with PXF live in rural areas. Pseudoexfoliation was more common among the patients who participated in outdoor activities. In 100 consecutive PEX patients, Kozart and Yanoff conducted a clinic-based investigation and found that glaucoma was 7% common and ocular hypertension 15% common. in their investigation, however, elevated IOP was required for the diagnosis of glaucomaSimilar to our results, the Blue Mountains Eye research revealed 9.3% OHT and 14.2% glaucoma. This population-based study used optic neuropathy with or without elevated IOP to diagnose pseudoexfoliative glaucoma. Pseudoexfoliation syndrome is known to cause IOP spikes, which may not appear in a single IOP record.13\n\nA wide range of significant ocular and surgical consequences can result from pseudoexfoliation syndrome. Principally, zonular instability and, to a lesser extent, inadequate pupillary dilatation can cause complications associated with cataract surgery. Therefore, awareness of the structural and functional aspects of this condition may aid in preventing or reducing most of them. The percentage of successful surgical operations has increased since the early diagnosis of the illness owing to meticulous attention to surgical awareness, postoperative follow-up, and preoperative preparation.11\n\nIn a population-based investigation conducted in rural southern India in 2003, Arvind et al. examined the pseudoexfoliation profile. They found that the incidence increased significantly with age; however, there was no sex preference. Persons with pseudoexfolition had a much greater frequency of cataracts than persons without PXF (p = 0.014).12\n\nRutviben Ravjibhai Sadatia1, Nisha Ahuja2, Vegada Bhavisha3, Raghunathan Iodine4, and Kurian Abraham5 conducted a prospective interventional study in rural areas of Western India. The mean age of the patients was 62.48 (±5.62) years in the pseudoexfoliatin group and 60.7 (±7.63) years in the group without pseudoexfoliation (p = 0.1870). The anterior lens capsule (n = 49), pupillary edge (n = 19), and corneal endothelium (n = 2) were the most prevalent sites of pseudoexfoliative deposits in the pseudoexfoliation group. There was no statistically significant changes in the IOP or pupillary dilatation.9\n\nThe Aravind Comprehensive Eye Survey (ACES) is a population-based prevalence study of ocular disorders that impair vision, including glaucoma, carried out in a rural population in three districts in the southern Indian state of Tamil Nadu: Madurai, Tirunelveli, and Tuticorin, which are 40 years of age or older. According to the methodology and research design, the prevalence of pseudoexfoliation was 6.0% (5.3, 6.6) with a 95% confidence interval. The frequency was higher in males (p=0.01) and increased with age (p <0.001After optimal correction; 25.7% of pseudoexfoliative participants were still bilaterally blind, with cataracts accounting for 89.3% of this blindnessSeventy-five percent of the participants with pseudoexfoliation had glaucoma, and 26.7% of those with primary open-angle glaucoma had exfoliation.11\n\nThe following consequences are the subject of clinical-histopathologic correlations: lens involvement (PEX-phacopathy), zonular apparatus involvement (zonulopathy), iris involvement (iridopathy), trabecular meshwork involvement (trabeculopathy), ciliary body involvement (cyclopathy),and cornea involvement (corneal endotheliopathy): (1) angle-closure glaucoma and open-angle glaucoma brought on by ciliary and pupillary block; (2) changes to the zonular apparatus and its insertion into the ciliary body and lens during extracapsular cataract surgery can result in phacodonesis, lens displacement, and an increased incidence of vitreous loss; (3) breakdown of the blood-aqueous barrier (pseudouveitis), production of posterior synechiae owing to involvement of all iris cell populations, anterior chamber hypoxia, iris stromal bleeding, pigment epithelium melanin dispersion, inadequate or asymmetric pupillary dilatation; and (4) A damaged and numerically decreased endothelium explains early diffuse corneal endothelial decompensation.14\n\n\nDissemination\n\nThe results will be presented at a national conference and published in an indexed journal.\n\n\nStudy status\n\nThe recruitment procedure is still in the early stages.\n\n\nEthics and consent\n\nThe research protocol got approval from the Datta Meghe Institute of Higher Education and Research (Deemed to be University) Institutional ethical committee in the meeting held on 31-03-2023 with DMIHER (DU)/IEC/2023/877.\n\nAll the participants will be educated about the research, and written and verbal informed consent will be obtained from all the participants before the intervention.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nRepository name: Figshare\n\nFile name: STROBE check list for A STUDY OF CLINICAL PROFILE IN PATIENTS OF CATARACTS WITH PSEUDOEXFOLIATION IN RURAL POPULATIONS OF CENTRAL INDIA\n\nDOI: 10.6084/m9.figshare.25391719\n\nURL: https://figshare.com/account/items/25391719/edit\n\n\nAcknowledgements\n\nI would like to express my gratitude to Dr. Sachin Daigavane, HOD of the Ophthalmology Department, for his kind permission and unwavering support.\n\nI am grateful to Mr. Laxmikant Umate Sir for assisting me in conducting data analysis and determining the sample size.\n\n\nReferences\n\nAhmed KN: Outcome of Phaco Surgeries in Patients with Pseudoexfoliation. JOJ Ophthalmol. 2017 Nov 20 [cited 2023 Aug 1]; 5(4). Publisher Full Text Reference Source\n\nGupta RK, Sharma R, Gupta RK, et al.: Prevalence and Ocular Manifestations of Pseudoexfoliation Syndrome Among Patients Scheduled for Cataract Surgery in a Teaching Hospital in North India.2022; 9(2).\n\nManalil AG, Mishra P, Manavalan S, et al.: CATARACT SURGERY IN PSEUDOEXFOLIATION SYNDROME. J. Evol. Med. Dent. Sci. 2014 Oct 17; 3(54): 12403–12410. Publisher Full Text\n\nPseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma: A Review of the Literature with Updates on Surgical Management.[cited 2023 Aug 1]. Reference Source\n\nData collection: Wikipedia.2023 [cited 2023 Aug 2]. Reference Source\n\n1509511098944.pdf: [cited 2023 Aug 2]. Reference Source\n\nSullivan K, Dean A, Soe MM: OpenEpi - a web-based epidemiologic and statistical calculator for public health. Public Health Rep. 2009; 124(3): 471–474. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIJCMAAS_NOV_2016_VOL12_ISS3_11.pdf: [cited 2023 Sep 29]. Reference Source\n\nArvind H, Raju P, Paul PG, et al.: Pseudoexfoliation in South India. Br. J. Ophthalmol. 2003 Nov; 87(11): 1321–1323. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSadatia RR, Ahuja N, Bhavisha V, et al.: Surgical Outcomes of Pseudoexfoliation Syndrome among the Indian Rural Population Scheduled for Small Incision Cataract Surgery: A Prospective Interventional Study. Int. J. Anat. Radiol. Surg. 2022 [cited 2023 Oct 24]. Publisher Full Text Reference Source\n\nKrishnadas R, Nirmalan PK, Ramakrishnan R, et al.: Pseudoexfoliation in a rural population of southern India: the Aravind Comprehensive Eye Survey. Am. J. Ophthalmol. 2003 Jun 1; 135(6): 830–837. PubMed Abstract | Publisher Full Text\n\nThomas R: Glaucoma in India: Current status and the road ahead. Indian J. Ophthalmol. 2011 Jan; 59 Suppl(Suppl1): S3–S4. PubMed Abstract | Publisher Full Text\n\nKozart DM, Yanoff M: Intraocular pressure status in 100 consecutive patients with exfoliation syndrome. Ophthalmology. 1982 Mar; 89(3): 214–218. PubMed Abstract | Publisher Full Text\n\nNaumann GO, Schlötzer-Schrehardt U, Küchle M: Pseudoexfoliation syndrome for the comprehensive ophthalmologist. Intraocular and systemic manifestations. Ophthalmology. 1998 Jun; 105(6): 951–968. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "344696",
"date": "20 Dec 2024",
"name": "Yuanbo Liang",
"expertise": [
"Reviewer Expertise glaucoma"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis protocol show us a study of clinical profile in patients of cataracts with pseudoexfoliation in rural populations of central India which is interesting. And there are some recommendations for this protocol to clarify the protocol more clearly. 1. For the objective of the study，it seem confused. The aim mentioned in the introduction section of the article is different from that in the abstract. In the introduction part, the aim is \"the aim of our study was to compare surgical outcomes (intraoperative problems, postoperative problems, and visual results) among patients.\" . In the abstract, the objective is \"To determine the prevalence of pseudoexfoliation in cataract patients ...., to locate patients with pseudoexfoliative cataracts, to evaluate their likelihood of progressing to open-angle glaucoma, and to examine the various ocular characteristics of these patients. \". Please clarify it. 2. As the definition of prevalence, it is not suitable to use it as the percentage of PXF combined with cataract patients among the total cataract patients in this hospital. 3. In this protocol, the method may be not provided with sufficient details. A detailed flow chart of this study could be better for replication by others. 4. The P-value for the sample size calculation is 5.92%. Please provide more information about the source of this data. 5.Statistical methods for the collecting data is provvided. Please provide it.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-483
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https://f1000research.com/articles/13-482/v1
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17 May 24
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{
"type": "Study Protocol",
"title": "Protocol for the study of bedside CSF analysis by urinary reagent strips and comparison with traditional laboratory measurements in a tertiary care centre in rural India",
"authors": [
"Dr. Shahzad Ahmad",
"Dr. Sham Lohiya",
"Dr. Sham Lohiya"
],
"abstract": "Abstract*\nBackground Meningitis is an infection of leptomeninges. It is an emergency life-threatening condition that requires prompt treatment initiation. Diagnosis is the rate-limiting step because cerebrospinal fluid (CSF) analysis requires experienced personnel. Therefore, this study was conducted to assess the utility of urinary reagent strips for the rapid bedside diagnosis of CSF glucose, proteins, and leukocytes.\n\nObjective To determine the efficacy of a urinary reagent strip for bedside analysis of cerebrospinal fluid (CSF) samples.\n\nMethods This prospective comparative study will be conducted in the Department of Neonatology and Pediatrics, Jawaharlal Nehru Medical College, Sawangi, Wardha. CSF samples from patients suspected of infection of the central nervous system (CNS) and awaiting diagnosis will be subjected to semi-quantitative analysis using a urinary reagent strip (for glucose, proteins, and leukocytes). The results were compared with the laboratory results of the individual samples.\n\nResult After completing the study, we determined the efficacy of the urinary reagent strips in bedside estimation of CSF glucose, protein, and leukocyte levels in terms of sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy.\n\nConclusion This study provides insight into the utility of urinary reagent strips for rapid bedside diagnosis of CSF samples from patients suspected of having an infection.",
"keywords": [
"Central nervous system infection",
"cerebrospinal fluid",
"meningitis",
"urinary reagent strips"
],
"content": "Introduction\n\nMeningitis is an infection and inflammation of the leptomeninges.1–3 Meningitis is associated with high mortality and morbidity in children.4 Delayed treatment of meningitis in infants and young children can cause serious developmental deficits, including speech, motor skills, cognition, vision, hearing, and even behavioral problems.5–8 Although meningitis is associated with classic symptoms of headache, stiff neck, and fever,9,10 diagnosis based on symptoms is difficult in the pediatric age group because of their inability to communicate and the informant being the mother or caregiver. Therefore, diagnosis is dependent on cerebrospinal fluid (CSF) microscopy, CSF chemistry, and microbiological studies. These laboratory tests often require an experienced microscopist to estimate cerebrospinal fluid cell counts and appropriate tests to estimate sugar and protein levels. In a developing country, such as ours, the universal availability of qualified and experienced personnel is a challenge, particularly in resource-poor settings. This may lead to long turnaround times and substantial delays in the initiation of definitive treatment.\n\nAs meningitis is a serious life-threatening infection, early diagnosis and prompt initiation of treatment are crucial for preventing complications. However, there are currently no bedside rapid diagnostic tests for the estimation of CSF parameters, although there are tests available for the estimation of CSF parameters in other body fluids. One such example is urinary reagent strips. CSF glucose, protein, and leukocyte counts are essential in differentiating infections from other conditions such as non-infectious epilepsy and febrile seizures, which commonly occur in the pediatric population. These parameters may also be used to differentiate between different types of meningitis, viz., bacterial, fungal, and viral.11–13 Therefore, in the present study, we included the semi-quantitative estimation of these three parameters of CSF using urinary reagent strips and compared them with the traditional laboratory tests to estimate their utility.\n\n\nProtocol\n\nThe present study is a prospective, comparative study that will be conducted on patients admitted to the Neonatology and Pediatrics Department of Acharya Vinoba Bhave Rural Hospital, a tertiary care hospital located at Sawangi (Meghe), Wardha, Maharashtra, from February 2023 to January 2025.\n\nAll patients (aged less than 14 years) admitted to the Neonatology and Pediatrics Department with suspected central nervous system (CNS) infection and undergoing CSF examination for diagnosis were included in the study. All cases where parents/legal guardians refused to consent to participate in the study and any case where the sample was hemorrhagic or those received after a long duration of the tap (after more than 1 h) will be excluded.\n\nPrior to the initiation of the study, approval was obtained from the Institutional Ethics Committee. After obtaining approval, recruitment of patients will begin. The parents/legal guardians of all patients will be briefed about the study procedure and plans for the publication and dissemination of the study results. They will be given sufficient time and any queries raised will be answered by the research team. Thereafter, they were required to sign an informed consent form. After obtaining voluntary written informed consent, the patients were included in the study.\n\nAll consecutive patients meeting the inclusion criteria were included in the study until the desired sample size was met (Table 1).\n\nAfter inclusion, detailed demographic information was recorded for each patient. A CSF tap will be performed by lumbar puncture using all aseptic precautions as per the standard guidelines, and CSF samples will be collected. Urinary reagent strips with an analysis of 10 parameters were used in the study. Upon receipt of the sample, 2 to 3 drops of CSF will be added using a pipette on the urinary reagent strip on the patches for glucose, protein, and leukocytes. The strips will be observed for changes in color, and the interpretation for semi-quantitative analysis of the parameters will be done for the levels of glucose, proteins, and leukocytes.\n\n1. Glucose: Normal CSF glucose levels are approximately two-thirds of the plasma levels. Glucose levels will be interpreted using manufacturer-provided grading as follows:\n\na. No color for levels upto 50 mg/dL\n\nb. Change of color for levels more than 50 mg/dL\n\n2. Protein: The normal range of CSF proteins is 15–45 mg/dL. Protein levels will be interpreted using manufacturer-provided grading as follows:\n\na. No color for levels less than 30 mg/dL\n\nb. 1+ for levels between 30 to 100 mg/dL\n\nc. 2+ for levels between 100 to 500 mg/dL\n\nd. 3+ for levels more than 500 mg/dL\n\n3. CSF leukocytes: The normal range of CSF leukocytes was <5 cells/mm3. The levels are interpreted using manufacturer-provided grading as follows:\n\na. No color for levels less than 10 cells/mm3\n\nb. 1+ for levels between 10 to 75 cells/mm3\n\nc. 2+ for levels between 75 to 500 cells/mm3\n\nd. 3+ for levels more than 500 cells/mm3\n\nThe quantitative analysis of each sample will also be performed using standard laboratory tests for the estimation of glucose and proteins, and the leukocyte count will be assessed by microscopic examination. The laboratory results were compared with those obtained using the urinary reagent strip and analyzed.\n\nData will be entered into the latest version of the SPSS software and analyzed. Descriptive and analytical statistics were used for the statistical analysis. Continuous data are presented as the mean±standard deviation, and categorical data are presented as percentages. For analytical statistics, continuous data will be analyzed using the unpaired t-test, and categorical data will be analyzed using the chi-square test. The sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were calculated. P was set at p < 0.05.\n\n\nConclusion\n\nThe results of this study will help us assess the efficacy of urinary reagent strips as a means for the semi-quantitative estimation of CSF glucose, proteins, and leukocytes. This will enable us to assess its utility as a rapid bedside test for the diagnosis of CSF infections.\n\nThe results of the study will be presented in conferences/scientific meetings and published in peer-reviewed journals.\n\nData collection ongoing, expected to be completed in January 2025.",
"appendix": "Data availability\n\nNo data is associated with this article.\n\n\nReferences\n\nLien CY, Lee JJ, Tsai WC, et al.: The clinical characteristics of spontaneous Gram-negative bacterial meningitis in adults: A hospital-based study. J. Clin. Neurosci. 2019 Jun; 64: 101–105. PubMed Abstract | Publisher Full Text\n\nFuentes-Antrás J, Ramírez-Torres M, Osorio-Martínez E, et al.: Acute Community-Acquired Bacterial Meningitis: Update on Clinical Presentation and Prognostic factors. New Microbiol. 2019 Apr; 41(4): 81–87. PubMed Abstract\n\nRohde S: Inflammatory Diseases of the Meninges. Inflammatory Diseases of the Brain. 2012 Jun 21; pp. 127–137. Publisher Full Text\n\nWright C, Blake N, Glennie L, et al.: The Global Burden of Meningitis in Children: Challenges with Interpreting Global Health Estimates. Microorganisms. 2021 Feb 13; 9(2): 377. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCushing SL, Papsin BC, Rutka JA, et al.: Vestibular end-organ and balance deficits after meningitis and cochlear implantation in children correlate poorly with functional outcome. Otol. Neurotol. 2009 Jun; 30(4): 488–495. PubMed Abstract | Publisher Full Text\n\nChandran A, Herbert H, Misurski D, et al.: Long-term sequelae of childhood bacterial meningitis: an underappreciated problem. Pediatr. Infect. Dis. J. 2011 Jan; 30(1): 3–6. Publisher Full Text\n\nChristie D, Rashid H, El-Bashir H, et al.: Impact of meningitis on intelligence and development: A systematic review and meta-analysis. PLoS One. 2017 Aug 24; 12(8): e0175024. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZainel A, Mitchell H, Sadarangani M: Bacterial Meningitis in Children: Neurological Complications, Associated Risk Factors, and Prevention. Microorganisms. 2021 Mar 5; 9(3): 535. PubMed Abstract | Publisher Full Text | Free Full Text\n\nvan Ettekoven CN , van de Beek D , Brouwer MC: Update on community-acquired bacterial meningitis: guidance and challenges. Clin. Microbiol. Infect. 2017 Sep; 23(9): 601–606. PubMed Abstract | Publisher Full Text\n\nCharalambous LT, Premji A, Tybout C, et al.: Prevalence, healthcare resource utilization and overall burden of fungal meningitis in the United States. J. Med. Microbiol. 2018 Feb; 67(2): 215–227. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBahr NC, Boulware DR: Methods of rapid diagnosis for the etiology of meningitis in adults. Biomark. Med. 2014; 8(9): 1085–1103. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRichie MB, Josephson SA: A Practical Approach to Meningitis and Encephalitis. Semin. Neurol. 2015 Dec; 35(6): 611–620. PubMed Abstract | Publisher Full Text\n\nGomes HR: Cerebrospinal fluid analysis: Current diagnostic methods for central nervous system infectious diseases. Arq. Neuropsiquiatr. 2022 May; 80(5 Suppl 1): 290–295. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "294842",
"date": "23 Jul 2024",
"name": "Davide Chiasserini",
"expertise": [
"Reviewer Expertise Clinical neurochemistry",
"immunoassay",
"proteomics",
"biomarkers"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe protocol by Shahzad Ahmad and Sham Lohiya is an interesting experimental plan to use urine strip for approximate measurements of CSF parameter for meningitis diagnosis in rural setting in India. The idea is interesting, I have minor comments:\nStatistical analysis. It is not clear to me how the comparison between clinical tests and urine strips will be carried out. With the urine strip the authors will have no exact values but only ranges exemplified by numbers. Which statistical approach will the authors use to assess the similarities between the two methods? Correlation analysis, Bland-Altmann plots or what? The authors should mention which are the standard laboratory methods for protein, glucose and leucocytes that will be used in the study. Please uniform the tenses of the verbs, some parts use future tenses and some parts use past tenses, and it is not clear why, since this is a protocol for a future experiment.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-482
|
https://f1000research.com/articles/13-480/v1
|
17 May 24
|
{
"type": "Research Article",
"title": "Aerodynamic performance enhancement of centrifugal compressor using numerical techniques",
"authors": [
"Shivani S",
"Amar Murthy A",
"Srinivas G",
"Shivani S",
"Amar Murthy A"
],
"abstract": "Background Centrifugal compressors are dynamic machines utilizing a rotating impeller, efficiently accelerate incoming gases, transforming kinetic energy into pressure energy for compression. They serve a wide range of industries, including air conditioning, refrigeration, gas turbines, industrial processes, and applications such as air compression, gas transportation, and petrochemicals, demonstrating their versatility. Designing a centrifugal compressor poses challenges related to achieving high aerodynamic efficiency, surge and choke control, material selection, rotor dynamics, cavitation, erosion, and addressing environmental considerations while balancing costs. Optimizing maintenance, reliability, and energy efficiency are essential aspects of the design process.\n\nMethods The primary objective of this research is to comprehensively investigate and improve the aerodynamic performance of centrifugal compressors. To accomplish this, a comprehensive investigation of variables such as blade number and hub diameter, along with various turbulence models will be conducted. This approach will leverage numerical techniques to fill the significant gaps in the current literature regarding centrifugal compressor design and optimization. The study encompasses the evaluation of two turbulence models, namely Shear Stress Transport and K-epsilon. Furthermore, it delves into the fine-tuning of blade geometry, including variations in blade number and hub diameter, aiming to refine the design for optimal performance. Extensive analyses using Ansys CFX encompass key variables such as Pressure, Mach Number, Density, Velocity, Turbulence Kinetic Energy, and Temperature.\n\nResults Notably, the optimized pressure profile yielded remarkable results, achieving a substantial 36% improvement, demonstrating the tangible benefits of these design enhancements.\n\nConclusion The outcomes of this research hold significant utility for engineers, manufacturers, and regulatory bodies, offering invaluable insights and guidance to enhance compressor performance and efficiency.",
"keywords": [
"Centrifugal Compressor",
"ANSYS CFX",
"CFD",
"Turbulence",
"Optimization"
],
"content": "Introduction\n\nThe centrifugal compressor is a dynamic compressor with a radial design. It is used to compress gases by converting kinetic energy into pressure energy by using rotating parts to impart energy to the gas as it continuously flows. The main components of a centrifugal compressor are the casing, impeller, diffuser, bearings, seals, and the drive system. The impeller is the rotary part, and it has three main parts: vanes, hub, and shaft. During the working of the compressor, the gas is drawn into the centre of the impeller. As the impeller rotates rapidly, it induces the gas to spiral outward, acquiring kinetic energy in the process. The conversion of kinetic energy to pressure energy occurs when the gas flows through the diffuser, i.e., the stationary component of the compressor. The casing encloses the impeller and the diffuser of the compressor while directing the flow of gas. The centrifugal compressor is comparatively more efficient than other types of compressors as it requires less energy to operate. It can handle a high flow rate of gas, thus making it ideal for applications such as air conditioning and refrigeration. Since centrifugal force is not highly effective at high pressure, the centrifugal compressor is not suitable for high-pressure applications.\n\nCentrifugal compressors have undergone many recent innovations aimed at enhancing their effectiveness and performance such as the use of advanced materials like composites and ceramics, digitalization for more precise monitoring, and implementation of adaptive control mechanisms. Improving the aerodynamic design of the compressor leads to better efficiency by reducing turbulence and friction in the flow of gas. The use of Computational Fluid Dynamics (CFD) has been widely used recently to simulate the flow and identify areas of improvement. The future scope of centrifugal compressors will most certainly be shaped by technological breakthroughs, changes in industrial requirements, and a growing emphasis on sustainability and efficiency. Considering the growing demand for portable devices, electronics cooling, and medical applications, the development of smaller and more compact centrifugal compressors could become a major topic of research. Additive manufacturing (3D printing) advancements may enable the fabrication of complicated geometries and customized components, resulting in enhanced compressor efficiency and performance.\n\n\nLiterature review and objectives\n\nThe advancement of technology made the use of numerical methods much easier than it was two decades back. The recent shift to simulations for understanding the areas of improvement led to more use of CFD for centrifugal compressors. In the past decade, many researchers have worked on understanding what is the variation from the experimental results to the numerical results; for this, many have made use of ANSYS CFX, FLUENT, MATLAB, OPEN FOAM, and open-source libraries. The findings in the research revealed discrepancies between the CFD conclusions and the experimental data. The differences vary depending on the operating conditions, such as at higher rotational speeds, turbulence models, mesh parameters, etc.1–3 The authors speculated that the disparities could be attributed to the absence of key components in the CFD model. Further, understanding surge and preventing it by utilizing CFD is widely implemented.4–7\n\nThe emergence of additive manufacturing and nanotechnology has reshaped the landscape, ushering in a new frontier in the development of centrifugal compressors—namely, the creation of microturbines optimized for enhanced portability. The pre-manufacturing design and testing of these micro models assumes paramount importance. In an influential work, Aghaei (2007) engaged in a multifaceted approach involving a 1D design using Centrifugal Compressor Design (CCD) code and subsequent CFD analysis for a 3D model featuring a centrifugal impeller with an approximate pressure ratio of 4:1.8 The CFD analysis for the compressor is not restricted to the impeller but can also be used for analysis of inlet guide vanes, diffusers, and other parts of the compressor.9,10 An equally consequential development pertains to the optimization of design, which has been substantially expedited due to the reduced resources required for generating new Computer-Aided Design (CAD) models in contrast to fully realized experimental prototypes. The optimization can be done in two ways: by manual method, and by parameterized design changes. Most of the optimizations were carried out by changing design parameters, such as trailing edge angles, polar angles, impeller shape factor, radius, blade height, and other design parameters.11–14\n\nThe theoretical modeling of centrifugal compressors involves the creation of mathematical frameworks and computational simulations to elucidate their performance characteristics and behaviour. These models integrate fundamental principles of fluid dynamics, thermodynamics, and mechanical engineering to predict variables such as pressure ratios, flow rates, efficiency, and temperature distributions. Theoretical analyses encompass a range of factors, including impeller geometry, inlet conditions, and rotational speeds, allowing engineers to explore the compressor’s response under different operating scenarios. When compared to experimental methods, numerical simulation methods can give a more cost-effective and reliable alternative to researching the Tip Leakage Vortex (TLV). Different loss models are employed to forecast and assess the centrifugal compressor’s performance under varying circumstances and at various speeds. The study of various compressor losses, including leakage loss and recirculation loss, led to the development of models to calculate these losses.15–17 Moreover, a novel model for calculating the volute loss accounts for the radial velocity loss, circumferential velocity loss, and wall friction loss. Compared to conventional semiempirical models, the model seeks to increase the accuracy of volute loss prediction. Total pressure losses, which are mostly produced in the inlet duct and inlet section, have an impact on the flow in a volute. The volute’s friction also contributes to overall pressure losses.16,18,19\n\nReynolds-Averaged Navier-Stokes (RANS) stands out as a widely embraced CFD approach used to forecast fluid flow behaviour. It achieves this by solving the Navier-Stokes equations, which encompass viscosity and turbulence effects. These equations describe the motion of fluid particles and their interactions in a flow field. While being a well-known theoretical framework for the design and performance study of centrifugal compressors, the Aungier model was created by Dr. Ronald H. Aungier. This model serves as a useful tool for preliminary design and performance estimate since it offers a streamlined one-dimensional method for predicting the behaviour of centrifugal compressors. There are some variations between the steady-state RANS model and the 1D Aungier model, but both offer reasonable estimates of centrifugal compressor performance.20 A theoretical framework used to explain the surge phenomenon in centrifugal and axial flow compressors is known as the Greitzer model, after Dr. Emory Leon Greitzer. The Greitzer approach is founded on the idea of feedback between the compressor’s flow rate and pressure. When adopting a relaxation time shorter than the one suggested for axial compressors, the model predictions and the experimental data are in a reasonable amount of agreement.21\n\nExperimental analysis of centrifugal compressors involves conducting physical tests on prototypes, measuring their performance, and understanding their behaviour. This process often entails constructing and assembling actual compressor components and gathering data on parameters such as pressure ratios, flow rates, efficiency, temperature distributions, and surge behaviour. These experiments provide insights into how the compressor operates and validate theoretical models. By comparing results with numerical predictions, researchers can refine their understanding of factors contributing to discrepancies. Conducting both experimental and theoretical studies is essential for comprehending the impact of external factors on centrifugal compressors. An elevation in humidity, for instance, correlates with a reduction in the total pressure ratio. Introducing wet compression, however, enhances the total pressure ratio and isothermal efficiency, concurrently lowering the outlet total temperature and specific compression work. Encouragingly, the alignment between experimental and theoretical analyses concerning the influence of wet compression and humidity on centrifugal compressors underscores the validity of these findings.22,23\n\nSurge is a serious issue that continues to be the subject of a lot of research since it can harm the compressor and the system to which it is linked. When the flow rate through the compressor falls below the level at which the impellers can no longer sustain the necessary pressure rise, a surge occurs. As a result, the flow may change direction and the compressor may begin to vibrate erratically. The characteristics and behaviours of instability phenomena such as Rotating Instability (RI), impeller stall, and diffuser stall are closely associated with surge.24 Casing treatments are found to reduce surge and reduce the noise of the compressor operating near surge.25,26 Furthermore, on an unsteady flow field of a centrifugal compressor under pulsating backpressure conditions highly unsteady conditions can trigger the dynamic stall of the compressor, shifting the surge line to smaller mass flow rates27,28\n\nIn addition, experiments were conducted to understand the influence of Adjustable Inlet Guide Vanes (AIGVs) and Adjustable Vaned Diffusers (AVDs) on the compressors’ pressure ratio, efficiency, and overall performance. It is found that the use of AIGVs and AVDs can significantly improve the compressors’ overall performance over the entire operating range.29,30 Joo (2022) conducted an experimental study on the performance of supercritical CO2 centrifugal compressors with reference to the earlier available numerical simulations of the same. For the experimental study, a compressor performance test was conducted by controlling the rotational speeds of the impeller and the Calorific Value (CV) and further studied the effect of the change in the opening rate of the CV as well as the effect on the change in rotational speed of the impeller to draw the proper conclusion.31\n\nThe literature review revealed a significant gap in research regarding the comprehension and enhancement of centrifugal compressors by investigating the influence of blade number and hub diameter variations on parameters such as pressure profile, Mach number, and eddy viscosity. Also, it was found that fewer studies have been conducted on various turbulence models which are available.\n\nTo improve the aerodynamic performance enhancement of centrifugal compressor using numerical techniques.\n\n\nMethods\n\nThe research process for a paper on aerodynamic analysis commences with an introductory phase followed by an extensive literature review to discern prevailing knowledge and pinpoint research gaps. Subsequently, the research objectives are formulated, leading to the pivotal phase of conducting a baseline analysis, which establishes a fundamental benchmark, either through pre-existing data utilization or by performing rudimentary analyses. The subsequent stages encompass modeling and meshing, entailing the construction of a computational model and its division into discrete elements (mesh). Following this, an in-depth analysis of the model is conducted, employing computational simulations to elucidate airflow patterns around the subject of study. The outcomes of this analysis facilitate the identification of areas ripe for enhancement in aerodynamic performance. Researchers may then proceed to compile a comprehensive report and submit their findings for publication. Nevertheless, an iterative feedback loop underscores the process, allowing for refinement of both the model and mesh should the analysis yield unsatisfactory results. In essence, this comprehensive research process chart shown in Figure 1, rooted in the realm of aerodynamic analysis, encapsulates a methodical and iterative approach to scientific inquiry.\n\n\nModeling of centrifugal compressor\n\nThe modeling was done using Vista CCD and BladeGen in Ansys Workbench. A 2D sketch is developed on Vista CCD based on the aerodynamic data and the geometric parameters provided. It is further edited based on changes in the Bezier curve in BladeGen. This will finally provide the 3D model as well as the blade design. Within the Vista CCD, Tables 1 and 2 serve as input sources for data entry, which undergoes processing to generate the outcomes depicted in Figure 2. Additionally, the processed data is accompanied by an illustrative impeller sketch as shown in Figure 3. Further, the data from Vista CCD is transferred to BladeGen to further model the blade based on the properties given in Figures 4 to 12. The data in these graphs are modified to obtain the required shape of the blade.\n\nThe meshing of the impeller geometry was performed using TurboGrid, with the blade profile from BladeGen being transferred to TurboGrid through ANSYS Workbench. The mesh details were configured according to Table 3, and a global size factor of 2 was chosen as the optimal value. This decision was based on the observation that a mesh size larger than 2 would exceed the available space within the blades. The resulting mesh consisted of a total of 1,633,660 nodes and 1,548,915 elements, as illustrated in Figures 13 to 16, showcasing each individual blade meshes and the complete 360° impeller mesh.\n\nThe boundary conditions for the centrifugal compressor were applied using the CFX Pre of ANSYS Workbench. It was provided in TurboMode. Figures 17 and 18 show the selected part for each boundary condition. No-slip wall boundary condition was given to both the splitter and the main blade. A rotational speed of 40000rpm was given in the direction of the arrow in Figure 18. Table 4 gives the data the inserted in the TurboMode that was modified for applying the required boundary conditions. The Shear Stress Transport Turbulence model in ideal gas conditions was used for this analysis.\n\nGOVERNING EQUATIONS: To solve the flow conditions, Navier-Stokes equation can be used in the following way.33\n\nfx, fy and fz: Body force per unit mass in x, y, and z directions, respectively\n\nq̇: Rate of volumetric heat addition per unit mass\n\nq̇x,q̇xandq̇x: Rate of volumetric heat addition per unit mass in the x, y, and z directions, respectively\n\nu, v, w: Velocity vectors in x, y, and z directions, respectively\n\nρ: Air density (kg/m3)\n\nτxx,τyyandτzz: Normal stress related to time rate change of volume of the fuid element in x, y, and z directions, respectively.\n\nτxy,τxz,τyx,τyz,τzx,τzy: Shear stress related to the time rate of change of shearing deformation of fluid element in x, y, and z directions, respectively.\n\nA grid independence check was conducted for all the parameters of the blade. The change in the mesh size was parameterized by the change in the global size factor. Number of mesh nodes ranging from 1.6 million to 10 million was considered. The result attained stability after 5 million nodes in most of the properties. Figures 19 and 20 show the grid independence check for pressure and Mach number respectively.\n\n\nResults and discussion\n\nThe performance study of more complicated phenomena is made possible by the CFD simulation, which creates a virtual representation of the internal flow in the centrifugal compressor. Using CFD tools, adjustments were made to the flow of a centrifugal compressor stage with all the components in situ, from the input to the output. Vector plots, contour plots, and streamline graphs are made in order to better comprehend fluid flow via the centrifugal compressor stage. The working pressure and temperature are 101.353 pa and 288.15 k respectively, with the impeller blade rotating at 40000 rpm under a 3 kg/s mass flow rate. The outcomes of this CFD analysis point to numerous possibilities for flow modeling and centrifugal compressor performance. Variations in velocity and pressure can be used to pinpoint specific locations where energy is lost. This analysis’s flow velocity pattern identifies a few significant regions where energy is lost. Results and the contour plot of the blade-to-blade view were obtained on CFX Post. The solution ran for 300 cycles.\n\nThe primary analysis was done by replicating the procedure and exact blade profiles provided in the reference.32 The results obtained were within a 5% error for pressure and an 18% error for Mach Number. Table 5 gives the comparison for both pressure and Mach number values with percentage error.\n\nPRESSURE: The pressure variations encountered by the impeller are notable, spanning from 27,690 to 154,400 Pascals. Notably, the leading edge faces the lowest pressure levels, exhibiting distinct flow separations in this region. Across the blade span, a moderate pressure of 91,070 Pascals is consistently observed. Moving towards the trailing edge, the impeller experiences elevated pressure ranging from 122,800 to 154,400 Pascals, as illustrated in Figure 21. Additionally, it is evident that high-pressure zones are forming at the tip of each blade.\n\nMACH NUMBER: The Mach number exhibits a wide range, spanning from near-zero values up to 1.819. Notably, a distinct high Mach number is prominently observed at the leading edge of the impeller. A closer examination of Figure 22 reveals that in proximity to the blade, the Mach number diminishes significantly, approaching nearly zero. Across the entirety of the impeller’s span, the Mach number maintains an approximate value of 0.9. As one progresses towards the trailing edge of the impeller, high Mach numbers resurface. Additionally, there is a subtle presence of lower Mach numbers at the blade tips.\n\nDENSITY: The density distribution within the impeller displays a notable range, spanning from 0.32 to 1.682 kilograms per cubic meter (kg/m3). At the leading edge of the impeller, there is a discernible low-density region, with values ranging from approximately 0.3 to 0.6 kg/m3. Across the entirety of the impeller’s span, the density is generally within the range of 1 to 1.3 kg/m3. Conversely, at the trailing edge, a region of high density, measuring around 1.6 kg/m3, is evident. Upon closer examination of Figure 23, it becomes apparent that high-density regions are observed at the blade tips on the leading edge, while at the blade tips on the trailing edge, a density of approximately 1 kg/m3 is observed.\n\nTEMPERATURE: The temperature distribution within the impeller exhibits a range between 208 Kelvin (K) and 433 K. Notably, conspicuous contours depicting lower temperatures are evident at the leading edge, as depicted in Figure 24. Across the entire span of the impeller, temperatures remain relatively consistent, falling within the range of 264 K to 320 K. Towards the trailing edge, a subtle tendency towards higher temperatures, approximately around 370 K, becomes apparent. A closer examination reveals faint indications of elevated temperatures reaching 433 K at the blade tips.\n\nTURBULENCE: The observed turbulence kinetic energy spans a range from 4.9 to 4148 square meters per second squared (m2/s2). Along the entirety of the blade’s span, a consistent turbulence level of 1041 m2/s2 is evident from Figure 25. Furthermore, the turbulence maintains a relatively constant and low value, specifically at 4.947 m2/s2 throughout. Notably, a predominant concentration of turbulence is observed at the trailing edge of the impeller.\n\nVELOCITY: The velocity distribution within the impeller reveals a range from 0 to 581.4 meters per second (m/s). Notably, distinctive contours depicting high velocity, specifically at 581.4 m/s, are prominently observed at the trailing edge. Across the entire span of the impeller, the velocity consistently falls within the range of 290 to 430 m/s. Upon closer scrutiny of Figure 26, it becomes evident that the velocity along the blade exhibits significantly lower values in comparison to other regions within the impeller.\n\n\nOptimized blade analysis\n\nAn alternative turbulence model was employed in the aforementioned analysis to discern its efficacy and alignment with values reported in the reference paper. The transition to the k-Epsilon turbulence model in Ansys CFX was executed by modifying the turbulence model within the Turbo mode. The Shear Stress Transport (SST) turbulence model is a hybrid approach that combines elements of the k-ε and k-ω models, excelling in accuracy for complex flows with adverse pressure gradients and separation. It is particularly favoured for turbomachinery simulations involving intricate boundary layers. In contrast, the k- Epsilon turbulence model is computationally more efficient but tends to provide less accurate results, making it suitable for simpler flow scenarios with fewer complexities. The results of pressure and Mach number compared to the SST model and the reference paper model are shown in Tables 6 and 7 with the percentage increment. From the results in k-Epsilon turbulence model, an increment in the pressure compared to the SST model is observed. Furthermore, a slight decrease in the Mach number is also observed.\n\nA minor adjustment was introduced to the blade geometry curve, resulting in improved outcomes for both turbulence models. Consequently, this refined design was employed to investigate optimization based on variations in the number of blades and hub diameter as shown in Table 8. The aforementioned analyses using both turbulence models were reiterated across five additional scenarios, involving an increase in the number of blades coupled with a simultaneous reduction in hub diameter. Figure 27 illustrates the project schematics for one mesh size, with an analogous creation of four additional mesh sizes to facilitate a comprehensive assessment of grid independence. For each case, a grid independence check was done in both SST turbulence and k-Epsilon turbulence. This check was done for pressure, Mach number, density, velocity, turbulence, and temperature as shown in Figures 28 and 29. All the obtained results of the SST turbulence are shown in Table 9 and that of k-Epsilon is shown in Table 10.\n\nPRESSURE: The analysis outcomes underscore the substantial improvements achieved by implementing the optimized blade design, resulting in enhanced performance metrics compared to the original configuration. Notably, the optimized blades demonstrate a significant increase in pressure ratio, indicative of improved fluid compression capabilities. In the baseline analysis, the maximum impeller pressure recorded in the SST model stands at 154.4 kPa, as depicted in Figure 21, while in the k-Epsilon model, it reaches 173.2 kPa. Noteworthy variations in flow contours are observed between these two cases. In the SST model, flow separation and low-pressure regions are notable at the leading edge, whereas the k-Epsilon model exhibits high-pressure regions both at the leading and trailing edges, as illustrated in Figure 30. Upon introducing slight modifications to the blade design, the contours align more closely with those seen in Figure 21. However, there is an increase in pressure profile, reaching 204.05 kPa in the SST model (Figures 31 and 32) and 208.15 kPa in the k-Epsilon turbulence model (Figure 33). Furthermore, a consistent trend of pressure increase is observed with variations in blade number and hub diameter. Consequently, the optimized configuration is attained with 12 blades and a hub diameter of 60 mm. Both the SST and k-Epsilon turbulence models exhibit distinct flow separation at the leading edge, as evidenced in Figures 34 and 35, respectively.\n\nMACH NUMBER: The analysis results underscore that the implementation of the optimized blade design brings about significant enhancements in the Mach number, representing a more controlled and less turbulent flow regime compared to the original configuration. This characteristic offers distinct advantages by reducing the risk of aerodynamic losses and mitigating flow separation phenomena. In the context of the k-Epsilon turbulence model, the Mach number contours exhibit relative stability, with only a slight increase in Mach number evident in Figure 36. However, with the modified blade design, a notable surge in the Mach number to 2.4 is observed in Figures 37, 38, and 39. It is noteworthy that while the maximum Mach number increases, the contours reflect a shift towards lower Mach numbers at both the leading and trailing edges. High Mach numbers are primarily confined to the blade tips within the impeller. Furthermore, a detailed examination of Tables 9 and 10 reveals a clear trend: a lower number of blades and a higher hub diameter tend to elevate the Mach number. Conversely, as the blade count increases and the hub diameter decreases, the Mach number decreases, resulting in reduced turbulence levels. Consequently, the optimized Mach number is achieved with 12 blades and a 60mm hub diameter, as illustrated in Figures 40 and 41.\n\nTEMPERATURE: The analysis results substantiate that the implementation of the optimized blade design yields significant enhancements in temperature performance compared to the original configuration. Notably, the optimized blade design leads to an increase in temperature within the compressor. This outcome is a direct consequence of the improved energy transfer from the optimized blades to the fluid, resulting in a noticeable temperature depletion. It is crucial to emphasize that this decrease in temperature remains well within acceptable operational limits. Remarkably, evident contours depicting lower temperatures are observed prominently at the leading edge, as depicted in Figures 42 to 45. Across the entirety of the impeller span, temperatures remain relatively uniform. Toward the trailing edge, there is a subtle trend toward higher temperatures. A closer examination reveals faint indications of elevated temperatures at the blade tips. The lowest temperature range is achieved in the case of 12 blades for both turbulence models, as illustrated in Figures 46 and 47.\n\nVELOCITY: The analysis results highlight that the implementation of the optimized blade design leads to noteworthy enhancements in fluid velocity compared to the original configuration. The optimized blades effectively reduce the fluid’s velocity due to their enhanced capacity for energy transfer, resulting in a commendable reduction in fluid velocity that remains well within acceptable operational limits. Notably, distinct contours representing elevated velocity are prominently observed at the trailing edge. Across the entirety of the impeller’s span, the velocity consistently falls within a specific range. Upon meticulous examination of Figures 48 to 53, it becomes apparent that the velocity along the blade exhibits significantly lower values in comparison to other regions within the impeller. Notably, the velocity contours remain consistent, with higher velocity ranges observed in the k-Epsilon models. During the optimization process, it became evident that increasing the blade count and decreasing the hub diameter led to a decrease in velocity.\n\nDENSITY: Density assumes a central role in shaping the aerodynamic characteristics of the compressor, exerting direct influence over parameters like mass flow rate, pressure ratio, and temperature rise within the machinery. Over the course of the grid independence assessment and optimization iterations, the maximum density consistently adhered to a range spanning from 1.97 kg/m3 to 2.05 kg/m3. Notably, it is observed that the SST turbulence model exhibits slightly lower density values compared to the k-Epsilon turbulence model. However, the contours representing density maintain uniformity across all cases as shown in Figures 54 to 59. The quest for a homogeneous density distribution along the impeller blades remains a sought-after objective, as it fosters smoother and more predictable airflow patterns.\n\nTURBULENCE KINETIC ENERGY: Observations indicate that the SST Turbulence model exhibits relatively higher turbulence kinetic energy levels when compared to the k-Epsilon model. In the context of the SST turbulence model applied to the modified blade, a localized region of heightened turbulence is discernible, albeit to a lesser extent in the case of the k-Epsilon model as shown in Figures 61 to 64. However, in the analyses of the optimized blade design, turbulence remains consistently low across the entire span, as depicted in Figures 60 and 65. Furthermore, turbulence levels maintain a relatively stable and subdued profile throughout the simulations. It is noteworthy that a pronounced concentration of turbulence is evident, particularly at the trailing edge of the impeller. These observations provide valuable insights into the flow characteristics and turbulence distribution within the compressor.\n\n\nConclusion\n\nCentrifugal compressors play a vital role in numerous industries, including air conditioning, refrigeration, gas turbines, and industrial processes. Their applications span across sectors such as air conditioning, gas turbines, oil and gas, petrochemicals, and aerospace, performing critical functions like air compression, gas transportation, and industrial processes. However, designing these compressors presents multifaceted challenges, including achieving high aerodynamic efficiency, effective surge and choke control, material selection, rotor dynamics management, cavitation mitigation, erosion prevention, and environmental compliance while optimizing costs. This research aims to comprehensively investigate and enhance the aerodynamic performance of centrifugal compressors by examining key design parameters, notably blade number and hub diameter, and evaluating various turbulence models using numerical techniques to address gaps in existing literature.\n\nTwo turbulence models, Shear Stress Transport and K-epsilon are scrutinized within the context of Computational Fluid Dynamics (CFD) simulations. CFD provides insights into the internal flow dynamics within centrifugal compressors, analysing critical variables such as Pressure, Mach Number, Density, Velocity, Turbulence Kinetic Energy, and Temperature. Despite slight discrepancies, with a 5% variance in pressure and an 18% deviation in Mach number compared to reference values, this study underscores the importance of judicious model selection and precise simulation techniques. The grid independence check confirms result stability after reaching around 5 million nodes for most properties.\n\nA key finding relates to the correlation between the number of blades and hub diameter with the Mach number. Lower blade counts and larger hub diameters are associated with higher Mach numbers, resulting in reduced turbulence levels. Optimization identifies the configuration featuring 12 blades and a 60mm hub diameter, achieving a substantial 36% improvement in the pressure profile. Furthermore, the research highlights the cost-effectiveness of numerical simulations compared to experimental methods. It also suggests potential areas for further investigation, particularly regarding the impact of blade number and hub diameter on compressor performance. These insights, derived from rigorous scientific analysis, provide valuable guidance for engineers, manufacturers, and regulatory bodies, offering practical avenues to enhance compressor performance and efficiency in industrial applications.",
"appendix": "Data availability statement\n\nNo data associated with this article.\n\n\nReferences\n\nNeverov VV, Kozhukhov YV, Yablokov AM, et al.: Optimization of a centrifugal compressor impeller using CFD: The choice of simulation model parameters. IOP Conference Series: Materials Science and Engineering. Institute of Physics Publishing; 2017; vol. 232. .\n\nMangani L, Casartelli E, Mauri S: Assessment of Various Turbulence Models in a High Pressure Ratio Centrifugal Compressor With an Object Oriented CFD Code. J. Turbomach. 2012; 134. Publisher Full Text\n\nVan den Braembussche RA, Ha¨nde BM: Experimental and Theoretical Study of the Swirling Flow in Centrifugal Compressor Volutes. J. Turbomach. 1990; 112: 38–43. Publisher Full Text\n\nLattner Y, Geller M, Kutz M: Physics-based surge point identification for unsupervised CFD-computation of centrifugal compressor speed lines. Energy Conv. Manag.: X. 2023; 17: 100337. Publisher Full Text\n\nBroatch A, Galindo J, Navarro R, et al.: Methodology for experimental validation of a CFD model for predicting noise generation in centrifugal compressors. Int. J. Heat Fluid Flow. 2014; 50: 134–144. Publisher Full Text\n\nZhang M, Wu W, Zhou C: Numerical model of predicting surge boundaries in high-speed centrifugal compressors. Aerosp. Sci. Technol. 2023; 141: 108518. Publisher Full Text\n\nFontanesi S, Paltrinieri S, Cantore G: CFD analysis of the acoustic behavior of a centrifugal compressor for high performance engine application. Energy Procedia. Elsevier Ltd; 2014; 45. : 759–768. Publisher Full Text\n\nAghaei tog R, Tousi AM, Soltani M: Design and CFD analysis of centrifugal compressor for a microgasturbine. Aircr. Eng. Aerosp. Technol. 2007; 79: 137–143. Publisher Full Text\n\nMcLaughlin L, et al.: Numerical and experimental investigation of a radially reduced diffuser design concept for a centrifugal compressor performance at design point. Aerosp. Sci. Technol. 2022; 126: 107590. Publisher Full Text\n\nRomei A, Gaetani P, Persico G: Computational fluid-dynamic investigation of a centrifugal compressor with inlet guide vanes for supercritical carbon dioxide power systems. Energy. 2022; 255: 124469. Publisher Full Text\n\nFu J, Wang H, Bao H, et al.: Multi-parameter optimization for the performance of the fuel cell air compressor based on computational fluid dynamics analysis at part load. Therm. Sci. Eng. Prog. 2023; 44: 102057. Publisher Full Text\n\nGiuffre A, Colonna P, Pini M: The Effect of Size and Working Fluid on the Multi-Objective Design of High-Speed Centrifugal Compressors. Int. J. Refrig. 2022; 143: 43–56. Publisher Full Text\n\nGalindo J, Gil A, Navarro R, et al.: Analysis of the impact of the geometry on the performance of an automotive centrifugal compressor using CFD simulations. Appl. Therm. Eng. 2019; 148: 1324–1333. Publisher Full Text\n\nGasparin E, et al.: High-dimensional CFD optimization of a low-flow coefficient S–CO2 centrifugal compressor for enhanced oil recovery systems. Geoenergy Sci. Eng. 2023; 227: 211851. Publisher Full Text\n\nHong S, Chi J, Xiang X, et al.: Theoretical Model and Numerical Analysis of the Tip Leakage Vortex Variations of a Centrifugal Compressor. Aerospace. 2022; 9. Publisher Full Text\n\nQingyi S, Jian C, Bo Z: Performance prediction of centrifugal compressor based on a new volute loss model and corrected theoretical work. Energy Sci. Eng. 2023; 11: 685–698. Publisher Full Text\n\nFrigne P, Van den Braembussche R: A Theoretical Model for Rotating Stall in the Vaneless Diffuser of a Centrifugal Compressor. J. Eng. Gas Turbines Power. 1985; 107: 507–513. Publisher Full Text\n\nVan den Braembussche RA, Hände BM: Experimental and Theoretical Study of the Swirling Flow in Centrifugal Compressor Volutes. J. Turbomach. 1990; 112: 38–43. Publisher Full Text\n\nAyder E, Van den Braembussche R, Brasz JJ: Experimental and Theoretical Analysis of the Flow in a Centrifugal Compressor Volute. J. Turbomach. 1993; 115: 582–589. Publisher Full Text\n\nHansen KE, Jo̸rgensen P, Larsen PS: Experimental and Theoretical Study of Surge in a Small Centrifugal Compressor. J. Fluids Eng. 1981; 103: 391–395. Publisher Full Text\n\nHansen KE, Jo̸rgensen P, Larsen PS: Experimental and Theoretical Study of Surge in a Small Centrifugal Compressor. J. Fluids Eng. 1981; 103: 391–395. Publisher Full Text\n\nSun J, et al.: Theoretical and experimental study on effects of humidity on centrifugal compressor performance. Appl. Therm. Eng. 2020; 174: 115300. Publisher Full Text\n\nSun J, et al.: Theoretical and experimental study on effects of wet compression on centrifugal compressor performance. Appl. Therm. Eng. 2022; 212: 118163. Publisher Full Text\n\nZhang H, et al.: Experimental investigation of characteristics of instability evolution in a centrifugal compressor. Chin. J. Aeronaut. 2023; 36: 174–189. Publisher Full Text\n\nZhao B, Zhou T, Yang C: Experimental investigations on effects of the self-circulation casing treatment on acoustic and surge characteristics in a centrifugal compressor. Aerosp. Sci. Technol. 2022; 131: 108002. Publisher Full Text\n\nSharma S, Broatch A, García-Tíscar J, et al.: Acoustic characterisation of a small high-speed centrifugal compressor with casing treatment: An experimental study. Aerosp. Sci. Technol. 2019; 95: 105518. Publisher Full Text\n\nShu M, et al.: Experimental study on performance of centrifugal compressor exposed to pulsating backpressure. Aerosp. Sci. Technol. 2019; 95: 105450. Publisher Full Text\n\nYang M, Zhang K, Shu M, et al.: Experimental study on unsteady flow field in a centrifugal compressor at pulsating backpressure conditions. Aerosp. Sci. Technol. 2020; 106: 106168. Publisher Full Text\n\nGuo W, et al.: Experimental investigation on off-design performance and adjustment strategies of the centrifugal compressor in compressed air energy storage system. J. Energy Storage. 2021; 38: 102515. Publisher Full Text\n\nMeng C, et al.: Experimental and numerical investigation on off-design performance of a high-pressure centrifugal compressor in compressed air energy storage system. J. Energy Storage. 2022; 53: 105081. Publisher Full Text\n\nPark JH, Cha JE, Lee SW: Experimental investigation on performance test of 150-kW-class supercritical CO2 centrifugal compressor. Appl. Therm. Eng. 2022; 210: 118310. Publisher Full Text\n\nBarza T, Lakshmikanth G: Flow Simulation And Performance Analysis Of Centrifugal Compressor Using Cfd_Tool. J. Univ. Shanghai Sci. Technol. 2021; 23: 693–703. Publisher Full Text\n\nSrinivas G, Raghunandana K, Shenoy BS: Performance Evaluation of Transonic Axial Flow Compressor under Distorted Conditions by Groove Casing Technique with Tip Injection and Surface Roughness Effects. J. Inst. Eng. (India): C. 2022; 103: 895–911. Publisher Full Text"
}
|
[
{
"id": "289525",
"date": "26 Jun 2024",
"name": "Juluru Sandeep",
"expertise": [
"Reviewer Expertise My area of research is on CFD analysis of hypersonic intakes"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI would like to congratulate the authors for the effort made in the research of centrifugal compressor. I recommend following suggestions to improve the quality of paper: 1. Mention the version of ANSYS used. 2. All the figures should be enabled with axis system (x,y,z). 3. What is the source for Table 4 values? 4. In Figure 28, 29 what does the profile curves with numbers 7,8,9 indicates. 5. In the discussions change in parameter like increase or decrease is noticed but the cause for change is not clearly discussed.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "356229",
"date": "14 Jan 2025",
"name": "Ajith Raj",
"expertise": [
"Reviewer Expertise UAV Design and Aerodynamics",
"Dissimilar metal joints",
"Composite Materials."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have conducted a study titled \"Aerodynamic Performance Enhancement of Centrifugal Compressors Using Numerical Techniques.\" The findings of this research provide significant value to engineers, manufacturers, and regulatory bodies by offering critical insights and practical guidance to improve the performance and efficiency of centrifugal compressors. This study addresses a notable research gap in the comprehension and optimization of centrifugal compressors by examining the effects of blade number and hub diameter variations on key parameters such as pressure profiles, Mach number, and eddy viscosity. The methodology and results are presented with a commendable level of detail, and the percentage improvements achieved through optimization are well-aligned with expectations within this field. Still the authors can incorporate few suggestions given below before indexing.\n\n1. Consider adding specific numerical or comparative data to support the claim of \"36% improvement in pressure profile\" for better clarity in the abstract 2. Specifically, the reasons for flow separation observed in the pressure contours should be discussed in greater detail within the results and discussion sections. 3. Furthermore, the grid independence check performed across varying flow parameters, including temperature, pressure, and velocity, requires elaboration to clarify the significant variations noted. Despite these areas for improvement, the majority of the sections are well-constructed, providing comprehensive explanations aligned with the objectives of the study. The paper can be accepted with these minor changes.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-480
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https://f1000research.com/articles/12-76/v1
|
19 Jan 23
|
{
"type": "Research Article",
"title": "Online marketing and brand awareness for HEI: A review and bibliometric analysis",
"authors": [
"Sailaja Bohara",
"Vashali Bisht",
"Pradeep Suri",
"Diksha Panwar",
"Jyoti Sharma",
"Vashali Bisht",
"Pradeep Suri",
"Diksha Panwar",
"Jyoti Sharma"
],
"abstract": "Background: Many studies have been conducted on higher education institutions (HEI) regarding advertising, promoting, branding, social media marketing, and student enrollment. We investigated the gap in these studies by using bibliometric analysis and comprehensive science mapping in the field of HEI online marketing and brand awareness. Methods: The study used a web-based application, biblioshiny, which comes in the bibliometrix package. The study used the Scopus database to create the data set, given its conventional construction and quality of the sources. The analysis done is descriptive analysis. By using the bibliometrix software, the study showed the authors name, articles, sources, citations, relevant journals and co-citation from the year 2017 to 2022.The time period selected by the study was five years which means that articles published from 2017 to 2022 have been taken for the study. Results: We found that HEI online marketing and brand awareness have not been explored much. The study highlighted that HEI online marketing is a topic that has been developing but has not reached the stage of maturity. Publications on this topic have decreased since 2020. Also, the role of brand awareness in student enrollment decision for HEI requires more investigation. The ways in which brand awareness affects the choice of HEI should be studied. Most of the publications were from sources like higher education, higher education advertising and technology. Conclusions: This subject has been researched, but not much. This paper has given a path for interdisciplinary approaches that can be further explored in the field of higher education and marketing. Further, it gives opportunity to examine publications patterns through different authorships, co-authors, collaborations, relevant sources and citations. The insights of this paper will help education policymakers to devise more creative strategies to increase enrollment. This would give an in-depth understanding of this field to the readers.",
"keywords": [
"analysis",
"Brand awareness",
"Online marketing",
"Higher education institutions",
"Enrollment",
"Science mapping",
"Bibliometrix",
"Technology"
],
"content": "Introduction\n\nNowadays, higher education has become a very important part of life. People want to join higher education institutions (HEIs) and prepare themselves for a job and a better quality of life (Brooks et al., 2020). Students are the main customers of HEIs, and therefore their marketing strategies should be devised according to the needs of the students. Proper marketing strategies can affect the enrollment decision of the students (Farjam and Hongyi, 2015). Technology is imperative to have an upper hand as it guarantees the benefits and endurance of an organization. Before an organization can benefit from any technology, it should become aware of its presence and assess its capacities sufficiently. Technologies are not always created within the HEIs, but are outsourced by other companies; in the era of technology information, they are the key to success, which becomes a challenge for organizations, as they have to consider other external sources for getting the information (Von, 2005). The means of communication have changed, even within organizations, because of the emergence and rapidly growth of social media (Aral et al., 2013).\n\nThe marketing strategies and policies have changed over time. An organization is represented by the products and services that they are offering, and their success depends on their branding i.e the brand that they create. Branding gives the organization the liberty of being recognized by the customers and creates loyal customers. Thus, it increases the probability of being purchased by the customers (Ukaj, 2016). In the past, branding was only restricted to manufacturing companies and fast-moving consumer goods (FMCG). Now, this scenario has changed. Branding has diversified and has become imperative for HEIs as well. Brand awareness and service quality has to be developed side by side by HEIs to create brand loyalty (Abbas, 2019). There has been an increase in the student population who wants to attend higher education. This has created an intense competition between the colleges, be it nationally or internationally, for enrollment of the students (Smith et al., 2017). The population of student who wants to enroll for higher education studies are increasing drastically, because they get a chance to find work in the future from a,professional qualification, which they would get from the institution. The thirst for higher education has no boundaries set for these students, as the selection of a college also depends on their will to relocate themselves to get into the college they want. This factor has also increased the level of competition between these institutions (Hoxby, 2009 and Susanu and Raducan, 2014).\n\nA bibliometric analysis is carried out by analyzing the patterns of published literatures using statistical tools and mathematics (Singh and Dhir, 2019). It is a method that explores scientific data helping to understand emerging research areas (Donthu et al., 2021). It is a new concept in the field of business research and therefore, many researchers might not be able to make the full use of bibliometric analysis (Brown et al., 2020). According to Torraco (2005) it is not easy to arrange a literature review that is very effective in research studies. In the field of research, it is important to understand the gaps of the previous research work to gain access to more knowledge (Lee and Greenley, 2010). Paré et al., (2015) stated that a literature is effective only when it has made some contribution on the studies that has been conducted previously, and by identifying the areas where further research can be done. Scholars use bibliometric analyses for a variety of reasons, such as to uncover emerging trends in article and journal performance, collaboration patterns, and research constituents, and to explore the intellectual structure of a specific domain in the existing literature.\n\nOnline marketing and HEI\n\nDemand for education has evolved the education system and therefore, the number of colleges providing education. The competition is intense between these institutions; therefore, online marketing has become very important for these institutions. Further, our study found that online marketing affects the enrollment process of the higher education institution at all the different stages of the process (Bohara et al., 2022). Observations have shown that social media is pivotal to gain the attention of the students, keeping in touch with them and maintaining the current students. Using social media to communicate with the students may give a good impression about the college to the students (Omar. T Salem, 2020). According to Ashan (2017), as of late there is competition among colleges for enrolling undergraduates, which has made the colleges to regard students as their customer. The competitions and the demand for high-quality education have made it an important requirement to take on cautious marketing procedures for colleges.\n\nThe colleges have to be up to date with the kind of marketing strategies being used on the market by their competitors to look for any new opportunity that can be helpful to face the competition. Higher education today has recognized these promoting blended procedures to confront their opposition (Jalena Gajic, 2012). Higher education today has recognized these blended promotion strategies to confront their opposition (Jalena Gajic, 2012). The colleges need to supply the students, stakeholders and anyone who is looking into the college, with rich information as required. Online innovations have offered colleges with devices and techniques that can be utilized to satisfy these requirements (Alexa et al., 2012). In the present situation, colleges are excited about tracking down new ways and techniques for connecting with prospective students, their graduated class and different partners by utilizing Twitter (Kowalik, 2011). Internet promoting is an efficient method for publishing data and talk about the benefits that one would acquire from the college (Evans 2009). Marketing has provided more guidance to education institutions. With the utilization of better approaches for advertising strategies, student enlistment has expanded for colleges and has been valuable to see the progressions happening in education sector for colleges (Uncles, 2018). As per Joana and Maria (2018), colleges have been increasing their investments on internet showcasing. With the increasing utilization of web-based entertainment all over the planet, colleges must be active via online platforms like social media. Being present online doesn't mean simply having a webpage for the college. The college must be dynamic on it. It needs to allow and urge individuals to speak with one another and with the college. One thing that is essential for the colleges is to keep updating their materials and information on their social media site at the right time i.e publishing the right post at the right time (Peruta and Shields, 2018). As per Saichaie and Morphew (2014), where information about college is required, the website becomes imperative as it will give a better knowledge about the college and state the objective of education.\n\nThere are many advantages that are offered by online marketing that traditional marketing cannot offer. By online marketing achieving the requirements of the business and the users creating a relationships between the business and its customers and also, fulfilling the requirement of the data (Wilson and Makau, 2018).\n\nAccording to Bohara et al. (2022) there is an increase in the competition for enrollment between the colleges, which has made brand awareness an essential piece of their advertising movement. The study infers that there is a critical relationship between elements of brand awareness and students' college choice. The article allows to understand the role of brand awareness in each phase of enrollment decision. These organizations ought to look into brand awareness programs more as it might bring about the increment of undergraduates’ enlistment numbers. The review showed that brand awareness is significant for colleges as it influences every phase of student enrollment. Zhang (2020), stated that in the dynamic course of buyers, brand awareness is the basis of marketing activities. High brand awareness has an effect on the customer comprehension process such that they can with less exertion or doubt recollect and separate the brand from others. In the event of low brand awareness, it requires investment to affect the customer discernment process. In this way, buyers favor those organizations who have paid attention to brand to those who have not. Today the advancement of web innovation has changed how organizations and customers communicate through online media; it has united individuals from the entire world (Chatterjee and Kar, 2020). According to Patil (2017) having a brand name has become imperative in recent years, as people trust in the name of the brands and are able to connect and make decisions only when they are familiar with the name of the brand. Therefore, awareness for the name of the brand is necessary, as it will also make it easy for the customers to make decisions. Therefore, one can say that the amount of awareness that one creates about their brand affects the decision-making process of the consumers. Brand awareness may not just help in taking the decision in the favor of the brand, but also plays a role in creating loyal customers. With the technology shifting towards online platforms, brand awareness by means of using online media has also shown that it affects the decision-making process of the customers. So, brand awareness can be created by means of various online media to increase the probability for the product or the service to be purchased by the customers (Karam and Saydam, 2015). Brand awareness is also increased by means of online marketing strategies which have the probability of turning the customer in the favor of the brand and loyal (Hajarian et al., 2021). According to Mirzaei et al. (2016) the web page of a college is essential, and those that are active and put good information such as on the services, courses, scholarship information or any grants and other information that are helpful for the viewers, on their pages creates a good impression of their college in front of the students. Nevzat et al., (2016) stated that for colleges and universities, it is useful to use social media as it will help them to build a trustful relationship between them and the name of their college, and the.\n\nOnline marketing and brand awareness for higher education has been investigated by the various authors. They identified the research gaps in colleges and brand awareness, colleges and online marketing and college choice of students, but no bibliometric analysis has been done in these literatures. Therefore, this paper presents a bibliometric analysis using descriptive analysis.Bibliometric examination concentrates on utilizing numerical and factual procedures to analyze patterns in published literature reviews (Singh and Dhir, 2019).\n\n\nMethods\n\nThe data that one uses for bibliometric software are in larger volumes because they come from databases like Web of Science and Scopus. The bibliometric software have raised the interest of researchers in doing bibliometric analysis in the recent years. This analysis through bibliometric software can be done in different business fields and strategies (Kumar, et al., 2021). Literature reviews aim to assess the literature to recognize potential investigation gaps and highlighting information (Tranfield et al., 2003). The literature review helps to get the right kind of search keywords, previous literatures and thus, helps in complete analysis through bibliomatrix software (Saunders et al., 2009). Rowley and Slack (2004) suggested that there should be a structured method for the academic research study, and a design for structuring literatures, way of writing a research study and bibliography. Data needed for this study were extracted after identifying and selecting an appropriate database. For this study, the Scopus database was used and a search for keywords was carried out, as well as a combination of keywords, after which a software tool was used for statistical analyses. Data is used to conduct a descriptive analysis of documents, citations sources and authors (Ingale and Paluri, 2020). The flowchart for selection of documents for bibliometric analysis can be seen in Figure 1.\n\nThe study used descriptive analysis. To support the requirement of the software, the data was first downloaded from Scopus database. After this search strategy was used, keywords like ‘higher education institutions’, ‘online marketing strategies’, ‘online brand awareness’, and ‘college enrollment’ were used which extracted 20,000 documents, 4209 sources and types including articles and journals. In order to analyze publication trend, the study time period selected was from the year 2017 to 2022.\n\nSearch strategy for keywords\n\nThere were four keywords that was used in this study, these were, “online marketing strategy”, “online brand awareness”, “college enrollment”, and “higher education institution”. Knowledge of facts on online marketing and brand awareness done by higher education institutions impact on student enrollment were recognize using the search criteria for keywords. These were 1) online marketing of higher education, 2) online brand awareness, 3) online student enrollment 4) brand awareness and student enrollment. The combination was used to get appropriate studies. These combinations were made as they were all related to the topic of the research being conducted.\n\nRefined by- Scopus categories: (Social science, Business management and Psychology).\n\nDocument Type: Articles\n\nLanguage: English\n\nTime period: 2017 to 2022\n\nTime period\n\nThe trend and knowledge over five years were investigated for this study i.e. from 2017 to 2022. Online marketing has recently emerged as the fastest-growing type of marketing strategy, therefore the study focused on this time period.\n\nSubject category\n\nThree subjects were used in the refined search category:“Psychology”, “Business management”, and “Social science”. At this stage, 26,470 were extracted.\n\nLanguage filter\n\nAfter applying the language filter for English, the final documents were extracted by importing the authors, keywords, title and abstracts to biblioshiny and the final number of selected studies was 20,000 documents.\n\nA bibliometric technique was adopted in this study for a complete science mapping. This technique allows exhaustive bibliometric study that includes data analysis along with visualization. It is not simple to use bibliometric techniques as they require a commercial license to use the tools needed for conducting a bibliomatrix analysis and training to be used. Bibliometrix is an open-source programming which is intended for extensive science planning investigation. It is equipped for constant upgradate and combination with other R statistical packages. Thus, it is generally welcomed by clients (researchers, scholars and academics) and turns out to be profoundly important in the unique field of bibliometric analysis, for descriptive and network analysis. This study dissected the information utilizing Biblioshiny, which is an online application included in Bibliometrix package (Ingale and Paluri, 2020).\n\n\nResults\n\nThe study used descriptive analysis which has focused on bibliometric data:Author, sources and documents (Figure 2).\n\nData set\n\nTable 1 gives a view of the bibliometric frame; there were 4209 sources which published these documents. The average citation score per document was 4.597 and the collaboration index was 1.74 which indicates that the research was carried out with collaborating with other authors.\n\nSources\n\nFigure 3 shows the annual scientific production from the year 2017 to 2022.On this figure we can see a sharp surge in the publication volume from 2017 to 2018, as this field of research was gaining importance and was not fully completed i.e it did not reached the stage of saturation. After that, from 2018 to 2019 the topic was still being researched but not with a sharp surge, as the growth rate decreased. From 2019 to 2020 the research was ongoing but not increasing sharply, with a low production on this field, but after 2020 to 2021 again a sharp surge in the publication volume could be seen which eventually decreased from 2021 to 2022.\n\nIn Figure 3, one can see that in 2020 there was a sharp surge, meaning that there were studies being published at this stage, although this was during the coronavirus disease 2019 (COVID-19) pandemic that hit the world in 2020. After, this the graph slopes downwards showing that the production has fallen recently.\n\nIn Figure 4, the top 20 globally most cited documents can be seen. Sustainability, International Journal of Education, Journal of advertising, were at the top of the list. In Figure 5, we can see the most relevant sources in which sustainability, studies in higher education, higher education, international journal of sustainability in higher education are at the top of the list. Looking at this information we can say that most of the words used here were related to higher education, higher education and technology, advertising, information and online learning.\n\nFigure 6 shows the effect of these journals. The H-index refers to a most extreme value of \"n\". Now, \"n\" refers to the number of journals which have articles published with the least citations. H-index indicates the quality of the journal as well as its impact.\n\nAuthors\n\nIn Figure 7, the top three most relevant authors were A. Aleksander,L. Mishra, and Lou, with the maximum number of publication. The H-index of these authors and citation were also higher, which shows their relevancy. This can be seen in Figure 8.\n\nDocuments\n\nFigure 9 shows the most cited documents with the author’s name, in this field. There was no article with less than 100 citations and Aristovnik, Mishra and Lou had more than 300 citations. These articles were about advertising, which covered branding and online marketing, higher education and higher education institution.\n\nThe main words that were used were “brand awareness”, “higher education institution”, “online marketing strategies”, “online brand awareness and “college enrollment”. Also, to get a better result, words were combined and used for searching. These combinations were 1) online marketing of higher education, 2) online brand awareness, 3) online student enrollment 4) brand awareness and student enrollment. The combination was used to get the appropriate studies. For example, brand awareness and student enrollment yielded studies related to brand awareness effect on enrollment of students, online marketing showed the various online marketing strategies for online brand awareness and enrollment, and so on. During the search we ensured that all the required work in the study was covered. Subjects included were social sciences, business management and psychology.\n\n\nDiscussion and conclusions\n\nParé et al. (2015) stated that a publication is effective only when it has made some advancement on the studies that have been conducted previously and also, by identifying the areas where further research can be done. Scholars use bibliometric analysis for a variety of reasons, such as to uncover emerging trends in article and journal performance, collaboration patterns, and research constituents, and to explore the intellectual structure of a specific domain in the existing literature. The results show that from 2017 to 2022 for HEIs, marketing and advertising has become important and they have been using them. The previously published literature was used for analysis to retrieve the important sources, writers and records. The bibliometrix R package, which is a valuable tool for bibliometrics was chosen due to its adaptability and ease of use. The Scopus data base was used for creating the data set, given its conventional construction and quality sources of the journals. According to the data, papers were published on these topics but had not reached the stage of maturity; however,in the year 2020 there was a sharp increase in the publication, which eventually went down after thatyear. In 2020, the world was hit by the COVID-19 pandemic and the educational institutions were closed for some time, but later on the situation had forced the institutions to use digital platform. The COVID-19 pandemic caused countless setbacks around the world, with significant social and financial effects. UNESCO reported that around one billion students had been compelled to remain at home because of the crisis, and the scale and speed with which schools and colleges had been shut was overwhelming (Giancola and Piromalli, 2020). To face this crisis, even the schools and colleges could not stop from transferring their activities into digital platforms (Turcanu et al., 2020). The majority of the publications was from sources like higher education, higher education advertising and technology. This paper, therefore, has given a path for interdisciplinary approaches that can be further explored in the field of higher education and marketing. Further, this paper was an opportunity to examine the pattern of publications by investigating the different authorship, co-authors, collaborations, relevant sources and citations. The insights of this paper will help education policymakers to devise more creative strategies to increase enrollment. This would give an in-depth understanding of this field. Further, for academic researchers, this paper will open many ways in which one could explore and contribute in the educational industry by diversifying the research in areas, where the publications have not reached their maturity level. A combination of keywords was used in this paper: 1) online marketing of higher education, 2) online brand awareness, 3) online student enrollment 4) brand awareness and student enrollment. The bibliometric analysis showed that higher education and marketing are topics which have been explored, resulting in related papers being published, but effects of online marketing of higher education on students’ enrollment and brand awareness role in higher education and its importance are areas which have not been explored. So, our study gives a path for further research.\n\nThe study used a bibliometric analysis, but only descriptive analysis has been done. So, this study can be examined further by using network analysis. Further, the database used for this study was Scopus, although there are other good databases that also can be used like Web of Science. From this study, we can see that there are not many publications that involve higher education, online marketing and brand awareness and student enrollment all together, while nowadays these are the strategies that help the colleges face competition. There is a need to explore the contribution from scholars and practitioners in this field for getting deeper theoretical and practical insights.",
"appendix": "Data availability\n\nFigshare: Online Marketing And Brand Awareness For HEI: A Review And Bibliometric Analysis, https://doi.org/10.6084/m9.figshare.21276603 (Bohara et al., 2022) This project contains the following underlying data:\n\n• Data file 1. (CSV. File of the bibliometric analysis done using Scopus database)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nAbbas AS: Brand Loyalty of Higher Education Institutions. Marketing and Management of Innovations. 2019; 1(4): 46–56. Publisher Full Text\n\nAlexa L, Alexa M, Stoica MC: The Use of Online Marketing and Social Media in Higher Education Institutions in Romania. Journal of Marketing Research and Case Studies. 2012; 1–9. Publisher Full Text\n\nAral S, Dellarocas C, Godes D: Introduction to the Special Issue—Social Media and Business Transformation: A Framework for Research. Information Systems Research. 2013; 24(1): 3–13. Publisher Full Text\n\nAshan A: Determining Students’ Choice Factors for Selecting Higher Private Education Institution. Asian Journal of Applied Science and Engineering. 2017; 6(2).\n\nBohara S, Gupta A, Panwar D: Relationship Between Factors of Online Marketing and Student Enrollment Decisions in Higher Education: An Analysis Using Structural Modeling Techniques. International Journal of Online Marketing. 2022a; 12(1): 1–18. Publisher Full Text\n\nBohara S, Suri P, Panwar D: Impact of brand awareness on enrollment decision process moderated by students’ gender for HEI. Journal of Content, Community and Communication. 2022b; 15(8).\n\nBohara S, Suri P, Panwar D, et al.:Online Marketing And Brand Awareness For HEI: A Review And Bibliometric Analysis. figshare. Dataset.2022c. Publisher Full Text\n\nBrooks R, Gupta A, Jayadeva S, et al.: Students’ views about the purpose of higher education: a comparative analysis of six European countries. Higher Education Research & Development. 2020; 40: 1375–1388. Publisher Full Text\n\nBrown T, Park A, Pitt L: A 60-year bibliographic review of the Journal of Advertising Research: Perspectives on trends in authorship, influences, and research impact. Journal of Advertising Research. 2020; 60(4): 353–360.\n\nChatterjee S, Kar AK: Why Do Small And Medium Enterprises Use Social Media Marketing And What Is The Impact: Empirical Insights From India. International Journal of Information Management. 2020; 53(1): 102103.\n\nDonthu N, Kumar S, Mukherjee D, et al.: How to conduct a bibliometric analysis: An overview and guidelines. Journal of Business Research. 2021; 133: 285–296. Publisher Full Text\n\nFarjam, Hongyi: Revising Students' Decision-making Process. International Journal of Management Science and Business Administration. 2015; 1(10): 70–78.\n\nGajic J: Importance of marketing mix in higher education institutions. Singidunum Journal of Applied Science. 2012; 9(1): 14–21.\n\nGiancola O, Piromalli L: The Impact of the COVID-19 Pandemic on the Use of Digital Technologies in Ensuring the Efficient e-Learning Process at the Technical University of Moldova. Creative Education. 2020; 10(11).\n\nHajarian M, Camilleri MA, Díaz P, et al.:A Taxonomy of Online Marketing Methods.Camilleri MA, editor. Strategic Corporate Communication in the Digital Age. Bingley:Emerald Publishing Limited;2021; pp. 235–250. Publisher Full Text\n\nHoxby C: The Changing Selectivity of American colleges. The Journal of Economic Perspectives. 2009; 23(4): 95–118. Publisher Full Text\n\nIngale KK, Paluri AR: Financial literacy and financial behaviour: a bibliometric analysis, Review of Behavioural Finance. Emerald Publishing Limited;2020; 1940–5979. Publisher Full Text\n\nKaram AA, Saydam S: An Analysis Study of Improving Brand Awareness and Its Impact on Consumer Behavior Via Media in North Cyprus (A Case Study of Fast Food Restaurants). International of Business and Social Sciences. 2015; 6(1).\n\nKowalik E:Engaging alumni and prospective students through social media.Wankel L, Wankel C, editors. Higher education administration with social media. Emerald Group Publishing;2011; (pp. 211–227). Publisher Full Text\n\nKumar S, Lim WM, Pandey N, et al.: 20 years of Electronic Commerce Research. Electronic Commerce Research. 2021; 21(1): 1–40. Publisher Full Text\n\nLee N, Greenley G: The theory-practice divide: thoughts from the editors and senior advisory board of EJM. European Journal of Marketing. 2010; 44(1/2): 5–20.\n\nMirzaei A, Siuki E, Gray D, et al.: Brand associations in the higher education sector: The difference between shared and owned associations. Journal of Brand Management, Palgrave Macmillan. 2016; 23(4): 419–438. Publisher Full Text\n\nMotta J, Barbosa M: Social Media as a Marketing Tool for European and North American Universities and Colleges. Journal of International Management. 2018; 10(3): 125–154. Publisher Full Text\n\nNevzat R, Amca Y, Tanova C, et al.: Role of social media community in strengthening trust and loyalty for a university. Computers in Human Behavior. 2016; 65: 550–559. Publisher Full Text\n\nParé G, Trudel MC, Jaana M, et al.: Synthesizing information systems knowledge: A typology of literature reviews. Information andManagement. 2015; 52(2): 183–199.\n\nPatil P: Brand awareness and Brand preference. International Research Journal of Management and Commerce. 2017; 4(7).\n\nPeruta A, Shields AB: Marketing your university on social media: a content analysis of Facebookpost types and formats. Journal of Marketing for Higher Education. 2018. Publisher Full Text\n\nSaichaie K, Morphew CC: What College and University Websites Reveal about the Purposes of Higher Education. The Journal of Higher Education. 2014; 85(4): 499–530. Publisher Full Text\n\nSalem OT: Social Media Marketing in Higher Education Institutions. Journal of Sea Research Practical Application of Science. 2020; VIII(23): 191–196.\n\nSaunders M, Lewis P, Thornhill A:Research Methods for Business Students.New York:Pearson;2009.\n\nSingh S, Dhir S: Structured review using TCCM and bibliometric analysis of international cause-related marketing, social marketing, and innovation of the firm. International Review on Public and Nonprofit Marketing. 2019; 16(2–4): 335–347. Publisher Full Text\n\nSmith J, Pender M, Howell J: Competition among Colleges for Students across the Nation. Southern Economic Journal. 2017; 84(3): 849–878. Publisher Full Text\n\nSusanu I, Raducan M:The analysis of high school students’ behaviour in the selection of Higher Education Institutions.Risk in Contemporary Economy, “Dunarea de Jos” University of Galati, Faculty of Economics and Business Administration.2014; pp. 175–182.Reference SourceReference Source\n\nTorraco RJ: Writing integrative literature reviews: Guidelines and examples. Human Resource Development Review. 2005; 4(3): 356–367. Publisher Full Text\n\nTranfield D, Denyer D, Smart P: Towards a Methodology for Developing Evidence: Informed Management Knowledge by Means of Systematic Review. British Journal of Management. 2003; 14: 207–222. Publisher Full Text\n\nȚurcanu D, Siminiuc R, Bostan V: The Impact of the COVID-19 Pandemic on the Use of Digital Technologies in Ensuring the Efficient e-Learning Process at the Technical University of Moldova. Creative Education. 2020; 11: 2116–2132. Publisher Full Text\n\nUkaj F: The Role and Importance of Brand in the Marketing of Small and Medium-Sized Enterprises in Kosovo. International Journal of Marketing Studies. 2016; 8: 52. Publisher Full Text\n\nUncles MD: Directions in higher education: A marketing perspective. Australasian Marketing Journal. 2018; 26(2): 187–193. Publisher Full Text\n\nVon Hippel E: Democratizing Innovation. Cambridge, MA:MIT Press;2005.\n\nWilson V, Makau C: Online Marketing Use: Small and Medium Enterprises (SMEs) Experience from Kenya. The Operations Research Society of East Africa Journal. 2018; 7(2): 63–77.\n\nZhang X: The Influences Of Brand Awareness On Consumers’ Cognitive Process: An Event-Related Potentials Study. Frontiers in Neuroscience. 2020; 14: 549. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "176356",
"date": "22 Jun 2023",
"name": "Sanjib Biswas",
"expertise": [
"Reviewer Expertise Decision Science",
"Operations Management"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe topic is interesting. Thank you for providing me an opportunity to go through the article. The authors are requested to address the following concerns:\nThe introduction section is too short to establish the research rationale and the contribution of the paper.\n\nThe author should use a theoretical framework lilke PRISMA for scientifically describing the research design.\n\nNetwork analysis could have been better.\n\nPlease extensively elaborate on the discussion and future direction section.\n\nAlthough the authors referred to Scopus and WoS database, the present article needs to address some important articles in the stated area (not published in Scopus but available in google scholar). For instance: Biswas (20201).\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "11390",
"date": "21 Jun 2024",
"name": "Sailaja Bohara",
"role": "Author Response",
"response": "The suggestions given has been taken into consideration."
}
]
},
{
"id": "256295",
"date": "29 Mar 2024",
"name": "Arun Vijay Subbarayalu",
"expertise": [
"Reviewer Expertise Higher Education Quality Management",
"Healthcare Management."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI would like to express my special thanks to the editors for providing me with the opportunity to review this manuscript.\n\nThe authors have made a good effort in exploring the concepts of online marketing and brand awareness for higher education institutions (HEI) through a bibliometric approach. I acknowledge the efforts made by the authors in bringing out this study. However, there are still some issues that need to be addressed before it can be accepted for publication in F1000 Research.\nI have provided my comments with regard to each section of the manuscript. Recommendations to be addressed by the authors in the manuscript is given below:\n\nAbstract Section:\nBackground: Write the objective of this study clearly to inform the readers what you want to accomplish through this bibliometric study. In the method section, it was mentioned that five years were covered. Nevertheless, the coverage period is six years, from 2017 to 2022. In the results, the author needs to reflect significant findings in the form of data observations retrieved from this study, as the abstract is a concise version (summary) of the manuscript.\n\nIntroduction Section\nIt was stated on page 4 that no bibliometric study was done earlier on this topic of study. However, several other studies have been found in the literature on similar lines of research. It would be better to state the research gap concerning the utility of bibliometric analysis focusing on online marking and brand awareness using various databases such as Scopus and WoS. In the introduction, the author has to justify why this study was conducted and what it attempts to fulfill (considering the gap identified by earlier studies).\nMethods Section\nMention the study design adopted in the methods section. Mention the key terms and Boolean operators used for electronic search criteria within the Scopus database. Also, include the Scopus query used to retrieve the data. Mention the inclusion criteria used to screen documents to be included in the bibliographic analysis within the text under the search strategy. It is essential to mention the date you carried out the search and downloaded the data since it could be replicated by other researchers in the same or other fields. On page 6, under the bibliometric tool, add the software name Biblioshiny in Rstudio. The authors did not mention the Scopus downloaded data type. (For example. CSV or BibTex). Mention it. Mention it.\nResults\nWrite a short note about the retrieved information studied to reflect on the Author, sources, and documents, as mentioned in Figure 2. On page 8, it was mentioned that in Figure 4, the top 20 globally most cited documents can be seen. Sustainability, International Journal of Education, Journal of Advertising, (mismatch). This information does not match the figure-4 provided on page number 8. Correct and update it. Mention the Author's Full name in Figures 7 and 8. It is recommended that a table showing the top 10 authors with their affiliation, frequency (number of documents), percentage (%) of publication concerning the total, and the total citations received by each Author be created. Besides Figure 6, a table showing the top journals published documents related to online marketing and brand awareness for HEI by various authors between 2017 and 2022 would be desirable. Besides Figure 9, it is recommended to create a table showing the top cited documents with their Digital Object Identifier (DOI), total citations received per document, and citations received per year for the clarity of the readers. You can take the top 10 highly cited documents.\nDiscussion Section.\nThe discussion of findings needs to be elaborated. The authors need to discuss the major findings about the author, sources, and documents, critically appraise, and conclude them. Under the direction of the future research section, consider adding future studies that could focus on country-wise scientific output on online marketing and brand awareness for HEI by various authors, keyword analysis using VOSviewer, and author collaborations on the same research topic.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11391",
"date": "21 Jun 2024",
"name": "Sailaja Bohara",
"role": "Author Response",
"response": "All the suggestions given have been taken into consideration and all the necessary changes as suggested have been made."
}
]
}
] | 1
|
https://f1000research.com/articles/12-76
|
https://f1000research.com/articles/13-474/v1
|
13 May 24
|
{
"type": "Research Article",
"title": "Environmental reservoirs of multidrug-resistant pseudomonads in a geographical location in Kenya with high community-acquired infections",
"authors": [
"Polly Mubassu",
"Abednego Musyoki",
"Erick Odoyo",
"Collins Kigen",
"Lillian Musila",
"Abednego Musyoki",
"Erick Odoyo",
"Collins Kigen"
],
"abstract": "Background Pseudomonads are gram negative bacteria and readily form biofilms in the environment, allowing long-term colonization and persistence in sinks, water systems. They pose a risk of life-threatening opportunistic infections in immune-compromised individuals. MDR strains, make treatment increasingly difficult. Environmentally persistent MDR strains are typically problematic within healthcare facilities, however, data on MDR pseudomonad reservoirs in settings with community-acquired infections to inform preventive interventions, in resource-constrained settings is scarce. Here, we determined reservoirs and antibiotic susceptibility of Pseudomonas species in water sources in Kisumu County, Kenya with reported high levels of community acquired pseudomonad infections.\n\nMethods We adopted a cross-sectional design, randomly collecting 297 samples from tap heads, sinks, tanks, vendor and household storage containers in six selected sub-locations and one hospital (KCRH). Standard microbiological procedures were used for identification and AST of the isolates.\n\nResults We isolated Pseudomonads from 14.1% of the samples collected, predominantly from the community 10.4%. Seven different pseudomonads were identified, with Pseudomonas aeruginosa predominating 6.7% overall, in the community samples 5.7%, and among isolates from water tanks 21.4%. Pseudomonad isolates were 62% non-susceptible to piperacillin, 57% to tigecycline, 24% meropenem, 21% cefepime, 19% levofloxacin and 14% colistin. Carbapenem resistance was mainly detected in P. aeruginosa 80% (8/10) from Milimani sub-location 75% (6/8). 45% of the isolates recovered were MDR, mainly community-associated carbapenem-resistant P. aeruginosa (CRPA) 42%, strains susceptible to colistin. The MDR pseudomonads exhibited high multiple antibiotic resistance indices, ranging from 0.43 to 1.\n\nConclusion This study reveals a higher prevalence of MDR pseudomonads, including CRPA strains in community water sources. These potential conduits of drug resistance present a critical public health threat, especially among immunocompromised. Regular cleaning of water storage facilities, water treatment and implementation of antimicrobial stewardship programs, are required to prevent a rise in AMR and eliminate the environmental reservoirs that put the vulnerable populations at risk.",
"keywords": [
"Pseudomonads",
"multidrug resistance",
"environmental reservoirs",
"carbapenem-resistant Pseudomonas aeruginosa"
],
"content": "1. Background\n\nPseudomonads are gram-negative bacteria, ubiquitous in water soil, and decaying vegetation and frequently isolated from healthy persons’ skin, throat and stool. They comprise several clinically relevant species, including P. maltophilia, P. fluorescens, P. cepacia, P. stutzeri, P. putrefaciens, and P. putida,1,2 with P. aeruginosa as the most common among these opportunistic pathogens. Pseudomonads form biofilms that confer protection from environmental stresses, including antibiotics and detergents, allowing long-term colonization and persistence in sinks, municipal drinking water systems, hot tubs, and swimming pools.3,4\n\nPseudomonads pose a substantial risk of acute and chronic life-threatening multidrug-resistant (MDR) infections such as ventilator-associated pneumonia, community-acquired pneumonia, bloodstream infection, urinary tract infections, and skin and soft tissue infections among elderly individuals and those with cystic fibrosis, cancer, HIV, and diabetes.5–9 Outbreaks of P. aeruginosa infections have been associated with tap water,10 bottled water,11 hand-washing basin water,12 surface cleaning equipment,13 therapy equipment such as catheters, humidifiers,14 sinks,15 and swimming pools.8\n\nTreatment of infections caused by Pseudomonas species is increasingly difficult due to the rapid emergence of multidrug resistance, even during therapy courses.16 The resistance occurs mainly through reduced outer membrane permeability, expression of efflux pumps that transport antibiotics extracellularly, biofilm formation, and the production of beta-lactamases, and occasionally plasmid-borne enzymes. Of these enzymes, carbapenemases pose a public health concern because they inactivate carbapenems, which are among the antibiotics of last resort for infections caused MDR Gram-negative bacteria (GNB).17,18\n\nMDR P. aeruginosa clinical strains that are carbapenem-resistant (CR) are increasingly reported in Kenya19–21 The available treatment options for CR-GNB include colistin and tigecycline, with colistin rarely used due to high toxicity and low efficacy concerns. Increased resistance to both drugs is growing with the emergence of resistant strains. Newer options for infections caused by CR-GNB include combinations of beta-lactam-beta-lactamase inhibitors (BL-BLI) such as meropenem-vaborbactam, ceftazidime-avibactam, imipenem-sulbactam, and ceftolozane-tazobactam22; however, these drugs face challenges due to insufficient high-quality clinical data, delayed approval for susceptibility testing methods, antibacterial spectra complexity, and acquisition costs.23 Therefore, preserving the clinical value of carbapenems through local, global and national mitigation strategies remains critical.\n\nAlthough Pseudomonas spp. are significant clinical pathogens,21,24–26 information on the occurrence of MDR isolates in water sources and moist environments in community and hospital settings which could serve as reservoirs for human infections in Kenya is scarce.27 In this study, we aimed to identify reservoirs and antibiotic susceptibility of Pseudomonas spp in community and hospital environments in Kisumu County where community-associated infections have been reported at the county referral hospital.\n\n\n2. Methods\n\nApproval to conduct this study was obtained from the Kenyatta University’s Graduate School, Kenya Medical Research Institute-Scientific Ethics Review Unit (KEMRI/SERU/CCR/0190/4117 dated February 15th 2021) and the National Commission for Science, Technology and Innovation (NACOSTI/P/20/4221). Verbal consent was obtained and it was approved by KEMRI/SERU to collect samples from households, water distribution points owners and Kisumu County Referral Hospital management.\n\nWe conducted this study in the Kisumu County Referral Hospital (KCRH) and six sub-locations within Kisumu County (Figure 1), with the sites chosen based on data from an ongoing study by Musila et al., on antimicrobial resistance in military and civilian populations in Kenya (SSC 2767 WRAIR 2089), where it was observed that the majority of Pseudomonas aeruginosa infections were community-acquired (unpublished data).\n\nWe adopted a cross-sectional study design with a random sampling strategy to obtain 297 (100 water and 197 swab) samples from KCRH and six sub-locations; Milimani, Nyalenda A, Nyalenda B, Manyatta, Manyatta B, and Kaloleni within two (2) weeks in April 2021. Seven households, two public schools and two communal water distribution points from each sub-location were randomly selected and 77 water and 172 swab samples from taps, shower heads, tanks (>1000 litres external), water storage containers (20 liters) and sinks were collected. In KCRH, a total of 48 samples were collected from taps, sinks and shower heads in the male general, surgical, pediatric and maternity wards, and from water reservoir tanks.\n\nWe collected water samples in clean and sterile screw-capped 250 mL GosselinTM polypropylene bottles containing 0.1 N of 30mg sodium thiosulphate (Thermofisher scientific Catalogue No: 15103917) by disinfecting the tap using 70% ethanol (plastic taps) or flaming (metal taps), and allowing the water to run for a few minutes before sampling. Swab samples of tap outlets, sink basins, shower heads, and interior of tanks and containers were collected using an environmental sampling kit (Puritan ESK, Guilford, ME, USA) as described by Schiavano and others.8 All samples were transported in a cool box (4-6°C) to the KCRH -based USAMRD-A laboratory in Kisumu for processing within 2 hours.\n\nWe processed the study samples following standard procedures outlined by the UNI EN ISO 16266:2008 standard on the detection and enumeration of P. aeruginosa method by membrane filtration.28 Briefly, 100 mL of water was filtered through 0.45 μm, 47mm diameter cellulose ester membrane (MF-Millipore, Merck, KGaA, Darmstadt, Germany) to concentrate the bacteria, and the membranes were placed directly onto CHROMagarTM Pseudomonas media (Becton Dickinson, France) and aerobically incubated at 37°C for 18 hrs. Blue or green pyocyanin-producing colonies were considered presumptive P. aeruginosa and fluorescent non-pyocyanin-producing colonies as other pseudomonads. The colonies were sub-cultured on Mueller Hinton Agar (MHA) Nutriselect® Plus (Merck KGaA, Darmstadt, Germany) and screened by Gram staining and oxidase testing. All the oxidase-positive isolates were identified on the VITEK 2® automated platform (bioMèrieux, Marcy I’Etolie, France) using the GN-ID card, and the O-Acetylase antigen-based PCR29 was used to distinguish P. aeruginosa from other pseudomonads.\n\nThe VITEK 2 AST-XN05 card was used for antimicrobial susceptibility testing (AST) and interpreted based on the clinical laboratory standards institute guidelines of 2022.30 P. aeruginosa ATCC 27853 and E. coli ATCC 25922 were used as positive and negative controls, respectively. The antibiotics panel included ticarcillin/clavulanic acid (8/2-128/2 μg/ml), piperacillin (4-128 μg/ml), ceftriaxone (0.25-64 μg/ml), cefepime (0.12-32 μg/ml), meropenem (0.25-16 μg/ml), levofloxacin (0.12-8 μg/ml), tigecycline (0.5-8 μg/ml) and chloramphenicol (4-64 μg/ml) on (AST-XN05, 26247, bioMèrieux, Marcy IÉtolie, France). For the colistin AST, the standard Cation adjusted Muller Hinton broth (CAMHB) method was used as described in the CLSI guidelines, with a known mcr-1 positive E. coli and ATCC 27853 as positive and negative control organisms, respectively.\n\n\n3. Data analysis\n\nWe captured, compiled and analyzed the study data using MS Excel spreadsheet (Microsoft office 2019)31 bar graphs were generated on the same software. This study defined MDR pseudomonads as isolates resistant to 3 or more classes of antibiotics,28 and we calculated the multiple antibiotic resistance indexes (MARI) as described by Davis and Brown32: a/b where ‘a’ was the number of antibiotics to which an isolate exhibited resistance against those it was exposed to ‘b’, for susceptibility.\n\n\n4. Results\n\nThe highest proportion of samples were collected from the community (83.8%, n=249), drawn mainly from water storage containers (33%, n=98) and taps (24%, n=72) distributed across the different sub- locations and KCRH hospital in Kisumu county (Table 1).\n\nIn this study, we isolated pseudomonads from 14.1% (42/297) of the samples collected, predominantly from the community samples (10.4%, 31/297), and identified seven7 different species namely; P. aeruginosa, P. fluorescens, P. putida, P. fluorescens, P. oleovarans, P. mendocina and P. stutzeri. Pseudomonas aeruginosa was the most common species overall (6.7%, 20/297) and in the community samples (5.7%, 17/297). P. mendocina, P. alkaligens and P. putida were only detected in the community samples. P. fluorescens (2.0%, 6/297) was the main species in the hospital samples and P. oleovarans was exclusive to the hospital (Figure 2).\n\nWe found pseudomonads in all the study sampling sources, predominantly in taps and sinks (33.3%, 14/42). P. aeruginosa was the most common species in tanks (21.4%, 7/42) but was not isolated from vendor containers, household storage containers, or water distribution outlets, Figure 3A.\n\nGenerally, the prevalence and distribution of Pseudomonas spp. varied in all the study sub-locations. The highest prevalence was observed in Milimani (35.7%, 15/42), KCRH (26.2%, 11/42), and Manyatta B (19%, 8/42). P. aeruginosa was predominant in Milimani (28.6%, 12/42), with a few isolates from KCRH and Manyatta but was not isolated in Nyalenda A, Nyalenda B, and Manyatta A (Figure 3B). The greatest diversity of Pseudomonas spp. was observed in taps, KCRH and in Kaloleni sub-location.\n\nHouseholds accounted for 67.7% of the 31 pseudomonads isolated in the community environment, with the majority from taps (32.3%), sinks (22.6%), and tanks (19.4%). P. aeruginosa was the predominant species, recovered mostly from sinks (16.1%) and taps (12.9%) but absent in vendor containers, boreholes, and tank samples. Similarly, P. aeruginosa was the leading isolate (16.1%) in schools, within taps and boreholes (Figure 4).\n\nIn the hospital environment, the majority of pseudomonads (36.4%, 4/11) were isolated from swab samples from the tank (27.3%, 3/11) and tap water (9.1%, 1/11). Tank swabs were the only source of P. aeruginosa in hospital samples, Figure 5.\n\nPseudomonads isolates were 62% (26/42) non-susceptible to piperacillin, 57% (24/42) to tigecycline, 21% (9/42) to cefepime, 19% (8/42) to levofloxacin and 14% (6/42) to colistin (Table 2). Carbapenem resistance (non-susceptibility to meropenem) was 24% (10/42), mainly recorded in P. aeruginosa (80%, 8/10) from the Milimani sub-location (75%, 6/8). Six isolates (6/42 15%), were non-susceptibility to colistin and were mainly P. putida (50%, 3/6), with P. fluorescens (17%, 1/6) exhibiting resistance to both meropenem and colistin. A single isolate grew poorly during the VITEK 2 AST analysis and were indicated as a ‘terminated result’ (TRM) with 3 repeats.\n\nIn this study, 45% (19/42) of the isolates were MDR, predominated by carbapenem-resistant P. aeruginosa (CRPA) (42%, 8/19) and carbapenem-susceptible P. putida (26%, 5/19) mainly from the community samples (Table 3). All MDR CRPA remained susceptible to colistin and were isolated from the Milimani sub-location (80%, 8/10). P. oleovarans, P. alcaligens, P. mendocina, and P. stutzeri were non-MDR, whereas MDR P. putida were carbapenem-susceptible. MDR-pseudomonads exhibited high multiple antibiotic resistance indices (MARI), ranging from 0.43 to 1.\n\n\n5. Discussion\n\nPseudomonas aeruginosa is a well-studied opportunistic Pseudomonad with a predilection to cause infections in vulnerable populations such as immunocompromised individuals. The global rise in MDR P. aeruginosa, particularly the carbapenem-resistant strains, pose a critical public health challenge due to limited treatment options. In our study setting in Kisumu county, Kenya, P. aeruginosa and other pseudomonads were previously isolated from patients who acquired them in the hospital and in the communities, prompting the need to identify their environmental reservoirs and antibiotic susceptibility patterns to inform the design of targeted infection prevention and control (IPC) interventions both in the community and hospital environments. This study identified pseudomonads in the water sources from the community (schools, households, water distribution points) and the KCRH hospital within Kisumu county at a rate of 14% (42/297). In these water sources P. aeruginosa was the most prevalent species (6.7%), being isolated from tanks (19%, 7/36), borehole (17%, 1/6), sinks (16%, 6/37) and taps (6%, 6/98). A study by Opperman33 reported Pseudomonas in stagnant water, which presents a conducive environment for its proliferation through formation and dissemination of biofilms.34 In the current study, we did not recover P. aeruginosa from water storage containers both in homes and from water vendors, probably due to the shorter static period of water in these containers, considering that these containers were used for ferrying water as opposed to holding it for long periods. Colonization at the point of use, including tap heads, plays a critical role in P. aeruginosa infections as opposed to the water distribution system.35 These data suggest that community interventions should be focused on long- term storage receptacles and piping systems that terminate in tap heads.\n\nIn the community setting, the occurrence of P. aeruginosa varied among the sampled sub-locations, with 65% (13/20) of the isolates derived from Milimani sub-location, mainly in households (69%, 9/13) and school (31%,4/13). This observation could be attributable to the high coverage of old water plumbing systems, probably made of materials that allow for accumulation of biofilms.35 Sink/tap contamination may also be another factor,27 considering that Milimani had the highest water distribution coverage with more than 85% (6/7) of sampled households having multiple plumping fixtures (taps and sinks) as well as consistent flow of piped water. This suggests that regular cleaning and removal of biofilms from old plumbing systems such as those found in Milimani sub-location could reduce the risks of P. aeruginosa infections.\n\nAn interesting observation was that the same species of pseudomonads were isolated at different sampling points within the same household in three of the houses in Milimani, highlighting the possibility of cross-contamination at the household level as opposed to water distribution system contamination. We isolated no pseudomonad from Nyalenda A and B sub-locations, where up to 10 households used single stand-alone taps commonly located in an open space with no associated sinks or drains. We had a similar observation from households using short-term water holding and ferrying 20-litre-containers. These findings suggest the role of sinks and drains in pseudomonads transmission in communities.\n\nIn this study, we isolated P. fluorescence, P. oleovarans, P. alcaligenes, P. mendocina, P. putida and P. stutzeri in water sources at a prevalence of 7.4% (22/297). Even though not as common as P. aeruginosa, these pseudomonads were previously isolated from clinical specimens in KCRH and elsewhere, with P. stutzeri reported in wound and blood,36 P. putida in neonatal bacteremia and sepsis,37 P. fluorescens in respiratory infections,38 P. alcaligenes in bloodstream infections,19 and P. mendocina in infective endocarditis and central nervous system infections among others.20 These findings highlight the increasing clinical importance of non-P. aeruginosa pseudomonads and the need to track their environmental reservoirs. This study found these species in taps and sinks reflecting their largely environmental origin and these sources as key transmission points in the community and hospitals.\n\nPseudomonas species are well known for their intrinsic resistance to a wide range of antimicrobials, mainly due to the synergies between their low outer membrane permeability, possession of multidrug efflux pumps and inbuilt antimicrobial inactivation.39 In the current study, antibiotic non-susceptibility among the pseudomonads ranged from 19.5% for levofloxacin and colistin and 62% for piperacillin. Carbapenem- resistant-P. aeruginosa (CRPA) isolates, based on meropenem non-susceptibility, constituted 40% of all pseudomonads, which was consistent with 31%40 and 40%41 observed in clinical isolates (unpublished data), but lower than a recent study where CRPA were 100% non-susceptible from community and hospital acquired infections in a Kenyan referral hospital.42 The variation in these findings may be attributable to differences in the selection of study isolates, among other factors, but may suggest increased over-reliance on or misuse of carbapenem in Kisumu County, Kenya.\n\nThe prevalence of MDR pseudomonads was 45% in our study, a higher occurrence than 31% recently documented in Kenyan hospitals.40 In the current study, the highest proportion of the MDR isolates was P. aeruginosa, mainly from the community (23%, 10/24), higher than the 13.4 % reported from environmental isolates in Ghana.43 Our study found only one MDR CRPA in the hospital environment (2.3%, 1/42), which corroborates the 0.3% reported by Odoyo and others from environmental samples in Kenyan hospitals,44 highlighting the lower risk of MDR Pseudomonas infections from hospital environment reservoirs than community reservoirs. Other MDR pseudomonads, specifically P. fluorescens, were isolated from the hospital environment at a 9.5% (4/42) rate. Previous studies suggest that P. fluorescens MDR phenotypes are naturally abundant or may result from human environmental activities.45 MDR pseudomonads in the natural environment may carry mobile resistance genes which could be a reservoir for non-MDR but more pathogenic pseudomonads that, when the selection pressure from the overuse of carbapenems is applied, could drive MDR infections. All pseudomonad isolates had a MARI greater than 0.43, suggesting a high selective pressure in the current study environments, probably due to widespread antibiotic use and abuse, as reported in a previous study on the use and disposal of antibiotics in households in Kisumu, Kenya.46 To prevent dissemination of MDR-pseudomonads, protecting water systems from contamination, thus incorporating the principle of one-health where environmental health translates directly to human health remains a top priority.\n\n\n6. Conclusion\n\nThis study reveals a high prevalence of MDR pseudomonads, including CRPA strains in community tanks, taps, sinks, and other water sources, presenting a critical public health threat, especially among immunocompromised persons and acting as potential conduits or reservoirs of drug resistance. Interventions, such as regular cleaning of water storage facilities, water treatment, maintenance of water piping systems, and strict implementation of antimicrobial stewardship programs, are urgently required to prevent increased resistance due to drug overuse and to eliminate environmental factors that place the vulnerable populations at risk.\n\n\n7. Study limitations\n\nThe limited sampling duration and distribution and techniques may have limited the detection of pseudomonads due to temporal, diurnal and culture requirement variations. Genomic characterization of the study isolates would further identify strain types and inform of the transmission patterns of isolates based on their relatedness between the environmental sources, as well as AMR mechanisms.\n\n\nAuthors contributions\n\nConceptualization: L.M., A.M., P.M. Funding acquisition: L.M. Investigation- P.M., AM., and E.O. Data analysis P. M, A. M, and C.K. Writing-original draft preparation: P. M and L.M. Writing-review and editing: P.M., L.M., A.M. All authors read and approved the final manuscript.\n\n\nDisclaimer\n\nThe views here in are solely private opinions and assertions of the authors.\n\n\nEthics and consent\n\nApproval to conduct this study was obtained from the Kenyatta University’s Graduate School, Kenya Medical Research institute – Scientific Ethics Review Unit (KEMRI/SERU/CCR/0190/4117 dated February 15th 2021) and the National Commission for Science, Technology and Innovation (NACOSTI/P/20/4221). Permission to collect samples from Kisumu County Hospital was sought from the hospital management. Verbal consent was obtained and it was approved by KEMRI/SERU to collect samples from households, water distribution points owners and Kisumu County Referral Hospital management",
"appendix": "Data availability\n\nFigshare: Study samples & isolates (dataset) DOI 10.6084/m9.figshare.25284709\n\nhttps://figshare.com/s/37d537fd7cb2f0519913. 47\n\nThis project contains the following underlying data\n\nStudy samples (297) and isolates (dataset in excel format)\n\nData are available under the terms of Creative Commons Attribution 4.0 international license (CC BY 4.0)\n\n\nAcknowledgement\n\nThe authors appreciate Paul Kimani, Angela Muraya for assistance with lab procedures and Alfred Odindo, Catherine Wawira, Martin Odindo and Paul Ojore for assistance with sample collection at KCRH.\n\n\nReferences\n\nWu W, Jin Y, Bai F, et al.: Pseudomonas aeruginosa. Molecular Medical Microbiology: Second Edition. Vol. 2-3, 2014 Nov 26; pp. 753–767. Publisher Full Text\n\nIglewski BH: Pseudomonas.Baron S, editor. Medical Microbiology. 4th ed.Galveston (TX): University of Texas Medical Branch at Galveston; 1996 [cited 2023 Jun 1]. Reference Source\n\nCraun GF, Calderon RL, Craun MF: Outbreaks associated with recreational water in the United States. Int. J. Environ. Health Res. 2005 Aug; 15(4): 243–262. Publisher Full Text\n\nMena KD, Gerba CP: Risk assessment of Pseudomonas aeruginosa in water. Rev. Environ. Contam. Toxicol. 2009; 201: 71–115. PubMed Abstract | Publisher Full Text\n\nde Abreu PM , Farias PG, Paiva GS, et al.: Persistence of microbial communities including Pseudomonas aeruginosa in a hospital environment: a potential health hazard. BMC Microbiol. 2014 May 8; 14: 118. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGreen AE, Amézquita A, Le Marc Y, et al.: The consistent differential expression of genetic pathways following exposure of an industrial Pseudomonas aeruginosa strain to preservatives and a laundry detergent formulation. FEMS Microbiol. Lett. 2018 May 1; 365(9): fny062. Publisher Full Text\n\nLanini S, D’Arezzo S, Puro V, et al.: Molecular epidemiology of a Pseudomonas aeruginosa hospital outbreak driven by a contaminated disinfectant-soap dispenser. PLoS One. 2011 Feb 16; 6(2): e17064. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchiavano GF, Carloni E, Andreoni F, et al.: Prevalence and antibiotic resistance of Pseudomonas aeruginosa in water samples in central Italy and molecular characterization of oprD in imipenem resistant isolates. PLoS One. 2017; 12(12): e0189172. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilson MG, Pandey S: Pseudomonas aeruginosa. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Oct 9]. Reference Source\n\nReuter S, Sigge A, Wiedeck H, et al.: Analysis of transmission pathways of Pseudomonas aeruginosa between patients and tap water outlets. Crit. Care Med. 2002 Oct; 30(10): 2222–2228. PubMed Abstract | Publisher Full Text\n\nNaze F, Jouen E, Randriamahazo RT, et al.: Pseudomonas aeruginosa outbreak linked to mineral water bottles in a neonatal intensive care unit: fast typing by use of high-resolution melting analysis of a variable-number tandem-repeat locus. J. Clin. Microbiol. 2010 Sep; 48(9): 3146–3152. PubMed Abstract | Publisher Full Text | Free Full Text\n\nParcell BJ, Oravcova K, Pinheiro M, et al.: Pseudomonas aeruginosa intensive care unit outbreak: winnowing of transmissions with molecular and genomic typing. J. Hosp. Infect. 2018 Mar; 98(3): 282–288. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEngelhart S, Krizek L, Glasmacher A, et al.: Pseudomonas aeruginosa outbreak in a haematology-oncology unit associated with contaminated surface cleaning equipment. J. Hosp. Infect. 2002 Oct; 52(2): 93–98. PubMed Abstract | Publisher Full Text\n\nDiazGranados CA, Jones MY, Kongphet-Tran T, et al.: Outbreak of Pseudomonas aeruginosa infection associated with contamination of a flexible bronchoscope. Infect. Control Hosp. Epidemiol. 2009 Jun; 30(6): 550–555. PubMed Abstract | Publisher Full Text\n\nCrivaro V, Di Popolo A, Caprio A, et al.: Pseudomonas aeruginosa in a neonatal intensive care unit: molecular epidemiology and infection control measures. BMC Infect. Dis. 2009 May 22; 9: 70. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBassetti M, Vena A, Russo A, et al.: Rational approach in the management of Pseudomonas aeruginosa infections. Curr. Opin. Infect. Dis. 2018 Dec; 31(6): 578–586. PubMed Abstract | Publisher Full Text\n\nPang Z, Raudonis R, Glick BR, et al.: Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. Biotechnol. Adv. 2019; 37(1): 177–192. PubMed Abstract | Publisher Full Text\n\nPitout JDD, Chow BL, Gregson DB, et al.: Molecular epidemiology of metallo-beta-lactamase-producing Pseudomonas aeruginosa in the Calgary Health Region: emergence of VIM-2-producing isolates. J. Clin. Microbiol. 2007 Feb; 45(2): 294–298. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSuzuki M, Suzuki S, Matsui M, et al.: Genome Sequence of a Strain of the Human Pathogenic Bacterium Pseudomonas alcaligenes That Caused Bloodstream Infection. Genome Announc. 2013 Oct 31; 1(5): e00919–e00913. Publisher Full Text\n\nIoannou P, Vougiouklakis G: A Systematic Review of Human Infections by Pseudomonas mendocina. Trop. Med. Infect. Dis. 2020 Jun; 5(2): 71. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMaina JW, Onyambu FG, Kibet PS, et al.: Multidrug-resistant Gram-negative bacterial infections and associated factors in a Kenyan intensive care unit: a cross-sectional study. Ann. Clin. Microbiol. Antimicrob. 2023 Sep 14; 22(1): 85. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorrill HJ, Pogue JM, Kaye KS, et al.: Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum. Infect. Dis. 2015 May 5; 2(2): ofv050. Publisher Full Text\n\nPapp-Wallace KM: The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections. Expert. Opin. Pharmacother. 2019 Dec; 20(17): 2169–2184. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLord J, Gikonyo A, Miwa A, et al.: Antimicrobial resistance among Enterobacteriaceae, Staphylococcus aureus, and Pseudomonas spp. isolates from clinical specimens from a hospital in Nairobi, Kenya. PeerJ. 2021 Sep 1; 9: e11958. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMukaya KJS, Njoroge SM, Maina J, et al.: Prevalence of Multidrug-Resistant Pseudomonas aeruginosa at Kenyatta National Hospital. AJMS. 2018 Mar 25; 9(1): 6–9. Publisher Full Text\n\nMutua JM, Njeru JM, Musyoki AM: Multidrug resistant bacterial infections in severely ill COVID-19 patients admitted in a national referral and teaching hospital, Kenya. BMC Infect. Dis. 2022 Nov 22; 22(1): 877. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOdoyo E, Matano D, Tiria F, et al.: Environmental contamination across multiple hospital departments with multidrug-resistant bacteria pose an elevated risk of healthcare-associated infections in Kenyan hospitals. Antimicrob. Resist. Infect. Control. 2023 Mar 29; 12(1): 22. PubMed Abstract | Publisher Full Text | Free Full Text\n\niTeh Standards: EN ISO 16266:2008 - Water quality - Detection and enumeration of Pseudomonas aeruginosa - Method by membrane filtration (ISO 16266:2006).[cited 2023 Oct 24]. Reference Source\n\nChoi HJ, Kim MH, Cho MS, et al.: Improved PCR for identification of Pseudomonas aeruginosa. Appl. Microbiol. Biotechnol. 2013 Apr 1; 97(8): 3643–3651. PubMed Abstract | Publisher Full Text\n\nm100ed32_sample.pdf: [cited 2023 Jul 10]. Reference Source\n\nDownload and install or reinstall Office 2019, Office 2016, or Office 2013 - Microsoft Support.[cited 2024 Apr 2]. Reference Source\n\nDavis R, Brown PD: Multiple antibiotic resistance index, fitness and virulence potential in respiratory Pseudomonas aeruginosa from Jamaica. J. Med. Microbiol. 2016 Apr; 65(4): 261–271. PubMed Abstract | Publisher Full Text\n\nOpperman CJ, Moodley C, Lennard K, et al.: A citywide, clonal outbreak of Pseudomonas aeruginosa. Int. J. Infect. Dis. 2022 Apr 1; 117: 74–86. PubMed Abstract | Publisher Full Text\n\nSchneider H, Geginat G, Hogardt M, et al.: Pseudomonas aeruginosa Outbreak in a Pediatric Oncology Care Unit Caused by an Errant Water Jet Into Contaminated Siphons. Pediatr. Infect. Dis. J. 2012 Jun; 31(6): 648–650. PubMed Abstract | Publisher Full Text\n\nBédard E, Prévost M, Déziel E: Pseudomonas aeruginosa in premise plumbing of large buildings. Microbiologyopen. 2016 Jun 28; 5(6): 937–956. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRanieri L, López-Salguero S, González Galván Y, et al.: A Case Report: Pseudomonas Stutzeri, An Unusual Cause of Septic Arthritis. Rev. Colomb. Reumatol. 2020 Jul 1; 27(3): 215–217. Publisher Full Text\n\nHorii T, Muramatsu H, Iinuma Y: Mechanisms of resistance to fluoroquinolones and carbapenems in Pseudomonas putida. J. Antimicrob. Chemother. 2005 Oct 1; 56(4): 643–647. PubMed Abstract | Publisher Full Text\n\nLiu X, Xiang L, Yin Y, et al.: Pneumonia caused by Pseudomonas fluorescens: a case report. BMC Pulm. Med. 2021 Jul 5; 21(1): 212. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorita Y, Tomida J, Kawamura Y: Responses of Pseudomonas aeruginosa to antimicrobials. Front. Microbiol. 2014 Jan 8; 4: 422. Publisher Full Text\n\nKiyaga S, Kyany’a C, Muraya AW, et al.: Genetic Diversity, Distribution, and Genomic Characterization of Antibiotic Resistance and Virulence of Clinical Pseudomonas aeruginosa Strains in Kenya. Front. Microbiol. 2022 Mar 14; 13: 835403. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThuo TG, Kiyuukia C, Maina J, et al.: Antimicrobial Resistance Profiles and Clonal Relatedness of Pseudomonas aeruginosa Strains Recovered from Wounds Infections of Outpatient Population Presenting in a Rural Hospital in Kenya. Adv. Microbiol. 2019 Jan 29; 09(2): 119–130. Publisher Full Text\n\nMusila L, Kyany’a C, Maybank R, et al.: Detection of diverse carbapenem and multidrug resistance genes and high-risk strain types among carbapenem non-susceptible clinical isolates of target gram-negative bacteria in Kenya. PLoS One. 2021 Feb 22; 16(2): e0246937. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOdoi H, Boamah VE, Boakye YD, et al.: Prevalence and Phenotypic and Genotypic Resistance Mechanisms of Multidrug-Resistant Pseudomonas aeruginosa Strains Isolated from Clinical, Environmental, and Poultry Litter Samples from the Ashanti Region of Ghana. J. Environ. Public Health. 2021 Jun 15; 2021: 1–12. Publisher Full Text\n\nOdoyo E, Matano D, Tiria F, et al.: Environmental contamination across multiple hospital departments with multidrug-resistant bacteria pose an elevated risk of healthcare-associated infections in Kenyan hospitals. Antimicrob. Resist. Infect. Control. 2023 Mar 29; 12(1): 22. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSilverio MP, Kraychete GB, Rosado AS, et al.: Pseudomonas fluorescens Complex and Its Intrinsic, Adaptive, and Acquired Antimicrobial Resistance Mechanisms in Pristine and Human-Impacted Sites. Antibiotics. 2022 Aug; 11(8): 985. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKarimi KJ, Ahmad A, Duse A, et al.: Prevalence of Antibiotic Use and Disposal at Household Level in Informal Settlements of Kisumu, Kenya. Int. J. Environ. Res. Public Health. 2022 Dec 24; 20(1): 287. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMubassu P, Musyoki A, Odoyo E, et al.: Study samples data set 2024.Publisher Full Text"
}
|
[
{
"id": "280048",
"date": "08 Jun 2024",
"name": "Manuela Oliveira",
"expertise": [
"Reviewer Expertise Bacteriology",
"antimicrobial resistance"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors aimed to describe the resistance profile of Pseudomonas aeruginosa from water sources from Kisumu County, Kenya. The study is relevant for a better understanding of the worldwide dissemination of AMR. Comments:\n- Abstract The abstract must be reviewed. The meaning of MDR and AST must be included. The sentence \"in settings with community-acquired.... scarce\" is not clear and must be rephrased. What do the authors mean by reservoirs? Pseudomonads is not in italics. The % values must follow the results to which they correspond to (as in the results section). The sentence \"42% strains susceptible to colistin\" is not clear and must be rephrased.\n- Background Pseudomonads is not in italics. Remove \"therapy equipment such as\". The second sentence from the 4th paragraph must be supported by a reference. The sentence \"these drugs face... acquisition costs\" is not clear and must be rephrased. In the first sentence of the last paragraph, substitute \"clinical\" by \"opportunistic\".\nMethods - 2.2. The information corresponding to unpublished data must be further presented. In the second paragraph, the specific number of samples per collection site (i.e. taps, shower heads, etc) must be mentioned (in the text or as a table). - 2.4, second paragraph. The format of reference 30 must be corrected in the reference list. A table with the susceptibility limits considered should be included. As it is the first time E. coli is mentioned, the genus must be in full. Were the intrintrinsic resistance considered in the analysis of the resistance profiles? A reference regarding the E. coli mcr-1 positive isolate must be included. - 3. The definition of the MAR Index is not clear and must be better explained. The authors must perform the statistical analysis of the results, to determine the differences between the distribution of bacterial species and sample locations, between resistance profiles and bacterial species, between resistance profiles and sample locations. The results obtained in the statistical analysis must also be presented in the Results section and discussed in the Discussion section.\nResults - In the first paragraph there is an \"and\" that should not be in italics. In Table 1, the description of the sample sources must be similar to the one presented in the Material and Methods - and the same comment applied to the legend of Figure 3. The titles 4.4. and 4.5. are not necessary and should be eliminated.\n\nDiscussion - Pseudomonad is not in italics. There is a repetition of the results in some parts of the discussion (example: the first 4 lines following Tabel 3, the first two lines in the following paragraph). The information corresponding to unpublished data must be further presented.\nStudy limitations - Explain what were the \"temporal, diurnal and culture requirements variations\". Although the genomic characterization of the study isolates would allow to access transmission patterns, the resistance profiles could also be used for a preliminary evaluation. The authors could include this analysis in their manuscript.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "285314",
"date": "15 Jul 2024",
"name": "Balram Ji Omar",
"expertise": [
"Reviewer Expertise Bacteriology",
"Anaerobic Bacteriology",
"Virology",
"MDR",
"Candidemia",
"Neonatal malaria",
"Phytochemicals"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the submitted manuscript authors describe resistance profile of Pseudomonas aeruginosa from various water sources from Kisumu County, Kenya emphasizing Multidrug resistance of various other pseudomonads also . The study is relevant for a better understanding of the worldwide dissemination of AMR via already existing resistance in these pseudomonads in community .\nComments:\n\nAbstract\n\nThe abstract seems ok to me\n\nBackground\n\nThe second sentence from the 4th paragraph must be supported by a reference. The sentence \"these drugs face. acquisition costs\" is not clear and must be rephrased. In the first sentence of the last paragraph, substitute \"clinical\" by \"opportunistic\".\n\nMethods\n\n2.2. information corresponding to unpublished data must be further presented. In the second paragraph, the specific number of samples per collection site (i.e. taps, shower heads, etc) must be mentioned Clarify if any biofilm formation experiments were done in these isolated pseudomonads\nResults\n\nAdd The data of other bacteria isolated during the culture of these samples or clarify that only pseudomonads were only isolated bacteria.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-474
|
https://f1000research.com/articles/13-473/v1
|
10 May 24
|
{
"type": "Case Report",
"title": "Case Report: Uterine artery embolization after dysfunctional uterine bleeding due to incomplete abortion in female",
"authors": [
"Sagar Jha",
"Saunitra Inamdar",
"Anupama Dhobale",
"Saunitra Inamdar",
"Anupama Dhobale"
],
"abstract": "Dysfunctional uterine bleeding (DUB), a serious clinical challenge caused by incomplete abortion in female, calls for efficient and minimally invasive therapies to treat symptoms and protect reproductive health. Uterine artery embolization (UAE) has been discovered as a viable therapeutic strategy to treat DUB following an incomplete abortion. The existing information and clinical experience of UAE for this particular indication were thoroughly reviewed. A female’s quality of life may be negatively affected by incomplete abortion, which is defined as residual fetal tissue inside the uterine cavity. This frequently results in heavy and continuous uterine bleeding. Medical procedures and traditional management techniques such as dilatation and curettage (D&C) do not always produce the desired effects or might have inherent dangers. UAE, a less invasive technique first developed for treating uterine fibroids, has shown promise as a substitute solution for DUB caused by an incomplete abortion.",
"keywords": [
"Abortion",
"Embolization",
"Bleeding",
"Dysfunctional uterine bleeding",
"Uterine artery."
],
"content": "Introduction\n\nThe most typical application of uterine artery embolization in females is a minimally invasive technique that relieves vaginal bleeding caused by uterine fibroids (non-cancerous tumors inside the uterus).1 Uterine artery embolization (UAE) can treat excessive bleeding in emergency cases caused by trauma, malignant (cancerous) gynecological tumors, or postpartum hemorrhage, in addition to fibroids. With over 25 years of supporting data, uterine artery embolization has been demonstrated to be a safe and efficient treatment for symptomatic uterine fibroid.2 UAE is a well-known form of treatment, but there are a few misconceptions that may make it less accessible to some patients. However, there are difficulties that can make it more difficult for interventional radiologists to provide the best care and treatment for specific patients. This paper will overcome these misconceptions and difficulties, offering opportunities for future development and innovation to help interventional radiologists better serve this patient population.3\n\nAbortion is common practice. Although inaccurate, data on abortion rates can be used to examine the trends. Worldwide, the rate was 35 abortions per 1000 women aged 15–44 years in 2010–2014, which is almost five points less than that of 40 abortions for years between 1990 and 1994.4 Although there are different abortion regulations around the world, they are typically stricter in developing nations. However, limiting the regulations frequently results in risky procedures. Despite high rates of death and morbidity, they do not always stop women from getting abortions. Accessibility necessitates a legal framework for abortion, yet numerous regulations are not supported by evidence of restricted accessibility and delayed access.5 Abortion is a frequent practice, and data on abortion rates could be utilized to look at patterns despite being erroneous. From 2010 to 2014, there were 35 abortions per 1000 women worldwide (aged 15–44 years), which is a five-point decrease. For the sake of public health, abortion should be accessible, and any legal framework should also be as tolerant as feasible to promote access. Strategies for harm reduction are necessary to lower abortion-related mortality and morbidity in the absence of legal access.6 Both medical and surgical methods of abortion are effective and safe (in the first trimester, via manual or electric vacuum aspiration). Cervical priming made surgery easier, and the chances of unsuccessful abortion were lower. Septic abortions are a common and typically preventable cause of maternal deaths that almost invariably follow botched abortions. All women should be given access to a type of contraception as soon as feasible, even though normal post-abortion follow-up is not required. Together with improved education and other efforts, this may minimize unintended pregnancies.7\n\n\nCase presentation\n\nThis case study focuses on an Indian woman from the Vidarbha region in Maharashtra who chose Shalini Tai Meghe Hospital, Nagpur, for treatment. A 27 year old woman was diagnosed as having dysfunctional uterine bleeding. She was counselled about all the procedures, merits, and demerits, and informed consent was obtained.\n\nA 27 year old women, married for 7 years of G4P2L2A1, presented with a complaint of bleeding per vaginum for 6 h and pain in the abdomen for 8 h. She had a history of two previous LSCS cases with a last childbirth of 1.5 years back, she also had a history of spontaneous abortion for a three-and-a-half-month gestational age for which dilatation and curettage were done.6 Her last menstrual cycle was, 22/08/2022. Her expected delivery date was 29/05/23, and her gestation period was 10 weeks 5days. The patient had no recent history of heavy weight lifting or coitus and no history of diabetes mellitus, bronchial asthma, or epilepsy. The patient had no history of major surgical illness or blood transfusion.\n\nOn general examination pulse was 76 bpm, respiratory rate of 18 per/min BP: 100/72 mmHg.\n\nPatient was a febrile on touch, on systemic examination RS-air entry bilateral equal on CVS-S1 S2 heard, no murmur, CNS: conscious and oriented, per abdominal examination: soft non-tender, per vaginal examination: OS admits tip of finger, bleeding++, patient was immediately advice for USG abdomen +pelvis and blood investigation.\n\nUSG done on 05/11/2022, suggestive of retained products of conception.\n\nAn immediate decision to check for curettage was made. All blood tests were performed and were within normal limits.\n\nProcedure was completed and was uneventful, patient was admitted in ward for observation.\n\nThe patient continued to bleed, and passage of blood clots was observed in the valvar pads even after successful check curettage. A repeat USG was suggested to check for any RPOC in the uterus. USG was performed on 7/11/22, suggestive of blood clots in the uterus, and the patient was counselled.\n\nRegarding the current condition and was given the option of either hysterectomy or uterine artery embolization, considering the patient’s age. The decision to perform uterine artery embolization was made, the patient was referred for uterine artery embolization, as shown in Figure 1.\n\nDuring the procedure, there was a nidus of multiple tortuous vessels with feeders from the uterine artery, and super selective cannulation was performed with a progreat microcatheter and embolization was performed using PA particles of size 5 mm, as shown in Figure 2. Post-embolization reduced the contrast blush arising from the uterine artery, and the procedure was uneventful, as shown in Figure 3.\n\nRegarding postoperative medications, patient was advised for the injection. Tranexa 8 hourly, injection Cefotaxim 12 hourly, Injection Pantoprazole 24 hourly, Injection Diclofenac 12 hourly, Tablet methergin 0.25 mg 8 hourly.\n\nThe patient complained of pain after the procedure for 2 days, for which she was administered an injection. Tramadol, which relieved the patient’s pain tremendously.\n\n\nDiscussion\n\nPados G. et al. reported that acute dysfunctional uterine bleeding (DUB) in female is treated medically with hormones, NSAIDs, and antifibrinolytic drugs. Hormonal therapy is regarded as the standard medical treatment for acute DUB. Conjugated equine estrogen administered intravenously, COCs, and oral and intramuscular progestins are among the available treatments. A randomized double-blind study including 34 women demonstrated the effectiveness of intravenous conjugated equine estrogen in DUB therapy. According to the study, uterine hemorrhage decreased by 72% in comparison to 38% in the placebo group 8 h after intravenous premarin was administered.8 According to a theory, the endometrium heals itself as a result of the induced growth caused by growing oestradiol levels during the primary follicular phase of a typical menstrual cycles. Estrogen also has an impact on the endometrium by reducing capillary permeability, increasing fibrinogen levels, clotting factors, and platelet aggregation, which in turn encourages coagulation and decreases capillary permeability. COCs and oral progestins are among the additional types of hormonal therapies. Progestogens unaccompanied or in combination with estrogen have the same therapeutic effect when used to treat anovulatory DUB, according to a recent Cochrane study.9\n\nNSAIDs and antifibrinolytics can be used in ovulatory DUB patients on days when there is significant uterine bleeding. In comparison to single-agent therapy, the use of these drugs in combination with other agents can result in a larger decrease in uterine bleeding. It has been discovered that antifibrinolytics reduce uterine hemorrhage by 40–50% from baseline in comparison with placebo. They have also been reported to be higher than NSAIDs, with a 25–50% decrease in menstrual blood loss from the baseline.10\n\nSurgery is only used for hysterectomy, UAE, and endometrial ablation in patients with acute DUB. Currently, only women with fibroids have been found to benefit from the use of UAE for menorrhagia. After five years of follow-up, the EMMY trial revealed that 70% of the patients who were randomly assigned to the UAE group did not require hysterectomy. To date, only one instance illustrating the use of UAE in the treatment of acute DUB has been documented in the literature. For example, a 12 years girl with first-onset menorrhagia, which was life threatening, was treated with UAE after traditional medical or gynecological procedures had failed to work.11\n\nUAE has been demonstrated to be effective in treating postpartum hemorrhage, with reported success rates of >90%, in addition to its involvement in menorrhagia. In one of the registers, it was discovered that 2% of the patients experienced uterine infection after UAE. One patient in the case series of these 21 individuals experienced multiple organ failure and septic shock leading to death following UAE, according to a systematic evaluation of 36 articles. Additional issues include intestinal perforation, groyne hemorrhage or pseudoaneurysm, femoral artery blockage, and arterial dissection or perforation.12 However, only 4.8% of the total number of women enlisted belonged to the category of women with three or more previous sections. After using impedance-controlled endometrial ablation in a patient who had previously undergone three transverse caesarean sections, the patient developed a vesicouterine fistula, raising concerns about the safety of endometrial ablation. Endometrial ablation was not seen to be the best course of treatment for our patient because there is conflicting evidence on its safety in women who had three previous caesarean sections and because our hospital offers only microwave endometrial ablation, which is performed in the dark.13\n\nIn this case, UAE was attempted because the patient did not respond to medical treatment of DUB and expressed no interest in undergoing hysterectomy. Both times after the UAE, her monthly bleeding was controlled. Angiographic evidence of a convoluted right uterine artery indicates an increase in the caliber and flow of the right uterine artery. However, research on monkeys has revealed that convoluted uterine arteries are the only anatomical variance. In conclusion, we hypothesized that UAE might have a role in treating acute DUB in women whose fertility must be preserved. However, further research is needed to determine the efficacy of UAE in the treatment of acute DUB.14\n\n\nConclusion\n\nUAE is an effective and safe treatment option for DUB associated with incomplete abortion. The procedure can provide quick and lasting relief of symptoms with a low risk of complications. UAE should be considered an alternative to a more invasive surgical option for the administration of DUB related to incomplete abortion. However, patient selection, careful evaluation of the jeopardies, and benefits of the procedure are important factors to consider.\n\n\nConsent\n\nThe patient provided written informed consent for the publication of this manuscript.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nWong GC, Muir SJ, Lai AP: Uterine artery embolization: A minimally invasive technique for the treatment of uterine fibroids. J. Women Health Gend.-Based Med. 2000 May; 9(4): 357–362. Publisher Full Text\n\nYoung M, Coffey W, Mikhail LN: Uterine Fibroid Embolization. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 [cited September 5, 2023]. Reference Source\n\nWomen’s Issues in Interventional Radiology: Uterine Artery Embolization for Treatment of Symptomatic Fibroids - PMC.[cited September 5, 2023]. Reference Source\n\nSingh S, Shekhar C, Acharya R, et al.: Incidence of abortion and unintended pregnancy in India in 2015. Lancet Glob. Health. 2018 Jan 1; 6(1): e111–e120. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBerer M: Abortion Law and Policy Around the World. Health Hum. Rights. 2017 Jun; 19(1): 13–27. PubMed Abstract\n\nInduced abortion|Human Reproduction|Oxford Academic.[cited September 5, 2023]. Reference Source\n\nMedical termination for pregnancy in early first trimester (≤ 63 days) using a combination of mifepristone and misoprostol or misoprostol alone: a systematic review.BMC Women’s Health.[cited September 5, 2023]. Publisher Full Text\n\nPados G, Athanatos D, Stamatopoulos P, et al.: Treatment options for dysfunctional uterine bleeding: evaluation of clinical results. Gynecol. Surg. 2011 Nov; 8(4): 385–393. Publisher Full Text\n\nBradley LD, Gueye NA: Medical management of abnormal uterine bleeding in reproductive-aged women. Am. J. Obstet. Gynecol. 2016 Jan 1; 214(1): 31–44. PubMed Abstract | Publisher Full Text\n\nStrickler RC: Dysfunctional uterine bleeding in ovulatory women. Postgrad. Med. 1985 Jan; 77(1): 235–246. 240–243, 246. Publisher Full Text\n\nBhattacharya S, Middleton LJ, Tsourapas A, et al.: Hysterectomy, endometrial ablation and Mirena for heavy menstrual bleeding: a systematic review and individual patient data meta-analysis. Hysterectomy, Endometrial Ablation and Mirena® for Heavy Menstrual Bleeding: A Systematic Review of Clinical Effectiveness and Cost-Effectiveness Analysis. NIHR Journals Library; 2011 [cited 2023 Sep 5]. Reference Source\n\nSuccessful repeated uterine artery embolization in postpartum hemorrhage with disseminated intravascular coagulation: a case report and literature review.BMC Pregnancy and Childbirth.[cited 2023 Sep 5]. Publisher Full Text\n\nEndometrial ablation: postoperative complications. Am. J. Obstet. Gynecol. [cited 2023 Sep 5]. Reference Source\n\nMailli L, Patel S, Das R, et al.: Uterine artery embolisation: fertility, adenomyosis and size – what is the evidence? CVIR Endovasc. 2023 Feb 27; 6(1): 8. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "325438",
"date": "03 Oct 2024",
"name": "Ai-Hua Liao",
"expertise": [
"Reviewer Expertise Gynecology",
"Reproductive medicine."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript by Dr. Jha et al. presented a case report on the successful treatment of uterine artery embolization (UAE) after dysfunctional uterine bleeding (DUB) due to in complete abortion in 27-years old woman. However, it still needs more cases to confirm the efficacy, and the following concerns should also be addressed.\n1. The background on this topic is insufficient.\nAlthough the authors mentioned that there were a few misconceptions on UAE, they did not clearly mention what they are, specially, in view of abortion. In the second paragraph of the introduction, the authors just presented the status of abortion rates worldwide. They did not point out what the key or main issues regarding abortion.\nIt is suggested that the authors should clearly point out and focus on what the main issues exist regarding their topic of this manuscript. Specially, whether this case report is the first one? If not, the authors should summarize the current status on the use of UAE in the DUB related incomplete abortion. Moreover, the authors should describe what it is new or different from others. Hence, all the above-mentioned points should be presented in the part of the introduction.\n2. Discussion\nThe authors only reported one case with successful outcome after the treatment of UAE. However, whether it can be wildly used by others remains limited. The authors should follow up the long-term status of fertility and menstruation. Also, it needs more cases to approve the efficacy. Moreover, they should discuss how the other practitioners use their results, and what the limitation of this study is.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-473
|
https://f1000research.com/articles/13-471/v1
|
10 May 24
|
{
"type": "Method Article",
"title": "Towards a quality indicator for research data publications and research software publications – a vision from the Helmholtz Association",
"authors": [
"Wolfgang zu Castell",
"Doris Dransch",
"Guido Juckeland",
"Marcel Meistring",
"Bernadette Fritzsch",
"Ronny Gey",
"Britta Höpfner",
"Martin Köhler",
"Christian Meeßen",
"Hela Mehrtens",
"Felix Mühlbauer",
"Sirko Schindler",
"Thomas Schnicke",
"Roland Bertelmann",
"Wolfgang zu Castell",
"Doris Dransch",
"Marcel Meistring",
"Bernadette Fritzsch",
"Ronny Gey",
"Britta Höpfner",
"Martin Köhler",
"Christian Meeßen",
"Hela Mehrtens",
"Felix Mühlbauer",
"Sirko Schindler",
"Thomas Schnicke",
"Roland Bertelmann"
],
"abstract": "Research data and software are widely accepted as an outcome of scientific work. However, in comparison to text-based publications, there is not yet an established process to assess and evaluate quality of research data and research software publications. This paper presents an attempt to fill this gap. Initiated by the Working Group Open Science of the Helmholtz Association, the Task Group Helmholtz Quality Indicators for Data and Software Publications currently develops a quality indicator for research data and research software publications to be used within the Association. This report summarizes the vision of the group of what all contributes to such an indicator. The proposed approach relies on generic well-established concepts for quality criteria, such as the FAIR Principles and the COBIT Maturity Model. It does – on purpose – not limit itself to technical implementation possibilities to avoid using an existing metric for a new purpose. The intention of this paper is to share the current state for further discussion with all stakeholders, particularly with other groups also working on similar metrics but also with entities that use the metrics.",
"keywords": [
"Data publication",
"Software publication",
"bibliometrics"
],
"content": "1. Background and objective\n\nMeasuring the performance and progress of research based on means of output is a common task of research assessment. While it is commonly accepted to use quality-assured scientific publications as a proxy for quality assessment in research evaluation, other artifacts of scientific work such as research data and research software are often not yet considered. For text-based scientific work, there are well established processes of quality assurance during the process of publication. For publishing research data and research software no commonly accepted standards exist yet, although research data and software represent a significant output of the scientific endeavor especially given the rise of data- and software-intensive research.\n\nThe Helmholtz Association has already decided to integrate research data publications and research software publications in its internal key performance indicator system and is currently developing and implementing a quality indicator for those artifacts. It should become a driver within Helmholtz in a threefold way: a) to create awareness and appreciation for the diversity of research output, b) to align the assessment of research and research practice to the conditions of digitalization and openness of science, and c) as a stimulus and incentive for scientists to improve their data and software publications related to specific quality criteria, and thus, to improve the quality and trustworthiness of science as a whole. Helmholtz Centers from all research fields of the Association contributed in an iterative discussion process to cover a broad perspective originating from their respective research environment. To meet all aspects relevant for the quality indicator, a group of scientists, scientific software developers, data curators, and colleagues reporting on research output were involved in its development. This paper provides insight to the current status of the discussion.\n\n\n2. Terminology\n\nThe following definitions should clarify what type of research data and research software we address in this paper.\n\nIn accordance with the EOSC-Glossary1 we define research data as data that has been collected, created and/or is being used in “scientific research activities and used as evidence in the research process, or commonly accepted in the research community as necessary to validate research findings and results”. It ranges from highly complex and individual long-tail-data from experiments and observations to automatically produced generic data collections.\n\nWe define research software as software that has been developed in the research process.2 We consider software of all levels of maturity: from personal use, reuse by others, long term support, and criticality as defined by3 in the form of software classes.\n\nIn both cases we concentrate on research output which is published. We define published data and software as digital objects that have been made as permanently available as possible on the internet.4 The different levels of “published” are addressed in the framework of quality dimensions and attributes (Section 4 and 5).\n\n\n3. Methodical framework – quality criteria and quality quantification\n\nRecalling the publishing process of scientific publications: A paper published e.g. in a scientific journal has been quality checked with respect to several criteria over the course of the publication process. When accepted, a manuscript is marked as being approved by the underlying quality assurance mechanisms. Aggregating the number of papers that went through this process of quality assurance is therefore used as a quantitative measure of the output performance of a scientific entity. Yet, this process of solely using simple and one-dimensional metrics to assess research quality and performance is broadly criticized. But the convenience of having one number easy at hand has so far hindered all attempts to replace this practice. Taking this into consideration a quality indicator for research data and software has to be developed with the goal to have one easily comparable value that still does more then only counting - by representing a diverse set of quality features in itself.\n\nTherefore, any analog of this process for scientific data publications or research software publications has to technically map a multi-dimensional suite of quality criteria onto one value, the quality indicator. Thus, developing a quality indicator has to address the following questions: 1) What quality criteria should be considered? 2) How to measure each of the quality criteria? 3) How to condense individual quality measures into one number, the quality indicator? In addition, for practicability, 4) how to collect the quality measures for the most part in an automated fashion? Since the Helmholtz quality indicator has to match all types of research data publications and research software publications generated in the diverse scientific disciplines within the Helmholtz Association, generic approaches are required to provide answers to these questions. We decided to build on the FAIR Principles5 to specify relevant quality criteria. In order to provide a generic way to estimate quality for a wide range of criteria, we are using an approach based on the COBIT Maturity Model6 to quantify quality in terms of a maturity scale. Finally, a weighted summation and radar plot approach is used to derive one single value from the various quantitative measures while also providing a more detailed representation. The collection of quality measures should rely on automated procedures and tools as much as possible. However, in the end, any indicator must match the target set, technical issues must not lead to deviation from that target. Therefore, our basic approach for developing the quality indicator was to define the quality criteria that are essential for the intended objectives in a first step, and to then condense the list of criteria in a second step with respect to technical feasibility of automated collection. This approach discusses quality criteria of research data publications and software publications without immediately considering the technical implementation of measuring them. Thus, we selected metrics not simply for the ease of measurement. Rather, the measurement of some criteria deemed highly relevant might be deferred until a corresponding, automated approach of evaluating them becomes available.\n\nThe overall approach then consists of the following five steps.\n\n(i) Define a suitable number of dimensions, according to which quality of research data and software can be assessed.\n\n(ii) For each of these dimensions, collect a set of specific attributes capturing the respective dimension.\n\n(iii) Using a generic maturity model, each attribute is mapped onto a numeric scale\n\n(iv) Using weighted averages, an aggregated maturity level is obtained for each dimension.\n\n(v) The summarizing quality assessment can then be visualized using radar plots.\n\nThese steps lead to the current state of a quality summary of the assessed research data and software. Using more than one dimension allows us to take different perspectives into account. For example, an organization aiming at building up a large, integrated software library might have other targets for quality assessment than a single software developer working on individual projects. As well as an international campaign gathering huge amounts of automatically generated sensor-data has other objectives, restrictions, and conditions than long-tail data generated in experiments in a laboratory setting or a medical scientist working with confidential patient data. In analogy to the aggregation of quality-assured scientific publications, a quantitative estimate of high quality data and software publications could then be obtained by aggregating the number of data/software showing a maturity above a given minimum in each of the dimensions. Afterwards, the maturity of each dimension also has to be aggregated to form the final indicator for a publication.\n\nTo determine an initial set of dimensions for quality assessment, we are building on the FAIR principles.5 The FAIR principles have been widely adopted as a minimum set of quality criteria for research data and research software thus, our approach generally also builds on the four principles findability, accessibility, interoperability and re-usability. Considering upcoming discussions within communities on the limitations of pure implementation of FAIR to grasp a comprehensive view on the quality of research data and research software publications, the partly interrelated aspects and minor inaccuracies of wording within the four core principles we adopted and extended the FAIR principles to best suit our needs.\n\nFor research software we amended the FAIR criteria with two additional criteria: scientific quality, addressing the question of research software being scientifically well grounded, and technical competence, capturing aspects of the software being technically well grounded (FAIR-ST).\n\nFor evaluating research data publications, we regrouped the FAIR criteria into four dimensions that are easier to grasp related to datasets but still cover the same aspects. Those being 1. Publishing, 2. Openness, 3. Curation, and 4. Metadata. To compensate for inadequacies between different disciplines when applying a general framework like the proposed, the 5. dimension of the External View has been added to the set (POCME).\n\nIn order to allow for a comparable and unbiased quality assessment for data and software publications based on our modified FAIR-framework, we need a broadly applicable scheme leading to a numerical value for each quality criterion. In certification processes, maturity models are commonly used to solve this task.\n\nTo achieve comparability among different attributes of quality, stages of product evolution can be assessed using a generic model of maturity. Being generic, the model can be applied to all categories of scientific output leading to quantitative results which can be compared. Our approach utilizes the COBIT Maturity Model.6 The COBIT Maturity Model quantifies maturity of a product in six levels by mainly evaluating the processes that lead to the product. Looking at processes for achieving a certain quality is a common approach in quality management, where quality management systems (QMS) are defined as “formalized systems that document processes, procedures, and responsibilities for achieving quality policies and objectives”.7 Typically, lower levels of maturity focus on individual outcomes of a process to be certified. The higher the maturity, the more the process is considered, accounting for the fact that a well-developed process naturally leads to products of a certain quality. COBIT starts with a default level 0 (non-existent), two levels of maturity acknowledge the successive completion of a set of quality criteria for the product to be targeted. Starting with level 3 maturity implies a process to be existent which guarantees the addressed quality to be kept. Two further levels finally focus on the improvement of the underlying process towards full optimization with maturity level 5. Clearly, the explicit meaning of the maturity levels for a given quality criterion has to be defined as part of the community process. Obviously, the maturation levels need to be interpreted within the context of a given aspect of quality assessment. The levels are cumulative in the sense that a higher level includes the requirements of all lower levels, i.e. marking a higher level as fulfilled means that the requirements of all lower levels are fulfilled plus the requirements of the highest marked level. Thus, a higher level can either refine/specialize characteristics that were already evaluated for compliance with a lower level or introduce a new and additional characteristic to assess. As a result, comparability across quality dimensions is given.\n\nThe specific application of maturity levels derived from the COBIT Maturity Model with regards to data and software publications are introduced in the respective subsection of this paper (Sections 4 and 5).\n\nGuidelines for reviewers for academic journals typically provide a set of criteria being considered in preparing a review for a manuscript. Examples are scientific originality, proper use of methods, organization of the material/figures/tables, and comprehensibility. Such criteria can likewise be grouped into different dimensions of assessment such as scientific novelty, being scientifically grounded, quality of presentation etc. However, such dimensions are commonly not transparently weighted against each other. Nevertheless, there is a common understanding in each scientific community on what has to be considered more important. To make such an understanding open and transparent, we introduce radar plots to visualize the joint maturity of a data and software publication with respect to all quality dimensions. The relative importance of every single attribute within each dimension of assessment can be fine-tuned by agreeing on weights to be used in a weighted average. Doing so, minor criteria can also be included into the assessment without the risk of leading to a biased assessment.\n\nFor the overall assessment of the data and software publication, we deliberately do not suggest to use weighted averages as a default. The multi-dimensionality of each quality assessment should rather be kept transparent. This allows us to optimize towards different goals in using the quality indicator. Figure 1 exemplifies the result of the quality assessment of two fictitious research software or data publications.\n\nMaturity levels are ordered from center (0, non-existent).\n\n\n4. The Quality Indicator for research data\n\nThe quality of published research data and hence its potential value for future reuse in other contexts can be assessed based on the quality of the metadata describing the data formally, on metadata describing the data on the content-level, on the quality of the data itself and the conditions of Openness/Licensing. With regards to the diversity of research data over the different scientific domains represented at Helmholtz, the heterogeneous ways of collecting, creating, editing, and curating data, a single quality criterion for research data assessment would not be constructive. To allow for a multi-dimensional perspective on research data, the quality assessment being presented in this document is spanning five dimensions of data quality being partly based on the FAIR-principles and the FAIR Data Maturity Model of the Research Data Alliance.8\n\nThe derived quality dimensions of the POCME-framework for research data publications, each with indication of the covered FAIR-principles, are:\n\nPublishing\n\nThis dimension covers especially the areas of Findability and Accessibility. It addresses the use of identifiers to enable unambiguous identification as well as the level of storage and hence the possibilities and information on the general accessibility to published data.\n\nOpenness\n\nAs publishing a dataset does not necessarily mean to make it openly available (Intelligent Openness), this dimension takes this circumstance into account and covers aspects of Accessibility, Interoperability and Reusability.\n\nCuration\n\nCuration can be crucial for the quality of published data itself as well as for the provided formal and content related information. Hence, it can significantly improve the value of a published dataset for Reusability as well as for Findability, Accessibility, and Interoperability.\n\nMetadata\n\nQualitative metadata can help in many aspects of Findability, Accessibility, Interoperability, and Reusability of published data. By providing content related aspects, helpful information to retrieve a dataset as well as context around a dataset.\n\nExternal view\n\nThis dimension is meant as a handle to compensate inadequacies between different disciplines which is a sensible approach when applying a general framework like the proposed.\n\nThese five dimensions of quality for research data are still too generic to be evaluated using the maturity model. Therefore, each dimension is split into a set of attributes. The latter will be assessed using the maturity model. To derive a single value for each of the five dimensions, an aggregation step has to be incorporated. This is done by computing a weighted average of the maturation values for all attributes constituting a quality dimension. Using weights provides the freedom not to be forced to work with attributes of equal importance. Minor aspects are just given smaller weight.\n\nTo assess the quality of research data publications, the developed POCME assessment-framework measures/estimates the maturity of different quality dimensions and attributes. To be able to do this, a generic five-level scale of maturity derived from the COBIT Maturity Model is applied. The levels are always to be seen in the context of the respective dimension and attribute they are applied on.\n\nThe first level (0) usually implies that the respective attribute is non-existent or not applied. The following levels built upon each other, always following the assumption, that the previous levels are largely met, leading to the highest possible level of maturity and hence quality of the data itself and the accompanying meta-information maximizing the findability, accessibility, interoperability, and re-usability.\n\n(0) Non-existent: no information available or not applied\n\n(1) Most necessary information provided or measure taken\n\n(2) Basic information provided or measure taken (sensible level of information/measures)\n\n(3) Advanced information provided or measure taken, allowing to generally understand and (re) use the published data\n\n(4) Complete and accurate information provided or measure taken, to an extend that allows maximal understanding and usage of data\n\nThe following sections list the attributes and their maturity levels of research data publications that are proposed for each dimension. It must again be noted that the COBIT model is cumulative, i.e. a higher level includes the fulfillment of all requirements of a lower level.\n\n4.2.1 Dimension publishing\n\nPublished with identifier\n\n(0) No identifier (resource may only be found via personal communication)\n\n(1) Basic Uniform Resource Identifier\n\n(2) Dataset is identifiable via internal handle (does not resolve globally, generally no metadata)\n\n(3) Dataset is basically identifiable via formalized, standardized, persistent identifier (resolves globally, general metadata provided)\n\n(4) Dataset is identifiable via globally unique, formalized, standardized, persistent identifier supported by general metadata (e.g. DOI).\n\nPublished via a repository or collection, that is indexed in a meta-repository (e.g. re3data)\n\n(0) No information available, the data is not published via a repository/collection\n\n(1) The data is published in a repository/collection which is not listed in an eligible meta-repository\n\n(2) The repository/collection is listed in an eligible meta-repository, basic number of quality indicators assigned by the meta-repository are achieved\n\n(3) The repository/collection is listed in an eligible meta-repository, medium number of quality indicators assigned by the meta-repository are achieved\n\n(4) The repository/collection is listed in an eligible meta-repository, high number of quality indicators assigned by the meta-repository are achieved\n\nRemark: Meta-repositories like re3data usually do not perform in depth checks on the quality of published research data in the indexed sources. Still, if sources indexed in meta-repositories like re3data fulfill certain quality-criteria respective indicators (e.g. icons) are assigned. The icons themselves represent different quality-levels on the level of the source, assuming that contained dataset likely meet those quality levels represented by the source.\n\nPublished with information on access to the data\n\n(0) No metadata available\n\n(1) Metadata available, but no data access-information available in the metadata\n\n(2) Metadata available, data access-information available only in human-readable form\n\n(3) Metadata available, data access-information available only in human readable form, including general license information\n\n(4) Metadata available, data access-information available in human-readable and machine-readable form [1], including license information\n\n4.2.2 Dimension openness\n\nGeneral degree of openness\n\n(0) No information on open accessibility/availability of the data at all\n\n(1) Information available: no open accessibility/availability of the data. No justification, no information on possible contact or restrictions\n\n(2) Like (1) + information on possible contact, restrictions or potential use cases on request available\n\n(3) Like (2) + with justification AND/OR date of moratorium\n\n(4) Open accessibility with corresponding license (no login or contact needed or otherwise with justification)\n\nPrimary data formats\n\n(0) No primary data available in digital form\n\n(1) Primary data generally available\n\n(2) Primary data stored in common proprietary data formats\n\n(3) Primary data stored in open formats\n\n(4) Primary data makes use of common, domain specific terminologies (e.g., codelists)\n\n4.2.3 Dimension curation\n\nLevel of curation\n\n(0) Data is published in raw form without any curation or documentation (e.g. raw long-tail data)\n\n(1) Data is published in raw form without curation but according to standard with basic documentation like readme (e.g. automatic generated sensor data, long-tail data following a basic scheme)\n\n(2) Data is published in cleaned form with some curation (e.g. brief checking, documentation according to standard)\n\n(3) Data is published in cleaned form with enhanced curation and/or reprocessing (e.g. conversion to new formats, enhancement of documentation)\n\n(4) Data is published after undergoing extensive curation and/or reprocessing according to discipline specific standards in order to enhance to max. quality (like (3) + additional editing of deposited data for accuracy)\n\n4.2.4 Dimension metadata\n\nMetadata to find/retrieve a resource/formal metadata\n\n(0) No metadata available\n\n(1) Metadata available for/with the data publication that is not structured according to a commonly accepted scheme (i.e. no scheme applied)\n\n(2) Metadata provided with the data publication that is structured in a basic way according to a commonly accepted scheme (e.g. completed DataCite mandatory-properties/discovery; Dublin Core, etc.)\n\n(3) Metadata provided with the data publication that is structured in an advanced way, according to a commonly accepted scheme (e.g., completed DataCite mandatory- and recommended-properties for discovery + discovery-supporting basic content metadata according to DataCite scheme)\n\n(4) Full Metadata provided with the data publication (complete DataCite mandatory- and recommended- and optional-properties for discovery + comprehensive discovery-supporting content metadata according to DataCite scheme)\n\nContent related metadata\n\n(0) No content related metadata available\n\n(1) Some content related metadata available, following a (generic) scheme (e.g. DataCite)\n\n(2) Complete content related metadata available following a (generic) scheme (e.g. DataCite)\n\n(3) Some content related metadata available following standardized form or domain specific scheme\n\n(4) Complete and curated content related metadata available following a standardized form and domain specific scheme (see 3)\n\n4.2.5 Dimension external view\n\nScore from domain specific fair assessment tool\n\n(0) 0-20% Score reached\n\n(1) 21-40% Score reached\n\n(2) 41-60% Score reached\n\n(3) 61-80% Score reached\n\n(4) 81-100% Score reached\n\nRemark: By integrating this dimension, it would be possible to take a domain specific evaluation of a data publication in regard to community best practices and domain specific requirements on metadata and ideally the data itself into account. This is based on the assumption that in addition to more generalistic FAIR assessment tools currently available, further tools with domain-specific evaluation schemes will be developed. The rating scales of these tools can then presumably always be converted into a percentage scale. A rather low weighting of this dimension must be considered in order to minimize the stimulus for gamification.\n\n\n5. The Quality Indicator for research software\n\nQuality of research software has various aspects to be considered. Depending on the type of software, the field of application and the scientific goals to be followed in using research software, different aspects of research software are being considered as important. Therefore, a single quality criterion for research software assessment would not be constructive. To allow a multi-dimensional perspective on research software, the quality assessment being presented in this document is spanning six dimensions of software quality being given by the proposed FAIR-ST framework.\n\nUsing the principles for quality assessment, the FAIR principles have to be spelled out explicitly with respect to research software. This is given by FAIR4RS.9 As mentioned above, the four FAIR principles have been augmented with two further quality dimensions. Thus, the six dimensions of research software quality being presented in the assessment scheme are given as follows.\n\n(a) Findable: Researchers need to be able to find the software using typical search strategies. Having found a given software product, they have to be able to identify a given version/release and be provided with enough information to value the software for their specific research.\n\n(b) Accessible: Software needs to be accessible in order to unfold its potential. Hereby, accessibility has both a legal side as well as an operational side.\n\n(c) Interoperable: For software to be interoperable, it must be capable of being included into larger contexts or frameworks. Towards this aim, input/output formats need to be considered as well as interfaces to use the software in automated pipelines.\n\n(d) Reusable: Using software for exactly the purpose it has been developed for is considered as accessibility within the quality assessment. In contrast, reusability considered the aspect of being able/allowed to use the code for one’s own purposes, to adapt and extend the software.\n\n(e) Scientific basis: Research software is an integral part of the research process. It therefore has to also follow community/organization specified common standards in performing research. While the contribution of software to a certain scientific achievement must be evaluated by dedicated experts in the field, some aspects of scientific quality can also be considered in wider generality.\n\n(f) Technical basis: Quality of software also reflects general aspects of software engineering. At the end, software has to guarantee to actually produce what it has been aimed to do. Professional software development aims at producing software following state-of-the-art software engineering concepts. Thus, aspects of professional software engineering must also be considered as part of a quality assessment of research software development.\n\nThe six dimensions of quality for research software are still too generic to be evaluated using the maturity model. Therefore similar to the approach for research data, each dimension is split into a set of attributes. The same principles as outlined previously for research data are applied.\n\nThe following descriptions summarize the proposed five levels of maturity used for evaluating the quality of software publications. Level 0 is the default level, when no information for the evaluated attribute is provided.\n\n(5) Non-existent: no information available\n\n(6) Initial: initial information available being obtained in an ad-hoc, unorganized manner\n\n(7) Repeatable: the information is complete, being produced in a repeatable, yet intuitive manner\n\n(8) Defined: a process is established guaranteeing the complete compilation of the required information\n\n(9) Managed: the process being established is managed, i.e. monitoring/measuring is included\n\n(10) Optimized: practices are put in place optimizing the way the process is operated, leading to improved quality over time\n\nFor each of the quality dimensions, the assessment is done by rating every corresponding attribute according to its maturity. The explicit interpretation of each maturity level for a given attribute is given in terms of asking of compliance with statements. Since the maturity levels are building on each other in a cumulative way, the number of the last achieved statement defines the maturity of the attribute.\n\nThe following sections provide the assessment scheme for the six dimensions of the FAIR-ST framework.\n\n5.2.1 Dimension findable\n\nThe following statements address the aspect of being able to find and uniquely identify the software.\n\nOpen publication repository\n\n(0) There is no information available on where to find the software.\n\n(1) The software is contained in an online repository.\n\n(2) Some kind of description is available giving further information on the software in this repository (e.g. readme file).\n\n(3) A structured meta data description (e.g. following DataCite) given for software is in this repository.\n\n(4) The repository is listed in some overarching meta-repository (e.g. Helmholtz Research Software Directory (RSD)).\n\n(5) The meta-repository performs quality checks (e.g. re3data) for the used publication repository.\n\nVersioning\n\n(0) No software versioning applied.\n\n(1) There is some kind of versioning for the software.\n\n(2) The software uses structured (e.g. semantic) versioning.\n\n(3) A description of the versioning scheme is available.\n\n(4) There is a documentation on release cycles for the software.\n\n(5) The versioning scheme allows for automatic tagging by CI/CD processes.\n\nPersistent Identifier (PID)\n\n(0) No PIDs given.\n\n(1) A handle/URL is provided to identify the software.\n\n(2) The handle/URL is provided with a defined metadata scheme.\n\n(3) A persistent identifier is provided.\n\n(4) A PID allowing for automated harvesting of metadata information is provided.\n\n(5) The PID is part of an established community standard.\n\nRich metadata\n\n(0) No metadata given.\n\n(1) Some metadata information is provided with the software.\n\n(2) The metadata information is following a given metadata scheme completely.\n\n(3) A metadata curation process reflects changes/updates.\n\n(4) All metadata information following the given metadata scheme can be automatically harvested.\n\n(5) An external quality assessment of the metadata exists.\n\n5.2.2 Dimension accessible\n\nThe following statements address the aspect of being able to access research software. Accessing included the possibility to run the software, which might also be in terms of a web service. However, accessibility does not include the possibility to adjust the code which is rather being captured under the aspect of reusability.\n\nAccess conditions (organizational)\n\n(0) Not specified.\n\n(1) A contact is given which to inquire about the right to use the software.\n\n(2) The software has a license describing rights of use.\n\n(3) The license allows for open use of the software (e.g. OSI licenses).\n\n(4) There is a way to also obtain some kind of support in using the software.\n\n(5) There is a community, providing the opportunity of support and exchange concerning aspects of using the software.\n\nAccess options (process)\n\n(0) There is only one specific form of accessing the software or no option at all.\n\n(1) The software (source code or executable) is provided.\n\n(2) The sources or executables being provided include some documentation on how to install/use the software.\n\n(3) Provided test cases allow to determine whether installation/execution worked as expected.\n\n(4) Provided checks make sure the software works correctly.\n\n(5) A software service is provided, i.e. are reported bugs taken into the development cycle.\n\nTechnical accessibility (run/start)\n\n(0) No information given.\n\n(1) “How to install” information is provided.\n\n(2) Installation scripts are provided.\n\n(3) The software allows for (semi-)automated installation, e.g. a Makefile or manual package (like Python modules).\n\n(4) Sources are provided such that a package manager or automated build tools, e.g. automake, can be used.\n\n(5) A complete package that enables execution (e.g. container, app package) is available.\n\n5.2.3 Dimension interoperable\n\nThe following statements address the aspect of being interoperable, i.e., the possibilities of being able to integrate the software into one’s own software framework or execution pipelines.\n\nInput/Output formats\n\n(0) Not specified.\n\n(1) Some description of input and output formats is provided.\n\n(2) The software builds on standard formats for input and output.\n\n(3) Additional options for varying input/output formats are provided.\n\n(4) The software builds on accepted community standards for input/output data.\n\n(5) The software provides in addition further tools for processing input/output data.\n\nAdaptability/Flexibility of use\n\n(0) No information given.\n\n(1) There is a way to use the software with one defined set of input data.\n\n(2) There are parameters to adjust the way the software is working.\n\n(3) There is some way of logging what is done during execution.\n\n(4) Documented API(s) are provided to integrate the software into one’s own framework.\n\n(5) There is a documented way to integrate the software into open workflows, e.g. via containers, web-services etc.\n\n5.2.4 Dimension reusable\n\nThe following statements address the aspect of being reusable. In addition of being accessible, i.e. executable, reusability includes the possibility to actually change/adapt the code.\n\nReusability conditions\n\n(0) Not clear.\n\n(1) The software uses a custom license allowing reuse.\n\n(2) The software uses a FOSS/OSI approved license including that license dependencies are at least being checked manually.\n\n(3) The software uses an appropriate license for different file types (code, text, images etc.) following e.g. the REUSE specification.\n\n(4) There is a process available for automatically checking e.g. the REUSE specification.\n\n(5) There is a process available such that all license dependencies are automatically controlled.\n\n5.2.5 Dimension scientific basis\n\nThe following statements address the aspect of the software being scientifically well grounded. While domain specific scientific requirements have to be assessed as part of a scientific peer-review process, certain generic aspect of good scientific practice can be assessed for all research software.\n\nCommunity standards\n\n(0) No information given.\n\n(1) The connection to known (scientific) standards is drawn.\n\n(2) The software follows the standards of the relevant scientific community.\n\n(3) The software complies with relevant scientific standards of the field.\n\n(4) There is an indication on how further evolution of community standards will be addressed.\n\n(5) A closed feedback-loop is established, making sure that further evolutions of community standards are being adopted.\n\nTeam expertise\n\n(0) No information given.\n\n(1) Clear expertise from a single, relevant domain is part of the software development team.\n\n(2) The software development team has access to expertise in several relevant domains.\n\n(3) The software development team has access to expertise in all relevant domains.\n\n(4) A fixed, established, interdisciplinary team works on the software.\n\n(5) An established and coordinated community of software developers works on the software.\n\nScientific embedding\n\n(0) No information given.\n\n(1) At least one scientific use case is documented.\n\n(2) A broader scientific context is documented including several examples.\n\n(3) The software development is at least loosely connected to some scientific initiative.\n\n(4) The software development is part of a larger scientific initiative.\n\n(5) The software development is part of a larger scientific initiative with dedicated processes for software development.\n\n5.2.6 Dimension technical basis\n\nThe following statements address aspects of professional software development leading to sustainable, high quality research software.\n\nProject management\n\n(0) No information on project management and code history being provided.\n\n(1) Some kind of version control is used.\n\n(2) A version control system is used.\n\n(3) A version control system being part of a code project management platform (e.g. GitHub, GitLab) and an associated ticket system is in place.\n\n(4) A transparent process for ticket resolving, code review by other developer, and merge requests is established.\n\n(5) A release process with guaranteed changelog generation, testing, and product provisioning is established.\n\nRepository structure\n\n(0) No information given.\n\n(1) All files are provided in some structured/unstructured way inside the repository.\n\n(2) The repository is structured albeit maybe in a manner such that every contributor is free to follow their own way of organizing files.\n\n(3) A contribution mechanism is documented, e.g. CONTRIBUTORS.md file, as well as a defined structure for the repository and a documented onboarding process.\n\n(4) A common template for the repository structure is available, as well as some kind of identification of deviation.\n\n(5) A repository structure is enforced following community standards.\n\nCode structure\n\n(0) No information given.\n\n(1) Every developer is free to use his/her own style of coding.\n\n(2) There are general recommendations for coding, albeit every developer being able to follow his/her own style.\n\n(3) There is some harmonization of code style being enforced following common standards including meaningful naming of functions/variables etc.\n\n(4) The code style is checked when accepting changes into the repository.\n\n(5) The code style is enforced via a review process (e.g. failed pipelines or auto-formatting).\n\nReproducibility (Code)\n\n(0) No tests, or duplicated code.\n\n(1) The code follows a modular structure allowing for component reusability.\n\n(2) Clear system requirements are documented with min/max versions, albeit version pinning, modularity etc. being enforced manually.\n\n(3) A package manager is used for dependency pinning and testing enforced.\n\n(4) Test coverage is measured, albeit tests may be written on a voluntary basis.\n\n(5) Automated testing for different system environments, requirements for minimal test coverage, and provisioning of containerized packages is done.\n\nCode change process\n\n(0) No information\n\n(1) Internal 4-eye principle for accepting changes\n\n(2) Code changes via transparent processes, e.g. merge/pull request\n\n(3) Approval of code changes via transparent processes and with a 4-eye principle\n\n(4) Integration of code changes into main development branch/releases only allowed for specifically named/trained persons.\n\n(5) Software releases involve an external review (by someone outside of the core developer team)\n\nSecurity\n\n(0) No security concepts given.\n\n(1) There are at least sporadic updates and dependency checks.\n\n(2) There is a systematic assessment of dependencies and documentation of the software stack.\n\n(3) Deployment is provided within a CI/CD framework for different environments including tools for check for security leaks.\n\n(4) There is some process for monitoring dependency updates including reporting.\n\n(5) There are regular and automated security monitoring and an automated update process in place allowing merges only of security checks have been passed.\n\n\n6. Results\n\nThe procedure described so far represents the result of the conceptualization phase of defining a quality indicator for data and software publications as initiated within the Helmholtz Association. For implementation of the procedure, we plan four phases: 1) proof of concept, 2) automatization supported by suitable tools, 3) piloting phase, 4) final implementation within the Helmholtz Association.\n\nFeasibility of the concept is currently evaluated in various research communities by running a couple of exemplifying pen and paper assessments. While the attributes for each quality dimension have been discussed and iterated in several rounds of community engagement, their actual application to assess the quality of given data or software will show whether the formulation of the attributes is clear enough to be applied in a wider community, where documentation of the assessment needs to be improved, or where even manual assessment is not easily possible at the moment.\n\nThe quality assessment should only lead to a minimal increase in resources required for the assessment itself. Therefore, the assessment of all quality dimensions and attributes should be automatized as much as possible, the final assessment and visualization should be done in a digital manner. We currently evaluate existing tools (such as r3data, F-UJI, HERMES, the Helmholtz Research Software Directory (RSD) or the ESCAPE-OSSR onboarding procedures) to identify the quality attributes that can already be assessed automatically. An additional issue in the evaluation is to find out the potential and effort for enhancement of existing tools to assess further quality attributes.\n\nThe piloting phase is considered as a test and improvement of the quality assessment procedure and tools in real world conditions. All Helmholtz Centers are asked to contribute to the piloting phase to get comprehensive feedback about strength and weakness of the quality assessment approach. Iterative improvement will take place in this phase to develop a suitable and robust approach and toolset for quality assessment.\n\nThe suitable and robust approach and toolset for quality assessment will be implemented in the Helmholtz Centers.\n\nThe value of our procedure for quality assessment can be summarized following: Result of the procedure are multi-dimensional quality indicators for data and software publications. A multi-dimensional assessment rather than single numbers will better reflect the complexity and diversity of research outcome and lead to a fairer assessment. Our approach for developing the quality indicators is primarily guided by quality criteria not by technical tools, it starts with defining essential quality criteria and to then condense the list of criteria with respect to technical tool support. Following this approach, we ensure that quality criteria are directed to the intended objectives of quality assessment and not technical feasibility.\n\n\n7. Conclusion\n\nThe described approach to derive multi-dimensional quality indicators for data and software publications has been initiated within the Helmholtz Association. The following main principles were guiding the developing process:\n\n• The indicator must match the quality criteria that are essential for the intended objectives, technical issues must not lead to deviation from that target. The objectives defined in the Helmholtz Association are: a) to create awareness and appreciation to the diversity of research output, b) to align the assessment of research and research practice to the conditions of digitalization and openness of science, and c) as a stimulus and incentive for scientists to improve their data and software publications related to specific quality criteria, and thus, to improve the quality and trustworthiness of science as a whole. Therefore, our basic approach for developing the quality indicator was to define the quality criteria that are essential for the intended objectives in a first step, and to then condense the list of criteria in a second step with respect to technical feasibility of automated collection.\n\n• The indicator should map a multi-dimensional suite of quality criteria onto one value, the quality indicator. The approach of solely using simple and one-dimensional metrics to assess research quality and performance is broadly criticized. Taking this into consideration the quality indicator for research data and research software publications should provide one easily comparable value that still does more then only counting - by representing a diverse set of quality features in itself.\n\n• The quality indicator has to match all types of research data publications and research software publications generated in the diverse scientific disciplines within the Helmholtz Association, generic approaches are required to provide answers to these questions.\n\n• The indicator should rely on generic well-established concepts for quality criteria and quality assessment to make use of already existing preliminary work.\n\nThe result of the conceptual development process is a generic multi-dimensional quality indicator based on a defined set of goal-oriented quality dimensions and attributes as well as well-established, maturity-based concepts for quality measurement.\n\nThe described approach to derive multi-dimensional quality indicators can be used not only to assess quality of data and software but also – in an analog way – the research endeavor as a whole. In the end, the adoption of a precise definition of these indicators, the fine-tuned weighting scheme of quality dimensions and attributes against each other, as well as the definition of a minimal level of maturity to be expected for research data and research software, will make the process of research assessment transparent and open. Moving towards multi-dimensional assessments rather than single numbers will better reflect the complexity and diversity of modern scientific work and, at the end, lead to a fairer assessment of the contributions of the various parts of the scientific system towards the common goal of contributing to increase collective human knowledge.\n\nWith this paper, we share the current state of the process within the Helmholtz Association. We invite all interested parties to further expand, refine, or change the dimensions and attributes being proposed here. It is our belief that any list of criteria has to be a living document to account for the dynamic nature of research. Only through constant evolution, the proposed framework is able to keep up with new thoughts, ideas, and findings on how to improve the scientific process.\n\n\nEthics and consent\n\nEthical approval and consent were not required.\n\n\nCRediT author statement\n\nWolfgang zu Castell Conceptualization, Methodology, Writing – Original Draft\n\nDoris Dransch Conceptualization, Investigation, Writing – Review and Editing, Supervision, Project administration\n\nGuido Juckeland Conceptualization, Writing – Review and Editing, Visualization, Supervision\n\nMarcel Meistring Conceptualization, Writing – Review and Editing, Supervision, Project administration\n\nBernadette Fritzsch Conceptualization, Writing – Review and Editing\n\nRonny Gey Conceptualization, Writing – Review and Editing\n\nBritta Höpfner Conceptualization, Writing – Review and Editing\n\nMartin Köhler Conceptualization, Writing – Review and Editing\n\nChristian Meeßen Conceptualization, Investigation, Writing – Original Draft\n\nHela Mehrtens Conceptualization, Writing – Review and Editing\n\nFelix Mühlbauer Conceptualization, Investigation, Writing – Original Draft\n\nSirko Schindler Conceptualization, Writing – Review and Editing\n\nThomas Schnicke Conceptualization, Writing – Review and Editing\n\nRoland Bertelmann Supervision, Project administration",
"appendix": "Data availability\n\nThis is a method article that proposes a new evaluation method for research data and software publications so there are no data associated with this article.\n\n\nAcknowledgements\n\nThis paper reflects the work of the Task Group Helmholtz Quality Indicators for Data and Software Publications of the Helmholtz Association from the past two years. While not all group members were able to participate in this paper, the authors acknowledge and highly appreciate the constructive discussions of the whole group, namely Gisbert Breitbach (Hereon), Torsten Bronger (FZJ), Stefanie Castell (HZI), Claas Faber (GEOMAR), Tamara Husch (HZB), Ulrike Kleeberg (Hereon), Matthias Kretz (GSI), Marco Nolden (DKFZ), Maria Nüchter (KIT), Florian Ott (GFZ), David Pfaff (CISPA), Will Rayner (HMGU), Marco Schaefer-Herte (DZNE), Dagmar Sitek (DKFZ), Christian Tacke (GSI), Anne Talk (HZI), Regine Tobias (KIT), and Andreas Walker (AWI).\n\nAn initial version of the paper was also shared with research software and data experts within the Helmholtz Association. The authors acknowledge and also incorporated comments to these early versions from Stephan Druskat (DLR), Tobias Huste (HZDR), Sven Kiele (HZDR), Uwe Konrad (HZDR), Tobias Schlauch (DLR), Bernard Silenou (HZI), and Thomas White (DESY).\n\nAn earlier version of this article can be found on arXiv (doi: https://doi.org/10.48550/arXiv.2401.08804).\n\n\nBibliography\n\nEuropean Open Science Cloud (EOSC): EOSC Glossary.2023. Reference Source\n\nGruenpeter M, Katz DS, Lamprecht A-L, et al.: Defining research software: a controversial discussion.2021. Publisher Full Text\n\nSchlauch T, Haupt C, Meinel M: Software Engineering Guidelines - From Theory To Practice.2018. Publisher Full Text\n\nLawrence B, Jones C, Matthews B, et al.: Citation and Peer Review of Data: Moving Towards Formal Data Publication. Int. J. Digit. Curation. July 2011; 6(2): 4–37. Publisher Full Text\n\nWilkinson MD, Dumontier M, Aalbersberg IJ, et al.: The FAIR Guiding Principles for scientific data management and stewardship. Sci. Data. March 2016; 3(1): 160018. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHaes SD, Grembergen WV: COBIT as a Framework for Enterprise Governance of IT. Enterprise Governance of Information Technology. Springer International Publishing; 2015; pp. 103–128.\n\nAmerican Society for Quality (ASQ): What Is a Quality Management System (QMS)?2023. Reference Source\n\nResearch Data Alliance FAIR Data Maturity Model Working Group: FAIR Data Maturity Model: specification and guidelines.2020. Publisher Full Text\n\nHong NPC, Katz DS, Barker M, et al.: FAIR Principles for Research Software (FAIR4RS Principles).2022. Publisher Full Text\n\n\nFootnotes\n\n1 The information is available in a structured form that allows, for example, that the respective information can be read out via script."
}
|
[
{
"id": "289917",
"date": "17 Jun 2024",
"name": "Oliver Karras",
"expertise": [
"Reviewer Expertise (Empirical) Software Engineering",
"Requirements Engineering",
"Knowledge Graphs",
"Data Science"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of the Article: This method article addresses the lack of an established process for assessing and evaluating the quality of research data and research software publications. The authors propose the development of a quality indicator for the publication of research data and research software that enables a corresponding evaluation. In particular, they present their vision of aspects contributing to such an indicator. The current approach that relies on generic and established concepts for quality criteria such as FAIR principles is presented for future discussion.\nSpecific Questions for Method Articles:\n1. Is the rationale for developing the new method (or application) clearly explained? Yes. However, the paper needs to work better with literature to substantiate some of the statements, as they are currently just claims.\n2. Is the description of the method technically sound? Overall, the authors have presented their method well, and their current structure is sound. However, the authors fail to explain several design decisions, so it is sometimes difficult to understand why the method was developed the way it is. I suggest adding a dedicated section on the development process of the method.\n3. Are sufficient details provided to allow replication of the method development and its use by others? No. The authors do not explain how the method has been developed. Furthermore, the author did not test their method, thus it also remains rather unclear how they would apply the method. I suggest adding a dedicated section on the development process of the method and a section on at least a proof of concept that shows the initial results of applying the proposed method.\n4. If any results are presented, are all the source data underlying the results available to ensure full reproducibility? No. The authors only present their plan to evaluate and implement their method but they do not provide any results. I suggest adding a section on at least a proof of concept that shows the initial results of applying the proposed method.\n5. Are the conclusions about the method and its performance adequately supported by the findings presented in the article? No. The authors do not present any results, thus there are no conclusions on the method and its performance supported by any findings. I suggest adding a section on at least a proof of concept that shows the initial results of applying the proposed method. These results must be discussed and used to provide a corresponding conclusion section.\nSummary to Support the Recommendation: Based on the majority of negative answers to the specific questions for method articles, I cannot approve the paper in its current form. The paper lacks details on the development process of the presented method, does not provide any kind of evaluation, and fails to discuss the method and its performance due to the lack of an evaluation. As methods articles describe a new experimental, observational or computational method, test or procedure (basic or clinical research) that should be well tested, I recommend not indexing this article for now since too many details are missing. However, I encourage authors to resubmit their article in a revised and extended version including information on the development process, an evaluation, and a discussion.\nDetailed Comments for the Authors:\nAbstract: Overall, the abstract is easy to read and the paper addresses an important topic. However, I got several questions in my mind while reading the abstract:\nWhat is the problem? Why is such a quality indicator needed? Why can we use one quality indicator for two different types of publications (data vs. software)? What is the objective of the paper? How was the indicator developed and evaluated? What are the current results of applying this indicator?\n\nOverall, the abstract lacks a lot of important information to provide a good overview of the paper for a reader. I suggest using a structured abstract consisting of five parts (Context/Motivation/Problem, Objective, Method, Result, and Conclusion). Using this structure, the abstract covers all important aspects needed for a reader to get a good overview of the paper.\n1. Background and objective From a scientific point of view, the paper must work better with literature. Only 9 references are used in total, which is very few in view of a 19-page article.\nThe authors argue: “…there are well-established processes of quality assurance during the process of publication.” However, they provide neither any references nor any examples that substantiate this claim. Since this claim is used as a central argument in the paper to justify the approach presented, the argument should also be supported with literature.\nI appreciate the authors’ efforts and their objective for developing the quality indicator. Their endeavor is worthwhile and certainly make a significant contribution to positively changing the handling and perception of research data and research software publications. While the authors present in more detail how the indicator was developed, the introduction does not provide any information about the actual results. I have the following open questions after reading the introduction:\nDid the authors develop one indicator for data and software or did they develop one indicator for data and one indicator for software? In the first case, I ask the authors to clarify why and how it is possible to assess data and software with the same indicator. In the second case, the author must revise their text to clarify. What does the indicator look like? What does the indicator consist of? How can the indicator be applied? How was the indicator validated? Did the authors apply the indicator already for tests? What is the contribution of this article in summary? How is the remaining article structured?\nGiven these questions, I suggest revising the introduction by providing more details on the indicator itself, its validation/evaluation, and a summary of the key contributions. In addition, the authors should add a description of the structure of the article at the end of the first section so that a reader gets a better overview of the content of the paper.\n2. Terminology First of all, I appreciate that the authors provide definitions, although not every definition needs to be a separate sub-section. Furthermore, this section lacks a stronger connection to the first section as the authors already use the terms in section 1 but do not point to their definitions in section 2. Furthermore, the papers lacks a related work section on existing similar approach for research data and research software assessment. This section is needed so that a reader understands the authors’ contribution to the state of the art.\nI suggest adding references in section 1 to the respective definitions and provide an overview of related work. In particular, section 1 could be a more general introduction into the topic of the paper and section 2 could provide the background, definitions, and related work.\nThe lack of a related work becomes obvious when reading the sentence “The FAIR principles have been widely adopted as a minimum set of quality criteria for research data and research software thus, our approach generally also builds on the four principles…” (page 4). If the FAIR principles are widely adopted as a minimum set of quality criteria for research data and software, the authors should be able to provide an overview of existing approach using the FAIR principles to assess the quality of research data and software.\n3. Methodical framework – quality criteria and quality quantification Given the first paragraph of this section, the authors’ idea seems to be to provide one easily comparable value to assess quality of research data and software. However, this value seems to be based on a diverse set of quality feature. This information is important and missing in the introduction. A reader struggles to understand what this intended quality indicator is without this explanation which is presented far too late in section 3 on page 3.\nThe presented questions guiding the development of the quality indicator are good. However, they should not be hidden in the running text. I suggest presenting them more prominently in a box as they are enumerated.\nGiven all the explanations of reusing the FAIR principles, adding criteria for research software, and even regrouping the FAIR criteria for research data, these explanations would benefit from a visualization providing an overview of the general structure of the indicator and its dimensions and criteria. The authors present many details without a clear higher-level overview of the general structure and approach. I suggest adding such a visualization to support a reader by diving into the details of the proposed approach based on a higher-level overview as a starting point.\nI need to ask: Why did the authors decide to use the COBIT maturity model in particular? Are there other options? If so, why COBIT? If not, this information should be stated explicitly.\n4. The Quality Indicator for research data The presentation of the derived quality dimension is slightly confusing, as the authors do not explain how they derived these dimensions. While section 3 states that they regrouped the FAIR principles, the actual process remains unknown.\nThe entire presentation of the dimensions, attributes, and their maturity levels only consists of text and listings. I strongly recommend creating an appropriate visualization for a better overview. Furthermore, the current textual presentation wastes a lot of space and do not provide any explanations. In most cases, the authors only list the attribute and its maturity level, without providing explanations that define the attribute and explain the reasons why the attribute was chosen. I suggest revising the section, sub-sections, even subsub-sections by using tables for a more condensed overview, defining the attriutes and explaining their motivation and rationale.\nFrom a scientific point of view, the paper lacks details on the development process of the dimensions, attributes, and maturity levels. At the moment, the paper only presents them without any information how and why they have been identified and defined. Therefore, the scientific soundness is limited. I suggest adding a section that better explains the development and at best validation process of the quality indicator.\nIn some cases the authors provide examples for specific parts of maturity levels, such as “Published with identifier - Level 4 - DOI” or “Primary data formats - Level 4 - Codelists”. I think if using a tabular format for the presentation in general, it might be worthwhile to provide an example for each level of each attribute, if applicable.\n5. The Quality Indicator for research software Given this section and section 4, the authors propose 2 quality indicators one for software and one for data. Therefore, I suggest revising the introduction and the title. At the moment, the title implies that one indicator for both artifacts is proposed. However, the authors present one indicator for each artifact.\nI need to ask: Why are the 5 levels of maturity used for evaluating the quality of software publications labeled (5) – (10) (cf. page 11, section 5.2)?\nSimilar to section 4, this sections only presents the dimensions, attributes, and maturity levels without any explanations which limits the scientific soundness of the paper. In addition, a reader does not understand why specific elements have been included or what the mean (as explanations of the development process, decisions, and even definitions (e.g., for the attributes) are missing.\n6. Results The name of this section is misleading. I expected to read about results of applying the quality indicators. However, the authors only present their plans for implementing the proposed approach. While I appreciate that the authors already have a detailed plan for implementing their approach, the paper lacks any kind of evaluation. According to the journal, “Method Articles describe a new experimental, observational, or computational method, test or procedure (basic or clinical research), and should have been well tested.” This paper does not even report on initial findings from the proof of concept. I suggest revising the paper by adding at least initial at best complete results of the proof of concept so that there are some results showing that the approach have been tested.\nIt would also be beneficial if the plan presented included at least a rough timetable so that the reader can better see when certain steps should theoretically be carried out.\n7. Conclusion While the conclusion is well-written, I missed a discussion of the proposed approach regarding its strengths and weaknesses, but also implications for academia and maybe even industry. The paper would benefit from a dedicated discussion section.\nMinor Comments:\nThe keywords lack at least topics such as “quality”, “assessment”, and “indicators”. I suggest coming up with more keywords. Section 1 could be named “Introduction”. The presented overall approach on page 4 is suitable for a visualization that breaks up the long continuous text and offers the reader visual access to the article.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? No\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? No",
"responses": [
{
"c_id": "12311",
"date": "28 Aug 2024",
"name": "Guido Juckeland",
"role": "Author Response",
"response": "Thank you very much for the detailed and helpful review. We are currently working on a major revision of the paper that hopefully addresses your raised issues."
}
]
},
{
"id": "289918",
"date": "27 Jun 2024",
"name": "Wilhelm Hasselbring",
"expertise": [
"Reviewer Expertise Software Engineering"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of the article ======================\nThe paper introduces a comprehensive model for evaluating the quality of research data publications and research software publications. The proposed model's evaluation criteria are built upon the FAIR principles: FAIR-ST for research software and POCME for research data. The authors incorporate the COBIT Maturity model to quantify each evaluation criterion. They recognize that scientific publications require multi-dimensional evaluation criteria and propose incorporating a radar plot as an alternative to one-dimensional metrics used for scientific papers. The proposed radar plot includes multiple dimensions, where each dimension presents a weighted average of all underlying attributes that constitute the dimension.\nContributions of the article ============================\nAs the paper mentions, there are two working groups for determining quality criteria and quality quantification for research data (RDA FAIR Data Maturity Model WG) and research software (RDA FAIR for Research Software (FAIR4RS) WG). The authors contribute with a new approach that acknowledges the existing efforts and includes two additional tools: a radar plot and the COBIT maturity model. The radar plot outstands one-dimensional metrics for being visually intuitive while maintaining multi-dimensional criteria. The COBIT maturity model generalizes the quantification of scientific publications, inviting community contributions from different disciplines to suggest attributes and weighted average metrics for each criterion.\nSuggestions ===========\nTo strengthen the proposed approach, we ask the authors to add a section on related works. Examples are:\n- RSMM: A Framework to Assess Maturity of Research Software Project (Deekshitha, et al.,2024) [REF-1] - The hidden REF https://hidden-ref.org/ - Technology Readiness Level (TRL) is a widely used assessment model generalized for evaluating the maturity of scientific outcomes and scientific projects (ISO 16290:2013) https://en.wikipedia.org/wiki/Technology_readiness_level. For example, the EU implements the use of TRL for Horizon 2020 and Horizon Europe (Horizon Europe Work Programme 2023-2025 13. General Annexes). Therefore, it is worthwhile to compare and assess the compatibility between TRL and COBIT as background work.\nIn Section 3.2, the authors propose implementing weighted averages for different attributes that constitute a quality dimension. However, the authors keep it implicit whether they do not recommend using weighted averages among dimensions or among attributes of a dimension. They also mention \"weighted summation\". So, average or sum? Please elaborate.\nIt is confusing that you suggest five levels for research data (0 - 4), while COBIT uses six (0-5). For research sofware, you use six.\nYour design decisions are not documented. What is the rationale for FAIR-ST and POCME, can you explain your choices?\nThe long list of levels for the attributes is somehow arbitrary, without a provided rationale. For instance, testing is only included with Level 5 in Project management. Why not including testing already in lower levels?\nSection 6 does not present results, it indicates some future work. The section heading should reflect that.\nEngaging real-world evaluation examples will help readers understand the goal of the paper and motivate them to collaborate on the proposed approach. Because the described quality indicator is generic, some concrete examples for research data and software will provide ideas where to start. The authors mention that they are already doing preliminary evaluations as proof of concept; therefore, providing some of its details (quality dimensions and quantifications with weighted averages that are used for research data and research software) and the resulting radar plot will make the paper more accessible.\nTo evaluate research software, the authors added two more quality dimensions to the existing FAIR principles: (1) scientific basis and (2) technical basis. However, the authors left it open for research data. Could there be a quality dimension of research data, which comes from its scientific basis?\nA major concern with the present paper is that the computation of the \"magic\" single number is not properly explained. The term \"quality indicator\" seems to be important, but this concept is not really explained. You write \"The indicator should map a multi-dimensional suite of quality criteria onto one value, the quality indicator\". We suggest to add some equations on how to compute that indicator / value.\nYou write \"A multi-dimensional assessment rather than single numbers will better reflect the complexity and diversity of research outcome and lead to a fairer assessment\", but you also propose to compute a single number. That's confusing.\nWhat is this \"easily comparable value\"? Do you mean the \"normalization\" of all dimensions to the range of 0 .. 5 ?\nThe use and modification of the COBIT maturity model may have to adhere to some of its restrictions because it is an intellectual property / commercial background. Therefore, it would be good to investigate the regulations. At least explain why this is no problem.\nHere are a few minor comments.\n- In Section 2.2, it should be \"application classes\", not \"software classes\"\n- Figure 1 depicts ``Minimum Requirement'' (orange line) and ``Maximum Score per Dimension'' (green line). The figure lacks a description for the ``Maximum Score per Dimension'' line. Why is the Maximum Score of Dimension 5, 4 and not 5 as with all other dimensions?\n- What do you mean with \"constructive\" in \"a single quality criterion for research data assessment would not be constructive\" ?\n- What do you mean by \"some aspects of scientific quality can also be considered in wider generality\". Can you give an example?\n- The term \"Technical basis\" in Section 5 is strange. We think, this should be called \"Engineering basis\".\n- The enumeration in Section 5.2 starts with \"(5)\" ?\n- In Section 5.2.5, can you give examples for \"standards of the relevant scientific community\" for software?\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? No\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? No",
"responses": [
{
"c_id": "12312",
"date": "28 Aug 2024",
"name": "Guido Juckeland",
"role": "Author Response",
"response": "Thank you very much for the detailed and helpful review. We are currently working on a major revision of the paper that hopefully addresses your raised issues."
}
]
}
] | 1
|
https://f1000research.com/articles/13-471
|
https://f1000research.com/articles/13-469/v1
|
09 May 24
|
{
"type": "Study Protocol",
"title": "An interventional cross-sectional study of electrolyte levels in newborns with hyperbilirubinemia before and after phototherapy in a tertiary care hospital in central India",
"authors": [
"Ankita Kiran Patel",
"Jayant Vagha",
"Jayant Vagha"
],
"abstract": "Introduction This study protocol outlines a comprehensive investigation into the impact of phototherapy on electrolyte levels in newborns with hyperbilirubinemia. With a focus on neonates admitted to the Neonatal Intensive Care Unit (NICU) at Jawaharlal Nehru Medical College and AVBR Hospital, Sawangi, Wardha, Central India, the research aims to contribute valuable insights into the physiological changes associated with this common neonatal condition. The study’s introduction highlights the rationale, significance, and gaps in current knowledge, emphasising the need for a detailed exploration of electrolyte dynamics before and after phototherapy.\n\nMethod The methodology involves a descriptive, interventional cross-sectional design with a calculated sample size of 264 neonates. Standardised protocols for data collection, including serum electrolyte analysis and urine-specific gravity assessment, will be employed. Inclusion and exclusion criteria are clearly defined to ensure a homogenous study population. Statistical analyses, utilising R Studio 4.3.1 will encompass descriptive statistics, comparative analysis, correlation analysis, and multivariate analysis to explore the nuanced relationships between variables. Rigorous ethical considerations and transparency in reporting will guide the data collection process.\n\nExpected Result Anticipated outcomes include a nuanced understanding of changes in serum electrolyte levels following phototherapy and the correlation of these changes with the treatment duration. The study is poised to shed light on the impact of gestational age and birth weight on electrolyte responses. Through rigorous statistical analysis, the research aims to provide evidence-based insights that can inform neonatal care protocols. The anticipated findings hold the potential to influence clinical practices, enhancing the quality of care provided to newborns with hyperbilirubinemia undergoing phototherapy.",
"keywords": [
"Hyperbilirubinemia",
"Phototherapy",
"Neonates",
"Electrolyte levels",
"Newborn care",
"Tertiary care hospital"
],
"content": "Introduction\n\nNeonatal hyperbilirubinemia remains a prevalent concern in newborn care, often necessitating interventions such as phototherapy for effective management. This study protocol delves into the intricate dynamics of electrolyte levels in neonates with hyperbilirubinemia, seeking to enhance our understanding of the physiological impact of phototherapy. According to the World Health Organization (WHO), approximately 60% of full-term newborns and 80% of preterm newborns experience jaundice, highlighting the significance of investigating therapeutic modalities for hyperbilirubinemia.1\n\nWhile phototherapy is a widely adopted treatment, the specific effects on serum electrolyte levels in neonates remain a subject of exploration.2 Previous studies have focused on the efficacy of phototherapy in reducing bilirubin levels, but a comprehensive understanding of its influence on electrolyte balance is yet to be elucidated.3 Electrolyte imbalances in neonates can have profound consequences, impacting various physiological processes, including renal function and neuromuscular excitability.4\n\nThis study, conducted at the Neonatology unit in Jawaharlal Nehru Medical College and AVBR Hospital, Sawangi, Wardha, Central India, aims to bridge this knowledge gap. We aspire to unravel the intricate relationship between phototherapy and changes in serum electrolyte levels by employing a descriptive, interventional cross-sectional design and a meticulously calculated sample size. Rigorous statistical analyses, guided by ethical considerations, will contribute to the academic discourse and inform evidence-based neonatal care protocols.\n\nThe significance of this research lies in its potential to offer nuanced insights that may shape clinical practices, ultimately improving outcomes for neonates with hyperbilirubinemia undergoing phototherapy. Through the lens of this study, we aspire to contribute to the ongoing efforts to enhance the quality of care and outcomes for newborns, addressing a crucial aspect of neonatal health.\n\nThis study’s primary aim is to investigate phototherapy’s impact on electrolyte levels in newborns with hyperbilirubinemia, thereby enhancing our understanding of the physiological changes associated with this common neonatal condition.\n\n\n\n1. To assess serum electrolyte levels: Determine and compare the levels of essential electrolytes (Sodium, Potassium, Calcium) in the serum of newborns with hyperbilirubinemia before and after the administration of phototherapy.\n\n2. To evaluate urine specific gravity levels: Examine and compare the specific urine gravity levels in newborns with hyperbilirubinemia before and after phototherapy, providing insights into potential changes in renal function.\n\n3. To correlate electrolyte changes with phototherapy: Establish a correlation between the changes in serum electrolyte levels and the duration/intensity of phototherapy, elucidating the relationship between the treatment and its physiological impact.\n\n4. To determine day-of-life impact: Investigate any variations in electrolyte levels concerning the day of life, recognising potential developmental patterns or trends.\n\n5. To explore gestational age and birth weight influence: Analyze the potential influence of gestational age and birth weight on the electrolyte response to phototherapy, contributing to a comprehensive understanding of individualised treatment effects.\n\n\nMethods\n\nThis study adopts a descriptive, interventional cross-sectional design to comprehensively analyse electrolyte levels in newborns with hyperbilirubinemia before and after phototherapy.\n\nThe study population comprises neonates admitted to the Department of Pediatrics Neonatology unit at Jawaharlal Nehru Medical College and AVBR Hospital, Sawangi, Wardha, Central India.\n\nThe research will be conducted within the confines of the Neonatology unit, providing a controlled and specialised environment for the study.\n\nInclusion criteria:\n\n1. Neonates admitted to the Neonatal Intensive Care Unit (NICU).\n\n2. Neonates diagnosed with hyperbilirubinemia.\n\n3. Neonates undergoing phototherapy.\n\n4. Neonates with a minimum age of 24 hours.\n\nExclusion criteria:\n\n1. Neonates with Conjugated Hyperbilirubinemia.\n\n2. Neonates requiring intravenous (IV) fluid and intensive care.\n\n3. Neonates exclusively formula-fed.\n\n4. Neonates with co-morbidities, such as acute renal failure.\n\nTo minimise potential biases in the study, several measures will be implemented:\n\n1. Selection bias:\n\n• To mitigate selection bias, the inclusion and exclusion criteria are clearly defined and strictly adhered to during enrollment.\n\n• Random sampling methods will be employed to select eligible neonates, reducing the likelihood of systematic bias in participant selection.\n\n2. Information bias:\n\n• Standardized protocols for data collection will be established and followed rigorously to ensure consistency and accuracy.\n\n• Researchers will be trained to collect data uniformly, reducing the chances of information bias.\n\n\n\n1. Recruitment:\n\n• Neonates meeting the inclusion criteria will be recruited from the NICU after obtaining informed consent from their parents or legal guardians.\n\n2. Informed consent:\n\n• A detailed information sheet in the local language will be provided to parents, explaining the study’s purpose, procedures, potential risks, and benefits. Informed written consent will be obtained before enrollment.\n\n3. Ethical considerations:\n\n• Ethical approval has been obtained and written informed consent will be taken before the commencement of the study, ensuring that ethical standards are met throughout the research process.\n\n4. Transparent reporting:\n\n• The enrollment process, including the number of eligible and enrolled participants, will be reported transparently to allow for external scrutiny and assessment of potential selection biases.\n\nThe data collection process for this study will involve a systematic and meticulous approach to ensure the acquisition of accurate and reliable information. Trained research personnel with a standardised data collection protocol will gather the necessary data from the enrolled neonates and their medical records.\n\nUpon admission to the Neonatal Intensive Care Unit (NICU), eligible neonates meeting the inclusion criteria will be identified. The research team will approach these neonates’ parents or legal guardians, and a detailed information sheet will be provided in the local language, explaining the study’s purpose, procedures, and potential implications. Informed written consent will be obtained from those willing to participate.\n\nThe data collection will include the day of life, serum electrolyte levels (specifically Sodium, Potassium, and Calcium), gestational age, and birth weight. Trained researchers will employ standard measurement techniques and calibrate instruments to collect blood samples for serum electrolyte analysis.\n\nTo assess urine-specific gravity levels, non-invasive methods will be employed, with urine samples collected before and after the administration of phototherapy. The timing and duration of phototherapy will be carefully documented to explore potential correlations between electrolyte changes and the treatment regimen.\n\nA detailed case report form (CRF) will systematically record the gathered information. The CRF will include sections for demographic details, medical history, laboratory results, and details of phototherapy. The research team will ensure the confidentiality and privacy of the collected data, assigning unique identifiers to each participant to maintain anonymity.\n\nRegular training sessions for the research personnel will be conducted to reinforce adherence to the standardised data collection procedures, minimising the risk of observer bias. Additionally, periodic quality checks and data audits will be performed to ensure the accuracy and completeness of the collected data.\n\nEthical considerations will be paramount throughout the data collection process, with strict adherence to privacy regulations and respect for the participants’ autonomy. The collected data will be securely stored and only accessible to the authorised research team members, contributing to the integrity and validity of the study outcomes.\n\nThe sample size for this study was determined using a formula that considers various parameters. In this case, with a population size of 10,000, a percentage frequency of hypocalcemia in neonates receiving phototherapy set at 22% (or 0.22), and a confidence limit of 5%, the calculated sample size is 264. The formula incorporates a design effect (DEFF), which, in this instance, is considered as 1. The confidence level chosen for the study is 95%, represented by the Z-score corresponding to the critical value of 1.96. This calculated sample size of 264 is expected to provide a robust representation of the population, ensuring a suitable level of confidence and precision in estimating the frequency of hypocalcemia in neonates undergoing phototherapy for hyperbilirubinemia within the given population size.\n\n\n\n1. Changes in serum electrolyte levels: The study expects to observe changes in serum electrolyte levels, particularly Sodium, Potassium, and Calcium, before and after the administration of phototherapy. Any significant alterations in these electrolytes may shed light on the physiological response of newborns to phototherapy.\n\n2. Correlation with phototherapy: The research aims to establish a correlation between the duration and intensity of phototherapy and the observed changes in serum electrolyte levels. Understanding this correlation could aid healthcare providers in optimising phototherapy regimens for neonates with hyperbilirubinemia.\n\n3. Urine-specific gravity levels: The study anticipates variations in urine-specific gravity levels before and after phototherapy, providing insights into the renal impact of the treatment. This information could be crucial for assessing renal function in neonates undergoing phototherapy.\n\n4. Day-of-life impact: The research will explore whether there are variations in electrolyte levels based on the day of life, potentially identifying patterns or trends in the response to phototherapy at different stages of neonatal development.\n\n5. Influence of gestational age and birth weight: The study aims to analyse the influence of gestational age and birth weight on the electrolyte response to phototherapy. This information could contribute to a better understanding of individualised treatment effects based on neonatal characteristics.\n\n6. Clinical implications: The expected outcomes can inform clinical decision-making in the management of hyperbilirubinemia in neonates. Understanding the electrolyte changes associated with phototherapy may guide healthcare professionals in tailoring treatment plans for improved efficacy and safety.\n\n7. Contribution to neonatal care guidelines: Positive findings from the study may contribute to developing or modifying neonatal care guidelines, providing evidence-based recommendations for managing hyperbilirubinemia in clinical settings.\n\nThe statistical analysis for this study will thoroughly examine the relationships between variables and derive meaningful insights from the collected data. SPSS Version 23 will be the tool of choice for conducting the analysis, employing various statistical methods tailored to the nature of the data. Descriptive statistics will present categorical variables in frequencies and percentages, such as the day of life and gestational age. Quantitative variables, including serum electrolyte levels and birth weight, will be described using measures of central tendency (mean or median) and dispersion (standard deviation or interquartile range).\n\nTo compare serum electrolyte levels before and after phototherapy, paired t-tests or Wilcoxon signed-rank tests will be applied, depending on the data distribution. The chi-square test or Fisher’s exact test will be employed for comparing categorical variables, such as the presence or absence of specific conditions. Correlation analysis will use Pearson correlation or Spearman’s rank correlation to assess the strength and direction of relationships between continuous variables, particularly exploring correlations between electrolyte changes and the duration or intensity of phototherapy.\n\nMultivariate analysis will be conducted through multiple linear regression to explore the simultaneous impact of multiple independent variables, such as gestational age and birth weight, on the dependent variable, which could be changes in electrolyte levels. Subgroup analyses may investigate the influence of specific factors (e.g., gestational age, birth weight) on outcomes within distinct subpopulations. Sensitivity analyses may also be conducted to assess the robustness of the findings, evaluating the impact of potential outliers or variations in the analytical approach.\n\nThroughout the analysis, a significance level (alpha) of 0.05 will be considered, and p-values will be reported to determine the statistical significance of the findings. The research team will interpret the results in the context of the study objectives and relevant literature, providing a comprehensive understanding of the impact of phototherapy on electrolyte levels in newborns with hyperbilirubinemia. The chosen statistical methods aim to enhance the validity and reliability of the study’s conclusions.\n\nThe Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (DU) has granted its approval to the study protocol (Reference number: DMIHER (DU)/IEC/2023/899. Date:31-03-2023). Before commencing the study, we will obtain written informed consent from all participants, providing them with a comprehensive explanation of the study’s objectives.\n\nAfter the completion of the study, we will publish it in an indexed journal or conference.\n\nThe study is yet to start. After the publication of the protocol, we will start recruitment in the study.\n\n\nDiscussion\n\nThe proposed study aims to investigate the impact of phototherapy on electrolyte levels in newborns with hyperbilirubinemia, contributing valuable insights to understanding physiological changes associated with this common neonatal condition. The discussion will explore the potential implications of the study findings in the context of existing literature and clinical practice.\n\nThe observed changes in serum electrolyte levels before and after phototherapy hold significance in managing hyperbilirubinemia. Previous studies have suggested that phototherapy may influence electrolyte balance in neonates, with reported alterations in sodium, potassium, and calcium levels.5,6 The proposed study will add to this body of knowledge by providing specific insights into these electrolyte changes in the central Indian neonatal population.\n\nThe correlation analysis between electrolyte changes and the duration/intensity of phototherapy is a crucial aspect of the study. It aligns with existing literature that underscores the importance of monitoring electrolyte levels during phototherapy.7 The findings may guide clinicians in optimising phototherapy regimens, ensuring efficacy while minimising potential electrolyte disturbances in neonates.\n\nThe exclusion criteria, including neonates with conjugated hyperbilirubinemia and those requiring intensive care, are aligned with previous studies that focused on uncomplicated hyperbilirubinemia.8,9 However, the decision to exclude neonates with formula feeding and co-morbidities like acute renal failure warrants consideration in the context of potential variations in electrolyte response. Further research may be needed to explore these exclusions’ rationale and their impact on the generalizability of the study findings.\n\nThe study’s strength lies in its rigorous methodology, including standardised data collection procedures and systematic control of confounding variables. However, the two-year duration may present challenges in maintaining consistency in data collection and potential changes in clinical practices over time. Regular data audits and periodic reassessment of protocols may mitigate these concerns.\n\nThe Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (DU) has granted its approval to the study protocol (Reference number: DMIHER (DU)/IEC/2023/899. Date:31-03-2023). Before commencing the study, we will obtain written informed consent from all participants, providing them with a comprehensive explanation of the study’s objectives.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nAnsong-Assoku B, Shah SD, Adnan M, et al.: Neonatal Jaundice. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.\n\nTan KL, Jacob E: Effect of phototherapy on neonatal fluid and electrolyte status. Acta Paediatr. Acad. Sci. Hung. 1981; 22: 187–194. PubMed Abstract\n\nWang J, Guo G, Li A, et al.: Challenges of phototherapy for neonatal hyperbilirubinemia (Review). Exp. Ther. Med. 2021; 21: 231. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHerin P, Aperia A: Neonatal kidney, fluids, and electrolytes. Curr. Opin. Pediatr. 1994; 6: 154–157. Publisher Full Text\n\nAlizadeh-Taheri P, Sajjadian N, Eivazzadeh B: Prevalence of Phototherapy Induced Hypocalcemia in Term Neonate. Iran. J. Pediatr. 2013; 23: 710–711. PubMed Abstract\n\nKhan M, Malik KA, Bai R: Hypocalcemia in jaundiced neonates receiving phototherapy. Pak. J. Med. Sci. 2016; 32: 1449–1452. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJafari Giv Z, Avan A, Hamidi F, et al.: Nutrients intake, and serum calcium and phosphorus levels: An evidence-based study. J. Clin. Lab. Anal. 2017; 32: e22235. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSubcommittee on Hyperbilirubinemia: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics. 2004; 114: 297–316. Publisher Full Text\n\nMaisels MJ: Phototherapy--traditional and nontraditional. J. Perinatol. 2001; 21 Suppl 1: S93–S97. discussion S104–S107. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "277005",
"date": "11 Jun 2024",
"name": "Jagdish Prasad Sahoo",
"expertise": [
"Reviewer Expertise Neonatology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. What is the research question? 2. What phototherapy machine will be used? Is it CFL phototherapy or LED phototherapy? 3. What may be the possible reasons of electrolyte disturbance in a baby recieving phototherapy? If there is a plausible biological mechanism for the electrolyte disturbance? The CFL phototherapy used previously may cause some weight loss and electrolyte imbalance. But in the present time when, CFL phototherapy is completely replaced by LED phototherapy, which is also called as Cold light phototherapy because of non-generation of heat, why the researchers felt so to undertake the study? 4. The researchers need to explain the methos of Bilirubin, electrolyte estimation? 5. As the difficult sampling may falsely increase the potasium levels, how the researchers will ensure the sample collected is free flow sample to avoid spurious hyperkalemia?\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "291762",
"date": "03 Jul 2024",
"name": "Asim Kumar Mallick",
"expertise": [
"Reviewer Expertise NEONATAL HYPER BILIRUBINEMIA"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n“……..understanding of the physiological impact of Phototherapy”: Please elaborate on the significance of electrolyte imbalance following phototherapy in the Introduction Section. Mention the underlying mechanism, and how phototherapy leads to the disturbance in electrolyte level. Please explain how your research contributes to the existing body of knowledge as found in (Tosson A. et al., 2022[Ref 1]), (Purohit A, et al., 2020[Ref 2]) If the neonate has any genetic predisposition towards electrolyte imbalance, that shall be informed while collecting of the data.\n\n“The significance of this research lies in its potential to offer nuanced insights that may shape clinical practices, ultimately improving outcomes for neonates with hyperbilirubinemia undergoing phototherapy…..”\nPlease elaborate the implication of the study and how it will benefit the clinicians.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-469
|
https://f1000research.com/articles/12-1546/v1
|
01 Dec 23
|
{
"type": "Research Article",
"title": "Assessment and comparison of quality of alcohol-based hand sanitizers, pre- and peri-COVID-19 pandemic outbreak in Kenya",
"authors": [
"Samuel Omari",
"Florence Ng'ong'a",
"James Kimotho",
"Florence Ng'ong'a",
"James Kimotho"
],
"abstract": "Background: In the wake of the coronavirus disease 2019 (COVID-19) pandemic, the World Health Organization recommended the use of alcohol-based hand rubs (ABHRs) to curb transmission, leading to increased production and use. This has posed a danger of production and use of poor-quality ABHRs.\nMethods: This study assessed and compared the quality of ABHRs in the Kenyan market that were produced before and after the outbreak of the COVID-19 pandemic in March 2020. Quality testing was carried out against European EN 1500:2013 and Kenyan EAS 789:2013 Standards.\nResults: The study found that 27.8% of the peri-pandemic sanitizers had less than 90% bactericidal reduction activity as compared to 12.5% manufactured pre-pandemic. Only 25% peri-pandemic ABHRs met the EAS 789:2013 acceptable limit of over 60% alcohol content. Product adulteration with methanol was found in 20 % of the samples with only 5% complying with FDA approval limit of <0.063% v/v methanol. Study found no correlation between the total alcohol content and the efficacy of ABHRs.\nConclusions: The study found that more substandard products were produced during the pandemic. This raises a concern about possible emergence of alcohol resistant strains of microorganisms. The study therefore recommends an adequate quality monitoring system to curb against substandard products.",
"keywords": [
"Coronavirus",
"COVID-19",
"Pandemic",
"Alcohol-based hand sanitizers",
"hand hygiene",
"Infection prevention"
],
"content": "Introduction\n\nIn the wake of the coronavirus disease 2019 (COVID-19) pandemic, the World Health Organization (WHO) widely recommended hand hygiene as one key containment strategy to the spread of the virus, which included frequent hand washing with soap and the use of antibacterial hand rubs (ABHRs) with more than 60% alcohol content.1 A 30-second application of ABHRs has been reported to have a better disinfection efficacy than traditional soap and water approaches, with more than 3.5 log10 reduction in bacterial counts. Two ABHRs formulations had subsequently been recommended by WHO, one containing 80% ethyl alcohol and another formulation containing 75% isopropyl alcohol.2 The use of sanitizer therefore has been embraced in both the hospital environment and community to prevent acquired infections (HAIs and CAI, respectively).3\n\nIn March 2020, the Kenyan government, as part of the measures adapted to curb spread of COVID-19, also recommended the use of ABHRs. This resulted in an increased production of different brands in the Kenyan market4 and their widespread use, which in turn increased the possible development of resistant strains of microorganisms.5 Exposure of microorganisms to inappropriately used or poor-quality ABHRs can lead to the survival of some strains, subsequently leading to resistance.5–8 Such resistance has been reported in Enterococcus faecium as well as Salmonella typhimurium.9,10 Carrying out studies on the quality and effectiveness of these brands of ABHRs as well as the emerging resistance due to poor-quality ABHRs is imperative.\n\nThe aim of this study was to assess and compare the quality and efficacy of alcohol-based hand sanitizers against Escherichia coli and Staphylococcus aureus pre- and peri-COVID-19 pandemic outbreak in Kenya.\n\n\nMethods\n\nA total of 90 ABHRs samples were collected for the study period through convenience sampling method, as the total number of ABHRs brands in the Kenyan market was not known. The KEMRI Innovation & Technology Division (KITTD) had collected ABHRs from shelves and archived them as part of its research and development activities before March 2020. A total of 55 archived sanitizers within the expiration period at the time of laboratory testing were selected for analysis. In addition, 35 different sanitizer brands from the local retail shelves manufactured during the pandemic period, i.e. after March 2020 to June 2021, were collected as peri-COVID-19 samples (Figure 1). During the peri-pandemic sanitizer sample collection highest priority was given to the brands found to have been already collected and archived during the pre-pandemic period. They were cross-checked for regulatory compliance using the Kenya Bureau of Standards USSD verification database.11 All hand sanitizers collected from the market were tested. In addition, control samples were prepared in the KITTD Laboratory using protocol as described by WHO for quality assurance so as to ensure validity and reliability of results obtained during efficacy testing.2\n\nThe assay profiled and quantified three analytes: ethanol, isopropyl alcohol and methanol using Shimadzu GC-2010 plus - Gas Chromatography with Flame Ionization Detector (GC-FID) following the protocol as described by Zhang.12 This was done as follows: the working solution (WS) was prepared by diluting glycerin in distilled water to a concentration of 4.6% (v/v). The alcohol calibration standards were prepared by adding aliquots of pure alcohols - ethanol, IPA, methanol, n-propanol (n-PA) - to distilled water. The internal standard (IS) acetonitrile (ACN) was added to the calibration solutions at a concentration of 5% (v/v). The quality control sample was prepared by diluting 25 μL of ethanol, 25 μL of IPA, and 50 μL of acetonitrile to 1 mL in distilled water. The gel ABHR samples were diluted before injection due to viscosity. These samples were analyzed in the GC-FID with the following analytical parameters:\n\n• Split/Splitless inlet: 250°C, split ratio 20:1\n\n• Injection volume: 0.2 μL\n\n• Carrier gas: helium\n\n• Column flow rate: 7 mL/min, constant flow mode\n\n• Oven: 50°C (5 min), 30°C/min to 230°C (3 min)\n\n• FID: 250°C, air: 400 mL/min, fuel gas (H2): 30 mL/min, constant make up flow: 18 mL/min\n\nDetermination of pH of ABHRs samples was measured using Thermo Scientific Orion Star A214 pH and ISE Benchtop Meter with limits as specified by KS EAS 789:2013 standard.\n\nEfficacy testing was carried out using quality control strains of E. coli ATCC 25922 and S. aureus ATCC 25923 as described in the European Standard (EN) 1500:201313 and KS EAS 789:2013. Briefly, 0.5 Mac Farland suspensions of the microorganisms were separately prepared as per the method described by the Clinical and Laboratory Standards Institute.14 As a quality control measure, so as to ensure validity and reliability of results obtained during efficacy testing, a control sample of 80% ethyl alcohol was prepared from absolute ethanol by mixing 800 mL of pure ethyl alcohol and 200 mL of distilled as guided by WHO2; this was further tested using an alcoholmeter to measure the alcohol percentage in the control sample. This was tested together with the ABHR samples. Means of the colony forming units were used in determining log reduction values.\n\nLogarithmic reduction factors (RF) were assessed based on pretreatment and post-treatment with the ABHRs and the results of each ABHRs manufactured during the pandemic period compared to those collected before the pandemic. The logarithmic reduction factors were expressed as a percent reduction. Log reduction was calculated as log10 (pretreatment A) - log10 (post treatment B) and the percent reduction was calculated as (A-B)/A% where; where A = number of viable microorganism at before treatment and B = number of viable microorganism after treatment.13\n\n\nResults\n\nIn the case of active ingredients, 41.08% of pre-COVID-19 sanitizers listed the active ingredient used; of these, 16.08% specifying the percentage composition of active ingredient which included ethanol, isopropyl alcohol (IPA) and 25% did not indicate the exact percentage composition. A total of 58.9 % did not list the active ingredient. For sanitizer samples collected in the peri-pandemic period, the majority of the brands (94.4%) listed the active ingredients used; of these, 66.7% listed >60%, alcohol as an active ingredient and 27.7% did not declare their exact percent alcohol content; sanitizers that did not declare the active ingredient composition accounted for 5.56% (Figure 2).\n\nThe shelf lives allocated to the sanitizers were highly varied. For pre-COVID-19 alcohol-based hand sanitizers, 16% did not state the manufacture and/or expiry dates, as compared to only 5.56% (n = 2) for the peri-pandemic period. The majority of the hand sanitizers manufactured during either of the periods under review had shelf lives of between two-three years, i.e. 44.6 % for pre-COVID and 41.7% for peri-pandemic ABHRs. Shelf life was one-two years (10.7%), three-four years (3.6%), four-five years (1.79%), more than five years (5.36%) for pre-pandemic ABHRS and one-two years (36.1%), three-four years (11.1%), four-five years (2.8%), and more than five years (2.8%) for peri-pandemic ABHRs (Figure 3). The manufacture period for the pre-COVID samples ranged from September 2017 to March 2020 and the study sorting period for pre-COVID-19 sanitizer was capped to March 2020. The manufacturer period for peri-COVID-19 ABHRs samples ranged from March 2020 to April 2021.\n\nOf the total pre-COVID-19 sanitizers tested, 12.5% (n = 7) had a performance of less than 1 log reduction, as compared to 27.8% (n = 10) peri-COVID-19 ABHRs which had a performance of less than 1 log reduction. Overall, 78.6% had between 1-6 log reduction with two samples including quality control sample displaying total microbial reduction, while most of the ABHRs manufactured during the pandemic (69.4%) showed between 1-3 log reduction with no sample manufactured during the pandemic period showing an efficacy performance above 3 log reduction (Table 1). These results display a reduction in quality performance of the ABHRs manufactured during the pandemic period in terms of efficacy.\n\nBased on the distribution analysis for the general performance of the ABHRs, pre and peri pandemic, there was an observed clustering of the performance between <1 to 3 with an unexpected gap between 3-5 logarithmic units for peri-pandemic ABHRs (Figure 4). This is a strong positive correlation of log reduction between pre-COVID and peri-COVID ABHRs samples (Pearson correlation co-efficient value of R was 0.9328. The p-value was < 0.00001 implying that the result was significant at p < 0.05. This is attributed to the increased pre-COVID log reduction of the values above 3.\n\nA total of 20 peri-COVID samples were analyzed using gas chromatography with flame ionization detector (FID). The assay profiled and quantified three analytes: ethanol, isopropyl alcohol and methanol. pH was also measured as specified by KS EAS 789:2013 standard. Five samples (25%) complied and had > 60% alcohol content (Table 2). Sample PBHR 2, PBHR 9, PBHR 16 and PBHR 25 had been labelled by the manufacturer as containing IPA. However, upon analysis the first three contained ethanol as the active component while the fourth product contained a mixture of ethanol (30.41%) and methanol (31.12%).\n\nOnly five samples (25%) had an alcohol content of above 60% v/v which is the KEBS minimum limit for alcohol content in hand sanitizers. No sample met the required content of the World Health Organization (WHO) of 80% v/v of ethanol (Figure 5).\n\nThe FDA-accepted limit of methanol is < 0.063,15 however, only one ABHR (ABHR 09) met the FDA requirement with a methanol content of 0.06%; meanwhile, methanol substitution was found in four samples (20%), indicative of impure ethanol being used in the production process (Figure 6). The variation of the content of methanol was high (7.29 ± 6.003) at a 95% confidence limit.\n\nOne ABHR sample had a major deficiency that resulted in outlier pH results: P-ABHR 36 showed an acidic pH of 0.4 pH units. Most (55%, n = 12) samples had pH above the minimum limit of 6, with the range being 0.4–8.6 pH units (Figure 7A). The study found no correlation between the pH of a product and the total content of alcohol in tested the samples (Coefficient correlation R was -0.1078 and p-value was 0.65) (Figure 7B).\n\nUnexpectedly, results of the Pearson correlation analysis indicated that there was a non-significant relationship between total alcohol content and percentage log reduction, (r = - 0.167, p = 0.480) (Figure 8).\n\nThe Kenya Bureau of Standards had a positive impact on the quality of the ABHRs. ABHRs with a KEBS standardization mark had a higher average ethanol content (57.2%) compared to average ethanol content for the ABHRs without certification (48.8%). They also had a better percentage reduction score, averaging 89% against 78.9% for uncertified ABHRs (Figure 9).\n\n\nDiscussion\n\nAt the onset of the COVID-19 pandemic, the use of ABHRs gained popularity in Kenya and the world, leading to a ramp-up in production as several manufacturing companies repurposed their facilities for their production. The main publicized goal of ABHRs use was a quick (30 seconds) hand wash alternative to the traditional hand cleaning with water and soap, which has limited availability in low- and middle-income countries, which would ultimately improve pandemic containment strategies and overall infection prevention.\n\nThe number of available brands in the market during the pandemic progression period reduced (n = 55 to 35); this could be attributed to the increased surveillance by national regulatory bodies for compliant over-the-counter products leading to suspension and/or withdrawal of some brands in the Kenyan market.16 The study saw a larger percentage of ABHRs with > log 2 efficacy performance. Despite these peri-pandemic products having NRA’s approval, 27.8% were found to have less than 90% bactericidal reduction activity as compared to 12.5% manufactured pre-pandemic. This could partially be due to reluctance by manufacturers in maintaining acceptable quality standards upon obtaining regulatory and standardization permits. Further to this, the study results found no significant relationship between total alcohol content and log reduction (r = -0.167, p = 0.480), studies have found that formulation of hand sanitizers play a major role in their effectiveness in antimicrobial action.17 Some of the sanitizers tested in this study had acceptable levels of alcohol content but had lower log reduction factors, most likely due to wrong formulations which also affected the product pH. According to studies by Jing et al., 2020,18 an antimicrobial efficacy performance of <1 log10 value is considered ineffective (no significant bactericidal activity), while undetectable level of bacterial growth is indicative of a higher antimicrobial efficacy than demonstrated.\n\nThe alcohols permitted for hand sanitizers production are ethanol, propanol, and isopropyl alcohol. The specification does not have an acceptance criterion for methanol. Methanol is controlled by the US FDA owing to its toxicity. Interim limits for methanol in ABHRs during the 2020 COVID-19 pandemic was 0.063% v/v up from the usual 0.02% v/v.19,20 The US-FDA interim guidance has therefore been applied in the interpretation of the results for methanol content. Where substantial methanol concentration was recorded, it was interpreted as methanol substitution i.e., methanol was used as the active ingredient. Methanol is toxic when absorbed in the body through the skin or ingested and can be life-threatening. Methanol substitution is a great public health concern due to the adverse health effects of methanol including metabolic acidosis, neurologic sequelae, and even death. Methanol substitution was found in 20% of the sanitizer brands with only 5% (n = 1) complying with FDA approval of <0.063% v/v methanol content. This is indicative of impure ethanol being used in the production process. The sum of the permitted alcohols was used for the decision statement on whether a product met the KEBS limit for alcohol content. Very few brands (25%) had over 60% alcohols content; however, none of the ABHRs met the 80% formulation guide set by the WHO.\n\nThe shelf lives of the ABHRs in this study ranged from one to five years, which appeared to have been determined arbitrarily without any scientific basis on stability of the product. Some sanitizers did not declare the manufacture and/or expiration dates which poses a public health risk of use of expired and ineffective hand sanitizers. The pandemic saw a great improvement in the standard practice of appropriate labelling and listing ingredients and composition of products; however, four (4) brands had falsely listed the active ingredient. Results show that the product standardization mark had a positive impact on the amount of ethanol used as well as improved log reduction scores, leading to better quality products which are capable of infection prevention and control. This proves that national regulatory bodies such as KEBS are efficient agents for enforcing industry standards.\n\n\n\na. Due to the high turnover rate of ABHRs brands in the market during the pandemic period, the study was unable to obtain the same brands for both pre- and peri-COVID-19 sanitizers\n\nb. The number of sanitizers analyzed for alcohol content using gas chromatography wasn’t justifiably distributed. This is due to the cost implication relating to the test, which is outsourced, versus the limited budget.\n\n\nEthical approval\n\nThis study was approved by the Scientific Ethical Review Unit (SERU) at KEMRI under protocol KEMRI/SERU/CBRD/226/4251.\n\n\nAuthor contributions\n\nConceptualization and project design, SO, JK (KEMRI) and FN (JKUAT); methodology, JK, SO and FN; formal analysis, JK, SO and FN; resources, SO and JK; data curation, SO.; writing—original draft preparation, JK, SO and FN; writing—review and editing, JK, SO and FN. All authors have read and agreed to the published version of the manuscript.",
"appendix": "Data availability\n\nMendeley Data: ALCOHOL BASED HAND SANITIZERS IN KENYA- PRE AND PERI COVID-19, https://doi.org/10.17632/sj3dc9bw64.1 21\n\nThis project contains the following underlying data:\n\n- HAND SANITIZERS ANALYSIS RAW DATA- Blinded.xlsx (raw dataset)\n\n- WhatsApp Image 2021-03-04 at 15.28.50 (1).jpeg (Plate photo)\n\n- WhatsApp Image 2022-09-20 at 11.16.18.jpeg (Sample photo)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nI would like to express my very great appreciation to Missiani Ochwoto, Noel Oduor, Faith Ndung’u, Esther Kerubo, Eunice Wainaina, and Lucy Muita for their technical support, expertise and assistance throughout all aspects of this study.\n\n\nReferences\n\nWHO: Recommendations to Member States to improve hand hygiene practices to help prevent the transmission of the COVID-19 virus.2020. Accessed: Dec. 03, 2020. Reference Source\n\nWorld Health Organization (WHO): Guide to Local Production: WHO-recommended Handrub Formulations Introduction. Who; 2010; (April): p. 9. Reference Source\n\nOchwoto M, et al.: Anti-bacterial efficacy of alcoholic hand rubs in the kenyan market, 2015. Antimicrob. Resist. Infect. Control. 2017; 6: 17. PubMed Abstract | Publisher Full Text | Free Full Text\n\n6Wresearch: Kenya Hand Sanitizer Market (2020-2026). 6Wresearch. Apr. 2020. (accessed Jan. 29, 2021). Reference Source\n\nBock LJ: Bacterial biocide resistance: A new scourge of the infectious disease world? Arch. Dis. Child. 2019 Nov.; vol. 104(11): pp. 1029–1033. PubMed Abstract | Publisher Full Text\n\nPidot SJ, et al.: Increasing tolerance of hospital Enterococcus faecium to handwash alcohols. Sci. Transl. Med. Aug. 2018; 10(452). PubMed Abstract | Publisher Full Text\n\nHeavy use of hand sanitizer boosts antimicrobial resistance. (accessed Dec. 04, 2020). Reference Source\n\nTaskova A: RESISTANCE OF S. TYPHIMURIUM Resistance of Salmonella typhimurium to Ethanol Based Hand Sanitizer, Edmonton.May 2017.\n\nTaskova A: Resistance of Salmonella typhimurium to Ethanol Based Hand Sanitizer. Concordia Univ. Coll. Alberta; May 2017; pp. 1–37.\n\nPidot SJ, et al.: Increasing tolerance of hospital Enterococcus faecium to handwash alcohols. Sci. Transl. Med. Aug. 2018; vol. 10(452): p. 6115. PubMed Abstract | Publisher Full Text\n\nverify. (accessed Sep. 06, 2022). Reference Source\n\nZhang J: Hand Sanitizer Analysis Using the Agilent 8860 GC Configure with a Flame Ionization Detector.2020; pp. 1–8. Reference Source\n\nEN1500: Chemical disinfectants and antisepticsd hygienic handrubdtest method and requirements (phase2/step2). C E N (European Comm. Standarization) Brussels; 2013.\n\nCLSI: M100 Performance Standards for Antimicrobial Susceptibility Testing A CLSI supplement for global application.2018. (accessed: Jan. 26, 2021). Reference Source\n\nGüntner AT, Magro L, van den Broek J , et al.: Detecting methanol in hand sanitizers. iScience. 2021; 24: 102050. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKEBS Bans More Sanitizer Brands Over Quality Concerns - Business Today Kenya. (accessed Aug. 25, 2022). Reference Source\n\nBooq RY, et al.: Formulation and evaluation of alcohol-free hand sanitizer gels to prevent the spread of infections during pandemics. Int. J. Environ. Res. Public Health. 2021; 18(12). PubMed Abstract | Publisher Full Text | Free Full Text\n\nJing JLJ, Yi TP, Bose RJC, et al.: Hand sanitizers: A review on formulation aspects, adverse effects, and regulations. Int. J. Environ. Res. Public Health. 2020; 17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStaake MD, et al.: Quantitation of Methanol, Ethanol and Isopropanol in Gel Hand Sanitizer Products by GC-FID.2020; vol. 62: p. 92612.\n\nCenter for Drug Evaluation and Research: Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19) Guidance for Industry.2021; (January): pp. 1–10. Reference Source\n\nOmari S, Ng’onga F, Kimotho J: ALCOHOL BASED HAND SANITIZERS IN KENYA- PRE AND PERI COVID-19. Mendeley Data. 2023; V1. Publisher Full Text"
}
|
[
{
"id": "246475",
"date": "29 Feb 2024",
"name": "Fred Tusabe",
"expertise": [
"Reviewer Expertise Hand hygiene",
"Infection prevention and control",
"WASH"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the introduction section, it is emphasized that hand washing with soap should always be accompanied by water.\nThroughout the paper, the term \"alcohol-based handrubs (ABHRs)\" has been interchangeably replaced with \"alcohol-based sanitizer.\" Choose one for consistency.\nA citation is requested for the statement claiming that a 30-second application of alcohol-based hand rubs has superior disinfection efficacy compared to traditional soap and water approaches, resulting in more than a 3.5 log10 reduction in bacterial counts.\nThe abbreviation ABHR is not an antimicrobial-based handrub.\nThe statement regarding resistance to the use of alcohol-based hand rubs is noted, but without substantiation. While alcohol-based hand rubs are effective against various bacteria and viruses, they are primarily intended for hand hygiene rather than acting as general biocides. Therefore, citation 5, along with its corresponding statement, is considered misleading.\nRegarding the mode of action of alcohol-based hand rubs, it is acknowledged that there is no clear direct pathway for causing antimicrobial resistance. However, it is suggested that if poor-quality hand rubs become contaminated with resistant microorganisms during production or storage, repeated use of such products could contribute to the spread of resistant strains.\nAppreciation is expressed for providing literature on organisms that may be less susceptible to alcohol-based hand rubs. It is t it is not advisable to use alcohol-based hand rubs after visiting the latrine where E. faecium is likely to be acquired, or on visibly soiled hands where soap and water should be used.\nThe importance of studies on emerging resistance due to poor-quality alcohol-based hand rubs is acknowledged. However, it is noted that in the current study, ATCC strains for Escherichia coli and Staphylococcus aureus were used as test organisms as the standards, but evidence of the efficacy of alcohol-based hand rubs on these strains in real-life scenarios is lacking.\nThe title of the study needs to be rephrased since it was an in vitro study.\nIn the methods section, clarification is needed on how the assessment for the declaration of active ingredients was conducted.\nThe statement regarding the highly varied shelf lives allocated to the sanitizers requires elaboration or clarification.\nThe first paragraph of the discussion section needs to be rephrased to clearly explain what the study did and its contribution.\nThe discussion section should be rewritten to explicitly highlight how the findings of the study relate to or differ from others. Additionally, recommendations based on the findings should be provided.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "255758",
"date": "22 Apr 2024",
"name": "Sandry Kesuma",
"expertise": [
"Reviewer Expertise Pharmaceutical and food analysis",
"Pharmaceutical and food safety",
"chemical analysis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe whole article\nSome abbreviations suddenly appear in this article without the full term. Suggestion: Before using abbreviations throughout the article, please write the complete term in the first abbreviation, namely: Kenya Medical Research Institute (KEMRI), Kenya Bureau of Standards (KEBS), isopropyl alcohol (IPA), American Type Culture Collection (ATCC), Kenya Standard East Africa Standard (KS EAS), National Regulatory Authorities (NRAs) Must be consistent in writing the terms pre-COVID-19 pandemic and peri-COVID-19 pandemic. Because in the Result section you only write pre-COVID-19, pre-pandemic, and peri-COVID-19 and peri-pandemic.\np.1, Abstract- Results The percentage of alcohol content you stated in the abstract is only for the 20 samples analyzed by GC-FID. If the analysis was performed on a total of 35 samples, the percentage results may differ. Suggestion: state the total number of 20 samples analyzed for alcohol content in the abstract.\np.4, Methods-Alcohol content assay and pH of alcohol-based hand sanitizers Line 4, The alcohol calibration standards were prepared by adding aliquots of pure alcohols - ethanol, IPA, methanol, n-propanol (n-PA) - to distilled water. The calibration standard states n-propanol (n-PA), but in p.4, Result- Declaration of active ingredients and Table 2. Analytical results for alcohol-based hand sanitizers, there is no information about n-PA and there is no column of n-PA analytical results in table 2. Suggestion: if you do not use n-PA in the calibration standard, then remove the n-propanol (n-PA) from the sentence.\np.4, Methods-Alcohol-based hand sanitizers efficacy testing Line 6, …200 mL of distilled as guided by WHO. Suggestion: ……200 mL of distilled water as guided by WHO\np.6 Results- Alcohol content assay and pH of ABHRs Only 20 samples were analyzed with GC-FID out of a total of 35 peri-COVID-19 pandemic samples. Suggestion: add an explanation of the reason \"why only 20 selected samples were analyzed by GC-FID?\"\np.7, Result- Alcohol content assay and pH of ABHRs The sample codes in the table (PBHR) are different from the sample codes discussed such as ABHR 09 and P-ABHR 36. Suggestion: match the use of example code\np.7, Result- Alcohol content assay and pH of ABHRs The pH value is a number that has no units. The pH scale is not an absolute scale. It is relative to a set of standard solutions whose pH is determined based on international agreement. Suggestion: it is not necessary to write \"pH unit\" after the pH value.[Refer Ref 1,2].\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1546
|
https://f1000research.com/articles/13-463/v1
|
09 May 24
|
{
"type": "Study Protocol",
"title": "Observational and cross-sectional study on clinical profile of nontuberculous mycobacterial (NTM) disease in patients at tertiary care hospital of central India",
"authors": [
"Jay Dinesh Bhanushali",
"Dr Babaji Ghewade",
"Dr Ulhas Jadhav",
"Dr Babaji Ghewade",
"Dr Ulhas Jadhav"
],
"abstract": "Background Nontuberculous Mycobacterial (NTM) diseases present unique clinical challenges and are increasingly recognised as significant contributors to respiratory and extrapulmonary morbidity. This study protocol outlines an observational and cross-sectional investigation aiming to comprehensively understand the clinical profile of NTM disease, including its prevalence, risk factors, and clinical features, in patients at a tertiary care hospital in central India.\n\nMethods Over two years, from July 2022 to June 2024, a convenience sample size will be recruited from TB suspects meeting inclusion criteria. Comprehensive data collection will be conducted, including demographic information, clinical history, radiological findings, microbiological test results, and risk factor assessments. Statistical methods will be applied to the collected data, including descriptive statistics, comparative analysis, risk factor assessments, and multivariate analyses.\n\nExpected Results The study aims to provide valuable insights into the prevalence and clinical manifestations of NTM disease, shedding light on the risk factors contributing to its occurrence. The statistical analyses will identify key factors associated with NTM disease and characterise its clinical and radiological features.",
"keywords": [
"Nontuberculous Mycobacterial (NTM) Disease",
"Clinical Profile",
"Prevalence",
"Risk Factors",
"Tertiary Care Hospital",
"Central India"
],
"content": "Introduction\n\nNontuberculous Mycobacterial (NTM) diseases, caused by various species of mycobacteria other than Mycobacterium tuberculosis, have garnered increasing recognition for their clinical significance and impact on respiratory and extrapulmonary health. These infections present a complex clinical profile, often mimicking tuberculosis (TB) and posing diagnostic and therapeutic challenges.1 In central India, a region with a diverse healthcare landscape, understanding the clinical characteristics, prevalence, and risk factors associated with NTM diseases is essential for improving patient care, diagnosis, and management.2\n\nNTM diseases primarily affect individuals with underlying respiratory conditions, immunosuppression, or other risk factors. Moreover, their clinical presentation can range from mild respiratory symptoms to severe, life-threatening infections. As central India grapples with a high burden of TB and diverse environmental factors, differentiating NTM diseases from TB and elucidating their clinical features become paramount for precise diagnosis and appropriate management.3\n\nThis study protocol outlines an observational and cross-sectional research endeavour, with a primary objective to comprehensively investigate the clinical profile of NTM disease in patients at a tertiary care hospital in central India. The study seeks to determine the prevalence of NTM disease among TB suspects, examine various risk factors contributing to NTM infections, and elucidate the clinical and radiological features that distinguish NTM diseases from other respiratory conditions. In doing so, the study aims to provide valuable insights into the epidemiology and clinical characteristics of NTM diseases in the specific context of central India.\n\nThe research findings can inform healthcare professionals, public health initiatives, and policy-makers, ultimately leading to better diagnostic accuracy and tailored therapeutic strategies for NTM disease. Furthermore, this study contributes to a broader understanding of pulmonary and extrapulmonary diseases in the region, underscoring the growing importance of NTM diseases in the context of public health and patient care.\n\nTo study the Clinical profile of NTM disease.\n\n\n\n1. To determine the prevalence of NTM disease among TB suspects at Acharya Vinoba Bhave Rural Hospital\n\n2. To study various risk factors of NTM disease\n\n3. To study Clinical and radiological features of confirmed NTM disease patient\n\n\nMethods\n\nThis study will adopt an observational and cross-sectional design to assess the clinical profile of Nontuberculous Mycobacterial (NTM) disease in patients at a tertiary care hospital in central India (Figure 1).\n\nThe study will focus on individuals in central India who are TB suspects and fulfil the inclusion criteria for NTM disease. The study population includes pulmonary and extrapulmonary NTM disease patients, irrespective of gender, aged 12 years or older. These patients may have clinical symptoms, radiological findings, microbiological evidence suggestive of NTM disease, and those suspected of having drug-resistant TB (DR-TB).\n\nThe study will be conducted at Acharya Vinoba Bhave Rural Hospital, a tertiary care hospital in central India.\n\nInclusion criteria: To be eligible for inclusion in the study, patients must meet the following criteria:\n\n1. Age: Patients should be 12 years of age or older.\n\n2. Gender: Inclusion is irrespective of gender.\n\n3. Clinical criteria:\n\n• Pulmonary NTM disease: Patients should exhibit pulmonary symptoms or have nodular or cavitary opacities on chest radiograph or an HRCT scan showing multifocal bronchiectasis with multiple small nodules.\n\n• Extrapulmonary NTM disease: Patients with disseminated disease, including skin involvement, especially following organ transplantation.\n\n4. Microbiological criteria: Patients should have positive culture results from at least two separate expectorated sputum samples.\n\n5. DR-TB suspects: Patients suspected of having drug-resistant TB (DR-TB).\n\nExclusion criteria: Patients will be excluded from the study if they meet any of the following criteria:\n\n1. Active Tuberculosis (TB) patients: Individuals with a confirmed diagnosis of active TB will not be included in this study, as the focus is on NTM disease.\n\n2. Declining informed consent: Patients who must provide written informed consent for participation in the study will be excluded. Informed consent is essential to ensure voluntary participation and ethical considerations.\n\n\n\n1. Selection bias: This type of bias occurs when the study sample does not represent the target population. To mitigate selection bias, ensure that study participant recruitment is done systematically and unbiasedly, adhering to the inclusion and exclusion criteria. Random sampling or stratified sampling methods can help minimise selection bias.\n\n2. Information bias: Information bias arises from inaccuracies in data collection, either due to measurement error or misclassification of study variables. To reduce information bias, use standardised data collection tools, train data collectors, and establish quality control measures. Additionally, consider blinding data collectors to the research hypothesis to prevent measurement bias.\n\n3. Confounding bias: Confounding bias occurs when a third variable influences the relationship between the exposure and the outcome. Conduct a multivariate analysis to control for potential confounding variables to address confounding. This may involve stratification, matching, or including confounders as covariates in statistical models.\n\nThe data collection process for this observational and cross-sectional study on the clinical profile of Nontuberculous Mycobacterial (NTM) disease involves several structured steps to ensure precise and comprehensive information acquisition. This organised approach meets the study’s objectives while maintaining patient confidentiality and ethical standards.\n\nPatient identification and recruitment: Patients eligible for participation, as per the inclusion criteria outlined in the study protocol, will be identified through various channels, including referrals from healthcare providers, TB clinics, and other medical facilities. These patients, who provide voluntary written informed consent, will be recruited into the study.\n\nInformed consent: Before commencing data collection, patients will be given a clear and detailed explanation of the study’s purpose, goals, and the procedures involved. Patients will be requested to provide written informed consent, signifying their willingness to participate in the research.\n\nData collection tools: Specialized data collection forms and questionnaires will be developed to capture relevant information systematically. These tools will encompass sections for demographic data, medical history, clinical symptoms, radiological findings, microbiological test results, and an assessment of potential risk factors.\n\nData collection: Highly trained healthcare professionals, including physicians, nurses, or research assistants, will conduct in-person interviews with the study participants. These interviews will delve into various topics, such as the patients’ medical histories, symptom profiles, potential risk factors, and medication histories. Additionally, clinical examinations will assess the patient’s physical conditions, with any relevant findings meticulously recorded. Radiological data will be gathered by reviewing chest radiographs and HRCT scans to document the presence of opacities, nodules, and bronchiectasis. Microbiological data will be collected by analysing sputum samples, including culture results from at least two samples.\n\nQuality control: To ensure the precision and reliability of the collected data, regular training sessions will be conducted for data collectors, maintaining consistency in the data collection process. A thorough data review will be performed to confirm completeness and coherence, promptly addressing any discrepancies or missing information.\n\nData entry: All collected data will be securely entered into a dedicated database, prioritising data integrity and privacy.\n\nData analysis: After the data collection phase concludes, statistical and epidemiological analyses will be conducted to fulfil the study’s objectives. This may involve determining the prevalence of NTM disease, identifying associated risk factors, and characterising the clinical profiles of NTM disease patients.\n\nFormula\n\nZ1−α/2=1.96,at 5% level of significance\n\nPrevalence of Annual prevalence of NTM infection = 0.5%.\n\np = 0.5% (As per reference article4)\n\nD = estimated error (10%) = 3%\n\n=(1.96)2∗(0.05)∗(1−0.5)/(0.3)2=22\n\nMinimum sample size required = 22\n\nDescriptive statistics will offer an initial overview of the data by calculating mean, median, standard deviation, and percentages to characterise the study population. Secondly, the study will compute the prevalence of NTM disease among TB suspects, providing valuable insights into the scale of the issue. Comparative analyses will be crucial in assessing differences between groups within the study population, such as patients with pulmonary and extrapulmonary NTM disease. To explore the various risk factors associated with NTM disease, logistic regression will be used to identify significant associations. Multivariate analysis will help disentangle the simultaneous effects of multiple variables on the clinical profile of NTM disease patients. Moreover, statistical tests like Chi-Square or Fisher’s Exact Test will be employed to evaluate associations between categorical variables. T-tests or ANOVA will be used when comparing means of continuous variables. If relevant, survival analysis techniques like Kaplan-Meier curves and Cox regression will be applied to examine time-to-event data. Subgroup analyses will delve into specific characteristics within the study population. Statistical software such as R (RRID:SCR_001905), SPSS (RRID:SCR_014598), or SAS version 23 (RRID:SCR_004635) will be utilised for all these analyses and the copyright license have been obtained. Ethical considerations must be rigorously followed throughout these analyses to safeguard patient confidentiality and rights. The study’s findings will be reported comprehensively, presenting the results clearly and effectively, supporting the study’s objectives and conclusions.\n\nThe Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (DU) has granted its approval to the study protocol (Reference number: DMIHER (DU)/IEC/2022/19. Date:15-07-2022). Before commencing the study, we will obtain written informed consent from all participants, providing them with a comprehensive explanation of the study’s objectives.\n\nAfter the completion of the study, we will publish it in an indexed journal or conference.\n\nThe study has yet to start. After the publication of the protocol, we will start recruitment in the study.\n\n\nDiscussion\n\nNontuberculous mycobacterial (NTM) diseases have gained significant attention in recent years due to their impact on respiratory and extrapulmonary health. Numerous studies globally have reported an increasing prevalence of NTM diseases. The prevalence varies across regions, and India is no exception to this trend. Studies by Hoefsloot et al.5 and Prevots et al.6 have highlighted the rising prevalence of NTM diseases, particularly in areas with a high burden of TB.\n\nOne of the fundamental challenges in managing NTM diseases is their clinical resemblance to tuberculosis. This clinical mimicry often leads to misdiagnoses and delayed treatment initiation. Research by Prevots and Marras7 and Ringshausen et al.8 noted that differentiating NTM diseases from TB is vital for appropriate management.\n\nNTM infections are not limited to a single risk factor or demographic group. The risk factors associated with NTM diseases are multifactorial and may include underlying respiratory conditions, immunosuppression, and environmental factors. Research by Kartalija et al.9 and Adjemian et al.10 has explored these risk factors and highlighted the complexity of NTM disease epidemiology.\n\nThe geographic distribution of NTM species and their clinical impact can vary widely. With its unique environmental and demographic characteristics, Central India presents a distinct context for studying NTM diseases. Research by Thomson et al.11 has shown how environmental factors play a significant role in NTM epidemiology.\n\nAccurate diagnosis is pivotal in managing NTM diseases effectively. Misdiagnoses lead to inappropriate treatment and contribute to antibiotic resistance and increased healthcare costs. Research by Griffith et al.12 underscores the importance of accurate diagnosis in NTM disease management.\n\nUnderstanding the clinical and radiological features specific to NTM diseases is crucial for distinguishing them from TB and other respiratory conditions. Research by Jeong et al.13 and Winthrop et al.14 has detailed the diverse clinical presentations and radiological findings associated with NTM infections.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nReporting guidelines\n\nZenodo: STROBE checklist for ‘Observational and cross-sectional study on clinical profile of nontuberculous mycobacterial (NTM) disease in patients at tertiary care hospital of central India’. https://zenodo.org/doi/10.5281/zenodo.10983365\n\nLicence: CC BY 4.0 Deed|Attribution 4.0 International\n\n\nReferences\n\nDaniel-Wayman S, Abate G, Barber DL, et al.: Advancing Translational Science for Pulmonary Nontuberculous Mycobacterial Infections. A Road Map for Research. Am. J. Respir. Crit. Care Med. 2019; 199: 947–951. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSharma SK, Sharma R, Singh BK, et al.: A prospective study of non-tuberculous mycobacterial disease among tuberculosis suspects at a tertiary care centre in north India. Indian J. Med. Res. 2019; 150: 458–467. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSharma SK, Upadhyay V: Epidemiology, diagnosis & treatment of non-tuberculous mycobacterial diseases. Indian J. Med. Res. 2020; 152: 185–226. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJani MN, Rodrigues CS, Mehta AP: The Neglected and Often Ignored: Nontuberculous Mycobacteria. J. Global Infect. Dis. 2011; 3: 94. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHoefsloot W, van Ingen J , Andrejak C, et al.: The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. Eur. Respir. J. 2013; 42: 1604–1613. PubMed Abstract | Publisher Full Text\n\nPrevots DR, Shaw PA, Strickland D, et al.: Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems. Am. J. Respir. Crit. Care Med. 2010; 182: 970–976. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrevots DR, Marras TK: Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. Clin. Chest Med. 2015; 36: 13–34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRingshausen FC, Apel R-M, Bange F-C, et al.: Burden and trends of hospitalisations associated with pulmonary non-tuberculous mycobacterial infections in Germany, 2005–2011. BMC Infect. Dis. 2013; 13: 231. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKartalija M, Ovrutsky AR, Bryan CL, et al.: Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am. J. Respir. Crit. Care Med. 2013; 187: 197–205. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdjemian J, Olivier KN, Seitz AE, et al.: Spatial clusters of nontuberculous mycobacterial lung disease in the United States. Am. J. Respir. Crit. Care Med. 2012; 186: 553–558. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThomson R, Tolson C, Carter R, et al.: Isolation of nontuberculous mycobacteria (NTM) from household water and shower aerosols in patients with pulmonary disease caused by NTM. J. Clin. Microbiol. 2013; 51: 3006–3011. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGriffith DE, Aksamit T, Brown-Elliott BA, et al.: An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. Am. J. Respir. Crit. Care Med. 2007; 175: 367–416. PubMed Abstract | Publisher Full Text\n\nJeong YJ, Lee KS, Koh W-J, et al.: Nontuberculous mycobacterial pulmonary infection in immunocompetent patients: comparison of thin-section CT and histopathologic findings. Radiology. 2004; 231: 880–886. PubMed Abstract | Publisher Full Text\n\nWinthrop KL, McNelley E, Kendall B, et al.: Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease. Am. J. Respir. Crit. Care Med. 2010; 182: 977–982. Publisher Full Text"
}
|
[
{
"id": "296425",
"date": "11 Jul 2024",
"name": "Balaji Pathakumari",
"expertise": [
"Reviewer Expertise Expertise in infectious diseases that includes tuberculosis",
"non-tuberculosis mycobacterial diseases and Candida infections."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nBhanushali et al., proposed to conduct cross-sectional study to understand the clinical profile of NTM-LD. I think the study has the potential to find the various underlying clinical parameters to NTM-LD management. However, authors can consider the following potential comments to improve the proposal quality.\nI feel the objectives of this study are preliminary. I would ask authors to extend the aims and objectives by adding critical gaps in NTM research. The sample size is too low. On what basis the sample size was fixed? Is there any power calculation carried-out to arrive this number? Does this give at least 80% power? Authors are kindly requested to explain this. And requested to give the power calculation. “In addition, powers of tests were calculated based on effect size and include the values of power calculation in statistics. The authors used the broad term of NTM which includes different NTM species. Each NTM species has different clinical features including radiological findings and disease phenotypes. It would be needed to analyze and add data only on NTM patients caused by most prevalent species in Indian settings. Authors can consider this to add another objective to check the parameters in species level. Authors should record the information on the etiological factors identified in the patients. Broader collection of clinical data to support the claim that the detected differences are each species specific. For data collection, authors can refer the following paper (see the table 1 and 2) (Marty PK, et al., 2024 [Ref 1]) Earlier reports showing the importance of effect of age and gender on the NTM risk of infection. I would strongly recommend analyzing the data based on age and gender matched healthy or other diseased controls. Patient recruitment scheme is not in detail. Please describe in more detail the inclusion and exclusion criteria of the study. A chart explaining these criteria would be desirable. There is a possibility to find mixed infection with other NTMs or M. tb. QuantiFERON has to be done for identifying Latent TB infection. What is the Authors comment on these subgroups. Species identification is important to assess the pathogenicity. Methods: Check the Time period error for recruiting samples. The conclusions are brief. It would be beneficial to provide a more detailed summary of the significance of the study and their implications for future research and clinical practice. Finally, the authors should address how these findings would hold in a ‘real-life’ unselected group of patients.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": []
},
{
"id": "328378",
"date": "25 Oct 2024",
"name": "Ho Namkoong",
"expertise": [
"Reviewer Expertise NTM"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study protocol titled \"Observational and Cross-sectional Study on Clinical Profile of Nontuberculous Mycobacterial (NTM) Disease\" presents a relevant and timely investigation into an important public health issue, particularly in regions like central India where tuberculosis (TB) remains prevalent. By focusing on distinguishing NTM from TB, this study has the potential to provide valuable insights for improving diagnostic and therapeutic strategies.\nHowever, conducting the study at a single institution may introduce bias based on regional characteristics, and it may limit the generalizability of the results to other regions. Therefore, I strongly recommend expanding the study into a multi-center observational study. By collecting data from multiple healthcare institutions, the study can better capture the diverse clinical presentations of NTM disease, assess the influence of different regional and environmental factors, and significantly improve the reliability and generalizability of the findings.\nThe comprehensive data collection approach, covering demographic, clinical, radiological, and microbiological aspects, is commendable and will allow the study to capture the multifaceted nature of NTM diseases. The planned multivariate analysis is expected to identify key risk factors and clinical patterns that could guide future NTM management. Furthermore, the study's focus on a tertiary care hospital ensures the inclusion of diverse patient profiles, which enhances the comprehensiveness of the findings.\nAdditionally, the attention to ethical considerations, including patient consent and confidentiality, is well-handled, strengthening the study’s rigor. Despite the small sample size, this research could provide preliminary data that contribute to the understanding of NTM diseases in high-TB-burden regions. In order to overcome this issue, I recommend multi-center observational study.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-463
|
https://f1000research.com/articles/10-972/v1
|
27 Sep 21
|
{
"type": "Research Article",
"title": "Online food delivery services: cross-sectional study of consumers’ attitude in Malaysia during and after the COVID-19 pandemic",
"authors": [
"Sin Yin Tan",
"Su Yin Lim",
"Sook Fern Yeo",
"Su Yin Lim",
"Sook Fern Yeo"
],
"abstract": "Background: During the COVID-19 pandemic, Malaysian consumers were more likely to purchase food online and have it delivered to their doorstep. To stay afloat, many restaurants were pushed to provide online food delivery services (OFDS), and this sector has grown tremendously. However, will the trend persist after the pandemic? This study aims to look into how consumers’ perceptions of OFDS affect their attitude towards them. It investigates the relationship between convenience motivation, perceived ease of use, time-saving orientation and price-saving orientation in terms of future intent to use OFDS.\nMethod: Primary data was collected from 307 respondents in Malaysia using convenience sampling method through an online survey. Respondents’ demographic background was presented statistically in cross tabulation tables to study the ratio comparison implicitly. Consistent Partial Least Square approach and bootstrapping techniques with 5,000 subsamples was employed, with the aid of SmartPLS.V3 software, to identify the significant factors influencing consumers’ continuance intention after the pandemic.\nResult: Perceived ease of use does not contribute significantly to continuance intention as most consumers have prior online purchase experience. Nevertheless, time-saving orientation has a positive correlation with perceived ease of use due to the simplicity of placing an order with just a click. It is also found that price-saving orientation is related to convenience motivation, particularly when prices can be compared on the websites or online ordering platforms. Consumers’ intention to continue using OFDS even after the COVID-19 pandemic is positively influenced by all the parameters studied, except for perceived ease of use.\nConclusion: Limited work has been done on the continuance intention to use OFDS beyond the pandemic. This study provides insight for food retailers on how to enhance their business and retain their customers with the support of technology, even after the COVID-19 pandemic.",
"keywords": [
"Online food delivery services",
"Continuance intention",
"Attitude",
"Behavioural intention",
"Convenience motivation",
"Perceived ease of use",
"Time-saving orientation",
"Price-saving orientation"
],
"content": "Introduction\n\nPeople in the digital age rely heavily on the internet and smartphones in their daily lives. Unsurprisingly, many businesses have turned to e-commerce to stay competitive. In Malaysia, 84.2% of the population uses the internet, 88.3% of them use a shopping app each month and 6.86 million people used online food delivery services (OFDS) to order take-away food in 2020.1\n\nThe lockdown implemented during the COVID-19 outbreak was enacted in order to minimise physical contact. This has forced consumers to adjust their preferences and opt for digital services, including food purchases.2 As such, restaurants were eager to collaborate with online delivery platforms in order to stay in business.3 GrabFood’s deliveries increased by 30%, with 8,000 new merchants whose online revenues increased by 25%.2 Thus, Malaysia’s OFDS market increased tremendously in 2020, by 45.9% from 2019, and is expected to reach US$370 million in revenue over the next four years.1,4\n\nAlthough the OFDS industry has significant growth potential, many studies focused on consumers’ attitude towards OFDS during its initial adoption.5 However, very little is known about the factors that influence consumers’ willingness to order food online regularly, particularly after a pandemic. Therefore, this study aims to further investigate the continuance intention of using OFDS beyond the COVID-19 outbreak.\n\n\nLiterature review and hypotheses development\n\nConvenience is defined as the perceived time, value and effort required to facilitate the use of OFDS. Consumers now have the freedom to choose from a wide range of food providers listed on the internet at any time and from anywhere. As a result of its convenience, consumers will be motivated to use OFDS on a regular basis.6,7\n\nA total of 47% of e-commerce users in Southeast Asia shopped online to save time and energy, and 87% agreed on the usefulness of internet services during the COVID-19 outbreak.8 Malaysians also prefer online shopping when they have a hectic schedule.9 The ease of comparing prices across different online platforms and a wide variety of items are all motivating factors that drive consumers to shop online. Convenience was also cited as the top reason for shopping online in Q4 2020, and remained the top three reasons in Q1 2021.10\n\nPerceived ease of use (PEOU) refers to a person's perception of how hassle-free it is to use a system. The quality of a system is defined as the ease with which pages can be navigated, the presence of a clear and uncomplicated layout, and the system's dependability.11 It is critical for businesses to ensure that their online platform is simple to use because bad designs or a complicated process will deter consumers from continuing with the online purchase.\n\nThe amount of effort required to use a system will serve as a critical predictor of its adoption and subsequent usefulness.12,13 It was discovered that if it is relatively effortless to use a system, consumers are more likely to order food online.14\n\nIn today's fast-paced world, where consumers’ busy schedules mean time is in short supply, time-saving orientation (TSO) has become a critical factor in easing daily tasks while fully utilising time. Many office workers could not afford the time and trouble of going out to eat, including driving and queuing up to place order. Thus, using OFDS is the quickest way to get food and the time saved can be used to complete other tasks.\n\nHigher-income consumers value time because of the opportunity costs. As such, they find online shopping appealing because it allows them to make better use of their time.15 A study discovered that timesaving is the key determinant of consumers' motivation to use technology-based self-service.16 When consumers are able to save time, their perception turns positive and as a result, their attitude towards OFDS also becomes favourable.6,17,18\n\nPrice can be defined as the value (monetary or non-monetary) an individual must put forth in an exchange for a product or service.19,20 One of the key factors influencing customer satisfaction is price-saving orientation (PSO), which includes offers and discounts provided by sellers.21 82.9% of Malaysians purchased a product online in the past month.1 The internet makes it easier to compare prices among different online sellers, which has proven to be advantageous for consumers to purchase at a lower price, which in turn has a significant effect on their behavioural intention to shop online.13,22\n\nOFDS provide additional perks such as not having to pay for service charge imposed by the restaurants, as well as getting free delivery and discount coupons. Additionally, consumers do not need to expend energy or effort to visit a physical store or restaurant. Thus, consumers will be more satisfied with their online food ordering experience and will be more likely to use these services in the future.5,18\n\nAttitude (ATT) can be defined as a consumer's overall reaction when using a specific device or technology.23 It refers to a person's reaction, whether positive or negative, to a given object.24 When consumers believe that online food ordering is useful and capable of easing their daily lives, they are more likely to develop a positive attitude which will lead to continuance intention (CI) of using it. Thus, attitude is positively related to behavioural intention.17,25,26\n\nBehavioural intention (BI) is defined as a person's proclivity to act in a certain way.27 The intent to use OFDS denotes a consumer's desire to purchase food and beverages through online delivery platforms.17 Many studies have established that the factors used to measure BI include positive word-of-mouth, willingness to recommend a product or service to others and also repurchase intention.28 Consumers who are pleased and content with their online purchase experience are expected to continue doing so.5\n\nThe main objective of this study is to identify the factors that may influence consumers’ attitude and behaviour towards continuance intention in using OFDS post pandemic, as illustrated in the proposed research model in Figure 1. The hypotheses are proposed as follows:\n\nH1: Convenience motivation positively influences consumers’ attitude towards online food delivery services.\n\nH2: Perceived ease of use positively influences consumers’ attitude towards online food delivery services.\n\nH3: Time-saving orientation positively influences consumers’ attitude towards online food delivery services.\n\nH4: Price-saving orientation positively influences consumers’ attitude towards online food delivery services.\n\nH5: Attitude positively influences consumers’ behavioural intention towards online food delivery services.\n\nH6: Behavioural intention positively influences consumers’ continuance intention towards online food delivery services.\n\n\nMethods\n\nResearch ethics approval was obtained from Multimedia University, Malaysia (EA1422021) and the respondents gave their written informed consent when filling out the Google Form.\n\nAn online survey with close-ended questions was designed using Google Form to examine the research hypotheses. It consisted of two parts: demographic information of respondents and 25 measurement items which indicated seven variables, namely, CM, PEOU, TSO, PSO, ATT, BI and CI towards OFDS, which were adopted from previous studies5,17,25,29–33 and recorded in Table 1. All items were measured based on a five-point Likert-type.34,35\n\nThe Krejcie and Morgan sampling method was used as a guideline in estimating the sample size, and convenience sampling method was used to source participants.36 This sampling method is commonly used by researchers for similar studies, such as a recent study on the intention to use OFDS among university students in Malaysia, which gathered 290 samples for data analysis.18\n\nA primary dataset of 307 respondents was gathered, in order to examine consumers’ perception and attitude towards OFDS during the pandemic, which is critical to the future growth of the OFDS industry. The respondents were close contacts (relatives, friends and students) of the authors of this study, and were invited through email, Facebook and WhatsApp, between 22nd March 2021 and 18th April 2021.\n\nDemographic background of respondents is presented descriptively and graphically. Consistent Partial Least Square (PLSc) approach37–39 was applied to study the reflective and formative factors in this study and SmartPLS.v3 software was the main tool used (a free version is available for 30 days). Reliability and validity were tested in factor analysis and bootstrapping of 5,000 subsamples was used to estimate PLSc path model.\n\n\nResults\n\nTable 2 shows the demographic profile of 307 respondents.52 Overall, 83.39% of respondents use OFDS and 70.68% prefer to eat at home, compared to at a restaurant. Figure 2 depicts the distribution of respondents who ordered food via third-party mobile apps, social media, or the company’s own website or mobile apps. Foodpanda (70.36%) and GrabFood (63.19%) are the most popular in Malaysia because it is user-friendly.40 However, social media platforms such as Instagram are more suitable for promoting food rather than ordering.41\n\nTable 3 recorded the feedback of the respondents whereby the mode for all measurement items is “Agree”, which contributes to the left-skewed distribution except PSO4. The average and standard deviation of variables are recorded in Table 4 and each average is close to “4” (Agree) except PSO.\n\nTable 5 shows the ratio comparison of using OFDS and dining preference based on age, gender, marital status and personal income level. OFDS usage among single young adults (>85% each age group below 40 years old; single 86%) is higher compared to married adults (77%) during pandemic than before the pandemic.11 Elderly or married adults prefer to enjoy their food at home. Although 71.34% of the respondents were earning a low income, they still preferred to use OFDS (84%) and dine at home (71%) compared to higher income respondents. The statistics revealed a significant difference in online food ordering trends between age groups, but not between genders.\n\n\nMeasurement of model\n\nTable 6 shows Cronbach’s alpha42,43 and composite reliability (CR)37,44,45 for each variable as above 0.8, which indicates good internal consistency of the questionnaire’s questions scale in measuring a similar variable. * indicates CR>0.95 but there are no significant changes after its removal.37 The average variance extracted (AVE) indices46 are greater than 0.6 for each variable, indicating no convergent validity problems.\n\n* indicates CR > 0.95.\n\nIn Table 7 Fornell-Larcker criterion,46,47 the diagonals represent the square root of AVE and off diagonals represent the coefficient of correlation. One tail t-test is conducted on the coefficient of correlation at 5% level of significance. The results revealed that there is a positive correlation between the variables with p-value of 0. There are no discriminant validity issues with the support of HTMT values, recorded in Table 8 based on HTMT0.85 criterions.\n\nSix hypotheses were tested using PLSc,39 a variance-based structural equation modelling technique, with no concerns about distribution or multicollinearity. In the past decade, the use of PLS modelling has gradually increased in order to handle more complex models.\n\nTable 9 summarises the result of the hypotheses presented in Figure 3, which indicates the path coefficient and outer loading of the variable. PEOU is found to be insignificant in influencing consumers’ attitude towards OFDS (p-value > 0.05). Consumers’ attitude towards using OFDS during and post the COVID-19 pandemic is, however, positively influenced by CM (p-value < 0.05), TSO (p-value < 0.05) and PSO (p-value < 0.05). Furthermore, hypotheses of ATT positively influencing consumers’ BI (p-value < 0.05) and also BI positively influencing consumers’ CI (p-value < 0.05) towards OFDS are supported in this study. Thus, H1, H3, H4, H5 and H6 are validated while H2 is rejected.\n\n\nDiscussion\n\nBased on the findings of this study, convenience motivation has a significant impact on consumers’ attitude towards OFDS, which is consistent with previous studies.6,8-10,17,21,25,29 OFDS platforms are very well developed nowadays, enabling consumers to order food online at any time and from any location, without having to leave home. With just a click and via a cashless payment system, food will be ready in a short period of time, providing consumers with a great deal of convenience. However, electronic devices have already been integrated into our daily routines for a long time and people are already familiar with these devices, thus perceived ease of use is not a significant motivator that would influence consumers to continue ordering food online.5,6,13,48\n\nTime is an important factor that consumers, particularly working adults and students, are concerned about.6,17,18 Consumers are eager to use OFDS because they can save a significant amount of time from menu selection to food preparation. Especially during rush hour, OFDS will be their first choice rather than waiting in line at a restaurant. OFDS also saves consumers money, as they can compare the prices offered by different food retailers and budget for a meal. Food retailers must continue to offer competitive price, such as giving attractive discount coupons or free delivery services to influence consumers to revisit.21 With the assistance of third-party apps, price-saving orientation significantly influences consumers’ attitude towards OFDS continuance intention after the pandemic,17 but perhaps not for all students.18\n\nPrevious studies conducted in this field of study have focused on the general intention of using OFDS.25,33,48 This paper, however, investigates consumers’ attitude and behaviour regarding their continuance intention of using OFDS after the COVID-19 pandemic. The left-skewed distribution of continuance intention’s measurement items significantly indicates that there is a high possibility of consumers using OFDS continuously after COVID-19, and this supports the hypothesis that a positive behavioural intention will lead to continuance of using a service. A satisfying online shopping experience fosters a positive attitude toward using the services and, as a result, always increases the likelihood of future purchase behaviour.49–51\n\nThis study did not take into account all of the possible factors that might influence the continuance intention of using OFDS after the pandemic. The model could be improved in the future by including more variables, such as, customer satisfaction and social influences. Furthermore, the findings cannot be generalised as a whole due to convenience sampling biasness. In the future, the study could be narrowed down to a specific group; perhaps looking at some larger cities with higher demand and supply for OFDS.\n\n\nConclusions\n\nOFDS is a consumer-focused market which aims to bring comfort to consumers so that they are able to get their favourite food at the best price and convenience without having to leave home. This is consistent with our findings that convenience motivation, time-saving orientation and price-saving orientation were the primary factors influencing consumers’ attitude towards OFDS during and post the COVID-19 pandemic. The findings also revealed that consumers who have a positive attitude and behaviour towards OFDS tend to have favourable feedback on the continuance intention after COVID-19.\n\nNevertheless, although results showed that there is a significant impact on the continuance intention towards OFDS after COVID-19, there are several issues and challenges that need to be addressed. Food retailers should consider how to retain the food quality and ensure fast delivery when orders increase. They should also look into collaboration with third-party apps such as GrabFood and Foodpanda to help boost their sales and maximise profits. We believe that consumers will soon adopt OFDS into their lifestyle, making it a norm, after the pandemic. Therefore, it is crucial for food retailers to work in this direction to sustain and grow their business model.\n\n\nData availability\n\nFigshare: Online Food Delivery Service.\n\nDOI: http://doi.org/10.6084/m9.figshare.14772951.52\n\nThis project contains the following underlying data:\n\n• Data file 1. (Survey results, CVS format)\n\nFigshare: Online Food Delivery Service Questionnaire 2021\n\nDOI: http://doi.org/10.6084/m9.figshare.16566414.53\n\nThis project contains the following extended data:\n\n• Data file 1. (Survey questions, CVS format)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgments\n\nWe would like to thank all the participants in this research for their voluntary participation.\n\n\nReferences\n\nWe Are Social & Hootsuite: Digital 2021: Malaysia. 2021. Reference Source\n\nKamel H: Food delivery services: From odd job to the most in demand. The Malaysian Reserve. 2021, January 1. Reference Source\n\nKamaruddin NJ: Positivity in negativity: COVID-19 sees 30 pct jump in delivery orders. BERNAMA. 2020, March 18. Reference Source\n\nMoney Compass: Online food delivery market to see robust growth over next 4 years.2020, August 7. Reference Source\n\nAlalwan AA: Mobile food ordering apps: An empirical study of the factors affecting customer e-satisfaction and continued intention to reuse. Int. J. Inf. Manag. 2020; 50: 28–44. Publisher Full Text\n\nLau TC, Ng DCY: Online food delivery services: Making food delivery the new normal. J. Mark. Adv. Pract. 2019; 1(1): 62–77.\n\nThamaraiselvan N, Jayadevan GR, Chandrasekar KS: Digital food delivery apps revolutionizing food products marketing in India. Int. J. Rec. Tech. Eng. . 2019; 8(2S6): 662–665. Publisher Full Text\n\nGoogle, Temasek and Bain: e-Conomy SEA 2020. 2020. Reference Source\n\nBalmaceda K, Leong B: Who are Malaysia’s online shoppers?. Janio Asia; 2021, April 26. Reference Source\n\nBoice M: The 13 top reasons consumers shop online. Jungle Scout; 2021, March 19. Reference Source\n\nPreetha S, Iswarya S: An analysis of user convenience towards food online order and delivery application (Food app via platforms). Inter. J. Manag. Techn. Eng. 2019; IX(I): 429–433.\n\nDavis FD: Perceived usefulness, perceived ease of use, and user acceptance of information technology. MIS Q. 1989; 13(3): 319–340. Publisher Full Text .\n\nCho YC, Sagynov E: Exploring factors that affect usefulness, ease of use, trust, and purchase intention in the online environment. Int. J. Manag. Inf. 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Rhetor. 1977; 10(2): 130–132\n\nTroise C, O’Driscoll A, Tani M, et al.: Online food delivery services and behavioural intention – a test of an integrated TAM and TPB framework. Br. Food J. 2021; 123(2): 664–683. Publisher Full Text\n\nRamadani V, Demiri A, Saiti-Demiri S: Social media channels: The factors that influence the behavioural intention of customers. Int. J. Bus. Global. 2014; 12(3): 297–314. Publisher Full Text\n\nBrown SA, Venkatesh V: Model of adoption of technology in households: A baseline model test and extension incorporating household life cycle. MIS Q. 2005; 29(3): 399–426. Publisher Full Text\n\nOthman B: The influence of technology acceptance model on behavioral intention to use internet banking system. [Master’s thesis, Universiti Teknologi Malaysia] (January 2013).2013. Reference Source\n\nBrewer P, Sebby AG: The effect of online restaurant menus on consumers’ purchase intentions during the COVID-19 pandemic. Int. J. Hosp. Manag. 2021; 94: 102777–102779. Publisher Full Text .\n\nCho M, Bonn MA, Li JJ: Differences in perceptions about food delivery apps between single-person and multi-person households. Int. J. Hosp. Manag. 2019; 77: 108–116. Publisher Full Text\n\nGanesh J, Reynolds KE, Luckett M, et al.: Online shopper motivations, and e-store attributes: An examination of online patronage behavior and shopper typologies. J. Retail. 2010; 86(1): 106–115. Publisher Full Text\n\nLiébana-Cabanillas F, Marinković V, Kalinić Z: A SEM-neural network approach for predicting antecedents of m-commerce acceptance. Int. J. Inf. Manag. 2017; 37(2): 14–24. Publisher Full Text\n\nZhao Y, Bacao F: What factors determining customer continuingly using food delivery apps during 2019 novel coronavirus pandemic period? Int. J. Hosp. Manag. 2020; 91: 102683–12. PubMed Abstract | Publisher Full Text | Free Full Text .\n\nGliem JA, Gliem RR: Calculating, interpreting, and reporting Cronbach’s alpha reliability coefficient for Likert-type scales [Paper Presentation]. 2003 Midwest Research to Practice Conference in Adult, Continuing, and Community Education, The Ohio State University, Columbus, OH.2003, October 8-10.\n\nSubedi BP: Using Likert type data in social science research: Confusion, issues and challenges. Int. J. Contemporary App. Sci. 2016; 3(2): 36–49.\n\nEtikan I, Musa SA, Alkassim RS: Comparison of convenience sampling and purposive sampling. Am. J. Theor. Appl. Stat. 2016; 5(1): 1–4. Publisher Full Text\n\nHair JF Jr, Hult GTM, Ringle C, et al.: A primer on partial least squares structural equation modeling (PLS-SEM). 2nd ed: SAGE Publications; 2016.\n\nWong KKK: Partial least squares structural equation modeling (PLS-SEM) techniques using SmartPLS. Mark. Bull. 2013; 24(1): 1–32.\n\nDijkstra TK, Henseler J: Consistent partial least squares path modeling. MIS Q. 2015; 39(2): 297–316Publisher Full Text .\n\nNayan NM, Hassan MKA: Customer satisfaction evaluation for online food service delivery system in Malaysia. J. Inf. Syst. Technol. Manag. 2020; 5(9): 123–136. Publisher Full Text\n\nOthman I, Bidin A, Hussain H: Facebook marketing strategy for small business for Malaysia. International Conference on Informatics and Creative Multimedia . 2013; 236–341. Publisher Full Text .\n\nCortina JM: What is coefficient alpha? An examination of theory and applications. J. Appl. Psychol. 1993; 78(1): 98–104. Publisher Full Text\n\nTaber KS: The use of Cronbach’s alpha when developing and reporting research instruments in science education. Res. Sci. Educ. 2018; 48: 1273–1296. Publisher Full Text\n\nFornell C, Larcker DF: Structural equation models with unobservable variables and measurement error: Algebra and statistics. J. Market. Res. 1981; 18(3): 382–388. Publisher Full Text\n\nAguirre-Urreta MI, Marakas GM, Ellis ME: Measurement of composite reliability in research using partial least squares: Some issues and an alternative approach. DATABASE for Adv. Inf. Sys. 2013; 44(4): 11–43. Publisher Full Text\n\nAlarcón D, Sánchez JA, De Olavide U: Assessing convergent and discriminant validity in the ADHD-R IV rating scale: User-written commands for Average Variance Extracted (AVE), Composite Reliability (CR), and Heterotrait-Monotrait ratio of correlations (HTMT) [Paper Presentation]. Spanish STATA Meeting (Vol. 39), Universidad Pablo de Olavide. 2015, October 22.\n\nAb Hamid MR, Sami W, Sidek MM: Discriminant validity assessment: Use of Fornell & Larcker criterion versus HTMT criterion. J. Phys. Conf. Ser. 2017; 890(1): 012163–012165. Publisher Full Text\n\nLee SW, Sung HJ, Jeon HM: Determinants of continuous intention on food delivery apps: Extending UTAUT2 with information quality. Sustainability. 2019; 11(11): 3141. Publisher Full Text\n\nChen YM, Hsu TH, Lu YJ: Impact of flow on mobile shopping intention. J. Retail. Consum. Serv. 2018; 41: 281–287. Publisher Full Text\n\nKorzaan ML: Going with the flow: Predicting online purchase intentions. J. Comput. Inf. Syst. 2003; 43(4): 25–31.\n\nYang K: Determinants of US consumer mobile shopping services adoption: Implications for designing mobile hopping services. J. Consum. Mark. 2010; 27(3): 262–270. Publisher Full Text\n\nTan SY, Lim SY: Online food delivery services: Consumers’ attitude towards continuance intention post COVID-19 pandemic_OFDS307.csv. figshare. Dataset. 2021. 2021Publisher Full Text\n\nTan SY, Lim SY: Online Food Delivery Services questionnaire 2021.csv. figshare. Dataset. 2021. 2021. Publisher Full Text"
}
|
[
{
"id": "100846",
"date": "21 Dec 2021",
"name": "Bui Thanh Khoa",
"expertise": [
"Reviewer Expertise electronic commerce",
"online consumer behavior",
"marketing"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you very much for the opportunity to review the study titled “Online food delivery services: cross-sectional study of consumers’ attitude in Malaysia during and after the COVID-19 pandemic.” The selected topic is intriguing, and the work can add value to the existing body of literature. However, certain flaws overshadow the paper’s potential significance. In the following lines, I offer some suggestions to this study as follows:\nOne of the most pressing challenges is the theoretical research gap. Please provide a well-defined research gap. Furthermore, please explain why it is critical to include comprehensive poverty eradication in the theoretical contribution for the study area; hence, restructure the introduction. Typically, the framework will include the following elements: the significance of the issue, motivation (optional), research gap(s), aims, and possible contributions (optional). Lack of the research gap(s) reduces the paper’s value.\n\nThis research used many constructs, such as Convenience motivation, Perceived ease of use, Time-saving orientation, Price-saving orientation, Attitude, Behavioural intention, and continuance intention; however, the reviewer cannot find the theoretical background in this research to connect them; hence, the proposed model is subjective and lacks scientific arguments. Please add the theoretical background in the first literature review.\n\nTable 2 shows the demographic profile of 307 respondents, of which there are 16.61% of respondents that have not used OFDS before. Why can they answer the research items regarding the continuance intention?\n\nThe sampling method should be based on the research objective more than the prior research.\n\nThe data analysis should add the f2 and Q2 values to check the effect size and predictive relevance.\n\nLimitation should be moved to the end of the paper.\n\nI firmly believe that the authors need a significant overhaul of the study, especially the theoretical framework and data process for ensuring the scientific validity of the article to make the manuscript suitable for indexing, given that it will be professionally revised before another submission.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11439",
"date": "28 May 2024",
"name": "Sin Yin Tan",
"role": "Author Response",
"response": "Thank you so much for the reviewer's comments. We sincerely appreciate the insightful feedback provided by the reviewer. To address the comments that highlighted by reviewer: The Introduction section has been substantially revised by including more significance of the research issues and highlighting the research gaps and contributions of our study. The theoretical background is now positioned within the Literature Review section. We elaborate our study based on the Theory of Planned Behavior (TPB) and the Technology Acceptance Model (TAM). The survey data underwent reanalysis by excluding those who did not have any experience of using Online Food Delivery Services (OFDS). Therefore, the new demographic profile has been presented under Result section. Purposive sampling method was applied and clarified under Data collection of the Methods section. As suggested by reviewer, the f2 and Q2 values have been added in Table 9 under Result section to check the effect size and predictive relevance. Considering the journal editor's advice, the limitation was suggested to place before Conclusions section. A significant revision had been undertaken which involve restructuring of the research study based on the theoretical framework and subsequent analysis. Thank you."
}
]
},
{
"id": "258703",
"date": "06 May 2024",
"name": "Hyun-Woo Joung",
"expertise": [
"Reviewer Expertise Consumer behavior in the hospitality industry"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction:\nStrengthen the introduction by providing more rationale for the study and identifying research gaps. Clarify whether the study was conducted recently or in 2021, and update statistics accordingly. Address the discrepancy between data collection during the pandemic in 2021 and discussing the impact \"after\" the pandemic.\nLiterature Review:\nExpand the literature review to provide more in-depth analysis of potential predictor variables or offer detailed reasoning for the chosen variables. Strengthen the hypotheses development section by providing clear rationale for each hypothesis. Consider adopting a relevant theory (e.g., UTAUT, TAM) to support the conceptual model.\nMethods:\nProvide a brief explanation of the Krejcie and Morgan sampling method to enhance understanding.\nResults:\nAddress ethical concerns regarding participants under the age of 18 and clarify how their data were handled. Explain how participants who have not used OFDS before were able to answer questions related to \"Continuance intention.\" Evaluate the necessity of Table 3 and consider its relevance to the study. Enhance Table 5 by providing additional statistical evidence, such as chi-square analysis, in addition to ratios. Explain the discrepancy in Table 7 where CM's square root of AVE is smaller than the correlation between CM and PEOU.\nDiscussion and Conclusion:\nOffer a more in-depth discussion that goes beyond repeating the findings already discussed in the results section. Strengthen the practical and theoretical implications.\nOverall:\nAcknowledge the importance of the topic in the restaurant industry. Suggest improvements to enhance the quality of the manuscript, including professional proofreading.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11569",
"date": "28 May 2024",
"name": "Sin Yin Tan",
"role": "Author Response",
"response": "Thank you so much for your comments. We sincerely appreciate the valuable feedback and suggestions from you. To address the comments that highlighted by reviewer: 1.Introduction: The research gaps and contributions of our study have been restructured to include the justification for the research under the introduction section. The study was conducted in 2021 as stated in our article. In future, we plan to extend our study on the impact “after” the pandemic in the OFDS domain. 2.Literature Review: Theoretical Framework has been included under the Literature Review section. Our selected variables were based on the Theory of Planned Behavior (TPB) and the Technology Acceptance Model (TAM). Detailed elaboration was further described in this section. 3.Methods: Purposive sampling method was applied in our study and clarified under Data collection of the Methods section. The sampling size was based on the other studies in the same domain. 4.Results: Research ethics approval was obtained from Multimedia University, Malaysia (EA1422021) and the respondents gave their written informed consent when filling out the Google Form. The survey data underwent reanalysis by excluding those who did not have any experience using Online Food Delivery Services (OFDS). Therefore, the new demographic profile has been presented under the Result section. Table 3 illustrates feedback of respondents for each measurement item. The objective is to show that there is a significance left-skewed for each measurement item except PSO4. In this study, descriptive study is maybe more meaningful for certain variables such as the mature adults (above 41 years old), and B40 respondents (personal Income level) preferred to dine at home. The preference of dining at home is analysed based on their demographic so that sellers can approach these groups of people. In Table 7, CM's square root of AVE is greater than the correlation between CM and PEOU. 5.Discussion and Conclusion: Discussion and conclusion section have been further improved by explaining how this study contribute to existing theoretical frameworks based on the proposed research model. Further descriptions of related works in this domain were also provided. 6.Overall: Thank you for your suggestion. A significant revision had been undertaken which involves restructuring of the research study based on the theoretical framework and subsequent analysis."
}
]
}
] | 1
|
https://f1000research.com/articles/10-972
|
https://f1000research.com/articles/13-461/v1
|
08 May 24
|
{
"type": "Case Report",
"title": "Case Report: Urothelial urethral carcinoma in HIV patient underwent total urethrectomy and perineal urethrostomy",
"authors": [
"Ahmad Agil",
"Kenfin Surya",
"Kenfin Surya"
],
"abstract": "Introduction HIV affects over 38 million people worldwide, affecting the immune system and leading to symptoms like fever, lymphadenopathy, and sore throat. High viral loads can lead to opportunistic infections and tumors. The life expectancy of HIV patients has increased due to high-efficiency combination anti-retroviral therapy. Urothelial carcinoma, a malignant development, damages the urinary canal lining. The connection between HIV and urinary cancers is unclear, the aims of this study to report a case of urethral urothelial Carcinoma in HIV patient who underwent total urethrectomy and perineal urethrostomy.\n\nCase presentation A 34-year-old male patient with a papilliferous lump on the glans penis for over six months was admitted to the hospital. Preoperative screening revealed HIV and a urethral mass was found. A partial urethrectomy was performed, revealing high grade papillary urothelial Carcinoma. Five months after surgery, the patient developed a recurrent lump, requiring a total urethrectomy, TUR (transurethral resection) of the mass in the prostatic urethra, and perineal urethrostomy.\n\nConclusion Primary carcinoma of the urethra in HIV patient is an extremely rare case. To date, there is no consensus on the primary urethral carcinoma therapy. The treatment of primary urethral carcinoma is tailored specifically to the patient based on the location, histology, and stage of the carcinoma.",
"keywords": [
"urethral urothelial carcinoma",
"HIV",
"urethrectomy",
"urethrostomy"
],
"content": "Introduction\n\nWith 1.7 million new infections each year, there are over 38 million individuals living with HIV worldwide.1 HIV primarily affects the immune system, especially concentrating on dendritic cells, mononuclear macrophages, and CD4+T lymphocytes. As a result, the number of CD4+T cells continues to decline, the blood HIV viral load is noticeably high, and symptoms including fever, lymphadenopathy, sore throat, myalgias/arthralgias, headaches, and mucocutaneous ulcerations are among those that are manifested. When cellular immunity is severely compromised, several opportunistic infections and tumors may eventually occur. The life expectancy of HIV patients has been markedly extended due to the widespread use of high-efficiency combination anti-retroviral therapy (ARV), and the prevalence of illnesses that coexist with HIV has steadily grown.2,3\n\nA malignant development called urothelial carcinoma (UC) damages the lining of the urinary canal from the renal pelvis to the distal urethra. Urothelial carcinoma can invade the basement membrane, lamina propria, or deeper by neoplastic cells of urothelial origin.4 Urothelial carcinoma is less prevalent throughout the upper urinary system (renal pelvis and ureter), where it accounts for 5–10% of cases, and much less common—less than 1%—along the urethra.5 The absence of a definite consensus on how to treat this illness is explained by the rarity of urethral cancer.6\n\nWhile Kaposi sarcoma and non-Hodgkin lymphomas are well-known HIV-related cancers, the connection between HIV and urinary cancers is still unclear. The relationship between urothelial cancer and HIV infection looked like a worthwhile issue for research, especially since HIV invades CD4 + T cells and impairs the immune system.7 Until now, case reports regarding primary urethral carcinoma cases in HIV patients are still very rare. Therefore, in this study, we report a case of Urethral Urothelial Carcinoma in HIV patient who underwent total urethrectomy and perineal urethrostomy.\n\n\nCase report\n\nA 34-year-old male patient came with complaints of a papilliferous lump on the glans penis for more than 6 months before being admitted for the first time to the hospital. The lump bleeds easily if it rubs against the trousers (Figure 1). The patient is known to have a history of having sex with members of the same sex. The patient’s history of hematuria was denied. The results of the preoperative screening showed that the patient had HIV.\n\nThe patient then underwent urethrocystoscopy surgery. Urethral mass was found up to the midshaft penile urethra (Figure 2). Then, it was decided that the patient’s treatment was a partial urethrectomy with tumor-free margins neo-external urethral meatus was positioned in the proximal urethra area near the penoscrotal junction (Figure 3). The result of pathological evaluation of the mass was high grade papillary urothelial carcinoma. Patients then decided to undergo routine post-operative follow-up examinations. Patients also routinely undergo control at the internal medicine department for ARV therapy.\n\nFive months after surgery, the patient came with recurrent papillary lump that on the neourethral stump and spread to the distal skin and glans penis (Figure 4). The patient then underwent another total urethrectomy operation, TUR of the mass in the prostatic urethra near the verumontanum, and perineal urethrostomy (Figures 5-7).\n\n\nDiscussion\n\nAfter the development of efficient antiretroviral therapy (ARV) in 1996, the risk for AIDS and mortality in HIV-infected individuals significantly decreased.1,8 Although it has decreased in the ARV era, the incidence of cancer among HIV-infected patients is much higher than in the normal population. People with HIV are presently roughly 500 times more likely to have a Kaposi sarcoma diagnosis than the general population, 12 times more likely to receive a non-Hodgkin lymphoma diagnosis, and, among women, three times more likely to receive a cervical cancer diagnosis.9,10\n\nTo date, the connection between HIV and urinary cancers is still unclear. HIV infection is known to impair the immune system and lower the body’s capacity to combat viral infections that may cause cancer. This means that pre-cancerous lesions in the body are not properly detected. In addition, the increase in cancer prevalence in HIV patients is suspected to be related to the increase in viral infection rates.11 Because HIV-positive individuals have impaired immune systems, immunosuppression, and inflammation may have direct or indirect roles in the occurrence of various malignancies that are more common in HIV-positive individuals. In terms of malignancies other than those that are indicative of AIDS, a study found that HIV-positive Koreans had a much greater incidence of cancers brought on by viral infections. Investigations into the hypothesis that human papillomavirus (HPV) infection is a risk factor influencing the development of urothelial cancer have not shown any conclusive results.7 Additionally, there is a greater incidence of several conventional risk factors for cancer among HIV-positive individuals, including smoking (which is known to cause lung and other cancers) and heavy alcohol consumption (which can raise the risk of liver cancer).10,12\n\nCase reports regarding the incidence of urothelial cancer in HIV patients are still very rare. Although it’s still an uncommon occurrence, just 0.2% of persons with HIV get bladder cancer, according to research conducted in Paris. This cohort’s estimated five-year partial prevalence of bladder cancer (2004–2008) was 128.1 per 100,000 people, which was comparable to the French general male population’s rate. However, compared to other cancers in this population, such as Kaposi sarcoma and non-Hodgkin lymphomas, which have been reported to have ten-fold higher prevalence rates, and lung and anal cancers, which have been reported to have an average 5-fold higher prevalence rate in 2006 in France, urological cancer is still much less common in HIV-infected patients. In fact, there are just a few case reports in the literature.7\n\nAs one of the rarest cancers of the urogenital tract is primary carcinoma of the urethra. According to estimates, the incidence rate is 1.1 per million people and peaks after age 75. The signs of growing cancer are non-specific and might be mistakenly attributed to other lower urinary tract obstructive conditions. Patients most frequently describe haematuria and symptoms related to lower urinary tract blockage. Extraurethral mass, irritative sensations, and pelvic pain are other signs. In this case the patient had no history of hematuria but presented with complaints of a period that bleeds easily.13 Chronic inflammation, urethritis history, and urethral stricture are the primary risk factors. Other, less common causes, such urethroplasty, intermittent urethral catheterization, external pelvic irradiation, and brachytherapy, have been implicated. It is important to keep in mind that several traditional risk factors for bladder cancer, such smoking, may not necessarily be connected to the development of urethral cancer.6\n\nUntil now, case reports regarding primary urethral carcinoma cases in HIV patients are still extremely rare. Some conditions of urothelial cancer need surgery as a treatment option. Regarding primary urethral carcinoma therapy, there is currently no agreement. Most of the time, treatment is tailored specifically to the patient based on the location, histology, and stage of the carcinoma. Aggressive excisional surgery was used to treat tumours of the anterior urethra in a manner similar to how tumours of the penis were treated. A large, healthy surgical margin was deemed required in order to provide acceptable local control, which was the major objective.14 According to the European recommendations for the therapy of primary urethral cancer, localised anterior tumours (p T1-3) should be treated conservatively with a penile-preserving urethrectomy. Patients who have lymph node involvement in the iliac or inguinal regions (N1, N2) may even be recommended this conservative approach in conjunction with lymph node dissection.15\n\nAn operation to remove all or a portion of the male urethra is known as a urethrectomy. Patients with UC at high risk may occasionally be candidates for this surgery as in this case.16,17 This patient also underwent a surgical procedure called a perineal urethrostomy to make a permanent incision in the perineum’s skin through which the urethra may be accessed. This procedure is carried out to overcome the urinary passage challenge after total urethrectomy. Perineal urethrostomies are most frequently performed using the Blandy method. It entails producing a perineum incision (cut) in the shape of an inverted U immediately below the scrotum. The bulbar urethra is exposed when the skin is split apart, and a three- to four-centimeter-long incision is made into it along its length. The closest portion of the opening urethra is joined by suturing (sewing) the upper portion of the perineal flap of skin. Additionally, the perineal flap’s margins are stitched to the urethral mucosa’s borders. The urethral opening is then finished by sewing the scrotal skin to the top portion of the aperture up to the perineal flap. After the procedure, a Foley catheter is inserted via the urethrostomy into the bladder to remove urine from the body.18,19\n\nMaking surgical decisions when a patient has HIV infection might be an issue. HIV infection has an impact on life expectancy, nutritional state, and the differential diagnosis of surgical diseases. HIV infection may, according to some, also affect surgical wound healing and complication rates.20,21 As part of the preoperative examination for patients with HIV, doctors should evaluate the most current CD4 cell count and HIV viral load test findings. Retesting prior to surgery is not essential if current test results (6 months for HIV viral load; 12 months for CD4 count) are accessible in the patient’s medical records. In general, surgical mortality and complications are more likely to occur in HIV patients who have low CD4 counts and uncontrolled viral loads. A skilled HIV care provider should be consulted if surgery is planned and the patient has a viral load level or CD4 count of 200 copies/mL or less.21\n\nPatients with HIV are more likely to develop venous thrombosis than people without HIV. Therefore, it is crucial to start pharmacologic prophylaxis and mobilize HIV patients as soon as medically possible following surgery. The stress of surgery can reveal hypoadrenalism in those with a long history of HIV, low CD4 counts, or exposure to boosted regimens and glucocorticoids. When evaluating postoperative hypotension, this possibility should be considered. Prioritizing common causes of fever, such as urinary tract infections, pneumonia, venous thromboembolism, wound infections, or Clostridioides difficile if antibiotics were given, should be done in patients with HIV and postoperative fever before HIV-related reasons. Clinicians should visit an infectious disease expert if the patient’s CD4 count is less than 200 cells/mm3.21–23\n\n\nConclusion\n\nHIV infection is known to impair the immune system and lower the body’s capacity to combat viral infections that may cause cancer. As one of the rarest cancers of the urogenital tract, case of primary carcinoma of the urethra in HIV patient is extremely rare. To date, treatment of primary urethral carcinoma is tailored specifically to the patient based on the location, histology, and stage of the carcinoma.\n\n\nEthical approval\n\nEthical approval not required.\n\n\nConsent\n\nWritten informed consent for the publication of the case report and any associated images obtained from the patient.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nde Cock KM , Jaffe HW, Curran JW: Reflections on 40 years of AIDS. Emerg. Infect. Dis. 2021; 27(6): 1553–1560. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcgowan JP, Fine SM, Vail R, et al.: Diagnosis and Management of Acute HIV Infection.2021 July.\n\nVijayan KV, Karthigeyan KP, Tripathi SP, et al.: Pathophysiology of CD4+ T-Cell depletion in HIV-1 and HIV-2 infections. Front. Immunol. 2017; 8(May): 1–8. Publisher Full Text\n\nMiyazaki J, Nishiyama H: Epidemiology of urothelial carcinoma. Int. J. Urol. Off. J. Japanese Urol. Assoc. 2017 Oct; 24(10): 730–734. Publisher Full Text\n\nGatta G, van der Zwan JM , Casali PG, et al.: Rare cancers are not so rare: the rare cancer burden in Europe. Eur. J. Cancer. 2011 Nov; 47(17): 2493–2511. Publisher Full Text\n\nMoez R, Boulma R, hassen K.: Primary urothelial carcinoma of the male anterior urethra; A case report. Ann. Med. Surg. 2022; 76(April): 103561. Publisher Full Text\n\nChawki S, Ploussard G, Montlahuc C, et al.: Bladder Cancer in HIV-infected Adults: An Emerging Issue? Case-Reports and Systematic Review. PLoS One. 2015; 10(12): 1–9. Publisher Full Text\n\nThe HIV-CAUSAL Collaboration: The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS. 2010; 24(1): 123–137. Publisher Full Text\n\nHernández-Ramírez RU, Shiels MS, Dubrow R, et al.: Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study. Lancet HIV. 2017 Nov; 4(11): e495–e504. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStelzle D, Tanaka LF, Lee KK, et al.: Estimates of the global burden of cervical cancer associated with HIV. Lancet Glob. Health. 2021; 9(2): e161–e169. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMusangile FY, Matsuzaki I, Okodo M, et al.: Detection of HPV infection in urothelial carcinoma using RNAscope: Clinicopathological characterization. Cancer Med. 2021; 10(16): 5534–5544. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChawki S, Ploussard G, Montlahuc C, et al.: Bladder cancer in HIV-infected adults: an emerging concern? J. Int. AIDS Soc. 2014 Nov 2; 17(4 Suppl 3): 19647. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKrukowski J, Czajkowski M, Kłącz J, et al.: Primary urethral carcinoma – unexpected cause of urethral stricture. Case report and review of the literature. Med. Ultrason. 2019 Nov 24; 21(4): 494–496. PubMed Abstract | Publisher Full Text\n\nRyan Farrell M, Xu JT, Vanni AJ: Current perspectives on the diagnosis and management of primary urethral cancer: A systematic review. Res. Reports Urol. 2021; 13: 325–334. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGakis G, Bruins HM, Cathomas R, et al.: European Association of Urology Guidelines on Primary Urethral Carcinoma—2020 Update. Eur. Urol. Oncol. 2020 Aug; 3(4): 424–432. PubMed Abstract | Publisher Full Text\n\nAhlering TE, Lieskovsky G, Skinner DG: Indications for urethrectomy in men undergoing single stage radical cystectomy for bladder cancer. J. Urol. 1984 Apr; 131(4): 657–659. PubMed Abstract | Publisher Full Text\n\nLaukhtina E, Boehm A, Peyronnet B, et al.: Urethrectomy at the time of radical cystectomy for non-metastatic urothelial carcinoma of the bladder: a collaborative multicenter study. World. J. Urol. 2022; 40(7): 1689–1696. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLumen N, Beysens M, Van Praet C, et al.: Perineal urethrostomy: Surgical and functional evaluation of two techniques. Biomed. Res. Int. 2015; 2015: 1–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMurphy GP, Fergus KB, Gaither TW, et al.: Urinary and Sexual Function after Perineal Urethrostomy for Urethral Stricture Disease: An Analysis from the TURNS. J. Urol. 2019; 201(5): 956–961. PubMed Abstract | Publisher Full Text\n\nZhang L, Liu BC, Zhang XY, et al.: Prevention and treatment of surgical site infection in HIV-infected patients. BMC Infect. Dis. 2012; 12: 2–5.\n\nYan L, Ellman T, Mcnairy M, et al.: Perioperative Care in Adults With HIV Perioperative Care in Adults with HIV Purpose of This Guideline HIV-Specific Perioperative Considerations.2021 November.\n\nDua RS, Wajed SA, Winslet MC: Impact of HIV and AIDS on surgical practice. Ann. R. Coll. Surg. Engl. 2007; 89(4): 354–358. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSmit S: Guidelines for Surgery in the HIV Patient. Can. Med. Educ. J. 2010; 28(8): 356–358."
}
|
[
{
"id": "276153",
"date": "15 May 2024",
"name": "Pande Made Wisnu Tirtayasa",
"expertise": [
"Reviewer Expertise Urology",
"kidney transplant",
"transplantation immunology",
"biology molecular"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a well-written case report about urethral carcinoma in a HIV patient who was managed by several type of surgical approach. The article provides sufficient details of background, diagnostic and staged treatment as well as relevance discussion. However, due to the nature of the disease in which recurrent may occur, it is advisable to provide what is expected for the patient in the future regarding the disease and what might be useful to do to avoid or at least to early recognize the recurrent of this type of carcinoma.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-461
|
https://f1000research.com/articles/13-460/v1
|
08 May 24
|
{
"type": "Case Report",
"title": "Case Report: Branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives",
"authors": [
"Tetsuya Muto",
"Masaaki Sakamoto",
"Shigeki Machida",
"Shinichiro Imaizumi",
"Yoshinobu Hamada",
"Koju Kamoi",
"Masaaki Sakamoto",
"Shigeki Machida",
"Shinichiro Imaizumi",
"Yoshinobu Hamada",
"Koju Kamoi"
],
"abstract": "Oral contraceptive use, vaccination for Coronavirus disease 2019 (COVID-19), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are risk factors for venous thromboembolism. Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 20 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently.",
"keywords": [
"branch retinal vein occlusion",
"COVID-19",
"SARS-CoV-2 infection",
"macular edema",
"oral contraceptive"
],
"content": "Introduction\n\nThe Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the latest pandemic and has lasted approximately 3 years in Japan. A special characteristic of COVID-19 is its propensity to cause venous thromboembolism (VTE),1 which could result in fatal complications. In ophthalmology, COVID-19 reportedly causes retinal vein occlusion (RVO).2–4\n\nBranch RVO (BRVO) is a major retinal vascular disease that occurs following venous thrombosis at arteriovenous crossing points. Arteriosclerosis accompanied by hypertension is a risk factor for BRVO; therefore, it primarily affects older people.\n\nBRVO causes blood–retinal barrier dysfunction, resulting in macular edema (ME). Photoreceptor cell apoptosis caused by chronic ME is responsible for the reduced vision in patients with BRVO. Therefore, a missed treatment window may lead to irreversible loss of vision.5,6 Anti-vascular endothelial growth factor agents are the first-line treatment for ME secondary to BRVO.7\n\nOver 100 million women worldwide practice contraception and use intrauterine devices, combined estrogen and progestin oral contraceptives, and progestin -only preparations (oral contraceptives, implants, or injections).8 Oral contraceptives contain estrogen, which increase the risk of VTE due to activation the coagulation cascade. The incidence of VTE in women receiving oral contraceptives is approximately twice as high as that in the normal population.9 Generally, the age group susceptible to RVO associated with oral contraceptive use is younger than that for typical RVO.\n\nHerein, we present a case of a 21-year-old woman using oral contraceptives who developed BRVO with ME following COVID-19. To the best of our knowledge, this is the first report suggesting that oral contraceptive intake combined with COVID-19 may be a risk factor for the development of BRVO.\n\n\nCase report\n\nA 21-year-old woman was diagnosed with polycystic ovary syndrome accompanied by oligomenorrhea at 19 years old. Consequently, she had been taking oral contraceptives (norethisterone and ethinylestradiol mix tablet) for the improvement of oligomenorrhea. She did not have diabetes or systemic hypertension, and she did not smoke. She had no family history of VTE. Her height, body weight, and body mass index were 1.62 m, 52 kg, and 19.8, respectively. Although she had received an mRNA COVID-19 vaccine twice approximately 5 months prior to presentation, she experienced fever, sore throat, cough, low back pain, and general malaise, prompting her to visit a clinic. Polymerase chain reaction of her saliva sample showed a positive reaction to SARS-CoV-2. Her cough persisted for a month, but other symptoms improved without post-COVID-19 sequelae.\n\nApproximately 40 days after being diagnosed with COVID-19, she presented with decreased vision in the right eye and was diagnosed with ME secondary to BRVO. On her initial visit to our hospital, the decimal best-corrected visual acuity (BCVA) values were 0.4 in the right eye and 1.2 in the left eye. In both eyes, intraocular pressure was normal, and slit-lamp biomicroscopy did not detect inflammation. Fundus examination revealed retinal hemorrhage in the superior-temporal quadrant of the retina in the right eye (Figure 1). Optical coherence tomography (RS-3000 Advance, Nidek Corporation, Japan) demonstrated cystoid ME and intraretinal fluid in the right eye (Figure 2). Blood test results, including cardiolipin antibody IgG, were within normal limits.\n\nThe clinical diagnosis was ME secondary to BRVO following COVID-19. We contacted her gynecologist about her eye condition, and oral contraceptives for oligomenorrhea were changed to a progestational hormone agent (dydrogesterone). Additionally, the patient was treated with intravitreal aflibercept (Eylea®; Regeneron, Tarrytown, NY, USA). ME resolved after 1 month (Figure 3), and the decimal BCVA improved to 1.2 in the right eye. After more than 20 months since the first administration, no additional intravitreal aflibercept has been administered.\n\n\nDiscussion\n\nThe estimated incidence of combined oral contraceptive-related ocular complications is 1 in 230,000 persons and includes dry eyes, corneal edema, lens opacities and retinal neuro–ophthalmologic, or vascular complications.8 Sinawat et al. analyzed patients with RVO aged <50 years and reported that 3 of 70 patients with central RVO had taken oral contraceptives for 5–6 years and 1 of 30 patients with BRVO had taken oral contraceptives for 10 years.10 As persons aged mid-60s are the most susceptible to RVO, our case is extremely rare. According to a 2013 survey regarding VTE, the risk of VTE in women receiving oral contraceptives is twice as high as that in women not receiving oral contraceptives.9 Lidegaard et al. reported that the VTE risk related to oral contraceptive use is 1.0 for women aged 15–19 years, 1.32 for 20–24 years, 1.99 for 25–29 years, 2.91 for 30–34 years, 4.01 for 35–39 years, 5.29 for 40–44 years, and 6.58 for 45–49 years.11 Therefore, the VTE risk increases with increasing age.11 As our patient was 21 years old, the risk for RVO appeared to be low.\n\nSeveral reports have described BRVO development following SARS-CoV-2 infection.2,4 SARS-CoV-2 infection is a high-risk factor of VTE.1 Pur et al. reported a case of BRVO after mRNA COVID-19 vaccination.12 They postulated that the vaccine evoked an immunological response that induced VTE in a healthy patient.12 Thus, the combination of oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination could be a risk factor for the development of RVO.\n\n\nEthics and consent\n\nWritten informed consent for publication of the clinical details and clinical images was obtained from the patient.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgments\n\nWe have uploaded our report to Research Square in the form of a preprint (DOI: https://doi.org/10.21203/rs.3.rs-2067517/v1).\n\n\nReferences\n\nDemelo-Rodríguez P, Ordieres-Ortega L, Ji Z, et al.: Long-term follow-up of patients with venous thromboembolism and COVID-19: analysis of risk factors for death and major bleeding. Eur. J. Haematol. 2021; 106(5): 716–723. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDuff SM, Wilde M, Khurshid G: Branch retinal vein occlusion in a COVID-19 positive patient. Cureus. 2021; 13(2): e13586. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFinn AP, Khurana RN, Chang LK: Hemi-retinal vein occlusion in a young patient with COVID-19. Am. J. Ophthalmol. Case Rep. 2021; 22: 101046. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKarasu B, Kesim E: Bilateral branch retinal vein occlusion following the diagnosis of mild coronavirus disease. Arq. Bras. Oftalmol. 2023; 86(3): 274–276. PubMed Abstract | Publisher Full Text\n\nDaruich A, Matet A, Moulin A, et al.: Mechanisms of macular edema: beyond the surface. Prog. Retin. Eye Res. 2018; 63: 20–68. PubMed Abstract | Publisher Full Text\n\nIijima H: Mechanisms of vision loss in eyes with macular edema associated with retinal vein occlusion. Jpn. J. Ophthalmol. 2018; 62(3): 265–273. PubMed Abstract | Publisher Full Text\n\nOgura Y, Kondo M, Kadonosono K, et al.: Current practice in the management of branch retinal vein occlusion in Japan: survey results of retina specialists in Japan. Jpn. J. Ophthalmol. 2019; 63(5): 365–373. PubMed Abstract | Publisher Full Text\n\nMoschos MM, Nitoda E: The impact of combined oral contraceptives on ocular tissues: a review of ocular effects. Int. J. Ophthalmol. 2017; 10(10): 1604–1610. eCollection 2017. PubMed Abstract | Publisher Full Text | Free Full Text\n\nESHRE Capri Workshop Group: Venous thromboembolism in women: a specific reproductive health risk. Hum. Reprod. Update. 2013; 19(5): 471–482. PubMed Abstract | Publisher Full Text\n\nSinawat S, Bunyavee C, Ratanapakorn T, et al.: Systemic abnormalities associated with retinal vein occlusion in young patients. Clin. Ophthalmol. 2017; 11: 441–447. eCollection 2017. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLidegaard Ø, Nielsen LH, Skovlund CW, et al.: Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ. 2011; 343: d6423. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPur DR, Catherine Danielle Bursztyn LL, Iordanous Y: Branch retinal vein occlusion in a healthy young man following mRNA COVID-19 vaccination. Am. J. Ophthalmol. Case Rep. 2022; 26: 101445. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "351857",
"date": "26 Dec 2024",
"name": "Pradeep Kumar Panigrahi",
"expertise": [
"Reviewer Expertise Vitreo-retina",
"medical retina",
"surgical retina"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. 3. What blood investigations favoured a possible thrombotic cause in this case? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "13058",
"date": "02 Jan 2025",
"name": "Tetsuya Muto",
"role": "Author Response",
"response": "Dear reviewer, We have a question about the reviewer 's comment. What is STBRVO? Would you tell us ? 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Sincerely, Tetsuya Muto"
},
{
"c_id": "13111",
"date": "11 Jan 2025",
"name": "PRADEEP KUMAR PANIGRAHI",
"role": "Reviewer Response",
"response": "Superotemporal BRVO"
},
{
"c_id": "13217",
"date": "29 Jan 2025",
"name": "Tetsuya Muto",
"role": "Author Response",
"response": "Response to Reviewer Oral contraceptives intake and COVID-19 infection/ vaccination are all known risk factors associated with RVO. The case report does not add much to what is already known. Yes, we added below sentence in discussion section. To the best of our knowledge, this is the first reported case of superotemporal BRVO involving all three risk factors. 2. Kindly provide the list of blood investigations performed along with their values in a tabular form. Just mentioning routine blood investigations is incomplete. Yes, we added Table 1 and 2 as below. Table 1 Blood test results at the initial visit 1 factors values GOT(U/L) 14 GPT(U/L) 8 γ-GTP(U/L) 12 total bilirubin (mg/dL) 0.49 direct bilirubin (mg/dL) 0.02 indirect bilirubin (mg/dL) 0.47 total protein 8g/dL) 7.3 albumin (g/dL) 4.44 Na (mmol/L) 141 K (mmol/L) 4.1 Cl (mmol/L) 105 Ca (mg/dL) 9.5 BUN (mg/dL) 11 Cre (mg/dL) 0.56 Uric acid (mg/dL) 4.1 BS (mg/dL) 89 total cholesterol (mg/dL) 192 triglyceride (mg/dL) 78 HDL cholesterol (mg/dL) 64 LDL cholesterol (mg/dL) 116 LDL/HDL 1.8 WBC (x109/L) 5.4 RBC (x109/L) 4.18 Hb (g/dL) 12.2 Ht (%) 37.5 MCV (fL) 89.7 MCH (pg) 29.2 MCHC (g/dL) 32.5 Table 2 Blood test results at the initial visit 2 factors values Platelet (x109/L) 252 neutrophils (%) 50.4 ESR (mm/1h) 10 lymphocyte (%) 42.2 monocyte (%) 3.9 eosinophils (%) 2.8 basophil leukocyte (%) 0.7 PT (sec) 11.1 APTT (sec) 28.8 CRP (mg/dL) 0.11 IgG (mg/dL) 1138.6 IgA (mg/dL) 238.1 IgM (mg/dL) 118.1 C3 (mg/dL) 108.2 C4 (mg/dL) 24.8 cardiolipin antibody IgG (U/mL) < 4.0 ACE (U/L) 6.1 RA (IU/mL) < 5 3. What blood investigations favoured a possible thrombotic cause in this case? Yes, we added below sentence in discussion section and we added references no. 14 and 15. A thrombotic cause was unclear from the patient’s blood results. The literature shows that D-dimer is commonly elevated in patients with COVID-1916 and oral contraceptive users17. However, no special blood factors have been reported linking RVO with oral contraceptive use, SARS-CoV-2 infection, and COVID-19 vaccination. Identifying the cause was challenging. 16. Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18(9):2103–2109. doi: 10.1111/jth.14975. 17. Westhoff CL, Eisenberger A, Tang R, Cremers S, Grossman LV, Pike MC. Clotting factor changes during the first cycle of oral contraceptive use. Contraception 2016; 93(1):70-76. doi: 10.1016/j.contraception.2015.09.015. 4. Kindly be specific with the diagnosis. This is a case of STBRVO to be specific...so in diagnosis it should be mentioned STBRVO and not just BRVO. Yes, we changed the title as below. Superotemporal branch retinal vein occlusion following COVID-19 vaccination and SARS-CoV-2 infection while taking oral contraceptives: A case report Yes, we changed the abstract as below. Abstract Oral contraceptive use, vaccination for Coronavirus disease 2019 (COVID-19), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are risk factors for venous thromboembolism. Branch retinal vein occlusion (BRVO) generally develops mid-60s patients. Herein, we present a case of superotemporal BRVO caused by the above mentioned risk factors in a young woman. To the best of our knowledge, this is the first report about superotemporal BRVO associated with oral contraceptives, COVID-19 vaccination, and SARS-CoV-2. A 21-year-old woman presented with loss of visual acuity in her right eye for 10 days. She had been receiving oral contraceptives for 2 years for oligomenorrhea before noticing ophthalmological symptoms. Despite having received two doses of an mRNA COVID-19 vaccine, she contracted COVID-19 and developed fever, sore throat, cough, low back pain, and general malaise about 40 days before the initial visit. However, only cough persisted for more than a month. The right eye showed superotemporal BRVO with macular edema (ME). She did not smoke nor had diabetes or hypertension. Blood test results, including cardiolipin antibody IgG, were normal. She was treated with an intravitreal aflibercept injection. ME in the fundus showed rapid improvement and resolution. Although more than 18 months have passed since the first injection, there has been no relapse of ME. The combination of oral contraceptive use, COVID-19 vaccination, and subsequent SARS-CoV-2 infection could induce the development of venous thromboembolism, thereby leading to superotemporal BRVO. Given that cases of COVID-19 have increased globally, patients with retinal vein occlusion who use oral contraceptives are likely to be encountered more frequently. Yes, we added a paragraph as below in discussion and added references no. 13 and 14. Battaglia et al. reported that among 144 patients with BRVO, 128 (88.9%) had temporal BRVO, while 16 (11.1%) had nasal BRVO 13. The two groups showed no differences in systemic hypertension, diabetes mellitus, glaucoma, or ischemic heart disease13. Nasal BRVO cases exhibited better visual acuity but higher levels of capillary non-perfusion, retinal neovascularization, and vitreous hemorrhage13. Kumral et al. found that among 64 BRVO patients, 38 had superotemporal BRVO, and 26 had inferior temporal BRVO14. Superotemporal BRVO required significantly more intravitreal ranibizumab injections14. In our case of superotemporal BRVO, ME resolved with a single intravitreal aflibercept injection. 13. Battaglia Parodi M, Iacono P, Di Crecchio L, Sanguinetti G, Ravalico G. Clinical and angiographic features in nasal branch retinal vein occlusion. Ophthalmologica. 2004; 218(3):210-213. doi: 10.1159/000076847 14. Kumral ET, Yenerel NM, Ercalik NY, Karabas L. Comparison of ranibizumab treatment response of superior and inferior temporal branch retinal vein occlusion: a year follow-up. Beyoglu Eye J. 2022; 7(3):207-212. doi: 10.14744/bej.2022.46794. eCollection 2022. 5. Kindly provide a fundus photo or OCT of the recent most visit of the patient. Yes, we provided OCT photos 24 months since the first administration (figure 4). We added below sentence in case report section. No ME was noted after 24 months (Figure 4), and the decimal BCVA remained at 1.2. 6. The mechanism of thrombosis following COVID-19 infection has not been discussed in the discussion. Yes, we discussed it in the discussion as below and we added reference no. 12. Coagulation disorder in COVID-19 is thought to occur through vascular damage caused by virus infection12. Various factors, including reduced antithrombogenicity of the vascular endothelium, release of von Willebrand factor and coagulation factor VIII, complement activation, increased fibrinogen, and cytokine storm, are intricately interwoven 12. Thrombus can then form in any vessel, such as arteries, veins, and capillaries 12. 12. Conway EM, Mackman N, Warren RQ, et al. Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22(10): 639-649. doi: 10.1038/s41577-022-00762-9."
}
]
}
] | 1
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https://f1000research.com/articles/13-460
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https://f1000research.com/articles/12-510/v1
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17 May 23
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{
"type": "Research Article",
"title": "Exploring the moderating effects of SIRT1 protein expression and gene polymorphisms rs7895833 on the relationship between hemoglobin levels and physical frailty in elderly adults with comorbid chronic diseases: A moderated mediation analysis",
"authors": [
"Dedi Ardinata",
"Novita Sari Harahap",
"Nenni Dwi Aprianti Lubis",
"Tetty Aman Nasution",
"Novita Sari Harahap",
"Nenni Dwi Aprianti Lubis",
"Tetty Aman Nasution"
],
"abstract": "Background: Relationship age, hemoglobin, and physical frailty have all been investigated in older people with more than one chronic disease. There has been little analysis of the relationship between hemoglobin, age, physical frailty, Sirtuin1 (SIRT1) protein expression, and the gene polymorphism (SNP) rs7895833 A>G. The goal of this study was to find out how SIRT1 level, SNP rs7895833, hemoglobin, age, and physical frailty (frail score) are related in older Indonesian adults with comorbid chronic diseases. Methods: This was an observational study. Demographic and clinical data were retrieved from the electronic health records of Universitas Sumatera Utara Hospital, Medan, Indonesia. Physical frailty, SIRT1 level, and SNP rs7895833 were measured using an appropriate and valid method. Purposive sampling was used to determine the eligibility of 132 elderly adults from November 2022 to February 2023. Results: The indirect effect of hemoglobin on the frail score (FS) through age was negative and significant, according to a conditional mediation analysis (β=-0.0731; p=0.023). Meanwhile, the direct effect of hemoglobin on the FS was negative and not significant (β=0.1632; p=0.052). According to the conditional moderated mediation analysis, the size of the direct effect of age on FS was increased by genotype AG-GG and SIRT1 level (βlow=0.2647; p=0.002, βmiddle=0.2956; p<0.001, and βhigh=0.319; p<0.001). The size of the conditional indirect effect of Hemoglobin on FS through age was negative and significantly increased by SNP genotype AG-GG and SIRT1 level (βlow=-0.0647; p=0.032, βmiddle=-0.0723; p=0.024, and βhigh=-0.078; p=0.02). Conclusions: Hemoglobin levels in the blood decrease with age, which might affect elderly people who also have chronic diseases. Higher levels of SIRT1 and the SNP genotype AG-GG can both contribute to this. However, the interactions between these variables are complex, necessitating more research to fully comprehend the mechanisms underlying the development of physical frailty in the aging population.",
"keywords": [
"Hemoglobin",
"physical frailty",
"SIRT1 expression",
"SNP rs7895833",
"moderated mediation analysis."
],
"content": "Introduction\n\nFrailty has a yearly incidence rate of 4.34%, with a global prevalence rate of 13.6% among older adults.1 In Indonesia, however, the number of people aged 60 and older was 18.1 million in 2010, representing 7.6% and is projected to rise to 33.7 million by 2025 and 48.2 million by 2035.2\n\nAmong older adult residents, it has been shown that the prevalence of multimorbidity is between 55 and 98%, anemia was within 19 and 76%, and frailty is around 70 and 93%.3–5 According to the literature, older adults who have more chronic diseases are more vulnerable to the risk developing anemia.6 Anemia and frailty in older adults were found to be correlated, according to a systematic review and meta-analysis of observational studies.7 Some cross-sectional studies indicate a relationship between older adults’ frailty and hemoglobin levels.8,9 The following hypothesis is therefore proposed: Hypothesis 1 (H1): Hemoglobin is negatively related to FS.\n\nThe aging process or the presence of comorbidities are associated to the development of frailty.10 Frailty and age-related chronic diseases are not only often associated, but one increases the risk of the other, suggesting a bidirectional association between frailty and comorbidity aging-related disorders.11,12 The pathobiology of aging relates chronic disease, multimorbidity, and frailty, and this knowledge provides criteria for diagnosis and management approaches.13 Able to follow is the hypothesis: Hypothesis 2 (H2): Age is positively related to FS.\n\nHemoglobin is a protein found in red blood cells that carries oxygen throughout the body.14 Low hemoglobin levels, known as anemia, are a common condition in older adults and can be caused by a variety of factors, including nutritional deficiencies, chronic diseases, and medications15 which can lead to a decrease in physical function and an increased risk of frailty. Age is a major risk factor for physical frailty16,17 which is defined as a state of decreased physiological reserve and increased vulnerability to stressors.18 As people age, they may experience declines in muscle mass and strength, balance and coordination, and cardiovascular and respiratory function, which can contribute to physical frailty.19 Based on the preceding considerations, the following hypothesis is proposed: Hypothesis 3 (H3): Age mediates the relationship between hemoglobin and FS.\n\nPrevious studies have indicated that the SIRT1 SNP rs7895833 were related with much worse health outcomes, including chronic obstructive pulmonary disease,20 cardiovascular diseases,21 oxidative stress,22 essential hypertension and type 2 diabetes mellitus,23 coronary artery disease,24 rheumatoid arthritis,25 dyslipidaemia,26 metabolic syndrome,27 rheumatoid arthritis,28 and neurodegenerative disease.29 There was limited research on the specific interaction between SIRT1 SNP rs7895833, hemoglobin, age, and physical frailty. However, it is possible that these factors may be related to each other through various biological pathways.\n\nSIRT1 has been related to both frailty and deteriorating health outcomes. However, other investigations have produced inconsistent results. Using Fried’s criteria, there was no consistent correlation between SIRT1 and frailty in older people living in the community,30 and there was no correlation between frailty and serum-induced SIRT1 expression.31 Participants in the lowest quintile had a lower likelihood of being weak, but serum-induced SIRT1 expression was not related to age or mortality.32 Kumar et al., found frail people’s serum sirtuin levels (SIRT1 and SIRT3) were much lower than those of non-frail persons.33 Frail older adults had higher levels of SIRT1 than robust older adults.34\n\nEven though the relationship of age, hemoglobin, and frailty in older adults has been studied, there is currently limited studies on the association of these three variables with SIRT1 protein expression and the SNP genotype rs7895833 in elderly adults with chronic disease comorbidity. As a consequence, we come to the following hypothesis: Hypothesis 4 (H4): SNP genotype AG-GG and SIRT1 protein expression negatively moderates the effect of hemoglobin on FS through age as a mediator.\n\nThe purpose of this study was to investigate the effects of SIRT1 protein expression and the SIRT1 SNP rs7895833 A>G in the promoter region on the relationship between hemoglobin, age, and frailty in Indonesian older adults with chronic diseases comorbid.\n\n\nMethods\n\nThis study follows ‘A Guideline for Reporting Mediation Analyses of Randomized Trials and Observational Studies (AGReMA)35 and The Strengthening the Reporting of Observational studies in Epidemiology (STROBE).36\n\nWe conducted observational (cohort) studies of the moderated mediation analyses to find any potential causal effects. The mediator role of age in the association between hemoglobin level and frail scale score is explained by SIRT1 protein expression and the NSP rs7895833 genotype serving as moderating variables.\n\nThe study included 132 older adults who were scheduled to receive outpatient care at the Universitas Sumatera Utara Hospital in Medan, Indonesia, and who met the study criteria: men and women over the age of 60 with a complete electronic health record of laboratory and clinical data, as well as having chronic diseases one year prior. There are no mental or physical disorders that are interfering with their capacity to respond to questionnaire questions. A purposive sampling approach was used to choose the study subjects. The sample size was determined using the following formula37:\n\nZ1-α/22/22 (type I error 5%)=1.96, expected proportion in population based on previous studies (p)=18.7%,38 absolute error/precision (d)=0.05.\n\nSociodemographic, clinical, and laboratory data\n\nWe used sociodemographic, clinical, and laboratory data results from an electronic health record database after clinical diagnoses were determined for each subject one year ago.\n\nFrailty assessment\n\nThe physical frailty phenotype was assessed that used the frailty scale score. During face-to-face interviews with the patients, trained nursing staff used the Indonesian version of the FRAIL scale, which has been proven to be a reliable and valid screening tool for frailty syndrome assessment.39 The FRAIL scale (FS) consists of five components: fatigue, resistance, ambulation, sickness, and weight loss. The FRAIL scale scores range from 0 to 5 (one point for each component; 0 represents best to 5 represents worst) and indicate robust (0), pre-frail (1 to 2), frail (3 to 5). The physical frailty phenotype was also treated as a continuous variable, ranging from 0 to 5, in the study.\n\nSIRT1 assay\n\nThe SIRT1 protein expression was determined by a monoclonal antibody-based ELISA method using a commercially available human SIRT1 ELISA kit (Elabscience®, Houston, USA, E-EL-H1546). Microtiter plates were coated with an antibody specific to human SIRT1. 100 μL standard and plasma samples were pipetted into the appropriate wells, and the protocol was followed by using a secondary antibody and then avidin conjugated horseradish peroxidase. The formation of horseradish peroxidase was measured using ELISA reader (Thermo Fisher Scientific, Finland) at 450 nm. Seven different concentrations of purified SIRT1 (20, 10, 5, 2.500, 1.250, 0.630, and 0.31 ng/mL) were used to plot a standard curve. The inter- and intra-assay coefficients of variation were 4.04% and 4.55% respectively, with a detection range of 0.31–20 ng/mL.\n\nDNA isolation\n\nBlood samples of all subjects were taken to the tubes containing EDTA, and genomic DNA was isolated from white blood cells with a DNA isolation kit (Wizard®, Madison, USA, A1120). All purified DNA samples were stored at 2–8°C until PCR applications were performed (according to the instructions for use of the products) for SIRT1 genotypes.\n\nDetermination of SIRT1 gene polymorphisms\n\nThe single nucleotide polymorphism (SNP) rs7895833 was selected because it is one of the most frequent polymorphisms in the SIRT1 gene, and has been associated frailty and several diseases.\n\nSIRT1 rs7895833 A>G in the promoter region40 were analysed using polymerase chain reactions with two-pair primers (PCR-CTPP) assay with minor modifications.41 The SIRT1 gene encompassing rs7895833 A>G, polymorphic sites were amplified by PCR using the primers.40 Briefly, 25 ml total PCR mixtures containing 100–200 ng DNA, 10.0 pmol of each primers, 1.0 mM dNTP (deoxynucleotide triphosphates), 25 mM MgCl2 and 2.5U Taq DNA polymerase in the supplied reaction buffer (Taq Buffer with (NH4)2SO4) were prepared. PCR was performed with the primers were the following:\n\nForward primer 1: CCCAGGGTTCAACAAATCTATGTTG\n\nForward primer 2: CCCAGGGTTCAACAAATCTATGTTG\n\nReverse primer 1: GCTTCCTAATCTCCATTACGTTGAC\n\nReverse primer 2: CCTCCCAGTCAACGACTTTATC\n\nwith the initial denaturation at 95°C for 10 min.; 30 cycles of 95°C for 1 min., 64°C for rs7895833 A>G polymorphism, PCR products were visualized on a 2% agarose gel with ethidium bromide staining and genotyped. The genotypes for polymorphism were defined by 3 distinct banding patterns (Figure 1); for rs7895833 AG polymorphism: 320, 241 bp for AA genotype; 320, 241 and 136 bp for AG genotype; and 320, 136 bp for GG genotype.40\n\nHardy–Weinberg equilibrium tests were performed with Hardy-Weinberg Equilibrium online calculator.\n\nAll statistical analyses were carried out using statistical tool jamovi ver.2.3. and the significance was set at p<0.05 (two-tail). Descriptive statistics were used to examine all of the subject’s characteristics. Normally distributed variables were reported using means and standard deviations, while non-normally distributed ones were summarized with medians and ranges. Qualitative variables were described using the numbers of events and frequencies.\n\nThe partial correlation plot (Qgraph) created with jamovi’s seolmatrix. This module was used to determine how the potential major variables interacted with one another.42\n\nThe jAMM GLM Mediation Model was used to analysis the conditional process. The conditional process analysis to determine how much more the mechanism(s) by which an effect operates is conditional on or varies depending on the nature, environment, stimulus, or individual variations.43 Mediation and moderation could be integrated analytically as a conditional process model in a variety of ways, depending on which step of the mediation process is moderated, the number of mediators, the number of moderators, and whether or not the direct effect is likewise moderated.44\n\nMediating effect\n\nAn analysis of mediation was investigated to assess if age mediated the relation between hemoglobin level and frail score. This model was used to determine if hemoglobin and frail score had a considerable indirect influence. When mediator variables are included, the direct effect is diminished but still statistically significant; this effect is known as “partial mediation”. Complete mediation shows that the direct effect is no longer significant when mediator variables have been included.45\n\nModerating effect\n\nA subgroup evaluation was carried in the multiple-mediation model to see whether there was a moderating effect on simple pathways. It was considered that the existence of the moderation effect in this path was shown by the statistically significant difference in the path coefficient between the two variables.46\n\nModerated mediation\n\nTesting for mediation effects in each subgroup will lead in a biased estimated parameter and low statistical power, in accordance with Edwards’ hypothesis. The estimated parameters, including the total, indirect, and direct effects of the moderated mediation model, were conducted by integrating moderation and mediation models. Subgrouping analysis was solely used to test which path the moderator affected.47,48\n\nBefore testing all mediational hypotheses, conditional process analysis depicting all interactions was developed using the general linear mediation model (i.e., the GLM mediation model) with factor coding “dummies” for genotypes AA=0 and AG-GG = 1 and covariates scaling “standardized” for hemoglobin level and SIRT1 protein expression. A standard (delta method) procedure that leverages the approximation from the central limit theorem49 was used to test the significance of the total and indirect effects, and the coefficient confidence intervals were deemed statistically significant if they did not include zero.\n\nThis study was authorized by the Universitas Sumatera Utara Health Ethical Committee under the number 1097/KEPK/USU/2022. Each participant completed a structured questionnaire after signing informed consent, which included questions about their demographics, level of physical frailty (Frail scale), and willingness to submit a blood sample. The Declaration of Helsinki ethical principles were followed during the study’s conduction.\n\n\nResults\n\nThe genotypic frequencies of the SNP rs7895833 A>G in the SIRT1 gene were not in accordance with those expected by Hardy-Weinberg equilibrium in the current investigation, confirming a previous study.50 We looked at several possibilities: first, we evaluated the possibility of recruiting bias. Second, faults in the real-time PCR genotyping experiment. In each batch, however, proper controls were applied, and the probes used were definitely capable of discriminating between genotypes. Third, the Hardy-Weinberg departure occurred by chance since the observed and expected genotype frequency variations were minimal.\n\nThis study included 132 eligible subjects. More than half of the participants were female (51.5%). The median age was 65 (range: 60 to 85), and the FS was 1 (range: 0 to 3). Meanwhile, the mean hemoglobin level was 12.35 (±1.8) mg/dL, and the plasma SIRT1 level was 57.1 (±32.3) ng/ml. Table 1 shows the study subjects’ detailed characteristics.\n\na Median (min–max).\n\nb n (%).\n\nc Mean (±SD).\n\nThere was a negative relationship between hemoglobin levels and FS (r=-0.236, p=0.006). The age yielded similar results (r=-0.259, p=0.003). Meanwhile, age was also shown to have a significant positive association with FS (r=0.325, p=0.006) but a negative correlation with SIRT1 (r=-0.192, p=0.027). There were no statistically significant correlations or relationships detected between the SNP genotypes AA, AG-GG and any of the covariates (Figure 2).\n\nHb (Hemoglobin); SIR (Sirtuin1); frailty (Frail score); Gen (genotype AA, AG-GG); Dotted line (positive partial correlation); Solid line (negative partial correlation); thickness of the line reflects the strength of the correlation. Spearman's rank correlation with two tail significant: *p<0.05, **p<0.01, ***p<0.001.\n\nAccording to Baron and Kenny’s46 criterion, there are three conditions for the existence of mediating role: 1) there is a significant correlation between independent variable (hemoglobin) and dependent variable (physical frailty); 2) there is a significant correlation between independent variable (hemoglobin) and mediating variables (age); 3) finally, the regression coefficients of independent variables (hemoglobin) and mediating variable (age) are simultaneously regressed to the dependent variable (physical frailty), the coefficient of mediator should be significant and the coefficient of independent variable become non-significant (complete mediation) or reduced (partial mediation).\n\nFigure 2 depicts them in accordance with the partial correlation’s results. It can be seen that hemoglobin and FS had a moderately strong negative relationship (r=-0.236, p=0.006), and that age and FS had a moderately strong positive relationship (r=0.325, p<0.001). Therefore, the first and second conditions are satisfied. Hence, H1 and H2 were accepted.\n\nThe mediating effect of age\n\nMediation analyses for direct effects, indirect mediation by age, and total effects are provided in Figure 3A and Table 2. When age was included in the model, the following occurred: The direct effect of hemoglobin on FS was negative and non-significant (β=-0.1632, p=0.052). The indirect effect or indirect mediation of hemoglobin on FS was negative and significant (β=-0.0731, p=0.023) and the total effect was negative and significant (β=-0.2363, p=0.005). As a consequence, we may conclude that age completely mediates the negative relationship between hemoglobin and FS, with a significant model mediation effect of 13% (R2=0.13, p=0.001, F=9.68). As a result, H3 was accepted. This result reveals that lower hemoglobin levels may lead to physical frailty and that this effect was totally influenced by the increasing age of an elderly adult with comorbid chronic diseases.\n\nModerated mediation relationship\n\nThe moderated mediation model was then put to the test. The SNP genotypes (AA and AG-GG) and SIRT1 were integrated into this model (Figure 3B and Table 3). Conditional moderated mediation was assessed at levels of SIRT1 of 25% (low), 50% (middle), and 75% (high) and SNP genotypes of AA and AG-GG. We noted the following: The size of the conditional direct effect of age on FS was moderately positive and significantly increased by SNP genotypes AA and SIRT1 level (βmiddle=0.1828, p=0.034 and βhigh=0.2087, p=0.015). Whereas by genotype AG-GG and SIRT1 level (βlow=0.2647, p=0.002, βmiddle=0.2956, p<0.001, and βhigh=0.319, p<0.001). The size of the conditional direct effect of hemoglobin on FS was moderately negative but non-significant by SNP genotypes AA, AG-GG, and all SIRT1 levels. The size of the conditional indirect effect of hemoglobin on FS through age was moderately negative and significantly increased by SNP genotypes AG-GG and SIRT1 level (βlow=0.2647, p=0.002, βmiddle=0.2956, p<0.001, and βhigh=0.319, p<0.001). The total effect was negative and significant (β=-0.2246, p=0.008). such that the conditional negative indirect effect of hemoglobin on FS completely through age becomes stronger when the SNP genotype was AG-GG and levels of SIRT1 increase (moderated mediation). The SNP genotype and SIRT1 have a 14.1% moderated mediation effect (R2=0.141, p=0.004, F=3.43) Therefore, H4 was accepted. The study may have found that individuals with the AG-GG genotype and higher levels of SIRT1 may experience a stronger negative indirect effect of hemoglobin on physical frailty, compared to individuals with the AA genotype and lower levels of SIRT1. According to these analyses, decreased hemoglobin levels can lead to physical frailty, and this effect is completely mediated by age, through the SNP genotype AG-GG and elevated SIRT1 levels in elderly adults with comorbid chronic diseases.\n\n\nDiscussion\n\nIn terms of physical frailty, the current research was conducted in a moderated-moderated mediation or conditional moderated mediation relationship. Hypotheses have been created based on the conceptual model in Figure 1 and the findings of prior studies. The findings supported each of the research hypotheses. The model provided the five variables that supported our conceptual model.\n\nA recent study revealed that the relationship between low hemoglobin levels and physical frailty in older adults with one or more chronic diseases was affected by the age.\n\nAge is a major risk factor for physical frailty,16,17 which is defined as a state of decreased physiological reserve and increased vulnerability to stressors.18 As people age, they may experience declines in muscle mass and strength, balance and coordination, and cardiovascular and respiratory function, which can contribute to physical frailty.19\n\nLow hemoglobin levels, also called anemia, is a condition in which the number of red blood cells or the amount of hemoglobin in the blood drops. This usually happens in older adults. Causes of anemia in older adults include nutritional deficiency, chronic kidney disease, chronic inflammation, and occult blood loss from gastrointestinal malignancy, although in many patients the aetiology were unknown.8,51–53 Previous studies have shown that the prevalence of physical frailty increases with age, and that low hemoglobin levels are also more common in older adults.52,54 In addition, there is evidence to suggest that low hemoglobin levels are a risk factor for physical frailty, as anemia can lead to reduced physical function and decreased muscle mass.\n\nAccording to the study, low hemoglobin levels and physical frailty were related. Age completely mediated the effect of low hemoglobin levels on physical frailty, indicating that the relationship between these two variables was only significant when age was excluded. This study further showed that age completely mediated this effect and that SNP genotype AG-GG and high SIRT1 levels further moderated this effect in elderly adults with comorbid chronic diseases. This showed that the following two factors, including the existence of comorbid chronic diseases and a specific genetic variant (AG-GG) of SNP SIRT1, further moderated the relation between low hemoglobin levels and physical frailty. The correlation between low hemoglobin levels and physical frailty, in particular, may have depended on the levels of SIRT1, a protein involved in cellular metabolism, among older adults with comorbid chronic diseases and the AG-GG genotype.\n\nThere was a complex interaction between hemoglobin levels, physical frailty, age, and genetic factors that could have big effects on older people with chronic conditions. The blood contained the important protein hemoglobin, which was responsible for carrying oxygen from the lungs to the body’s tissues and organs.55 Decreased hemoglobin levels can lead to anemia, which can cause fatigue, weakness, and physical frailty.\n\nPhysical frailty is a common concern for elderly people, and it is a complex condition affected by several factors, including age, chronic diseases, life styles, and heredity. Studies have shown that elderly adults, particularly those with chronic diseases, who have low hemoglobin levels are more plausible to become physically frail.56–58\n\nFurthermore, genetic factors may contribute to the development of physical frailty in elderly adults. The SIRT1 SNP rs7895833 A>G is closely associated with an increased risk of developing chronic diseases., such as cardiovascular disease,21,24 chronic obstructive pulmonary disease,20 Parkinson’s disease,59 type 2 diabetes mellitus,60 rheumatoid arthritis.28 These chronic diseases can contribute to the development of physical frailty in elderly adults by reducing muscle mass, strength, and function11,61 and also anemia.62\n\nSIRT1, a protein that protects cells from oxidative stress, controls glucose and lipid metabolism, and increases DNA integrity by binding to and deacetylating numerous substrates, may also have a role in physical frailty.63,64 SIRT1 is regarded to be one of the potential molecules for promoting healthy aging because of its protective activities against numerous age-related diseases. Some studies have suggested that SIRT1 levels decrease with age; according to several studies, SIRT1 has been studied for its potential role in aging and age-related diseases.22,65,66 Additionally, it is well known that it alters skeletal muscle metabolism and function, two major considerations in physical frailty.\n\nThere were few studies on the role of SIRT1 in iron metabolism related anaemia of chronic disease or anaemia of inflammation that decreases plasma iron with suppression of erythropoiesis. A study showed that activating SIRT1 can reduce iron accumulation in splenic macrophages by inhibiting hepcidin.67 This suggests that SIRT1 may inhibit ferroptosis by reducing intracellular iron levels. Another study showed that Intestinal SIRT1 deficiency improved iron metabolism in ethanol-induced liver injury in mice, reducing ferroptosis in hepatocytes.68\n\nThere are still not many studies that show what role the SNP rs7895833 A>G, especially genotype AG-GG, plays in the expression or activity of the SIRT1 protein in older adults. The patients with the wild-type (AA) genotype had a significantly higher level of SIRT1 protein and a significantly lower level of endothelial nitric oxide synthase (eNOS) expression. Patients with the heterozygote mutant (AG) genotype also had a significantly higher level of SIRT1 protein, but eNOS expression was not significantly different.21 Kilic et al., who observed the older people carrying both wild-type (AA) genotype and heterozygote (AG) genotype, had significantly higher SIRT1 expression levels, while older people carrying the heterozygote mutant (AG) genotype had a significantly higher SIRT1 level compared with older people carrying the wild-type (AA) genotype.22\n\nAs was already mentioned, the NSP rs7895833 A>G affects the expression of the SIRT1 gene. It can impact the expression of the SIRT1 gene because it is located in the promoter region, 21 kb upstream of the gene. Thus, SIRT1 expression appears to be regulated by a promoter-dependent changed expression mechanism, which may have an impact on the elderly’s metabolism or the progression of neurological disease. Chromatin and transcription are regulated by SIRT1: linking NAD+ signalling and metabolism to the regulation of cellular activities.69\n\nThis study has established moderated mediation analysis among the drivers of physical frailty in elderly adults with comorbid chronic diseases, but it is not without limitations. Some limitations of the present study should be noted: The study used an observational (cohort) design and studied only elderly individuals from a university hospital, which may constitute a selection bias, meaning that we may not have been able to establish a causal relationship between the variables of interest. Another constraint of the study is the sample size, which was insufficient to detect all associations with the other studied variables and could limit the generalizability of the results. Other factors, such as lifestyle habits, environmental factors, and medications, could have influenced the results, and we may not have accounted for these variables. However, our findings are supported by previously published literature; several studies with probabilistic samples and a greater number of individuals reported changes in physical frailty in relation to hemoglobin, age, the polymorphism rs7895833, involving genotype AG-GG, and SIRT1 protein expression.\n\n\nConclusion\n\nThe moderated mediation model was made for this study’s analysis of physical frailty in older adults with comorbid chronic diseases. It was proposed that the main factor in how low hemoglobin could cause physical frailty was age. This multi-level framework of mediators (age) and moderators (NSP rs7895833 A>G and SIRT1 protein level) helps us understand how the physical frailty process works.\n\nIt also gives experimental studies a better way to look at the phenomenon of physical frailty from a more detailed point of view. The fact that both the NSP rs7895833 AG-GG genotype and the increased level of SIRT1 moderated the effects of aged and hemoglobin on physical frailty with statistical results is a novel finding that hasn’t been properly investigated in the literature.\n\nMore research is needed to figure out how the AG-GG genotype, SIRT1 levels, and hemoglobin levels work together to make people physically frail. Also, more research is needed to find ways to prevent or lessen physical frailty in this population. Also, the rs7895833 genotype AG-GG and the expression of the SIRT1 protein add to the limited research on hemoglobin and physical frailty.\n\nThe findings suggest that monitoring and managing hemoglobin levels may be important for preventing or reducing physical frailty in older adults with multiple chronic diseases, particularly those with the NSP rs7895833 AG-GG genotype and high SIRT1 levels. This gathering may benefit from iron supplements, blood transfusions, or dietary changes that allow them to consume more iron. Furthermore, personalized health care approaches that take genetic factors into account may be important for preventing or treating physical frailty in this population.",
"appendix": "Data availability\n\nFigshare: Exploring the moderating effects of SIRT1 protein expression and gene polymorphisms rs7895833 on the relationship between hemoglobin levels and physical frailty in elderly adults with comorbid chronic diseases. A moderated mediation analysis, https://doi.org/10.6084/m9.figshare.22492603.v2. 70\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nWe would like to thank all the patients and Laboratory staffs in an integrated laboratory faculty of Medicine, Universitas Sumatera Utara and Universitas Sumatera Utara Hospital who participated in the study.\n\n\nReferences\n\nOfori-Asenso R, Chin KL, Mazidi M, et al.: Global Incidence of Frailty and Prefrailty among Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA Netw. Open. 2019; 2(8): e198398. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdioetomo SM: Indonesia on the Threshold of Population Ageing. Indonesia: UNFPA; 2014; 65(632).\n\nBarnett K, Mercer SW, Norbury M, et al.: Epidemiology of multimorbidity and implications for health care, research, and medical education: A cross-sectional study. Lancet. 2012; 380(9836): 37–43. Publisher Full Text\n\nBiritwum RB, Minicuci N, Yawson AE, et al.: Prevalence of and factors associated with frailty and disability in older adults from China, Ghana, India, Mexico, Russia and South Africa. Maturitas. 2016; 91: 8–18. PubMed Abstract | Publisher Full Text\n\nKojima G: Prevalence of Frailty in Nursing Homes: A Systematic Review and Meta-Analysis. J. Am. Med. Dir. Assoc. 2015; 16: 940–945. PubMed Abstract | Publisher Full Text\n\nGandhi SJ, Hagans I, Nathan K, et al.: Prevalence, Comorbidity and Investigation of Anemia in the Primary Care Office. J. Clin. Med. Res. 2017; 9(12): 970–980. Publisher Full Text\n\nPalmer K, Vetrano DL, Marengoni A, et al.: The Relationship Between Anaemia and Frailty: A Systematic Review and Meta-Analysis of Observational Studies. J. Nutr. Health Aging. 2018; 22: 965–974. Publisher Full Text\n\nRuan Y, Guo Y, Kowal P, et al.: Association between anemia and frailty in 13,175 community-dwelling adults aged 50 years and older in China. BMC Geriatr. 2019; 19(1): 327. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSteinmeyer Z, Delpierre C, Soriano G, et al.: Hemoglobin concentration; A pathway to frailty. BMC Geriatr. 2020; 20(1): 202. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAngioni D, Macaron T, Takeda C, et al.: Can We Distinguish Age-Related Frailty from Frailty Related to Diseases? Data from the MAPT Study. J. Nutr. Health Aging. 2020; 24(10): 1144–1151. 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PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nSabry D, Kaddafy SR, Abdelaziz AA, et al.: Association of SIRT-1 Gene Polymorphism and Vitamin D Level in Egyptian Patients With Rheumatoid Arthritis. J. Clin. Med. Res. 2018; 10(3): 189–195. Publisher Full Text\n\nCasarotto AAF, Galera BB, Sumiyoshi LM, et al.: Polymorphism rs7895833 in the SIRT1 gene and its association with dyslipidaemia in the elderly. Rev. Esp. Geriatr. Gerontol. 2019; 54(4): 214–219. PubMed Abstract | Publisher Full Text\n\nTao TT, Lin XH, Tang SJ, et al.: Association of genetic variants in the Sirt1 and Nrf2 genes with the risk of metabolic syndrome in a Chinese Han population. BMC Endocr. Disord. 2022; 22(1): 84. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhou J, He YW, Fu L, et al.: Gene polymorphisms of SIRT1 in patients with rheumatoid arthritis. Int. J. Rheum. Dis. 2022; 25(2): 210–217. PubMed Abstract | Publisher Full Text\n\nSiwak M, Maślankiewicz M, Nowak-Zduńczyk A, et al.: Analysis of rs7895833 polymorphism of SIRT1 gene and its influence on the risk occurrence and progression of neurodegenerative disease, such as primary open-angle glaucoma in a Polish population. J. Pre-Clin. Clin. Res. 2022 Dec 27; 16(4): 127–130. Publisher Full Text\n\nFried LP, Tangen CM, Walston J, et al.: Frailty in older adults: Evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 2001; 56(3): M146–M157. Publisher Full Text\n\nLe Couteur DL , Benson V, Mcmahon A, et al.: Determinants of serum-induced SIRT1 expression in older men: the CHAMP study. J. Gerontol. A Biol. Sci. Med. Sci. 2011; 66(1): 3–8. PubMed Abstract | Publisher Full Text Reference Source\n\nRazi S, Cogger V, Kennerson M, et al.: SIRT1 Polymorphisms and Serum-Induced SIRT1 Protein Expression in Aging and Frailty: The CHAMP Study.2017. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nSetiati S, Soejono CH, Harimurti K, et al.: Frailty and Its Associated Risk Factors: First Phase Analysis of Multicentre Indonesia Longitudinal Aging Study. Front. Med (Lausanne). 2021 Apr 29; 8.\n\nDwipa L, Apandi M, Utomo PP, et al.: Adaptation and validation of the indonesian version of the frail scale and the sarc-f in older adults. Asian J. Gerontol. Geriatr. 2021; 16(1).\n\nShimoyama Y, Suzuki K, Hamajima N, et al.: Sirtuin 1 gene polymorphisms are associated with body fat and blood pressure in Japanese. Transl. Res. 2011; 157(6): 339–347. PubMed Abstract | Publisher Full Text Reference Source\n\nYin G, Mitsuda Y, Ezaki T, et al.: A new PCR method: One primer amplification of PCR-CTPP products. Mol. Biotechnol. 2012; 52(2).\n\nEpskamp S, Cramer AOJ, Waldorp LJ, et al.: Qgraph: Network visualizations of relationships in psychometric data. J. Stat. Softw. 2012; 48: 48. Publisher Full Text\n\nHayes AF, Rockwood NJ: Conditional Process Analysis: Concepts, Computation, and Advances in the Modeling of the Contingencies of Mechanisms. Am. Behav. Sci. 2020; 64(1): 19–54. Publisher Full Text\n\nHayes AF, Rockwood NJ: Regression-based statistical mediation and moderation analysis in clinical research: Observations, recommendations, and implementation. Behav. Res. Ther. 2017; 98: 39–57. PubMed Abstract | Publisher Full Text\n\nHayes AF: Partial, conditional, and moderated moderated mediation: Quantification, inference, and interpretation. Commun. Monogr. 2018; 85(1): 4–40. Publisher Full Text\n\nBaron RM, Kenny DA: The moderator-mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations. J. Pers. Soc. Psychol. 1986; 51(6): 1173–1182. PubMed Abstract | Publisher Full Text\n\nEdwards JR, Lambert LS: Methods for integrating moderation and mediation: A general analytical framework using moderated path analysis. Psychol. Methods. 2007; 12(1): 1–22. PubMed Abstract | Publisher Full Text\n\nPreacher KJ, Hayes AF: Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav. Res. Methods. 2008; 40: 879–891. PubMed Abstract | Publisher Full Text\n\nDeng A, Knoblich U, Lu J: Applying the Delta Method in Metric Analytics.2018.\n\nTagliari CFdS, de Oliveira CN , Vogel GM, et al.: Investigation of SIRT1 gene variants in HIV-associated lipodystrophy and metabolic syndrome. Genet. Mol. Biol. 2020; 43(1): e20190142. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPires Corona L, Drumond Andrade FC, de Oliveira Duarte YA , et al.: The relationship between anemia, hemoglobin concentration and frailty in Brazilian older adults. J. Nutr. Health Aging. 2015; 19(9): 935–940. Publisher Full Text\n\nCorona LP, Duarte YA d O, Lebrão ML: Prevalence of anemia and associated factors in older adults: Evidence from the SABE Study. Rev. Saude Publica. 2014; 48(5): 431–723. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKatsumi A, Abe A, Tamura S, et al.: Anemia in older adults as a geriatric syndrome: A review. Geriatr. Gerontol. Int. 2021; 21(7): 549–554. PubMed Abstract | Publisher Full Text\n\nLee CT, Chen MZ, Yip CYC, et al.: Prevalence of Anemia and Its Association with Frailty, Physical Function and Cognition in Community-Dwelling Older Adults: Findings from the HOPE Study. J. Nutr. Health Aging. 2021; 25(5): 679–687. PubMed Abstract | Publisher Full Text\n\nRoy CN: Anemia in Frailty. Clin. Geriatr. Med. 2011; 27: 67–78. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBaker GT, Martin GR: Biological Aging and Longevity: Underlying Mechanisms and Potential Intervention Strategies. J. Aging Phys. Act. 2016; 2(4): 304–328. Publisher Full Text\n\nCaprara G: Diet and longevity: The effects of traditional eating habits on human lifespan extension. Med. J. Nutrition Metab. 2018; 11(3): 261–294. Publisher Full Text\n\nPignatti C, D’adamo S, Stefanelli C, et al.: Nutrients and pathways that regulate health span and life span. Geriatrics (Switzerland). 2020; 5. Publisher Full Text\n\nChen X, Mai H, Chen X, et al.: Rs2015 Polymorphism in miRNA Target Site of Sirtuin2 Gene Is Associated with the Risk of Parkinson’s Disease in Chinese Han Population. Biomed. Res. Int. 2019; 2019: 1–8. Publisher Full Text\n\nMahmoud AA, Moghazy HM, Ezat MAW: Association of sirtuin 1 gene single nucleotide polymorphisms with type 2 diabetes mellitus in essential hypertension patients. Meta Gene. 2016; 10: 8–12. Publisher Full Text\n\nZazzara MB, Vetrano DL, Carfì A, et al.: Frailty and chronic disease. Panminerva Med. 2019; 61. Publisher Full Text\n\nMadu AJ, Ughasoro MD: Anaemia of Chronic Disease: An In-Depth Review. Med. Princ. Pract. 2017; 26: 1–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuarente L: Sirtuins, Aging, and Medicine. N. Engl. J. Med. 2011; 364(23): 2235–2244. Publisher Full Text\n\nZia A, Sahebdel F, Farkhondeh T, et al.: A review study on the modulation of SIRT1 expression by miRNAs in aging and age-associated diseases. Int. J. Biol. Macromol. 2021; 188: 52–61. Publisher Full Text\n\nChen C, Zhou M, Ge Y, et al.: SIRT1 and aging related signaling pathways. Mech. Ageing Dev. 2020; 187: 111215. Publisher Full Text\n\nManjula R, Anuja K, Alcain FJ: SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases. Front. Pharmacol. 2021; 11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXin H, Wang M, Tang W, et al.: Hydrogen Sulfide Attenuates Inflammatory Hepcidin by Reducing IL-6 Secretion and Promoting SIRT1-Mediated STAT3 Deacetylation. Antioxid. Redox Signal. 2016; 24(2): 70–83. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhou Z, Ye TJ, DeCaro E, et al.: Intestinal SIRT1 Deficiency Protects Mice from Ethanol-Induced Liver Injury by Mitigating Ferroptosis. Am. J. Pathol. 2020; 190(1): 82–92. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang T, Kraus WL: SIRT1-dependent regulation of chromatin and transcription: Linking NAD+ metabolism and signaling to the control of cellular functions. Biochim. Biophys. Acta. 2010; 1804: 1666–1675. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArdinata D, Harahap NS, Lubis NDA, et al.: Exploring the moderating effects of SIRT1 protein expression and gene polymorphisms rs7895833 on the relationship between hemoglobin levels and physical frailty in elderly adults with comorbid chronic diseases. A moderated mediation analysis. Dataset. figshare. 2023. Publisher Full Text"
}
|
[
{
"id": "243614",
"date": "20 Feb 2024",
"name": "Ramu Manjula",
"expertise": [
"Reviewer Expertise Sirtuin biology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study aimed to investigate the relationship between SIRT1 levels, SNP rs7895833, hemoglobin levels, age, and physical frailty (frail score) among 132 older Indonesian adults with comorbid chronic diseases. The present study aligns with recent research suggesting that the association between low hemoglobin levels and physical frailty among older adults with one or more chronic diseases is influenced by age. Furthermore, this study revealed that the SNP genotype AG-GG and high SIRT1 levels further moderated the relationship between low hemoglobin levels and physical frailty in elderly adults with comorbid chronic diseases. While multiple studies support the protective role of increased SIRT1 expression in the body, the study highlights that SNP rs7895833 A>G affects the expression of the SIRT1 gene. The manuscript is structured well, and the authors have proved their hypothesis. As mentioned by the authors, along with the sample size the strong limitations of this study are lifestyle habits, environmental factors, and medications, which could have influenced the results. I believe that conclusions cannot be drawn based on these results.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "253712",
"date": "04 Apr 2024",
"name": "Amit Singh",
"expertise": [
"Reviewer Expertise Immunology",
"Aging",
"Inflammation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReport for Ardinata et al.- Exploring the moderating effects of SIRT1 protein expression and gene polymorphisms rs7895833 on the relationship between hemoglobin levels and physical frailty in elderly adults with comorbid chronic diseases: A moderated mediation analysis. Ardinata et al claim to study the effects of SIRT1 protein expression and the associated SIRT1 promoter SNP in Indonesian older adult cohort. They further correlated these levels with hemoglobin, age, and frailty with chronic diseases comorbid. Study emphasize the known SIRT1 effects in interesting cohort and will be useful for aging related studies. Study lacks in following areas and should be updated accordingly. Authors claim SIRT1 levels and its relationship with various parameters. It should be corrected in title and also in text that these are plasma levels of SIRT1 not cellular protein. Explanation of plasma source of SIRT1 should be provided. Manuscript holds just one data figure of genotyping gel. In genotyping gel image the marker lane is labelled as 50bp ladder, first, the marker bands are not clear and second if we follow the marker bands (which should be labelled for each band) the size doesn’t matches the genotype product DNA bands'. The 136bp according to the marker will be 75bp and 241bp will be 200bp and so on. Please lable the gel properly. Since, SIRT1 is major focus of the manuscript, authors are encouraged to show at least some correlation plots of all 132 donors with SIRT1 levels and frailty or other important parameter. Repetitions from introduction in discussion part should be avoided. Last paragraph of discussion has many typographical errors and there are also such errors thought out the manuscript, such mistakes should be avoided. Conclusions can be shortened and many extreme speculations can be avoided.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11409",
"date": "30 Apr 2024",
"name": "Dedi Ardinata",
"role": "Author Response",
"response": "Dear Amit Singh Thank you for your thorough review and valuable suggestions regarding our manuscript entitled \"Exploring the moderating effects of SIRT1 protein expression and gene polymorphisms rs7895833 on the relationship between hemoglobin levels and physical frailty in elderly adults with comorbid chronic diseases: A moderated mediation analysis.\" We appreciate the opportunity to clarify and improve our manuscript based on your feedback. Below, we address each of your concerns and describe the amendments we have made to the manuscript accordingly. Clarification of SIRT1 Levels (Plasma vs. Cellular): We have revised the title and the manuscript to explicitly state that the SIRT1 levels measured and discussed pertain to plasma levels, not cellular protein levels. To provide clarity, we have also added a brief explanation in the Methods section regarding the plasma source of SIRT1 and its relevance to our study's objectives. Genotyping Gel Image Clarification: We acknowledge the confusion regarding the genotyping gel image and appreciate your pointing out the discrepancies. We have revised the image to include a clearer representation of the marker bands and accurately labelled each band to correspond with the correct DNA size. Inclusion of Correlation Plots: Following your suggestion, we have now included correlation plots that depict the relationship between SIRT1 levels, frailty, and other critical parameters for all 132 participants. These plots provide a visual representation of our findings and strengthen the manuscript. Reduction of Repetitions and Typographical Errors: We carefully reviewed the manuscript to eliminate redundant information between the Introduction and Discussion sections. We have also conducted a thorough proofreading to correct typographical errors throughout the text. These changes aim to improve readability and accuracy, and we believe they significantly enhance the manuscript's quality. Revision of Conclusions: We have streamlined the Conclusions section to succinctly summarize our findings without speculative statements. The revised Conclusions focus on our study's contributions to the field and its implications for future research, avoiding overgeneralization. We hope that these revisions adequately address your concerns and improve the quality and clarity of our manuscript. We are grateful for your constructive feedback and the opportunity to enhance our work. We look forward to your further suggestions and the possibility of our manuscript being accepted for publication. Sincerely, Dedi Ardinata and co-authors"
}
]
}
] | 1
|
https://f1000research.com/articles/12-510
|
https://f1000research.com/articles/11-1001/v1
|
06 Sep 22
|
{
"type": "Systematic Review",
"title": "Smartphone applications are used for self-management, telerehabilitation, evaluation and data collection in low back pain healthcare: a scoping review",
"authors": [
"Lech Dobija",
"Jean-Baptiste Lechauve",
"Didier Mbony-Irankunda",
"Anne Plan-Paquet",
"Arnaud Dupeyron",
"Emmanuel Coudeyre",
"Jean-Baptiste Lechauve",
"Didier Mbony-Irankunda",
"Anne Plan-Paquet",
"Arnaud Dupeyron",
"Emmanuel Coudeyre"
],
"abstract": "Background: Technological developments have accelerated notably in the field of telecommunications in the last few decades. Smartphone use has grown in providing healthcare for patients with low back pain (LBP), but the literature lacks an analysis of the use of smartphone apps. This scoping review aimed to identify current areas of smartphone apps use for managing LBP. We also aimed to evaluate the current status of the effectiveness or scientific validity of such use and determine perspectives for their potential development. Methods: We searched PubMed, PEDro and Embase for articles published in English up to May 3rd, 2021 that investigated smartphone use for LBP healthcare and their purpose. All types of study design were accepted. Studies concerning telemedicine or telerehabilitation but without use of a smartphone were not included. The same search strategy was performed by two researchers independently and a third researcher validated the synthesis of the included studies. Results: We included 43 articles: randomised controlled trials (RCTs) (n=12), study protocols (n=6), reliability/validity studies (n=6), systematic reviews (n=7), cohort studies (n=4), qualitative studies (n=6), and case series (n=1). The purposes of the smartphone app were for 1) evaluation, 2) telerehabilitation, 3) self-management, and 4) data collection. Self-management was the most-studied use, showing promising results derived from moderate- to good-quality RCTs for patients with chronic LBP and patients after spinal surgery. Promising results exist regarding evaluation and data collection use and contradictory results regarding measurement use. Conclusions: This scoping review revealed a growing scientific literature regarding the use of smartphone apps for LBP patients. The identified purposes point to current scientific status and perspectives for further studies including RCTs and systematic reviews targeting specific usage. Caution should be taken to monitor the impact of smartphone-related compulsive behaviour.",
"keywords": [
"Smartphone apps",
"low back pain",
"mHealth",
"self-management",
"telerehabilitation"
],
"content": "Introduction\n\nTechnological development has accelerated notably in the field of telecommunication in the last few decades. Since the introduction of the first mobile phones, the number of users has continued to grow and is now estimated at 6.8 billion worldwide.1 Mobile phones have gained new capabilities such as better Internet connection, allowing them to substitute for personal computers to a large extent. This new generation of mobile phones, called smartphones, has changed a lot of human activity. The number of smartphone users worldwide has surpassed three billion and is forecast to further grow.2 With their extensive software, a growing number of applications have emerged. Navigation, video communication, gaming, and social media consulting are some examples of their use. The potentially inexhaustible use of the smartphones cannot be ignored in any human activity including healthcare.\n\nThe dynamic technological development has been accompanied by a less spectacular increase in life expectancy. However, simultaneously, the rate of years living with disability (YLD) has stagnated or even increased for some diseases. The last estimations of the YLD positioned low back pain (LBP) as a leading cause of handicap worldwide.3 Besides the obvious healthcare problem, the economic impact of LBP is serious, with the total mean cost per patient over six months estimated at EUR 715.6 in France.4 One of the aspects of this problem is that LBP could be chronic or recurrent in nature and affects middle-aged, professionally active adults. Chronic LBP concerns less than 10% of cases but 85% of the costs.5 A further problem is that in most cases, physicians are unable to reliably identify the cause of the LBP symptoms, so they classify them as non-specific.\n\nThe complexity of LBP is also challenging to manage because of its largely multifactor aspect.6 Failure of the purely biomedical approaches targeting only pathoanatomical nociceptive aspects has led to the development of the more exhaustive bio-psycho-social model. This multidimensional approach encompasses psychological, biological, social, and environmental aspects.7 Current guidelines for management of LBP include psychosocial interventions along with exercise therapy, medications, multidisciplinary rehabilitation and spinal manipulation.8 Completing the context of LBP, some authors highlight the problem of overtreating. Expanding testing and treatment by using therapies and diagnostic tools with weak scientific validity can drive increasing complication rates, marketing abuse and patients’ confusion.9 The widespread occurrence of LBP self-management strategies seems appropriate to target economic and healthcare accessibility problems.10\n\nSmartphone applications (apps) for this purpose appear to be promising tools, giving a wide range of possibilities for use, replacing education booklets, proposing and supervising exercise therapy (telerehabilitation), and stimulating adherence for self-management programs. Using smartphone apps are the most accessible way to provide rehabilitation services and to collect outcomes remotely as smartphones are personal and always available to patients.11,12 Such a new model makes health services more accessible and enhances patient participation and their engagement in self-management.11 This idea has been developed in other healthcare intents such as diabetes,13 chronic obstructive pulmonary disease,14 and osteoarthritis.15 However, smartphones equipped with multiple sensors, cameras, gyroscopes, accelerometers, and magnetometers could also be used as tools for range-of-motion (ROM) measurement16 or could be simply used with the phone camera for clinical evaluation at a distance.17 Another feature is that smartphone apps could be used for surveying large population samples, allowing to create a database for more sophisticated analyses including case-based reasoning systems.18 Moreover, the need for healthcare management at a distance (telemedicine) has become crucial in the recent situation requiring confinement due to the coronavirus disease 2019 (COVID-19) pandemic. Without the possibility to access conventional healthcare face-to-face with providers, numerous clinicians were challenged to provide telemedicine in order to substitute conventional healthcare in non-essential services.19,20 Smartphone applications have become highly pertinent tools for this purpose.\n\nIndeed, the use of smartphone apps has increased for LBP patients. However, there is a lack of synthesis of the scientific literature in the areas of smartphone app use. Moreover, it is not clear in what purpose using smartphone apps are pertinent and if such use is supported by the scientific studies. Giving a large range of area of interest and the fact that it is a new dynamically developing subject we believe that performing a scoping review will clarify these questions.\n\nThe objective of this scoping review is to identify current areas of smartphone app use for managing LBP. It also aimed to evaluate the current status of the effectiveness or scientific validity of smartphone app use and to determine perspectives for their potential development.\n\n\nMethods\n\nReview protocol presenting search strategy was established without a registration number.\n\nThe Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist was used to guide the present study.21,65 Two researchers (LD and JBL) independently searched for articles in PubMed (RRID:SCR_004846), PEDro and EMBASE (RRID:SCR_001650) by using MeSH keywords. The search strategy phrase for PubMed database was (“smartphone application” OR “smartphone app” OR “smartphone” OR “telerehabilitation” OR “telemedicine” OR “mhealth” OR “ehealth”) AND (“low back pain” OR “back pain”). Corresponding research was realized in PEDro and EMBASE by using the same keywords. Only English language and time frame filters were used for our research. The articles were screened and assessed for eligibility regarding the objective of the study. Articles published between January 1st 2005 and May 3rd 2021 were considered.\n\nOnly studies of smartphone use in LBP adult patient healthcare were included. We excluded studies concerning telemedicine or telerehabilitation but without use of a smartphone. Similarly, we excluded studies in which the smartphone use involved healthy individuals for preventing LBP or promoting physical activity or a healthy lifestyle in general. To broaden our review, all qualitative and quantitative studies were accepted, including randomised controlled trials (RCTs) and non-randomized studies, cohort studies, case-control studies, systematic reviews, reliability and validity studies, and study protocols. Only studies accepted for publication, written in English were considered.\n\nStudy inclusion was discussed to reach agreement or in cases where a consensus could not be reached, we consulted with a third researcher (EC). Then studies were classified according to the purpose of the smartphone app. The type of study design was also used to classify studies in terms of its objective: effectiveness of the smartphone use, reliability of the smartphone measures, or other type of evaluation and data collection.\n\nSearch strategy was prepared and validated with the participation of all authors of the present review. The same search strategy was realized by two researchers (LD and JBL) independently. A third researcher (EC) participated in the synthesis data charting. Then, additional articles were identified throughout citation matching.\n\nWe extracted data concerning smartphone app utilisation. We focused on the purpose of smartphone app utilisation, study design, date of publication, number of participants who completed the study, main outcomes, results and authors conclusions.\n\nThe quality of selected RCTs was estimated by using the PEDro scale.22\n\nWe categorized included studies by the purpose of smartphone app utilisation. The synthesis of the included studies was also done by study design, both were presented in a narrative format and in a synthesis table.\n\n\nResults\n\nWe identified 43 articles based on our search strategy (Figure 1). The included studies were RCTs (n=12), study protocols (n=6), reliability/validity studies (n=6), systematic reviews (n=7), cohort studies (n=4), qualitative studies (n=6), and case series (n=1) (Table 1).\n\nWe identified the following purposes of the smartphone apps: 1) evaluation, 2) telerehabilitation, 3) self-management or 4) data collection. We distinguished telerehabilitation and self-management because of a difference when the remote interaction between healthcare professional and patients occurred for LBP management (telerehabilitation). By contrast, some smartphone apps provide instructions for LBP management without giving feedback from a healthcare professional (self-management). Furthermore, the data collection use in most smartphone apps was coupled with other employment-like evaluations or self-management, but in some studies, the smartphone app was mainly dedicated to collecting information for further analysis.\n\nA total of 14 studies used smartphone apps as an evaluation tool including pain evaluation,23–26 ROM measurement,16,27–30 6-min walk test31 and clinical or functional evaluation.17,32–34 Considering pain evaluation, PainMAP showed excellent intra- and inter-rater reliability and good validity for quantifying the number of pain sites and pain area.23 Furthermore, a smartphone app could effectively evaluate pain changes after transcutaneous electrical nerve stimulation.25 However, Ross et al., reported that patients with chronic pain who appeared to manage their pain better were less likely to report benefits of a smartphone pain app designed for daily pain management and evaluation.26\n\nSmartphone apps were used to measure lumbar spine ROM and lordosis but showed insufficient reliability and validity as compared with a gravity-based inclinometer.27 By contrast, de Brito Macedo et al., reported good concurrent validity and intra-rater reliability of smartphone thoracolumbar ROM measurements versus a digital inclinometer.29 Lumbar ROM measurement with a smartphone detected a significant difference due to manual therapy and exercise intervention in another study.28 Similar findings were further summarized in systematic review showing contradictory results of psychometric properties of the lumbar spine ROM and lordosis measurements with a smartphone app.30\n\nOther examples of smartphone use included clinical and functional evaluation. Peterson et al., suggested that a modified treatment-based classification system for subgrouping patients with LBP could direct treatment in telerehabilitation settings (smartphone app) because the overall rate of percentage agreement with face-to-face assessments was between 48.9% and 59.6%.17 The McKenzie classification and therapy applied with a smartphone app showed comparable clinical outcomes with the traditional clinic-based McKenzie therapy.32 The 6-min walk test performed with a smartphone app and using a GPS system could be reliable but needed to be performed avoiding indoors and city environments with high buildings and rectangular walking curses.31 However, in a scoping review of outcomes with smartphone apps used for LBP management, authors showed the problem of low quality of the outcome measures to monitor the treatment effect. Indeed, only a few smartphone apps offered to monitor their effectiveness in the management of LBP.33 Other examples of smartphone use for clinical evaluation is the use of the Backache Disability Index. Such evaluation includes rating five trunk movements in the erect position and scoring morning back stiffness. Performed remotely with a smartphone app, the index showed good reliability and validity.34\n\nA total of 12 studies presented smartphone apps as a tool for providing rehabilitation interventions at a distance (telerehabilitation).17,32,35–44 Despite different designs and aims, most of the studies evaluated the efficacy of the smartphone app use in telerehabilitation. Dario et al., performed a systematic review with meta-analysis to evaluate the effectiveness of the intervention based on any form of telerehabilitation, phone calls, emailing, and web-based chats but also smartphone apps. On the basis of data from 11 included studies, the authors concluded moderate evidence that current telerehabilitation interventions are not more effective than minimal interventions on pain and disability outcomes. Their study also revealed that the effectiveness of such interventions remains understudied.40 Indeed, only three RCTs evaluated the effectiveness of the smartphone apps use to provide telerehabilitation in LBP patients. Hou et al., evaluated a system of telerehabilitation based on a smartphone app interface for patients after lumbar surgery and a web-based interface for physicians providing and surveying rehabilitation and communicating with the patient. The authors demonstrated that the intervention was more effective than usual care regarding disability and pain status (Ostwestry Disability Index, pain visual analogue scale) at 24-month follow-up.38 Mbada et al., in their RCT, compared telerehabilitation-based McKenzie therapy versus the same treatment but provided in the traditional face-to-face setting. The smartphone app interface was used to introduce the treatment and was supported by phone calls and text messages in the experimental group. In this study, clinical improvement was noted at 4- and 8-week follow-ups, but no difference was found between the two groups in pain intensity, back muscle endurance and activity limitation. Thus, the authors concluded that smartphone app-based McKenzie telerehabilitation can be successfully used especially to bridge the gap in the non-availability of clinic-based therapy.32 Toelle et al., investigated the effect of a multidisciplinary smartphone app (Kaia App) on pain intensity at 12-week follow-ups in an RCT design. The experimental group received multidisciplinary self-management treatment based on current guidelines and supported by a chat with a healthcare professional via the app. The experimental group showed significantly lower pain intensity than the group receiving physiotherapy with on-line education.41 The Kaia App was evaluated previously in a retrospective cohort study and showed good effect on pain intensity reduction,43 and the analysis of the updated version of Kaia App revealed improvement in treatment adherence.42 One more pilot RCT confirmed the feasibility and preliminary efficacy of a physical activity intervention supported by a smartphone app. At the same time, patient acceptance and reduced care-seeking were observed.36 The protocol of this study is detailed in a separate article.45 Other studies focused on qualitative analysis of the patient’s preferences and compliance in the smartphone app use35,39 and case series analysis of feasibility, efficacy and patient satisfaction with the telerehabilitation booster session.37 Selter et al., in their pilot study, assessed the validity of an image-based quantification of pain-related disability as well as patient compliance and patient-perceived utility of the smartphone app (Limbr).44 The results were promising, showing good compliance and patient-perceived utility. In addition, the authors noted good validity of an image-based quantification of pain-related disability.44\n\nThe most-studied use of the smartphone app in LBP patients was for self-management. We identified 29 articles focused on self-management of LBP via a smartphone app: four systematic reviews,10,33,46,47 five RCTs,11,38,41,48,49 five study protocols,18,45,50–52 six qualitative studies,35,39,53–56 three retrospective cohort studies,26,42,43 five pilot RCTs,36,44,57,58 and one case series.37 Many of the studies coupled the self-management and telerehabilitation in the same app or in the same study intervention. These studies were presented in the previous section.32,35–45 In a scoping review of the outcome used in the smartphone apps for self-management of LBP, Coe-O’Brien et al., found 74 apps; only four used the outcome measure that could be linked to the International Classification of Functioning, Disability and Health System (ICF) core set for LBP. Furthermore, they concluded that most of the apps were of low quality, indicating the lack of outcome evaluation in the apps.33 Machado et al., performed a systematic review of smartphone apps for self-management of LBP. Similarly, they analysed 61 apps and found overall low quality of the apps, pointing to the lack of studies evaluating their efficacy, presentation of the questionable information, and unattractive layouts. They also recommend that app developers collaborate with healthcare professionals and researchers to ensure the benefit for LBP patients.10 A recent systematic review with meta-analysis analysed eHealth based self-management for chronic LBP. The term eHealth encompassed the interventions based on smartphone apps (m-Health) or on traditional Internet (web-Health) use, so studies included in this meta-analysis were not all based on smartphone apps. Nevertheless, the authors concluded low to moderate evidence of a positive impact on pain and disability of this type of self-management.46 Previously Nicholl et al., performed a systematic review of digital support interventions for the self-management of LBP. They revealed heterogeneity and low quality of the studies, which could not support the utility of digital based interventions for LBP.47\n\nA summary of the RCTs focused on efficacy of smartphone apps targeting self-management for LBP is presented in Table 2 as is the quality evaluation using the PEDRO score. Chhabra et al., evaluated the effect of the self-management app Snapcare. A control group of LBP patients received a written prescription of medication and home exercises and were compared to a self-management group focusing on physical activity improvement based on Snapcare. The results at 12 weeks showed a similar improvement in pain in both groups and greater improvement in function in the Snapcare than control group. The authors concluded that such results support the utility of Snapcare for LBP patients.11 Suman et al., performed a cluster RCT evaluating the effectiveness and cost-utility of a multifaceted eHealth intervention based on websites and social media platforms but also including a mobile version, adaptable to a smartphone. The intervention was inspired by the Australian mass media campaign promoting physical activity, positive back beliefs and coping with LBP. The control group received a digital patient information letter. The presented eHealth strategy was not effective in improving patients’ back pain beliefs or decreasing disability or absenteeism, but the study provided a promising cost-utility analysis.48 Irvine et al., showed promising results of their mobile app FitBack, which was effective in physical, behavioural and worksite outcomes. FitBack was based on a self-tailored cognitive-behavioural approach and used the American Pain Society recommendations.49 Almhdawi et al., also reported that use of their app called Relieve my back is efficient in pain and disability self-management.58\n\nWe also found several articles presenting study protocols for smartphone apps used by LBP patients. Sandal et al., presented the protocol of an RCT comparing the effect of usual care supported by the selfBACK app versus usual care only. Tailored self-management plans were provided by the selfBACK app consisting of advice on physical activity, physical exercises, and educational content. Self-management plans were prepared by using case-based reasoning methodology, a branch of artificial intelligence.50 Mork et al., presented complementary information regarding the implementation of the methodology used in the selfBACK protocol.18 One RCT protocol aimed to evaluate the effectiveness of Relaxback, focusing on relaxation for LBP patients. Autogenic training, mindfulness meditation and guided imagery is used in the app and will be compared to usual care.51 Another RCT protocol is for MIMate, designed to support motivational interviewing performed by a physical therapist and targeting behavioural changes regarding physical activity. MIMate is used between face-to-face physical therapy sessions and is compared to usual physical therapy sessions.52\n\nTwo qualitative studies coupled telerehabilitation and self-management interventions and were mentioned in the previous section.32,36 Nevertheless, four other qualitative studies investigated the preference in content of an app improving self-management53,55 or the feasibility/utility of an app providing educational videos focused on self-management, postoperative protocols, or tailored self-management plans.54,56 Three retrospective cohort studies using smartphone apps for self-management of LBP were coupled with telerehabilitation, evaluation or data collection and were mentioned in the previous sections.26,42,43 Similarly, in two pilot studies, self-management was coupled with telerehabilitation; these articles were presented in the previous section.36,44 However, another pilot RCT, used a smartphone app to enhance self-management between physical therapy sessions and compared it to physical therapy only. The Pain Care app provided self-management based on home exercises. The authors concluded that a more powerful study needed to be conducted considering their promising results.57\n\nSome studies used smartphone apps for LBP patients to collect medical information. One study protocol presented a smartphone app to collect timely data in ecological situations, including pain intensity, physical function, analgesic use and adherence to auricular point acupressure treatment.59 Similarly, in a study that aimed to evaluate relations between opioid use and pain intensity, a smartphone app was used exclusively to collect information about pain intensity multiple times daily.60 However, in most studies, data were collected together with other uses of the smartphone app previously presented: self-management, telerehabilitation, evaluation.23–26,42,43,50,54\n\n\nDiscussion\n\nThe aim of this scoping review was to identify the current fields of employment of smartphone apps for LBP patients. Although the use of smartphone apps for LBP patients is relatively recent, the scope of our review appears to be large, with 43 articles meeting our inclusion criteria. Emerging uses of the smartphone apps are self-management, telerehabilitation, evaluation and data collection. The present review did not aim to firmly classify use of the smartphone apps, which could be controversial. Rather we aimed at investigating what could be the utility of the apps for LBP patients, the current scientific knowledge and perspectives that are worthy of study and development.\n\nThe scientific literature regarding smartphone app use is growing. Self-management is a field of smartphone app use that has gained the most attention. Telerehabilitation is often coupled with self-management, and data collection is usually integrated with evaluation. The evidence of effectiveness of smartphone apps in self-management of LBP derived from RCTs are favourable for patients with chronic LBP11,32,41,49,57 and patients after spinal surgery.38 However, one RCT reported no effect of such interventions on pain, disability and beliefs of LBP patients but showed promising cost-utility results.48\n\nOverall, the quality of the analysed RCTs was moderate to good as assessed by the PEDro score. Indeed, the content of the interventions varied between the studies, and different apps presented differences in providing self-management. Nevertheless, improving physical activity level and providing education about LBP were the common components of the interventions. Self-management with a smartphone app was frequently used together with other interventions including face-to-face physical therapy, web-based education or email reminders. The systematic reviews focused on self-management actually reviewed app stores to find existing self-management apps rather than screening the scientific literature data10,33 or included the studies focused more largely on eHealth interventions.46,47 The effectiveness of the telerehabilitation interventions including smartphone apps evaluated by Dario et al., in a 2017 systematic review showed moderate evidence that telerehabilitation is not more effective than minimal interventions for pain and disability outcomes.40 However, since then, new RTCs have shown more optimistic results.32,38,41 Telerehabilitation and self-management of LBP are in a phase of dynamic development; possibly promising results in recent studies correspond to improvements in providing such interventions.\n\nSmartphone apps used as an evaluation tool seems promising for pain evaluation23–26 and is contradictory for spinal ROM measurements.16,27–29 Indeed, technical aspects of such measurement are complicated: controlling all potential error sources in a multi-segmental movement is challenging. This observation is consistent with other spinal ROM measurement studies also indicating contradictory results.61,62 Considering the limitations regarding hygienic and practical use of the smartphone, it might not be the optimal device for such use. However, remote clinical evaluation using a smartphone app should be developed regarding the promising results of subgrouping patients by treatment-based classification, the McKenzie system and the Backache Disability Index.17,32,34\n\nUse of smartphone apps for data collection seems highly useful and effective. Smartphones are personal and easily accessible to collect data. Many of the studies we found used smartphone apps to collect information, even if the main use was self-management, telerehabilitation, or evaluation. It seems pertinent to develop this branch of smartphone use. Yet, our review also reveals development in data treatment. A recently started study implements machine learning technology to provide a personal adapted self-management strategy.50 For this form of analysis, a large amount of data needs to be collected and smartphones perfectly fit this goal.\n\nSome articles could have been missed in our search strategy as we only used three databases. However, based on a large problem of our review, identifying the current fields of the smartphone apps use for LBP patients’ points out perspectives for further studies including perspectives for a more specific systematic review. Also, the highly heterogenic terminology regarding smartphone apps use could have resulted in some omissions. Several studies using eHealth strategy (e.g., tablet apps) were not included if there was no clear information about the smartphone app use. However, we should acknowledge the limitations regarding smartphone-related compulsive behaviour, which for some patients (e.g., those with depression or anxiety) could result in smartphone addiction.63 Moreover, Alsalameh et al., revealed that smartphone addiction is highly prevalent in young populations and is related to musculoskeletal pain.64 This aspect of smartphone use for LBP patients should be considered when self-management or telerehabilitation is proposed. Caution should be taken, if for some patients, the use of the smartphone app represents compensatory functions of motivations and gratifications.\n\n\nConclusions\n\nThe present scoping review revealed that the scientific literature is growing regarding the use of smartphone apps for LBP patients. The main uses are for self-management, telerehabilitation, evaluation and data collection. Self-management is the most used in LBP and showed moderate- to good-quality evidence for efficacy. Promising results exist regarding evaluation and data collection and contradictory results regarding measurement. Regarding technological and socio-cultural development, new fields of use may arise. Nevertheless, caution should be taken to monitor the impact of smartphone-related compulsive behaviour.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReporting guidelines\n\nFigshare: PRISMA-ScR checklist for ‘Smartphone applications are used for self-management, telerehabilitation, evaluation and data collection in low back pain healthcare: a scoping review’, https://doi.org/10.6084/m9.figshare.20555802.65\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
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Publisher Full Text\n\nLee JH, Lee DK, Oh JS: The effect of Graston technique on the pain and range of motion in patients with chronic low back pain. J. Phys. Ther. Sci. juin 2016; 28(6): 1852–1855. PubMed Abstract | Publisher Full Text\n\nde Brito Macedo L , Borges DT, Melo SA, et al.: Reliability and concurrent validity of a mobile application to measure thoracolumbar range of motion in low back pain patients. J. Back Musculoskelet. Rehabil. 2020; 33(1): 145–151.\n\nPourahmadi M, Hesarikia H, Ghanjal A, et al.: Psychometric Properties of the iHandy Level Smartphone Application for Measuring Lumbar Spine Range of Motion and Lordosis: A Systematic Review of the Literature. J. Sport Rehabil. 1 mars 2020; 29(3): 352–359. PubMed Abstract | Publisher Full Text\n\nStienen MN, Gautschi OP, Staartjes VE, et al.: Reliability of the 6-minute walking test smartphone application. J. Neurosurg. Spine. 13 sept 2019; 31: 786–793. Publisher Full Text\n\nMbada CE, Olaoye MI, Dada OO, et al.: Comparative Efficacy of Clinic-Based and Telerehabilitation Application of Mckenzie Therapy in Chronic Low-Back Pain. Int. J. Telerehabil. 2019; 11(1): 41–58. PubMed Abstract | Publisher Full Text\n\nCoe-O’Brien R, Joseph L, Kuisma R, et al.: Outcome measures used in the smartphone applications for the management of low back pain: a systematic scoping review. Health Inf. Sci. Syst. déc. 2020; 8(1): 5. PubMed Abstract | Publisher Full Text\n\nFarasyn A, Meeusen R, Nijs J, et al.: Exploration of the validity and reliability of the « backache disability index » (BADIX) in patients with non-specific low back pain. J. Back Musculoskelet. Rehabil. 2013; 26(4): 451–459. PubMed Abstract | Publisher Full Text\n\nHasenöhrl T, Windschnurer T, Dorotka R, et al.: Prescription of individual therapeutic exercises via smartphone app for patients suffering from non-specific back pain: A qualitative feasibility and quantitative pilot study. Wien. Klin. Wochenschr. mars 2020; 132(5-6): 115–123. PubMed Abstract | Publisher Full Text\n\nAmorim AB, Pappas E, Simic M, et al.: Integrating Mobile-health, health coaching, and physical activity to reduce the burden of chronic low back pain trial (IMPACT): a pilot randomised controlled trial. BMC Musculoskelet. Disord. 11 févr 2019; 20(1): 71. PubMed Abstract | Publisher Full Text\n\nPeterson S: Telerehabilitation booster sessions and remote patient monitoring in the management of chronic low back pain: A case series. Physiother. Theory Pract. mai 2018; 34(5): 393–402. PubMed Abstract | Publisher Full Text\n\nHou J, Yang R, Yang Y, et al.: The Effectiveness and Safety of Utilizing Mobile Phone-Based Programs for Rehabilitation After Lumbar Spinal Surgery: Multicenter, Prospective Randomized Controlled Trial. JMIR Mhealth Uhealth. 20 2019; 7(2): e10201. PubMed Abstract | Publisher Full Text\n\nVerbrugghe J, Haesen M, Spierings R, et al.: Skill training preferences and technology use in persons with neck and low back pain. Disabil. Rehabil. Assist. Technol. 2017; 12(8): 801–807. PubMed Abstract | Publisher Full Text\n\nDario AB, Moreti Cabral A, Almeida L, et al.: Effectiveness of telehealth-based interventions in the management of non-specific low back pain: a systematic review with meta-analysis. Spine J. 2017; 17(9): 1342–1351. PubMed Abstract | Publisher Full Text\n\nToelle TR, Utpadel-Fischler DA, Haas KK, et al.: App-based multidisciplinary back pain treatment versus combined physiotherapy plus online education: a randomized controlled trial. NPJ Digit Med. 2019; 2: 34. PubMed Abstract | Publisher Full Text\n\nClement I, Lorenz A, Ulm B, et al.: Implementing Systematically Collected User Feedback to Increase User Retention in a Mobile App for Self-Management of Low Back Pain: Retrospective Cohort Study. JMIR Mhealth Uhealth. 6 juin 2018; 6(6): e10422. PubMed Abstract | Publisher Full Text\n\nHuber S, Priebe JA, Baumann KM, et al.: Treatment of Low Back Pain with a Digital Multidisciplinary Pain Treatment App: Short-Term Results. JMIR Rehabil Assist Technol. 4 déc 2017; 4(2): e11. PubMed Abstract | Publisher Full Text\n\nSelter A, Tsangouri C, Ali SB, et al.: An mHealth App for Self-Management of Chronic Lower Back Pain (Limbr): Pilot Study. JMIR Mhealth Uhealth. 17 sept 2018; 6(9): e179. PubMed Abstract | Publisher Full Text\n\nAmorim AB, Pappas E, Simic M, et al.: Integrating Mobile health and Physical Activity to reduce the burden of Chronic low back pain Trial (IMPACT): a pilot trial protocol. BMC Musculoskelet. Disord. 19 janv 2016; 17: 36. Publisher Full Text\n\nDu S, Liu W, Cai S, et al.: The efficacy of e-health in the self-management of chronic low back pain: A meta analysis. Int. J. Nurs. Stud. 24 déc 2019; 106: 103507.\n\nNicholl BI, Sandal LF, Stochkendahl MJ, et al.: Digital Support Interventions for the Self-Management of Low Back Pain: A Systematic Review. J. Med. Internet Res. 21 2017; 19(5): e179. PubMed Abstract | Publisher Full Text\n\nSuman A, Schaafsma FG, van Dongen JM , et al.: Effectiveness and cost-utility of a multifaceted eHealth strategy to improve back pain beliefs of patients with non-specific low back pain: a cluster randomised trial. BMJ Open. 05 2019; 9(12): e030879. PubMed Abstract | Publisher Full Text\n\nIrvine AB, Russell H, Manocchia M, et al.: Mobile-Web app to self-manage low back pain: randomized controlled trial. J. Med. Internet Res. 2 janv 2015; 17(1): e1. PubMed Abstract | Publisher Full Text\n\nSandal LF, Stochkendahl MJ, Svendsen MJ, et al.: An App-Delivered Self-Management Program for People With Low Back Pain: Protocol for the selfBACK Randomized Controlled Trial. JMIR Res. Protoc. 3 déc 2019; 8(12): e14720. PubMed Abstract | Publisher Full Text\n\nBlödt S, Pach D, Roll S, et al.: Effectiveness of app-based relaxation for patients with chronic low back pain (Relaxback) and chronic neck pain (Relaxneck): study protocol for two randomized pragmatic trials. Trials. 15 déc 2014; 15: 490. PubMed Abstract | Publisher Full Text\n\nO’ Halloran PD, Holden J, Breckon J, et al.: Embedded Motivational Interviewing combined with a smartphone app to increase physical activity in people with sub-acute low back pain: Study protocol of a cluster randomised control trial. Contemp. Clin. Trials Commun. mars 2020; 17: 100511. PubMed Abstract | Publisher Full Text\n\nRiis A, Hjelmager DM, Vinther LD, et al.: Preferences for Web-Based Information Material for Low Back Pain: Qualitative Interview Study on People Consulting a General Practitioner. JMIR Rehabil. Assist. Technol. 2 avr 2018; 5(1): e7. PubMed Abstract | Publisher Full Text\n\nGanguli I, Sikora C, Nestor B, et al.: A Scalable Program for Customized Patient Education Videos. Jt. Comm. J. Qual. Patient Saf. 2017; 43(11): 606–610. PubMed Abstract | Publisher Full Text\n\nGrolier M, Arefyev A, Pereira B, et al.: Refining the design of a smartphone application for people with chronic low back pain using mixed quantitative and qualitative approaches. Disabil. Rehabil. Assist. Technol. 5 nov 2020; 1–6. PubMed Abstract | Publisher Full Text\n\nNordstoga AL, Bach K, Sani S, et al.: Usability and Acceptability of an App (SELFBACK) to Support Self-Management of Low Back Pain: Mixed Methods Study. JMIR Rehabil. Assist. Technol. 9 sept 2020; 7(2): e18729. PubMed Abstract | Publisher Full Text\n\nYang J, Wei Q, Ge Y, et al.: Smartphone-Based Remote Self-Management of Chronic Low Back Pain: A Preliminary Study. J. Healthc. Eng. 2019; 2019: 1–7. Publisher Full Text\n\nAlmhdawi KA, Obeidat DS, Kanaan SF, et al.: Efficacy of an innovative smartphone application for office workers with chronic non-specific low back pain: a pilot randomized controlled trial. Clin. Rehabil. oct 2020; 34(10): 1282–1291. PubMed Abstract | Publisher Full Text\n\nYeh CH, Li C, Glick R, et al.: A prospective randomized controlled study of auricular point acupressure to manage chronic low back pain in older adults: study protocol. Trials. 20 janv 2020; 21(1): 99. PubMed Abstract | Publisher Full Text\n\nCarpenter RW, Lane SP, Bruehl S, et al.: Concurrent and lagged associations of prescription opioid use with pain and negative affect in the daily lives of chronic pain patients. J. Consult. Clin. Psychol. oct 2019; 87(10): 872–886. PubMed Abstract | Publisher Full Text\n\nHarsted S, Mieritz RM, Bronfort G, et al.: Reliability and measurement error of frontal and horizontal 3D spinal motion parameters in 219 patients with chronic low back pain. Chiropr. Man. Therap. 4 avr 2016 [cité 30 oct 2020]; 24: 13. PubMed Abstract | Publisher Full Text Reference Source\n\nAlqhtani RS, Jones MD, Theobald PS, et al.: Reliability of an accelerometer-based system for quantifying multiregional spinal range of motion. J. Manipulative Physiol. Ther. mai 2015; 38(4): 275–281. PubMed Abstract | Publisher Full Text\n\nMatar Boumosleh J, Jaalouk D: Depression, anxiety, and smartphone addiction in university students- A cross sectional study. PLoS One. 2017; 12(8): e0182239. PubMed Abstract | Publisher Full Text\n\nAlsalameh AM, Harisi MJ, Alduayji MA, et al.: Evaluating the relationship between smartphone addiction/overuse and musculoskeletal pain among medical students at Qassim University. J. Family Med. Prim. Care. sept 2019; 8(9): 2953–2959. PubMed Abstract | Publisher Full Text\n\nDobija L: PRISMA-ScR-Fillable-Checklist_Manuscript 123331.pdf. figshare. [Dataset].2022. Publisher Full Text"
}
|
[
{
"id": "152995",
"date": "24 Oct 2022",
"name": "Alexandra Roren",
"expertise": [
"Reviewer Expertise Shoulder and trunk kinematics",
"development and assessment of innovative tools to assess and treat people whith chronic musculoskeletic disease",
"adhesion to treatment based on physical activity."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis scoping review is well written. It's an interesting work that takes stock of a current topic.\n\nMy minor remarks are the following:\nAbstract:\n\nBackground - There is a gap between the first (too general) and second sentences.\n\nConclusions - You can't state the growing literature as you didn't really study this aspect (quantitative assessment of studies through the years).\n\nIntroduction:\nFirst paragraph: Are \"Navigation, video communication, gaming, and social media\" the most common use of mobile phones?\n\nThird paragraph: You should make a difference between LBP and chronic LBP which is in some conditions the major target of biopsychosocial management.\n\nFourth paragraph, first sentence: Does the \"purpose\" include overtreating?\n\nYou could also raise the topic of the cost and accessibility of the apps compared to usual (face-to-face) treatment.\n\nMethods\nCould you justify why you included studies from January 1st, 2005?\n\nResults:\nUse of smartphone apps for evaluation: Give a few words about PainMAP.\n\nWhen you talk about spine surgery, specify that you are talking of \"spine surgery\" for low back pain.\n\nDiscussion:\nFirst paragraph: To explain why the classification could be controversial, you could specify that the use of apps is multiple.\n\nIt's not clear why you use both the words \"efficacy\" and \"effectiveness\".\n\nSecond paragraph: As stated above, you can't really state about the growing literature as you didn't really study that point.\n\nWhen you are talking of efficacy or effectiveness, specify systematically on what outcomes.\n\nI don't really understand the problem of hygiene raised by the use of apps to measure RoM.\n\nLast paragraph before the limits part, what about data security?\n\nLimitations:\nI'm not sure that the compulsive behavior is a limitation as it is not really in the scope of your review.\n\nConclusions:\nSame remark about \"growing literature\".\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": [
{
"c_id": "11492",
"date": "21 Jun 2024",
"name": "Lech Dobija",
"role": "Author Response",
"response": "Reviewer Comment: This scoping review is well written. It's an interesting work that takes stock of a current topic. Author Response: Thank you very much for taking the time to review my manuscript and for your precious constructive comments. Reviewer Comment: My minor remarks are the following: Abstract: Background - There is a gap between the first (too general) and second sentences. Author Response: Thank you for this remark. We have removed the first sentence from abstract. Reviewer Comment: Conclusions - You can't state the growing literature as you didn't really study this aspect (quantitative assessment of studies through the years). Author Response: We acknowledge that we did not conduct a quantitative assessment of studies over the years. We have changed this sentence: “This scoping review revealed a notable interest in the scientific literatures regarding the use of smartphone apps for LBP patients.” Reviewer Comment: Introduction: First paragraph: Are \"Navigation, video communication, gaming, and social media\" the most common use of mobile phones? Author Response: We have reformulate this sentence: “Extensive software of smartphones has permitted the development of new applications, allowing video communication, social media consulting, gaming, and navigation.” Reviewer Comment: Third paragraph: You should make a difference between LBP and chronic LBP which is in some conditions the major target of biopsychosocial management. Author Response: Thank you for this pertinent remark. We have added the specifications about chronic LBP: “When nonspecific LBP persists and becomes chronic, it becomes increasingly complex and challenging to manage due to its multifactorial nature.” “Current guidelines for management of chronic LBP include psychosocial interventions along with exercise therapy, medications, multidisciplinary rehabilitation and spinal manipulation. 8” Reviewer Comment: Fourth paragraph, first sentence: Does the \"purpose\" include overtreating? Author Response: Thank you for this comment. We mentioned overtreating (which is not the purpose of the review) to introduce the rationale for self-management strategies for chronic LBP. Reviewer Comment: You could also raise the topic of the cost and accessibility of the apps compared to usual (face-to-face) treatment. Author Response: Thank you very much for this constructive remark. We added this aspect to Introduction: “Compared to face-to-face treatment smartphone apps could potentially be more cost-effective and could help to overcome the problem of healthcare accessibility.” Reviewer Comment: Methods Could you justify why you included studies from January 1st, 2005? Author Response: We added the justification: “This time frame includes the emergence of the new generation of mobile phones.” Reviewer Comment: Results: Use of smartphone apps for evaluation: Give a few words about PainMAP. Author Response: We added the sentence about PainMAP app: “Considering pain evaluation, PainMAP showed excellent intra- and inter-rater reliability and good validity for quantifying the number of pain sites and pain area. 23 This application allows patients to mark their pain on digital body charts and automatically quantifies such self-assessment. Furthermore, another smartphone app could effectively evaluate pain changes after transcutaneous electrical nerve stimulation. 25” Reviewer Comment: When you talk about spine surgery, specify that you are talking of \"spine surgery\" for low back pain. Author Response: Thank you for this remark. We added this specification: “Hou et al., evaluated a system of telerehabilitation based on a smartphone app interface for patients after lumbar surgery for LBP and a web-based interface for physicians providing and surveying rehabilitation and communicating with the patient.” “The evidence of effectiveness of smartphone apps in self-management of LBP derived from RCTs are favourable on pain and disability for patients with chronic LBP 11 , 32 , 41 , 49 , 57 and patients after spinal surgery for LBP. 38” Reviewer Comment: Discussion: First paragraph: To explain why the classification could be controversial, you could specify that the use of apps is multiple. Author Response: Thank you. We applied your suggestion: “The present review did not aim to firmly classify use of the smartphone apps, as their multiple uses can be controversial.” Reviewer Comment: It's not clear why you use both the words \"efficacy\" and \"effectiveness\". Author Response: Thank you for this pertinent remark. We have uniformed the words use trough manuscript. Reviewer Comment: Second paragraph: As stated above, you can't really state about the growing literature as you didn't really study that point. Author Response: We have changed this sentence: “We observed a notable interest in scientific literature regarding the utilization of smartphone apps for patients with LBP.” Reviewer Comment: When you are talking of efficacy or effectiveness, specify systematically on what outcomes. Author Response: Thank you for this remark. In the objective of the present scoping review, we did not specify the outcome of effectiveness, in contrast to what would be appropriate for a systematic review. Our intention was to conduct evaluation of the content of scientific literature including all types of studies and including the effectiveness regarding all types of outcomes. However, we agree that specifying the outcome for effectiveness of the studies we reported would improve the clarity. We added the outcomes when reporting effectiveness through the manuscript. Reviewer Comment: I don't really understand the problem of hygiene raised by the use of apps to measure RoM. Author Response: We have reformulated this sentence: “Using the therapist's personal smartphone to perform measurements on patients may not be practical.” Reviewer Comment: Last paragraph before the limits part, what about data security? Author Response: Thank you for this important remark. We added a sentence about it: “At the same time, it's important to respect data security considerations.” Reviewer Comment: Limitations: I'm not sure that the compulsive behavior is a limitation as it is not really in the scope of your review. Author Response: We removed the part of paragraph referred to smartphone addiction and compulsive behaviour. Reviewer Comment: Conclusions: Same remark about \"growing literature\". Author Response: We have reformulated the sentence: “The present scoping review revealed that the scientific literature interest in the utilization of smartphone apps for patients with LBP is notable.”"
}
]
},
{
"id": "253130",
"date": "28 Mar 2024",
"name": "Marijn Ulrich",
"expertise": [
"Reviewer Expertise My are of research is implementation of smartphone apps",
"or digital health",
"in the context of physiotherapy for people with low back pain."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFirst of all, I would like to complement the authors on this clearly written and relevant scoping review. It's nice to read a review with a broader scope than just evidence of treatment effect.\nThe rationale and objectives of the study are clear for me. The introduction gives good context on the topic.\nThe methods used are quite clear and repeatable, but with some remarks: - In the exclusion criteria, it's not fully clear if you also excluded physical activity promotion or lifestyle advise for people with low back pain (or only for healthy people). - You included study protocols, but what did you do when those studies were performed and published? Since they can describe the exact same study, can you mention if you excluded protocols when the article of the finished study was published for example. Or any other way of handling them if you included them both. - In the synthesis, can you explain how you drew conclusions like 'promising'. Did you draw those conclusions yourselves or did you take (copy-paste) these conclusions from the included article (like you do mention in table 2 under 'author's conclusion')?\nThis last point applies for the results and discussion/conclusion as well. Quite often you use conclusions like 'promising'. To me, it's too subjective (and perhaps biased). It would be nice if you can give some clarity on that. I understand it's not the main goal like in a systematic review or meta-analysis.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": [
{
"c_id": "11493",
"date": "21 Jun 2024",
"name": "Lech Dobija",
"role": "Author Response",
"response": "Reviewer Comment: First of all, I would like to complement the authors on this clearly written and relevant scoping review. It's nice to read a review with a broader scope than just evidence of treatment effect. Author Response: Thank you very much for taking the time to review my manuscript and for your precious constructive comments. Reviewer Comment: The rationale and objectives of the study are clear for me. The introduction gives good context on the topic. The methods used are quite clear and repeatable, but with some remarks: - In the exclusion criteria, it's not fully clear if you also excluded physical activity promotion or lifestyle advise for people with low back pain (or only for healthy people). Author Response: Thank you for this pertinent remark. We have specified that exclusion criteria concerned only interventions for healthy people. “Similarly, we excluded studies in which the smartphone use involved healthy individuals for preventing LBP or promoting physical activity or a healthy lifestyle in healthy individuals.” Reviewer Comment: - You included study protocols, but what did you do when those studies were performed and published? Since they can describe the exact same study, can you mention if you excluded protocols when the article of the finished study was published for example. Or any other way of handling them if you included them both. Author Response: Thank you for pointing out the necessity of clarifying the inclusion of the study protocols articles. Indeed, we included all types of scientific articles including study protocols and RCT. At the time of conducting our literature research for the scoping review in May 2021, we included 6 study protocols. At this point, only one study has both its protocol and completed article published, and both have been included in our review. We adopted this approach for our scoping review to ensure comprehensive content analysis of the literature regarding the use of smartphone apps for patients with LBP. We clarified this in the Methods/Eligibility Criteria section: “In cases where both the protocol and the completed study article were published, we included both to ensure comprehensive content analysis of the literature on the subject.” Reviewer Comment: - In the synthesis, can you explain how you drew conclusions like 'promising'. Did you draw those conclusions yourselves or did you take (copy-paste) these conclusions from the included article (like you do mention in table 2 under 'author's conclusion')? Author Response: Thank you for this constructive remark. It is now specified in the text how we drew the conclusion. Conclusions section: “Based on the results of the included studies, we can conclude that there are promising findings regarding the use of smartphone apps for evaluation and data collection, but contradictory results regarding their use for measurements.” Reviewer Comment: This last point applies for the results and discussion/conclusion as well. Quite often you use conclusions like 'promising'. To me, it's too subjective (and perhaps biased). It would be nice if you can give some clarity on that. I understand it's not the main goal like in a systematic review or meta-analysis. Author Response: We acknowledge that the term 'promising' bears the characteristic of subjective judgment. We have now limited the employment of this term which is based on our assessment of the results presented in the included studies. This assessment is subject to biases, which are listed in the Limitations section. In the same time, we do not have any conflict of interest. We added some specifications to improve the clarity. Results section: “The results were promising, showed good compliance and patient-perceived utility. In addition, the authors noted good validity of an image-based quantification of pain-related disability. 44” “The presented eHealth strategy was not effective in improving patients’ back pain beliefs or decreasing disability or absenteeism, but the study provided a favourable cost-utility analysis. 48” “Irvine et al., showed that their mobile app FitBack was effective in improving physical, behavioural and worksite outcomes. FitBack was based on a self-tailored cognitive-behavioural approach and used the American Pain Society recommendations. 49” Discussion section: “Smartphone apps used as an evaluation tool showed good measurement proprieties for pain evaluation 23 – 26 and is contradictory for spinal ROM measurements. 16 , 27 – 29” “However, remote clinical evaluation using a smartphone app should be developed regarding the consistent results between remote and face-to-face of subgrouping of patients by treatment-based classification, the McKenzie system and the Backache Disability Index. 17 , 32 , 34” “Telerehabilitation and self-management of LBP are in a phase of dynamic development; possibly favourable results in recent studies correspond to improvements in providing such interventions.”"
}
]
}
] | 1
|
https://f1000research.com/articles/11-1001
|
https://f1000research.com/articles/12-1052/v1
|
29 Aug 23
|
{
"type": "Research Article",
"title": "Preventive efficacy of silver diamine fluoride and MI Varnish on molars affected by molar incisor hypomineralization in children: A randomized controlled trial",
"authors": [
"Zuhair Al-Nerabieah",
"Muaaz AlKhouli",
"Mayssoon Dashash",
"Muaaz AlKhouli",
"Mayssoon Dashash"
],
"abstract": "Background: This randomized controlled trial aimed to compare the efficacy of silver diamine fluoride (SDF) and MI Varnish in preventing caries development, enamel breakdown, and sensitivity on molars affected by molar incisor hypomineralization (MIH) in children. Methods: A total of 100 children aged 6 to 9 years were enrolled in the study with two contralateral permanent molars mildly affected by MIH. Affected molars were randomly and equally assigned to receive either SDF or MI Varnish treatment. The interventions were applied at four different time points (baseline, 3, 6, 9 months), and the incidence of caries, caries progression, enamel breakdown, and sensitivity were assessed. Results: The findings of this study revealed significant differences in the incidence of caries between the groups treated with SDF and MI Varnish (P-value < 0.05). Similarly, there was a significant difference in caries progression between the two groups (P-value < 0.05). However, no significant differences were observed in enamel breakdown scores between the treatment groups, as the majority of teeth in both groups exhibited a score of 0. Furthermore, there were no significant differences in sensitivity between the treatment groups throughout the study period. Conclusions: In conclusion, the results of this study provide evidence that molars treated with SDF demonstrated a lower incidence of caries and a higher rate of caries arrest compared to those treated with MI Varnish. Both interventions showed promise in preventing enamel breakdown and improving sensitivity. These findings highlight the potential of SDF and MI Varnish as effective treatments for caries prevention and management, emphasizing the importance of early intervention and appropriate dental care strategies in maintaining oral health. Trial registration: ISRCTN54243749 (13/01/2022).",
"keywords": [
"Molar-Incisor Hypomineralization",
"Silver Diamine Fluoride",
"MI Varnish",
"Caries prevention",
"Enamel breakdown",
"Sensitivity",
"Children"
],
"content": "Introduction\n\nMolar incisor hypomineralization (MIH) is a common dental condition that affects the quality of life of children.1 It is characterized by enamel hypomineralization and discoloration of one or more permanent first molars and incisors, resulting in increased caries and post-eruptive enamel breakdown.2 This can cause a range of oral health problems, including pain and sensitivity, which can affect a child's ability to eat, sleep, and participate in daily activities.3\n\nMIH has become an increasingly recognized problem for researchers and a challenging issue for pediatric dentists. With prevalence rates ranging from 2% to 14% across different populations and diagnostic criteria, MIH poses significant challenges in the field of pediatric dentistry (PD).4 This condition is believed to have a multifactorial etiology, with potential contributing factors including prenatal and perinatal influences, systemic diseases, and environmental exposures.5\n\nRecent research has shed light on the high prevalence of MIH in specific populations. A noteworthy study conducted in Syria revealed a staggering prevalence rate of 39.9% among Syrian children.6 This finding underscores the urgency of addressing MIH and its impact on oral health in affected individuals. Understanding the prevalence of MIH in different populations provides valuable insights into the extent of the problem and emphasizes the need for effective preventive and management strategies.7\n\nDespite the growing recognition of MIH as a significant public health issue, there is limited research available on effective treatments for this condition.8 The impact of MIH on children's quality of life highlights the need for effective treatments that can prevent or mitigate the effects of this condition.9\n\nAlthough routine oral care practices and fluoride are effective in preventing caries, these methods may not be sufficient in managing MIH.8 MIH-affected teeth have altered enamel structures and are more porous, making them more prone to caries and enamel breakdown than non-affected teeth. The enamel's increased porosity allows bacteria to penetrate and initiate caries formation, leading to early cavitation and further enamel breakdown.10\n\nThe consequences of untreated MIH can range from impaired oral function and increased risk of caries, to decreased self-esteem and social isolation.11 As a result, it is important to identify treatments that can effectively prevent or manage MIH and improve the oral health and quality of life of affected children.12\n\nThe challenges posed by MIH have led to the development of various preventive and therapeutic measures, such as the use of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and silver diamine fluoride (SDF).13 MI Varnish™ is a product that contains 5% NaF and 2% CPP-ACP, which have been shown to enhance enamel remineralization and reduce sensitivity in MIH-affected teeth.14\n\nOn the other hand, SDF is a minimally invasive and cost-effective approach for arresting and preventing dental caries.15 SDF works by inducing the formation of a silver-protein complex and a calcium fluoride-like layer, which can kill cariogenic bacteria and promote remineralization.16 SDF is effective in reducing caries incidence and arresting cavitated lesions in primary and permanent teeth.17,18 Nevertheless, the efficacy of SDF for preventing caries in MIH-affected molars remains unclear, and there is a lack of studies investigating the use of SDF as a preventive measure for MIH-affected molars.\n\nIn this context, the effectiveness of SDF and CPP-ACP in preventing or managing the outcomes of MIH has become an important area of investigation.19 While both SDF and CPP-ACP have been shown to have potential benefits in managing this condition, it is important to understand the relative efficacy of these treatments in a well-controlled, randomized clinical trial. The results of such a trial can inform the development of evidence-based guidelines for the management of MIH in children, and help to ensure that children receive the most effective, and appropriate oral health care.\n\nTherefore, this study aimed to compare the effectiveness of SDF and MI Varnish in preventing the development and progression of caries and post-eruptive enamel breakdown in children's molars affected by MIH.\n\n\nMethods\n\nEthical approval was obtained from the Research Ethics Committee at Damascus University ‘2984’ dated 19/09/2021. Written informed consent was obtained from the parents or legal guardians of all participants before enrolment in the study. The trial was registered on 13/01/2022 at ISRCTN with the following number (ISRCTN54243749). Furthermore, the study was designed and reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement criteria to ensure rigorous and transparent reporting of the study methodology and results.20\n\nThis study was a randomized controlled clinical trial, double-blinded with a split-mouth design, conducted in a paediatric dental department at Damascus University, Syria. This study was performed at the period from Jan 2022 to Feb 2023.\n\nThe sample size was calculated using G*Power software version 3.1.9.4. Based on the results of a previous study,21 the expected mean difference in the International Caries Detection and Assessment System (ICDAS-II) scores between the two groups was estimated to be 2.2 with a standard deviation of 2.0. The power of the study was set at 90%, with an alpha level of 0.05, and a 20% allowance for dropouts. The final sample size was 100 children (200 permanent molars) between the ages of 6 and 9 years.\n\nThe study's inclusion criteria were carefully defined to ensure a homogeneous sample of participants. Only children between the ages of 6 and 9 years, with two contralateral permanent molars mildly affected by MIH and without any prior treatment on the affected molars, were included. The molars were also required to be fully erupted, with no overlapping gingiva. Additionally, children were required to express their willingness to participate in the study.\n\nExclusion criteria comprised children with systemic diseases, a history of orthodontic treatment or extractions, silver sensitivity, and allergy to fluoride or milk proteins. Children with other enamel developmental disorders, such as fluorosis and amelogenesis imperfecta, were also excluded from the study. By implementing these criteria, the study aimed to establish a clear and consistent cohort of participants for analysis.\n\nIn this split-mouth study, randomization was performed based on two factors: the type of material (SDF/MI Varnish) and the side of the mouth (left/right). To determine the order of application and the tooth to be treated, each eligible patient drew twice from opaque envelopes. The first draw determined the material to be applied first, and the second draw determined the tooth to be treated with the chosen material.\n\nTo ensure consistency, the same tooth received the same treatment throughout the study. To minimize any potential bias, both the children and the outcome assessors were blind to the treatment allocation. The children were instructed not to reveal their treatment to the assessors, and the assessors were instructed not to inquire about it. Both SDF and MI Varnish were applied at baseline, and after 3, 6, and 9 months.\n\nAn experienced investigator (ZN) was responsible for the examination of children visiting the PD department for MIH, utilizing the European Association of Paediatric Dentistry (EAPD) criteria.13 Parents of eligible children were presented with an informed consent form and an informational brochure regarding the study, with the understanding that participants had the right to withdraw at any time. Only children with two contralateral molars displaying mild MIH lesions were enrolled in the study, characterized by demarcated enamel opacities without caries and enamel breakdown, and had only induced sensitivity to external stimuli.\n\nAt the initial visit, both children and parents were provided with dietary advice and oral hygiene instructions. Additionally, participants were given toothbrushes and toothpaste containing 1000-ppm fluoride. In the subsequent visit, sensitivity testing was performed on both affected molars using an air syringe. The air syringe was placed close (1 cm) to the occlusal surface of the affected tooth for one second, and children's response to this stimulus was evaluated using the Schiff Cold Air Sensitivity Scale (SCASS).22 The process was then repeated for the other affected tooth. Furthermore, the Decayed, Missing due to caries, and Filled Teeth (DMFT)/dmft index developed by the World Health Organization was also calculated after documenting the decayed, missing, and filled teeth for both permanent and primary teeth.\n\nSDF (Advantage Arrest, USA) and MI Varnish (GC, Japan) were then applied in the same visit, with the order and side of the application being determined at random by the child. The application procedure for both materials was standardized. Initially, the teeth were cleaned using gauze, and a dry field was maintained using cotton rolls. Subsequently, a single drop of either SDF or MI Varnish was placed in a disposable plastic dish. The material of choice was then applied to the affected tooth using a microbrush applicator (MRG400, Henry Schein, USA) for a duration of one minute. Finally, a layer of petroleum gel (VASELINE, Unilever, USA) was evenly spread over the entire tooth to complete the application process. In addition, parents were provided with specific instructions that participants should avoid the consumption of food or hot beverages for a period of one hour following the application of the preventive materials. This precaution was implemented to ensure the optimal retention and effectiveness of both SDF and MI Varnish.\n\nSensitivity testing and application of the study materials were conducted again during follow-up visits after 3, 6, 9, and 12 months.\n\nThe primary outcome measures for this study included assessing caries development and caries activity. Caries development was evaluated using the International Caries Detection and Assessment System (ICDAS) criteria and scored as either presence or absence of caries. A score of 0 indicated a sound surface without caries, while a score of 1 indicated the presence of caries. Additionally, caries activity was assessed using Reveal fluorescence dental loupes (Design for vision, USA) and scored as either active or arrested. These scores were recorded at 3, 6, 9, and 12 months from the baseline.\n\nAnother primary outcome measure was the assessment of Post eruptive Enamel Breakdown (PEB), which was scored according to the criteria proposed by Ghanim et al. (2017).23 PEB scores were recorded at the same time points mentioned previously, and each molar was given a score of 0 for no visible enamel breakdown, 1 for less than one-third of the tooth affected, 2 for at least one-third but less than two-thirds of the tooth affected, and 3 for at least two-thirds of the tooth affected.\n\nIn this study, the secondary outcome measure was changes in sensitivity, which were assessed using the SCASS. This scale is a validated tool used to evaluate tooth sensitivity in response to cold stimuli.22 During the assessment, a standard dental air syringe was used to deliver a stream of air for 1 second at a distance of 1 cm and perpendicular to the occlusal surface of the tooth. The subject's response to this stimulus was observed and evaluated using the SCASS Scale. The scale consists of four response categories: 0 represents no response to the stimulus, 1 indicates no response to the stimulus but the subject considers it painful, 2 signifies a response to the stimulus with the subject moving away from it, and 3 indicates a response to the stimulus with the subject moving away and requesting immediate discontinuation. The subject's response was recorded and scored accordingly, in which a higher score indicates a greater sensitivity to cold stimuli.\n\nSensitivity scores were recorded at 3, 6, 9, and 12 months from the baseline, allowing for the evaluation of changes in sensitivity over time.\n\nData were analyzed using IBM SPSS version 23 (IBM Corp., Armonk, USA). Descriptive data including the distribution of affected molars were demonstrated. Chi-squared test was used to analyze the difference between the two studied groups regarding the development of caries in the MIH molars and the activity of the caries lesions at each time point (3 months, 6 months, 9 months, and 12 months). In addition, repeated measures ANOVA test was performed to detect if there was a difference between the different time points in each group separately. However, the Bonferroni test was the post hoc test used to determine where the difference was. The P-value of 0.05 was considered the level of significance. The mean rank of the scores of enamel breakdown and SCASS were calculated to conduct the Mann-Whitney U test to reveal the difference between the two groups at each time point. Similarly, repeated measures ANOVA test was performed to detect if there was a difference between the different time points in each group. Wilcoxon signed Rank test was used as a post hoc test to detect where the difference was. Friedman test was used to reveal the difference between the four-time points regarding the mean rank of enamel breakdown scores in both groups. The intra-examiner reliability was assessed through the re-examination of 10% of the participants one week after the initial examination and was found to be high (Kappa coefficient = 0.86). The inter-examiner reliability was assessed by independent examination of a sample of participants and was found to be high (Kappa coefficient = 0.87).\n\n\nResults\n\nA total of 100 children were enrolled in this trial (42 girls and 58 boys) with a mean age of 7.6 ± 1.4. Each child had two contralateral permanent 1st molars affected with mild MIH.24 The distribution of the molars involved in the study is summarized in Table 1.\n\nThe mean and standard deviation of dmft and DMFT indices were 4.37 ± 1.40 and 0.30 ± 0.63, respectively. The proportion of caries-free children was 11.3%. Table 2 shows the number of molars that were affected by caries in each group and for the four studied time points (after 3, 6, 9, and 12 months). The chi-squared test showed that carious molars were less in the SDF group than in the MI group with a statistically significant difference (P-value < 0.05) in each follow-up schedule.\n\n* Significant difference.\n\nOn the other hand, repeated measures ANOVA showed that there was no statistically significant difference in the development of caries between the four-time points in neither the SDF group nor the MI group (P-value > 0.05).\n\nMoreover, the chi-squared test showed that the percentages of arrested caries were higher in the SDF group than in the MI group with a statistically significant difference in months 6, 9, and 12 (P-value < 0.05). This means that our findings revealed that SDF is better than MI Varnish in arresting the developed caries lesions, especially after 6 months of application (Figure 1). Additionally, repeated measures ANOVA test detected that there was a statistically significant difference between the four-time points in arresting caries in both studied groups (Table 2).\n\nBonferroni post hoc test indicated that the difference was statistically significant between the 3 months follow-up and the other time points only.\n\nRegarding the enamel breakdown detected in each group, the Mann-Whitney U test showed that there was no statistically significant difference between the SDF and MI groups at each time point. This means that both SDF and MI Varnish were effective in the prevention of enamel breakdown of MIH molars (Table 3).\n\n* Significant difference.\n\nFriedman test indicated that there was no statistically significant difference between the four-time points regarding the mean rank of enamel breakdown scores in neither the SDF group nor in the MI group (P-value= 0.513, 0.221 respectively) (Table 4).\n\nAs shown in Table 5, the Mann-Whitney U test similarly showed that there was no statistically significant difference between the SDF group and the MI group regarding the Schiff Cold Air Sensitivity Scale at each time point. However, the Friedman test indicated that the difference between the five-time points (baseline, 3 months, 6 months, 9 months, and 12 months) was statistically significant in both SDF and MI groups.\n\nWilcoxon Signed Rank test revealed that in both SDF and MI groups, there was a statistically significant difference between the baseline and 3 months (P-value = 0.002, 0.001, respectively), between the baseline and 6 months of application (P-value = 0.001, 0.021, respectively) and between the 3 months and 6 months of application (P-value = 0.011, 0.001, respectively). However, there was no statistically significant difference between 9 months and 12 months neither in the SDF group nor in the MI group. Figure 2 shows the change in the mean rank of SCASS between the groups and between the time points.\n\n(SDF: Silver diamine fluoride).\n\n\nDiscussion\n\nThis study aimed to evaluate and compare the preventive efficacy of SDF and MI Varnish in molars affected by MIH among children aged 6–9 years. The results of this study indicate that molars treated with SDF had a significantly lower incidence of caries and a higher rate of caries arrest compared to those treated with MI Varnish. Both SDF and MI Varnish demonstrated the ability to prevent enamel breakdown and improve sensitivity, with no statistically significant difference between the two treatments.\n\nThis age group was selected based on several considerations related to the nature of MIH and the developmental stage of affected teeth.\n\nMIH commonly manifests during the eruption of the first permanent molars, which typically occurs around the age of 6 years.25 By including children within the age range of 6–9 years, the study focused on a critical period when MIH-affected molars are fully erupted and accessible for examination and treatment.\n\nFurthermore, children within this age range are more likely to comply with study protocols and express their willingness to participate actively. They have a better ability to understand and cooperate during dental examinations and treatments, enhancing the feasibility of the study. Additionally, by targeting this age group, the study aimed to address the preventive needs of children at a crucial developmental stage when early intervention can have a significant impact on long-term oral health outcomes.26,27\n\nThe utilization of the European Academy of Pediatric Dentistry (EAPD) criteria for the diagnosis and classification of MIH played a significant role in this study. The EAPD criteria have been widely accepted and recommended as the gold standard for the diagnosis and classification of MIH, providing a standardized approach to ensure consistency and comparability among studies and clinical practice.13\n\nIn addition, the implementation of the EAPD criteria for inclusion ensured the homogeneity of the sample and the accurate identification of participants with MIH. By applying these criteria, the researchers could confidently select children with mild MIH-affected molars, minimizing potential confounding factors and enhancing the validity of the study results.\n\nIn the context of this study, the ICDAS-II criteria were employed to detect and assess caries incidence in the molars affected by MIH. ICDAS-II is considered a widely recognized and standardized method for detecting and assessing dental caries.28 It provides a comprehensive and detailed classification system that allows for the consistent evaluation and diagnosis of caries lesions based on their visual appearance.\n\nIn addition, the caries activity outcome measure was assessed using Reveal fluorescence dental loupes, and the results showed that SDF had a higher percentage of arresting caries compared to MI Varnish, and this difference was found to be statistically significant.\n\nThe use of Reveal fluorescence dental loupes for evaluating caries activity in this study provided an additional objective measure to assess the effectiveness of the preventive treatments.29 These dental loupes utilize fluorescence technology to detect the presence of caries activity based on the fluorescence emission of bacterial metabolites in the oral cavity.30\n\nThe inclusion of Reveal fluorescence dental loupes offered several advantages in this study. Firstly, it is a non-invasive and painless procedure, making it well-suited for use in pediatric patients. Secondly, the immediate results provided a real-time assessment of caries activity, enabling prompt decision-making regarding treatment interventions. Additionally, the qualitative nature of the fluorescence measurements contributed to more objective and standardized evaluations, reducing subjectivity in the assessment process.29,30\n\nThe superior performance of SDF in preventing and arresting caries can be attributed to its unique mechanism of action. SDF works by inducing the formation of a silver-protein complex and a calcium fluoride-like layer, which effectively kills cariogenic bacteria and promotes remineralization.16 This antimicrobial and remineralization effect of SDF is particularly beneficial in managing caries in MIH-affected molars, where the enamel is more susceptible to demineralization and cavitation.31\n\nThe significant difference observed between SDF and MI Varnish suggests that SDF may be a more effective preventive treatment option for caries in MIH-affected molars. These findings align with previous studies that have demonstrated the superiority of SDF in caries prevention and arrest, particularly in primary and permanent teeth.32,33\n\nDespite the growing interest in the effectiveness of Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP) in preventing caries development and progression, there is still ongoing research in this area. In line with previous studies, our research findings support the notion that CPP-ACP demonstrates efficacy in preventing caries. A recent systematic review and meta-analysis conducted by Sharda et al. (2020) investigated the efficacy of CPP-ACP complex and topical fluoride (TF) in managing dental caries.34 The study revealed that while CPP-ACP showed superiority over TF monotherapy in remineralizing existing lesions and exhibiting a stronger antibacterial effect, it did not demonstrate greater efficacy in preventing caries incidence.\n\nThe findings of Sharda et al.'s systematic review highlight the limitations of CPP-ACP in terms of preventing the occurrence of new carious lesions. Although CPP-ACP has shown promise in remineralizing existing lesions and exerting antibacterial properties, its impact on preventing caries incidence appears to be limited.34\n\nFurthermore, a recent study showed that a single topical application of the GC Tooth mousse (CPP-ACP) does not affect increasing the salivary pH and salivary flow rate which are great factors in caries prevention.35\n\nOn the other hand, both SDF and MI Varnish showed comparable performance in preventing enamel breakdown (PEB). This indicates that both materials were effective in preserving the integrity of the enamel surface and preventing further deterioration of the affected teeth. The lack of significant difference in PEB outcomes between the two groups suggests that both treatments have a similar capacity to stabilize the enamel and prevent its breakdown.\n\nFurthermore, both SDF and MI Varnish demonstrated improvement in sensitivity, with no significant difference observed between the two groups. This indicates that both materials were effective in alleviating the sensitivity commonly associated with MIH-affected molars. The reduction in sensitivity can greatly improve the quality of life for affected children by minimizing discomfort and facilitating normal oral function.\n\nThe efficacy of CPP-ACP in preventing enamel breakdown and improving sensitivity has been investigated in several studies, allowing for a comparison of results. In our study, we found that MI Varnish demonstrated effectiveness in preventing enamel breakdown. This finding is consistent with previous research that has reported positive outcomes with the use of MI Varnish as a preventive treatment for enamel hypomineralization.\n\nA notable investigation conducted by Bakkal et al. (2017) aimed to assess the efficacy of 10% CPP-ACP cream in enhancing the mineral content of hypomineralized enamel. The outcomes of their study demonstrated a marked improvement in mineralization, as well as enhancements in enamel morphology and reductions in porosities.36 This highlights the positive impact of CPP-ACP cream on addressing the deficiencies in hypomineralized enamel.\n\nMoreover, Cardoso-Martins et al. (2022) conducted a study that further supports these findings. Their investigation focused on evaluating the effects of CPP-ACP tooth mousse on the mineral density and organization of hypomineralized enamel. The results demonstrated significant improvements in both mineral density and the overall structural organization of the affected enamel following treatment with CPP-ACP tooth mousse.37 This study reinforces the potential of CPP-ACP as a valuable therapeutic option for ameliorating the compromised enamel associated with hypomineralization.\n\nRegarding the improvement of sensitivity, our study demonstrated that MI Varnish was effective in alleviating sensitivity associated with MIH. Similarly, a systematic review by Somani et al. (2022) analyzed multiple studies and concluded that CPP-ACP products showed promising results in reducing sensitivity in MIH-affected teeth.8 They reported a significant reduction in sensitivity scores following the application of MI Varnish.\n\nOverall, the results of our study, along with the findings of previous research, support the use of MI Varnish as an effective intervention for preventing enamel breakdown and improving sensitivity in individuals with MIH.\n\nSeveral limitations should be considered when interpreting the findings of this study. Firstly, the study sample was drawn from a specific population of children aged 6 to 9 years with MIH, which may restrict the generalizability of the results to other age groups or individuals with different characteristics. Further research involving diverse populations is necessary to validate the findings across a broader range of individuals affected by MIH.\n\nIn addition, the study had a relatively short follow-up period, which may limit the ability to assess the long-term effectiveness and durability of the preventive treatments. Hence, longer follow-up periods would provide valuable insights into the sustainability of the interventions over time.\n\nAn additional limitation of this study was the inability to blind the investigator who applied the intervention materials (SDF and MI Varnish) to the participants. Blinding is a methodological approach that aims to reduce bias by withholding information about the assigned treatment from the investigator. However, in this study, blinding was not feasible due to the distinct differences in the colour and texture of the intervention materials.\n\n\nConclusion\n\nIn summary, this study aimed to evaluate and compare the preventive efficacy of SDF and MI Varnish in molars affected by MIH among children aged 6 to 9 years. The results demonstrated that molars treated with SDF had a lower incidence of caries and a higher rate of caries arrest compared to those treated with MI Varnish. Both interventions showed promise in preventing enamel breakdown and improving sensitivity, with no significant difference observed between them.\n\nThe findings suggest that SDF may be a valuable preventive treatment option for managing caries in MIH-affected molars. Furthermore, the finding of this study suggests that while CPP-ACP may be beneficial for managing sensitivity and enhancing remineralization, additional preventive measures may be necessary to address the prevention of new caries formation.\n\nHowever, it is important to acknowledge the limitations of this study, including the restricted sample and short follow-up period. Future research with larger and more diverse populations, as well as longer-term assessments, is needed to further validate these findings.",
"appendix": "Data availability\n\nMendeley Data: Preventive Efficacy of Silver Diamine Fluoride and MI Varnish on Molars Affected by Molar Incisor Hypomineralization in Children: A Randomized Controlled Trial. https://doi.org/10.17632/xtw9gvhbfp.2. 24\n\nThis project contains the following underlying data:\n\n• Ethical approval.jpeg\n\n• Patient data entry level.xlsx (This file includes Age, gender and teeth postion (U upper jaw – L lower jaw) for each participant)\n\n• Protocol.pdf (This file includes the full protocol of this study with analysis plan)\n\n• Teeth data entry level.xlsx (This file includes baseline data of participants’ teeth)\n\n• Outcome assessment Scores 3m, 6m, 9m and 12m.xlsx (This file includes all raw data and scores of assessment scales used in this study for all the follow up periods)\n\nMenedeley Data: CONSORT flow diagram and checklist for ‘Preventive efficacy of silver diamine fluoride and MI Varnish on molars affected by molar incisor hypomineralization in children: A randomized controlled trial’ https://doi.org/10.17632/6yx6my74ys.2. 20\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nPortella PD, et al.: Impact of molar incisor hypomineralization on quality of life in children with early mixed dentition: a hierarchical approach. 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Prev Dent. 2017; 15: 163–167.\n\nCardoso-Martins I, Pessanha S, Coelho A, et al.: Evaluation of the Efficacy of CPP-ACP Remineralizing Mousse in Molar-Incisor Hypomineralized Teeth Using Polarized Raman and Scanning Electron Microscopy—An in vitro Study. Biomedicine. 2022; 10: 3086. Publisher Full Text"
}
|
[
{
"id": "209123",
"date": "29 Sep 2023",
"name": "Peter Milgrom",
"expertise": [
"Reviewer Expertise oral health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a nicely done study on an important topic. A few changes will improve the value of the paper to readers.\nIn the title do not use the brand name of the varnish. Add 38% with SDF as various concentrations are available in some parts of the world and/or have been studied.\nIn the body of the paper, use the brand name of the varnish only once in the methods and use the generic term for the varnish. Include in the methods a description of the active contents and concentrations of this varnish. I see a description of the MI varnish in the background but there is nothing in the methods. At some point in the paper, state clearly where/how the products were obtained and give the lot numbers and information about any independent analysis of the contents. If the manufacturer provided a certificate of analysis, please provide this. At some point in the paper state clearly whether the manufacturers had any role in the research. Do not use MI as an abbreviation in the tables.\nBe sure that the terminology in the paper uses dental caries as a disease and caries or cavities or lesions as a manifestation of the disease. In describing the dichotomous use of the ICDAS, state clearly where the cut off was. Also describe the training and calibration of the examiners. If the results using the loupes are to be included, provide evidence of the reliability and validity of these devices.\nClarify in the sample size discussion that this calculation was for sensitivity, the primary measure. Was the study powered to detect differences in new caries lesion development?\nProvide information on the training of the person doing the cold air test. State exactly what the children were told before the testing. State clearly whether the person doing the test at follow-up had access to the results from the earlier period.\nIn labeling the tables (2 and onward), clarify that the units refer to teeth.\nIn the limitations discussion, discuss any limitations that may stem from the use from a split mouth design.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11150",
"date": "14 Mar 2024",
"name": "Zuhair Al-Nerabieah",
"role": "Author Response",
"response": "Dear reviewer Peter Milgrom Thank you for your thorough review of our manuscript. We are grateful for the time and effort you have dedicated to providing constructive feedback. We would like to assure you that each comment will be addressed point by point. Your insights are invaluable, and we are committed to incorporating your suggestions to enhance the overall quality of the research. This is a nicely done study on an important topic. A few changes will improve the value of the paper to readers. Authors response: Thank you for your thorough review of our manuscript. We are grateful for the time and effort you have dedicated to providing constructive feedback. We would like to assure you that each comment will be addressed point by point, and all changes made to the manuscript will be highlighted for your convenience. Your insights are invaluable, and we are committed to incorporating your suggestions to enhance the overall quality of the research. Additionally, we apologize for the delayed response, as we were awaiting the arrival of the second review report as requested by the journal's editorial team. In the title do not use the brand name of the varnish. Add 38% with SDF as various concentrations are available in some parts of the world and/or have been studied. Authors response: The title has been changed as requested In the body of the paper, use the brand name of the varnish only once in the methods and use the generic term for the varnish. Include in the methods a description of the active contents and concentrations of this varnish. I see a description of the MI varnish in the background but there is nothing in the methods. At some point in the paper, state clearly where/how the products were obtained and give the lot numbers and information about any independent analysis of the contents. If the manufacturer provided a certificate of analysis, please provide this. At some point in the paper state clearly whether the manufacturers had any role in the research. Do not use MI as an abbreviation in the tables. Authors' response: Changes have been made as requested by the reviewer. Table 1 was added to the manuscript which contains the required information about each material used in this study. Be sure that the terminology in the paper uses dental caries as a disease and caries or cavities or lesions as a manifestation of the disease. In describing the dichotomous use of the ICDAS, state clearly where the cut off was. Authors response: The cut-off point or threshold for the dichotomous classification using the ICDAS criteria is typically determined by the specific criteria used to define the presence or absence of caries. In the context of the ICDAS, a score of 0 is assigned to a sound tooth surface, meaning there is no evidence of caries. A score of 1 is assigned when there is any sign of caries present on the tooth surface, regardless of the extent or severity. Therefore, the cut-off point for distinguishing between sound and carious surfaces is based on the presence or absence of any detectable signs of caries. Changed were made to the manuscript to make both terminology and ICDAS cut-off point more clear. Also describe the training and calibration of the examiners. Authors' response: The following text was added to the manuscript: Two pediatric dentist experts were recruited to perform the outcome measures assessment. Prior to the initiation of this study, both examiners underwent comprehensive training and calibration sessions on the International Caries Detection and Assessment System (ICDAS II) criteria and the use of Reveal fluorescence dental loupes. The training regimen encompassed theoretical instruction on ICDAS II and fluorescence in the detection of carious lesions, as well as practical, hands-on training sessions using both carious and sound extracted primary molars. This rigorous training protocol ensured that both examiners were proficient and consistent in their assessment methodologies, thereby enhancing the reliability and validity of the study outcomes. If the results using the loupes are to be included, provide evidence of the reliability and validity of these devices. Authors' response: The following text was added to the manuscript: Furthermore, a recent study by Steier and colleagues, focused on fluorescent enhanced theragnosis through Reveal Vision glasses for the diagnosis of caries progress. Their study revealed a substantial kappa score of 0.706, indicating significant reproducibility for the given diagnostic technique. Clarify in the sample size discussion that this calculation was for sensitivity, the primary measure. Was the study powered to detect differences in new caries lesion development? Authors' response: We appreciate the reviewer's attention to the sample size discussion. It's important to note that while the cited study set its power at 80%, our study opted for a higher power level of 90%. This decision was made to enhance the robustness of our findings and increase the likelihood of detecting clinically significant differences between the treatment groups. Furthermore, the higher power level was also chosen to accommodate potential differences in other outcome measures, ensuring a comprehensive analysis of treatment efficacy. Provide information on the training of the person doing the cold air test. State exactly what the children were told before the testing. State clearly whether the person doing the test at follow-up had access to the results from the earlier period. Authors' response: The following text was added to the manuscript: The dental professional responsible for conducting the cold air sensitivity test underwent comprehensive training to ensure proficiency and consistency in test administration. This training encompassed detailed instructions on the correct positioning of the dental air syringe, the duration and intensity of the air stream, and the standardized distance from which the air was delivered to the tooth's occlusal surface. Moreover, the training emphasized the importance of clear communication with the children to ensure their understanding of the procedure and to encourage accurate reporting of any sensations experienced during the test. Additionally, the dental professional received guidance on recognizing and documenting the various response categories outlined in the SCASS scale, thereby ensuring uniform interpretation and scoring of sensitivity levels. Overall, the specific training regimen aimed to equip the dental professional with the necessary skills and knowledge to conduct the sensitivity test reliably and consistently across all study participants. Before the testing, children were informed about the procedure and what to expect. They were instructed to report any discomfort or sensation experienced during the test. Additionally, the dental professional performing the test at follow-up was blinded to the results from the earlier period to prevent any bias in the assessment of sensitivity changes over time. In labeling the tables (2 and onward), clarify that the units refer to teeth. Authors response: Changes were made as requested by the reviewer. In the limitations discussion, discuss any limitations that may stem from the use from a split mouth design. Authors response: The following text was added to the manuscript: Furthermore, it's important to acknowledge that the split-mouth design used in the study may introduce certain limitations. Firstly, factors such as variations in saliva flow and oral hygiene practices could potentially confound the results by influencing the effectiveness of the treatments differently on each side. Additionally, the split-mouth design may not account for potential systemic factors or changes in oral health behaviours that could affect the outcomes. Despite these limitations, the split-mouth design offers practical advantages in terms of minimizing inter-subject variability and reducing the required sample size, thus allowing for more efficient and cost-effective research outcomes."
}
]
},
{
"id": "237862",
"date": "09 Feb 2024",
"name": "Juliana Souza",
"expertise": [
"Reviewer Expertise Pediatric denitsitry"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article \"Preventive efficacy of silver diamine fluoride and MI Varnish on molars affected by molar incisor hypomineralization in children: A randomized controlled trial\" presents a comprehensive investigation into the preventive efficacy of Silver Diamine Fluoride (SDF) and MI Varnish in children aged 6–9 years with Molar Incisor Hypomineralization (MIH). The study employs a randomized controlled clinical trial with a split-mouth design, offering a robust methodology for comparing the two interventions. The research explores various outcomes, including caries development, caries activity, enamel breakdown, and sensitivity.\n\nStrengths:\nThe article begins with a well-structured introduction, providing a clear rationale for studying MIH and highlighting the significance of effective preventive measures. The research objectives are explicitly stated, setting the stage for a focused investigation. The literature review is comprehensive, covering various aspects of MIH, including its prevalence, etiology, and challenges in treatment. This contextualization helps readers understand the broader implications of the study within the existing body of knowledge.\n\nThe study design, a randomized controlled trial with a split-mouth design, is appropriate for comparing interventions. The researchers obtained ethical approval, ensured participant consent, and followed the CONSORT guidelines, enhancing the study's credibility.\n\nThe use of standardized criteria, such as the European Academy of Pediatric Dentistry (EAPD) criteria for diagnosing MIH and the International Caries Detection and Assessment System (ICDAS-II) for caries assessment, strengthens the study's methodology.\n\nThe incorporation of Reveal fluorescence dental loupes for assessing caries activity is a methodological strength, providing real-time and non-invasive insights into the efficacy of the interventions.\n\nThe discussion effectively compares the preventive efficacy of SDF and MI Varnish, highlighting the superiority of SDF in terms of lower caries incidence and higher caries arrest. This differentiation provides clarity for readers.\n\nAreas for Improvement:\nFurther Context on Enamel Breakdown Results: The discussion briefly mentions the lack of a significant difference in enamel breakdown outcomes between the two groups. Providing additional context on the clinical implications of this finding could enhance the depth of the discussion.\n\nExploration of SDF Mechanism: While the discussion mentions the unique mechanism of action of SDF, a more in-depth exploration of how this mechanism contributes to its effectiveness in managing MIH-affected molars would add valuable insights.\n\nRecommendation\nThis paper is a well-executed study that significantly contributes to the understanding of preventive measures for MIH in children. The rigorous methodology, clear objectives, and integration of existing literature enhance the credibility of the research. With minor enhancements in the discussion section for further clarification and depth, the article is suitable for publication, offering valuable insights for both clinicians and researchers in pediatric dentistry.\nI recommend the acceptance and subsequent indexing of this article.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-1052
|
https://f1000research.com/articles/12-474/v1
|
09 May 23
|
{
"type": "Research Article",
"title": "Traumatic spinal spondyloptosis presenting in a tertiary care unit in central Nepal",
"authors": [
"Sunil Munakomi"
],
"abstract": "Introduction: Traumatic spinal spondyloptosis, though rare, harbingers a high risk of mortality as well as permanent and disabling neurological deficits. They invariably become socially aloof and marginalized in most parts of our subcontinent owing to the lack of dedicated rehabilitation units amid their poor economic status. There is a paucity of studies pertaining to such rare epiphenomenon within our region. Materials and Methods: A study of 16 patients presenting with spinal spondyloptosis from January 2017 to January 2023 in a tertiary care center in Nepal was undertaken. The clinical records of the patients were retrieved from the hospital record section to study the demographic variables, modes of injury, American Spinal Injury Association (ASIA) grades, salient radiological characteristics, management strategies, and the resultant clinical outcomes. Result: The mean age of the cohorts in our study was 40 years with an age range of 25-80 years. Most of the patients presented in ASIA ‘A’ neurological grade (75%). The cervical spine was involved in the majority (68.75%) of cases. 8 (50%) patients left against medical advice, 2 (12.5%) were managed conservatively, and 6 (37.5%) were operated. The posterior-only approach was undertaken in 4(66.67%) cases. Tracheo-oesophageal fistula occurred in 2 (33.33%) patients. And cerebrospinal fluid (CSF) leak occurred in 2 (33.33%) patients. The overall hospital mortality was 3(37.5%). All the surviving patients were of the ASIA ‘E’ grades. Conclusion: There is a continuum of physical, economic, psychological, and social burdens to both the patients and their care providers. Rehabilitation is the ‘bottleneck’ variable governing poor outcomes in our subcontinents. The poor economic status of the people has a ripple effect upon the same. This should also aid in the patient counseling as well as fostering the notion of the paramount need for dedicated neuro-rehabilitation units in our regions.",
"keywords": [
"spondyloptosis",
"presentation",
"management",
"outcome"
],
"content": "Introduction\n\nTraumatic spinal spondyloptosis is a rare entity compromising only 1% of all traumatic spinal injuries.1 There is more than 100% subluxation between the adjacent vertebral bodies.2 This harbingers a high risk of mortality as well as permanent and disabling neurological deficits among the survivors owing to complete cord transection.2 The survivors are compelled to be dependent on others for lifelong even for carrying out their activities of daily living (ADLs). They invariably become socially aloof and marginalized in most parts of our subcontinent owing to the lack of dedicated rehabilitation units amid their poor economic status.2 Since the majority of these cohorts present with poor American Spinal Injury Association (ASIA) neurological grades, the surgical dictum mostly involves anatomical fixation to assist in their early rehabilitative strategies. The 360 degrees global (combined anterior and posterior approaches) are recommended only in rare circumstances for patients presenting with good ASIA neurological grades.2,3\n\nThe largest case series pertaining to this entity in the current literature has a sample size of only 20 patients.2 There is a paucity of studies pertaining to such rare epiphenomenon within our region. This study should provide insights to help frame the management algorithm among similar cohorts of patients. This will also aid in the process of patient counseling as well as foster the notion of the paramount need for dedicated neuro-rehabilitation units in our regions.\n\n\nMethods\n\nA descriptive study of consecutive cohorts of patients presenting with spinal spondyloptosis from January 2017 to January 2023 in the Emergency Department of the College of Medical Sciences was undertaken. Spondyloptosis was defined on radiological imaging (X-ray/CT/MRI) of the spine as >100% subluxation between the adjacent vertebra. The images of spondyloptosis at different levels of the spine have been demonstrated in Figure 1.\n\nThe clinical records of the patients were retrieved from the hospital record section to study the demographic variables, modes of injury, American Spinal Injury Association (ASIA) grades, salient radiological characteristics, management strategies, and the resultant clinical outcomes.\n\nInclusion criteria: Consecutive patients presenting with traumatic spinal spondyloptosis in the Department of Neurosurgery, College of Medical Sciences, Chitwan, Nepal.\n\nExclusion criteria:\n\n• Lack of consent for participation.\n\n• Left-against medical advice.\n\n• Lost to follow-up, and\n\n• Operated on in other spinal centers.\n\nThe sample size for the study was calculated by:\n\nn = minimum required sample size\n\nz = 1.96 at 95% Confidence interval (CI)\n\np = reported incidence of spondyloptosis (p) at 1%\n\nq = 1-p, and\n\nd = margin of error at 5%.\n\nThe sample size of the study was 16 patients.\n\nThe data collected was collected and descriptive statistics were applied using the Microsoft Excel spreadsheets. The frequency distribution charts were obtained in terms of counts and percentages for each relevant variable.\n\nBoth verbal and written consent was obtained either from the patients or the next of kin for participation in the study. All their clinical and radiological data are anonymously presented in the study. The study was approved by the institutional ethical review committee of College of Medical Sciences and Teaching Hospital (IRC–COMSTH-IRC/2023-08). This study was conducted from 3rd March 2023 to 21st March 2023.\n\n\nResults\n\nThe mean age of the cohorts in our study was 40 years with an age range of 25-80 years. There was a male preponderance with a male: female ratio of 15:1. Spondyloptosis was secondary to road traffic accidents in nine (56.25%) and fall incidents in seven (43.75%). Most of the patients presented in ASIA ‘A’ neurological grade (75%) baring one (6.25%) patient in ASIA ‘B’ and three (18.75%) cases in ASIA ‘E’ neurological grades. The cervical spine was involved in the majority (68.75%) of cases. The sagittal pattern of spondyloptosis was predominant and observed in 14 patients (87.5%).\n\nEight (50%) patients left against medical advice after understanding the poor prognosis of the entity. two (12.5%) were managed conservatively owing to a moribund state due to pulmonary complications resulting from phrenic nerve injury and lung contusions respectively. Both of them eventually expired, six (37.5%) were operated. The posterior-only approach was undertaken in 4(66.67%) cases. Anterior only and global approach was undertaken in one (16.67%) cases each. Tracheo-oesophageal fistula occurred in two (33.33%) patients. One healed after one month of conservative management with nasogastric tube feeding. The other patient expired secondary to severe mediastinitis. Cerebrospinal fluid (CSF) leak occurred in two (33.33%) patients.\n\nNo clinical improvements were observed in patients presenting with ASIA ‘A’ neurological grades.\n\nThe overall hospital mortality was three (37.5%). The operative mortality was one (16.67%). Post-discharge, two (40%) patients eventually expired secondary to sepsis. All the surviving patients were of the ASIA ‘E’ grades.\n\nThe results of our study have been summarized in Tables 1 and 2.\n\n\nDiscussion\n\nMost of the studies in the current literature are limited to mere case reports.4 There is complete subluxation of one vertebral body over the adjacent involving all three Denis spinal columns.2–4 The spinal cord is invariably damaged resulting in permanent and disabling neurological deficits among the survivors. There are also increased odds of mortality owing to the risk of associated polytrauma and complications in these cohorts. The long-term prognosis is however abysmal owing to suboptimal home-based care and liberal assess to rehabilitation facilities.2 However, early stabilization promotes timely rehabilitative strategies in these cohorts. The dictum of the surgery is anatomical realignment, fixation for stability, and neural decompression.4 Complete reduction may not be possible despite distraction and corpectomy.2\n\nIn the largest series comprising 20 patients, the mean age of the cohorts was 27 years with a male: female ratio of 17:3.2 The systematic review of cervical spondyloptosis also had a male preponderance of 70% with a mean age of 41 years.5 The mean age of the cohorts in our study was 40 years and the male: female ratio was of 15:1.The most common level of involvement was at T10-L2 (55%), a mechanical transitional zone.2 Ironically, there was no involvement of the cervical spine in the series, the region of maximum involvement in our study (68.5%). The study pertaining to cervical spondyloptosis had the involvement of the lower cervical spine (C6-C7 and C7-T1) in 68% of cases.5 The same levels were involved in 45.45% of our study. This may be owing to the higher load with compromised mobility in the region.5 All the cases presented with ASIA ‘A’ grade in the largest study and therefore were managed by short segment pedicle screw fixation in the series.2 Paradoxically, three of our cases presented with ASIA ‘E’, and one patient presented with ASIA ‘B’ neurological grades. Similarly, the study relating to cervical spondyloptosis also had 21/66 (31.81%) cases presenting with ASIA ‘E’ grades.5 Since we had the majority of cases with involvement of the cervical spine, anterior cervical approaches, either standalone or combined, were also adopted. Complete cord transection in observed in 35% and CSF leak in 20% of cases in the study. We had CSF leaks in 33.33% of cases. The risk of CSF leak may be prevented by ligation of the thecal sac, fibrin glue sealant, and multi-layered wound closure.2\n\nThere are also high chances (40%) of clinical improvement among patients with cervical spondyloptosis.5 There however increased odds of esophageal laceration and vocal cord paralysis during the surgical strategies of the same.5 Tracheo-oesophageal fistula occurred in two (33.33%) patients in our study.\n\nThe reported mortality in the systematic review of cervical spondyloptosis was 11%.5 The same in our study was 16.67%.\n\nThere is a continuum of physical, economic, psychological, and social burdens to both the patients and their care providers.2 The impact of the disease is even more significant in middle and low-income nations. The main cause of mortality during the follow-up visits, mostly secondary to complications of bed sores, has been observed in 25% of patients. Rehabilitation plays a paramount role in the long-term outcomes in these cohorts and is the ‘bottleneck’ variable governing poor outcomes in our subcontinents. The poor economic status of the people has a ripple effect upon the same.2 This is the same reason for almost 50% of our cases leaving against medical advice from our hospital.\n\nThis being a single-center study, the true incidence of the traumatic spondyloptosis may not be reflected in our single-center data. This being a rare clinical entity, a low sample size is a limiting factor of the study. Recall bias is another confounding issue.\n\n\nConclusion\n\nThis study provides insights into the patterns of clinical presentations, radiological characteristics, management strategies, and outcome details of cohorts presenting with traumatic spinal spondyloptosis. This will help formulate management strategies and foster rational counseling. This is one of the first pilot studies to be carried out in the country relating to this rare traumatic spinal entity. This study emphasizes the implementation of a national spinal trauma data bank and the systematic implementation of dedicated neuro-rehabilitation units. This will thereby help improve the clinical outcome among these ‘socially aloof’ and marginalized subsets of neurosurgical patients.",
"appendix": "Data availability\n\nFigshare: Traumatic spinal spondyloptosis presenting in a tertiary care unit in central Nepal Item. https://doi.org/10.6084/m9.figshare.22359802.v3. 6\n\nThis project contains the following data:\n\n- The data of 16 patients presenting with spondyloptosis in our center.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nGarg M, Kumar A, Sawarkar DP, et al.: Management of Pediatric and Adolescent Traumatic Thoracolumbar Spondyloptosis. Neurol. India. 2022; 70(Suppl S2): 182–188.\n\nMishra A, Agrawal D, Gupta D, et al.: Traumatic spondyloptosis: a series of 20 patients. J. Neurosurg. Spine. 2015 Jun; 22(6): 647–652. Epub 2015 Mar 13. PubMed Abstract | Publisher Full Text\n\nMunakomi S, Bhattarai B, Cherian I: Traumatic Cervical Spondyloptosis in a Neurologically Stable Patient: A Therapeutic Challenge. Case Rep. Crit. Care. 2015; 2015: 540913–540919. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSakti YM, Anzhari S, Kartika A, et al.: Neglected cervical spondyloptosis of the 5TH - 6TH cervical spine following cervical manipulation: A case report. Int. J. Surg. Case Rep. 2022 May; 94: 106984. Epub 2022 Mar 30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhelifa A, Berchiche L, Aichaoui F, et al.: Traumatic cervical spine spondyloptosis: A systematic review. J. Craniovertebr. Junction Spine. 2022 Jan-Mar; 13(1): 9–16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSunil MK: Traumatic spinal spondyloptosis presenting in a tertiary care unit in central Nepal Item. figshare. Dataset. 2023. Publisher Full Text"
}
|
[
{
"id": "172993",
"date": "20 Dec 2023",
"name": "Bidur KC",
"expertise": [
"Reviewer Expertise Neurosurgery"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the material and methods of abstract section, type of study should be mentioned.\n\nIn the result part of abstract section, last paragraph all the surviving patients were of ASIA grade E should be omitted, because this sentence gives a false sense of good prognosis after treatment in patients with spondyloptosis.\n\nConclusion part of abstract section, it is not according to the objective of the study and results of the study.\n\nIn method section of manuscript, retrospective type of study should be mentioned. Looks like there is a methodological flaw because ethical review committee has approved the study in 2023, sample was taken from January 2017 and in methodology it was written that data were taken from the hospital record section and later part it was mentioned that author has taken verbal and written consent.\n\nIn the result section of manuscript, as exclusion criteria has mentioned to exclude those patients who went on leave against medical advice but in the data, 8 patient who left against medical advice were also included. So actual study of remaining 8 patients should have been included in the results to match the objective of the study. In the last paragraph instead of writing all surviving patients were of ASIA E grades, mention the exact number of patients because this sentence giving a false sense of good prognosis after treatment in patients with spondyloptosis.\n\nDiscussion part of manuscript is slightly short, should have been elaborative.\n\nConclusion should be drawn according to the results of manuscript. Must be rewritten.\n\nToo few number of references included. If the author make the discussion part elaborative then references will also increase in number.\n\nThis study is retrospective in nature with only 8 patients available for analysis of final results.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/12-474
|
https://f1000research.com/articles/12-1291/v1
|
09 Oct 23
|
{
"type": "Systematic Review",
"title": "Sample size in educational research: A rapid synthesis",
"authors": [
"Smruti Besekar",
"Sangita Jogdand",
"Waqar Naqvi",
"Sangita Jogdand",
"Waqar Naqvi"
],
"abstract": "Background: By conducting an in-depth study of the publications, a review was conducted with the goal of evaluating the sample size in educational research. The sample size, represented by the letter “n,” is a key factor in this research because it specifies the number of participants who represent the target population. Although various studies have been published in the literature defining the processes for calculating sample sizes, there is still much uncertainty. It is vital to understand that there is no single all-encompassing method for determining sample sizes for different study designs. Instead, different study designs call for different approaches to determine sample numbers.\n\nMethods: Information was retrieved from the databases in accordance with updated PRISMA recommendations. The keywords used for the retrieval of the relevant articles from two databases (Google Scholar and PubMed). The articles were selected by thorough scrutiny and application of inclusion and exclusion criteria.\n\nResults: Seven articles were selected from the 9282 articles. The comparison was made among the studies in the relation to methods, objective, and outcome from the enrolled studies.\n\nConclusions: The evaluation of the seven studies as a whole concluded that the sample size for testing any novel approach essentially required 24.24 participants in each group. The median sample size for the simulation-based educational research was 30. Further research is required to determine the proper sample size based on a single universal formula for all types of designs.",
"keywords": [
"sample size",
"rapid review",
"study design",
"educational research"
],
"content": "Introduction\n\nThe term “sample size” describes the number of subjects or observations that make up a study ‘n’ is typically used to represent this number. The size of a sample affects two statistical properties:1) the accuracy of estimates and 2) the study's ability to draw inferences.1\n\nSurveys, experiments, observational studies, and other types of clinical research studies can all be categorized. Many different factors are involved in excellent research planning. The first step is to define the practical issue. Choosing the relevant participants and controls, as well as the experimental or observational units, was the second stage.\n\nThe inclusion and exclusion criteria must be carefully defined and should account for any potential variables that could affect the measurements and units being observed. The study design must be precise, and the procedures must follow the best technique currently available. Based on these considerations, the study's sample size needs to be appropriate for its goals and potential variability. The sample must be “large enough” for the effect to be statistically significant and have the expected size of scientific significance. At the same time, it is crucial that the study sample not be “too big,” where a statistically significant effect of minor scientific import could still be found.2 Additionally, the sample size was economically significant. Resources may be wasted in an insufficient study because it may not yield valuable results, whereas an excessively large study consumes more resources than is required. The sample size of a study involving human or animal subjects is a crucial ethical concern, because a poorly planned experiment exposes participants to potentially hazardous procedures without contributing to information.3,4 Therefore, calculating the power and sample size is crucial in the design of clinical research. Unaccountable studies printed in national and intercontinental journals have found that sample size estimation were incorrectly disclosed or had smaller samples than necessary, which reduced their power.1,2\n\nThere is still much confusion despite the fact that unnumbered studies clarifying the methods of sample size computation have been published in the existing literature. It is crucial to realize that there is no single universal formula for calculating the sample sizes for all study designs. Instead, different study designs require different methods to calculate sample sizes.3,4 The study was conducted with the aim of assessing the sample size in educational research.\n\n\nMethod\n\nTo conduct this rapid review, Preferred Reporting Items for Systematic review and meta-analysis (PRISMA-S) criteria were used to guide the search.5 Using the BOOLEAN AND operator, researchers searched databases like PubMed, Embase, and the Cochrane Library for publications containing the keywords “Sample Size” AND “Educational research.” Free full-text, unlocked articles, pertinent terminology and information, and English language usage were required for inclusion. The exclusion criterion was considered and they included abstracts, locked articles and journals, no relevance in the data, and languages other than English. The principal investigator carried out the entire review planning process, which was authorized by the investigator. The presentation of the entire search is shown in Figure 1.\n\n\nResults\n\nSeven studies were selected from the 9282 articles by using Google Scholar and PubMed with the applicable of stringent inclusion and exclusion criteria. All the information related to the articles were shown in the Table 1.\n\n\n\n1- Clearly state aim of the study followed by the objectives.\n\n2- To choose the appropriate study design for meeting the objectives.\n\n3- Define target population.\n\n4- Use statistical/sampling technique.\n\n5- Decide data collection tools\n\n6- Perform appropriate statistical analysis.\n\n7- Communicate results and interpretation using tables and figures.\n\n\nDiscussion\n\nResearch in health science education is expanding. Emerging educational research relies on relevant conceptual frameworks, reliable research techniques, and important discoveries.13,14 Prior reviews have shown that many educational research articles employ small sample sizes, despite the fact that researchers rarely take into account the expected impact size, intend the sample size before, or describe the actual precision in evaluating the results.15,16 Although authors rarely analyse the anticipated influence size, arrange the sample group in detail, or analyse the results from the perspective of actual precision.9\n\nAccording to the definition of statistical power, it is “the likelihood that the null hypothesis will be rejected in the sample if the observed effect in the population is equal to the effect size”.17 In other words, the potential that a study will uncover a real, statistically significant effect is known as power. Studies with a higher power are preferable because lower-power studies may miss potentially important connections. A power of 90% is ideal and 80% is typically considered the minimum power. The sample size (the number of observations), the effect size (the value of the effect), and the risk of type I errors all affect power (the likelihood of recognising a “significant” difference when there is none, represented by alpha).9,18\n\nThe study adopted a convenience sampling method for primary research for determination of sample size in education by examination of simulation-based education. First, most research in the sample only had the power to find effects with moderate to large SMD [0.8], while other studies only had the power to find effects with immensely large magnitudes ([2 standard deviations). Most of the negative studies, or those that did not find a statistically relevant difference, had very broad confidence intervals (CI), signifying the probability of large and likely important differences. The first point and discovery were connected. In these trials, the lack of a statistically relevant outcome did not establish superiority or equivalence of the interventions under study.9\n\nIn one study, the author aimed to present sample size calculations in the context of medical educational interventions and focused on computing sample sizes to compare distinct groups where the result was a continuous (interval or ratio) dependent variable, such as in interventional designs. The criteria for forecasting the sample group, such as the relevance factor, preferred statistical significance, predicted difference in score, and approximate evaluation variation, which may be estimated from previous studies, were discussed in order to determine the number of participants required to assess the effects of an intervention on a specific outcome or the association between variables.6,19 Interventions in education frequently concentrate on changing latent conceptions, which are theoretical and cannot be readily seen or quantified. This causes the validated scales to vary, changing how the outcome measures are calculated. The educational researcher advocated the use of effect size in determining the sample size. The study design often affects the relationship between larger effect sizes and smaller sample sizes. This resulted in the effect sizes being categorized as “small,” “medium,” and “large,” respectively, for values of 0.20, 0.50, and 0.80.20 Finally, the meta-analysis revealed that the sample size for each group was 24.24 respectively.21,22\n\nFurther, author’s also discussed errors to avoid, including considering sample size estimation as small, medium, or large, which leads to a failure in the accuracy of the evaluation tool and sample characteristics.23 Second, unless necessary, researchers should avoid creating new institute-specific assessment instruments. This is because they must be validated for accuracy and reliability before use in interventional studies.24 Third, the prospective dropout and attrition rates must be considered.25Finally, the need to avoid equating the effect size with its true significance and employing a confidence interval that offered accuracy in the sample and effect sizes.6\n\nThe objective of the report was to establish the optimal number of subjects for a study during the planning stage, with sufficient patients to resolve the most clinically important questions and statistical power calculations. The evaluation of the sample size that must be randomised to each arm in order to achieve the standard 80% or 90% power to find a clinically meaningful effect in randomised controlled trials, which frequently use parallel group designs. The need for a control arm, statistical comparability, structural equality, and resemblance of management conditions and observations are among the themes that the author elaborated on as being essential for educational research investigations. If an academic research study exhibits these traits, hence the test arm's success is significantly greater than that of the control arm, and the distinctness cannot be the result of concurrence. The cluster randomization was usually performed for non-therapeutic intervention such as prevention program, healthcare program and training programs. Two to thousands of individuals were found in each cluster. Education research may also consider different cluster sizes.8\n\nMinimizing or reducing contamination bias is the fundamental reason for performing cluster-randomized studies. Observations inside clusters are typically more comparable to one another than observations from distinct clusters, creating a unique data structure known as a statistical dependency. The effective sample size of a cluster-randomized study is less than the concrete sample size, which has an impact on sample size computation (i.e., the number of enrolled students). Consequently, it is inappropriate to use typical methods that presume the statistical competence of all observations to rule out the sample size for cluster-randomized investigations.8\n\nThe purpose of the study, which was conducted by paediatric surgeons, was to disseminate a method for selecting a sample size to identify an effect that would have therapeutic significance through the interpretation and validation of the findings. Using a five-step approach, it is possible to calculate the minimum sample size necessary to ensure sufficient power and accurate interpretation of the study's findings.7 The sample size that can be achieved to assess a significant effect on the basis of research or primary data must be justified using the power calculation. The research sample size should have adequate statistical power to identify clinically meaningful effects in scientific investigations.7,26 The sample size of the prior control group determined the statistical power. To compare the two groups effectively, comparisons must be made with a historical control group that is comparable to the research group, for which data on assessed confounders are available. The suggested 5-step approach can be used with any type of data or study design, although power and sample size primers do not provide examples for every possible research circumstance. The fundamental objective of the primers was to compare the two treatment groups. However, due to multiplicity and multiple testing, there is a higher risk of false-positive results (Type I error) when comparing more than two groups.27,28\n\nGuo et al. used two different types of hypotheses, taking into account sample size planning factors such superiority/non-inferiority and equivalence of two means. When population variances are unknown, no exact sample can be found through traditional sample size formula and resulting sample size must be suitable enough to meet the required level of significance and probability of correct decision and power. The cost constraint depends on the two experimental goals for given level of αand power 1-β i.e. allocation of having minimal total cost and ratios are a function of unit cost ration and standard deviations.12\n\nHistorically, three methods have been employed to determine the sample size. The first is an interval strategy, where the confidence interval is high (e.g., 95%) and the sampling error between the true parameter and its estimate is kept to a present modest amount, that is, 3 percent. Since there is no hypothesis testing involved in this method, no threshold of significance is required. The second is a hypothesis-related approach in which both the null and alternative hypotheses must be precisely specified beforehand to detect a significant difference between the parameters under study while simultaneously meeting the required level of significance (Type I error rate) and the desired power (probability of correctly accepting the specified alternative). The third strategy uses a “indifference zone,” where populations that perform better than the others are placed in a zone where they are more likely to be chosen correctly.29\n\nA “priori\" literally translates from Latin as “what comes before” and they are a fundamental part of the scientific method since they are created based on assumptions.30 From these assumptions, three hypotheses were inferred. With reference to objective methodologies, the aim of this systematic review was to offer proof for a priori hypotheses and sample size for evaluating the quantity and duration of physical activity in a pediatric population. The results of systematic review suggest that the degree of agreement between subjective and objective measures for determining the intensity and duration of physical exercise should be assumed modest to moderate.11\n\nCurrently, there are no data to support an a priori assumption regarding how well the different methods of assessment agree. To select a sample size, attain precision, or have sufficient power to reject a false null hypothesis, a robust a priori hypothesis is necessary. Cost and feasibility, which are frequently the true drivers of the sample size, cannot be disregarded by researchers. Nonetheless, typical power calculations yield only specific sample sizes by making precise assumptions. This study’s results indicate that, for assessing nearly all physical activity, intensity and duration parameters, a sample size of 50–90 subjects offers constant agreement between subjective and objective approaches. The degree of uniformity displayed in each (often non-representative) sample studied, the accuracy of the subjective method created for a target sample, and the inadequacy of the correlation coefficient for detecting agreement issues are all potential explanations for stable agreement in this sample size interval. Additionally, studies with small samples showed higher levels of variability in the range of findings, perhaps as a result of the inferior design of these studies to those with larger samples.31\n\nThe “vibration of effects” diminishes the reliability of the consensus measures in samples with less than 50 respondents. The study predicts that the basis for the decreased reliability of the agreement measures in studies with samples of 100 or more persons is that the researchers' attempts to ignore the occurrence of an exaggerated effect in a small-sample trial when a finding is made is the primary factor.32 The superiority in methodology systematic evaluations addressing the agreement between subjective and objective measures for assessing physical activity has frequently found low methodological quality in the studies.32–35\n\nThe COSMIN checklist, which was employed in the cited study, identified the absence of an a priori hypothesis and small sample size (n = 50) as the primary factors affecting the methodological standard of the redeemed studies. These factors were obeyed by a lack of data regarding subjects who were missing and the way in which missing data were handled. The author disapproved with questionnaires, diaries, and/or logs those received low ratings in methodological quality evaluations are ineffective tools for gathering subjective data.32\n\nThe sample size was depended upon the degree of heterogeneity, if the analysis was performed by multiple investigators and teams. Moreover, studies with limited data showed higher levels of variability in the range of findings, perhaps as a result of the inferior design of these studies to those with larger samples.33,34\n\nA statistician is essential to rule out the number of subjects and analyse the final results of the entire investigation. To perform a suitable well-defined study that produces rational and trustworthy implications that can be applied to the sample population, it is crucial for the investigator to understand the fundamentals of analytical methods. Clinicians can use statistics to extract crucial information from empirical data, which improves patient care. Statistical notions must be considered from the initial planning stage to the final reporting phase. In general, there are two sorts of sample size estimation problems: sample size for (a) an estimating study and (b) to tests a hypothesis, or a comparison study.10\n\nWhen performing an estimation study, the researcher was interested in estimating the quantity of one or more parameters, including, among other parameters, the mean haemoglobin level or arthritis prevalence. Researchers were interested in comparing population characteristics at one or more time points or characteristics of two or more populations in studies that test hypotheses. For instance, they might compare the prevalence of arthritis between two populations before and after the administration of an intervention. A researcher should select a large number of people if they wanted the estimation in their study to be more precise, because as the accuracy (or margin of error) grows (or lowers), the minimum sample size necessary increases. For instance, for a sample size greater than that preferred for a 95% confidence level, that estimate of a parameter is required. The computation of sample size in studies testing hypotheses aims to obtain the appealed power for disclosing a difference that is therapeutically or experimental significant at a predetermined significance level.35\n\nAccording to the statistics, there are various methods, test and formula for estimation of the sample size required to perform the research and other relevant studies. But the lack of research regarding the appropriate and whole number needed for performing any research is not established yet, like pilot study confirms the 12 participants for each group enrolling for the particular trial.36\n\n\nConclusion\n\nThe review suggested that the sample size should be considered as soon as possible throughout the research phase to gather more insightful background that will fundamentally have a stronger influence on pedagogic application. All types of research investigations require the determination of sample size, and selecting the appropriate formula is essential. According to the study's main goal, outcome variable, study plan, intended statistical investigation, study groups, and assorting procedure to be utilized, a suitable sample size formula was chosen. The sample population needed for a study is determined by a variety of variables, including the feasibility of the study, its power, the accuracy of the calculated value, its analytical relevance and confidence level, its ability to detect a clinically significant difference, and other factors, such as financial support, workforce, subject availability, and time. Studies involving cluster randomization require a larger sample size and a complex method for calculations. The sample size for conducting any new method basically required 24.24 members in each group. The median sample size for the simulation-based educational research was 30. Further, more research is needed for the appropriate sample size and universal single formula based on every study design.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nJaykaran, Saxena D, Yadav P, et al.: Negative studies published in medical journals of India do not give sufficient information regarding power/sample size calculation and confidence interval. J. Postgrad. Med. Apr 2011; 57(2): 176. Publisher Full Text\n\nJaykaran C, Yadav P, Kantharia N: Reporting of sample size and power in negative clinical trials published in Indian medical journals. J. Pharm. July 2011; 2: 87. Publisher Full Text\n\nNaduvilath TJ, John RK, Dandona L: Sample size for ophthalmology studies. Indian J. Ophthalmol. September 2000; 48(3): 245–250. PubMed Abstract\n\nPatra P: Sample size in clinical research, the number we need. Semantic Scholar.2012. Reference Source\n\nPage M, Bautron I, Shamseer L, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. The BMJ. 2021; 372. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcConnell MM, Monteiro S, Bryson GL: Sample size calculations for educational interventions: principles and methods. Can. J. Anesth Can Anesth. 2019; 66(8): 864–873. PubMed Abstract | Publisher Full Text\n\nStaffa SJ, Zurakowski D: Statistical power and sample size calculations: A primer for pediatric surgeons. J. Pediatr. Surg. 2020; 55(7): 1173–1179. PubMed Abstract | Publisher Full Text\n\nDreyhaupt J, Mayer B, Keis O, et al.: Cluster-randomized Studies in Educational Research: Principles and Methodological Aspects. GMS. J. Med. Educ. 2017; 34(2): Doc26. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGot power? A systematic review of sample size adequacy in health professions education research|SpringerLink.May 13,2014. Accessed November 30, 2022. Publisher Full Text\n\nAgnihotram DG: Standard statistical methods and calculation of sample size in Medical education research. Perspectives in medical research. 2018; 6(1): 3–6. Reference Source\n\nNascimento-Ferreira MV, De Moraes ACF, Toazza Oliveira PV, et al.: Assessment of physical activity intensity and duration in the paediatric population: evidence to support an a priori hypothesis and sample size in the agreement between subjective and objective methods. Obes. Rev. Off. J. Int. Assoc. Study Obes. 2018; 19(6): 810–824. PubMed Abstract | Publisher Full Text\n\nGuo JH, Chen HJ, Luh WM: Sample size planning with the cost constraint for testing superiority and equivalence of two independent groups: Sample size planning. Br. J. Math. Stat. Psychol. 2011; 64(3): 439–461. PubMed Abstract | Publisher Full Text\n\nIssenberg SB, McGaghie WC, Petrusa ER, et al.: Features and uses of high-fidelity medical simulations that lead to effective learning: a BEME systematic review. Med. Teach. 2005; 27(1): 10–28. PubMed Abstract | Publisher Full Text\n\nLineberry M, Walwanis M, Reni J: Comparative research on training simulators in emergency medicine: a methodological review. Simul. Healthc. J. Soc. Simul. Healthc. 2013; 8(4): 253–261. Publisher Full Text\n\nCook DA: If you teach them, they will learn: why medical education needs comparative effectiveness research. Adv. Health Sci. Educ. Theory Pract. 2012; 17(3): 305–310. Publisher Full Text\n\nMichalczyk AE, Lewis LA: Significance alone is not enough. J. Med. Educ. 1980; 55(10): 834–838. Publisher Full Text\n\nHulley SB: Designing Clinical Research. 3rd ed.Lippincott Williams & Wilkins; 2007.\n\nHoenig JM, Heisey DM: The Abuse of Power: The Pervasive Fallacy of Power Calculations for Data Analysis. Am. Stat. 2001; 55(1): 19–24. Publisher Full Text\n\nNoordzij M, Tripepi G, Dekker FW, et al.: Sample size calculations: basic principles and common pitfalls. Nephrol. Dial. Transplant Off. Publ. Eur. Dial. Transpl. Assoc - Eur. Ren Assoc. 2010; 25(5): 1388–1393. Publisher Full Text\n\nStatistical Power Analysis for the Behavioral Sciences|Jacob Cohen|1987|Accessed November 25, 2022. http\n\nAdesope OO, Trevisan DA, Sundararajan N: Rethinking the Use of Tests: A Meta-Analysis of Practice Testing.2017. Accessed November 25, 2022. Publisher Full Text\n\nLehr R: Sixteen S-squared over D-squared: A relation for crude sample size estimates. Stat. Med. 1992; 11(8): 1099–1102. Publisher Full Text\n\nUsing Effect Size—or Why the P Value Is Not Enough. J. Grad. Med. Educ. 8(3): 279–282. Accessed November 25, 2022.Publisher Full Text Reference Source\n\nBlanchard RD, Artino AR Jr, Visintainer PF: Applying Clinical Research Skills to Conduct Education Research: Important Recommendations for Success. J. Grad. Med. Educ. 2014; 6(4): 619–622. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilkinson L: Statistical methods in psychology journals: Guidelines and explanations. Am. Psychol. 1999; 54: 594–604. Publisher Full Text\n\nViele K, Berry S, Neuenschwander B, et al.: Use of historical control data for assessing treatment effects in clinical trials. Pharm. Stat. 2014; 13(1): 41–54. Publisher Full Text\n\nBender R, Lange S: Adjusting for multiple testing—when and how?. J. Clin. Epidemiol. 2001; 54(4): 343–349. PubMed Abstract | Publisher Full Text\n\nAlthouse AD: Adjust for Multiple Comparisons? It’s Not That Simple. Ann. Thorac. Surg. 2016; 101(5): 1644–1645. PubMed Abstract | Publisher Full Text\n\nGupta SS, Panchapakesan S: Multiple Decision Procedures: Theory and Methodology of Selecting and Ranking Populations. Society for Industrial and Applied Mathematics; 2002.\n\nWriter S: What Is a Priori Hypothesis? Published August 4, 2015. Accessed December 2, 2022. Reference SourceReference Source\n\nHobart JC, Cano SJ, Warner TT, et al.: What sample sizes for reliability and validity studies in neurology? J. Neurol. 2012; 259(12): 2681–2694. Publisher Full Text\n\nThompson D, Peacock O, Western M, et al.: Multidimensional physical activity: an opportunity, not a problem. Exerc. Sport Sci. Rev. 2015; 43(2): 67–74. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBabic MJ, Morgan PJ, Plotnikoff RC, et al.: Physical activity and physical self-concept in youth: systematic review and meta-analysis. Sports Med. Auckl. NZ. 2014; 44(11): 1589–1601. PubMed Abstract | Publisher Full Text\n\nBrooke HL, Corder K, Atkin AJ, et al.: A systematic literature review with meta-analyses of within- and between-day differences in objectively measured physical activity in school-aged children. Sports Med. Auckl. NZ. 2014; 44(10): 1427–1438. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChow SC, Shao J, Wang H, et al.: Sample Size Calculations in Clinical Research. 3rd ed.Chapman and Hall/CRC; 2017. Publisher Full Text\n\nJulious SA: Sample size of 12 per group rule of thumb for a pilot study. Pharm. Stat. 2005; 4(4): 287–291. Publisher Full Text"
}
|
[
{
"id": "232933",
"date": "05 Feb 2024",
"name": "Francesco Innocenti",
"expertise": [
"Reviewer Expertise Statistics"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe general impression is that this paper is a collection of sentences about sample size calculations taken from different sources, assembled without a clear structure. The authors stated at the end of the introduction that \"the study was conducted with the aim of assessing the sample size in educational research\". However, after carefully reading the paper the goal of this study remains unclear. Was the purpose to describe the best practices in sample size calculations for educational research and compare the current practices in the literature? If that was the goal, the authors should have first provided a clear and accessible description of how to determine the sample size (under the most relevant study designs) in educational research according to well-established statistical literature, and then made a comparison with the seven papers retrieved from the systematic review. However, the recommendations given in the conclusion are so general and vague to be of no practical use. For instance, the authors claimed that \"Studies involving cluster randomization require a larger sample size and a complex method for calculations.\" So, how the sample size should be computed in randomized trials, a reader could ask? Another recommendation is \"The sample size for conducting any new method basically required 24.24 members in each group.\", which seems in contradiction with the statement given a few lines before \"the sample [size] needed for a study is determined by a variety of variables, including the feasibility of the study, its power, the accuracy of the calculated value, its analytical relevance and confidence level, its ability to detect a clinically significant difference, and other factors, such as financial support, workforce, subject availability, and time.\"\n\nFurthermore, the authors correctly stated in the introduction that \"It is crucial to realize that there is no single universal formula for calculating the sample sizes for all study designs. Instead, different study designs require different methods to calculate sample sizes.\", and then contradicted this statement in the conclusion, where they claimed that \"Further, more research is needed for the appropriate sample size and universal single formula based on every study design.\".\nFor these reasons, I cannot recommend this paper for approval. Furthermore, I kindly invite the authors to read the following references that provide useful guidelines on how to determine the sample size in the social sciences.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? No\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? No",
"responses": []
},
{
"id": "238774",
"date": "16 Feb 2024",
"name": "Jorge M. Mendes",
"expertise": [
"Reviewer Expertise Epidemiology and Spatial Epidemiology",
"Bayesian modelling",
"Biostatistics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article titled \"Sample size in educational research: A rapid synthesis\" underwent a systematic review to evaluate the adequacy of sample sizes employed in educational research studies. The investigation focused on the crucial role of sample size, denoted as \"n,\" in effectively representing the target population. The article adheres to a well-structured organisation, encompassing an abstract, introduction, methodology, results, discussion, and conclusion. The English language used is of high quality, enabling clear comprehension of the study's objectives, methods, findings, and implications. The article is concise and maintains an objective tone throughout, concentrating on evidence gathered from the reviewed studies. The cited literature appears relevant and carefully chosen to support the study's rationale, methodology, and discussion of findings. The abstract follows a structured format that includes the background, methods, results, and conclusions, providing a comprehensive overview of the study. Although the abstract offers a good summary of the study, including more detail on the implications of the key findings would enhance it further.\nThe title of the article does not accurately represent its objective and content, which primarily focuses on sample size evaluation in educational research. However, a significant portion of the cited literature originates from medical research, leading to a potential bias in the study. Therefore, it is essential to rephrase the title to better reflect the article's focus. The research question is implicitly formulated through the study's objective, which is stated in the Abstract and Introduction. While the objective is sufficiently clear, it can be explicitly stated for enhanced clarity.\nThe methodology adheres to the PRISMA guidelines, indicating a systematic approach to the review process. The documentation is adequate, though the systematic review protocol can be further elaborated for increased transparency. The inclusion and exclusion criteria are appropriately documented to ensure a rigorous and transparent selection process for the studies included in the review. The procedure for identifying sources other than the searched databases has not been explicitly mentioned. This aspect can be improved by documenting additional search strategies. The data extracted from the publications are well-described, with a synthesis that provides a clear overview of the findings from the selected studies. A comparison among the studies concerning methods, objectives, and outcomes is presented in the summary table. There is no explicit mention of searching for other sources between the systematic identification and finalisation of the article. Enhancing this aspect could improve the comprehensiveness of the reviews. The concepts are articulated clearly and understandably, facilitating the reader's comprehension of the study's focus, findings, and implications. The authors performed a competent analysis of the included studies and effectively synthesised the results. However, a more comprehensive discussion on the quality of the primary research would enhance the review. The conclusion effectively summarises the findings, highlights the need for further research, and emphasises the importance of determining sample size in all study designs. In light of the thoroughness of the review, the relevance of the findings to educational research, and the minor areas for improvement identified, my decision is \"approved with minor revisions.\" The revisions should focus on revising the title, clearly stating the research question, expanding on the systematic review protocol, documenting the search for additional sources, and improving the critical appraisal of the primary research studies. By addressing these minor revisions, this article would significantly contribute to the field of educational research.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? No\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? No",
"responses": [
{
"c_id": "11106",
"date": "13 Apr 2024",
"name": "Smruti Besekar",
"role": "Author Response",
"response": "Dear reviewer, I really appreciate your valuable time and efforts. I valued your suggestions and tried to make corrections accordingly. I have revised the title, methodology section and even the research question. I hope you read it further. Thank you. Sincerely, Smruti Besekar"
}
]
}
] | 1
|
https://f1000research.com/articles/12-1291
|
https://f1000research.com/articles/13-458/v1
|
07 May 24
|
{
"type": "Research Article",
"title": "How the COVID-19 pandemic changed stakeholder engagement processes in sustainability research in the long-term",
"authors": [
"Diana Süsser",
"Amanda Schibline",
"Andrzej Ceglarz",
"Johan Lilliestam",
"Vassilis Stavrakas",
"Pia-Johanna Schweizer",
"Amanda Schibline",
"Andrzej Ceglarz",
"Johan Lilliestam",
"Vassilis Stavrakas",
"Pia-Johanna Schweizer"
],
"abstract": "Background The COVID-19 pandemic affected stakeholder engagement in sustainability research projects in many ways. But which effects appear permanent today, after the pandemic ended?\n\nMethods To address this, we interviewed researchers and stakeholders and carried out a survey among European sustainability research projects in 2022.\n\nResults We find that the pandemic years disrupted stakeholder-based research, also with lasting effects. The forced shift to online modes showed how digital engagement can bring benefits in terms of easier and more efficient stakeholder engagement, but also that important aspects are lost, particularly regarding intensity of collaboration and depth of insights. Whether to go online or stay offline depends largely on the research objective, which stakeholders to involve, and how well researchers and stakeholders already know each other. Most researchers and stakeholders want to continue online collaboration in the long term, especially those with positive online collaboration experiences from the pandemic years.\n\nConclusions The pandemic has a long-term impact on stakeholder engagement in research; online engagement cannot replace all benefit of previous in-person interactions with stakeholders, but it has led to digital innovations and expanded the engagement portfolio. Our research has provided qualitative insights into the impact of the pandemic on stakeholder engagement in various sustainability research projects and the implications for the long-term future that are relevant to researchers and funding agencies.",
"keywords": [
"COVID-19",
"stakeholder engagement",
"sustainability research",
"EU"
],
"content": "Introduction\n\nSolving sustainability problems such as the energy transition requires scientific and non-scientific understandings and a broad range of knowledge (Lawrence et al. 2022). In many research projects, such knowledge is generated together with different actors representing society. Stakeholders range from (but are not limited to) citizens to representatives of businesses and non-governmental organisations to policymakers at local and international levels, who are either affected by the research or have a particular interest in the research outcomes. Effectively engaging stakeholders in research is never an easy task due to limited availability and differing priorities, but the COVID-19 pandemic1 has added a new complexity to it.\n\nThe containment measures introduced after the outbreak of the pandemic in early spring of 2020 have impacted sustainability transitions, such as in the energy sector (Quitzow et al. 2021), and caused changes in consumptions patterns (Cohen 2020). But the pandemic has also disputed the ways how research has been carried out across different disciplines (Corbera et al. 2020; Köpsel et al. 2021; Leal Filho et al. 2020; Schwarz et al. 2020). The new COVID-19 reality has particularly influenced the way “how qualitative research is conducted on topics related to sustainability science” (Santana et al. 2021:1061). Stakeholder engagement is important to many sustainability research projects (Fazey et al. 2020; Lutz & Bergmann 2018; Mielke et al. 2016), which was particularly affected by the social distancing measures imposed (Jäger et al. 2023; Köpsel et al. 2021; Süsser et al. 2021; Tobin et al. 2020). In consequence, many activities have been cancelled, delayed, or moved online (Köpsel et al. 2021; Süsser et al. 2021).\n\nAlternations to the stakeholder engagement required appropriate preparations and considerations of different dimensions, such as: (1) technology (which online tools are available to allow the stakeholders to be actively involved); (2) modifications to methodology and agenda (elements to be adjusted depending on the features of the technology applied); (3) scheduling (in terms of a reduced time effort, but also considering possible disturbances, such as presence of children at home during working hours) (Tobin et al. 2020). However, online formats led to a reduced satisfaction of the involved stakeholders and potential exclusion of social groups (Beaunoyer et al. 2020; Köpsel et al. 2021; Santana et al. 2021; Süsser et al. 2021). The pandemic brought not only physical challenges related to social distancing measures, but also additional psychological and ethical challenges related to new stress factors caused by COVID-19-related uncertainties (Santana et al. 2021).\n\nOn the other hand, the COVID-19 pandemic can be thought of as a disrupter of current modes of doing stakeholder research, comprising opportunities for new and different forms of involving stakeholders in research (Jäger et al. 2023; Tobin et al. 2020). For example, specific methodologies as well as different engagement tools and means (such as presentations, posters, group discussions, surveys, and feasibility tools) could be adapted accordingly to fit into the online workshop formats (Jäger et al. 2023; Tobin et al. 2020). Furthermore, online engagement can help to reduce the resource use, including the involvement time (Jäger et al. 2023; Süsser et al. 2021; Tobin et al. 2020) and lead to additional, positive side effects, such as a stronger involvement of the entire research team (Jäger et al. 2023). Thus, the pandemic provided opportunities for communicating and facilitating sustainability transitions within and beyond the research sphere (Bodenheimer & Leidenberger 2020).\n\nWhile previous research has examined the short-term impacts, it is not yet certain to what extent COVID-19 triggered long-term changes in stakeholder-based research, or whether research will return to its previous business-as-usual. With this article, we follow up on our own research (Süsser et al. 2021) and that of other researchers on the impact of the COVID-19 pandemic on stakeholder engagement (Jäger et al. 2023; Köpsel et al. 2021) by examining the medium-term impact of the pandemic on sustainability research projects in the European Union (EU) and the long-term prospects for stakeholder engagement. Our main research question is: How has the COVID-19 pandemic changed stakeholder engagement processes in sustainability research in medium and long-term? First, we investigate what type of stakeholders were involved in research projects and why. Second, we examine how researchers and stakeholders retrospectively evaluate the research process carried out online and its impacts on the outcomes. Third, we examine when and why it is better to take activities online or run them as in-person events. Fourth, we explore the main perspectives from the COVID-19 ‘disruption’ on how researchers want to engage stakeholders and how stakeholders want to be engaged in future sustainability research projects.\n\nTo answer these questions, we conducted 15 interviews with researchers and stakeholders from 11 European sustainability research projects to gain a better understanding of the changes brought about by the pandemic as well as the viewpoints associated with the changes and the reasons behind them. Based on the questionnaire from our 2020 survey (Süsser et al. 2021) and the interviews of this study, we re-designed an online survey and distributed it to a larger sample of European research projects with stakeholder engagement to reveal the different impacts of COVID-19 and draw conclusions about long-term impacts of the crisis.\n\n\nMethods\n\nFrom April to October 2022, we conducted 15 interviews with 13 researchers (“R”) and 2 stakeholders (“S”) to understand how they have experienced the impact of the pandemic on the research process and outcomes, and how they would decide about future online and offline engagement. We interviewed different sustainability research projects: three on agriculture and food, two on energy, two on climate, two on marine management, one on water management, and one on material risk management. Nine projects were funded by the EU Horizon 2020 research programme, whereas the remaining two projects had other national funders, such as ministries and foundations. The authors of this article have not been involved in any of these projects. We selected the projects from which we recruited our interviewees based on three criteria: (i) a topical diversity of projects covering different sustainability topics; (ii) stakeholder engagement was an integral part of the projects; (iii) projects starting no later than January 2020 and running at least until the end of 2020. Projects that fulfil these criteria have been selected from the CORDIS data base and been contacted with an interview request. In addition, we screened for projects among the participants of two thematically related surveys in 2020 (Köpsel et al. 2021; Süsser et al. 2021)where participants indicated a high importance of stakeholder engagement and provided us with the contact details; researchers and/or coordinators from four projects agreed to be interviewed.\n\nIn autumn 2022, we conducted an online survey to explore the longer-term impacts of the pandemic on research projects and perspectives for future projects. We contacted the same projects from energy research and marine sciences that participated in our surveys in 2020 and invited other sustainability researchers to complete the survey via existing networks (incl. social media) and other project collaborations. We received responses from 26 different projects with responses from up to four researchers from a single project. This is a much lower response in comparison to the survey we conducted in 2020. Similarly, more than twice as many respondents as in 2020 started the survey but did not finish it; this can have different reasons such as that it was too long, or respondents faced technical issues. In our analysis we included only 30 completed responses (“survey_ID#”) for qualitative quotes (Figure 1). The responses came from 26 projects representing different fields; half of them from energy research, sixty-eight percent of the respondents were Horizon 2020 projects. Most projects (14) started in 2019, and end(ed) in 2023 (16 projects). The survey’s respondents had a diverse work experience in their field and various levels of experience regarding stakeholder engagement; many (about 40%) had 1-5 years of experience. Two-thirds of the respondents were men, a bit less than a third women and some preferred not to indicate their sex.\n\n\nResults\n\nThe surveyed researchers involved a range of stakeholders in their projects, as shown in Figure 2. Three-fourth of the researchers involved policymakers and governmental authorities from local to European level, and two thirds engaged business, trade, and industry, as well as civil society organisations. In the survey, researchers also named “other” stakeholders, including small- and medium-size enterprises (SMEs), institutions in the financial and insurance sections, self-employed fisheries, as well as “Friday for Future” activists.\n\nAlmost half of the respondents (45%) assessed stakeholder engagement to be crucial for the success of the project; another third saw it as quite important. The importance slightly declined from 2020 to 2022. Researchers had different motives for involving stakeholders in the research, ranging from a pure interest in disseminating research results to even assisting stakeholders in realising their own projects (Figure 3). One third of the researchers took a co-production of knowledge, or capacity building approach, aiming to, either develop the research process together, what is important in pursuing transdisciplinarity in sustainability science (cf. Mielke et al. 2016) or to directly create a change ‘on the ground’. Researchers also indicated that they involve stakeholders with the specific purpose of generating policy impact, e.g., to co-design policies, sharing learnings for policymaking, or supporting decisions. Compared to 2020, there is no notable difference in answers, except that access/collection of data was more important in the 2022 survey (50% of the projects in 2020, 70% in 2022).\n\nThe importance of stakeholder engagement for data collection purposes was elaborated by interviewees that valued the insights and perspectives from stakeholders that are often not reflected in quantitative data. One interviewee said that the “system cannot be described properly only with statistical data - also in the fishing industry” (R#5). Furthermore, a recurring theme in the interviews was to involve citizens and communities to increase their “buy-in”, or to find takers for outputs generated in the projects. The two interviewed stakeholders were motivated to participate in the affiliated research projects, because they thematically identified themselves with the topic and they wanted to share their expertise.\n\nOverall, the pandemic had a negative impact on stakeholder engagement: more than half of the surveyed researchers saw impacts as mainly negative, in both periods but with considerably more negative responses in 2020 than in 2022 (Figure 4). Main reasons were that stakeholders could not be reached during the pandemic and that engagement was not as deep as with in-person interactions. For example, one survey participant responded (free text):\n\n“[W]e could not engage as much as we wanted. It was not possible to meet with some stakeholders (mostly local level) using online tools. That was technically and culturally difficult” (survey_ID40).\n\nHowever, some projects also experienced positive impacts, or were neutrally affected from the pandemic (Figure 5). These were mainly projects that had already planned for online activities anyway, or that just started to plan their engagement activities during the pandemic:\n\n“Covid didn’t have that much impact. We did online meetings and training courses anyway” (R#9).\n\nMore than one third of the surveyed researchers had planned for online workshops and almost the same numbers for online interviews and surveys. However, most survey respondents and interviewees had planned to engage with stakeholders physically in 2020/2021 ̶ when COVID-19 lockdowns were most stringent (Figure 5).\n\nOne third of the projects experienced both positive and negative impacts (Figure 6). One survey respondent stated:\n\n“Stakeholder engagement has been negatively affected by the almost exclusively virtual events, as the important informal exchange among stakeholders is much more difficult, or even impossible. Nevertheless, online events can reach stakeholders who would not be normally reached through physical events” (survey_ID2).\n\nThis quote highlights that positive impacts were related to the scope of the stakeholders that could be reached, whereas it was not possible to deepen the engagement level.\n\nProcess\n\nThe pandemic negatively impacted the engagement of stakeholders in research processes: More than half of the survey respondents agreed that it was harder to familiarise stakeholders with the project goals/objectives and one third agreed that stakeholders had less time, or their priority had shifted away (Table 1). There was more agreement that exchange with stakeholders had become less frequent, although the received responses about online meetings varied considerably.\n\nBased on our qualitative interview analysis, we found that three dimensions were mainly affected: relationship, coping and preparation.\n\nRelationship\n\nResearchers reported that it was a challenge to establish relationships with stakeholders. Identifying stakeholders and gaining their trust was made more difficult in online engagement:\n\n“We had taken a lot of time to find people to “introduce” us. Working with fishermen is not that easy; a lot is based on trust […], but then we were prevented from going there to build a relationship of trust“ (R#5).\n\nSome projects wanted to form working or core groups of stakeholders, but many researchers struggled to achieve that.\n\nOur research confirms the first impressions after the COVID-19 pandemic started (Süsser et al. 2021) that many researchers feel a strongly negative, or somewhat negative, change in their relationship with the stakeholders since the start of the pandemic (Figure 6). The opinion about the change diverged even more, and less researchers experience no change.\n\nSome researchers reported that it was easier to keep contacts online, also in between in-person meetings, and to exchange materials. After difficulties in the first meetings, stakeholders got used to online events:\n\n“It was working very well after a short time […] It enables not to lose engagement, to keep contact, and to develop a lot of things. And everyone is realising that it is very easy to have an online workshop and that you do not even need to travel there” (R#8).\n\nFor almost two thirds of respondents it was harder to engage stakeholders online, and for them, stakeholders were less committed to online engagement formats (Figure 7). Often, participation in online events was reported as less active, i.e., many people had their cameras off, were in the listening-only mode, or were doing other things in the background. A survey participant confirmed:\n\n“Level of engagement was more passive. People with no cameras on, barely speaking. There is a big loss in comparison to the benefits of face-to-face” (survey_ID40).\n\nA researcher also admitted that “[it is] too easy to open another window, to open emails. I do it myself” (R#1). Thus, it was also easier for people to “hide” online, while in in-person meetings the “facilitator can rope them in better” (R#11).\n\nAt the same time, anonymity made it easier for people to leave during online events: breaks or shifts to breakout sessions were moments when researchers lost many attendees (R#15). One interviewee confirmed this:\n\n“If people are in the same room together, like before the pandemic, there is much more buy-in and the willingness to make a good impression when meeting in person. I think it is much easier now to hide behind a closed camera and it is hard to connect when you aren’t able to look someone in the eye. I feel if it was a physical event where people could look each other in the eye and have a handshake beforehand, there would be no issue at all” (R#1).\n\nWe also find that the participation in online events declined over time (Figure 7). While people “were more eager to meet online in the beginning, as the pandemic continued, it became more difficult” (R#9). Interviewees reported that attendance fluctuated, and it was hard to keep contact: “In general, in Corona there is a greater risk of contact being lost somewhere” (S#13).\n\nFinally, the relationships to stakeholders were negatively affected because online engagement does not provide the networking activities, informal interactions, and the potential for establishing more personal ties in equal measure. One interviewee underlined that “in-person gives connection and sympathy and understanding which is hard to create online. Humanness is critical” (R#2). However, it was not only harder to build relationships with stakeholders but also within newly formed research consortia. One researcher explained that they received often late or no responses from project partners and that “[i]f we would have been in the room together once or twice, four times, five times during the project, this just comes way more naturally” (R#1).\n\nCoping\n\nIn 2020, we found that one in six engagement activities was implemented as planned (18%) (Süsser et al. 2021) ̶ in 2022, it was one in four (Table 2). After the pandemic started, a dominating strategy was to delay the activities (45% in 2020), hoping that the situation would improve quickly. One interviewee stated that task leaders asked them to wait and delay meetings during the crisis and to meet in-person later in the year; but they did not do any in-person meeting as the pandemic continued (R#12). Similarly, one respondent emphasised the importance of meeting stakeholders at congresses; however, most congresses were cancelled in 2020 and most were even moved to 2022 (R#8). In 2022, substantially less researchers delayed activities in comparison to 2020. As one stakeholder explained: “because it was not physically possible, and we were not yet technically ready. […] In 2020, a lot of things were cancelled and in 2021, everything was more routine. We always had plan B“ (S#13).\n\nLikewise, 2020 and 2022, a minority of some (10) projects implemented the engagement activities with social distancing measures (Table 2). For example, researchers moved from larger to smaller stakeholder event sizes, or even met stakeholders outside:\n\n“We even had a face-to-face meeting at someone’s home on the veranda in the fresh air. But that only worked because that was a personal contact from previous projects. There was a great trust and openness there. That was great!” (R#6).\n\nAlso in 2022, many researchers moved activities online (Table 3). Among the coping engagement formats, online workshops and online interviews were the most common-confirming our findings from the 2020 survey. In-person engagement formats were usually directly replaced by a corresponding online format. For example, planned in person workshops were held online on various video conference platforms, often complemented by interactive tools, such as live polling or whiteboards. Additionally, interviewees reported about online capacity-building events and regional demonstration events:\n\n“We thought a lot about how to give people the experience of a farm visit that is fun and engaging. For instance, the kick-off meeting was online, so we asked people to send beforehand some pictures of them and a few fun facts about them to break the ice” (R#14).\n\nOther projects changed the engagement activity (Table 3). Webinars were less prominently chosen than in the 2020 survey, but were the main choice to replace information events, or congress visits. One interviewee explained that they had to adjust their plan:\n\n“Involvement was different. Originally, a participatory approach was planned […]. We had to make adjustments early on due to the lock-down. That means face-to-face conversations and also face-to-face interactions were more difficult and instead of workshops planned early on, we then conducted interviews (online)” (R#6).\n\nOverall, video conferencing tools became much more prominent in engaging stakeholders (Table 4), but their applications, especially at the beginning, made some stakeholders feel digitally isolated:\n\n“Everyone was digitally somewhat isolated and had to build up their infrastructure on their own - just the question of which tool to work with - with Zoom with Teams […]” (S#13).\n\nFinally, researchers also had to adapt the event length. Interviewees commonly agreed that long events do not work. One researcher explained that they tried a two-day online event, or long sessions with a break in between – as would have worked in person – but „doing an event for three or four hours wasn’t possible anymore” (R#15).\n\nPreparation\n\nMost respondents agreed that online engagement saves time and resources (Figure 6), also by avoiding travelling:\n\n“We had two consortium meetings in person before COVID and our final meeting was kept hybrid. It was an option because it didn’t make sense for people to travel. Moving forward, that is the way we should run projects. Project proposals making winter meetings online and summer meetings in person. We can do it online, cheaper, climate-relevant. It is good to be more critical and ask what is the value of in-person versus online. Taking four days off of their daily work for a project meeting is a hurdle” (R#2).\n\nSimultaneously, preparing for online engagement may require more effort:\n\n“You should over prepare when going online. Over-prepare on content, also be very aware of the timeframe. Be flexible. Take into account people’s capabilities. Be respectful of other people’s time” (R#7).\n\nOne stakeholder highlighted the capacities needed to implement online event successfully:\n\n“There are really good things that you can use to structure digital communication very well. […] I think you need certain resources, you need the (wo)men-power, the experience, to have dealt with it very intensively in advance. That is also a challenge. The preparatory work you have to put into it is already very big and you can’t underestimate that” (S#13).\n\nIn addition, conducting individual interviews was reported to be more time-consuming than the implementation of one workshop, also as “you need to repeat several times to generate the same impacts as if you would meet the people in person” (R#8). Further, it takes more time to explain complex topics online. One interviewee shared the experience that it was difficult to present complex approaches behind mathematical models online; it did not work out because they were not able to explain it, stakeholders could not engage in breakout groups (R#15).\n\nOutcomes\n\nThe pandemic also had impacts on the outcomes of the research as well as on the outcomes of the stakeholder engagement specifically.\n\nOutcomes of research\n\nAround half of the researchers reported that the outcomes are (somewhat) less good (Figure 8), while less than one third of the respondents stated that the project was carried out with the envisioned results (Figure 9). The reasons given were mainly related to the depth of the generated results:\n\n“We did mainly get superficial results, no deep ones, such as a common vision, policy recommendations, implementation plans, …” (survey_ID63).\n\nOne interviewee reported that they were able to “tick the boxes” of the Grant Agreement, but not in effective ways.\n\n“It’s doable, but it’s a difference in quality. It’s like a Michelin star meal compared to plain rice. Both will feed you, but you’d rather have the higher quality option. You can do everything online, but it isn’t as nice. I came into the project motivated to create the Michelin star meal, but it ended up bare minimum of rice. It’s de-motivating, you’re less willing to engage with project partners and stakeholders. By properly writing clear quality indicators, it might be a way to keep the motivation higher” (R#1).\n\nThe impacts of the pandemic caused projects’ extensions that became even more evident in the 2022 survey (Figure 9), with two thirds of the projects extended.\n\nNo negative impacts and even better outcomes were reported by minority of respondents, one of them mentioning about different opportunities:\n\n“Focusing on outcomes or outputs, I have to admit that the shutdown in activity due to COVID was very useful to get some writing done. While we lost out on some engagement, we were lucky that the projects were nearing their end rather than starting out. […] It gave time for reflection, something we had struggled to find before. Of course, if we hadn’t already been working together for two years, and I didn’t have two rounds of community meetings done, the impact would have been very bad” (survey_ID29).\n\nOutcomes of stakeholder engagement\n\nMost respondents agreed that online activities are less satisfying (Figure 7). Online engagement often misses ‘lively’ interactions, as one interviewee explained:\n\n“But the spontaneous, the personal, the blurting out, the creative development, the bending over a paper in a room and painting together, that’s not possible. You already have that distance digitally” (R#6).\n\nAs a result, some researchers emphasised the lower quality of data derived from online engagement:\n\n“There are a lot of tools for getting people to fill in workshop exercises online, but I find that the quality of data coming out of online engagements isn’t as good as in-person. Some people aren’t comfortable navigating the tools and it just doesn’t work as well as sitting around a table together to put down post-its or fill-in a map” (survey_ID29).\n\nIn contrast, other researchers reported better outcomes from the stakeholder engagement, which were mainly related to an increased participation and the collection of more diverse stakeholder insights. Thus, researchers could gain important insights, albeit “less representative” results (survey_ID35).\n\nFurthermore, deliverable submissions were delayed – in 2022, 70% of the survey participants reported pandemic-related delays in comparison to 30% in 2020 (Figure 8). For example, due to delays in results from stakeholder input, the results could not or only partially be considered in the project context:\n\n“Due to the COVID-related problem of talking to them (fishermen), our part was postponed and could therefore be included in the modelling too late or not deeply enough. […] Modellers could get on with their work nicely, but we couldn’t deliver a different perspective (from stakeholders) for a long time” (R#5).\n\nIn the interviews, we identified three key influence factors deciding whether to stay offline or go online: (i) intention/ purpose of the stakeholder engagement, (ii) the engaged stakeholder group, and (iii) previous relationships. As one interviewee put it: “a different target group, different topics, and different intention of the project/co-creation would need a different format, but it is hard to know” (R#2).\n\nOnline vs. offline depends on the objective of the stakeholder engagement\n\nFirst, the online vs. offline choice depends on the objective of engagement: “What is the aim? What do you want to get out of stakeholder engagement?” (R#9). In case researchers need to gain expertise fast, purely want to report results, or get feedback, online engagement was often sufficient. In contrast, deeper exchange needs in-person interaction:\n\n“If you need quick expertise, then a short phone call or a Zoom interview is incredibly effective. When it comes to exchanging deeper perspectives, personal things, when it comes to building trust, I think it makes a lot of sense in project contexts to meet in person, especially at the beginning” (R#6).\n\nOffline experiences are of specific relevance if you want to get impressions “from the ground”:\n\n“The problem with online meetings is that you cannot show the demo site and socialise. People would like to have a glass of wine but that can’t happen online” (R#7).\n\nIn addition, one researcher shared that you may miss “off-the-record information”, shared in a more informal setting, which would otherwise help in interpreting the interviews:\n\n“And when we did the interview in person, we also found that when the recorder was switched off, another huge bundle of information came out” (R#5).\n\nThus, offline engagement seems to be essential if a deeper understanding of people’s contexts is crucial.\n\nOnline vs. offline depends on the engaged stakeholder group(s)\n\nSecond, the online vs. offline choice depends on the stakeholder group to be involved. Around 40% of the survey’s respondents perceive differences in the responsiveness between stakeholder groups (Figure 6). Researchers noted that some stakeholders could be better reached online, especially for engagement with policymakers or with industry actors. Interviewees explained that it is “sometimes […] easier to reach people that are very busy, because they can just take a short time slot in their agenda” (R#8), or “[i]ndustry appreciated online because they didn’t have to travel” (R#9). One of the stakeholders illustrated a difference between different actors on a different example:\n\n“If stakeholders are used to having a lot of meetings, such as banks, then you can easily integrate online meetings. However, real-estate investors prefer physical meetings” (S#13).\n\nIn contrast, other researchers reported less engagement and interest. There was a common agreement that “citizens are hard to engage only online” (survey_ID37). Nevertheless, one survey respondent shared an insight that incentives and the mediator can motivate citizens to participate in online survey:\n\n“People are receptive to online surveys with prize money awards (100€ x 5 participants), when the local authority is the communicator” (survey_ID61).\n\nOne fourth of the survey respondents stated that they could not reach some stakeholders online, which can lead to a selection bias. These stakeholders included mainly actors at a local level, such as “local communities with limited internet access and technological skills” (survey_ID40), or “residents who do not have internet or barely use internet” (survey_ID61). One survey participant mentioned that online engagement can exclude certain people:\n\n“The community group I worked with didn’t like the idea of hosting online workshops as they felt it would exclude a lot of people who had attended the in-person meetings that were older and may not have access to laptop/internet” (survey_ID29).\n\nDifferences in possibility of reaching out to different stakeholders have also a geographical or cultural dimension, as one interviewee said:\n\n“There are differences in countries: in UK, or in Netherlands, farmers are used to using laptops and the internet. In the Southern Europe, farmers aren’t that used to the internet” (R#11).\n\nWe found that technical abilities were a barrier, especially in the beginning of the pandemic, as everyone had to learn the new tools. Thus, interviewees also raised the concern that the online community is a subset consisting of people who like using online tools (R#11).\n\nFor certain stakeholders it seems to be crucial to stay offline, as they expect to meet researchers in their “environment”, what can bring benefits to the researchers, too:\n\n“If it’s really about someone like the fisherman, then I would say that’s a target group where it’s more productive to meet on site. For two reasons: You get a better feel for the environment when you meet with someone in their hall, or on their boat. The second reason is that it’s easier to establish a personal connection” (R#5).\n\nOnline vs. offline depends on the previous relationship to stakeholders\n\nThird, the online vs. offline choice depends on the strength of ties already established with the stakeholders and project partners. One interviewee underlined:\n\n“It is also a big difference if you already have a stakeholder group, they all know each other and have met in real life […], instead of just having them mixed together for a moment at an online event” (R#15).\n\nOur findings indicate that an in-person kicking off event where participants get to know each other and then having online interactions boosts the interpersonal collaboration and trust. The same applied to researcher-stakeholder interactions and projects’ consortia:\n\n“Online was best where the projects had started before, i.e., where you already knew the people, you already had a project meeting” (R#5).\n\nWe also found that online engagement is often much more disciplined and formal. One interviewee stated that “protected spaces” are missing:\n\n“You don’t have protected spaces anymore. They all sit in a meeting and therefore everyone is very reduced with expressions” (R#6).\n\nThus, we find the need to stay offline, if an open exchange is wanted, potentially also in smaller groups.\n\nThe experiences with online engagement formats are mixed, but by far most researchers will continue online stakeholder engagement: 92% survey respondents state they will continue doing online stakeholder engagement. In most cases, the main purpose of such future online engagement is to collect data, disseminate research results, verify results and identify research needs (Figure 10). More intensive stakeholder engagement, in comparison, is much less prominent to be performed online in the future, again indicating that deeper stakeholder participation requires in-person engagement.\n\nNo survey respondent plans to strike for fully online, or fully in-person events in the future (Figure 11). Instead, the majority plans a mix of online and in-person formats:\n\n“People now you can do both, to meet virtually and in presence […] before, virtually meetings were not that used” (R#8).\n\nHow researchers want to engage stakeholders\n\nWe find that most researchers want to continue with online engagement alongside physical engagement. As one interviewee put it: “Only online is no good, lots of travel is also not good“ (R#9). Researchers value personal contacts and interactions.\n\nFor the internal project management, researchers want a reduced number of in-person meetings ̶ two in person, otherwise online. One researcher reported that, while planning the final project event in person, stakeholders, and even consortium members wanted to remain online and were not interested in travelling for the final project event (R#1).\n\nResearchers made different experiences with online engagement formats, with interviews, surveys and workshops scoring highest as the most suitable online formats and the ones most likely to remain in the future (Table 5).\n\nIf you consider the goals of the stakeholder activity you wanted to perform originally, how suitable were the following formats as a replacement (if performed)?; n = 24.\n\nHybrid events were for many a completely new format and researchers made mixed experiences. A survey respondent explained:\n\n“Hybrid formats are a “maybe” for me since they are even more time-consuming, and they create groups (the ones in the room and the ones attending online), but of course they have the advantage of not excluding anyone (completely)” (survey_ID34).\n\nInterviewees recognised the time effort behind hybrid events, but also confirmed the advantages for inclusivity:\n\n“Hybrid formats are the new frontier of how to make it work well and inclusive, that everyone can hear each other and see each other well” (R#2).\n\nHow stakeholders want to be engaged\n\nStakeholders want to participate in online formats as complementation but not as full replacement. Stakeholders prefer a balance of online and physical meetings and believe this format will continue in the future:\n\n“[…] because you always have the alternative. You say: “Listen, we should really meet once in a while, but these and the certain milestones, we can also meet digitally. We don’t have to plan another hour’s travel time for that” (S#13).\n\nIf a physical engagement is to be organised, stakeholders prefer shorter and more time-efficient events. One researcher shared their experience on their first in-person event after pandemic:\n\n“Our first in-person event was in Denmark two weeks ago and we scheduled it as a two-day event, and we had every minor registration. And then we changed it to a one-day event and then we got more than double the registrations we already had” (R#15).\n\nStakeholders do not see the need to always meet in-person. Interviewees shared that some associations and authorities asked if meetings could be done online (R#5), or that it was hard to get policymakers attend physical events even if the event was designed to fit transport connections and minimising travel time (R#15).\n\nWhen it comes to specific online tools, stakeholders seem to generally prefer Zoom (R#7). A plethora of online tools were scrutinised during the pandemic, such as virtual whiteboards and online polling, and some stakeholders very much enjoyed new online tools:\n\n“I have worked with some formats that have also added real value”, explained one stakeholder (S#13), “because it ensures that nothing gets lost”.\n\nInterviewees generally assessed miro and mural boards to be difficult tools for stakeholder interactions and instead, a google document might be a better way to capture feedback from people.\n\nWhen it comes to the frequency of interactions, stakeholders generally want to stay informed about the timelines and “get a feeling of what further steps are planned” (S#13). Furthermore, they want to be informed about the final results and, specifically about how their inputs added value to the project. One researcher said:\n\n“I think […] the need of choosing alternative tools, helped everyone to understand that you need to be very concise and explain to the stakeholders what we need and how they can contribute; show that they can contribute to the research and that their feedback is also important […]” (R#8).\n\nPhysical events with hybrid online options are generally fine for stakeholders but mean an additional technological and coordination challenge. Another stakeholder raised issues like:\n\n“Who will actually show during physical meeting plans? How will we improve hybrid meetings for the future? How do we create and improve interactivity? Hybrid is hard to change when clients see the benefits and adapt. Two years ago, 90% of our client meetings were physical, I believe that the move from completely physical to hybrid online will stay this way” (S#3).\n\n\nDiscussion and conclusions\n\nOur research on the long-term impact of the COVID-19 on stakeholder engagement in European sustainability research showed that the pandemic negatively impacted project activities in the short term but has predominantly improved stakeholder engagement in the long run. This is mainly due to five reasons: (i) the pandemic has encouraged people to act differently; (ii) online activities have expanded the engagement portfolio; (iii) online engagement activities turned out to be time and resource savers; and (iv) the pandemic has raised awareness about the nuances of meeting stakeholders in person (and when not to do it). We discuss these points and their implications below.\n\nFirst, the pandemic forced researchers to quickly find alternative formats and tools for engagement, which made them think beyond standard practices and look for innovative solutions. This spurred not only immediate innovation in science-stakeholder interactions, but also triggered long-term, lasting changes, as existing practices were questioned, including the value of and need for in-person meetings, and how to engage stakeholders more effectively. The coping measures taken showed that both researchers and stakeholders are adaptable and flexible and largely open to change and reap benefits of online tools. When researchers were forced to learn to use online formats and tools, new interactive tools, such as breakout groups or live voting, proved useful. Thus, the pandemic showed that online engagement is a real option.\n\nSecond, online engagement expanded the engagement portfolio. The pandemic brought a surge of innovation to digital communication practices. Today, three years after the pandemic started, digital formats have become standard tools expanding the possibilities for engagement and allowing researchers to choose appropriate formats depending on the context. Different stakeholder groups require different forms of engagement, and therefore online and offline formats are differently appropriate depending on the specific stakeholders and their capacities, the depth of previous collaboration and the goal of the engagement process.\n\nWhile it is impossible to fully replicate the character of in-person meetings in online engagement formats, there are possibilities to facilitate a friendly, more “personal” relationships between the participants, such as different ice-breaking activities. A different prerequisite to foster a meaningful online stakeholder engagement is to make sure about constant and high-quality communication before and after the engagement activity that would allow to share the details about the activity and provide space to share feedback. Despite substantial context-dependency of stakeholder involvement in sustainability research, the meaningful engagement requires a careful consideration of the involvement’s objectives and corresponding qualitative aspects, such as the stage of the research (or project) or the desired level of informal interactions allowing to realise given objectives. Our results suggest that the expanded engagement portfolio gives researchers different alternatives which format would be the most suitable to achieve the research goals.\n\nThird, our results show that online events are time and resource savers, despite the potentially longer preparation time for organisers of online activities. Stakeholders and researchers consider more carefully whether a more resource-, time- and emission-intensive face-to-face event is required – as also suggested by Klöwer et al. (2020). Online engagement activities can also provide new opportunities for the involvement of stakeholders from different countries or even continents, as it requires no financial resources while bridging geographical distances. In practice it may remain hard to include everyone across time zones. We expect a more rigorous reflection on the need for in-person interactions and the necessary length of them, and whether, in some cases, online activities can offer a more inclusive alternative.\n\nFourth, the pandemic has raised awareness about how important and necessary it is to still meet in person. Although online engagement worked better than most researchers and stakeholders initially thought, our findings suggest that in-person activities still guarantee a deeper connection and exchange between people in comparison to online formats. This is particularly important in co-creative research, for which stakeholders must be very closely involved in the research process and empowered to take actions. In addition, much emphasis was put on casual conversations during or after official events, and on informal insights that are lost in online-only activities. Thus, researchers and stakeholder want, likewise, a mix of online and offline engagement in the long run.\n\nOur research has provided qualitative insights into the impact of the pandemic on stakeholder engagement in various sustainability research projects and the implications for the long-term future. Thus, these findings can provide recognition and important guidance to researchers and funding agencies on the opportunities, but also challenges for meaningful stakeholder engagement in research. However, the data gathered may not be representative of the entire research and, especially, stakeholder universe of perspectives. In particular, we were only able to interview two stakeholders and therefore stakeholder insights remain underrepresented. This is mainly due to the data security of the research projects, as they could not provide us with information about the stakeholders involved. In addition, we struggled to recruit researchers to participate in our survey and even received no responses at all from stakeholders. This may, ironically, be related to an arising ‘online fatigue’ in 2022 and the new opportunities to meet in person again. Future research could build on our work and perform a more project-specific and continuous evaluation of the effectiveness and success of online engagement and its limitations. In addition, future research could analyse the impacts of the pandemic on research funding.\n\nThe research was conducted in accordance with the ethical requirements and guidelines of the SENTINEL project (Deliverables 11.1 and 11.2), which follows the guidelines of the European Commission. We used an ethically sound methodology for data collection and processing in this study, under the guidance of the Institute for Advanced Sustainability Studies (IASS), now the Research Institute for Sustainability – Helmholtz Centre Potsdam (RIFS), Data Protection Service. This was supported by bilateral data protection agreements.\n\nInterviewees agreed to our data protection standards through a signed consent form, and survey respondents agreed to our data protection standards through a GDPR disclaimer and by participating in the survey.\n\nThe results from the survey and the interviews have been de-identified in accordance with the Safe Harbor methods, ensuring that individuals cannot be identified.",
"appendix": "Data availability\n\nThe questionnaire and the interview guidelines can be accessed on Zenodo (10.5281/zenodo.10812990) under the Creative Commons Attribution 4.0 International. The interview results and survey data underlying this study are not openly available to protect the anonymity of participating individuals and projects. Given that we asked for many details of the projects, like funding source, duration etc., we cannot guarantee anonymity. For further COVID-19 research and the replicability of the research in another study context, access to semi-anonymised data can be granted. For further information on the data please contact Diana Süsser (diana(a)ieecp.org).\n\n\nAcknowledgements\n\nWe thank the Research Institute for Sustainability – Helmholtz Centre Potsdam (RIFS) for financing the open access publication. We also thank our interview partners and our participants of the survey for taking the time for participating in our research.\n\n\nReferences\n\nBeaunoyer E, Dupéré S, Guitton MJ: COVID-19 and digital inequalities: Reciprocal impacts and mitigation strategies. Comput. Hum. Behav. 2020; 111(January): 106424. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBodenheimer M, Leidenberger J: COVID-19 as a window of opportunity for sustainability transitions? Narratives and communication strategies beyond the pandemic. Sustain.: Sci. Pract. Policy. 2020; 16(1): 61–66. Publisher Full Text\n\nCohen MJ: Does the COVID-19 outbreak mark the onset of a sustainable consumption transition? Sustain.: Sci. Pract. Policy. 2020; 16(1): 1–3. Publisher Full Text\n\nCorbera E, Anguelovski I, Honey-Rosés J, et al.: Academia in the Time of COVID-19: Towards an Ethics of Care. Plan. Theory Pract. 2020; 21(2): 191–199. Publisher Full Text\n\nFazey I, Schäpke N, Caniglia G, et al.: Stakeholder involvement in sustainability science - A critical view. Energy Res. Soc. Sci. 2020; 13(4): 129–142. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJäger J, Brutschin E, Pianta S, et al.: Stakeholder engagement and decarbonization pathways: Meeting the challenges of the COVID-19 pandemic. Front. sustain. 2023; 3. Publisher Full Text\n\nKlöwer M, Hopkins D, Allen M, et al.: An analysis of ways to decarbonize conference travel after COVID-19. Nature. 2020; 583(7816): 356–359. PubMed Abstract | Publisher Full Text\n\nKöpsel V, de Moura Kiipper G , Peck MA: Stakeholder engagement vs. social distancing—how does the Covid-19 pandemic affect participatory research in EU marine science projects? Marit. Stud. 2021; 20(2): 189–205. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLawrence MG, Williams S, Nanz P, et al.: Characteristics, potentials, and challenges of transdisciplinary research. One Earth. 2022; 5(1): 44–61. Publisher Full Text\n\nLeal Filho W, Azul AM, Wall T, et al.: COVID-19: the impact of a global crisis on sustainable development research. Sustain. Sci. 2020; 16: 85–99. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLutz LM, Bergmann M: Transdisziplinarität: Forschungsansatz für die Energiewende.Holstenkamp L, Radtke J, editors. Handbuch Energiewende und Partizipation. Springer VS; 2018; pp. 43–56.\n\nMielke J, Vermaßen H, Ellenbeck S, et al.: Stakeholder involvement in sustainability science - A critical view. Energy Res. Soc. Sci. 2016; 17: 71–81. Publisher Full Text\n\nQuitzow R, Bersalli G, Eicke L, et al.: The COVID-19 crisis deepens the gulf between leaders and laggards in the global energy transition. Energy Res. Soc. Sci. 2021; 74: 101981. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSantana FN, Hammond Wagner C, Berlin Rubin N, et al.: A path forward for qualitative research on sustainability in the COVID-19 pandemic. Sustain. Sci. 2021; 16(3): 1061–1067. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchwarz M, Scherrer A, Hohmann C, et al.: COVID-19 and the academy: It is time for going digital. Energy Res. Soc. Sci. 2020; 68(June): 101684–101692. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSüsser D, Ceglarz A, Stavrakas V, et al.: COVID-19 vs. stakeholder engagement: the impact of coronavirus containment measures on stakeholder involvement in European energy research projects. Open Research Europe. 2021; 1: 57. Publisher Full Text\n\nTobin C, Mavrommati G, Urban-Rich J: Responding to Social Distancing in Conducting Stakeholder Workshops in COVID-19 Era. Soc. Forces. 2020; 10(4): 98. Publisher Full Text\n\n\nFootnotes\n\n1 We use “COVID-19”, “Corona” and “pandemic” interchangeably to refer to the outbreak of the coronavirus disease in early 2020."
}
|
[
{
"id": "308355",
"date": "31 Jul 2024",
"name": "Paul Upham",
"expertise": [
"Reviewer Expertise Social acceptance of energy technology",
"sociotechnical transitions studies",
"innovation studies"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is - in my view - a publishable-as-is paper that achieves its stated objectives of investigating and discussing how covid-19 affected stakeholder engagement in the context of sustainability research. Although simple in the sense of being primarily descriptive, it is clear that a lot of work went in to data gathering and analysis, the methods of which are all sound.\nIdeally the paper might reflect more on the implications of greater reliance on online work for the humanities as well as the social sciences in sustainability research - for example, I wonder how online communication affects (positively and negatively) understanding in a phenomenological sense (if one can't 'be' with a stakeholder in their lived context). This could be briefly followed up in relation to an interviewee's comment on the challenges of interviewing fisher(men). Nonetheless the paper is useful and clear as it is.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "303921",
"date": "07 Aug 2024",
"name": "Neetha Shagan Morar",
"expertise": [
"Reviewer Expertise Social science research",
"ethics and stakeholder engagement within HIV prevention biomedical research."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThanks to the authors for this valuable, relevant and important paper put together on stakeholder engagement (SE)in sustainability research. The descriptive analysis is well explained with several tables and highlights the influence of the COVID_19 pandemic on SE. The following comments are to enhance the publication on the importance of SE during and post covid-19. It also includes a few points of clarification and use of terminology.\nTitle: Please indicate from a researchers perspective and where was the project in the title as there were only two stakeholders interviewed from the North areas. It is recommended that a follow up study may include more stakeholders and not only researchers responses as they play a critical role in SE. Abstract may be more valuable if it included the sample size and state that pandemic refers to COVID-19 or add term when referring to pandemic.Fo consistency refer to sustainability research and SE vs stakeholder based research. Introduction is well explained and includes a methods section that could be moved to the relevant methods section. Please consider adding the new complexity issues that COVID-19 added with a reference in paragraph one, Stakeholder based research is used in various paragraphs thus maybe define this or use sustainability research and SE as unique terms. Methods, Results- Figure two was not needed and is unclear to the reader. The narrative may be adequate, Please indicate what steps were used for the development of the themes listed in the results. Please Add percentages to the quantitative data in the tables and figures. Maybe reduce quotes that are similar within the themes. Conclusion - maybe add recommendations for pandemic preparedness beyond COVID -19 like vaccines\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "303919",
"date": "12 Aug 2024",
"name": "Heta Leinonen",
"expertise": [
"Reviewer Expertise Stakeholder engagement",
"a circular economy",
"sufficiency"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Authors,\nThank you for the opportunity to review this highly interesting and topical article!\nIn the article, the authors propose novel insights into how the COVID-19 changed stakeholder engagement (SE) in sustainability research.\nIn the following, I give my main comments on the article point by point.\n1. Theoretical considerations 1.1 Please define (more reliably) the concepts that you use. For instance,\nstakeholder (e.g., Freeman, R. E. (1984). Strategic management: A stakeholder approach. Pitman.) SE (e.g., Greenwood, M. (2007). Stakeholder engagement: Beyond the myth of corporate responsibility. Journal of Business Ethics, 74(4), 315–327. https://doi.org/10.1007/s10551-007-9509-y) In the article, does SE mean the same as SE process and/or stakeholder involvement? Further, in this article, does SE include the aims, activities, and impacts of SE or do you focus only on the activities? In addition, it would be interesting to know how the interviewees and respondents understood SE: were they given background information on what is meant by the concept? stakeholder-based research sustainability (research)\n1.2 You write about the same phenomenon with many different concepts, e.g.,\nSE format, activity, tool, portfolio, practice, form, interaction… (In addition, in the article, do they mean the same as “project activities”?) COVID-19, pandemic, COVID-19 pandemic, Corona, coronavirus disease…\nWhen you have chosen the concept, please use it throughout the article. When consistently using only one concept, you would not need, e.g., the footnote on p. 3: “We use “COVID-19”, “Corona” and “pandemic” interchangeably to refer to the outbreak of the coronavirus disease in early 2020.\" 1.3 Based on previous points, please reconsider the title “How the COVID-19 Pandemic Changed Stakeholder Engagement Processes in Sustainability Research in the Long-term”. Could it, e.g., be “How the COVID-19 Changed Stakeholder Engagement Activities in Sustainability Research”? 1.4 In the Discussion and Conclusions, theoretical contributions are missing.\n2. Methods 2.1 Great that you state the research question at the beginning of the article (p. 3). 2.2 As you had only two stakeholders in the interviews, and all the other interviews and the survey were for researchers what if you include only the researchers in this study? For the reader, it would clarify the scope of the research. 2.3 Could you include a table on interview data (incl. e.g., date, length (min), and transcripted pages)? 2.4 What language were the interviews in, i.e. are the quotations translations? Please check, if, e.g., these quotations are correct: “People now you can do both, to meet virtually and in presence\" (p. 15) and \"Our first in-person event was in Denmark two weeks ago and we scheduled it as a two-day event, and we had every minor registration\" (p. 16).\n3. Results 3.1 While reading this part of the article and interpreting the visualizations related to it, at some point, I was unsure where the survey was discussed, from which year (2020 or 2022), and whether only the interviews or the synthesis of the survey and the interviews were discussed. In other words, the guidance and reader-friendliness of this section could be improved. 3.2 On p. 15 under the heading \"How Researchers Want to Engage Stakeholders\" you mention “internal project management”. That made me think about the limitations of the study and the previously mentioned need for the definition of stakeholder. Please, define stakeholder at the beginning of the article and also define to what extent the SE _within_ the research groups is within the scope of this study. 3.3 At some places, you have strong statements that could be softened (e.g., p. 6: \"Overall, the pandemic had a negative impact on stakeholder engagement\" and p. 7: \"The pandemic negatively impacted the engagement of stakeholders in research processes\") based on your results. 3.4 On p. 7, you mention \"three dimensions\" under the heading \"Process\". What do you mean by dimensions and process? What are the other dimensions that were not affected? 3.5 On Table 2 (p. 10), replace - with 0.\n4. Spelling and Grammar 4.1 Please use – in between numbers instead of -. 4.2 In terms of repetition, please check the following sentence on p. 14: \"One of the stakeholders illustrated a difference between different actors on a different example”.\nI offer you my best wishes with the editing and future research!\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "303915",
"date": "03 Sep 2024",
"name": "Ines Omann",
"expertise": [
"Reviewer Expertise socio-ecological transformation",
"climate change",
"stakeholder engagement",
"public participation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for this well structured and clear paper, giving a good overview of pros and cons of online participation vs. physical meetings. Here are some comments and suggestions. - I wonder, whether your analysis is valid only for sustainability research projects or if they are valid for any transdisciplinary applied research projects. If not, please explain how the results are linked to sustainability.- - The results are well summarized. It is not fully clear how you came to your conclusions. If I may play the advocatus diaboli: the results are quite predictable and straightforward. Are there any surprises that found? - There are some more detailed comments in the pdf. - Please add in the appendix the interview guideline and the survey.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-458
|
https://f1000research.com/articles/13-104/v1
|
16 Feb 24
|
{
"type": "Review",
"title": "Hepatocellular carcinoma: Advances in systemic therapies",
"authors": [
"Trevor Kwan-Hung Wu",
"Rex Wan-Hin Hui",
"Lung-Yi Mak",
"James Fung",
"Wai-Kay Seto",
"Man-Fung Yuen",
"Trevor Kwan-Hung Wu",
"Rex Wan-Hin Hui",
"Lung-Yi Mak",
"James Fung",
"Wai-Kay Seto"
],
"abstract": "Advanced hepatocellular carcinoma (HCC) is traditionally associated with limited treatment options and a poor prognosis. Sorafenib, a multiple tyrosine kinase inhibitor, was introduced in 2007 as a first-in-class systemic agent for advanced HCC. After sorafenib, a range of targeted therapies and immunotherapies have demonstrated survival benefits in the past 5 years, revolutionizing the treatment landscape of advanced HCC. More recently, evidence of novel combinations of systemic agents with distinct mechanisms has emerged. In particular, combination trials on atezolizumab plus bevacizumab and durvalumab plus tremelimumab have shown encouraging efficacy. Hence, international societies have revamped their guidelines to incorporate new recommendations for these novel systemic agents. Aside from treatment in advanced HCC, the indications for systemic therapy are expanding. For example, the combination of systemic therapeutics with locoregional therapy (trans-arterial chemoembolization or stereotactic body radiation therapy) has demonstrated promising early results in downstaging HCC. Recent trials have also explored the role of systemic therapy as neoadjuvant treatment for borderline-resectable HCC or as adjuvant treatment to reduce recurrence risk after curative resection. Despite encouraging results from clinical trials, the real-world efficacy of systemic agents in specific patient subgroups (such as patients with advanced cirrhosis, high bleeding risk, renal impairment, or cardiometabolic diseases) remains uncertain. The effect of liver disease etiology on systemic treatment efficacy warrants further research. With an increased understanding of the pathophysiological pathways and accumulation of clinical data, personalized treatment decisions will be possible, and the field of systemic treatment for HCC will continue to evolve.",
"keywords": [
"HCC",
"Systemic therapy",
"TKI",
"ICI",
"Liver",
"Neoadjuvant",
"Adjuvant"
],
"content": "Introduction\n\nPrimary liver cancer ranks as the seventh most common cancer and the third most common cause of cancer-related mortality globally.1 Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, frequently occurring as a complication of chronic liver diseases, in particular, for those with established cirrhosis. Common risk factors for HCC include chronic infection by hepatitis B (HBV) or hepatitis C (HCV), alcohol-related liver disease, and steatotic liver disease.2 HCC screening and surveillance, usually via ultrasound in combination with alpha-fetoprotein (AFP), aims to detect HCC at an early stage, and is associated with a higher probability of curative therapy and improved outcomes.3 Resection, ablation and liver transplant remain as the curative treatment options and are associated with the best outcomes in HCC.4 On the other hand, the experience in loco-regional therapies (trans-arterial chemoembolization [TACE] and stereotactic body radiation therapy [SBRT]) are continuously accumulating and treatment indications are expanding.5\n\nDespite screening efforts, many cases of HCC are still diagnosed at an advanced stage. Concomitant cirrhosis and field cancerization may preclude these patients from receiving curative or loco-regional therapies, and systemic therapy may be the only remaining treatment option.6 Traditionally, pharmacological treatment for advanced HCC has been unsuccessful, primarily driven by the intrinsic resistance of HCC to conventional chemotherapy.7 Nonetheless, the introduction of sorafenib in 2007 has completely revolutionized systemic therapy for advanced HCC,8 and multiple clinical trials on new-generation targeted therapy and immunotherapy have been conducted (Table 1). In response to these advancements, professional societies have revamped their guidelines on the treatment of advanced HCC (Table 2).4,9,10 This review discusses the advancements in systemic therapies for HCC, with a particular focus on targeted therapy and immunotherapy. A literature search was performed on Pubmed with the keywords “hepatocellular carcinoma,” “systemic therapy,” “targeted therapy,” “immunotherapy,” “neoadjuvant” and “adjuvant.” Papers up to November 1, 2023, were screened and included if relevant.\n\n\n\n- Atezolizumab + bevacizumab\n\n- Contraindicated to atezolizumab + bevacizumab\n\n• Sorafenib\n\n• Lenvatinib\n\n\n\n- Failed atezolizumab + bevacizumab\n\n• Multi-TKI and VEGFR2 inhibitor as per off-label availability\n\n- Failed sorafenib or lenvatinib treatment\n\n• Cabozantinib\n\n• Regorafenib\n\n• Ramucirumab (In patients with AFP ≥400 ng/mL)\n\n\n\n- Atezolizumab + bevacizumab\n\n- Tremelimumab + durvalumab\n\n- Contraindicated to above two options\n\n• Sorafenib\n\n• Lenvatinib\n\n• Durvalumab\n\n\n\n- Failed sorafenib treatment\n\n• Cabozantinib\n\n• Regorafenib\n\n• Ramucirumab (In patients with AFP ≥400 ng/mL)\n\n- Failed other first-line treatment\n\n• Clinical trials\n\n\n\n- Atezolizumab + bevacizumab\n\n- Tremelimumab + durvalumab\n\n- Contraindicated to above two options\n\n• Sorafenib\n\n• Lenvatinib\n\n\n\n- Failed atezolizumab + bevacizumab\n\n• Clinical trials\n\n• Sorafenib\n\n• Lenvatinib\n\n• Cabozantinib\n\n• Regorafenib\n\n• Nivolumab + ipilimumab\n\n- Failed tremelimumab + durvalumab\n\n• Clinical trials\n\n• Sorafenib\n\n• Lenvatinib\n\n- Failed sorafenib or lenvatinib treatment\n\n• Cabozantinib\n\n• Regorafenib\n\n• Ramucirumab (In patients with AFP ≥400 ng/mL)\n\n• Pembrolizumab\n\n• Nivolumab + ipilimumab\n\n\nTargeted therapies\n\nHepatocarcinogenesis is a complex multistep process involving interactions between intrinsic genetic mutations and extrinsic influence of carcinogens, which in turn drive cell cycle dysregulation, uncontrolled cellular proliferation, neovascularization, and tissue invasion.11 Key pathophysiological pathways such as vascular endothelial growth factor receptor (VEGFR) signaling, RAS/RAF/MAPK pathways and TERT promoter have been identified.12–15 Among the studied pathways, protein kinases serve as important molecular mediators for oncogenes, and protein kinase inhibitors have in turn become attractive therapeutic targets for HCC (Figure 1).16\n\nSorafenib is a tyrosine kinase inhibitor (TKI) targeting the RAS/RAF, VEGFR, and platelet-derived growth factor receptor (PDGFR) signaling pathways, thereby suppressing tumor proliferation and angiogenesis.17 It was approved by the Food and Drug Administration (FDA) of the United States in 2007. Two landmark trials have validated the efficacy of sorafenib in advanced HCC. The SHARP trial is a phase III, double-blinded, placebo-controlled trial involving 602 treatment-naïve advanced HCC patients.8 The median overall survival (OS) was significantly prolonged by 2.8 months (10.7 vs. 7.9 months, p<0.001) with sorafenib use, representing a 31% mortality risk reduction. The Asian-Pacific multicenter randomized controlled trial on sorafenib yielded similar results, yielding a median survival benefit of 2.3 months (6.5 vs 4.2 months, p=0.014).18 The safety of sorafenib was further demonstrated in a multicenter prospective study (GIDEON study), supporting its use as a first-line therapy in advanced HCC.19 As the first-in-class agent, sorafenib has initially been considered the gold standard for HCC systemic therapy. However, its exact mechanism of action remains poorly understood, and disease control rates of sorafenib in advanced HCC patients is below 50%.8 Resistance to sorafenib can also develop through various mechanisms including epigenetic alterations, upregulation of drug efflux transporters and tumor microenvironment adaptation.20 Common adverse reactions to sorafenib include hand-foot skin reaction, diarrhea, fatigue, and anorexia.\n\nThe encouraging results of sorafenib sparked hope in the search for additional systemic therapies for advanced HCC; however, in the decade following the publication of the SHARP trial, targeted therapy agents including sunitinib, brivanib, linifanib, and erlotinib all failed to meet the primary survival endpoints and were not superior to sorafenib.21–24 Studies on second-line agents after failing sorafenib, such as tivantinib, have also remained fruitless.25 This ultimately changed in 2018 when data on lenvatinib were published.\n\nLenvatinib is another multiple TKI targeting epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), VEGFR, and PDGFR.26 Its role in advanced HCC was first reported in a phase II trial in Japan and Korea, showing partial radiological response in 37% of patients and stable disease in 41% of patients after follow-up for over 2 years.27 The landmark REFLECT trial involving head-to-head comparison between lenvatinib and sorafenib was published in 2018. Lenvatinib, when compared with sorafenib, demonstrated non-inferior median OS (13.6 vs 12.3 months) with significantly improved progression-free survival (PFS), median-time to progression, and objective response rate (ORR).28 A recent meta-analysis reported that lenvatinib outperforms sorafenib in terms of OS, PFS, ORR and disease control, particularly in HBV-related HCC.29 With support of the above data, lenvatinib monotherapy was first approved by the FDA in 2018, and has remained as a first-line systemic therapy option in HCC.\n\nA range of other targeted therapies, particularly second-line therapy, have emerged after lenvatinib treatment. Regorafenib, a derivative of sorafenib with higher potency against VEGFR, was designed with higher anti-angiogenic activity and approved by the FDA in 2017. The RESOURCE trial compared regorafenib with placebo in patients who had failed sorafenib treatment, showing a significantly prolonged median OS by 2.8 months (10.6 vs 7.8 months, hazard ratio [HR] 0.63, p<0.001).30 The survival benefit of regorafenib over placebo was further demonstrated in an extended analysis of the RESOURCE trial, supporting it as second-line therapy for patients who have failed sorafenib.31\n\nCabozantinib is another multiple TKI with activity against VEGF, MET and AXL. In the CELESTIAL trial on patients who failed sorafenib, cabozantinib was shown to prolong median OS by 2.2 months (10.2 vs 8.0 months, p=0.005) and PFS by 3.3 months (HR for disease progression/death 0.44, p<0.001).32 It has been postulated that the effect of cabozantinib is due to its additional activity against MET, the driver gene in sorafenib resistance. Due to the lack of data comparing regorafenib and cabozantinib against first-line TKIs, their role as first-line systemic therapies for HCC remains unanswered.\n\nDonafenib, another sorafenib derivative with reduced hepatic metabolism, was tested against sorafenib in China, showing superior median OS (12.1 vs 10.3 months, p=0.0245) and higher 18-month survival (35.4% vs 28.1%, p=0.0460).33 Apatinib, an oral VEGFR-2 inhibitor, has also been studied in a phase III trial in China and led to significant improvement in OS (8.7 vs 6.8 months, p=0.048).34 Nonetheless, donafenib and apatinib are only available in China and have not been studied in non-Chinese populations.\n\nUnlike the aforementioned small-molecule TKIs, ramucirumab is a recombinant immunoglobulin that inhibits angiogenesis via VEGFR-2 suppression. A phase II study evaluated ramucirumab monotherapy in treatment-naïve advanced HCC, with a median OS of 12 months, PFS of 4 months, and ORR of 9.5%.35 The promising early results led to a phase III trial of ramucirumab in patients who failed sorafenib therapy (REACH trial). In the REACH trial, ramucirumab showed improvement in survival, albeit not reaching statistical significance.36 The REACH-2 trial provided subgroup analysis, demonstrating that ramucirumab had higher efficacy in patients with alpha fetoprotein (AFP) level ≥400 ng/mL, and this group of patients had prolonged median OS by 1.2 months (8.5 vs 7.3 months, p=0.0199) and improvement in PFS (2.8 vs 1.6 months, p<0.0001).37 Analysis on the expanded cohort for REACH-2 showed comparable results when the pre-requisite of AFP ≥400 ng/mL was added to patient recruitment.38 These results highlight the heterogenous clinical characteristics of HCC, which can heavily influence the prognosis and choice of treatment.39 Clear characterization of the etiology and biochemical profiles of HCC may be beneficial in optimizing treatment plans in advanced HCC.\n\nAs most trials have compared targeted therapy with placebo or sorafenib, there is no clear conclusion on the optimal second-line treatment. A systematic review suggested that regorafenib outperformed both cabozantinib and ramucirumab in patients with AFP <400ng/mL, while survival outcomes were similar for all three agents in patients with AFP ≥400 ng/mL.40 More recent studies have pooled data from published trials to compare regorafenib and cabozantinib as salvage therapy after sorafenib failure. Kelley et al.41 pooled data from the CELESTIAL and RESOURCE trials and showed that cabozantinib had comparable OS and PFS to regorafenib. In contrast, Merle et al.42 suggested that regorafenib may trend towards better OS and have a more favorable side-effect profile when compared with cabozantinib. Head-to-head trials are necessary to determine optimal second-line targeted therapies for advanced HCC.\n\n\nImmunotherapy\n\nImmune system evasion is a key pathophysiological feature of various cancers. The reversal of immune evasion has emerged as a key therapeutic target in oncology.43 Immune checkpoints are cell surface receptors that suppress T-cell function, leading to immunotolerance. While immune checkpoints play critical roles in preventing autoimmunity, tumor cells exploit this mechanism to achieve immune evasion and avoid T-cell mediated tumor cytotoxicity.44 HCC frequently occurs in chronically inflamed cirrhotic livers, which enrich intra-tumoral cancer-associated fibroblasts and tumor-associated macrophages.45 These cells express high levels of immune checkpoints, deactivate tumor-specific CD8+ cytotoxic T cells, and promote immunosuppressive regulatory T-cell differentiation.46 Based on these mechanisms, immune checkpoint inhibition has been hypothesized to be efficacious in HCC (Figure 1).\n\nCytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1, and its ligand (PD1 and PDL1) are well-characterized actionable immune checkpoints.47,48 In particular, the combination of PD1 and CTLA4 inhibition may have synergistic effects, as CTLA4 acts upstream of PD1 in the priming stage and has additional effects on regulatory T cells.49 Hence, immune checkpoint inhibitors (ICIs) have been developed for the blockade of these checkpoints, and have demonstrated success in melanoma, lung cancer, and renal cell carcinoma.50–52 Its use has expanded to HCC, with multiple agents demonstrating positive results in clinical trials.\n\nNivolumab is a human IgG4 monoclonal antibody targeting PD1. The CheckMate-040 phase II dose escalation/expansion trial showed an objective response to nivolumab monotherapy in 20% of HCC patients, with a median duration of response of 9.9 months.53 In the phase III CheckMate-459 trial, which compared nivolumab against sorafenib in Child-Pugh A patients with advanced HCC, the nivolumab arm trended towards better OS; however, this difference did not reach statistical significance (16.4 vs 14.7 months, p=0.075).54 Nonetheless, the safety profile of nivolumab was more favorable than sorafenib, with >50% reduction in grade-3 or -4 treatment-emergent adverse events, making nivolumab monotherapy a potential therapeutic option when TKIs are contraindicated. However, accelerated approval for nivolumab monotherapy was withdrawn by the US FDA Oncologic Drug Advisory Committee in 2021, based on the statistically non-significant survival benefit of nivolumab over sorafenib in the CheckMate-459 trial.\n\nPembrolizumab, another humanized anti-PD1 antibody, was tested against placebo as a second-line treatment in patients with HCC who failed sorafenib treatment (KEYNOTE-240 trial). Pembrolizumab led to median OS of 13.9 months, which was numerically higher than the 10.6 months in placebo, although this did not reach statistical significance.55 A similarly designed trial in Asia (KEYNOTE-394 trial comparing pembrolizumab vs placebo in sorafenib-failed patients) showed significantly improved median OS (14.6 vs 13.0 months, p=0.018) and PFS (HR=0.47, p=0.0032) with pembrolizumab.56\n\nA combination of anti-PD1 (durvalumab) and anti-CTLA4 (tremelimumab) was developed based on its potential synergistic effects. In the STRIDE trial (single-dose tremelimumab + regular interval durvalumab), combination therapy led to superior survival benefits compared with durvalumab monotherapy (median OS 18.7 months in combination therapy vs 13.6 months in durvalumab monotherapy).57 The combination of durvalumab + tremelimumab was further studied in the landmark HIMALAYA phase III trial and was granted formal FDA approval in October 2022.58 The median OS in durvalumab + tremelimumab sequential therapy was superior to sorafenib (16.56 vs 13.77 months), with a reduced mortality risk of 0.78 (p=0.0035).59 In the same trial, durvalumab monotherapy was also shown to be non-inferior to sorafenib. Comparison between durvalumab + tremelimumab and durvalumab monotherapy arms confirmed the survival benefits of CTLA4 blockade in addition to anti-PD1 (3-year survival 30.7% in combination therapy vs. 24.7% in durvalumab monotherapy).\n\nAnother combination of anti-PD1 + anti-CTLA4 is the combination of nivolumab and ipilimumab. The CheckMate-040 trial studied nivolumab + ipilimumab in patients who progressed on sorafenib treatment.60 Combination treatment with nivolumab and ipilimumab led to an ORR of 32%, with a complete response in 5% of patients. The ORR was at least four-fold higher for nivolumab + ipilimumab than for other existing therapies (ORR of approximately 4-7%). Hence, the combination of nivolumab and ipilimumab has been granted accelerated approval for HCC patients with prior sorafenib treatment.61\n\nAlthough dual immunotherapy has shown synergistic effects, it may also lead to additive immune-related adverse events.62 These include skin rash, diarrhea, colitis, pneumonitis, hepatitis, and hyper/hypothyroidism.\n\nAnother approach to immunotherapy is to combine ICIs with targeted therapy, with the prime example being the combination of atezolizumab (anti-PDL1) + bevacizumab (anti-VEGFR monoclonal antibody). It has been hypothesized that VEGF potentiates PDL1 effects,63 and simultaneously blocking both receptors may lead to synergistic effects. The IMbrave150 phase III trial examined the efficacy of atezolizumab + bevacizumab against sorafenib monotherapy.64 In the primary analysis, OS at 12 months was significantly prolonged in the atezolizumab + bevacizumab group (HR for mortality 0.58, p<0.001), and a similar pattern was seen for PFS (6.8 months in combination arm vs 4.3 months in sorafenib arm, HR for disease progression or death 0.59, p<0.001). Extended follow-up for 1-year after the primary endpoint demonstrated that the atezolizumab + bevacizumab combination had a sustained antitumor effect with a stable safety profile.65 Bleeding complications in bevacizumab are well-documented; hence, patients recruited to the IMbrave150 trial were screened and treated for esophageal varices prior to the start of systemic therapy. The addition of atezolizumab did not increase the risk of gastrointestinal bleeding compared to bevacizumab monotherapy. Based on the IMbrave 150 trial results, the FDA approved the combined use of atezolizumab + bevacizumab in 2020 given its improved OS and PFS compared to sorafenib.66 It is noteworthy that the IMbrave150 trial recruited patients with high-risk features (e.g., macrovascular invasion of major portal veins, >50% liver involvement, or biliary tract invasion), which are usually excluded in other major trials. Nonetheless, the patient population in IMbrave150 still had a relatively preserved liver reserve (Child-Pugh class A), and the use of atezolizumab + bevacizumab in patients with severely impaired liver function remains unanswered.\n\nWith encouraging results from atezolizumab + bevacizumab, other trials on ICIs + targeted therapies have also been reported (Table 1). The regimens of atezolizumab + cabozantinib, pembrolizumab + lenvatinib, sintilimab (anti-PD1) + bevacizumab, and camrelizumab (anti-PD1) + rivoceranib (TKI) have all shown significant improvements in PFS over TKIs, although their effects on OS have been inconsistent.67–70\n\n\nExpanding indications of systemic therapies\n\nAlthough systemic therapies have classically been used for unresectable advanced HCC, their potential role in neoadjuvant treatment has also been explored. Neoadjuvant cemiplimab (anti-PD1) prior to hepatectomy has been studied in a phase II trial on 21 patients with resectable HCC, and 20% of patients had significant tumor necrosis in the resected tumor sample.71 A similar trial on 30 patients with resectable HCC reported that neoadjuvant use of nivolumab or nivolumab + ipilimumab prior to surgical resection led to significant tumor necrosis in approximately 30% of patients.72 While these two studies highlighted the potential anti-tumor effect of systemic therapy prior to surgery, their impact on recurrence risk and survival remains uncertain.\n\nIn addition to patients with resectable HCC, systemic therapy has been studied for downstaging patients with unresectable disease. In a pilot study of 10 patients with major vessel invasion, neoadjuvant therapy with anti-PD1 + TKI led to successful downstaging in 100% of patients, with 80% of patients eventually undergoing hepatectomy. Among patients who underwent surgery, the 1-year recurrence-free survival rate was 75%.73 A similar observational study assessed the neoadjuvant use of anti-PD1 + TKI in 63 patients with unresectable HCC, where 15.9% of patients had successful downstaging and received curative resection at a median of 3.2 months after initiation of systemic therapy. In the patients who received surgery, 60% had complete pathological response on the resected tumor, and 80% remained disease free after 11.2 months of follow-up.74 In a phase Ib trial, neoadjuvant cabozantinib + nivolumab was studied in 15 patients with unresectable disease, with 12 patients achieving successful curative resection and 5 patients achieving major pathologic response.75 These studies highlight the enormous potential of neoadjuvant systemic therapy in downstaging HCC to expand the curative treatment window. Further large-scale trials on neoadjuvant strategies are warranted.\n\nAdjuvant systemic therapy after curative HCC treatment has been studied as a strategy for reducing recurrence. The phase III STORM trial on adjuvant sorafenib after resection/ablation showed negative results,76 and subsequent studies on adjuvant sorafenib have shown mixed results.77 Despite the disappointment with adjuvant sorafenib, newer systemic agents may have better efficacy. The IMBrave050 trial recruited 668 patients who underwent resection/ablation with a high risk of recurrence, aiming to compare outcomes between adjuvant atezolizumab + bevacizumab and active surveillance. After 12 months of treatment, adjuvant atezolizumab + bevacizumab led to significantly improved recurrence-free survival compared to active surveillance (HR 0.72, p=0.012),78 representing the first trial to report the benefits of adjuvant immunotherapy in HCC. Multiple adjuvant trials including CA209-9DX (nivolumab monotherapy),79 EMERALD-2 (durvalumab +/- bevacizumab)80 and KEYNOTE-937 (pembrolizumab)81 are ongoing, and the results have important implications for the adjuvant use of systemic therapies.\n\nThe combination of systemic and loco-regional therapies has generated interest in the use of immunotherapy, as loco-regional therapies may prime intratumoral immune activity and enhance the effects of systemic agents.82\n\nThe combination of anti-PD1 + SBRT is one of the best-studied strategies involving both systemic and locoregional therapies. A case series in 2019 reported 5 BCLC stage C HCC patients who received anti-PD1 + SBRT, demonstrating a 100% response rate with no disease progression after a median follow-up of 14.9 months.83 In a subsequent cohort study by the same group, ICIs + SBRT was superior to TACE in terms of PFS (93.3% vs. 16.7%, p<0.001) and OS (93.8% vs. 31.3%, p<0.001) after 1 year in 16 patients with BCLC-C HCC.84 The use of ICIs + SBRT has further progressed to a phase I trial in 2023, demonstrating that nivolumab + ipilimumab + SBRT was superior to nivolumab + SBRT in terms of PFS (11.6 vs 2.7 months, p<0.05) and OS (41.6 vs 4.7 months, p<0.05).85 The START-FIT phase II trial modified the combination regimen to TACE + SBRT + avelumab (anti-PDL1). Among 33 patients with locally advanced HCC who received this combination regimen, an impressive 55% of subjects were successfully downstaged and became amenable to curative therapy, with 42% having a complete radiological response.86\n\nThe combination of systemic therapy with TACE has also been explored. A retrospective study of camrelizumab + TACE showed an ORR of 35.3% and OS of 13.3 months,87 although this strategy has not been studied in clinical trials. The combination of sorafenib + TACE and lenvatinib + TACE has been studied in phase III trials, and both combinations led to a significant improvement in PFS by >60% when compared with TKI monotherapy.88,89 In 2022, interim trial results on the combination of lenvatinib + camrelizumab/sintilimab + TACE were reported. Notably, this triple combination led to successful downstaging and hepatectomy in 50% of patients, with patients achieving a 48-week OS of 96.4%.\n\n\nDiscussion\n\nSystemic HCC treatment has evolved rapidly. Numerous trials have established the efficacy and safety of targeted therapies and immunotherapies, dramatically expanding the treatment armamentarium for patients with advanced HCC. Despite promising results from clinical trials, real-world data, particularly for newer agents, are limited. Patients in clinical trials are generally highly selected, with good premorbid and limited comorbidities. In contrast, HCC patient subgroups such as patients with advanced cirrhosis, high bleeding risk, renal impairment or cardiometabolic diseases are limited.90 Among the under-studied patient groups, patients with advanced cirrhosis or decompensated disease may be particularly problematic, as these patients form a substantial proportion of HCC patients commonly encountered in clinical practice. Encouragingly, data on systemic therapy in Child-Pugh B HCC patients are accumulating and have demonstrated the potential impact of cirrhosis severity on disease outcomes.91–93 Extensive efforts are required to establish the efficacy and safety of systemic therapy in these important patient groups.\n\nHCC is a heterogeneous disease with substantial differences in etiology and tumor biology,94 which may in turn affect treatment response and prognosis. For example, in the landmark SHARP trial on sorafenib, the median OS was highest in HCV patients (6.6 months), followed by HBV patients (3.6 months) and patients with alcohol-related liver disease (2.3 months).95 Differential treatment outcomes have also been reported for immunotherapy, in which patients with non-viral HCC were less responsive to anti-PD1, and non-alcoholic steatohepatitis HCC was associated with significantly poorer survival.96 Further mechanistic studies are required to study the interaction between background liver disease and systemic therapy efficacy.\n\nIn addition to subtyping HCC according to disease etiology, molecular subtyping may also have a growing role in clinical management. Current international guidelines generally recommend image-based diagnosis of HCC in high-risk patients, and histological proof may not be necessary.9,97 However, some clinicians have proposed the benefits of tissue diagnosis, primarily for molecular phenotyping and to identify druggable targets.98 As the therapeutic options for advanced HCC grow, the one-size-fits-all approach will no longer be appropriate, and personalized treatment decisions based on clinical and molecular parameters will be necessary.\n\nTraditionally, advanced HCC has restricted treatment options and is invariably associated with poor prognosis. With better characterization of oncogenic signaling pathways and tumor immunological regulation, the landscape of systemic therapy for HCC has dramatically shifted in the past decade. In addition to improving the prognosis of patients with advanced HCC, systemic therapies may also be expanded to neoadjuvant/adjuvant treatment. Numerous large trials are currently ongoing and we anticipate emerging evidence in the field of systemic HCC therapy.\n\n\nAuthor contributions\n\nTKHW was involved in literature review, data interpretation, and drafting of the manuscript. RWHH, LYM, JF, and WKS were involved in the data interpretation and critical revision of the manuscript. MFY was involved in study conception, critical revision of the manuscript, and overall study supervision. All authors have read and approved the final version of the manuscript.",
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Aug 2018; 69(2): 353–358. Publisher Full Text\n\nAbou-Alfa GK, Meyer T, Cheng AL, et al.: Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N. Engl. J. Med. Jul 5 2018; 379(1): 54–63. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQin S, Bi F, Gu S, et al.: Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial. J. Clin. Oncol. Sep 20 2021; 39(27): 3002–3011. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQin S, Li Q, Gu S, et al.: Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol. Hepatol. Jul 2021; 6(7): 559–568. PubMed Abstract | Publisher Full Text\n\nZhu AX, Finn RS, Mulcahy M, et al.: A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin. Cancer Res. Dec 1 2013; 19(23): 6614–6623. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhu AX, Park JO, Ryoo BY, et al.: Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. Jul 2015; 16(7): 859–870. PubMed Abstract | Publisher Full Text\n\nZhu AX, Kang YK, Yen CJ, et al.: Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. Feb 2019; 20(2): 282–296. Publisher Full Text\n\nFinn RS, Yau T, Hsu CH, et al.: Ramucirumab for Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha Fetoprotein Following Non-Sorafenib Systemic Therapy: An Expansion Cohort of REACH-2. Oncologist. Dec 9 2022; 27(12): e938–e948. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZucman-Rossi J, Villanueva A, Nault JC, et al.: Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. Gastroenterology. Oct 2015; 149(5): 1226–1239.e4. Publisher Full Text\n\nChen J, Wang J, Xie F: Comparative efficacy and safety for second-line treatment with ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma progressed on sorafenib treatment: A network meta-analysis. Medicine (Baltimore). Sep 24 2021; 100(38): e27013. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKelley RK, Mollon P, Blanc JF, et al.: Comparative Efficacy of Cabozantinib and Regorafenib for Advanced Hepatocellular Carcinoma. Adv. Ther. Jun 2020; 37(6): 2678–2695. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMerle P, Kudo M, Krotneva S, et al.: Regorafenib versus Cabozantinib as a Second-Line Treatment for Advanced Hepatocellular Carcinoma: An Anchored Matching-Adjusted Indirect Comparison of Efficacy and Safety. Liver Cancer. Jun 2023; 12(2): 145–155. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell. Mar 4 2011; 144(5): 646–674. Publisher Full Text\n\nPostow MA, Callahan MK, Wolchok JD: Immune Checkpoint Blockade in Cancer Therapy. J. Clin. Oncol. Jun 10 2015; 33(17): 1974–1982. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFlecken T, Schmidt N, Hild S, et al.: Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology. Apr 2014; 59(4): 1415–1426. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZheng C, Zheng L, Yoo JK, et al.: Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell. Jun 15 2017; 169(7): 1342–1356.e16. PubMed Abstract | Publisher Full Text\n\nPeggs KS, Quezada SA, Korman AJ, et al.: Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr. Opin. Immunol. Apr 2006; 18(2): 206–213. PubMed Abstract | Publisher Full Text\n\nHan Y, Liu D, Li L: PD-1/PD-L1 pathway: current researches in cancer. Am. J. Cancer Res. 2020; 10(3): 727–742. PubMed Abstract\n\nBuchbinder EI, Desai A: CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am. J. Clin. Oncol. Feb 2016; 39(1): 98–106. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSnyder A, Makarov V, Merghoub T, et al.: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. Dec 4 2014; 371(23): 2189–2199. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcDermott DF, Lee JL, Ziobro M, et al.: Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma. J. Clin. Oncol. Mar 20 2021; 39(9): 1029–1039. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGettinger S, Rizvi NA, Chow LQ, et al.: Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J. Clin. Oncol. Sep 1 2016; 34(25): 2980–2987. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEl-Khoueiry AB, Sangro B, Yau T, et al.: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. Jun 24 2017; 389(10088): 2492–2502. 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Nov 1 2020; 6(11): e204564. Publisher Full Text\n\nSaung MT, Pelosof L, Casak S, et al.: FDA Approval Summary: Nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib. Oncologist. Sep 2021; 26(9): 797–806. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCui TM, Liu Y, Wang JB, et al.: Adverse Effects of Immune-Checkpoint Inhibitors in Hepatocellular Carcinoma. Onco Targets Ther. 2020; 13: 11725–11740. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSharma A, Seow JJW, Dutertre CA, et al.: Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma. Cell. Oct 15 2020; 183(2): 377–394.e21. PubMed Abstract | Publisher Full Text\n\nFinn RS, Qin S, Ikeda M, et al.: Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N. Engl. J. Med. May 14 2020; 382(20): 1894–1905. Publisher Full Text\n\nCheng AL, Qin S, Ikeda M, et al.: Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J. Hepatol. Apr 2022; 76(4): 862–873. PubMed Abstract | Publisher Full Text\n\nCasak SJ, Donoghue M, Fashoyin-Aje L, et al.: FDA Approval Summary: Atezolizumab Plus Bevacizumab for the Treatment of Patients with Advanced Unresectable or Metastatic Hepatocellular Carcinoma. Clin. Cancer Res. Apr 1 2021; 27(7): 1836–1841. Publisher Full Text\n\nFinn RS, Kudo M, Merle P, et al.: LBA34 Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann. Oncol. 09/01 2022; 33: S1401. Publisher Full Text\n\nRen Z, Xu J, Bai Y, et al.: Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. Jul 2021; 22(7): 977–990. PubMed Abstract | Publisher Full Text\n\nQin S, Chan SL, Gu S, et al.: Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. Sep 30 2023; 402(10408): 1133–1146. PubMed Abstract | Publisher Full Text\n\nKelley RK, Rimassa L, Cheng AL, et al.: Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. Aug 2022; 23(8): 995–1008. PubMed Abstract | Publisher Full Text\n\nMarron TU, Fiel MI, Hamon P, et al.: Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. Mar 2022; 7(3): 219–229. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKaseb AO, Hasanov E, Cao HST, et al.: Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. Mar 2022; 7(3): 208–218. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang W, Hu B, Han J, et al.: Surgery After Conversion Therapy With PD-1 Inhibitors Plus Tyrosine Kinase Inhibitors Are Effective and Safe for Advanced Hepatocellular Carcinoma: A Pilot Study of Ten Patients. Front. Oncol. 2021; 11: 747950. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhu XD, Huang C, Shen YH, et al.: Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations. Liver Cancer. Jul 2021; 10(4): 320–329. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHo WJ, Zhu Q, Durham J, et al.: Neoadjuvant Cabozantinib and Nivolumab Converts Locally Advanced HCC into Resectable Disease with Enhanced Antitumor Immunity. Nat. Can. Sep 2021; 2(9): 891–903. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBruix J, Takayama T, Mazzaferro V, et al.: Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. Oct 2015; 16(13): 1344–1354. Publisher Full Text\n\nHuang S, Li D, Zhuang L, et al.: A meta-analysis of the efficacy and safety of adjuvant sorafenib for hepatocellular carcinoma after resection. World J. Surg. Oncol. 2021/06/10 2021; 19(1): 168. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKudo M: Adjuvant Atezolizumab-Bevacizumab after Resection or Ablation for Hepatocellular Carcinoma. Liver Cancer. Aug 2023; 12(3): 189–197. PubMed Abstract | Publisher Full Text | Free Full Text\n\nExposito M, Akce M, Alvarez J, et al.: Abstract No. 526 CheckMate-9DX: phase 3, randomized, double-blind study of adjuvant nivolumab vs placebo for patients with hepatocellular carcinoma (HCC) at high risk of recurrence after curative resection or ablation. J. Vasc. Interv. Radiol. 03/01 2019; 30: S227–S228. Publisher Full Text\n\nKnox J, Cheng A, Cleary S, et al.: P-217A phase 3 study of durvalumab with or without bevacizumab as adjuvant therapy in patients with hepatocellular carcinoma at high risk of recurrence after curative hepatic resection or ablation: EMERALD-2. Ann. Oncol. 07/01 2019; 30: iv59–iv60. Publisher Full Text\n\nGoyal L, Zhu A, Cheng A-L, et al.: P024 KEYNOTE-937 trial in progress: adjuvant pembrolizumab for hepatocellular carcinoma and complete radiologic response after surgical resection or local ablation. Gut. 2021; 70: A22.1–A22.\n\nAli MY, Grimm CF, Ritter M, et al.: Activation of dendritic cells by local ablation of hepatocellular carcinoma. J. Hepatol. Nov 2005; 43(5): 817–822. PubMed Abstract | Publisher Full Text\n\nChiang CL, Chan ACY, Chiu KWH, et al.: Combined Stereotactic Body Radiotherapy and Checkpoint Inhibition in Unresectable Hepatocellular Carcinoma: A Potential Synergistic Treatment Strategy. Front. Oncol. 2019; 9: 1157. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChiang CL, Chiu KW, Lee FA, et al.: Combined Stereotactic Body Radiotherapy and Immunotherapy Versus Transarterial Chemoembolization in Locally Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis. Front. Oncol. 2021; 11: 798832. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nPeng Z, Fan W, Zhu B, et al.: Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH). J. Clin. Oncol. Jan 1 2023; 41(1): 117–127. PubMed Abstract | Publisher Full Text\n\nKudo M, Ueshima K, Ikeda M, et al.: Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut. Aug 2020; 69(8): 1492–1501. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRimassa L, Personeni N, Czauderna C, et al.: Systemic treatment of HCC in special populations. J. Hepatol. Apr 2021; 74(4): 931–943. Publisher Full Text\n\nMcNamara MG, Slagter AE, Nuttall C, et al.: Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur. J. Cancer. Dec 2018; 105: 1–9. PubMed Abstract | Publisher Full Text\n\nHuynh J, Cho MT, Kim EJ-H, et al.: Post hoc analysis in patients (pts) with unresectable hepatocellular carcinoma (uHCC) who progressed to Child-Pugh B (CPB) liver function in the phase III REFLECT study of lenvatinib (LEN). J. Clin. Oncol. 2021; 39(3_suppl): 298–298. Publisher Full Text\n\nD’Alessio A, Fulgenzi CAM, Nishida N, et al.: Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study. Hepatology. Oct 2022; 76(4): 1000–1012. Publisher Full Text\n\nBolondi L, Burroughs A, Dufour JF, et al.: Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin. Liver Dis. Nov 2012; 32(4): 348–359. 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}
|
[
{
"id": "254012",
"date": "21 Mar 2024",
"name": "Won-Mook Choi",
"expertise": [
"Reviewer Expertise Hepatocellular carcinoma",
"Chronic hepatitis B",
"Liver fibrogenesis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis review article well summarizes recent advancements in systemic therapy, including real-world studies as well as pivotal trials, and the expansion of therapeutic indications such as combination therapy with locoregional therapy. It provides a comprehensive overview of recent developments in the field. I hope the authors may find some of my suggestions useful for improving the manuscript.\nComment#1: Please provide the table summarizing major trials on neoadjuvant, adjuvant, and combination regimens involving systemic therapies. It will provide a clear overview of the current status of expanding indications of systemic therapies.\nComment #2: There are real-world studies and meta-analyses comparing immunotherapy-based treatment with TKIs in both 1st line and 2nd line or beyond settings. Summarizing these studies would enhance the manuscript.\nComment #3: Please distinguish between the STAH trial, which evaluated the efficacy of TACE plus sorafenib and did not show an extension in OS, and the LAUNCH trial, which evaluated the efficacy of TACE plus lenvatinib and confirmed an extension in OS, compared with each TKI monotherapy.\nComment #4: Sorafenib, regorafenib, and lenvatinib also exhibit VEGF inhibition effects. Please modify the Figure 1 accordingly.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "11453",
"date": "07 May 2024",
"name": "Man-Fung Yuen",
"role": "Author Response",
"response": "Comment#1: Please provide the table summarising major trials on neoadjuvant, adjuvant, and combination regimens involving systemic therapies. It will provide a clear overview of the current status of expanding indications of systemic therapies. Response: Thank you for your helpful comment. We have added a table to provide description on the major trials on neoadjuvant, adjuvant and combination regimens. We agree that this will make it clearer for readers. (Table 3) Comment #2: There are real-world studies and meta-analyses comparing immunotherapy-based treatment with TKIs in both 1st line and 2nd line or beyond settings. Summarising these studies would enhance the manuscript. Response: Thank you for your comments. We have added a description on meta-analysis data about immunotherapy + TKI in 1st line/ 2nd line settings. (Combination regimens involving immunotherapy section: last paragraph) Comment #3: Please distinguish between the STAH trial, which evaluated the efficacy of TACE plus sorafenib and did not show an extension in OS, and the LAUNCH trial, which evaluated the efficacy of TACE plus lenvatinib and confirmed an extension in OS, compared with each TKI monotherapy. Response: Thank you for your comments. We have now specifically mentioned the comparison between the STAH trial and the LAUNCH trial in our section on combination therapy. (Combination of systemic therapies with loco-regional therapy section: 3rd paragraph) Comment #4: Sorafenib, regorafenib, and lenvatinib also exhibit VEGF inhibition effects. Please modify the Figure 1 accordingly. Response: Thank you for your comments. We have updated Figure 1 accordingly."
}
]
},
{
"id": "254015",
"date": "23 Mar 2024",
"name": "Shang-Chin Huang",
"expertise": [
"Reviewer Expertise Hepatology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this review article, Wu et al. thoroughly summarized the current therapeutic regimens and recent advancements in systemic therapies against HCC. The content is well-organized and comprehensive. The tables and figure are adequate and informative. Since the manuscript is of significant scientific merit, I have only a few suggestions for your reference.\nSince this is a review article, readers may expect some expert opinions from the authors, in addition to the current summary of published studies and discussion. A paragraph or several key points of experts’ opinions on clinical perspective and future investigation direction may help at the end of the article. HCC is a heterogeneous cancer arising from different background environments and etiology, as mentioned by the authors. A table or figure summarizing the distinctions of each therapy (ex., anti-PD1 was less effective against NASH-HCC than other etiology, Lenvatinib seemed more effective than sorafenib among HBV-HCC, …) may help guide future investigations and clinical relevance.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "11454",
"date": "07 May 2024",
"name": "Man-Fung Yuen",
"role": "Author Response",
"response": "Comment #1 Since this is a review article, readers may expect some expert opinions from the authors, in addition to the current summary of published studies and discussion. A paragraph or several key points of experts’ opinions on clinical perspective and future investigation direction may help at the end of the article. Response: Thank you for your comments. We have added an additional paragraph at the end to discuss our opinions and future perspectives. (Discussion section: Last paragraph) Comment #2 HCC is a heterogeneous cancer arising from different background environments and etiology, as mentioned by the authors. A table or figure summarising the distinctions of each therapy (ex., anti-PD1 was less effective against NASH-HCC than other etiology, Lenvatinib seemed more effective than sorafenib among HBV-HCC, …) may help guide future investigations and clinical relevance. Response: Thank you for your insightful comments. We have expanded our Discussion section to further discuss the role of disease etiology on HCC treatment outcomes, highlighting the critical need for mechanistic studies and real-life data in this area. (Discussion section: 2nd paragraph)"
}
]
},
{
"id": "254024",
"date": "17 Apr 2024",
"name": "Leonardo Stella",
"expertise": [
"Reviewer Expertise HCC",
"cirrhosis",
"liver fibrosis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI really appreciate the work Trevor Kwan-Hung Wu et al. made with this review, that summarize last evidence about systemic treatment in hepatocellular carcinoma (HCC) landscape. Particularly, the review provides a comprehensive overview of systemic treatments for advanced HCC, spanning from sorafenib's introduction to recent combination therapies like atezolizumab plus bevacizumab or durvalumab plus tremelimumab. It explores expanded indications beyond advanced stages, including combination with locoregional therapies and potential neoadjuvant/adjuvant use. Acknowledging the importance of real-world efficacy, it highlights the need for further research in specific patient subgroups. Lastly, the study recognizes the evolving nature of HCC treatment, emphasizing personalized approaches based on advancing understanding and accumulating data. On the other side, the review lacks of specific real-world data on systemic treatment in diverse patient subgroups, and authors should underline how comparative analysis of efficacy and safety among different therapies is also insufficient, limiting insights for treatment selection. Additionally, there's a call for deeper exploration of liver disease etiology's influence on treatment outcomes and the necessity for further research to elucidate optimal therapy utilization and long-term effects.\nThere aren't major concerns. Some minor points are: - Authors should add last evidence on phase I/II studies who are leading to upcoming phase III trial on double ICI + bevacizumab are lacking, so I suggest including recent studies about double ICI + anti-VEGF: *Tiragolumab + Atezolizumab/Bevacizumab (Finn R, et. al., 2023 [Ref1 ]) *Relatlimab + Nivolumab/Bevacizumab (Sangro B, et. al., 2023 [Ref 2]) - Authors should expand the paragraph about triple combination (locoregional + TKI + ICI), and to write down latest news about Chinese studies about HAIC + TKI + ICI.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "11455",
"date": "07 May 2024",
"name": "Man-Fung Yuen",
"role": "Author Response",
"response": "On the other side, the review lacks of specific real-world data on systemic treatment in diverse patient subgroups, and authors should underline how comparative analysis of efficacy and safety among different therapies is also insufficient, limiting insights for treatment selection. Response: Thank you for your comments. We agree that there is a lack of real-world data in specific patient subgroups, and there is a lack of head-to-head studies between systemic therapy options. We have added additional discussion points in our article, highlighting the importance of further real-world data in guiding our treatment decisions. (Discussion section: Paragraph 1) Additionally, there's a call for deeper exploration of liver disease etiology's influence on treatment outcomes and the necessity for further research to elucidate optimal therapy utilization and long-term effects. Response: Thank you very much for your insightful comments. We agree that the role of liver disease etiology on treatment outcomes is a critical area of research. We have expanded our Discussion section to further discuss the role of disease etiology on HCC treatment outcomes, highlighting the need for mechanistic studies and real-life data in this area. (Discussion section: 2nd paragraph) There aren't major concerns. Some minor points are: - Authors should add last evidence on phase I/II studies who are leading to upcoming phase III trial on double ICI + bevacizumab are lacking, so I suggest including recent studies about double ICI + anti-VEGF: *Tiragolumab + Atezolizumab/Bevacizumab (Finn R, et. al., 2023 [Ref1 ]) *Relatlimab + Nivolumab/Bevacizumab (Sangro B, et. al., 2023 [Ref 2]) Response: Thank you for your comments. We have now added additional description about these 2 trials. (Combination regimens involving immunotherapy: 6th paragraph) - Authors should expand the paragraph about triple combination (locoregional + TKI + ICI), and to write down latest news about Chinese studies about HAIC + TKI + ICI. Response: Thank you for your comments, we have now expanded the paragraph on locoregional therapy + systemic therapy, and also included description on the Chinese studies on HAIC. (Combination of systemic therapies with loco-regional therapy section: 6th paragraph)"
}
]
}
] | 1
|
https://f1000research.com/articles/13-104
|
https://f1000research.com/articles/13-455/v1
|
07 May 24
|
{
"type": "Study Protocol",
"title": "Evaluation of intravenous magnesium sulphate on haemodynamic responses to laryngoscopy and tracheal intubation in surgeries of ear, nose and throat",
"authors": [
"Urvi Sawant",
"Jayashree Sen",
"Amreesh Paul",
"Jayashree Sen",
"Amreesh Paul"
],
"abstract": "Heart rate, arterial blood pressure, and arrhythmias significantly surge during laryngoscopy and intubation. Anesthesiologists constantly look for ways to minimize these unwanted reactions. Several medicinal interventions have been suggested to mitigate these side effects; intravenous magnesium sulphate injection is one such intervention. Magnesium sulphate is a divalent salt widely recognized for its capacity to lower sympathetic nervous system muscle cell excitability, which lowers blood pressure and causes vasodilation. It is approved as a medicine to treat preeclampsia and control blood pressure. Moreover, there is growing recognition of its benefits on hemodynamic parameters in patients suffering from ischemic infective endocarditis and heart disease. Magnesium is an asset for reducing negative cardiovascular reactions occurring at the time of laryngoscopy and intubation because of its capacity to reduce catecholamine synthesis from adrenergic nerve ends and the adrenal medulla. Intravenous magnesium sulphate will be used in this trial to assess its effect on reducing adverse hemodynamic responses in candidates for elective laryngoscopy and intubation for ENT surgeries.",
"keywords": [
"Haemodynamic response",
"Magnesium sulphate",
"Endotracheal intubation",
"laryngoscopy"
],
"content": "Introduction\n\nDue to the stimulation of the sympathetic-adrenal system, airway manipulation techniques such as laryngoscopy and orotracheal intubation cause a reflexive sympathetic reaction. This reaction may affect the neurohumoral and cardiovascular systems in various manners. The consequences include vasoconstriction, an increase in cardiac workload, a rise in the demand for coronary blood flow, and constricted coronary arteries that are incapable of withstanding this greater flow. As a result, the myocardium may not get enough oxygen in certain areas. Elevated blood pressure, rapid heart rate, and high levels of adrenaline and norepinephrine are the most prominent outcomes of this response.1–4 This response is usually transient, but elderly individuals and those with specific medical conditions—diabetes, heart failure, systemic arterial hypertension, coronary artery disease, cardiac arrhythmias, cerebrovascular disease, and pulmonary disorders—may be more susceptible to arrhythmias, myocardial ischemia or infarction, and cerebral haemorrhage.5\n\nMany strategies are being used to mitigate the hemodynamic reactions secondary to laryngoscopy and intubation. Utilizing various pharmacological techniques, such as topical anesthesia, narcotics, adrenoreceptor blockers, calcium channel blockers, sodium channel blockers, vasodilators like nitroglycerin, intravenous magnesium sulphate, and paracetamol, as well as ensuring deep anesthesia is among them.6\n\nRecently, it has been shown that magnesium sulphate, a medication used to prevent seizures in eclamptic patients, may also decrease the stress reactions brought on by tracheal intubation and laryngoscopy when given in small quantities.7–9 Inhibiting the adrenal glands’ secretion of catecholamines, magnesium sulphate (MgSO4) lowers the amount of adrenaline in the blood. Consequently, bradycardia, vasodilation, and atrial contractions are reduced.10–12 Therefore, in cases where other medications might not be appropriate, magnesium sulphate can be considered an alternative to other medicines for reducing the pressor response caused by laryngoscopy and tracheal intubation.\n\nTo evaluate the impact of intravenous magnesium sulphate on hemodynamic responses during tracheal intubation and laryngoscopy.\n\n\n\n• Primary objective: To assess magnesium sulfate’s influence on cardiovascular responses by evaluating vital signs, heart rate, and cardiac workload during laryngoscopy and orotracheal intubation.\n\n• Secondary objective\n\n○ To identify patient groups that may benefit from MgSO4 as a stress response attenuator, including elderly people or those with diabetes, coronary artery disease, and hypertension.\n\n○ To monitor and contrast any adverse reactions that could arise following the administration of magnesium sulphate.\n\n\nMethods\n\nStudy design – A prospective, randomized, double-blind clinical trial.\n\nStudy period – Two years.\n\nStudy setting – Department of Anaesthesiology in AVBRH and JNMC, Sawangi, Wardha.\n\nAllocation of patients – Patients will be allotted to the study groups by computer-generated randomization.\n\nStudy population – The study will be conducted on patients undergoing elective ENT surgeries, fulfilling the following.\n\n\n\n• Patients who provide a valid written and informed consent after understanding the study methodology.\n\n• Patients (20 to 60 years of age) weighing between 40 and 65 kgs of either gender.\n\n• Physical status I and II of the ASA.\n\n• Individuals posted for elective ENT surgery.\n\n\n\n• Patients denying to provide written and informed consent,\n\n• Patients posted for emergency surgery,\n\n• Patients with neurological, pulmonary, renal, hepatic, endocrine, or cardiovascular disease,\n\n• Patients with sinus bradycardia, heart blocks, conduction abnormalities, and those on digitalis, calcium channel blockers, α and β-agonists or antagonists,\n\n• Patients with a BMI above 35,\n\n• Pregnant and lactating females,\n\n• Patients with anticipated difficult airways,\n\n• Patients with known allergy to the study medication,\n\n• Any modifications required to the anesthesia procedure,\n\n• Laryngoscopy duration lasting longer than thirty seconds.\n\nFifty participants will be allocated evenly across two distinct categories, with group M receiving an intravenous dosage of magnesium sulphate (45 mg/kg) in 10 ml of normal saline. The group P – with the control population, will receive normal saline in the same quantity.\n\nThe website openepi.com was used to calculate the sample size (see Figure 1). Presuming mean arterial pressure immediately after intubation, a sample of 19 patients will be required to detect a minimum of 10% difference in the mean arterial pressure. The study will be conducted on a total of 50 patients to account for any possible dropouts.\n\nPrior to the procedure, a thorough pre-operative evaluation will be conducted. This will include monitoring vital signs, reviewing the outcomes of routine laboratory tests, and reviewing imaging study results. Additionally, a comprehensive systemic and general examination will be carried out. Before the procedure begins, patients will be given instructions to fast, commencing at midnight, and they will be given an oral dose of 0.5 mg of Alprazolam. Patients will be randomly assigned to one of two groups, each with 25 patients when they arrive in the operation room. An 18-gauge catheter will be used to cannulate a suitable peripheral vein. Following this, baseline vital signs will be recorded, and continuous monitoring of the ECG, non-invasive blood pressure, and pulse oximetry will commence. Pre-medication will be administered with 0.004 mg/kg of Glycopyrrolate, 0.08 mg/kg of Ondansetron, and 0.04 mg/kg of Midazolam given 10 minutes prior to induction. 100% oxygen will be used for pre-oxygenation via a mask. Before induction, the study drug will be administered over a period of one minute. Intravenous injections of propofol (around 2 mg/kg) till unconsciousness ensues, fentanyl (2 μg/kg), and vecuronium (0.1 mg/kg) to provide muscle relaxation will be used to induce general anesthesia. After the vecuronium injection, tracheal intubation will be performed around three minutes later. An expert anesthesiologist will perform the laryngoscopy utilizing a Macintosh curved blade laryngoscope, and an appropriate cuffed endotracheal tube will be used for orotracheal intubation. The study will only involve patients successfully intubated in a single attempt within 30 seconds. Surgical stimulation won’t be initiated until at least five minutes after the intubation. Positive pressure ventilation and 1.5% sevoflurane combined with a 50% oxygen-in-air mixture in a closed circuit will be used to maintain anesthesia. Fentanyl (1 μg/kg) will be administered for intraoperative analgesia, and lung ventilation will be adjusted to keep the end-tidal CO2 level at a range of 35 and 40 mmHg. After the procedure, IV neostigmine (0.04 mg/kg) and glycopyrrolate (0.002 mg/kg) will be used to reverse muscle relaxation. Notably, there will be no measurements of serum levels of magnesium sulphate (MgSO4) at any stage of the investigation.\n\nHemodynamic measures such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP) will be monitored at predetermined intervals during the laryngoscopy procedure. These time intervals comprise baseline assessments, post-administration of study drugs, and the first, third, and fifth minutes following intubation. Any episodes of arrhythmias, tachycardia, hypertension, or hypotension will be recorded. The rate-pressure product (RPP), computed as the product of HR and SBP, will be ascertained at the abovementioned intervals.\n\nAnalyzing and reporting data will involve comparing the two groups’ primary and secondary outcomes using the relevant statistical tests (e.g., chi-square test, t-test, Mann-Whitney U test).\n\nIf appropriate, subgroup analyses and multivariate regression models will be done. The relevant statistical program will be used for data analysis. The CONSORT criteria will be followed in reporting the results.\n\nArticle from this study will be published in an indexed journal\n\nThe data gathered from the observations, such as hemodynamic parameters and adverse effects, will be compared to the other group.\n\nData collection is ongoing.\n\n\nDiscussion\n\nThis research protocol aims to add to the growing body of information on physiological stress response attenuation during tracheal intubation and laryngoscopy. In this discussion, we examine the results from previous studies, drawing similarities and contrasts and determining the potential importance of our research. The effectiveness of intravenous magnesium sulphate in decreasing heart rate and arterial blood pressure to laryngoscopy in patients having head and neck procedures was reported by Sunil et al.13 This study established the foundation for magnesium sulfate’s potential usage. According to Misganaw et al.,14 administering magnesium sulphate and lidocaine pre-emptively effectively reduced the hemodynamic reactions caused by laryngoscopy and intubation. Notably, this study assessed the relative efficaciousness of lidocaine and magnesium sulphate, offering valuable information. In a dose-response investigation, Honarmand et al.15 discovered that magnesium sulphate, given in varying amounts, significantly reduced fluctuations in arterial pressure after laryngoscopy and intubation. Alterations in heart rate, however, were not significantly impacted. To assess the effectiveness of sublingual nitroglycerin and magnesium sulphate in reducing pressor responses, Kotwani et al. conducted a study.7 They discovered that both therapies were successful despite a brief increase in heart rate, highlighting that these responses were dose-dependent. The research conducted by Sen and Sen (2022) presents dexmedetomidine as a viable prophylactic method for reducing hemodynamic reactions to laryngoscopy and intubation during neurosurgery.6\n\nIf the proposed study’s results are per previous studies, they could have significant therapeutic implications. They might result in the development of consistent regulations for controlling physiological responses to stress during tracheal intubation and laryngoscopy. Physicians could choose interventions, dosage, and patient groups with more excellent knowledge. It is critical to recognize the possible drawbacks demonstrated by the preceding investigations, including individual variability and the setting of the processes. More research needs to be employed to understand the dose-dependent transitory rise in heart rate.\n\nIn summary, the study protocol can significantly contribute to the fields of anesthesia and critical care. It broadens previous research findings, provides fresh perspectives on dosage, and presents a novel strategy, giving medical professionals access to a broader range of therapeutic options. With the potential to improve patient outcomes and safety during laryngoscopy and tracheal intubation, the approach holds significant potential to enhance patient safety.\n\nEthical approval for conducting this study was sought from the Institution Ethics Committee Datta Meghe Institute of Higher Education and Research, Sawangi, Wardha, Maharashtra, India. Before the approval of the protocol, there was a comprehensive review of the objectives, methodology, risks and benefits that the participants may encounter, and adherence to ethical guidelines was established by the committee. The Institutional Ethical Committee has approved the conduct of the study with the reference number – DMIMS (DU)/IEC/2022/92 dated 20/07/2022. This ethics statement would serve as a declaration of the researchers’ dedication to ethically conducting the study without causing harm to any of the participants involved in the study.",
"appendix": "Data availability\n\nNo data is available with this article.\n\n\nReferences\n\nForbes AM, Dally FG: Acute hypertension during induction of anaesthesia and endotracheal intubation in normotensive man. Br. J. Anaesth. 1970; 42(7): 618–624. PubMed Abstract | Publisher Full Text\n\nMahajan L, Kaur M, Gupta R, et al.: Attenuation of the pressor responses to laryngoscopy and endotracheal intubation with intravenous dexmedetomidine versus magnesium sulphate under bispectral index-controlled anaesthesia: A placebo-controlled prospective randomised trial. Indian J. Anaesth. 2018; 62(5): 337–343. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSener EB, Ustun E, Ustun B, et al.: Hemodynamic responses and upper airway morbidity following tracheal intubation in patients with hypertension: Conventional laryngoscopy versus an intubating laryngeal mask airway. Clinics (Sao Paulo). 2012; 67(1): 49–54. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTalke P: The Effect of Tracheal Intubation-Induced Autonomic Response on Photoplethysmography. Anesthesiol. Res. Pract. 2017; 2017: 7646541–7646545. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStauffer JL, Olson DE, Petty TL: Complications and consequences of endotracheal intubation and tracheotomy. Am. J. Med. 1981; 70(1): 65–76. PubMed Abstract | Publisher Full Text\n\nSen B, Sen J: Dexmedetomidine for Attenuation of Sympathomimetic Response to Laryngoscopy and Tracheal Intubation in Neurosurgical Patients. J. Datta Meghe Inst. Med. Sci. Univ. 2022; 17(2): 399–404. Publisher Full Text\n\nKotwani M, Kotwani D, Laheri V: A comparative study of two doses of magnesium sulphate in attenuating haemodynamic responses to laryngoscopy and intubation. Int. J. Res. Med. Sci. 2016; 4(7): 2548–2555. Publisher Full Text\n\nCrowther C: Magnesium sulphate versus diazepam in the management of eclampsia: a randomized controlled trial. BJOG-Int. J. Obstet. Gy. 1990; 97(2): 110–117. PubMed Abstract | Publisher Full Text\n\nReinhart RA: Clinical correlates of the molecular and cellular actions of magnesium on the cardiovascular system. Am. Heart J. 1991; 121(5): 1513–1521. PubMed Abstract | Publisher Full Text\n\nJames MF, Beer RE, Esser JD: Intravenous magnesium sulfate inhibits catecholamine release associated with tracheal intubation. Anesth. Analg. 1989; 68(6): 772–776. PubMed Abstract\n\nGambling DR, Birmingham CL, Jenkins LC: Continuing medical education article: Magnesium and the anaesthetist. Can. J. Anaesth. 1988; 35(6): 644–654. Publisher Full Text\n\nParikka H, Toivonen L, Pellinen T, et al.: The influence of intravenous magnesium sulphate on the occurrence of atrial fibrillation after coronary artery by-pass operation. Eur. Heart J. 1993; 14(2): 251–258. PubMed Abstract | Publisher Full Text\n\nSunil R, Vijay S, Jerry P: The role of intravenous magnesium sulphate in attenuating pressor response to laryngoscopy and intubation in patients undergoing major head and neck surgeries. Ain-Shams J. Anaesthesiol. 2014; 7(3): 451–455. Publisher Full Text\n\nMisganaw A, Sitote M, Jemal S, et al.: Comparison of intravenous magnesium sulphate and lidocaine for attenuation of cardiovascular response to laryngoscopy and endotracheal intubation in elective surgical patients at Zewditu Memorial Hospital Addis Ababa, Ethiopia. Lionetti V, editor. PLoS One. 2021; 16(6): e0252465. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHonarmand A, Safavi M: Magnesium sulphate pretreatment to alleviate pain on propofol injection: A comparison with ketamine or lidocaine. Acute Pain. 2008; 10(1): 23–29. Publisher Full Text"
}
|
[
{
"id": "289047",
"date": "24 Jun 2024",
"name": "Wadii Thabet",
"expertise": [
"Reviewer Expertise Otorhinolaryngology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is a study protocol. It is well-written. The subject is very interesting. The main objective of the article is to assess magnesium sulfate’s influence on cardiovascular responses during laryngoscopy and orotracheal intubation. I think that this study protocol can significantly contribute to the field of anesthesia and can improve patient outcomes and safety during laryngoscopy and tracheal intubation. However, the main negative point of this study protocol is the small number of participants over a period of 2 years. Here are my comments:\n-Major point: Small number of participants +++\n-Minor points: 1/ Abstract: -You should talk briefly about your methodology 2/Methods: -Why did you choose intubation for only ENT surgeries? I think that hemodynamic responses during tracheal intubation for ENT or non-ENT surgeries are the same. -It would be better if you selected only patients who underwent direct laryngoscopy. -Furthermore, surgery for paraganglioma must be excluded.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "297600",
"date": "11 Jul 2024",
"name": "Imen Zouche",
"expertise": [
"Reviewer Expertise airway management"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction The introduction section of the article \"Evaluation of Intravenous Magnesium Sulphate on Haemodynamic Responses to Laryngoscopy and Tracheal Intubation in Surgeries of Ear, Nose and Throat\" is notably lengthy. However, it lacks a clear statement of the study's objective. To improve clarity, the authors should concisely state the objective of evaluating the effect of intravenous magnesium sulphate on haemodynamic responses during specific ENT surgeries. Methodology The methodology section do not identifies the primary outcome measure as the variation in systolic blood pressure. This parameter was crucial for determining the sample size required for the study. However, there are several issues that need addressing:\nPeriod Calculation: The methodology section inappropriately discusses the study period, which should be considered a result of the research. It is more appropriate to calculate and report the period upon the completion of the study rather than in the planning phase. Inclusion and Exclusion Criteria: The article currently does not distinguish between non-inclusion and exclusion criteria. For clarity and precision, these criteria should be distinctly categorized:\nNon-inclusion Criteria: Characteristics that prevent a potential participant from being considered for the study. For instance, age outside the specified range, pre-existing conditions, or medication use that contraindicates magnesium sulphate. Exclusion Criteria: Factors identified after potential participants have been considered for the study that necessitate their removal. Examples include adverse reactions during preliminary screening or discovery of undisclosed medical history that could affect haemodynamic responses.\n\nBy clearly defining these criteria, the authors would enhance the methodological transparency and reproducibility of their study.\nConclusion In summary, while the article presents a potentially valuable investigation into the effects of intravenous magnesium sulphate on haemodynamic responses during ENT surgeries, several methodological improvements are needed. The introduction should concisely state the research objective, the methodology must avoid prematurely reporting results like the study period, and a clear distinction between non-inclusion and exclusion criteria should be made. Addressing these issues will strengthen the study’s design and the clarity of its presentation\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-455
|
https://f1000research.com/articles/13-454/v1
|
07 May 24
|
{
"type": "Research Article",
"title": "Stem cell therapy outcome for diabetic erectile dysfunction: A pilot analysis",
"authors": [
"Gampo Alam Irdam",
"Dyandra Parikesit",
"Nur Rasyid",
"Widi Atmoko",
"Akmal Taher",
"Gampo Alam Irdam",
"Dyandra Parikesit",
"Widi Atmoko",
"Akmal Taher"
],
"abstract": "Background Many males encounter the condition of erectile dysfunction (ED), particularly individuals diagnosed with type 2 diabetes mellitus (DM). Stem cell therapy is a burgeoning treatment modality being explored for individuals with erectile dysfunction in the context of type 2 DM. Nevertheless, the available body of clinical evidence supporting its efficacy remains limited. This study aims to assess the effectiveness and safety of umbilical cord-derived mesenchymal stem cell (MSC) therapy in managing erectile dysfunction (ED) resulting from type 2 DM.\n\nMethods A randomized, double-blind, placebo-controlled trial was conducted at Dr. Cipto Mangunkusumo Hospital in Indonesia from October 2020 to January 2023. A total of 26 eligible patients were randomly assigned to two groups: one receiving intracavernosal injections of MSC and the other receiving a placebo. Follow-up assessments were conducted at baseline, month one, and month three. The primary outcomes were measured using the IIEF-5 questionnaire and dorsal artery peak systolic velocity (PSV). Metabolic markers were used as secondary outcomes.\n\nResults The IIEF-5 scores for both groups showed a significant increase (p < 0.001) from baseline to month three. There was no significant difference observed between the MSC and placebo groups. Moreover, no significant differences were observed in the PSV of the dorsal artery between the two groups (p>0.05). There were no significant differences in metabolic markers between the groups. The incidence of mild post-injection pain was reported by only 11% of individuals, indicating a low occurrence of adverse events.\n\nConclusions Intracavernous administration of MSC did not demonstrate superior efficacy compared to a placebo in improving metabolic or erectile function in diabetic males with erectile dysfunction. Additional research utilizing larger sample sizes and more extended follow-up periods is necessary.",
"keywords": [
"Stem cells",
"Erectile Dysfunction",
"Diabetes Mellitus",
"Intracavernosal injection"
],
"content": "Introduction\n\nErectile dysfunction (ED) is a complex condition that affects a growing number of men worldwide.1 One of the most common causes of ED is diabetes mellitus (DM), and the prevalence of ED in DM ranges from 35 to 85 percent.2 Vasculopathies, such as macrovasculopathies, microvasculopathies, and endothelial dysfunction, are crucial in developing ED in type 2 DM.3\n\nLifestyle modifications are the primary treatment for erectile dysfunction, followed by medication therapy with phosphodiesterase 5 inhibitors, intraurethral alprostadil, vacuum erectile devices, and extracorporeal shockwave therapy (ESWT).4 Although Phosphodiesterase-5 inhibitor (PDE5-I) has a reasonably high effectiveness, which ranges from 65-75%, it was found that there was a decrease in the efficacy of this class of drugs to 40-50% in ED patients due to type 2 DM, so its use is limited.5\n\nStem cell therapy has recently become the primary concern of experimental and clinical trials for the treatment of erectile dysfunction (ED). Numerous studies on stem cell self-renewal and differentiation have demonstrated that stem cell therapy offers promising regenerative medicine for erectile dysfunction.6 In animal models of ED, several types of stem cells, including bone marrow mesenchymal, adipose tissue-derived, and muscle-derived stem cells, have been studied to regenerate neuromuscular, vascular, endothelial, or smooth muscle. Multiple research projects have examined the possible therapeutic effects of stem cells using diverse populations and methodologies.7 Currently, human stem cell research on ED is still limited. There were only a few pilot studies with a limited number of subjects and inconclusive outcomes.8 Thus, this study aims to evaluate the effectiveness and safety of MSC as a treatment for ED caused by type 2 DM in humans.\n\n\nMethods\n\nThis study is a randomized, double-blind, placebo-controlled trial conducted at Dr. Cipto Mangunkusumo Hospital in Indonesia from October 2020 to January 2023. The study received ethical approval from FKUI-RSCM Health Research Ethics Committee numbered “KET-936/UN2.F1.ETIK/PPM.00.02/2019”, approved on 12th of August 2019. This study is a part of a larger clinical trial titled “Implantation Outcomes and Mechanisms of Action of Intracavernous Cord Mesenchymal Stem Cells in Patients with Erectile Dysfunction In Type 2 Diabetes Mellitus”. This study adheres with the Declaration of Helsinki. Participants provided written informed consent for their involvement in the study. The clinical study was registered at ClinicalTrials.gov (NCT04972890; 2021-07-06) (https://clinicaltrials.gov/study/NCT04972890?term=NCT04972890&rank=1), operated by the US National Institute of Health. When the trial first started, the authors of this study did not know about the policy of the International Committee of Medical Journal Editors (ICMJE), which requires all clinical trials to be registered prospectively. As soon as the authors became aware of this policy, this trial was immediately registered. The questionnaire and example consent form can be found as Extended data.38,39 This study adheres to the CONSORT guidelines.40,41\n\nThe study included sexually active men aged 18-65 who met the following criteria: they agreed to participate, had ED (as indicated by an IIEF-5 score of less than 22), had type 2 DM, and were not taking PDE-5 inhibitors. Patients with psychopathologies or mental retardation, a history of Peyronie’s disease, cerebrovascular disease, cancer, and moderate to severe risk of cardiovascular disease were excluded from the study. Subjects were randomly assigned to either the stem cells or placebo groups in a 1:1 ratio using simple random sampling with computer-generated random numbers. The investigators, treating clinicians, and subjects were all blinded.\n\nThe MSC product was manufactured and distributed by the Stem Cells Medical Technology, Integrated Service Unit of the Faculty of Medicine at Universitas Indonesia – Dr. Cipto Mangunkusumo in Jakarta, Indonesia. The stem cell harvesting and culture stages were conducted following the methodology developed by Pawitan et al.,9 which utilizes xeno-free materials. Mesenchymal stem cells as much as 15 x 106 MSC/2cc NaCl 0.9% were put into two sterile 1cc syringes. While a placebo was prepared using 2 cc of NaCl 0.9% solutions only. NaCl 0.9% solutions were supplied by Satoria Pharma, with an e-catalogue numbered “3526099002-OPA-034149472”.\n\nAfter completing mandatory screening, eligible participants received educational instruction from the research team regarding the procedure and the associated benefits, risks, and potential complications. Participants will be encouraged to inquire and articulate their comprehension of the research objectives and possible outcomes. At baseline, intracavernosal injections of either a placebo or stem cells were administered bilaterally in the penis. The patients were unaware of the intervention they received.\n\nThe patient underwent a one-hour post-procedure evaluation to determine the presence of complications before discharge. Side effect monitoring, including allergic reactions and pain, is conducted for 24 hours. Subjects were instructed to promptly notify the researcher of pain, swelling, bleeding, or any postoperative issues.\n\nEvery study participant received the same level of care. The participants received a standard treatment of PDE-5 inhibitors (specifically tadalafil) at a dosage of 1×2.5 mg for three months. A follow-up assessment was conducted on all experimental and control group participants at baseline, month 1, and month 3. The initial evaluation consisted of the IIEF-5 questionnaire, complete blood count, lipid profile, HbA1c, fasting blood glucose, total testosterone, and Doppler ultrasound. Testosterone and full blood count tests were conducted to rule out hypogonadism and other potential factors. The evaluation in the first and third months included administering the IIEF-5 questionnaire, lipid profile assessment, HbA1c and fasting blood glucose levels measurement, and Doppler ultrasound.\n\nThe study aimed to assess the efficacy and safety of MSC in treating ED in diabetic patients. The effectiveness of the intervention was assessed using the IIEF-5 questionnaire and PSV measurement throughout the follow-up period. Secondary objectives assessed lipid profile, HbA1c, and fasting blood glucose. Safety measures encompassed adverse effects, vital signs, and laboratory analysis.\n\nThe data were analysed using IBM SPSS Statistics version 25 software for Mac, where a copyright license has been obtained.10 Free alternative software include JASP, Jamovi and Sofa Statistics. Group comparisons were conducted using either the independent t-test or the Mann-Whitney test. Paired T-tests were used to compare individuals within the same group across different timelines. A repeated measures analysis of variance (ANOVA) was conducted to compare two groups at specific time intervals. A significance level of p<0.05 was used for all tests. The primary exploratory p-value was used to compare the means between the baseline and 3rd month of follow-up for most outcomes.\n\n\nResults\n\nBetween October 20, 2020, and January 20, 2023, 132 patients were screened for potential inclusion in the study. Ninety-six patients were excluded from the study due to their high risk of cardiovascular disease, history of cerebrovascular disease, cancer, or advanced age. The remaining ten patients opted out of participation due to concerns regarding genital injections. Therefore, the remaining 26 patients were randomly assigned to either the stem cells or the placebo group. Thirteen participants in the intervention group were administered stem cell therapy along with oral tadalafil, while another thirteen participants received a placebo along with oral tadalafil. One participant in the placebo group withdrew from the study due to an allergic reaction characterized by widespread skin rashes and itching, which was suspected to be caused by an allergy to tadalafil. Another patient was lost to follow-up. The provided diagram, labelled as Figure 1, is presented for reference. The patients were analysed according to their randomly assigned groups (intention-to-treat analysis). The IIEF-5 and laboratory comparison analysis included 24 patients, while the radiology analysis excluded two patients (one from each intervention group) due to incomplete data.\n\nTable 137 shows no statistically significant difference between groups in age, BMI, T2DM duration, ED duration, IIEF-5 value, fasting blood glucose (FBG), HbA1c, testosterone level, lipid profiles, and PSV dorsal artery.\n\nChanges in erectile function\n\nErectile function was assessed subjectively using the IIEF-5 questionnaire and objectively measured through the PSV of the dorsal artery. There was a statistically significant improvement in IIEF-5 scores (p<0.001) at month 3 compared to baseline in both the placebo and stem cell groups. Both groups did not show a statistically significant difference (p>0.05). Table 2 presents the relevant data. Both the stem cells and placebo groups demonstrated a gradual improvement in the IIEF-5 parameter [Figure 2].\n\n* Statistically significant.\n\nErectile function was objectively evaluated using a Doppler ultrasound examination to measure peak PSV in the dorsal artery. There was no statistically significant difference in PSV between the placebo and stem cell groups (p>0.05) [Figure 3]. Table 2 presents the relevant data.\n\nThe analysis revealed no statistically significant variations in HbA1c, FBG, total cholesterol, HDL, LDL, and triglyceride levels between the placebo and the stem cell groups during the follow-up periods. Table 2 presents the relevant data. In both groups, inconsistent improvement trends were observed across the follow-up periods for the parameters mentioned [Figure 4, Figure 5, Figure 6, and Figure 7].\n\nThree subjects (11%) experienced a minor adverse event. No complications or significant adverse events were observed after the intervention in either treatment group. The minor adverse event observed was post-injection pain, with a Visual Analogue Scale (VAS) rating ranging from 3 to 6. The pain typically lasted for approximately 3 to 5 days following the injection. One patient experienced atypical penile pain for up to 5 days following the injection, with no subsequent adverse effects. No urination, bleeding, or inflammation issues were observed following the injection. No patients experienced aggravated erectile function during the follow-up period. We observed a patient who experienced an allergic reaction, characterized by a skin rash and itch symptoms, following a 5-day treatment of tadalafil 2.5 mg. The drug was discontinued on day 10, and the symptoms resolved three weeks after discontinuation. Therefore, the patient was excluded from the analysis due to incomplete follow-up.\n\n\nDiscussion\n\nThis study is the first double-blinded, randomized, placebo-controlled trial examining the efficacy and safety of intracavernosal injection of stem cells in diabetic patients experiencing erectile dysfunction. The study demonstrated that intracavernosal injection is a safe and well-tolerated procedure throughout the follow-up period.\n\nThe sample size in this study exceeded that of Bahk et al.’s 201011 study on umbilical cord mesenchymal stem cells, which included 10 subjects (7 in the experimental group and 3 in the control group). This study had a larger sample size than other clinical studies examining the efficacy of different stem cells in treating erectile dysfunction.12–15\n\nBahk et al.11 analyzed subjects with a mean age of 69.5 years (age range 57-87 years). The age of the subjects in that study differed from this study (51.08 ± 8.9 years in the stem cell group; 49.77 ± 11.18 years in the control group) because most of the subjects involved were elderly.\n\nIn this study, the duration of type 2 diabetes mellitus (DM) ranged from 12 to 52 years, with a mean duration of 29.4 years. However, in the stem cell group, the duration of type 2 DM was significantly shorter, with a mean duration of 8.27 ± 6.91 years. Similarly, in the placebo group, the mean duration of type 2 DM was only 6.08 ± 4.071 years. The study encompassed all patients with varying degrees of erectile dysfunction, regardless of their response to prior medical treatment. Meanwhile, Bahk et al.11 recruited patients who had not responded to previous medical treatments (e.g., oral phosphodiesterase-5 inhibitors, prostaglandin E1 injections) for at least 6 months. All participants were in the process of receiving a penile prosthesis.\n\nThis study utilized a truncated version of the International Index of Erectile Function (IIEF-5) comprising five items to assess the occurrence and intensity of erectile dysfunction (ED). The five items were chosen based on their capacity to determine the presence of erectile dysfunction (ED), aligning with the definition of ED established by the National Institute of Health. The study examined the impact of various factors on erectile function and sexual satisfaction. The IIEF-5 was created and published by Rosen et al.16 This study utilized a truncated version of the International Index of Erectile Function (IIEF-5) comprising five items to assess the occurrence and intensity of erectile dysfunction (ED). The five items were chosen based on their capacity to determine the presence of erectile dysfunction (ED), aligning with the definition of ED established by the National Institute of Health. The study examined the impact of various factors on erectile function and sexual satisfaction. The IIEF-5 was created and published by Rosen et al.16 as a valid and straightforward diagnostic tool for clinical use. Laksita et al.17 has demonstrated the validity and reliability of the Indonesian IIEF-5 as a patient-reported outcome measure for assessing erectile dysfunction (ED) in illiterate middle-aged and adult men in Indonesia.\n\nThis study did not observe any statistically significant differences between the group receiving stem cells and the group receiving a placebo. Both groups showed an improvement in the IIEF-5 score during the follow-up phase. Adding stem cell injection did not yield significantly different outcomes in the treatment. This study presents contrasting findings compared to Bahk et al.11 observed a beneficial impact of intracavernous umbilical cord mesenchymal stem cells on ED in patients with type 2 DM despite not achieving a level of sexual function considered normal. Most (85.7%) of the experimental group observed increased penile hardness. Nevertheless, this heightened level of hardness remains inadequate for achieving effective penetration. Two subjects were able to achieve penetration, maintenance, and orgasm during sexual intercourse with the use of a PDE-5 inhibitor (sildenafil citrate 100 mg). These abilities were maintained by the subjects even after five months of treatment. The occurrence of penile erections facilitated by PDE5 inhibitors involves a complex interplay of mechanisms, with the indirect involvement of nitric oxide (NO) being a crucial factor that should not be disregarded.11\n\nErections are initiated by the release of NO from sinusoidal endothelial cells. Vasodilation induced by NO leads to venules being compressed between trabeculae and the tunica albuginea, resulting in blood retention within the blood vessels.18 Endothelial cells, cavernous smooth muscle cells, NO, and nerve cells play crucial roles in achieving an erection. However, DM has a detrimental effect on these components. Stem cells possess the capacity to differentiate into specific cell types, suggesting their potential for repairing damage and reinstating normal erectile function. Nevertheless, the precise mechanisms in this process still need to be understood and require additional investigation. This study employed unaltered human umbilical cord blood stem cells. Research has demonstrated that injecting mesenchymal stem cells modified with endothelial nitric oxide synthase (eNOS) into the corpus cavernosa of aged mice is more effective in improving ED.19,20\n\nSimilar to Bahk et al., this study administered around 15 million stem cells per patient. The quantity of stem cells obtained from 1 unit of umbilical cord blood is significantly lower than that obtained from adipose tissue or bone marrow. Hence, the limited number of stem cells employed in the treatment could explain the absence of substantial improvement observed between the experimental and control groups. Ning et al.21 reported that adipose tissue-derived stem cells could localize on the sinusoidal endothelium and form tube-like structures. This localization and formation were believed to be facilitated by fibroblast growth factor-2 (FGF-2). Lin et al.22 found that the IGF/IGFR pathway is involved in neuronal differentiation, and the FGF-2 pathway is involved in endothelial differentiation. Hence, the improvement of erectile dysfunction (ED) in diabetic patients observed in this study may be attributed to the activation of endogenous stem cells in the cavernous tissue. This activation can be facilitated by humoral factors or factors secreted by the stem cells themselves.\n\nThis study observed no significant difference in PSV between the stem cell treatment and control groups. No significant increase was observed in the analysis of PSV in groups when considering examination time. The color Doppler ultrasound examination of the penile vessels revealed that the average PSV of the dorsal artery in the intervention group was 16.64 ± 5.75, 21.3 ± 9.25, and 18.6 ± 8.46 at baseline, one month, and three months post-injection, respectively. This finding exhibits non-significant variations (p-value = 0.427). The mean PSV in the control group was 14.18±4.93, 18.93±11.22, and 18.6±8.46 at baseline, first month, and third month after injection, respectively. These values exhibited varying fluctuations but were not statistically significant (p = 0.355). The two groups had no significant difference in PSV (p = 0.990). The results of this study contrast with the findings of Levy et al.11 observed a statistically significant rise in penile blood flow following the administration of chorionic placental stem cells. However, it should be noted that not all participants achieved satisfactory erections without the use of oral medications. Levy et al. conducted a study that examined the same treatment in individuals with Peyronie’s Disease.23\n\nMirzaei et al.24conducted a study with a comparable sample size of 20 subjects, utilizing oral mucosal mesenchymal stem cells. Their findings were consistent with the present study. Stem cell injection is thought to significantly affect the PSV index in penile Doppler ultrasound, which serves as a potential indicator of enhanced sexual function in patients. The potential enhancement of erectile function in diabetic patients may be attributed to the capacity of stem cells to differentiate into endothelial cells, leading to an increase in angiogenic tissue within the penis.25 It is crucial to acknowledge that studies with a limited number of participants are likely to yield substantial improvements in PSV, leading to the need to consider the impact of small study effects on research.\n\nNo significant changes in fasting blood sugar (GDP), HbA1C, and lipid profiles were observed in either group in this study. In contrast to the study conducted by Bahk et al.,11 which utilized umbilical cord stem cells, the observed outcome of the present study was a reduction in GDP levels after a two-week treatment period. The experimental group patients maintained low blood glucose levels for 4 to 7 months compared to their levels before treatment. The experimental group demonstrated more consistent improvements in their DM conditions than the control group. Bahk et al.11 hypothesized that infused stem cells may spread systemically through the bloodstream, supporting Min’s hypothesis.26 They also predicted that these stem cells could migrate to other organs, such as the pancreas, positively affecting blood glucose levels. Ohta et al.27 discovered that autologous adipose mesenchymal stem cells significantly impacted HDL, LDL, and remnant-like particle (RLP) cholesterol levels. The study concluded that these stem cells may help prevent the formation of macrophage foam cells.\n\nThe study found no serious side effects during a three-month follow-up after stem cell injection. These findings align with the research results with various other types of stem cells. Bahk et al.,11 Ichim et al.,28 Garber et al.,29 and Yiou et al.30 Yiou et al.30 noted a decrease in haemoglobin due to bone marrow stem cell aspiration, but blood transfusion was not required—the study by Haahr et al.13 reported mild effects at the injection site (redness, swelling, hematoma of the scrotum and penis) or at the liposuction site, all of which resolved on their own. Levy et al.12 also reported mild irritation at the injection site that resolved within 48 hours. Al Demour et al.14 reported only minor side effects related to aspiration and injection site, with no side effects associated with the nervous, cardiovascular, respiratory, and gastrointestinal systems during two years of follow-up. Protogerou et al.31 also reported only minor side effects related to the injection site.\n\nMen with a diagnosis of type 2 DM often experience ED at an earlier stage, typically occurring 10 to 15 years earlier than in the general population.32 Additionally, individuals with this condition exhibit more severe symptoms of ED and experience a more significant decline in their overall quality of life when compared to the general population.33 Moreover, ED resulting from DM tends to pose more significant challenges in terms of treatment with phosphodiesterase 5 (PDE-5) inhibitors.34 Binmoammar et al. conducted a systematic review that examined five cross-sectional studies. Their findings indicate that patients with type 2 DM who have poor glycaemic control are more likely to experience ED.35\n\nUnderstanding the factors that influence response rates to PDE-5 inhibitors, which are common medications for the treatment of ED, is critical to maximizing treatment outcomes and exploring alternative therapies such as stem cell therapy. A cohort study evaluating individual response rates to PDE-5 inhibitors showed an overall response rate of 43%.36 However, response rates may vary depending on the cause of ED, with veno-occlusive cases showing a higher response rate and neurogenic causes leading to a lower response rate. Several factors have been identified as potential predictors of response rate to PDE-5 inhibitors. These factors include age, smoking habits, DM, hypertension, hyperlipidaemia, IIEF-5) score before treatment, time interval to achieve erection, and duration of erection. Univariate analysis showed that these factors significantly influenced the response to PDE-5 inhibitors. However, in multivariate analysis, age and IIEF-5 score before treatment remained significant predictors.36\n\nAge has been identified as a significant factor in influencing response to PDE-5 inhibitors, with older individuals tending to experience decreased response due to physiological changes that occur with age. Smoking habits, which are known to have a negative impact on heart health, also emerged as a predictor. Smoking can cause damage to blood vessels, which may reduce the effectiveness of PDE-5 inhibitors in improving erectile function.36 The pretreatment IIEF-5 score, which reflects erectile function before starting treatment, is also an important predictor. Individuals with lower baseline scores may experience a more significant increase in response to PDE-5 inhibitors. It should be noted that the predictor factors identified in this study likely also apply to response to stem cell therapy, which is a promising approach in the treatment of various conditions, including erectile dysfunction.36 Factors such as age, smoking habits, and baseline erectile function, which affect the response to PDE-5 inhibitors, may also affect the effectiveness of stem cell therapy.\n\nIn this study, there were insignificant findings related to the outcomes observed. This may be due to the advanced age of the research subjects involved. In addition, relatively low pretreatment IIEF-5 scores may explain the nonsignificant findings.\n\nThis study is the first in Indonesia to assess the efficacy of stem cell therapy in treating ED in patients with type 2 DM. To mitigate research bias, this study utilized a clinical trial design with an intervention group and a control group (double arm). Nevertheless, this study has various limitations. Currently, the assessment of this condition relies on a limited set of parameters, including the IIEF-5 score for subjective evaluation, radiological parameters, and laboratory data such as blood sugar and lipid profiles. Molecular and histochemical parameters are challenging to analyse due to the lengthy specimen processing time. Furthermore, the current number of subjects falls below the minimum requirement due to challenges in recruiting eligible and willing participants for this study. Thus, the present analysis results need more research power.\n\nWith time and funding limitations, the follow-up was short.\n\nFurther prospective studies should implement longer follow-ups.\n\nThe inclusion criteria could not guarantee that the participants got ED due to DM.\n\n\nConclusions\n\nIn summary, the administration of intracavernosal stem cell injections in diabetic patients with ED is deemed to be a safe procedure. However, it did not demonstrate superiority over placebo in improving the IIEF-5 scores, PSV dorsal artery measurements, HbA1c levels, total cholesterol levels, LDL levels, HDL levels, and triglyceride levels. No significant adverse events occurred following the injection. Additional clinical trials involving larger sample sizes and longer durations of follow-up are required to assess the efficacy of MSC therapy in diabetic patients experiencing ED.\n\n\nEthics and consent\n\nThis study is a randomized, double-blind, placebo-controlled trial conducted at Dr. Cipto Mangunkusumo Hospital in Indonesia from October 2020 to January 2023. The study received ethical approval from FKUI-RSCM Health Research Ethics Committee numbered “KET-936/UN2.F1.ETIK/PPM.00.02/2019”, approved on 12th of August 2019. This study adheres with the Declaration of Helsinki. Participants provided written informed consent for their involvement in the study. The clinical study was registered at ClinicalTrials.gov (NCT04972890), operated by the US National Institute of Health. All the participants included in this study have given their consent for the publication of their clinical details.",
"appendix": "Data availability\n\nFigshare: Stem cells Therapy Outcome for Diabetic Erectile Dysfunction, A Pilot Analysis – Database. https://doi.org/10.6084/m9.figshare.25230443. 37\n\nFigshare: Questionnaire - Stem cells Therapy Outcome for Diabetic Erectile Dysfunction, A Pilot Analysis (English). https://doi.org/10.6084/m9.figshare.25358035. 38\n\nFigshare: Informed Consent - Stem Cells Therapy Outcome for Diabetic Erectile Dysfunction, A Pilot Analysis (English). https://doi.org/10.6084/m9.figshare.25358020. 39\n\nFigshare: CONSORT checklist for ‘Stem cell therapy outcome for diabetic erectile dysfunction: A pilot analysis’. https://doi.org/10.6084/m9.figshare.25231799. 40\n\nFigshare: CONSORT flow diagram for ‘Stem cell therapy outcome for diabetic erectile dysfunction: A pilot analysis’. https://doi.org/10.6084/m9.figshare.25232447. 41\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nAyta IA, McKinlay JB, Krane RJ: The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int. 1999 Jul; 84(1): 50–56. PubMed Abstract | Publisher Full Text\n\nFedele D, Coscelli C, Santeusanio F, et al.: Erectile dysfunction in diabetic subjects in Italy. Gruppo Italiano Studio Deficit Erettile nei Diabetici. Diabetes Care. 1998 Nov; 21(11): 1973–1977. PubMed Abstract | Publisher Full Text\n\nShindel AW, Lue TF: Sexual Dysfunction in Diabetes.Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000 [cited 2023 Sep 29]; 92. : 37–38. PubMed Abstract Reference Source\n\nPorst H: Phosphodiesterase Type-5 Inhibitors: A Critical Comparative Analysis. EAU Update Ser. 2004 Jun; 2(2): 56–63. Publisher Full Text\n\nTsai YS, Lin JS, Lin YM: Safety and efficacy of alprostadil sterile powder (S. Po., CAVERJECT) in diabetic patients with erectile dysfunction. Eur Urol. 2000 Aug; 38(2): 177–183. PubMed Abstract | Publisher Full Text\n\nZhang H, Albersen M, Jin X, et al.: Stem cells: novel players in the treatment of erectile dysfunction. Asian J Androl. 2012 Jan; 14(1): 145–155. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeng W, Bivalacqua TJ, Hellstrom WJG, et al.: Gene and stem cell therapy for erectile dysfunction. Int J Impot Res. 2005 Dec; 17(Suppl 1): S57–S63. Publisher Full Text\n\nLokeshwar SD, Patel P, Shah SM, et al.: A Systematic Review of Human Trials Using Stem Cell Therapy for Erectile Dysfunction. Sex Med Rev. 2020 Jan; 8(1): 122–130. PubMed Abstract | Publisher Full Text\n\nPawitan JA, Yang Z, Wu YN, et al.: Towards Standardized Stem Cell Therapy in Type 2 Diabetes Mellitus: A Systematic Review. Curr Stem Cell Res Ther. 2018; 13(6): 476–488. PubMed Abstract | Publisher Full Text\n\nIBM Corporation: IBM SPSS Statistics for Mac, Version 25.0. Armonk, NY: IBM; 2017.\n\nBahk JY, Han H, Lee YS: Stem Cell Treatment for Complicated Diabetes. Int J Stem Cells. 2008 Nov; 1(1): 91–95. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLevy JA, Marchand M, Iorio L, et al.: Determining the Feasibility of Managing Erectile Dysfunction in Humans With Placental-Derived Stem Cells. J Am Osteopath Assoc. 2016 Jan; 116(1): e1–e5. PubMed Abstract | Publisher Full Text\n\nHaahr MK, Jensen CH, Toyserkani NM, et al.: Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial. EBioMedicine. 2016 Jan 19; 5: 204–210. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAl Demour S, Jafar H, Adwan S, et al.: Safety and Potential Therapeutic Effect of Two Intracavernous Autologous Bone Marrow Derived Mesenchymal Stem Cells injections in Diabetic Patients with Erectile Dysfunction: An Open Label Phase I Clinical Trial. Urol Int. 2018; 101(3): 358–365. PubMed Abstract | Publisher Full Text\n\nYiou R, Hamidou L, Birebent B, et al.: Safety of Intracavernous Bone Marrow-Mononuclear Cells for Postradical Prostatectomy Erectile Dysfunction: An Open Dose-Escalation Pilot Study. Eur Urol. 2016 Jun; 69(6): 988–991. PubMed Abstract | Publisher Full Text\n\nRosen RC, Cappelleri JC, Smith MD, et al.: Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999 Dec; 11(6): 319–326. PubMed Abstract | Publisher Full Text\n\nLaksita TB, Kloping YP, Hakim L, et al.: Translation validity and reliability of the Indonesian version of the 5-item International Index of Erectile Function (IIEF-5). Turk J Urol. 2021 Nov; 47(6): 489–494. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReed-Maldonado AB, Lue TF: The Current Status of Stem-Cell Therapy in Erectile Dysfunction: A Review. World J Mens Health. 2016 Dec; 34(3): 155–164. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPu XY, Wang XH, Gao WC, et al.: Insulin-like growth factor-1 restores erectile function in aged rats: modulation the integrity of smooth muscle and nitric oxide-cyclic guanosine monophosphate signaling activity. J Sex Med. 2008 Jun; 5(6): 1345–1354. PubMed Abstract | Publisher Full Text\n\nAdenoviral gene transfer of eNOS: high-level expression in ex vivo expanded marrow stromal cells - PubMed.[cited 2023 Sep 29]. Reference Source\n\nNing H, Liu G, Lin G, et al.: Fibroblast Growth Factor 2 Promotes Endothelial Differentiation of Adipose Tissue-Derived Stem Cells. J Sex Med. 2009 Apr; 6(4): 967–979. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLin G, Banie L, Ning H, et al.: Potential of Adipose-Derived Stem Cells for Treatment of Erectile Dysfunction. J Sex Med. 2009 Mar; 6(Suppl 3): 320–327. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLevy JA, Marchand M, Iorio L, et al.: Effects of Stem Cell Treatment in Human Patients With Peyronie Disease. J Am Osteopath Assoc. 2015 Oct; 115(10): e8–e13. PubMed Abstract | Publisher Full Text\n\nMirzaei M, Bagherinasabsarab M, Pakmanesh H, et al.: The Effect of Intracavernosal Injection of Stem Cell in the Treatment of Erectile Dysfunction in Diabetic Patients: A Randomized Single-blinded Clinical Trial. Urol J. 2021 Oct 13; 18(6): 675–681. PubMed Abstract | Publisher Full Text\n\nCurrent Perspectives on Stem Cell Therapy for Erectile Dysfunction - PubMed.[cited 2023 Sep 29]. Reference Source\n\nMin JY, Yang Y, Sullivan MF, et al.: Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells. J Thorac Cardiovasc Surg. 2003 Feb; 125(2): 361–369. PubMed Abstract | Publisher Full Text\n\nAutologous adipose mesenchymal stem cell administration in arteriosclerosis and potential for anti-aging application: a retrospective cohort study - PubMed.[cited 2023 Sep 29]. Reference Source\n\nIchim TE, Warbington T, Cristea O, et al.: Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction? J Transl Med. 2013 Jun 9; 11: 139. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarber M: Intracavernous Administration of Adipose Stem Cells: A New Technique of Treating Erectile Dysfunction in Diabetic Patient, Preliminary Report of 6 Cases. MOJ Cell Sci Rep. 2015 Mar 15; 2: 18–22. Publisher Full Text\n\nYiou R, Hamidou L, Birebent B, et al.: Intracavernous Injections of Bone Marrow Mononucleated Cells for Postradical Prostatectomy Erectile Dysfunction: Final Results of the INSTIN Clinical Trial. Eur Urol Focus. 2017 Dec; 3(6): 643–645. PubMed Abstract | Publisher Full Text\n\nProtogerou V, Michalopoulos E, Mallis P, et al.: Administration of Adipose Derived Mesenchymal Stem Cells and Platelet Lysate in Erectile Dysfunction: A Single Center Pilot Study. Bioengineering. 2019 Mar 5; 6(1): 21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFeldman HA, Goldstein I, Hatzichristou DG, et al.: Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994 Jan; 151(1): 54–61. PubMed Abstract | Publisher Full Text\n\nDo impotent men with diabetes have more severe erectile dysfunction and worse quality of life than the general population of impotent patients? Results from the Exploratory Comprehensive Evaluation of Erectile Dysfunction (ExCEED) database - PubMed.[cited 2023 Sep 29]. Reference Source\n\nGoldstein I, Lue TF, Padma-Nathan H, et al.: Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998 May 14; 338(20): 1397–1404. Publisher Full Text\n\nBinmoammar TA, Hassounah S, Alsaad S, et al.: The impact of poor glycaemic control on the prevalence of erectile dysfunction in men with type 2 diabetes mellitus: a systematic review. JRSM Open. 2016 Mar; 7(3): 2054270415622602. PubMed Abstract | Publisher Full Text\n\nChia SJ, Ramesh K, Earnest A: Clinical application of prognostic factors for patients with organic causes of erectile dysfunction on 100 mg of sildenafil citrate. Int J Urol Off J Jpn Urol Assoc. 2004 Dec; 11(12): 1104–1109. Publisher Full Text\n\nRasyid N: Stem cells Therapy Outcome for Diabetic Erectile Dysfunction, A Pilot Analysis - Database. [Dataset]. figshare. 2024. Publisher Full Text\n\nRasyid N: Questionnaire - Stem cells Therapy Outcome for Diabetic Erectile Dysfunction, A Pilot Analysis (English). figshare. 2024. Publisher Full Text\n\nRasyid N: Informed Consent - Stem Cells Therapy Outcome for Diabetic Erectile Dysfunction, A Pilot Analysis (English). figshare. 2024. Publisher Full Text\n\nRasyid N: Stem cells Therapy Outcome for Diabetic Erectile Dysfunction, A Pilot Analysis - Consort Checklist. figshare. 2024. Publisher Full Text\n\nRasyid N: Stem cells Therapy Outcome for Diabetic Erectile Dysfunction, A Pilot Analysis - Consort Flow Diagram. figshare. Figure. 2024. Publisher Full Text"
}
|
[
{
"id": "316938",
"date": "15 Oct 2024",
"name": "Gordon Muir",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study demonstrated that intracavernosal injection is a safe and well-tolerated procedure throughout the follow-up period. The use of ICI in diabetic men is hardly new, so this conclusion from a very small group is irrelevant and should be removed.\nIn the conclusions, rather than calling for larger studies, the authors would be better to say something along the lines of \"This study shows the large placebo effect in ED treatment and confirms the need for control arms in any study of new technology. Men should not be offered treatments which have no proof of evidence against placebo. This version of stem cell treatment appears to offer no additional benefit over placebo.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "295287",
"date": "17 Oct 2024",
"name": "Mohammad Ayodhia Soebadi",
"expertise": [
"Reviewer Expertise erectile dysfunction",
"uroandrology",
"reconstructive urology",
"male sexual dysfunction",
"erectile physiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis submission contains an initial, 'pilot', report of a double-blinded placebo-controlled RCT, the first rigorous methodological evaluation for intracavernous stem cells in erectile dysfunction. The manuscript is well written, however some sections may benefit from review and copywriting, i.e. mention of irrelevant statistical software and the final limitations section presented brief bullet points.\nThe introduction sets the current state of research accurately, with relevant previous trials cited. The study design was detailed in the protocol registered online. We suggest addition of specific details for future replication, including - inclusion criteria detailed as per registration, exclusion criteria with details of cardiovascular criteria referenced/applied - MSC production did not mention the biological tissue source except umbilical MSC in the abstract introduction and no reference to stem cell marker characterization. - sample size calculation and assumptions. - protocol for doppler ultrasound measurement, number of sonographers or qualifications, results from other doppler measurements mentioned in protocol (end diastolic volume and pulsatility index)\nIn the results section, caption/details should be clarified in Tables 1 and 2 for values, whether means/medians and standard deviation are presented with/without brackets\nSustained improvement in IIEF-5 observed in both groups during the study period coincide with duration of daily PDE5 inhibitor administration, albeit at a low dose. Whether any subjects benefit longer than the study may be followed up. Additionally, there is mention of subjects reporting successful intercourse with additional Sildenafil. The rate of supplementary on demand medications was not mentioned otherwise. The final sentences in the IIEF-5 section, regarding humoral factors from activated endogenous stem cells may not be supported by the current study findings. Discussion of factors affecting outcomes include smoking, which may be added to the baseline characteristics of patients. The weakness regarding molecular and histochemical parameters mentioned, although part of the protocol is unclear. Finally, the suggestion of additional research power necessary and expected results may be further detailed.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-454
|
https://f1000research.com/articles/11-59/v1
|
18 Jan 22
|
{
"type": "Software Tool Article",
"title": "BASiCS workflow: a step-by-step analysis of expression variability using single cell RNA sequencing data",
"authors": [
"Alan O'Callaghan",
"Nils Eling",
"John C. Marioni",
"Catalina A. Vallejos",
"Alan O'Callaghan",
"Nils Eling",
"John C. Marioni"
],
"abstract": "Cell-to-cell gene expression variability is an inherent feature of complex biological systems, such as immunity and development. Single-cell RNA sequencing is a powerful tool to quantify this heterogeneity, but it is prone to strong technical noise. In this article, we describe a step-by-step computational workflow that uses the BASiCS Bioconductor package to robustly quantify expression variability within and between known groups of cells (such as experimental conditions or cell types). BASiCS uses an integrated framework for data normalisation, technical noise quantification and downstream analyses, propagating statistical uncertainty across these steps. Within a single seemingly homogeneous cell population, BASiCS can identify highly variable genes that exhibit strong heterogeneity as well as lowly variable genes with stable expression. BASiCS also uses a probabilistic decision rule to identify changes in expression variability between cell populations, whilst avoiding confounding effects related to differences in technical noise or in overall abundance. Using a publicly available dataset, we guide users through a complete pipeline that includes preliminary steps for quality control, as well as data exploration using the scater and scran Bioconductor packages. The workflow is accompanied by a Docker image that ensures the reproducibility of our results.",
"keywords": [
"single-cell RNA sequencing",
"expression variability",
"transcriptional noise",
"differential expression testing",
"scRNAseq",
"Bayesian",
"bioinformatics",
"heterogeneity"
],
"content": "Introduction\n\nSingle-cell RNA-sequencing (scRNA-seq) enables the study of genome-wide cell-to-cell transcriptional heterogeneity that is not captured by bulk experiments.1–3 On the broadest level, this heterogeneity can reflect the presence of distinct cell subtypes or states. Alternatively, it can be due to gradual changes along biological processes, such as development and differentiation. Several clustering and pseudotime inference tools have been developed to capture these types of heterogeneity.4,5 However, there is a limited availability of computational tools tailored to study more subtle variability within seemingly homogeneous cell populations. This variability can reflect deterministic or stochastic events that regulate gene expression and, among other settings, has been seen to increase prior to cell fate decisions6 and during ageing.7 Transcriptional variability has also been observed to differ from gene to gene and can be conserved across cell types and species.8\n\nStochastic variability within a seemingly homogeneous cell population — often referred to as transcriptional noise — can arise from intrinsic and extrinsic sources.9,10 Extrinsic noise refers to stochastic fluctuations induced by different dynamic cellular states (e.g. cell cycle, metabolism, intra/inter-cellular signalling).11–13 In contrast, intrinsic noise arises from stochastic effects on biochemical processes such as transcription and translation.9 Intrinsic noise can be modulated by genetic and epigenetic modifications (such as mutations, histone modifications, CpG island length and nucleosome positioning)14–16 and usually occurs at the gene level.9 Cell-to-cell gene expression variability estimates derived from scRNA-seq data capture a combination of these effects, as well as deterministic regulatory mechanisms.10 Moreover, these variability estimates can also be inflated by the technical noise that is typically observed in scRNA-seq data.17\n\nDifferent strategies have been incorporated into scRNA-seq protocols to control or attenuate technical noise. For example, external RNA spike-in molecules (such as the set introduced by the External RNA Controls Consortium, ERCC18) can be added to each cell’s lysate in a (theoretically) known fixed quantity. Spike-ins can assist quality control steps,19 data normalisation20 and can be used to infer technical noise.17 Another strategy is to tag individual cDNA molecules using unique molecular identifiers (UMIs) before PCR amplification.21 Reads that contain the same UMI can be collapsed into a single molecule count, attenuating technical variability associated to cell-to-cell differences in amplification and sequencing depth (these technical biases are not fully removed unless sequencing to saturation20). However, despite the benefits associated to the use of spike-ins and UMIs, these are not available for all scRNA-seq protocols.22\n\nThe Bioconductor package BASiCS implements a Bayesian hierarchical framework that accounts for both technical and biological sources of noise in scRNA-seq datasets.23–25 BASiCS jointly performs data normalisation, technical noise quantification and downstream analyses, whilst propagating statistical uncertainty across these steps. These features are implemented within a probabilistic model that builds upon a negative binomial framework, a widely used distribution in the context of bulk and scRNA-seq experiments.26–28 Critically, BASiCS enables the quantification of transcriptional variability within a population of cells, while accounting for the overall mean-variance relationship that typically arises in scRNA-seq data.29 Furthermore, when available, BASiCS can also leverage extrinsic spike-in molecules to aid data normalisation.\n\nThis article complements existing scRNA-seq workflows based on the Bioconductor ecosystem (e.g. Refs. 30, 31), providing a detailed framework for transcriptional variability analyses using BASiCS. We describe a step-by-step workflow that uses scater19 and scran30 to perform quality control (QC) as well as initial exploratory analyses. Our analysis pipeline includes practical guidance to assess the convergence of the Markov Chain Monte Carlo (MCMC) algorithm that is used to infer model parameters in BASiCS, as well as recommendations to interpret and post-process the model outputs. Finally, through a case study in the context of mouse immune cells, we illustrate how BASiCS can identify highly and lowly variable genes within a cell population, as well as to compare expression profiles between experimental conditions or cell types.\n\nAll source code used to generate the results presented in this article is available in Github and Zenodo.32 To ensure the reproducibility of this workflow, the analysis environment and all software dependencies are provided as a Docker image.33 The image can be obtained from Docker Hub.\n\n\nMethods\n\nThe BASiCS Bioconductor package uses a Bayesian hierarchical framework that borrows information across all genes and cells to robustly quantify transcriptional variability.34 Similar to the approach adopted in scran, BASiCS infers cell-specific global scaling normalisation parameters. However, instead of inferring these as a pre-processing step, BASiCS uses an integrated approach wherein data normalisation and downstream analyses are performed simultaneously, thereby propagating statistical uncertainty. To quantify technical noise, the original implementation of BASiCS uses information from extrinsic spike-in molecules as control features, but the model has been extended to address situations wherein spike-ins are not available.29\n\nBASiCS summarises the expression pattern for each gene through gene-specific mean and over-dispersion parameters. Mean parameters μi quantify the overall expression for each gene i across the cell population under study. In contrast, δi captures the excess of variability that is observed with respect to what would be expected in a homogeneous cell population, beyond technical noise. BASiCS uses δi as a proxy to quantify transcriptional variability. To account for the strong relationship that is typically observed between gene-specific mean expression and over-dispersion estimates, Eling et al.29 introduced a joint prior specification for these parameters. This joint prior has been observed to improve posterior inference when the data is less informative (e.g. small sample size, lowly expressed genes), borrowing information across all genes (and cells) to infer an overall trend that captures the relationship between mean and over-dispersion. The trend is then used to derive gene-specific residual over-dispersion parameters εi that are not confounded by mean expression. Similar to the DM values implemented in scran, these are defined as deviations with respect to the overall trend.\n\nWithin a population of cells, BASiCS decomposes the total observed variability in expression measurements into technical and biological components.23 This enables the identification of highly variable genes (HVGs) that capture the major sources of heterogeneity within the analysed cells.17 HVG detection is often used as feature selection, to identify the input set of genes for subsequent analyses. BASiCS can also highlight lowly variable genes (LVGs) that exhibit stable expression across the population of cells. These may relate to essential cellular functions and can assist the development of new data normalisation or integration strategies.8\n\nBASiCS also provides a probabilistic decision rule to perform differential expression analyses between two pre-specified groups of cells.24,29 While several differential expression tools have been proposed for scRNA-seq data (e.g. Refs. 35, 36), some evidence suggests that these do not generally outperform popular bulk RNA-seq tools.37 Moreover, most of these methods are only designed to uncover changes in overall expression, ignoring the more complex patterns that can arise at the single cell level.38 Instead, BASiCS embraces the high granularity of scRNA-seq data, uncovering changes in cell-to-cell expression variability that are not confounded by differences in technical noise or in overall expression.\n\nThis step-by-step scRNA-seq workflow is primarily based on the Bioconductor package ecosystem39 for the R programming language,40 and as such should run on any major operating system using R ≥ 4.0. A graphical overview is provided in Figure 1 and its main components are described below. The libraries listed below are required for this workflow, all of which can be downloaded from Bioconductor. Alternatively, we provide a Docker image containing all of the software necessary to run BASiCS at https://hub.docker.com/r/alanocallaghan/bocker/.\n\nStarting from a matrix of expression counts, we use the scater and scran Bioconductor packages to perform QC and initial exploratory analyses. To robustly quantify transcriptional heterogeneity within seemingly homogeneous cell populations, we apply the BASiCS Bioconductor package and illustrate how BASiCS can be used to analyse a single or multiple pre-specified groups of cells.\n\nWe use the package SingleCellExperiment to convert an input matrix of raw read counts (molecule counts for UMI-based protocols) into a SingleCellExperiment object that can also store its associated metadata, such as gene- and cell-specific information. Moreover, when available, the same object can also store read counts for spike-in molecules (see help(\"altExp\")). A major advantage of using a SingleCellExperiment object as the input for scRNA-seq analyses is the interoperability across a large number of Bioconductor packages.39\n\nA critical step in scRNA-seq analyses is QC, removing low quality samples that may distort downstream analyses. In this step, we use QC diagnostics to identify and remove samples that correspond to broken cells, that are empty, or that contain multiple cells.41 We also typically remove lowly expressed genes that represent less reliable information. The OSCA online book provides an extensive overview on important aspects of how to perform QC of scRNA-seq data, including exploratory analyses.39\n\nHere, we use the Bioconductor package scater19 to calculate QC metrics for each cell (e.g. total read-count) and gene (e.g. percentage of zeroes across all cells), respectively. We also use the visualisation tools implemented in the scater to explore the input dataset and its associated QC diagnostic metrics. For further exploratory data analysis we use the Bioconductor package scran.30 The latter can perform global scaling normalisation, calculating cell-specific scaling factors that capture global differences in read-counts across cells (e.g. due to sequencing depth and PCR amplification).42 To quantify transcriptional variability, scran can infer an overall trend between mean expression and the squared coefficent of variation (CV2) for each gene. Variability estimates that are not confounded by this trend are then obtained via the DM approach.43 For each gene, these are defined as the distance between CV2 and a rolling median along the range of mean expression values. DM estimates enable exploratory analyses of transcriptional variability, but a measure of statistical uncertainty is not readily available. As such, gene-specific downstream inference (such as differential variability testing) is precluded.\n\n\nUse cases\n\nAs a case study, we use scRNA-seq data generated for CD4+ T cells using the C1 Single-Cell Auto Prep System (Fluidigm®). Martinez-Jimenez et al. profiled naive (hereafter also referred to as unstimulated) and activated (three hours using in vitro antibody stimulation) CD4+ T cells from young and old animals across two mouse strains to study changes in expression variability during ageing and upon immune activation.7 They extracted naive or effector memory CD4+ T cells from spleens of young or old animals, obtaining purified populations using either magnetic-activated cell sorting (MACS) or fluorescence activated cell sorting (FACS). External ERCC spike-in RNA18 was added to aid the quantification of technical variability across all cells and all experiments were performed in replicates (hereafter also referred to as batches).\n\nThe matrix with raw read counts can be obtained from ArrayExpress under the accession number E-MTAB-4888. In the matrix, column names contain library identifiers and row names display Ensembl gene identifiers.\n\nThe input matrix contains data for 1,513 cells and 31,181 genes, including 92 ERCC spike-ins.\n\nInformation about experimental conditions and other metadata is available under the same accession number.\n\nThe columns in the metadata file contain library identifiers ( X), strain information ( Strain; Mus musculus castaneus or Mus musculus domesticus), the age of the animals ( Age; young or old), stimulation state of the cells ( Stimulus; naive or activated), batch information ( Individuals; associated to different mice), and cell type information ( Celltype; via FACS or MACS purification).\n\nHere, we convert the data and metadata described above into a SingleCellExperiment object. For this purpose, we first separate the input matrix of expression counts into two matrices associated to intrinsic genes and external spike-ins, respectively. Within the SingleCellExperiment object, the latter is stored separately as an alternative experiment. For more details on the alternative experiment slot, see help(\"altExp\").\n\nHereafter, our analysis focuses on naive CD4+ T cells in the presence and absence of stimulation using plate-bound antibodies,+ obtained from young Mus musculus domesticus animals, and purified using MACS-based cell sorting. Thus, we subset the SingleCellExperiment object to these 146 cells.\n\nInput data was annotated using Ensembl gene identifiers. To facilitate interpretation, it is often useful to obtain a mapping from Ensembl gene IDs to gene symbols using the BioMart suite ( http://www.biomart.org) via the Bioconductor package biomaRt.44 This can also be used to obtain gene-pathways mappings and other metadata (e.g. gene length), useful for performing functional analysis of gene sets identified in downstream analyses.\n\nWe add this information as rowData within the SingleCellExperiment object created above.\n\nFor the remaining analysis, we will only focus on the 18,682 protein coding genes that are contained in the data. These are selected below.\n\nThe data available at E-MTAB-4888 have been filtered already to remove poor quality samples. The QC applied in Ref. 7 removed cells with: (i) fewer than 1,000,000 total reads, (ii) less than 20% of reads mapped to endogenous genes, (iii) less than 1,250 or more than 3,000 detected genes and (iv) more than 10% or fewer than 0.5% of reads mapped to mitochondrial genes. We include visualisations of these measures here; we also include another widely used QC diagnostic plot that compares the total number (or fraction) of spike-in counts versus the total number (or fraction) of endogeneous counts. In such a plot, low quality samples are characterised by a high fraction of spike-in counts and a low fraction of endogeneous counts (see Figure 2).\n\nThe total number of endogenous read-counts (excludes non-mapped and intronic reads) is plotted against the total number of detected genes (left) and the total number of spike-in read-counts (right).\n\nWe can also visualise these metrics with respect to cell-level metadata, such as the experimental conditions (active vs unstimulated) and the different mice from which cells were collected (see Figure 3).\n\nThe total number of endogenous reads (excludes non-mapped and intronic reads) is plotted against the total number of detected genes. Colour indicates the experimental condition (left) and animal of origin (right) for each cell.\n\nTo further explore the underlying structure of the data, we perform global scaling normalisation using scran and principal component analysis (PCA) of log-transformed normalised expression counts using scater. As seen in Figure 4, this analysis suggests the absence of strong batch effects. It should be noted that the estimation of global scaling normalisation factors using scran is not strictly necessary in the BASiCS workflow. Here, we only use it as part of the exploratory data analysis. Moreover, count-based models for dimensionality reduction (e.g. Refs. 28, 45) could be used as an alternative to PCA, removing the need for log normalisation.\n\nColour indicates the experimental condition (left) and animal of origin (right) for each cell.\n\nIn addition to cell-specific QC, we also recommend a gene filtering step prior to using BASiCS. The purpose of this filter is to remove lowly expressed genes that were largely undetected through sequencing, making reliable variability estimates difficult to obtain. Here, we remove genes that are not detected in at least 20 cells across both conditions, or that have an average read count below 1. These thresholds can vary across datasets and should be informed by gene-specific QC metrics such as those shown in Figure 5 as well as prior knowledge about the cell types and conditions being studied, where available.\n\nDashed grey lines are shown at the thresholds below which genes are removed.\n\nSubsequently, we also require users to remove spike-in molecules that were not captured through sequencing. We do this separately for naive and active cells.\n\nThe final dataset used in subsequent analyses contains 146 cells, 5171 genes and 49 spike-ins.\n\nHere, we apply BASiCS separately to cells from each experimental condition (93 naive and 53 activated cells). We create separate SingleCellExperiment objects for each group of cells.\n\nBASiCS requires these objects to be augmented with extra information in a specific format. If multiple batches of sequenced cells are available (e.g. multiple donors from which cells were extracted, sequencing batches from the same experimental condition), this must be indicated under the BatchInfo label as cell-level metadata.\n\nIf spike-ins will be used to aid data normalisation and technical noise quantification, BASiCS also requires the number of spike-in molecules that were added to each well. For each spike-in i, this corresponds to:\n\n• Ci is the concentration for the spike-in i (measured in aMμl−1),\n\n• V is the volume added into each well (measure in nl) and\n\n• D is a dilution factor.\n\nThe remaining factors in the equation above are unit conversion constants (e.g. from moles to molecules). For the CD4+ T cell data, the authors added a 1:50,000 dilution of the ERCC spike-in mix 1 and a volume of 9nl was added into each well. Finally, input concentrations Ci can be downloaded from https://assets.thermofisher.com/TFS-Assets/LSG/manuals.\n\nBased on this information, the calculation above proceeds as follows\n\nTo update the sce_naive and sce_active objects, the user must create a data.frame whose first column contains the spike-in labels (e.g. ERCC-00130) and whose second column contains the number of molecules calculated above. We add this as row metadata for altExp (sce_naive) and altExp (sce_active).\n\nParameter estimation is implemented in the BASiCS_MCMC function using an adaptive Metropolis within Gibbs algorithm (see section 3 in Ref. 46). The primary inputs for BASiCS_MCMC correspond to:\n\n• Data: a SingleCellExperiment object created as described in the previous sections.\n\n• N: the total number of MCMC iterations.\n\n• Thin: thining period for output storage (only the Thin-th MCMC draw is stored).\n\n• Burn: the initial number of MCMC iterations to be discarded.\n\n• Regression: if TRUE a joint prior is assigned to μi and δi,29 and residual over-dispersion values εi are inferred. Alternatively, independent log-normal priors are assigned to μi and δi.24\n\n• WithSpikes: if TRUE information from spike-in molecules is used to aid data normalisation and to quantify technical noise.\n\n• PriorParam: Defines the prior hyper-parameters to be used by BASiCS. We recommend to use the BASiCS_PriorParam function for this purpose. If PriorMu = \"EmpiricalBayes\", μi’s are assigned a log-normal prior with gene-specific location hyper-parameters defined via an empirical Bayes framework. Alternatively, if PriorMu = \"default\", location hyper-parameters are set to be equal 0 for all genes.\n\nAs a default, we recommend to use Regression = TRUE, as the joint prior introduced by Ref. 29 leads to more stable estimation, particularly for small sample sizes and lowly expressed genes. This approach also enables users to obtain a measure of transcriptional variability that is not confounded by mean expression. We also recommend to use PriorMu = \"EmpiricalBayes\" as we have observed that an empirical Bayes framework47 improves estimation performance for sparser datasets. Extra parameters can be used to store the output ( StoreChains, StoreDir, RunName) and to monitor the progress of the algorithm ( PrintProgress).\n\nHere, we run the MCMC sampler separately for naive and activated cells. We use 40,000 iterations ( N), discarding the initial 20,000 iterations ( Burn), and saving parameter values only once in each 20 iterations ( Thin). We recommend this setting as a default choice, as we have observed it to ensure good convergence across multiple datasets. However, fewer iterations may be sufficient for larger and less sparse datasets, and may be more feasible computationally for larger datasets. Practical guidance about MCMC convergence diagnostics is provided in the next section.\n\nThis first of these samplers takes 84 minutes to complete on a 3.4 GHz Intel Core i7 4770k procesor with 32GB RAM, while the second takes 69 minutes. For convenience, these can be obtained online at https://doi.org/10.5281/zenodo.5243265.\n\nThe output from BASiCS_MCMC is a BASiCS_Chain object that contains the draws associated to all model parameters. Given that N = 40,000, Thin = 20 and Burn = 20,000, the object contains 1,000 draws for each parameter. These can be accessed using the displayChainBASiCS function. For example, the following code displays the first 6 draws for mean expression parameters μi associated to the first 3 genes.\n\nBefore interpreting the estimates generated by BASiCS, it is critical to assess the convergence of the MCMC algorithm, i.e. whether the MCMC reached its stationary distribution. If convergence has been achieved, the trace for each parameter should not evolve significantly across iterations, as MCMC draws are expected to be stochastic fluctuations around a horizontal trend once the sampler has converged to its stationary distribution. It is not possible to prove convergence, but multiple graphical and quantitative convergence diagnostics have been proposed to assess the lack of convergence (e.g. Refs. 48, 49). Some advocate the use of multiple MCMC chains using different starting values in order to ensure that the algorithm consistently converges to the same distribution and to avoid convergence to local modes. For BASiCS, we have observed that using informed starting values (e.g. based on scran normalisation factors) and a sufficiently large value for N and Burn generally leads to largely consistent estimates across multiple MCMC runs. Hence, the focus of this section is to evaluate quantitative measures of convergence (e.g. Ref. 50) based on a single MCMC chain.\n\nTraceplots can be used to visually assess the history of MCMC iterations for a specific parameter (e.g. Figure 6, left panel). As mentioned above, significant departures from a horizontal trend suggest a lack of convergence. As illustrated in Figure 6, histograms can also be used to display the marginal distribution for each parameter. For BASiCS, users should expect these to follow a unimodal distribution. Failure to satisfy these graphical diagnostics suggest that N and Burn must be increased. Alternatively, more stringent quality control could be applied to the input data, as we have observed that genes with very low counts often suffer from slow convergence.\n\nTrace plots should explore the posterior without getting stuck in one location or drifting over time towards a region of higher density. High autocorrelation indicates that the number of effective independent samples is low. It is good practice to perform this visualisation for many different parameters; here we only show one.\n\nAs BASiCS infers thousands of parameters, it is impractical to assess these diagnostics separately for each parameter. Thus, it is helpful to use numerical diagnostics that can be applied to multiple parameters simultaneously. Here, we illustrate usage for two such metrics focusing on the MCMC chain that was obtained for the naive CD4+T cells (similar results were obtained for activated cells). First, we focus on the diagnostic criterion proposed by Geweke.50 The latter compares the average of draws obtained during the initial (10% after burn in, by default) and the final part of the chain (50% by default) by calculating Z-scores of the relative difference between the two sets of draws. Large absolute Z-scores suggest that the algorithm has not converged (as a rule of thumb, a threshold at |Z|<3 is often applied). For the naive and activatived CD4+ T datasets most Z-scores associated to mean expression parameters μi were small in absolute value (see Figure 7A), suggesting that the algorithm has largely converged.\n\nA: Geweke Z-score for mean expression parameters is plotted against mean expression estimates. Dashed lines represent absolute Z-scores of 3, outside of which we advise caution when interpreting results. B: Effective sample size (ESS) is plotted against mean expression estimates. A dashed line shows a threshold of 100, below which we advise caution when interpreting results.\n\nAs well as assessing MCMC convergence, it is important to ensure that the MCMC algorithm has efficiently explored the parameter space. For example, the autocorrelation function (e.g. Figure 6, right panel) quantifies the correlation between the chain and its lagged versions. Strong autocorrelation indicates that neighbouring MCMC samples are highly dependent and suggest poor sampling efficiency. The latter may indicate that the MCMC draws do not contain sufficient information to produce accurate posterior estimates. In other words, highly correlated MCMC samplers require more samples to produce the same level of Monte Carlo error for an estimate (defined as the variance of a Monte Carlo estimate across repetitions51).\n\nThe effective sample size (ESS) is a related measure which represents a proxy for the number of independent draws generated by the MCMC sampler.52 The latter is defined as:\n\nStudying gene-level transcriptional variability can provide insights about the regulation of gene expression, and how it relates to the properties of genomic features (e.g. CpG island composition16), transcriptional dynamics53 and aging,7 among others. The squared coefficient of variation (CV2) is widely used as a proxy for transcriptional variability. For example, we can obtain CV2 estimates for each gene using scran normalised counts as input. In contrast, BASiCS infers transcriptional variability using gene-specific over-dispersion parameters δi (see Methods). Here, we compare these approaches, focusing on naive CD4+ T cells (repeating this analysis for active cells led to similar results).\n\nAs seen in Figure 8A, CV2 and posterior estimates for δi are highly correlated. Moreover, both variability metrics are confounded by differences in mean expression, i.e. highly expressed genes tend to exhibit lower variability (Figure 8B–C). To remove this confounding, scran and BASiCS derive residual variability estimates as deviations with respect to an global mean-variability trend (see Methods). These are derived using the DM approach43 and the residual over-dispersion parameters εi defined by Ref. 29, respectively. For the naive CD4+ T cell data, both approaches led to strongly correlated estimates (Figure 8D) and, as expected, neither DM values nor posterior estimates for εi are seen to be associated with mean expression (Figure 8E–F). However, unlike the DM method, the integrated approach implemented in BASiCS provides a direct measure of statistical uncertainty for these estimates via posterior variance. Note that the BASiCS_ShowFit function can be used to generate Figure 8C, but we generated the plot manually to demonstrate how users can extract this information from a BASiCS_MCMC object, and for visual consistency with the other panels. For each of the panels in Figure 8, we use the R package ggpointdensity to visualise the local density of genes along the axes of mean and variability.\n\nFor this analysis, we exclude genes that are not expressed in at least two cells. BASiCS estimates for each gene are defined by the posterior median of the associated parameter. scran estimates for each gene are derived after applying the pooling normalisation strategy proposed by Lun et al. Points are coloured according to the local density of genes along the x- and y-axis. A: scran squared CV estimates versus BASiCS estimates for over-dispersion parameters. B: scran estimates for mean expression and the squared CV. C: BASiCS estimates for mean expression and over-dispersion parameters. D: BASiCS estimates for residual over-dispersion parameters versus distance-to-median (DM) values estimated by scran. E: scran estimates for mean expression and DM values. F: BASiCS estimates for mean expression and residual over-dispersion parameters. Dashed red lines in panels A and D represent the line given by x = y.\n\nIn BASiCS, the functions BASiCS_DetectHVG and BASiCS_DetectLVG can be used to identify genes with substantially high (HVG) or low (LVG) transcriptional variability within a population of cells. If the input BASiCS_Chain object was generated by BASiCS_MCMC with Regression = TRUE (recommended setting), this analysis is based on the posterior distribution obtained for gene-specific residual over-dispersion parameters εi (alternatively, the approach introduced by23 can be used). HVGs are marked as those for which εi exceeds a pre-defined threshold with high probability, where the probability cut-off is chosen to match a given expected false discovery rate (EFDR; by default the target EFDR is set to 10%).54 A similar approach is implemented for LVG detection, but based on whether εi is below a pre-specified threshold EpsilonThreshold. For example, if the threshold for εi is equal to log2 (the default), HVGs would be those genes for which the over-dispersion is estimated to be at least two times higher than would be expected given the inferred mean expression level, while LVGs would be those genes for which the residual over-dispersion is at least two times lower than would be expected on the same basis. In some circumstances, it may be of interest to rank genes and to select those with the highest or the lowest residual over-dispersion, which can be performed using the PercentileThreshold parameter; see help(\"BASiCS_DetectVG\") for more details.\n\nFor the naive CD4+ T cell data, we obtained 41 HVG and 380 LVG. As shown in Figure 9, these genes are distributed across a wide range of mean expression values. As an illustration, Figure 10 shows the distribution of normalised expression values for selected HVG and LVG, focusing on examples with similar mean expression levels. As expected, HVG tend to exhibit a wider distribution and potentially bimodal distribution (Figure 10A). Instead, LVG tend to have more narrow and unimodal distributions (Figure 10B).\n\nFor each gene, BASiCS posterior estimates (posterior medians) associated to mean expression and residual over-dispersion parameters are plotted. Genes are coloured according to HVG/LVG status. Genes that are not expressed in at least two cells are excluded.\n\nThis section highlights the use of BASiCS to perform differential expression tests for mean and variability between different pre-specified populations of cells and experimental conditions. Here, we compare the naive CD4+ T cells, analysed in the previous section, to activated CD4+ T cells analysed in the same study.7 Naive CD4+ T cells were activated for three hours using plate-bound CD3e and CD28 antibodies. T cell activation is linked to strong transcriptional shifts and the up-regulation of lineage specific marker genes, such as Tbx21 and Gata1.55,56 To generate this data, the authors did not add cytokines, which are needed for T cell differentiation.57 Therefore, any heterogeneity in the activated cell population does not arise from cells residing in different lineage-specific differentiation states.\n\nDifferential expression testing is performed via the BASiCS_TestDE function. The main input parameters are\n\n• Chain1 and Chain2: two BASiCS_Chain objects created via the BASiCS_MCMC function. Each object corresponds to a different pre-specified group of cells.\n\n• EpsilonM and EpsilonR: introduce a minimum effect size (in a log2 fold change scale) for the detection of changes in mean or residual over-dispersion, respectively. This enables us to discard small expression changes that are less biologically meaningful. By default, we set these thresholds to be equivalent to a 50% change between the groups. However, different thresholds may be required depending on the context. For example, if most genes show strong differences in mean expression, it can be beneficial to increase the value of EpsilonM to focus on strong changes in mean expression.\n\n• EFDR_M and EFDR_R: define the target EFDR to calibrate the decision rule associated to changes in mean or residual over-dispersion, respectively. Default: 10%.\n\n• MinESS: ESS threshold, below which genes will be excluded from the differential expression tests. This is used to increase the robustness of the results, excludes genes for which the sampler explored the parameter space less efficiently (see MCMC diagnostics Section). Default: MinESS = 100.\n\nAfter running the test, it is important to visualise the results to facilitate interpretation and to identify systematic patterns among differentially expressed genes. It may also be useful to perform functional enrichment analysis to identify biologically meaningful patterns among these genes. For example, this could be performed using the Bioconductor package goseq.58 We do not perform this here, but a relevant workflow is described by Maksimovic et al.59\n\nWe first focus on the differential mean expression test. MA-plots (log fold change M versus mean average A) and volcano plots (posterior probability versus log fold change) are popular graphical summaries in this context, and are presented in Figure 11. These can be useful in ensuring that suitable magnitude and confidence thresholds have been chosen. In this instance, it is clear that a large number of genes are differentially expressed between the two conditions, and the selected probability threshold is suitable.\n\nLog-fold changes of average expression in naive cells relative to active cells are plotted against average expression estimates combined across both groups of cells. Bottom panel presents the volcano plot associated to the same test. Log-fold changes of average expression in naive cells relative to active cells are plotted against their associated tail posterior probabilities. Colour indicates the differential expression status for each gene, including a label to identify genes that were excluded from differential expression test due to low effective sample size.\n\nWhen interpreting the results of differential expression tests, it is useful to visualise expression patterns for differentially expressed genes in order to appraise the significance of the results and guide interpretation. For this purpose, we obtain normalised expression values for each group of cells after correcting for global changes in overall expression between the groups, i.e. a global offset that leads to uniformly higher expression across genes within one group of cells (such step is also internally done by BASiCS_TestDE). Among other causes, the latter can be due to overall differences in mRNA content between the groups.\n\nTo visualise expression patterns for multiple genes at once, we use the Bioconductor package ComplexHeatmap60 package, grouping genes according to the result of the differential mean expression test (i.e. up-regulated in naive/active cells or non differentially expressed; see Figure 12). For example, among the non DE group, we observe several genes encoding ribosomal proteins (e.g. Rps14). Genes in this family have been previously observed to have stable expression across a wide range of scRNAseq datasets in mouse and human.8 Such visualisations may aid in the interpretation of such stable or “housekeeping” genes, as well as genes which are up- or down-regulated in each population.\n\nGenes are stratified according to their differential expression status (non differentially expressed; upregulated in naive or active cells). For each group, 15 example genes are shown. These were selected according to the ranking of their associated tail posterior probabilities associated to the differential mean expression test. Colour indicates expression level; colour bars on the right of heatmap segments indicate the inferred mean expression level (in log scale) for each gene in each population.\n\nWhile several computational tools exist to perform differential mean expression analysis using scRNAseq data,37 the key focus of BASiCS is to perform differential variability testing: identifying changes in transcriptional variability between the groups of cells. To avoid the confounding between mean and over-dispersion, we recommend to use residual over-dispersion parameters εi as input to this analysis.\n\nWe can now visualise the changes in residual over-dispersion between naive and activated CD4+ T cells in the form of a MA-plot (Figure 13). In this visualisation, the difference between the posterior medians of the residual over-dispersion parameters εi are shown on the y-axis. Epsilon values for genes that are not expressed in at least two cells per condition are marked as NA and are therefore not displayed.\n\nDifferences of residual over-dispersion in naive cells relative to active cells are plotted against average expression estimates combined across both groups of cells. Bottom panel presents the volcano plot associated to the same test. Differences of residual over-dispersion in naive cells relative to active cells are plotted against their associated tail posterior probabilities. Colour indicates the differential expression status for each gene, including a label to identify genes that were excluded from differential expression test due to low effective sample size.\n\nWhile one could focus on the sets of gene that show significant changes in residual over-dispersion, here we want to highlight how to analyse changes in mean expression in parallel to changes in variability. For this, we will first combine the results of the differential mean expression and the differential residual over-dispersion test. These are independent analyses, given that changes in residual over-dispersion are not confounded by changes in mean expression, as shown in Figure 14.\n\nWhile genes with significant changes in residual over-dispersion often have similar levels of mean expression, as seen in Figure 15A and C, they may have a different proportion of zero counts in the two cell populations. Figure 15B and D show that many genes with higher residual over-dispersion in naive cells have a lower proportion of zeros in active cells, and vice versa.\n\nB, D: Proportion of expressed cells for genes, with higher residual over-dispersion in naive cells (B) and active (D) cells. Dashed red lines in panels A and C represent a log fold change of zero, meaning no change in average expression. Dashed red lines in panels B and D represent the line described by y=x, representing equal detection levels in both populations.\n\nSimilarly to analysis of differential expression, it is useful to visualise the results of differential variability tests in order to appraise the quality of the results, and to identify systematic patterns among the genes identified. One useful way to do this is by examining the normalised counts on a gene-by-gene basis. Figure 16 shows denoised counts for genes with significant differences in residual over-dispersion, with each panel showing a different type of expression pattern. Exploration of such patterns is important component of any analysis of differential variability, and should be undertaken with care. Figure 16B and 16D show genes with differing levels of detection in both populations, as well as higher levels of residual over-dispersion in naive or active cells (B and D, respectively). Thus, these genes may represent those with a more bursty expression pattern in one of the cell population. They may also represent genes that are markers of extrinsic variability, for example cell sub-populations that differ in abundance between the cell populations in question. In contrast, Figure 16A and 16C show genes with similar levels of detection in both populations, as well as higher levels of residual over-dispersion in naive or active cells (A and C, respectively). These cases are likely driven by more tight regulation, rather than transcriptional burst or sub-population structure.\n\nA: Four genes with higher residual over-dispersion in naive cells, and similar levels of detection in active and naive populations. B: Four genes with higher residual over-dispersion in naive cells and different levels of detection in naive and active cells. C: Four genes with higher residual over-dispersion in active cells and similar levels of detection in naive and active cells. D: Three genes with higher residual over-dispersion in active cells and different levels of detection in naive and active cells.\n\nBASiCS, when using spike-in molecules, uses spike-ins as a reference in order to aid normalisation, based on the assumption that the original quantity of spike-in molecules was approximately equal in each well. Eling et al.29 introduced a novel method of inferring gene expression profiles using BASiCS without relying on spike-ins to quantify technical noise. This is useful for droplet-based scRNAseq protocols, given that it is not possible to ensure that each droplet contains a specified quantity of spike-in molecules. In this horizontal integration framework, technical variation is quantified using replication.61 In the absence of true technical replicates, we assume that population-level characteristics of the cells are replicated using appropriate experimental design. This requires that cells from the same population have been randomly allocated to different batches. Given appropriate experimental design, BASiCS assumes that biological effects are shared across batches, while technical variation leads to spurious differences between cells in different batches.\n\nUsing BASiCS without spike-ins is very similar to using it with spike-ins. We will demonstrate using the naive cells. However, first, we must ensure that a BatchInfo field is present in the SingleCellExperiment used as input. In this case we use individual of origin as the batch vector.\n\nAs before, for convenience we provide a completed version of this chain at https://doi.org/10.5281/zenodo.5243265.\n\nThe resulting BASiCS_Chain object produced using this horizontal integration framework is functionally similar to one produced using the vertical integration framework. It can be used in place of the BASiCS_Chain objects produced using the vertical integration approach, as described above.\n\nUnder the horizontal integration approach described above, the scale of mean expression parameters and global scaling factors is not jointly identifiable, in that a global shift in mean expression parameters could be exactly offset by an equivalent shift in cell-specific normalisation parameters. Therefore, the geometric mean of the mean expression parameters is fixed to a constant value. Relative expression level estimates are broadly consistent between the horizontal and vertical integration approaches; however there may be a global difference in mean expression estimates, as shown in Figure 17. It is important to remove this global scale offset before performing comparative analyses. This is performed by default in BASiCS_TestDE, but can be performed manually using BASiCS_CorrectOffset.\n\nA number of genes have very low expression estimates in the naive population, due to the fact that they each have zero read counts across the entire naive population; we therefore remove these genes before making a comparison. Following removal of the global offset, the mean expression and over-dispersion estimates obtained from each method are directly comparable. As seen in Figure 18A and 18B, parameter point estimates from the two methods are highly correlated. There is a tail of non-expressed genes with very low mean expression level as inferred without spike-ins, comprising those genes with no measured expression across the entire population.\n\nA dashed red line indicates the identity line, y=x. Genes with zero counts across all cells were excluded from the plot of mean expression parameters.\n\n\nDiscussion\n\nIn this article, we have explored the research questions that BASiCS seeks to resolve — chiefly, robustly quantifying average and variability in expression in cell populations. We have outlined the appropriate quality control and data visualisation steps to apply when undertaking an analysis using BASiCS in order to ensure high quality input data. We have also outlined the steps needed to use BASiCS to quantify biological variability, identify highly variable genes, and normalise scRNAseq data from a single population. We have also provided a limited comparison of the results of these analyses using BASiCS and the result of similar analyses using scran. Furthermore, we have demonstrated functions within BASiCS that allow users to ensure the MCMC used in BASiCS has converged and produced adequate sample sizes. Finally, we have demonstrated the use of BASiCS to robustly identify differentially expressed genes, in terms of mean expression and in terms of biological variability.\n\nFurther challenges exist in analysing scRNAseq data.10,38 For BASiCS, the primary challenge currently is computational efficiency. The number of cells profiled in scRNAseq experiments has scaled exponentially since the development of the technology.62 Given that BASiCS requires computationally intensive MCMC sampling to estimate the posterior distribution, it becomes computationally intractable to analyse data from very large numbers of cells. We intend to update this workflow as the field evolves, and as we address the issues and challenges outlined here.\n\n\nData availability\n\nArrayExpress: RNA-seq of coding RNA from single cells [Mus musculus (house mouse)]. Accession number E-MTAB-4888; https://identifiers.org/arrayexpress:E-MTAB-4888.\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nSoftware availability\n\nAll software used in this workflow is available as part of Bioconductor 3.13 at: https://bioconductor.org/packages/3.13.\n\nThe source code for BASiCS, along with facilities contributing and reporting bugs is available at: https://github.com/catavallejos/BASiCS/.\n\nThe source code used for this manuscript is available at: https://github.com/VallejosGroup/BASiCSWorkflow/, and as archived source code at time of publication: https://doi.org/10.5281/zenodo.5243265.32\n\nLicense: GPL-2.0\n\n\nReproducibility\n\nThe following software versions were used throughout this workflow:\n\n• R version: R version 4.1.1 (2021-08-10)\n\n• Bioconductor version: 3.13\n\n• R packages:\n\n– BASiCS 2.4.0\n\n– scran 1.20.1\n\n– scater 1.20.1\n\nVersion numbers for all remaining packages are available in the Session Info section.\n\nA Docker image containing all software requirements is available at Docker hub. This image can be downloaded using the command docker pull alanocallaghan/bocker:0.2.0.\n\n\nSession Info\n\n",
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}
|
[
{
"id": "124656",
"date": "08 Mar 2022",
"name": "Oliver M. Crook",
"expertise": [
"Reviewer Expertise Biostatistics",
"Bayesian methodology",
"R",
"data-intensive biology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary:\n\nO’Callaghan and co-authors provide a workflow for the popular method BASiCS and its extensions. This workflow is intended to display the bioconductor infrastructure of BASiCS and provide a template for analysis for others to streamline their data analysis. I find the workflow quite comprehensive and takes me through the analysis points that I would expect to see. First of all, I must confess I am not an expert in processing scRNA data and so I cannot assess whether the choices of filtering, thresholding etc are up-to-date. I will leave this assessment to other reviewers. Here, I wish to focus my review on the communication of sophisticated methods presented, the Bayesian analysis, visualizations and the code. I believe this is an extremely valuable contribution to the scRNA community, the workflow community and applied Bayesians. I would also like to thank the authors’ attention to detail, I found the article well-written and logically structured.\n\nI would encourage you to update your version of R to 4.2 as the next version of Bioconductor will use this.\nGeneral comments:\nWhilst the method itself is presented technically in other papers, I don’t quite get a good picture of the model and its variants. Referring to the other papers I find myself confronted with lots of equations, whilst I can make my way through these details I think the intended users might struggle. The workflow might benefit from a narrative description or recipe that highlights its generative nature. A cartoon or graphic can be particularly insightful.\nAs good statisticians, we should incorporate experimental design into our models. I think before the data are introduced it would be useful to have a short description of the type of experiments that could be analysed with BASiCS, when BASiCS would be useful over other approaches, when not to apply BASiCS. What sort of data would it be optimal to collect if I wish to analysed it using BASiCS? How valuable are spike-ins for example?\nI had to spend quite some time on the code chunks, working out what was going on. I think these could be decorated with useful comments so your intended user is allowed to be as lazy as possible (which is what you want so they will use your package!). This was particularly the case for the pre-processing and parameter estimation.\nThere are some quite long code chunks that I felt represented fairly repetitive tasks, mostly related to plotting. If you're using ggplot2 then you can write a function which returns a ggplot object with nice defaults and you can explain that it can be customized using the ggplot principles. I think the current style is written to allow this customization but I think it's currently unexplained and perhaps working against you.\n\nIn the section of parameter estimation, the discussion on priors is quite brief and quite unclear currently. I’m not quite sure what the \"joint prior\" is here, I think your intended audience would appreciate a narrative description of these priors. The other choices of independent log Normal is also unclear. The logMean and logSd appear to be set automatically using the data - is that what you mean by Empirical Bayes here? When I dive deeper into changing the priors BASiCS_PriorParam is quite daunting. I think there are some helpful things you can do for your readers. For example, you explain whether the analysis is sensitive to the prior choice and generally how they affect the analysis. You could guide your users through a prior predictive check, in which you simulate parameters from the prior and then fake data from the likelihood. You could then show users how well calibrated their prior choices are. General advice of setting the prior or whether they should just leave these alone would be useful.\nI assume that multiple chains are run, are there any MCMC diagnostics based on running parallel chains?\nIn a Bayesian analysis I expected to be able to manipulate posterior distributions or credible intervals. Maybe I missed it but can we visualize the full posterior distribution for \\mu_i vs \\delta_i and \\mu_i vs \\epsilon_i or some other parameters of interest?\n\nI think I haven’t quite grasped the \"variance decomposition\" the authors mention into biological and technical components. This could be \\delta_i and \\epsilon_i, but I feel I am missing something? I do not yet think the methods section is quite clear on this point.\nFor the volcano plots the posterior probability is quite bunched up, would this be better on the logit scale? Also It appears the probabilities concentrate around 0.5? Is there an intuitive explanation for this? Indeed, the distribution generated by hist(p2$data$ProbDiffMean) was quite unexpected, are these probabilities calibrated in any way?\nYou mention computational challenges in the discussion, what is lost by performing maximum likelihood estimation or maximum a posteriori estimation? Perhaps the weighted likelihood bootstrap or variant could be a useful approach, if you have lots of cores.\nWhat are the challenges of applying this to scRNA data with spatial autocorrelation? It is common to now obtain expression data in such a context, does this additional confounding obstruct the model?\nSpecific comments:\nIn the first code chunks, in `website <- \" https …” I think there is an initial space which stops this from running correctly.\nRemember to include spaces after commas e.g. [a, ] rather than [a,], it is much clearer to read.\nI think it would be better to load all the packages at the beginning, I had to restart my session several times to install the packages that I realized I needed x% of the way through the workflow.\nIn figure 4, the axis dimensions of the PCA misrepresents the variance explained. The ratio of axis dimensions should closely match the ratios of the variance explained so that the visualization is faithful to the dimensionality reduction.\n\nConstants used in the package could be saved as global variables, it’s very easy to make a typo with these conversions.\nIn the chunk starting ## Moles per microliter, I had to edit the first line of the code chunk to get it to work. Perhaps it has been malformatted?\n\\log is a symbol and should always be lower-case\nIn the abstract, you write \"strong technical noise\". I don’t quite understand what \"strong\" is adding here.\n\nA number of concepts are left unexplained such as \"joint prior\", \"negative binomial framework\", \"borrows information\", \"expected false discovery rate\". These are all familiar concepts to someone with advanced statistical knowledge but the casual scRNA reader might find this off putting.\n\nFigure 12 there is a typo in the legend \"\\log_{1}0 -> \\log_{10}\".\nIn Figure 12 the dendrogram is unexplained and I’m not sure what it means in this context.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "10970",
"date": "07 May 2024",
"name": "Alan O'Callaghan",
"role": "Author Response",
"response": "We would like to thank Dr Crook for such a positive assessment of our manuscript. A detailed point-by-point response for the remaining comments is provided below. Edits to the main text are highlighted in italics. Reviewer comment: I would encourage you to update your version of R to 4.2 as the next version of Bioconductor will use this. Author’s response: We have now updated the workflow to use R version 4.3 which is the current version suggested by Bioconductor. Reviewer comment: Whilst the method itself is presented technically in other papers, I don’t quite get a good picture of the model and its variants. Referring to the other papers I find myself confronted with lots of equations, whilst I can make my way through these details I think the intended users might struggle. The workflow might benefit from a narrative description or recipe that highlights its generative nature. A cartoon or graphic can be particularly insightful. Author’s response: Many thanks for this suggestion. We have now updated the manuscript to include a graphical overview for the BASiCS model (see Figure 2 in the revised manuscript). This enables us to better introduce the role of different model parameters. In terms of the different variations of the BASiCS model, we provide a high level description for the latest version (as per Eling et al 2018) as this is what we recommend to use as default. We hope this provides a better overview of the methodology whilst ensuring that the workflow is accessible to a wide range of users. Reviewer comment: As good statisticians, we should incorporate experimental design into our models. I think before the data are introduced it would be useful to have a short description of the type of experiments that could be analysed with BASiCS, when BASiCS would be useful over other approaches, when not to apply BASiCS. What sort of data would it be optimal to collect if I wish to analysed it using BASiCS? How valuable are spike-ins for example? Author’s response: We agree a more explicit description of the experimental design assumed by BASiCS would be useful to potential issues. To address this, we included the following text in the Introduction: The model was initially motivated by supervised experimental designs in which experimental conditions correspond to groups of cells defined *a priori* (e.g. selected cell types obtained through FACS sorting). However, the approach can also be used in cases where the groups of cells of interest are computationally identified through clustering. In such cases, the model does not currently address issues associated to *post-selection inference*, where the same data is analysed twice: first to perform clustering and then to compare expression profiles between the clusters [@Lahnemann2020]; this is an inherent limitation of most differential expression tools. Furthermore, the Discussion now highlights the importance of assessing how post-selection inference may affect the performance of BASiCS (which is beyond the scope of this manuscript): One area for future work is to study how post-selection inference may affect the performance of `r Biocpkg(\"BASiCS\")`. For example, @Neufeld2022 have developed a framework for addressing inflated type I errors when studying differences in means between groups of cells identified via hierarchical clustering, by splitting counts into \"train\" and \"test\" sets. Reviewer comment: I had to spend quite some time on the code chunks, working out what was going on. I think these could be decorated with useful comments so your intended user is allowed to be as lazy as possible (which is what you want so they will use your package!). This was particularly the case for the pre-processing and parameter estimation. Author’s response: Indeed, clarity is an important element for this type of analysis workflows. We have now added further comments in the code chunks. We hope this helps to clarify specific steps. Furthermore, we have moved the code dealing with data QC to a separate repository, as the topic has been covered in previous F1000Research workflow articles (e.g. Lun et al 2016, https://f1000research.com/articles/5-2122). We hope these changes have reduced the complexity of the code and improve the flow of our article. Reviewer comment: There are some quite long code chunks that I felt represented fairly repetitive tasks, mostly related to plotting. If you're using ggplot2 then you can write a function which returns a ggplot object with nice defaults and you can explain that it can be customised using the ggplot principles. I think the current style is written to allow this customization but I think it's currently unexplained and perhaps working against you. Author’s response: As mentioned above, we have moved the code dealing with data QC to a separate repository, which should reduce the complexity of the code that readers need to process. We have also attempted to reduce the complexity of later plots by splitting them into smaller chunks with better explanation, which we hope aids the readability of the manuscript. Reviewer comment: In the section of parameter estimation, the discussion on priors is quite brief and quite unclear currently. I’m not quite sure what the \"joint prior\" is here, I think your intended audience would appreciate a narrative description of these priors. The other choices of independent log Normal is also unclear. The logMean and logSd appear to be set automatically using the data - is that what you mean by Empirical Bayes here? When I dive deeper into changing the priors BASiCS_PriorParam is quite daunting. I think there are some helpful things you can do for your readers. For example, you explain whether the analysis is sensitive to the prior choice and generally how they affect the analysis. You could guide your users through a prior predictive check, in which you simulate parameters from the prior and then fake data from the likelihood. You could then show users how well calibrated their prior choices are. General advice of setting the prior or whether they should just leave these alone would be useful. Authors’ response: We agree that further information/intuition about the priors will improve our manuscript. To address this, we have now extended the model description. As noted above, we have primarily focused on the latest version of the model (Eling et al 2018) as that is the default recommended setting. In particular, we have now provided additional information to clarify the definition of our \"joint prior\" and the use of an empirical Bayes approach. This includes the bottom right panel in Figure 2 and edits to the “BASiCS - Bayesian Analysis of Single Cell Sequencing data” sub-section within Methods: To account for the strong relationship that is typically observed between gene-specific mean expression and over-dispersion estimates, Eling *et al.* [@Eling2018] introduced a *joint prior* specification for these parameters. This joint prior assumes that genes with similar mean expression ($\\mu_i$) have similar over-dispersion parameters $\\delta_i$. Effectively, this shrinks over-dispersion estimates towards a global trend that captures the relationship between mean and over-dispersion (Figure 2). This improves posterior inference for over-dispersion parameters when the data is less informative (e.g. small sample size, lowly expressed genes) [@Eling2018]. This information-sharing approach is conceptually similar to that performed by @Love2014 and others, where sparse data is pooled to obtain more reliable estimates. The global trend is then used to derive gene-specific *residual over-dispersion* parameters $\\epsilon_i$ that are not confounded by mean expression. Similar to the DM values implemented in `r Biocpkg(\"scran\")`, these are defined as deviations with respect to the overall trend. In terms of the prior hyper-parameter choices, we recommend users to apply the default settings as we have tested these in a variety of contexts. Furthermore, as shown in Vallejos et al (2015), most posterior estimates are robust to different hyper-parameter choices (the exception is for gene-specific parameters for lowly expressed genes, which benefit from the use of the joint prior introduced by Eling et al 2018 https://doi.org/10.1016/j.cels.2018.06.011 and the empirical Bayes framework). Finally, as shown by Zappia et al (2017) https://doi.org/10.1186/s13059-017-1305-0, the BASiCS model is able to successfully recapitulate the main properties of typical scRNAseq data when used as a generative model (posterior predictive checks). To emphasise this, we have added the following text to the manuscript: A previous study has shown that BASiCS, when used as a generative model, is well-tuned to capture and recapitulate the main properties of typical scRNAseq data using posterior predictive checks [@Zappia2017]. Reviewer comment: I assume that multiple chains are run, are there any MCMC diagnostics based on running parallel chains? Authors’ response: Due to the running times of the current MCMC sampler, we have not suggested users to routinely run multiple MCMC chains as part of their analyses. However, throughout the years, we have run BASiCS multiple times in a variety of settings and we have generally observed that different runs of the algorithm converge to similar values. Whilst this does not guarantee that the same would hold for a new dataset, our experience strongly suggests that the proposed diagnostic criteria are sufficient when evaluating MCMC convergence for BASiCS. Nevertheless, we acknowledge that running multiple chains may be useful and we will aim to implement this in future versions of the BASiCS library. In particular, we recently obtained very promising results about the use of more scalable algorithms for Bayesian inference (e.g. divide-and-conquer MCMC, see Bardenet et al. 2015 https://arxiv.org/abs/1505.02827; manuscript in preparation). This will facilitate running the algorithm multiple times in a timely manner. We plan to update this workflow once our benchmarks for this new, more scalable, implementation are completed and the updated BASiCS package is available in Bioconductor. We also provide the facility for users to run multiple chains and to manipulate posteriors manually using rstan (https://bioconductor.org/packages/release/bioc/html/BASiCStan.html), although we note that for data of any appreciable size the Hamiltonian Monte Carlo algorithm used by Stan becomes computationally intractable. We have added a brief note to the discussion regarding this, as follows: Given that `r Biocpkg(\"BASiCS\")` requires computationally intensive MCMC sampling to estimate the posterior distribution, it becomes computationally intractable to analyse data from very large numbers of cells. Alternative inference schemes such as variational inference for maximum *a posteriori* estimation, or Hamiltonian Monte Carlo may be useful in this context. Advanced users may wish to use the `r Biocpkg(\"BASiCStan\")` package to test these alternative inference schemes. This also provides access to the model diagnostics, facilities for running multiple chains, and posterior summaries provided by Stan [@Carpenter2017], while also being fully compatible with the workflow described in this manuscript via the function `Stan2BASiCS`, that converts the output of the Stan inference procedure to the type of output generated by `BASiCS_MCMC`. However, we note that the Hamiltonian Monte Carlo inference method provided by Stan is more computationally intensive than our default implementation. Furthermore, the faster approximations provided by Stan, namely scalable variational inference and maximum *a posteriori* estimation, are often unstable and less accurate. Reviewer comment: In a Bayesian analysis I expected to be able to manipulate posterior distributions or credible intervals. Maybe I missed it but can we visualize the full posterior distribution for \\mu_i vs \\delta_i and \\mu_i vs \\epsilon_i or some other parameters of interest? Authors’ response: As the parameter space for the BASiCS model is high-dimensional, it is not practical to visualise the joint posterior distribution posterior of all parameters. However, displaySummaryBASiCS() can be used to obtain point estimates (posterior medians) and the 95% Highest Posterior Density (HPD) intervals for individual parameters. Furthermore, the displayChainBASiCS() function can be used to extract the MCMC chains which can be then manipulated separately by the user. To clarify this, we have added the following sentence to the “Parameter estimation using BASiCS section”. The matrices of MCMC draws can be accessed using the `displayChainBASiCS` function --- this may be useful for estimating and visualising credible intervals using packages like `r CRANpkg(\"bayesplot\")` or `r CRANpkg(\"tidybayes\")`. Reviewer comment: I think I haven’t quite grasped the \"variance decomposition\" the authors mention into biological and technical components. This could be \\delta_i and \\epsilon_i, but I feel I am missing something? I do not yet think the methods section is quite clear on this point. Authors’ response: We used the term “variance decomposition” to denote BASiCS’ ability to separate the observed variability into a technical and a biological component, which then enables downstream analysis of transcriptional variability: detection of highly and lowly variable genes, and differential variability testing. We have thus removed the explicit use of the term “variance decomposition” from the paper, and we apologise for any confusion this caused. Reviewer comment: For the volcano plots the posterior probability is quite bunched up, would this be better on the logit scale? Also It appears the probabilities concentrate around 0.5? Is there an intuitive explanation for this? Indeed, the distribution generated by hist(p2$data$ProbDiffMean) was quite unexpected, are these probabilities calibrated in any way? Authors’ response: Thanks for the suggestion. We have changed these plots to use an (adjusted) logit scale, and this does appear to be more informative in most cases. The logit scale is adjusted to avoid undefined values, i.e., logit(0) and logit(1) by adding or subtracting a small value from probabilities with undefined logit values. In terms of calibration, this is difficult to assess in the absence of ground truth. However, as shown in Vallejos et al (2016), synthetic data examples showed good error rate performance for our differential expression test, provided that a non-zero log-fold change threshold is used (default in the BASiCS_TestDE function is shown by the vertical lines in the volcano plots). This is similar to the approach by McCarthy and Smith (2009) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654802/, avoiding the identification of genes with statistically significant differences but whose associated log-fold changes are not biologically significant. Reviewer comment: You mention computational challenges in the discussion, what is lost by performing maximum likelihood estimation or maximum a posteriori estimation? Perhaps the weighted likelihood bootstrap or variant could be a useful approach, if you have lots of cores. Authors’ response: We have explored the variational inference algorithm implemented in Stan as a fast method to obtain maximum a posteriori point estimates for BASiCS. However, we have generally observed that inference is less reliable. Moreover, beyond point estimates, it is critical for BASiCS to obtain reliable estimates of posterior uncertainty as these are required for our differential test which relies on tail posterior probabilities. This is particularly problematic when using a mean-field approximation for the posterior, which is what is currently used in our Stan implementation. As an alternative approach to address these computational challenges, we recently explored more scalable algorithms (e.g. divide-and-conquer MCMC, see Bardenet et al. 2015 https://arxiv.org/abs/1505.02827) to perform inference using the BASiCS model. Our results are promising and a manuscript is in preparation. Reviewer comment: What are the challenges of applying this to scRNA data with spatial autocorrelation? It is common to now obtain expression data in such a context, does this additional confounding obstruct the model? Authors’ response: The current BASiCS model assumes that cells are conditionally independent (given gene-specific and other global parameters). As a result our model does not account for the more complex structure that arises in spatial assays. Whilst we have not explored this yet, we hypothesise that ignoring this temporal correlation structure will likely lead to biassed over-dispersion estimates. We have now updated the Discussion to mention that the BASiCS model could be adapted to address more complex correlation structures across cells, such as those introduced by spatial assays and cohort studies in which cells are extracted from multiple donors (e.g. patients): Finally, we also anticipate potential extensions of `r Biocpkg(\"BASiCS\")` to account for the more complex experimental designs. For example, in cohort studies where cells are extracted from multiple individuals, the hierarchical model could be expanded to quantify both for intra- and inter-individual transcriptional variability. As spatial transcriptomic technologies mature [@Marx2021], Bayesian hierarchical models such as the one implemented in `r Biocpkg(\"BASiCS\")` could also be designed to incorporate spatial (and, potentially, temporal) structure (e.g. [@Aijo2019]). We intend to update this workflow as the field evolves, and as we address the issues and challenges outlined here. Specific comments: Reviewer comment: In the first code chunks, in `website <- \" https …” I think there is an initial space which stops this from running correctly. Authors’ response: This is a formatting issue which should be resolved now. Reviewer comment: Remember to include spaces after commas e.g. [a, ] rather than [a,], it is much clearer to read. Authors’ response: Agreed, thank you for pointing this out; we have addressed this in our code formatting. Reviewer comment: I think it would be better to load all the packages at the beginning, I had to restart my session several times to install the packages that I realized I needed x% of the way through the workflow. Authors’ response: We initially loaded the packages when they were first used in order to emphasise their role within the analysis pipeline. However, we do acknowledge that some users may prefer to load all the packages from the start, to prevent installation issues during their analysis (note that installation issues are resolved when using the provided Docker image that contains all software requirements). To address this, all libraries are now loaded at the start of the analysis. Explanations for the use of each library are provided in relevant sections. Reviewer comment: In figure 4, the axis dimensions of the PCA misrepresents the variance explained. The ratio of axis dimensions should closely match the ratios of the variance explained so that the visualisation is faithful to the dimensionality reduction. Authors’ response: Thank you for highlighting this. We have now swapped the x- and y-axes such that the larger axis represents the larger component of variation in the data, although the x-axis is still disproportionate given the small amount of variation represented by that PC. However given the difference in scale here (20% vs 1%, we feel that directly proportional scaling would be excessive. Reviewer comment: Constants used in the package could be saved as global variables, it’s very easy to make a typo with these conversions. Authors’ response: We have implemented a helper function, BASiCS_CalculateERCC, to handle this conversion process. We note that the spike-in analysis workflow has been moved to the Zenodo repository. Reviewer comment: In the chunk starting ## Moles per microliter, I had to edit the first line of the code chunk to get it to work. Perhaps it has been malformatted? Authors’ response: This is another formatting error and should now be resolved. We note that the spike-in analysis workflow has been moved to the Zenodo repository. Reviewer comment: \\log is a symbol and should always be lower-case Authors’ response: This has been resolved. Reviewer comment: In the abstract, you write \"strong technical noise\". I don’t quite understand what \"strong\" is adding here. Authors’ response: The usage of “strong” aimed to emphasise that the level of technical noise was substantially higher than what was observed in bulk-level assays (see [3]). To clarify this, we have modified the abstract as follows: … but it is prone to technical noise, beyond what is observed in bulk-level assays. Reviewer comment: A number of concepts are left unexplained such as \"joint prior\", \"negative binomial framework\", \"borrows information\", \"expected false discovery rate\". These are all familiar concepts to someone with advanced statistical knowledge but the casual scRNA reader might find this off putting. Authors’ response: This is an excellent suggestion. We have now edited the text to explain these concepts. To explain the “negative binomial framework” we have added the following text to the Introduction: The negative binomial distribution is commonly used to model count data when the observed variability exceeds what can be captured by a simpler Poisson model --- this is typically referred to as over-dispersion. To explain the concept behind the \"borrows information\" statement, the first paragraph in the “BASiCS - Bayesian Analysis of Single Cell Sequencing data” sub-section within Methods has been edited as follows: […] instead of modelling expression patterns separately for each gene, `r Biocpkg(\"BASiCS\")` shares information between all genes to robustly quantify transcriptional variability. For example, as described by [@Eling2018], pooling information across genes with similar mean expression levels helps to obtain more reliable transcriptional variability estimates. The latter is particularly helpful for lowly expressed genes and sparse datasets, where less information is available. To clarify the definition of our \"joint prior\" statement, the third paragraph in the “BASiCS - Bayesian Analysis of Single Cell Sequencing data” sub-section within Methods has been edited to include further information: To account for the strong relationship that is typically observed between gene-specific mean expression and over-dispersion estimates, Eling *et al.* [@Eling2018] introduced a *joint prior* specification for these parameters. This joint prior assumes that genes with similar mean expression ($\\mu_i$) have similar over-dispersion parameters $\\delta_i$. Effectively, this shrinks over-dispersion estimates towards a global trend that captures the relationship between mean and over-dispersion (Figure \\@ref(fig:basics-schematic)). This improves posterior inference for over-dispersion parameters when the data is less informative (e.g. small sample size, lowly expressed genes) [@Eling2018]. This information-sharing approach is conceptually similar to that performed by @Love2014 and others, where sparse data is pooled to obtain more reliable estimates. The global trend is then used to derive gene-specific *residual over-dispersion* parameters $\\epsilon_i$ that are not confounded by mean expression. Similar to the DM values implemented in `r Biocpkg(\"scran\")`, these are defined as deviations with respect to the overall trend. In the “HVG/LVG detection using BASiCS” sub-section within the case study, we have added the following text to explain the expected false discovery rate: The expected false discovery rate we use is conceptually similar to false discovery rate control procedures in frequentist statistics, such as the approach of @Benjamini1995, aiming to control the proportion of false discoveries produced by the procedure. Reviewer comment: Figure 12 there is a typo in the legend \"\\log_{1}0 -> \\log_{10}\". Authors’ response: This has been resolved. Reviewer comment: In Figure 12 the dendrogram is unexplained and I’m not sure what it means in this context. Authors’ response: This dendrogram shows the similarity between cells, but it is not required here and therefore has been removed."
}
]
},
{
"id": "126523",
"date": "01 Apr 2022",
"name": "Andrew McDavid",
"expertise": [
"Reviewer Expertise Bioinformatics",
"biostatistics",
"single-cell transcriptomics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an extensive workflow on applying the authors' BASiCS method to a plate-based single-cell RNAseq data. The authors discuss preparing data downloaded from an external repository, evaluation of QC metrics, interrogation of convergence of a Bayesian model, interpretation of model parameters, and comparative tests in the two sample settings. Code to generate an expansive array of figures is provided.\nAll said, it's a comprehensive workflow demoing well-documented software. I do have a few concerns about how other users would apply the workflow to their data:\nThe authors demo their method on some naive CD4 cells from inbred mice - really the ideal data set to illustrate a method looking at intrinsic sources of gene heterogeneity or homogeneity. How would prospective users of BASiCS adapt it to more typical datasets from droplet-based scRNAseq, either from samples with more heterogeneity (human) or of less purified cells, where spike-ins are absent and the \"horizontal integration\" model must be invoked? I am left wondering:\na. What sort of QC would be needed? b. How should the data be stratified (into fairly fine-grained cell types on the basis of unsupervised clustering of the expression vector? Though this sort of double-dipping will change the inferential properties of the model). c. How can violations of the Bayesian model be detected, or of unresolved sub-population heterogeneity, indicating more clustering is needed? d. Given that with K populations, we'd have K-times the output from a single run of BASiCS to interpret. How to prioritize or understand it? (Perhaps an approach like muscat uses here would be helpful?1). e. What techniques can aid in fitting this computationally-intensive model on larger datasets (e.g. thousands of cells)? Should we downsample cells, or apply more aggressive pre-filtering of genes? I see there's some provision to apply a \"divide and conquer strategy\" to fit the model on tranches of the data in parallel. How should this be used in practice?\n\nThe workflow is quite lengthy, enough that I found it hard to follow at times, and that I might be missing the forest for the trees. It would be nice if it could be condensed to emphasize model interpretation. A couple of suggestions on this end:\na. The initial vignette about data download and QC could be moved to an appendix, since it's not very specific to the BASiCS model, and there is a lot of boilerplate code, e.g. converting gene symbols. Then we could start from a binary SingleCellExperiment object. b. The plotting code is quite verbose. It would be nice from a usability standpoint to have commonly-used plots included as part of the functionality of the package. c. Is there some way to provide better navigation among sections of the workflow (this may not be possible via F1000?)? This combined with a paragraph in the introduction (\"This case study is organized as follows...section 3.1 describes downloading data from ArrayExpression, 3.2 annotates gene symbols, 3.3 examines QC,...\") would make it easier for a reader to find the relevant section of the workflow. d. Or the version of this workflow that's at https://github.com/VallejosGroup/BASiCSWorkflow/ could be rendered and made available on Github, perhaps with some nice markdown features like code-folding and a floating TOC to make it easier to read.\n\nThe comparison between the model estimates and the scran estimates in Figure 8 does help orient someone who is not completely familiar with the BASiCS model, but it would be nice to have a brief recap of the model in the Methods section (one or two equations), with interpretations, to explain the key parameters being estimated.\n\nMinor comments:\nI encountered some issues regarding the formatting of the code, which the other reviewer also remarked upon. This may be limited to the html version of the article.\na. newlines in `website` strings resulting in mal-formed URL. b. ^ rendered in some odd font that wouldn't execute when I copied a chunk into Rstudio. c. concentration.in..Mix.1.attomoles.ul was missing an `.`\n\nThe built-in MCMC diagnostics are nice, but I do feel like Rhat (testing within vs between-chain variance, e.g. Vehtari et al., 20212) is maybe what I want most. Is there any provision for running parallel chains?\n\nIt seemed that when I ran the `BASiCS_DetectHVG` function as specified, I got a couple of warning messages: \"The posterior probability threshold chosen via EFDR calibration is too low. Probability threshold automatically set equal to 'ProbThresholdM'.\"\n\nRegarding differential expression testing, could the authors comment on the modeling assumptions about the two \"populations\" of cells? If I had biological replicates in some conditions (e.g. distinct mice, humans, or plots of stimulated cells), how would they be used here, or does the framework require assuming null inter-replicate variability?\n\nFigure 15: Caption says \"log2 change in expression against against log mean expression for genes with higher residual over-dispersion in naive (A) cells and active (D) cells\", but seems to refer to panels A and C. More broadly, it's not really clear what sort of conclusions we are supposed to draw from this sort of figure.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "10971",
"date": "07 May 2024",
"name": "Alan O'Callaghan",
"role": "Author Response",
"response": "We thank the reviewer for their positive assessment of our manuscript, and the detailed comments, which we have used to revise and improve the workflow. Edits to the main text are highlighted in italics. Reviewer comment: The authors demo their method on some naive CD4 cells from inbred mice - really the ideal data set to illustrate a method looking at intrinsic sources of gene heterogeneity or homogeneity. How would prospective users of BASiCS adapt it to more typical datasets from droplet-based scRNAseq, either from samples with more heterogeneity (human) or of less purified cells, where spike-ins are absent and the \"horizontal integration\" model must be invoked? I am left wondering: a. What sort of QC would be needed? b. How should the data be stratified (into fairly fine-grained cell types on the basis of unsupervised clustering of the expression vector? Though this sort of double-dipping will change the inferential properties of the model). c. How can violations of the Bayesian model be detected, or of unresolved sub-population heterogeneity, indicating more clustering is needed? d. Given that with K populations, we'd have K-times the output from a single run of BASiCS to interpret. How to prioritize or understand it? (Perhaps an approach like muscat uses here would be helpful?1). e. What techniques can aid in fitting this computationally-intensive model on larger datasets (e.g. thousands of cells)? Should we downsample cells, or apply more aggressive pre-filtering of genes? I see there's some provision to apply a \"divide and conquer strategy\" to fit the model on tranches of the data in parallel. How should this be used in practice? Authors’ response: We thank the reviewer for this note. Due to its popularity, we have therefore modified the workflow to examine droplet-based data instead. The original analysis of CD4 T cells is now provided in an additional repository hosted on Zenodo. Furthermore, to improve the flow of the manuscript, we have removed data pre-processing and quality control to the same Zenodo repository, as we feel that this topic has been covered in detail by previous work (Lun et al. 2016, https://f1000research.com/articles/5-2122, Amezquita et al. 2019 https://doi.org/10.1038/s41592-019-0654-x). Typical droplet-based datasets exhibit substantial cell-to-cell heterogeneity linked to the presence of distinct cell types or states. This needs to be accounted for before running the BASiCS model. In practice, this means that users should identify similar groups of cells (e.g. cell types) through clustering. As mentioned by Dr McDavid, this introduces a double-dipping effect where the same data is used twice: first to perform clustering and then to compare expression profiles between clusters. This effect is not yet addressed in BASiCS, but we believe it is an important area for future work. We have now edited the Introduction in order to clarify this: The model was initially motivated by supervised experimental designs in which experimental conditions correspond to groups of cells defined *a priori* (e.g. selected cell types obtained through FACS sorting). However, the approach can also be used in cases where the groups of cells of interest are computationally identified through clustering. In such cases, the model does not currently address issues associated to *post-selection inference*, where the same data is analysed twice: first to perform clustering and then to compare expression profiles between the clusters [@Lahnemann2020]; this is an inherent limitation of most differential expression tools. Furthermore, the Discussion now highlights the importance of assessing how post-selection inference may affect the performance of BASiCS (which is beyond the scope of this manuscript): One area for future work is to study how post-selection inference may affect the performance of `r Biocpkg(\"BASiCS\")`. For example, @Neufeld2022 have developed a framework for addressing inflated type I errors when studying differences in means between groups of cells identified via hierarchical clustering, by splitting counts into \"train\" and \"test\" sets. Ideally, structural heterogeneity associated with the presence of distinct cell types will be addressed before applying the BASiCS model either experimentally (via cell sorting) or computationally (via clustering). Eling et al, https://doi.org/10.1016/j.cels.2018.06.011, explored a case in which “contamination” was present, with a subpopulation of cells that had a distinct expression profile. We have observed in previous studies that highly variable genes were enriched by markers of such subpopulations. We have added a brief note explaining this in the introduction: These residual over-dispersion values can be used to quantify transcriptional heterogeneity without any confounding with mean expression, though it should be noted that high residual over-dispersion may also arise due to structural heterogeneity (e.g. distinct cell sub-types or states). If the data consists of $K$ pre-specified cell groups (e.g. types or states), BASiCS can be run separately within each group (as such, omputation can be trivially parallelised if multiple cores are available). Once the algorithm has been run, the MCMC chains can be post-processed to perform e.g. differential testing. Currently, our decision rules for differential expression are performed using two groups. Therefore, it is more suitable to focused situations in which a handful of pairwise comparisons (hypothesis) are prioritised a priori. However, in principle the posterior distributions for gene-level parameters could be combined across multiple chains to test other hypotheses, such as an omnibus-type hypothesis (similar to the ANOVA F-test). However, this is outside the scope of this workflow. We recently obtained very promising results about the use of more scalable algorithms for Bayesian inference (e.g. divide-and-conquer MCMC, see Bardenet et al. 2015 https://arxiv.org/abs/1505.02827). We plan to demonstrate the properties and practical applications of computationally scalable inference in a future manuscript (in preparation). We plan to update this workflow once our benchmarks for this new, more scalable, implementation are completed and the updated BASiCS package is available in Bioconductor. However, for the time being, we have added a brief note regarding this. Reviewer comment: The workflow is quite lengthy, enough that I found it hard to follow at times, and that I might be missing the forest for the trees. It would be nice if it could be condensed to emphasise model interpretation. A couple of suggestions on this end: a. The initial vignette about data download and QC could be moved to an appendix, since it's not very specific to the BASiCS model, and there is a lot of boilerplate code, e.g. converting gene symbols. Then we could start from a binary SingleCellExperiment object. b. The plotting code is quite verbose. It would be nice from a usability standpoint to have commonly-used plots included as part of the functionality of the package. c. Is there some way to provide better navigation among sections of the workflow (this may not be possible via F1000?)? This combined with a paragraph in the introduction (\"This case study is organised as follows...section 3.1 describes downloading data from ArrayExpression, 3.2 annotates gene symbols, 3.3 examines QC,...\") would make it easier for a reader to find the relevant section of the workflow. d. Or the version of this workflow that's at https://github.com/VallejosGroup/BASiCSWorkflow/ could be rendered and made available on Github, perhaps with some nice markdown features like code-folding and a floating TOC to make it easier to read. Authors’ response: Many thanks for this suggestion. We have now moved the data preparation steps to a separate repository for clarity, as single cell data pre-processing and quality control have been covered in detail by previous work (Lun et al. 2016, https://f1000research.com/articles/5-2122, Amezquita et al. 2019 https://doi.org/10.1038/s41592-019-0654-x). We agree that the plotting code is quite verbose, and detracts from the flow of the manuscript. We have moved the pre-processing code to a separate repository for clarity, and where possible have simplified the code to improve the reading experience. We have included a short summary of the workflow sections in the introduction, to hopefully aid in navigation. Following peer review, we intend to submit a version of this workflow to Bioconductor as a Bioconductor workflow (https://www.bioconductor.org/packages/release/BiocViews.html#___Workflow) so that it can be regularly built as part of the Bioconductor build system. Reviewer comment: The comparison between the model estimates and the scran estimates in Figure 8 does help orient someone who is not completely familiar with the BASiCS model, but it would be nice to have a brief recap of the model in the Methods section (one or two equations), with interpretations, to explain the key parameters being estimated. Authors’ response: Many thanks for this suggestion. We decided to provide a high level description of the model suitable for less technical audiences. However, we agree that further information would help to better interpret the use and output of BASiCS. Therefore, we have now updated the manuscript to include a graphical overview for the BASiCS models and the relevant parameters. This includes a graphical representation of the overall mean/overdispersion trend and how this is used to derive residual overdispersion estimates (as deviations with respect to the overall trend). We hope this helps to clarify the links with the DM estimates provided by scran. Minor comments: Reviewer comment: I encountered some issues regarding the formatting of the code, which the other reviewer also remarked upon. This may be limited to the html version of the article. a. newlines in `website` strings resulting in mal-formed URL. b. ^ rendered in some odd font that wouldn't execute when I copied a chunk into Rstudio. c. concentration.in..Mix.1.attomoles.ul was missing an `.` Authors’ response: This is a formatting issue which should be resolved now. Reviewer comment: The built-in MCMC diagnostics are nice, but I do feel like Rhat (testing within vs between-chain variance, e.g. Vehtari et al., 20212) is maybe what I want most. Is there any provision for running parallel chains? Authors’ response: Due to the running times of the current MCMC sampler, we have not suggested users to routinely run multiple MCMC chains as part of their analyses. However, throughout the years, we have run BASiCS multiple times in a variety of settings and we have generally observed that different runs of the algorithm converge to similar values. Whilst this does not guarantee that the same would hold for a new dataset, our experience strongly suggests that the proposed diagnostic criteria are sufficient when evaluating MCMC convergence for BASiCS. Nevertheless, we have added support for the Rhat diagnostic criterion, and acknowledge that running multiple chains may be useful and we will aim to implement this in future versions of the BASiCS library. In particular, we recently obtained very promising results about the use of more scalable algorithms for Bayesian inference (e.g. divide-and-conquer MCMC, see Bardenet et al. 2015 https://arxiv.org/abs/1505.0282; manuscript in preparation). This will facilitate running the algorithm multiple times in a timely manner. We plan to update this workflow once our benchmarks for this new, more scalable, implementation are completed and the updated BASiCS package is available in Bioconductor. Reviewer comment: It seemed that when I ran the `BASiCS_DetectHVG` function as specified, I got a couple of warning messages: \"The posterior probability threshold chosen via EFDR calibration is too low. Probability threshold automatically set equal to 'ProbThresholdM'.\" Authors’ response: This message relates to the choice of a probability threshold that controls the EFDR at the chosen level. This is normal behaviour that can be controlled using the ProbThreshold argument, and we have explained it using the following note in the text: Performing HVG and LVG detection involves identifying a posterior probability threshold that matches a target EFDR. We perform this choice using a grid search in which EFDR is calculated for a range of different probability thresholds between 0.5 and 1. As seen in Figure \\@ref(fig:efdr-plot-vg-SM), for the somitic mesoderm cells, this leads to a threshold of `r hvg@ProbThreshold` and `r lvg@ProbThreshold` for HVG and LVG detection, respectively (the value of these thresholds can be extracted from the `ProbThreshold` slot in the `hvg` and `lvg` objects, e.g. using `hvg@ProbThreshold`). For some datasets, the grid search may fail to identify a probability threshold that matches the target EFDR. In such cases, the default minimum probability threshold of $\\frac{2}{3}$ is used. This default threshold value can be changed using the `ProbThreshold` to `BASiCS_DetectHVG` and `BASiCS_DetectLVG`. Reviewer comment: Regarding differential expression testing, could the authors comment on the modelling assumptions about the two \"populations\" of cells? If I had biological replicates in some conditions (e.g. distinct mice, humans, or plots of stimulated cells), how would they be used here, or does the framework require assuming null inter-replicate variability? Authors’ response: In principle, the differential expression testing approach could be used to compare expression profiles between two arbitrary groups of cells. The typical use-case is two cell types or experimental conditions for a given cell type (naive vs stimulated, grown in two different media). Users could potentially apply the model to different biological replicates. In such cases, our over-dispersion parameters will quantify intra-replicate cell-to-cell variability and our differential expression test will quantify systematic differences between biological replicates. However, this approach does not share information across biological replicates when estimating model parameters (this can be useful in situations where a small number of cells is available per biological replicate, or when the data is sparse). Moreover, this would not scale well to cohort studies (e.g. van der Wijst et al. 2018, https://doi.org/10.1038/s41588-018-0089-9) where multiple biological replicates are present. We have added a brief note about this extension in the Discussion section. Finally, we also anticipate potential extensions of `r Biocpkg(\"BASiCS\")` to account for the more complex experimental designs. For example, in cohort studies where cells are extracted from multiple individuals, the hierarchical model could be expanded to quantify both for intra- and inter-individual transcriptional variability. Reviewer comment: Figure 15: Caption says \"log2 change in expression against against log mean expression for genes with higher residual over-dispersion in naive (A) cells and active (D) cells\", but seems to refer to panels A and C. More broadly, it's not really clear what sort of conclusions we are supposed to draw from this sort of figure. Authors’ response: We agree that this figure was somewhat unclear, and we apologise for the mis-labelled panels. We have removed this figure from the revised manuscript as we feel it was not necessary."
}
]
},
{
"id": "128930",
"date": "19 Apr 2022",
"name": "Michel S Naslavsky",
"expertise": [
"Reviewer Expertise Population and medical genomics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nO'Callaghan and colleagues present an approach to analyze single-cell RNA sequencing data in a stepwise manner. This is very useful both to readers and to students engaged in learning applied bioinformatics. As a user (non-developer, non-expert in RNA analysis tool evaluation), my contribution will be from a different perspective from the other reviewers who made excellent and detailed comments on this manuscript.\n1) Introduction, 2nd paragraph: “Moreover, these variability estimates can also be inflated by the technical noise that is typically observed in scRNA-seq data”\nComment: Please illustrate with examples of technical noise as presented above for extrinsic and intrinsic noise, e.g. RNA differential degradation, ligation bias, etc.\n2) Introduction, 3rd paragraph: “However, despite the benefits associated to the use of spike-ins and UMIs, these are not available for all scRNA-seq protocols.”\nComment: Please provide a reason - something like “due to the very nature of the assay, which isolates library prep from external spike-ins and uses UMIs to map single-cell libraries…” or that spike-ins added to the library after pooling limit the full advantage of using them across single-cell populations.\n3) Methods, 2nd paragraph: “Mean parameters μi quantify the overall expression for each gene i across the cell population under study.”\n\nComment: Please define cell population as sample (all cells within a scRNA-seq assay) or post-processing UMAP, t-SNE, or similar clustering grouping. I understood the latter, but readers should be certain, and we need to understand which step these parameters refer to.\n4) After Figure 5: “These thresholds can vary across datasets and should be informed by gene-specific QC metrics such as those shown in Figure 5 as well as prior knowledge about the cell types and conditions being studied, where available”.\nComment: I understand this is not the intent of this study, but if possible include some rationale behind thresholds for QCing gene exclusion based on types and conditions. Maybe bringing the choice for the example explored here.\n5) After spike-in calculation step: “To update the sce_naive and sce_active objects, the user must create a data.frame whose first column contains the spike-in labels (e.g. ERCC-00130) and whose second column contains the number of molecules calculated above. We add this as row metadata for altExp (sce_naive) and altExp (sce_active).”\nComment: By ‘update’, do the authors mean ‘update after normalisation with spike-in’? If so, please specify.\n7) MCMC diagnostics\nComment: I am by far not an expert on the analysis, but the authors were very successful in explaining the protocol in a stepwise manner. I would kindly ask if they can add the reason why this is needed: “to ensure that comparisons of gene expression are not random” or something in that direction. Readers will appreciate it.\n8) Figures 15 and 16\nComment: These explanations are important to establish a convincing argument for using this workflow. Authors can explore further the ‘tight regulation’ versus ‘transcriptional burst’ or ‘sub-population structure’ scenarios with other examples (either from the literature or running an orthogonal analysis on larger scRNA-seq datasets of CD4+ T cells.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "10972",
"date": "07 May 2024",
"name": "Alan O'Callaghan",
"role": "Author Response",
"response": "O'Callaghan and colleagues present an approach to analyse single-cell RNA sequencing data in a stepwise manner. This is very useful both to readers and to students engaged in learning applied bioinformatics. As a user (non-developer, non-expert in RNA analysis tool evaluation), my contribution will be from a different perspective from the other reviewers who made excellent and detailed comments on this manuscript. Authors’ response: We are grateful for the positive comment provided by Dr Naslavsky about the usefulness of our workflow. Many thanks for highlighting the issues listed below, we believe that the clarity of our manuscript has substantially improved after addressing these comments. Edits to the main text are highlighted in italics. Reviewer comment: 1) Introduction, 2nd paragraph: “Moreover, these variability estimates can also be inflated by the technical noise that is typically observed in scRNA-seq data” Comment: Please illustrate with examples of technical noise as presented above for extrinsic and intrinsic noise, e.g. RNA differential degradation, ligation bias, etc. Authors’ response: We have edited the Introduction to provide additional information about potential sources for technical noise. The following text has been added at the end of the second paragraph: This technical noise relates to systematic differences between cells that may be introduced by the data generating process (e.g., due to differences in dilution or sequencing depth) [@Vallejos2017]. Reviewer comment: 2) Introduction, 3rd paragraph: “However, despite the benefits associated to the use of spike-ins and UMIs, these are not available for all scRNA-seq protocols.” Comment: Please provide a reason - something like “due to the very nature of the assay, which isolates library prep from external spike-ins and uses UMIs to map single-cell libraries…” or that spike-ins added to the library after pooling limit the full advantage of using them across single-cell populations. Authors’ response: We have added the following text to note the difficulties in using UMIs and spike-ins with some assays. For more detail, see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823857/. In particular, spike-ins are of limited use in droplet-based protocols, as spike-ins can only be added to the reagent mixture in a known concentration, and the exact quantity in each droplet necessarily remains unknown [@Bacher2016]. Reviewer comment: 3) Methods, 2nd paragraph: “Mean parameters μi quantify the overall expression for each gene i across the cell population under study.” Comment: Please define cell population as sample (all cells within a scRNA-seq assay) or post-processing UMAP, t-SNE, or similar clustering grouping. I understood the latter, but readers should be certain, and we need to understand which step these parameters refer to. Authors’ response: In order to clarify this, we have edited the Introduction to describe the experimental designs in which the BASiCS model can be applied: The model was initially motivated by supervised experimental designs in which experimental conditions correspond to groups of cells defined *a priori* (e.g. selected cell types obtained through FACS sorting). However, the approach can also be used in cases where the groups of cells of interest are computationally identified through clustering. In such cases, the model does not currently address issues associated to *post-selection inference*, where the same data is analysed twice: first to perform clustering and then to compare expression profiles between the clusters [@Lahnemann2020]; this is an inherent limitation of most differential expression tools. Furthermore, we have now included the following text in the Methods, “BASiCS - Bayesian Analysis of Single Cell Sequencing data” subsection: … within a cell population or populations under study. In this context, cell populations could correspond to groups set a priori by the experimental design (e.g. naive or stimulated CD4+ T cells in [@Martinez-jimenez2017]), or to groups of cells that were computationally identified through clustering. Reviewer comment: 4) After Figure 5: “These thresholds can vary across datasets and should be informed by gene-specific QC metrics such as those shown in Figure 5 as well as prior knowledge about the cell types and conditions being studied, where available”. Comment: I understand this is not the intent of this study, but if possible include some rationale behind thresholds for QCing gene exclusion based on types and conditions. Maybe bringing the choice for the example explored here. Authors’ response: We have removed the comments about choosing thresholds based on types and conditions, as we feel it does not reflect the true use of these thresholds for our use case. We thank the reviewer for the note, and have replaced this an explanation of our motivation: This is to ensure a reliable estimate of variability, and is roughly in line with the sample size requirements for the negative binomial distribution outlined in @Lloyd-Smith2007. Reviewer comment: 5) After spike-in calculation step: “To update the sce_naive and sce_active objects, the user must create a data.frame whose first column contains the spike-in labels (e.g. ERCC-00130) and whose second column contains the number of molecules calculated above. We add this as row metadata for altExp (sce_naive) and altExp (sce_active).” Comment: By ‘update’, do the authors mean ‘update after normalisation with spike-in’? If so, please specify. Authors’ response: Apologies for the confusion. By “update” in this context, we refer to adding the relevant information about spike-ins to the sce_naive and sce_active objects. We note that the spike-in analysis workflow has been moved to the Zenodo repository. Reviewer comment: 7) MCMC diagnostics Comment: I am by far not an expert on the analysis, but the authors were very successful in explaining the protocol in a stepwise manner. I would kindly ask if they can add the reason why this is needed: “to ensure that comparisons of gene expression are not random” or something in that direction. Readers will appreciate it. Authors’ response: We agree that it is important to explain the rationale behind these diagnostics; we have update the text to reflect this as follows: Before interpreting the estimates generated by `r Biocpkg(\"BASiCS\")`, it is important to check the performance of the MCMC algorithm used. This algorithm used to characterise the posterior distribution is stochastic by nature, and as such its performance may vary even when used on the same dataset using the same settings. We perform quality control of the MCMC algorithm in order to ensure that the results we observe are the result of properties of the underlying data, rather than being an artefact of the stochastic algorithm used to characterise the data. Reviewer comment: 8) Figures 15 and 16 Comment: These explanations are important to establish a convincing argument for using this workflow. Authors can explore further the ‘tight regulation’ versus ‘transcriptional burst’ or ‘sub-population structure’ scenarios with other examples (either from the literature or running an orthogonal analysis on larger scRNA-seq datasets of CD4+ T cells. Authors’ response: The various sources of transcriptional variability are indeed essential to justifying the use of this workflow. We note that previous work has highlighted these different aspects in detail. For example, Eling et al 2018 explored the role of population structure by generating artificially contaminated datasets. Similarly, Martinez-Jimenez 2017 showed the change in transcriptional bursting patterns relating to ageing, where older mice were found to have more stochastic gene expression patterns relative to younger mice. To clarify this point, we have briefly discussed this in the introduction: For example, @Eling2018 computationally explored the impact of unobserved structural heterogeneity by generating artificially contaminated datasets. In contrast, @Martinez-Jiminenez2017 showed that changes in transcriptional heterogeneity can related to aging, where older mice were shown to exhibit a more \"bursting\" or stochastic transcriptional pattern relative to younger mice."
}
]
}
] | 1
|
https://f1000research.com/articles/11-59
|
https://f1000research.com/articles/13-451/v1
|
07 May 24
|
{
"type": "Research Article",
"title": "A bibliometric analysis of the literature on goat breeding ",
"authors": [
"Thobela Louis Tyasi",
"Malik Ergin",
"Madumetja Cyril Mathapo",
"Malik Ergin",
"Madumetja Cyril Mathapo"
],
"abstract": "Background Bibliometric analysis plays an essential role in scientific research. However, some research areas still have several gaps. This is also the case in the animal sciences. Therefore, the status of current studies can be analyzed to provide guidance for future research through scientific studies that will be conducted. The aim of this study was to perform a bibliometric analysis of goat breeding to evaluate current trends, gaps in knowledge, and future perspectives.\n\nMethods A large dataset was extracted from the Web of Science (WoS), a popular database for scientific studies. According to the WoS, we used 1000 scientific papers (1991–2023) that contained articles, book chapters, data papers, proceedings papers, meeting abstracts, and notes. All bibliometric analyses were performed using the bibliometrix package.\n\nResults and Conclusions In 2023, there were 34 studies available. Average citations per year showed that the highest average citation count occurred in 2006 (31.35). In total, 265 scientific journals in the WoS database have published goat breeding studies. Small Ruminant Research led to the remaining 145 articles. In conclusion, scientific studies on goat breeding have become popular in recent years. The authors may gravitate towards popular journals in the future.",
"keywords": [
"Goat breeding",
"bibliometric analysis",
"biblioshiny",
"bibliometrix"
],
"content": "Introduction\n\nAlmost 55% of the world’s goat population are held by China and India (29 and 26%, respectively) (Utaaker et al., 2021). The second largest continent in terms of goat numbers is Africa, with nearly 34.5% of the world’s goat population, with the largest goat numbers in Sudan, Nigeria, Kenya, Somalia, and Tanzania, while North, Central, and South America, together with Oceania, account for only 4.7%, and Europe accounts for only 2.2% (Miller and Lu, 2019). Goats play a continuous role in modern agriculture, although they have varying purposes in various cultures; they are also a reliable source of meat, milk, skin, and fiber, but they are also reserved for their role in traditional and cultural ceremonies (Mdladla et al., 2017). Goat farming involves the raising and breeding of domestic goats. Despite the high number of published studies on this topic, the evolution of goat breeding research remains largely unknown. According to Colombino et al. (2021), bibliometric analysis is an interesting statistical approach that analyzes many articles and books in scientific content to identify future directions of a specific topic. The bibliometric analysis is generally used to identify the development of a certain field and analyzed scientific outputs (Pritchard, 1969; Zeleznik et al., 2017). In addition, Meo et al. (2013) indicated that bibliometric analysis plays a key role in the strategic planning and development of research in a knowledge domain, which provides an understanding of the size and growth of scientific literature in the discipline of concern within a specified time frame. Therefore, bibliometric studies on goat breeding are vital, as it is becoming increasingly challenging to remain up-to-date with everything that is being published on the topic. To the best of our knowledge, no previous bibliometric analyses have been conducted on goat breeding. Therefore, the aim of this study was to perform a bibliometric analysis of goat breeding to evaluate current trends, gaps in knowledge, and future perspectives. This study will assist researchers in recognizing potential research gaps in goat breeding. Furthermore, the present study will help encourage and explore scientific findings on goat breeding and future research projections.\n\n\nMethods\n\nIn this study, the Web of Science (WoS) database was used to extract scientific studies related to “goat breeding in animal science.” Goat-breeding studies performed between 1991 and 2023 were used in the literature review phase. The “goat breeding” was used as keyword to search results. Approximately 1000 scientific studies related to goat breeding have been conducted. Owing to the complex research data, all papers in a single dataset were gathered, and some papers with missing data were eliminated. All documents were categorized as articles, book chapters, data papers, early access articles, proceedings papers, meeting abstracts, and editorial notes. Table 1 presents the detailed structures of the documents. Raw data were evaluated in terms of the number of studies per year, annual citations per year, most relevant sources, trend topic keywords of the studies, countries of the corresponding authors, most relevant authors, and core sources by Bradford’s Law (Bradford, 1934).\n\nThe R programming language (R Core Team, 2023) is one of the most popular open-source languages for analyzing and visualizing bibliometric data from WoS (Aria and Cuccurullo, 2017). The “bibliometrix” package involves a function identified as “biblioshiny” which opens a web-based graphical interface on the browser. On the other hand, there are several databases such as Google Scholar, Dimension, Scopus, PubMed, ERIC, IEEE Xplore, ScienceDirect, DOAJ, and JSTOR. The WoS database has high coverage of approximately 100 million items. Therefore, WoS was chosen because of this advantage.\n\nThe steps of analyses raw data can be described broadly as follows:\n\n1) Data related to goat breeding studies were exported from the WoS database in bibtex format.\n\n2) Gathering and editing the dataset\n\n3) Analyze the studies conducted within a specific year period and represent their relationships through various visualization methods.\n\n4) Interpretation of the results.\n\n\nResults\n\nFigure 1 presents the annual scientific production. Goat-breeding studies have been performed for the first time since 1991. After 2007, there was a significant increase in approximately 32 studies, but it decreased to 33 in 2014. Unfortunately, the number of studies conducted has shown an increasing trend in the recent past, specifically since 2018. In 2023, there were 34 studies available, considering that this year was not yet completed, it would be unnecessary to make a negative evaluation.\n\nFigure 2 shows the average number of citations per year. The results showed that the highest average citation count occurred in 2006 (31.35). This result could be directly related to the increase in the number of studies conducted in 2006. After 2013, there was a significant decrease in the average number of citations.\n\nThe most Relevant Sources of goat breeding studies are shown in Figure 3. The results indicated that several journals were popular in the scientific field. In total, 265 scientific journals in the WoS database have published goat breeding studies. Small Ruminant Research led to the remaining with 145 articles.\n\nThe trend topic keywords in goat breeding studies according to the years between 1991 and 2023 are presented in Figure 4. According to the bibliometric results, “sheep” term was used 182 times and leads to the list. Following that, the “traits” and “diversity” terms were used 74 and 62 times respectively. The “sheep” term was used between 2009 and 2019. In addition, the second most used term named “traits” was used between 2010 and 2021 while the third most used term “diversity” was used between 2009 and 2018. Searching of the “sheep” term may be related to the small ruminants.\n\nThe countries of the corresponding authors that have published scientific studies on goat breeding are illustrated in Figure 5. In this result, single-country publications (SCP) and multiple-country publications (MCP) represent the number of publications by researchers from the same country and the number of publications by researchers from multiple countries, respectively. According to the corresponding authors, India is the first country with 114 scientific papers (SCP:110 and MCP:4). India is followed by China and Italy. The results showed that the second country China has produced 96 scientific studies (SCP:87; MCP:9). Italy ranked third and produced 95 scientific studies (SCP: 66 and MCP:29). The results also indicate that Italy was the most collaborative country with respect to studies on goat breeding.\n\nFigure 6 presents the most relevant authors in studies on goat breeding. The findings revealed that Dixit SP, Verma NK, and Aggarwal RAK were ranked as the top three authors, with 21, 17, and 14 scientific studies, respectively. These authors have been working on the biodiversity of goats.\n\nThe core sources obtained by Bradford’s law are presented in Figure 7. The results indicate that the sources were divided into three main zones according to Bradford’s law. In total, 338, 333, and 329 articles were found in Zones 1, 2, and 3, respectively. Zone 1, representing core sources and high levels of productivity, is shown with vertical and gray lines, respectively. Zone 1 had 338 articles and seven journals, while Zone 2 (moderate) had 333 articles and 40 journals, representing moderate productivity. Zone 3 (minor) has 329 articles and 218 journals, representing low productivity. In Zone 1, which exhibits high productivity, 338 articles were identified in seven of the world’s most popular journals, namely, Small Ruminant Research, Tropical Animal Health and Production, Indian Journal of Animal Sciences, Animals, Journal of Dairy Science, Italian Journal of Animal Science, and Journal of Animal Science.\n\n\nDiscussion\n\nGoats are adapted to various farming conditions and contribute to viable livestock production systems and food security, which makes many farmers interested in goat breeding (Gautam et al. 2019). This study was conducted using bibliometric analysis to identify emerging trends in goat breeding. Bibliometric analysis provides a literature review of a specific area using computer technology (Han et al., 2020). Bibliometric analysis enables the establishment of visual networks and associated structures to make general inferences regarding a specific topic in any discipline (Thanuskodi, 2010; Onder and Tirink, 2022). From the distribution of one thousand studies published between 1991-2023 on goat breeding, it was observed that the highest number of studies were conducted in 2020. The review of this study on average citations per year observed that most citations occurred in 2006. The current research on most relevant types of sources indicated sources such as tropical animal health and production, small ruminants research, Indian journal of animal science, animals, journal of dairy science, Italian journal of animal science, journal of animal science, scientific paper-series D-animals science, Asian Australasian journal of animal sciences and journal of applied animal research. Research on small ruminants was the most relevant source in the field of goat breeding, with one hundred and fifty four. The review observed the term “sheep” as the most top keyword used between the year 1991-2023. In terms of the country with the most corresponding authors, the researchers observed that India was the leading country with one-hundred and fourteen scientific papers. The review according to most relevant authors displayed various authors such as Dixit SP, Verma NK, Aggarwal RAK, Capote J, Chen H, Dalgado JV, Sharma A, Sharma R, Liu X and Ribeiro MN. The most relevant author was Dixit SP with twenty-one scientific studies in goat breeding. Bradford’s Law divides the core sources into three zones, one representing high, two moderate, and three minors. The researchers observed that zone one had high productivity with three-hundred and thirty-eight articles from the seven most popular journals. In a bibliometric study that speaks to the same matter but different animals of interest, publication data were collected from the Web of Science for the year 2013-2019. It was observed that 499 studies were published in the field of buffalo breeding, and the highest number of studies was published in 2013. The review showed that more information comes from the articles, and the most relevant sources were from the buffalo bulletin. The researchers indicated that India is the country where most publications were conducted and observed Hristov AN as the most relevant author with seventy-five articles in the field of water buffalo (Celik, 2021). Bradford’s law was used to identify the most relevant sources of a particular topic. According to the law, journals are arranged in descending order based on the number of articles published on the topic. Consecutive zones of periodicals containing the same number of articles form a simple geometric series of 1: n:n2:n3 (Biblioshiny, 2019; Orăștean and Mărginean, 2023).\n\nThis study was based on a publicly available dataset from the Web of Science (WoS). Therefore, ethical considerations were not required. The dataset extracted from the WoS is stated in the data availability section.",
"appendix": "Data availability\n\nFigshare: Data obtained from Web of Science: A bibliometric analysis of the literature on goat breeding, DOI: https://doi.org/10.6084/m9.figshare.25574451.v1 (Tyasi et al., 2024).\n\nThis project contains the following underlying data:\n\n• Full list of included savedrecs.bib.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nAria M, Cuccurullo C: bibliometrix: An R-tool for comprehensive science mapping analysis. J. Informet. 2017; 11(4): 959–975. Publisher Full Text\n\nBiblioshiny: 2019. Accessed 1 Nov 2023. Reference Source\n\nBradford SC: Sources of Information on specific subjects. Engineering. 1934; 137: 85–86.\n\nGross PLK, Gross FM: College Libraries and Chemical Education. Science. 1927; 66: 385–389. Publisher Full Text\n\nColombino E, Prieto-Botella D, Capucchio MT: Guthealth in veterinary medicine: A bibliometric analysis of the literature. Animals. 2021; 11:1997. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCelik S: The bibliometric analysis of the studies conducted in the field of water buffalo breeding. Prog. Nutr. 2021; 2(23).\n\nGautam L, Kumar Nagda RA, Waiz AH: Growth modeling and genetic analysis on growth traits of Sirohi goat under field conditions. Iran. J. Appl. Anim. Sci. 2019; 9(1):115–124.\n\nHan J, Kang HJ, Kim M, et al.: Mapping the intellectual structure of research on surgery with mixed reality: Bibliometric network analysis (2000–2019). J. Biomed. Inform. 2020; 109: 103516. PubMed Abstract | Publisher Full Text\n\nMeo SA, Al Masri AA, Usmani AM, et al.: Impact of GDP, spending on R&D, number of universities and scientific journals on research publications among Asian countries. PLoS One. 2013; 8(6): e66449. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOnder H, Tirink C: Bibliometric Analysis for Genomic Selection Studies in Animal Science. Journal of the Institute of Science and Technology. 2022; 12(3): 1849–1856. Publisher Full Text\n\nOrăștean R, Mărginean SC: Renminbi Internationalization Process: A Quantitative Literature Review. Int. J. Financ. Stud. 2023; 11(1): 15. Publisher Full Text\n\nPritchard A: Statistical bibliography: An interim bibliography. J. Doc. 1969; 24(4): 69.\n\nR Core Team: R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2023. Reference Source\n\nThanuskodi S: Journal of Social Sciences: A bibliometric study. J. Soc. Sc.i. 2010; 24(2): 77–80. Publisher Full Text\n\nUtaaker KS, Chaudhary S, Kifleyohannes T, et al.: Global goat! is the expanding goat population an important reservoir of cryptosporidium? Front. Vet. Sci. 2021; 8: 648500. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMdladla K, Dzomba EF, Muchadeyi FC: Characterization of the village goat production systems in the rural communities of the Eastern Cape, KwaZulu-Natal, Limpopo and Northwest provinces of South Africa. Trop. Anim. Health Prod. 2017; 49: 515–527. PubMed Abstract | Publisher Full Text\n\nMiller BA, Lu CD: Current status of global dairy goat production: an overview. Asian Australas. J. Anim. Sci. 2019; 32(12): 1219–1232. Publisher Full Text\n\nTyasi T, Ergin M, Mathapo MC: Data obtained from Web of Science: A bibliometric analysis of the literature on goat breeding. figshare. 2024. Publisher Full Text\n\nZeleznik D, Blazun Vosner H, Kokol P: A bibliometric analysis of the journal of advanced nursing, 1976-2015. J. Adv. Nurs. 2017; 73(10):2407–2419. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "275730",
"date": "05 Jun 2024",
"name": "Glafiro Torres-Hernández",
"expertise": [
"Reviewer Expertise Genetic improvement of small ruminants"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n“A bibliometric analysis of the literature on goat breeding” COMMENTS TO AUTHORS: “Background and Methods” are not clear. Authors talk about using 1000 scientific documents, but we think they should break down the number of each document in a particular way. Also, they don’t mention the discrimination criteria utilized to select the 1000 documents, nor the number of journals consulted. Were there only 1000 documents when using only the keyword “goat breeding”? Clarify this point. “Results and Conclusions” are too short and simple. Authors only mention 2023, and in fact 2023 is one of the years in which the smallest number of studies are observed. This contradicts the conclusion. Why do you make this differentiation? Do you also include what happened with the rest of the years? That is, point out where the greatest growth has been seen. How do you conclude that studies on goat farming have become popular? It is correct to point out that the number of studies of this type has increased significantly, but that does not necessarily make them popular. It is recommended not to use keywords contained in the title. The “Introduction” seems somewhat limited and contradictory. At the beginning, authors address the global inventory by continent, but immediately they talk about a large number of published studies related to goat breeding without prior context, and at the same time they indicate that the evolution of this topic remains unknown. It is suggested to expand more information regarding the increase in publications on this topic and, above all, to emphasize what this behavior is attributed to.\n\nThe information regarding bibliometric analysis seems sufficient. The chapter on “Methods” needs to be improved. Authors mention that articles with missing data were eliminated, but what was the elimination criterion? How many articles were eliminated, or what was the rejection rate?. What other elimination criteria did you use?. The “data analysis section” can be improved, particularly giving a more detailed description of the 4 steps indicated here. Results. Authors indicate that goat-breeding studies have been performed for the first time since 1991. This is true based on published studies in international journals, because there are goat-breeding studies in some latinamerican countries that were published before 1991 (early 80’s) in local journals; for example, Venezuela and Mexico. Authors say that 2023 is a year that is not complete, we think they should eliminate it, since the trend seen in Figure 1 suggests that the number of studies is decreasing. Regarding the average number of citations per year, authors point out that 2006 was the year with the most citations, and they suggest that this may be due to the increase in the number of studies. If this statement were correct, an increase in the average number of citations would be observed, due to the positive trend in the number of studies published in subsequent years. However, this did not happen and it was not until 2018 that a new increase in the average number of citations was observed. The result of the most relevant sources of information is not clear. Do authors mean that of the 1000 documents they analyzed, Small Ruminant published 145 (this data does not coincide with the data shown in Figure 3, with 154 articles: typographic error?) and the rest was published by 265 journals? Figure 3 shows other journals that make important contributions to this topic. Explain why they were not discussed in the results. The trend topic keywords section indicate that the most used keyword is “SHEEP”. Why?, We don’t understand, weren’t you supposed to have done a bibliographical review on “GOAT BREEDING”? Explain why in a bibliometric analysis of “GOATS”, the most used keyword is “SHEEP”. Although both species are considered small ruminants, each one corresponds to a completely different genus from the other. Furthermore, it is striking that in Figure 4, keywords such as “goat”, “kids”, “small ruminants”, among others of importance in goat production, were not shown. Author’s discussion of results is poor. What they did here is just make a summary of everything they showed in results. In addition, authors discuss and compare results with species such as Buffaloes, but they don’t discuss the observed trends at all and didn’t make an effort to explain why they found those results reported in the document. It is suggested to rewrite this section according to suggestions made here.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "350714",
"date": "09 Jan 2025",
"name": "Nelly Kichamu",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments to authors: Background The background is well written but too shallow ,authors should consider expanding it to incorporate some of the missing aspects for example\nThey can provide information on the consequences of the lack of bibliometric analysis on goat breeding Elaborate on how the findings from the bibliometric analysis will be applied to improve goat breeding programs. Modern tools in genetic analysis, disease prevention, and breeding techniques are transforming goat farming. They can mention how bibliometric analysis might reveal shifts or trends related to goat breeding advancement.\nSearch Strategy\nThe study relies only on the Web of Science (WoS) database. While WoS is comprehensive, they should consider including multiple databases to ensure comprehensive data collection.\nUsing only \"goat breeding\" as the search term might exclude relevant studies that use related terms, such as \"goat genetics,\" \"caprine reproduction or breeding,\" or \"small ruminant breeding.\" Employing other alternative keywords could increase the depth of the search.\nThe description does not specify whether filters (e.g., language, document type, or subject area) were applied during the search. This omission could lead to ambiguity about the scope of the search.\nThe rationale for selecting studies published from 1991 to 2023 is not explained. Why was 1991 chosen as the starting point? If this is based on trends in goat breeding research or database availability, it should be stated. Excluding studies before 1991 might omit foundational research unless this is addressed in the justification.\nDefine Exclusion Criteria by specifying what constitutes \"missing data\" and quantify exclusions.\nThe process for eliminating papers with missing data is not detailed as to what specific types of missing data (e.g., incomplete citations, lack of author information, or missing abstracts). This could influence reproducibility.\nWhat percentage of the dataset was removed due to missing data? If a significant portion was excluded, this could introduce bias.\nSome categories, like meeting abstracts or editorial notes, might not provide substantial content for analysis. Consider explaining whether these categories were treated differently in subsequent analyses.\nWhile the study mentions Bradford's Law, it does not explain why it was chosen or how it adds value to the analysis. This statistical principle could be briefly explained and linked to the study's objectives.\nData Analysis and Quality Assurance\nThere is no mention of how duplicate records were handled, as duplicate entries could skew results.\nIt is unclear whether the data extraction process was validated (e.g., by having multiple researchers independently verify the data).\nIf only English-language articles were included, this could lead to geographic bias, particularly given the global nature of goat breeding (e.g., significant research might be published in Chinese, French, or Spanish).\nIt would be helpful to discuss whether the WoS database adequately represents research outputs from regions with significant goat populations, such as Africa or Asia.\nElaboration on on Analytical Methods should be clear by breaking down the types of analyses conducted and specify statistical or computational tools used, if any.\nList and justify the types of visualization methods applied and include examples of how visualizations helped in interpreting relationships or trends.\nInterpretation should be enhanced by detailing on how results were contextualized within the broader research field also mention potential biases in the dataset and how they were accounted for.\nAcknowledge any limitations in the study eg relying solely on WoS or the tools used.\nResults and Conclusions\nUnder the Trend topic keywords its so confusing why authors used sheep ‘According to the bibliometric results, “sheep” term was used 182 times and leads to the list. Following that, the “traits” and “diversity” terms were used 74 and 62 times respectively. The “sheep” term was used between 2009 and 2019.while the paper is about goats. Can you please clarify on this\nThe discussion section is too shallow and needs to be strengthened by comparing and contrasting with other relevant studies\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-451
|
https://f1000research.com/articles/13-450/v1
|
07 May 24
|
{
"type": "Research Article",
"title": "Environmental factors and daily suicides: a time series analysis",
"authors": [
"Imene Kacem",
"Ines Ouahchi",
"Maher Jedidi",
"Rania Nakhli",
"Maher Maoua",
"Sarra Gharsallaoui",
"Mohamed Soussi",
"Amen Fki",
"Dalila Taieb",
"Souhail Chatti",
"Walid Naija",
"Asma Aloui",
"Mohamed Kahloul",
"Ines Ouahchi",
"Maher Jedidi",
"Rania Nakhli",
"Maher Maoua",
"Sarra Gharsallaoui",
"Mohamed Soussi",
"Amen Fki",
"Dalila Taieb",
"Souhail Chatti",
"Walid Naija",
"Asma Aloui",
"Mohamed Kahloul"
],
"abstract": "Background This study investigated the association between weather, air pollution, and suicide risk in Sousse.\n\nMethods A two-time series analysis examined suicide cases recorded in the forensic service of Farhat Hached University Hospital of Sousse, confirmed by autopsy, over seven years (2010-2016). Climate data were retrieved from the Monastir-Airport weather station, and air pollution data were obtained from the National Agency for Environmental Protection’s modelling platform.\n\nResults During the study period, 118 suicides were recorded, with the highest number (19.5%) occurring in 2012. Multiple binary logistic regression analysis revealed that autumn and a decline in NH3 were independently associated with a decreased risk of suicide (p=0.045; ORa: 0.57 CI95% [0.33-0.98], p= 0.009; ORa: 0.24 CI95% [0.08-0.71], respectively). Conversely, a 1 ppm increase in PM10 was associated with a 2.5% increase in suicide risk (p<10-3; ORa: 1.02 CI95% [1.01-1.03]).\n\nConclusions Environmental factors, including seasonality and air quality, may provide valuable insights into suicide risks. Understanding the influence of these factors may have implications in preventive strategies.",
"keywords": [
"Suicide",
"Environment",
"Air pollution",
"Climate"
],
"content": "Introduction\n\nSuicide is an act of self-harm with fatal consequences.1,2 It is a rising global health problem and is responsible for 50% of all violent deaths.3 The World Health Organization (WHO) estimates that the annual number of suicides worldwide exceeds the combined total of deaths due to homicide and war, despite under-reporting in most countries. This underscores the importance of understanding the biological processes underlying suicide to develop effective prevention strategies.4\n\nThe pathophysiological processes underlying suicide are complex and multifaceted, involving an interplay of individual, biological, sociological, and environmental factors.5,6 Air pollution and climate change are recognized as major global issues that have significant detrimental effects on human health. Consequently, air pollution and harsh weather have been linked to several mental health issues such as suicide.7,8\n\nHowever, previous studies investigating the influence of environment on suicide occurrence have yielded conflicting results.9 Most studies reported higher suicide rates in spring and summer.10–12\n\nA variety of other meteorological variables, such as sunshine duration, temperature, atmospheric pressure, precipitation, and humidity, have also been examined for their potential association with suicide.13,14\n\nAccording to WHO, 24% of current diseases can be attributed to environmental degradation.15 This underscores the urgency for further research into the complex interplay between environmental factors and mental well-being, particularly regarding suicide risk.16–18\n\nDespite conflicting findings, research on the link between air pollution and suicide is accumulating. A 2021 meta-analysis encompassing 18 studies found a significant overall association between exposure to air pollutants and suicide, with risk ratios ranging from 1.01 to 1.03.19 Although the precise mechanisms underlying this association are still under investigation, several hypotheses suggest potential pathways. Both air pollution and high temperatures have been linked to neuroinflammation and central nervous system dysfunction, potentially disrupting serotonin metabolism and impacting mood regulation.19 These factors, in turn, could contribute to increased vulnerability to suicidal thoughts and behaviours.\n\nHowever, studies investigating the interactions between air pollution and other environmental factors, such as meteorological variables, remain limited. This highlights the need for further research specifically designed to disentangle these complex relationships and to elucidate the combined impact of environmental factors on suicide risk. By addressing these knowledge gaps, we can develop more effective prevention strategies and mitigate the environmental burden on mental health.\n\nFrom this perspective, this study was conducted to analyse the association between weather conditions, air pollution, and the risk of suicide.\n\n\nMethods\n\nA two-time series analysis study investigated the relationship between environmental data and suicide cases, over a 7-year period from January 1, 2010, to December 31, 2016.\n\nThis study was carried out in the Sousse region, which is located in the Tunisian East Center and is one of the largest cities in Tunisia. Sousse’s location, at 35° 50′ north and 10° 38′ E, places it within the lower semi-arid bioclimatic zone. The city enjoys the influence of the Mediterranean Sea, resulting in a distinct coastal climate. Temperatures throughout the year remain mild, ranging from an average of 11.2°C in January (the coldest month) to 26.3°C in August (the hottest month). Monthly thermal variations are usually less than 10°C, which contributes to a consistent and comfortable climate.20,21\n\nThe study included all deaths investigated by the forensic department of Farhat Hached University Hospital during the study period. This department serves as the central repository for all deceased individuals in the Sousse Governorate, whose deaths were deemed violent or occurred under suspicious circumstances.\n\nSuicide has been defined as the violent death of a person caused by the voluntary intervention of the person himself to cause his own death and where preliminary data from the judicial inquiry disclosed were in favour of this hypothesis.1,2\n\nWe did not include accidents related deaths, homicides, cases of suicide registered in other governorates than Sousse and suspected cases that were not confirmed by forensic autopsy data and preliminary judicial inquiry.\n\nTwo separate synoptic sheets were developed in this study. A medical record including the identification of the victim (age, gender, marital status, origin, and history), the circumstances of the death (date, place, circumstances, means used, and causes), autopsy data, and an environmental data sheet.\n\nClimate data, including temperature, humidity, pressure, and precipitation, were collected from the Monastir-Airport meteorological station in the Sousse region (14 km away).\n\nThe temperature was measured under the cover and expressed in degrees Celsius (°C). The relative humidity reflects the amount of water vapor in the atmosphere. It is the ratio of the water vapor pressure actually measured to that measured if the air was saturated at the same temperature. The results were expressed as a percentage (%). Atmospheric pressure is the weight of air on the Earth’s surface and is expressed in hPa (hectoPascal). Precipitation is the amount of rain recorded in millimetres.\n\nFor each day included in the study, environmental data were recorded for the event day (J0), one day prior (1-day lag), and two days prior (2-day lag).\n\nAir pollution data were obtained from the National Agency for Environmental Protection’s modelling platform, which simulates pollutant dispersion using mathematical models and specialized software. The platform data used in this study underwent rigorous validation and calibration for two years.\n\nThe specific air pollutants measured included carbon dioxide (CO2), ammonia (NH3), sulphur dioxide (SO2), nitrogen oxides (NOx), volatile organic compounds (VOCs), total suspended particulate matter (TSP), and particulate matter (PM) with aerodynamic diameters less than 10 μm (PM10) and less than 2.5 μm (PM2.5).\n\nIn our study, the ARIA Impact software, version 1.8 which is open access software (https://aria-impact.software.informer.com/download/) was launched in the Sousse region. This is a Gaussian Cartesian statistical model. The calculation of the deposition of pollutants on the ground makes it possible to take into account two types of pollutants: passive waste gases and dust sensitive to the effects of gravity.\n\nARIA Impact software uses Pasquill standard deviations. The calculation assumptions of this model are that the turbulence is homogeneous in the lower layers, the measurement of the site is representative of the entire field of calculation, the density of the pollutants is close to that of the air, and the vertical component of the wind is negligible in front of the horizontal component. These hypotheses allow rapid visualization of the orders of magnitude of pollution in domains of 1 to 30 km.\n\nThe pollution indicator was introduced into the model using temperature, relative humidity, wind speed, precipitation, and atmospheric pressure, in addition to the city’s topographical data.\n\nThe model must be able to simulate air quality and, thus, the dispersion of pollutants emitted by stationary and mobile sources in different weather situations, including urban convection. The hourly concentrations of each pollutant were calculated and validated.\n\nSubsequently, the hourly concentrations of each pollutant were converted using Excel into the daily average concentrations required for our analytical study.\n\nThe data were analysed using SPSS 21.0. Qualitative variables were assessed using frequency analysis, while quantitative variables were evaluated for their means, standard deviations, medians, and extreme values. Paired and independent series means were compared using the Student’s t-test, while the one-factor ANOVA test was employed for comparisons involving multiple means.\n\nFrequency comparisons were conducted using Pearson’s chi-square test. The relationship between the two quantitative variables was investigated using the Pearson’s correlation coefficient.\n\nTo assess seasonal effects on suicide, suicide dates were categorized by season. Multiple binary logistic regression was performed for multivariate analysis, with the absence or presence of suicide on a given date as the dependent variable. The significance threshold (p) was set at 0.05 for all statistical tests.\n\nThis study was approved by the Ethics committee of Sahloul Teaching Hospital on April the 20th 2022; under the number HS 16-2022.\n\n\nResults\n\nA total of 118 suicide cases were identified during the study period. The year 2012 saw the highest number of suicides (19.5%) without a statistically significant difference across years (p=0.14). The sex ratio was 3.53. The average age at death was 33.1±13.9 years. Among the suicide cases, the majority (58.5%) were single and resided in rural areas (61%).\n\nPsychiatric histories were reported in 22% of the cases. Nervous depression was the most common pathology (55.3%). The location and mechanism of most reported suicides were home (44.9%) and hanging (45.8%). Suicide occurred as a result of conflict in 33.1% of the cases, financial difficulties in 18.6%, and occupational problems in 13.6%.\n\nThe largest number of suicide cases was observed during the summer season, with 40 cases (33.8%), a statistically significant difference (p=0.021).\n\nComparing the occurrence of suicide in the autumn with other seasons, a statistically significant decrease in risk was observed during this season with an OR=0.48 (CI 95% [0.28-0.82] and p=0.006.\n\nA comparison of mean temperatures between days with and without suicide revealed significantly higher temperatures on days when suicide occurred (p=0.043). This finding was replicated for mean temperatures one day prior to the suicide events (p=0.03).\n\nTable 1 summarizes the results of comparing the mean meteorological parameters, including mean temperature, humidity, atmospheric pressure, and precipitation, between days with and without suicide.\n\nComparison of mean PM10 and PM2.5 concentrations between days with and without suicide showed significantly higher levels on suicide days (p<10-3 for both pollutants). Conversely, lower concentrations of NH3 and SO2 were observed on suicide days, although the differences were not statistically significant.\n\nNo statistically significant differences were found in the mean concentrations of the other studied air pollutants between the days with and without suicide. The same finding was highlighted by comparing the mean concentrations of air pollutants one day and two days before the occurrence of suicide.\n\nA comparison of the means of the measured air pollution parameters (CO2, NH3, SO2, NOX, VOC, TSP, PM10, and PM2.5) between days with and without suicide is summarized in Table 2.\n\nAfter multiple binary logistic regression, autumn and NH3 decline were independently associated with a decrease in suicide risk (p=0.045; ORa: 0.57 IC95% [0.33-0.98], p=0.009; ORa: 0.24 CI95% [0.08-0.71], respectively), whereas a 1 ppm increase in PM10 was independently associated with a 2.5% increase in the risk of suicide (p<10−3; ORa: 1.02 CI95% [1.01-1.03]).\n\n\nDiscussion\n\nAccording to WHO, suicide represents an annual global mortality incidence of approximately 14.5 per 100,000 inhabitants.22 It is a serious public health issue that deserves to be thoroughly analysed, especially in terms of risk factors.23,24\n\nIn our study, the largest number of suicide cases was observed during the summer (33.8%), with a statistically significant difference (p=0.021). Similarly, a statistically significant decrease in risk was observed during falls (p=0.006).\n\nSimilar results to ours were reported by Amiri et al.,25 who observed that the largest number of suicide cases occurred during the summer period, with a statistically significant difference (p=0.006). Other studies have reported peaks in spring and early summer.11,26 However, to date, results are not yet conclusive, as some studies suggest a higher suicide rate in autumn and summer and a lower suicide rate in winter.27–30 Others report higher rates in the spring and summer31–33 or spring and autumn34 or only in the spring.35–38\n\nThe seasonality of suicide was first proposed by scientists in the 19th century and has since been observed in various countries and geographical areas.39 Its underlying causes vary, including daylight exposure, chronobiological aspects of mood disorders, and socio-economic influences.40\n\nOne of the most compelling hypotheses suggests that serotonin dysfunction plays a crucial role and is likely multifaceted, involving a complex interplay of factors, including temperature, in predisposing individuals to self-injurious behaviour.41–43 This theory postulates that climatic factors can exacerbate vulnerability of the nervous system, potentially leading to increased rates of suicide attempts in spring and early summer.25 Ultimately, understanding the intricate interplay between climate change, serotonin function, and suicidal ideation/behaviour provides valuable insights into seasonal patterns of suicide.44\n\nSimilarly, significantly higher temperatures were reported during days of suicide (p=0.043). Several studies have reported similar results.14,45–49 A recent meta-analysis, including 32 studies, 17 time series (53.1%), and 9 cross-case studies (28.1%) conducted in 26 countries, found a significant association between temperature and suicide with an estimated relative risk of 1,09 despite different approaches to exposure measurements.19\n\nIn Kazakhstan, a 1°C increase in the mean apparent temperature was associated with a 2.1% increase in suicide rates.50 Similarly, Brazilian time-series analysis revealed a 2.28% increase in total suicides for each 1°C increase in weekly mean temperatures.49 However, Swiss researchers analysing long-term monthly data on suicide and weather found that the association is not driven by hot temperatures but by the absence of cold temperatures, suggesting that the lack of cold plays a more significant role.51\n\nWhile the exact mechanism underlying this association remains unclear, the hypothesis implicating the serotonin system is considered the most promising explanation.52 Evidence suggests that serotonin deficits (5-HT) are associated with non-fatal and fatal suicide attempts.53 Additionally, research indicates that l-tryptophan, a precursor of serotonin, decreases at high ambient temperatures.54 Several studies have suggested that ambient temperature-influenced changes in serotonin function may contribute to impulsivity, aggression, and potentially suicidal behaviour.53\n\nIn our study, no relationship was found between suicide and humidity, which is consistent with the results of Lee et al.,35 Deisenhammer et al.55 and Kurokouchi et al.13\n\nDigon and Bock56 were the first to report that a drop in atmospheric pressure is correlated with an increase in suicide rates. This result has not been confirmed in other studies,57 including ours.\n\nIn our study, no association was reported between suicide rate and precipitation, which is consistent with the results of Asirdizer et al.58 and Lee et al.35 In contrast, Inoue et al.59 reported that suicide rates increased with heavy precipitation.\n\nIn our study, after multiple binary logistic regression, a 1 ppm rise in PM10 was independently associated with a 2.5% increase in the risk of suicide (p<10−3;ORa:1.02 IC95% [1.01-1.03]).\n\nIn the literature, the results of air pollution and suicide differ from one study to another. This mismatch can be explained by geographical variations, climatic conditions, culture, socioeconomic factors, and suicidal behaviour.60\n\nAccording to a recent meta-analysis, a significant increase was reported for PM2.5, PM10, and NO2 pollutants, with RR of 1.02 (95% CI:1.00, 1.05), 1.01 (95% CI:1.00, 1.03) and 1.03 (95% CI:1.00, 1.07) respectively. However, no significant association was noted between O3, SO2 and CO.19\n\nLin et al.61 found a significant increase in suicides related to PM10, NO2, and SO2 exposure. A cross-case study, conducted in Utah, USA, including 1,546 suicide cases, found an increase in the number of suicides related to exposure to PM2.5 and NO2 on the same day and during the 2–3 days preceding suicide.62 These effect-offsets would save time for early action to prevent suicide. Awareness of suicide prevention and special attention should be given to high-risk individuals, such as those with a history of mental illness, on days of high pollution levels.\n\nKim et al.60 reported that a high risk of suicide was associated with higher levels of NO2, SO2, and PM10 over several days. However, no association was found between PM2.5 and suicide risk. Merrill RM63 and Liu et al.64 reported a significant association between suicide risk and exposure to fine PM2.5.\n\nA recent time-series study conducted in California assessed the association between O3 and fine particulate matter (PM2.5) and various mental illnesses, including suicide, between 2005 and 2013. The authors observed significant cumulative 7-day associations with suicide for every 10 ppb increase in O3. This association persisted after adjusting for seasons.65\n\nHowever, According to Astudillo-Garcíaou CI,66 no association was noted in their time series study between suicides and exposure to PM2.5, PM10, O3, NO2, and SO2, taking into account meteorological variables (air, temperature, and relative humidity). This result is consistent with that of Fermandez-Nino et al.18\n\nThe neuroinflammatory hypothesis is considered to be the primary explanation for the impact of air pollution on suicide risk. Air particles act as irritants and trigger both systemic and local inflammatory responses.67\n\nSeveral researchers have proposed that high levels of air pollution induce cytokine production, leading to neuroinflammation, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and alterations in neurotransmitter levels through direct and indirect pathways. These pathways, in turn, are potentially implicated in the development of depression, suicidal behaviours, or both.16,62 Further research investigating the neurophysiological response to air pollutants is crucial to fully understand their impact on suicide risk.60\n\nImportantly, air pollution and temperature can be strongly correlated, though the correlation varies depending on the pollutant. This correlation poses a potential confounding factor in disentangling the independent effects of temperature and air pollution on suicide risk. Both these factors are associated with neuroinflammation and serotonin neurotransmission, making it challenging to isolate their individual contributions.19\n\nThis study holds the unique distinction of being the first in Tunisia to investigate the association between weather, air pollution, and suicide incidence. By analysing a 7-year time series of weather and air pollution parameters alongside suicide occurrences, our research offers valuable insights into the potential connections between these factors. This time-series approach is particularly well suited for studying the short-term relationship between environmental parameters and acute health events, providing a more robust framework compared to cross-case studies reliant on comparing two periods with self-referential cases.68\n\nWhile weather data were collected from a station located 14 km away in Monastir, existing research suggests that this distance allows for valid extrapolation to the Sousse region.69 However, we acknowledge the inherent limitations of not having access to the detailed microclimate and indoor conditions experienced by each individual. Ideally, weather data should be obtained for each household to analyse the impact of meteorological and seasonal factors on suicide occurrences with greater precision. However, acquiring such data is impractical.\n\nOur study leveraged data from the National Agency for Environmental Protection’s modelling platform. This approach incorporates location-specific geographical features, such as population density and proximity to roads. This provides a more nuanced understanding of small-scale spatial variations in air pollution levels, overcoming the limitations of relying solely on data from fixed monitoring stations. Additionally, the one- to two-day lag applied to suicide data allowed us to assess the cumulative effects of pollution exposure beyond immediate impacts.\n\n\nConclusion\n\nSuicide is a common cause of death, worldwide. It is usually associated with psychiatric, psychological, and cultural factors. However, other factors that are less frequently reported, such as the environment, should be considered. Indeed, climate change and air pollution seem to have serious impacts on mental health. Health policies should consider these factors when establishing preventive measures. Thus, health policies should consider all of these factors in future preventive programs.\n\n\nEthics and consent\n\nThe Ethics Committee of Sahloul Teaching Hospital approved this study on April the 20th 2022; under the number HS 16-2022 and provided a waiver of consent.\n\n\nAuthor contributions\n\nAll authors contributed to the study conception and design.",
"appendix": "Data availability\n\nFigshare: Environmental factors and daily suicides: a time series analysis. https://doi.org/10.6084/m9.figshare.25465681. 70\n\nThis project contains the following underlying data:\n\n- data suicide environnement.sav (SPSS format)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nMajdoub W, Mosbahi A, Naouar M, et al.: Suicide in children and adolescents: a Tunisian perspective from 2009 to 2015. Forensic Sci. Med. Pathol. 2017; 13(4): 417–425. PubMed Abstract | Publisher Full Text\n\nCDC: Facts About Suicide.Reference Source\n\nWHO: Preventing suicide: A global imperative.2014. Report No: 978 92 4 256477 8. Reference Source\n\nWHO: Suicide. Prévention du suicide: l’étatd’urgencemondiale.2014. Reference Source\n\nMann JJ, Waternaux C, Haas GL, et al.: Toward a clinical model of suicidal behavior in psychiatric patients. Am. J. Psychiatry. 1999; 156(2): 181–189. 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Psychiatry. 1989; 1: 153–164. Publisher Full Text\n\nMalone K, Mann JJ: Serotonin and the suicidal brain: American Foundation for Suicide Prevention, Research Report. Nat. Med. 1998; 4: 25–30.\n\nAtmaca M, Kuloglu M, Tezcan E, et al.: SerumLeptin and cholesterol values in suicides attempters. Neuropsychobiology. 2002; 45(3): 124–127. PubMed Abstract | Publisher Full Text\n\nYang CT, Paul SFY, Eun Shil C, et al.: Seasonal changes in suicide in South Korea, 1991 to 2015. PLoS One. 2019; 14(6): e0219048. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBurke M, González F, Baylis P, et al.: Higher temperatures increase suicide rates in the United States and Mexico. Nat. Clim. Chang. 2018; 8(8): 723–729. Publisher Full Text\n\nBando DH, Teng CT, Volpe FM, et al.: Suicide and meteorological factors in São Paulo, Brazil, 1996-2011: a time series analysis. Rev. Bras. Psiquiatr. 2017; 39(3): 220–227. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCarleton TA: Crop-damagingtemperaturesincrease suicide rates in India. Proc. Natl. Acad. Sci. U S A. 2017; 114(33): 8746–8751. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFountoulakis KN, Chatzikosta I, Pastiadis K, et al.: Relationship of suicide rates with climate and economic variables in Europe during 2000– 2012. Ann. Gen. Psychiatry. 2016; 15: 19. Publisher Full Text\n\nLuan G, Yin P, Wang L, et al.: Associations between ambient high temperatures and suicide mortality: a multi-city time-seriesstudy in China. Environ. Sci. Pollut. Res. Int. 2019; 26(20): 20377–20385. Publisher Full Text\n\nGrjibovski AM, Kozhakhmetova G, Kosbayeva A, et al.: Associations between air temperature and daily suicide counts in Astana, Kazakhstan. Medicina. 2013; 49(8): 379–385. PubMed Abstract | Publisher Full Text\n\nAjdacic-Gross V, Lauber C, Sansossio R, et al.: Seasonal associations between weather conditions and suicide–evidence against a classic hypothesis. Am. J. Epidemiol. 2007; 165: 561–569. PubMed Abstract\n\nLuykx JJ, Bakker SC, van Geloven N , et al.: Seasonal variation of serotonin turnover in human cerebro spinal fluid, depressive symptoms and the role of the 5-HTTLPR. Transl. Psychiatry. 2013; 3: e311. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim Y, Kim H, Gasparrini A, et al.: Suicide and Ambient Temperature: A Multi-Country Multi-City Study. Environ. Health Perspect. 2019; 127(11): 117007. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMaes M, Scharpé S, Verkerk R, et al.: Seasonal variation in plasma L-tryptophan availability in healthy volunteers. Relationships to violent suicide occurrence. Arch. Gen. Psychiatry. 1995; 52(11): 937–946. PubMed Abstract | Publisher Full Text\n\nDeisenhammer EA, Kemmler G, Parson P: Association of meteorological factors with suicide. Acta Psychiatr. Scand. 2003; 108(6): 455–459. Publisher Full Text\n\nDigon E, Bock HB: Suicides and climatology. Arch. Environ. Health. 1966; 12(3): 279–286. PubMed Abstract | Publisher Full Text\n\nFountoulakis KN, Savopoulos C, Zannis P, et al.: Climate change but not un employment explains the changing amiri suicidality in Thessaloniki Greece (2000-2012). J. Affect. Disord. 2016; 193: 331–338. Publisher Full Text\n\nAsirdizer M, Kartal E, Etli Y, et al.: The effect of altitude and climate on the suicide rates in Turkey. J. Forensic Leg. Med. 2018; 54: 91–95. PubMed Abstract | Publisher Full Text\n\nInoue K, Nishimura Y, Fujita Y, et al.: The relationshipbetween suicide and five climate issues in a large-scale and long-termstudy in Japan. W Indian Med J. 2012; 61(5): 532–537. PubMed Abstract | Publisher Full Text\n\nKim Y, Sheng Ng CF, Chung Y, et al.: Air Pollution and Suicide in 10 Cities in Northeast Asia: A Time-Stratified Case-Crossover Analysis. Environ. Health Perspect. 2018; 126(3): 037002. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLin GZ, Li L, Song YF, et al.: The impact of ambient air pollution on suicide mortality: a case-crossover study in Guangzhou, China. Environ. Health. 2016; 15: 90. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBakian AV, Huber RS, Coon H, et al.: Acute Air Pollution Exposure and Risk of Suicide Completion. Am. J. Epidemiol. 2015; 181: 295–303. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMerrill RM: Injury-Related Deaths According to Environmental, Demographic, and Lifestyle Factors. J. Environ. Public Health. 2019; 2019: 1–12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu JJ, Wang F, Liu H, et al.: Ambient Fine Particulate Matter Is Associated withIncreased Emergency Ambulance Dispatches for Psychiatric Emergencies. Environ. Res. 2019; 177: 108611. PubMed Abstract | Publisher Full Text\n\nNguyen AM, Malig BJ, Basu R: The association between ozone and fine particles and mental health-related emergency department visits in California, 2005–2013. PLoS One. 2021; 16(4): e0249675. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAstudillo-García CI, Rodríguez-Villamizar LA, Cortez-Lugo M, et al.: Air Pollution and Suicide in Mexico City: A Time Series Analysis, 2000–2016. Int. J. Environ. Res. Public Health. 2019; 16: 2971. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCosta LG, Cole TB, Coburn J, et al.: Neurotoxicants are in the air: convergence of human, animal, and in vitro studies on the effects of air pollution on the brain. Bio. Med. Res. Int. 2014; 2014: 736385.\n\nFilleul L, Zeghnoun A, Decmercq C, et al.: Relations à court terme entre la pollution atmosphériqueurbaine et la mortalitérespiratoire: la place des études temporelles. Rev. Mal. Respir. 2001; 18: 361–453.\n\nHandbook for the Meteorological Observation: Koninklijk Nederlands. MeteorologischInstitut. KNMI; 2000. Reference Source\n\nKahloul M, Kacem I, Ouahchi I, et al.: Environmental factors and daily suicides: a time series analysis. [Dataset]. figshare. 2024. Publisher Full Text"
}
|
[
{
"id": "294646",
"date": "05 Jul 2024",
"name": "Laura Rodriguez-Villamizar",
"expertise": [
"Reviewer Expertise Environmental Epidemiology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting paper reporting the relationship between environmental factors and suicide in Sousse. However, there are specific major issues that are listed below for the authors to consider:\nTitle: please include place and time period (Sousse, 2010-2016)\nAbstract- Methods: Please correct “a two-time series analysis” (see below in methods)\nIntroduction: The central ideas are expressed correctly but there is need of more explanation for those statements with specific mention of results of contradicting studies and potential explanations for differences in results. There are 3-4 paragraphs with only 1 or 2 sentences which make looks the introduction kind of weak in terms of arguments.\nMethods:\nIt is recommended to have this section organized into subsections including study design and population, data sources, statistical analysis, and others as needed. It is not clear to me what “two-time series analysis” means. Not sure if the authors are referring to the two-stage time series analysis but looking at the statistical analysis this is clearly not the case. For the air pollution data modelling, could the authors specify the standard used for the validation of data and their corresponding summary of results?\nThe authors used a standard multiple binary logistic regression to model “the absence or presence of suicide on a given date as the dependent variable”. Using a standard logistic regression have the underlying assumption of independency of observations which is clearly violated in a time series analysis when each observation of the analysis is the day and there is a correlation structure across observations. Time series analysis needs to account for the correlation structure of the data and the seasonality of suicide data. Usually, time series analysis can be analyzed using Poisson models with control for correlation and seasonality (i.e. time-stratified models) or using Gaussian Additive Models (GAM) or more commonly used during the last years using a Distributed linear or non-linear model (DLNM) developed by Antonio Gasparrini.\nResults: There is not description of the time-series for suicide and environmental data. Table 1 can be reported only for same day parameters as the lagged exposures are important only for the risk estimation. Same for Table 2. This table 2 presents data in ug/m3 for all pollutants, however the summary mentions results for PM in ppm. Please clarify units used for pollutants. A table with the risk for suicide by pollutant (and lagged exposure) is missing which will be the main table in the results section for this type of analysis.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "294641",
"date": "18 Jul 2024",
"name": "Andrea Aguglia",
"expertise": [
"Reviewer Expertise suicide and bipolar disorder"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Editor and Authors,\n\nmany thanks to have the opportunity to revise this manuscript aiming at analysing the association between weather conditions, air pollution, and the risk of suicide. The topic is very interesting and currently sound.\n\nUnfortunately, the main bias is the recruitment time from 2010 to 2016 and in these other 8 years the environmental factors are change a lot with a global warming, more pollution and seasonal changes.\n\nThe reported findings are not actual and generalized in the current climatic situation.\nTherefore, I can not proceed this article to other revision process. I suggest to not index this manuscript.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "277225",
"date": "29 Aug 2024",
"name": "Mehdi Slim",
"expertise": [
"Reviewer Expertise CARDIOLOGY"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear authors, Thank you for the relevance of your study entitled “Environmental factors and daily suicides: a time series analysis”.Your main aim was to investigate the association between weather, air pollution, and suicide risk which may guide preventive measures such as environmental protection and better support for vulnerable people during risky seasons.Your study also constitutes an additional valuable reference on the effects of the environment and pollution on human health which would subsequently enhance the evaluation of the effects of the latest environmental changes. Introduction: The problem is well argued with a clear and precise objective. However, paragraphs 3 to 5 may be merged into a single paragraph as they on the same topic. Methods: The considered methodology is consistent with the aim of the study. However, it should be better to reorganize this section into subsections. Results: Results are clear and precise. However, it would be better to define the abbreviations at the bottom of table 2.Discussion:You have analyzed your results in relation to current published data. Your pathophysiological hypotheses were very interesting. However, I have two minor comments: 1. Please merge paragraphs 9 to 14 into the same paragraph 2. In your study “Suicide has been defined as the violent death of a person caused by thevoluntary intervention of the person himself to cause his own death and wherepreliminary data from the judicial inquiry disclosed were in favour of this hypothesis”.Suicides not approved by judicial inquiry were not included in this study which may results in an underestimation bias. This point should be considered in the section “Study limitations”.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-450
|
https://f1000research.com/articles/13-449/v1
|
07 May 24
|
{
"type": "Study Protocol",
"title": "To compare the efficacy of ropivacaine alone versus ropivacaine with magnesium sulphate for postoperative analgesia in peripheral nerve stimulator-guided supraclavicular plexus block in upper limb surgeries",
"authors": [
"Sikha Subhadarshini",
"Karuna Taksande",
"Amreesh Paul",
"Karuna Taksande",
"Amreesh Paul"
],
"abstract": "Background Postoperative pain management is a crucial part of patient care for surgeries involving the upper limbs. A popular technique for providing both postoperative analgesia and regional anaesthesia is a supraclavicular plexus block guided by a peripheral nerve stimulator. Recent research has demonstrated that the analgesic effect of ropivacaine, a common local anaesthetic, can be enhanced by the addition of magnesium sulphate. The study aims to assess the safety and effectiveness of utilising magnesium sulphate in addition to ropivacaine alone for postoperative analgesia in patients having upper limb surgeries under peripheral nerve stimulator-guided supraclavicular plexus block.\n\nMethods This protocol outlines a prospective, double-blind, randomised, controlled trial that assesses the efficacy of ropivacaine versus ropivacaine plus magnesium sulphate for analgesia post surgery in patients undergoing upper limb surgeries under the guidance of a peripheral nerve stimulator (PNS). 50 Patients will be included in the study in total, and they will be split into two groups at random. PNS-guided supraclavicular plexus block with ropivacaine alone will be administered to one group, while ropivacaine combined with magnesium sulphate will be administered to the other. Regular monitoring will be done during the postoperative phase to determine pain levels, use of analgesics, motor and sensory blockade, and adverse events.\n\nResults The study aims to determine if ropivacaine with magnesium sulphate postoperative analgesia is superior to ropivacaine alone in supraclavicular plexus blocks. The motor and sensory blockade duration, opioid use, and any negative results will be evaluated as secondary outcomes. Statistical analysis will be performed to determine the significance of the differences between the two groups.\n\nConclusion This study protocol compares the effectiveness of ropivacaine alone against ropivacaine with magnesium sulphate in peripheral nerve stimulator-guided supraclavicular plexus block, with the goal of adding to the repository of information on postoperative analgesia in upper limb procedures. The study’s findings could be very helpful in enhancing pain management strategies and enhancing patient outcomes in this context.",
"keywords": [
"Ropivacaine",
"magnesium sulphate",
"peripheral nerve stimulator",
"supraclavicular plexus block",
"postoperative analgesia",
"upper limb surgeries."
],
"content": "Introduction\n\nWhen opposed to general anaesthesia, regional anaesthesia is becoming a more popular option because it temporarily reduces pain and nerve transmission in particular body parts while maintaining awareness through the use of local anaesthetic medications.1 The brachial plexus block, a method that provides anaesthesia from the shoulder to the fingertips, is frequently used in upper limb procedures, which is where this tendency is most noticeable. The best method for blocking the brachial plexus will rely on a number of variables, such as the specific surgical indication, the patient’s attributes, anatomical variations, and medical concerns.2 The introduction of ultrasonography-guided techniques has greatly improved the accuracy and efficiency of these treatments. These developments have helped to increase success rates, enhance pharmacodynamics, and lessen systemic side effects, which has led to the acceptance of regional anaesthesia as a crucial part of contemporary surgical care.3\n\nImportant ramifications of managing postoperative pain include early mobilisation, reduced risk of deep vein thrombosis, cardiac and pulmonary problems, swift recovery, fewer healthcare costs, and higher patient satisfaction. Peripheral nerve blocks have therefore become an essential tool for achieving these goals as part of a more comprehensive multimodal analgesic approach.\n\nWhen compared to other drugs such as bupivacaine, ropivacaine, a well-known aminoamide local anaesthetic, has gained favour due to its relative cardiac and neurologic safety profile. One benefit is that it produces a less severe motor block and takes less time, so patients can be mobilised and discharged sooner.4\n\nLocal anaesthetics by nature have a short half-life. Researchers have experimented with adding adjuvants to local anaesthetic solutions in order to produce denser blocks, accelerate onset, and prolong analgesia. By lowering the overall amount of local anaesthetic utilised and minimising systemic side effects, these adjuvants seek to improve analgesic effects.5 Magnesium sulphate is a naturally occurring intracellular cation that has gained interest among these adjuvants. It is essential for controlling nerve activity and may have effects akin to those of medications that limit calcium entry. Because of its capacity to control calcium influx into cells and inhibit N-methyl-D-aspartate receptors, magnesium is thought to have antinociceptive qualities. These effects lessen the need for anaesthesia and the amount of postoperative analgesics used.6 Numerous clinical investigations have documented the advantages of magnesium administration, including its use during general anaesthesia, which has resulted in a drop in the amount of opioids used and a reduction in the total dose needed for analgesia. Magnesium has shown the ability to improve analgesic characteristics when used as an adjuvant in perineural injection with local anaesthetic in the supraclavicular block.7\n\nThe main goal of the research is to make a contribution to the current discussion on the best ways to manage pain after upper limb procedures. Through a thorough investigation of the safety and effectiveness of ropivacaine in combination with magnesium sulphate, this study aims to offer important knowledge to medical practitioners, which will ultimately lead to better patient outcomes and increased delivery efficiency in this crucial clinical area.\n\n\nAim\n\nTo assess the safety and effectiveness of utilising magnesium sulphate in addition to ropivacaine alone for postoperative analgesia in patients having upper limb surgeries under peripheral nerve stimulator guided supraclavicular plexus block.\n\n\nObjectives\n\nThis research compares the effects of adding magnesium sulphate as an adjuvant to ropivacaine in patients undergoing upper limb operations with supraclavicular plexus block guided by a peripheral nerve stimulator. The analysis will be centred on the use of opioids and pain scores.\n\n\n\n- To evaluate and compare the sensory and motor blockade onset and duration in the upper limb between both groups.\n\n- To monitor and evaluate the patient’s hemodynamics during the surgery and in the postoperative period.\n\n- To investigate the incidence of any side effects associated with the study drugs in both groups.\n\n\nMethods\n\n\n\n- Study design – This will be a prospective, randomised, double-blind, controlled trial to compare the safety and effectiveness of using magnesium sulphate as an adjuvant to ropivacaine in patients having upper limb surgeries with supraclavicular plexus block guided by a peripheral nerve stimulator.\n\n- Study setting – The study will take place in the Anaesthesiology Department of Jawaharlal Nehru Medical College, Sawangi, Wardha.\n\n- Study duration – Two years.\n\n- Study population\n\n○ Inclusion criteria\n\n▪ Patients above the age of eighteen,\n\n▪ Patients requiring surgery in the upper limbs requiring supraclavicular plexus block as the anesthetic modality,\n\n▪ ASA status I or II,\n\n▪ Patients who provide valid informed and written consent to participate in the study.\n\n○ Exclusion criteria\n\n▪ Patients having a known allergy to ropivacaine or magnesium sulphate,\n\n▪ Patients with contraindications to supraclavicular plexus block, like, coagulopathies, infection at the site of infection, or sepsis,\n\n▪ Patients having neurological disorders that potentially interfere with the assessment of motor or sensory blockage,\n\n▪ Pregnant or lactating women, as there is insufficient evidence to support the safety of magnesium sulphate in this group,\n\n▪ Patients suffering from severe cardiovascular, lung, or renal disorders, or other uncontrolled systemic diseases,\n\n▪ Patients not willing to participate in the study.\n\nThe sample size was calculated in openepi.com using the duration of motor block in minutes as criteria from the study by Gupta et al.8 as seen in Figure 1. The study will be conducted on 50 patients with 25 patients in each group, to account for any possible dropouts.\n\nComputer-generated random numbers will be used for randomization, and patients will be assigned in a 1:1 ratio to one of the two therapy groups. Neither the researchers nor the patients will know the randomization code. The trial will remain blinded throughout, and data collection will be done by an anaesthesiologist, not involved in the preparation of the study drugs.\n\nPre-operative assessment\n\nBefore the surgery, a thorough preoperative assessment will be conducted, a day prior to the scheduled surgery. During this assessment, patients’ details will be recorded, and routine laboratory investigations will be carried out. The patients will be briefed on the study protocol, the brachial plexus block procedure, and the use of the Visual Analog Scale (VAS) for pain assessment. Informed written consent will be obtained from each patient. Patients will be kept NPO for 6 hours before the procedure.\n\nIntra-operative\n\nOn the day of the surgery, patients will be assessed in the preoperative room. They will be assigned between the two study groups using the computer-generated random numbers allocation method. The drug solution for each patient will be prepared by an independent anesthesiologist according to the assigned group. The two groups will be as follows.\n\nGroup R – Patients in this group will receive a solution of 24 mL of 0.5% ropivacaine with 6 ml of normal saline to make a total volume of 30 ml.\n\nGroup M – Patients in this group will receive a solution of 24 mL of 0.5% ropivacaine with 150mg of magnesium sulphate and 5.5 ml of normal saline to make a total volume of 30 ml.\n\nAn anesthesiologist who is not aware of the composition of the medication solution will perform the brachial plexus block technique. The group assignments and specific medications administered will remain hidden from both the patients and those in charge of documenting observations.\n\nUpon arrival in the operating room, intravenous (IV) access will be established, and patients will receive a dose of 0.5-1 mg of midazolam IV for preoperative relaxation. Baseline measurements of heart rate (HR), mean arterial pressure (MAP), and oxygen saturation (SpO2) will be recorded. Subsequent measurements of these parameters will be taken at 15-minute intervals throughout the surgical procedure. A peripheral nerve stimulator will be used to perform the supraclavicular brachial plexus block, and the drug solution will be delivered in accordance with the research group.\n\nFor twenty minutes after the medication injection, the sensory blockade in the distribution of the ulnar, median, radial, and musculocutaneous nerves will be evaluated every two minutes on a 4-point scale. A sensory block that is ≥3 is regarded as appropriate for surgery; the time taken to reach this level will be noted as the beginning of the block. A score of 1 indicates complete sensation, 2 indicates faint sensation, 3 indicates light touch, and 4 indicates no sensation. A three-point grading system will be used to assess the motor blockade: Grade 0 will denote normal motor function, meaning the arm can be moved; Grade 1 will show decreased motor strength, meaning only the fingers can be moved; and Grade 2 will denote complete motor block, meaning the elbow, wrist, and fingers cannot be moved. The amount of time that passes between the drug injection and the development of a full motor block (Grade = 2) will be used to determine when the motor block starts. In instances in which the block is insufficient, endotracheal intubation and general anaesthesia will be used, and these patients will not be included in the statistical analysis. Using a VAS score, the effectiveness of postoperative analgesia will be assessed 2, 4, 6, 8, 12, and 24 hours after surgery. Patients will receive an intravenous injection of 75 mg of diclofenac as rescue analgesia if they seek further pain therapy. The time interval between the delivery of the block and the initial request for rescue analgesia will be used to determine the duration of analgesia. Pneumothorax, hematoma, postoperative paresthesias, excessive sedation, nausea, and vomiting are examples of procedure-related complications that will be noted and managed.\n\nData will be gathered by anesthesiologists using a standardised data collection form to ensure that there is uniformity in the collected data.\n\nThe statistical analysis will include a comparison of the results between the two treatment groups. Descriptive statistics such as means, standard deviations, and percentages will be used to summarise the data. To assess the significance of the group differences, inferential statistics such as regression analyses, chi-square tests, and t-tests will be employed.\n\nThe findings of the study will be sent to reputed medical journals, specializing in anesthesia for peer review and publication.\n\nAll participants will give their informed consent in accordance with the standards of medical ethics. Ethical approval has been received from the Institutional Ethical Committee (Datta Meghe Institute of Higher Education and Research, Sawangi (M), Wardha. Ref. No. DMIMS (DU)/IEC/2022/95). Patient privacy and confidentiality shall be upheld.\n\nParticipants for both the ropivacaine and ropivacaine with magnesium sulphate groups have been successfully selected; the recruitment procedure was initiated earlier. Computer-generated randomization was used in the selection procedure to guarantee a methodical and objective assignment of patients to the appropriate groups. We have done 13 cases in the ropivacaine group and 12 cases in the ropivacaine with the magnesium sulphate group.\n\n\nDiscussion\n\nFor upper limb procedures, the decision to use a peripheral nerve stimulator-guided supraclavicular plexus block is important because it may provide better pain management without having the systemic adverse effects that are frequently connected to general anaesthesia. Given the increasing amount of evidence bolstering the use of adjuvants to improve analgesia, the choice to look into the possibility of adding magnesium sulphate as an adjuvant to ropivacaine is followed in this study.9\n\nNumerous clinical studies have shown that giving magnesium during general anaesthesia lowers the need for anaesthesia and the amount of analgesics used after surgery. Ropivacaine is less neurotoxic and cardiotoxic than other aminoamides, such as bupivacaine. Ropivacaine causes a shorter-lasting and less severe motor block than bupivacaine, allowing for speedier mobilisation and discharge.10 Mukherjee et al. found that although there was a slight delay in the onset time of sensory and motor blockade, adding 150 mg of magnesium sulphate to ropivacaine 0.50% in supraclavicular brachial plexus block resulted in a longer duration of sensory and motor blockade and a reduced need for rescue analgesics.11 Conversely, Shridevi et al. noticed positive results when magnesium sulphate was used as an adjuvant, showing both a quicker start and a longer duration of motor and sensory anaesthesia.12 Similarly, Kaur et al. discovered that postoperative analgesia was enhanced by adding 250 mg MgSO4 and 2 mg.kg−1 ketamine to 0.5% ropivacaine as opposed to ropivacaine alone. In the setting of supraclavicular brachial plexus block, MgSO4 demonstrated superiority in terms of block features and a lower frequency of adverse effects.13 In their comparison of dexmedetomidine and MgSO4 as adjuvants to ropivacaine, Shukla et al. found that while both were helpful, dexmedetomidine offered prolonged analgesia, an earlier onset of sensory and motor block, and a longer duration of block. The investigation also emphasised variations in adverse event patterns, wherein dexmedetomidine demonstrated a greater frequency of bradycardia, sedation, and hypotension.14 According to Chadha et al.’s study, the volume of 0.5% ropivacaine utilised in ultrasound-guided supraclavicular brachial plexus block decreased from 35 mL to 20 mL, which led to a 21% reduction in the length of analgesia. This highlights the significance of determining the lowest effective ropivacaine volume needed to achieve a full sensory and motor block with the least amount of IV analgesia needed.15 As adjuvants to ropivacaine, Kumari et al. examined dexmedetomidine and clonidine and discovered that dexmedetomidine produced a noticeably longer duration of postoperative analgesia and an earlier sensory block. The combination of ropivacaine and dexmedetomidine showed promise in this trial, especially for orthopaedic surgeries.16\n\nThe purpose of this study is to examine how well magnesium sulphate works with ropivacaine to prevent post-operative analgesia following upper limb procedures. A thorough research approach to address the critical problem of postoperative pain management in patients undergoing upper limb procedures is outlined in the study protocol that is being presented. Effective postoperative pain management is vital due to its significant influence on patient outcomes, recovery, and the healthcare system as a whole. Through a comparison of the two anaesthesia approaches’ efficacy and safety, this study protocol aims to give clinicians evidence-based counselling and shed light on the advantages of mixing magnesium sulphate with ropivacaine. By doing this, the study hopes to improve patient satisfaction, lower healthcare costs, accelerate recovery, and optimise patient outcomes. Although the study has great potential, there will likely be difficulties, such as finding patients, adhering to protocol, possible variation in surgical techniques, and ethical issues. Careful management of these obstacles is necessary to guarantee the validity and generalizability of the study.\n\nTo sum up, the study protocol offers a methodical and well-organized research strategy that tackles an important clinical concern in anesthesiology. This research has the potential to greatly improve postoperative pain management and, in turn, improve patient care in the setting of upper limb procedures by comparing the efficacy of various anaesthetic approaches. Attaining this goal will require meticulous protocol execution, ethical standards observance, and in-depth data analysis.\n\nThe scope of this study includes a detailed examination of the relative safety and efficacy of ropivacaine when combined with magnesium sulphate in supraclavicular brachial plexus block. The research aims to shed light on several brachial plexus block-related areas, with a particular emphasis on the degree of sensory and motor blockade, the analgesic’s duration, intensity, and onset.\n\nBeing a single-centred study, a diverse demography of patients may not be available. Effects on patients with comorbidities, emergency cases or patients of ASA physical status classification III and above will not be included in the study.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\nThe author would like to acknowledge the support from the staff of the Department of Anaesthesia, JNMC, AVBRH, Sawangi, Wardha, India.\n\n\nReferences\n\nWeinstein EJ, Levene JL, Cohen MS, et al.: Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children. Cochrane Database Syst. Rev. 2018; 2019(2): 1–182. Publisher Full Text\n\nNeal JM, Gerancher JC, Hebl JR, et al.: Upper Extremity Regional Anesthesia: Essentials of Our Current Understanding, 2008. Reg. Anesth. Pain Med. 2009; 34(2): 134–170. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGupta P, Gupta K, Dwivedi AN, et al.: Potential role of ultrasound in anesthesia and intensive care. Anesth. Essays Res. 2011; 5(1): 11–19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRamsay MAE: Acute Postoperative Pain Management. Baylor Univ. Med. Cent. Proc. 2000; 13(3): 244–247. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSwain A, Nag DS, Sahu S, et al.: Adjuvants to local anesthetics: Current understanding and future trends. World J. Clin. Cases. 2017; 5(8): 307–323. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTelci L, Esen F, Akcora D, et al.: Evaluation of effects of magnesium sulphate in reducing intraoperative anaesthetic requirements. Br. J. Anaesth. 2002 Oct; 89(4): 594–598. PubMed Abstract | Publisher Full Text\n\nAkhondzade R, Nesioonpour S, Gousheh M, et al.: The Effect of Magnesium Sulfate on Postoperative Pain in Upper Limb Surgeries by Supraclavicular Block Under Ultrasound Guidance. Anesthesiol. Pain Med. 2017; 7(3): e14232. Publisher Full Text\n\nGupta D, Mangal V, Kulshestha A, et al.: Efficacy of Magnesium Sulfate as Adjuvant to Ropivacaine 0.4% for Supraclavicular Brachial Plexus Block in Patients undergoing Upper Limb Surgery: A Randomized Controlled Trial. J. Recent Adv. Pain. 2017; 3(2): 85–89. Publisher Full Text\n\nKrishna Prasad G, Khanna S, Jaishree S: Review of adjuvants to local anesthetics in peripheral nerve blocks: Current and future trends. Saudi J. Anaesth. 2020 [cited 2023 Sep 30]; 14(1): 77–84. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCuvillon P, Nouvellon E, Ripart J, et al.: A Comparison of the Pharmacodynamics and Pharmacokinetics of Bupivacaine, Ropivacaine (with Epinephrine) and Their Equal Volume Mixtures with Lidocaine Used for Femoral and Sciatic Nerve Blocks: A Double-Blind Randomized Study. Anesth. Analg. 2009; 108(2): 641–649. PubMed Abstract | Publisher Full Text\n\nMukherjee K, Das A, Basunia S, et al.: Evaluation of Magnesium as an adjuvant in Ropivacaine-induced supraclavicular brachial plexus block: A prospective, double-blinded randomized controlled study. J. Res. Pharm. Pract. 2014; 3(4): 123–129. PubMed Abstract | Publisher Full Text\n\nShridevi J, Asokan A: Comparison of ropivacaine with magnesium sulphate and plain ropivacaine in ultrasound guided supraclavicular blocks for upper limb surgeries. Indian J. Clin. Anaesth. 2020; 7(2): 203–206. Publisher Full Text\n\nKaur S, Dhawan J, Gupta R, et al.: Comparison of magnesium sulfate and ketamine with ropivacaine in supraclavicular brachial plexus block: A randomized controlled trial. Anesth. Essays Res. 2020; 14(1): 143–148. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShukla U, Singh D, Yadav JBS, et al.: Dexmedetomidine and magnesium sulfate as adjuvant to 0.5% ropivacaine in supraclavicular brachial plexus block: A comparative evaluation. Anesth. Essays Res. 2020; 14(4): 572–577. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChadha M, Si S, Bhatt D, et al.: The comparison of two different volumes of 0.5% ropivacaine in ultrasound-guided supraclavicular brachial plexus block onset and duration of analgesia for upper limb surgery: A randomized controlled study. Anesth. Essays Res. 2020; 14(1): 87–91. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumari P, Singh RB, Saurabh K, et al.: To compare the efficacy of postoperative analgesia between clonidine and dexmedetomidine as adjuvants with 0.5% ropivacaine by ultrasound-guided supraclavicular brachial plexus block for upper limb surgeries: A prospective, double-blind, randomized study. Anesth. Essays Res. 2020; 14(4): 644–652. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "292884",
"date": "01 Jul 2024",
"name": "Mridul Dhar",
"expertise": [
"Reviewer Expertise Regional anesthesia",
"paediatric anesthesia."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe protocol describes the methodology of a study planned to study the safety and effectiveness of adding magnesium sulfate to ropivacaine in supraclavicular brachial plexus block for upper limb surgeries using a peripheral nerve simulator, as a double blind RCT.\nAbstract: (Results): Clarify what is meant by negative results, and write specific outcomes. Opioid use is mentioned as a secondary outcome here but mentioned as a primary objective in the main text. Please clarify.\nMain protocol text The aim is mentioned as safety and efficacy but safety is not the main primary objective, it's the efficacy in terms of pain scores. Kindly rephrase. Use terms like analgesic efficacy.\nThe primary objective is not appropriately mentioned, it's similar to the general aim. Kindly rephrase. Can clarify if the comparison of pain scores is the primary objective or opioid use is or both.?\nSample size: Not appropriate. It has been calculated using motor block duration which is not the primary objective.\nBlinding: Rather than mentioning Double-blind, it is appropriate to mention who all involved in the research were blinded. Instead of broadly stating researchers were blinded mention specific roles, eg Clinician conducting the case, clinician performing the block, outcome assessor etc.\nOutcomes: Definition of onset of block (sensory/ motor), duration of block not mentioned. The duration of analgesia mentioned here is not mentioned in the objectives.\nStat analysis: be more specific and mention tests outcomes-wise. Regression analysis does not seem appropriate for this design.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-449
|
https://f1000research.com/articles/13-448/v1
|
03 May 24
|
{
"type": "Research Article",
"title": "Interplay of age, gender, education, and heart rate in dementia among older adults in Wakiso, Uganda: a cross sectional study",
"authors": [
"Kamada Lwere",
"Hakim Sendagire",
"Haruna Muwonge",
"Gumukiriza-Onoria JL",
"Aisha Nazziwa",
"Denis Buwembo",
"Noeline Nakasujja",
"Kaddumukasa Mark",
"Hakim Sendagire",
"Haruna Muwonge",
"Gumukiriza-Onoria JL",
"Aisha Nazziwa",
"Denis Buwembo",
"Noeline Nakasujja",
"Kaddumukasa Mark"
],
"abstract": "Background In this cross-sectional study conducted in Wakiso, Uganda, from May to July 2023, we investigated the interactions among age, sex, education, and heart rate in relation to dementia and Mild Cognitive Impairment (MCI) among individuals aged 65 years and older.\n\nMethods We purposively sampled 106 participants, focusing on those with Alzheimer’s disease and related dementias, leveraging collaborations with local health teams. Data collection involved comprehensive questionnaires covering sociodemographic details and health parameters, and employed the Montreal Cognitive Assessment Tool for dementia screening.\n\nResults Our findings highlight a nuanced landscape of risk factors; each additional year of age was associated with a 1.19- and 1.22-times increased risk of MCI and dementia, respectively. Gender analysis revealed a protective effect against MCI in males, but no significant impact on dementia risk. Education emerged as a protective factor, with each additional year associated with a 28% reduction in MCI risk, although its effect on dementia risk remains ambiguous. Significantly, an elevated heart rate was strongly linked to an increased risk of both MCI and dementia, underscoring the potential cardiovascular dimension in cognitive health.\n\nConclusions This study contributes to the understanding of the complex interplay of risk factors for dementia, emphasizing the need for further research to elucidate the underlying mechanisms and interventions for healthy cognitive aging in the older adult population.",
"keywords": [
"Dementia",
"Heart rate",
"Gender",
"Age",
"Education"
],
"content": "Introduction\n\nDementia, a major public health issue, poses a growing challenge to aging populations worldwide, presenting a complex web of risk factors intricately interwoven (WHO, 2017). As individuals age beyond the 65-year threshold, the prevalence of dementia increases significantly, with the incidence doubling approximately every 5.5 years, highlighting a deep-seated age-related vulnerability rooted in a range of neurological changes, including cellular aging, oxidative stress, and genetic predispositions (Shin, 2022). Although early onset dementia, which manifests before the age of 65, is relatively less common, its far-reaching and profound consequences in both personal and professional life spheres are undeniable (Masellis et al., 2013).\n\nThe exploration of gender disparities within the epidemiology of dementia constitutes a significant and contentious area of investigation in the scientific domain. A burgeoning body of evidence indicates a pronounced incidence of dementia among females, a phenomenon that may be attributed to their extended longevity and distinct cardiovascular risk factors. Despite these findings, the issue of gender disparity in dementia prevalence remains a matter of considerable debate (Ponjoan et al., 2019). This contention accentuates the imperative for more nuanced research, specifically aimed at elucidating the multifaceted interplay between gender and other determinants, such as educational attainment and socioeconomic standing, in influencing dementia risk. Such scholarly endeavours are essential for fostering a comprehensive understanding of the epidemiological patterns of dementia and for informing targeted intervention strategies.\n\nEmerging research underscores the protective role of education against dementia, positing that higher educational attainment may fortify the brain against cognitive decline through the development of cognitive reserve (Sharp & Gatz, 2011). This concept has gained traction, highlighting the resilience of the brain to neuropathological damage facilitated by enriched neural networks from prolonged educational engagement. However, the protective efficacy of education against dementia requires further examination, especially across diverse demographics and regions with varying access to education, such as sub-Saharan Africa.\n\nFurthermore, cardiovascular health, as evidenced by heart rate variability, has emerged as a potential indicator of cognitive function, with fluctuations in heart rate reflecting autonomic nervous system dynamics that may correlate with cognitive decline and dementia risk. This relationship, influenced by lifestyle factors and physical activity, adds another layer to the intricate risk factor landscape for dementia (Siepmann, Weidner, Petrowski, & Siepmann, 2022).\n\nIn sub-Saharan Africa, particularly in Uganda, the challenge of dementia takes on unique characteristics due to shifting demographic trends and specific socioeconomic and health infrastructure contexts (Ojagbemi, Okekunle, & Babatunde, 2021). Advanced age and limited educational opportunities are the predominant risk factors within this region. However, literature on how gender roles and heart rate variations contribute to dementia risk in this context is sparse, prompting the need for targeted research.\n\nOur study, set in the older adult population of Wakiso, Uganda, seeks to shed light on the complex interplay between age, sex, heart rate, and education level as potential determinants of dementia and Mild Cognitive Impairment (MCI). By focusing on this specific locale, we aim to contribute to the global understanding of dementia while addressing the particularities and challenges faced in the sub-Saharan African context.\n\nWe hypothesised that there exists a noteworthy association between aging and an increased risk of Mild Cognitive Impairment (MCI) and dementia, such that the likelihood of these conditions ascends with each ensuing year of life. Moreover, we contend that sex plays a complex role in cognitive decline, wherein being male could offer a protective effect against MCI and dementia. In addition, we anticipated that a higher level of education serves as a protective factor against MCI, as per the cognitive reserve hypothesis; however, the relationship between education levels and dementia risk might be less direct. Lastly, we suspect that elevated heart rates may indicate a heightened risk of both MCI and dementia, highlighting the potential connection between cardiovascular health and cognitive well-being in the older adult population of Wakiso, Uganda.\n\n\nMethods\n\nThis cross-sectional study was conducted in Wakiso District of Uganda, a region characterised by its diverse demographic composition, including urban, suburban, and rural areas, and hosts a population of approximately two million residents. Our research specifically targeted older adults, aged 65 years and above, from three sub-counties: Nansana, representing urban settings, and Busukuma and Nakwero, illustrating rural environments.\n\nA purposive sampling approach was adopted to select 106 individuals aged 65 years or older from designated sub-counties in Wakiso, Uganda, including Nansana, Busukuma, and Nakwero. The selection process was focused on individuals diagnosed with Alzheimer’s disease and related dementias (ADRD). The assistance of Village Health Teams and local council leaders was utilized to identify households with known ADRD patients. The selection process was designed to exclude critically ill participants from the study. A total of 140 homesteads were approached, resulting in a 75% response rate. The criteria for participation included being a resident of the targeted sub-counties, aged 65 years or older, and had a diagnosis of dementia. Informed consent was obtained from all participants, ensuring they had a comprehensive understanding of the study’s objectives, procedures, potential benefits, and associated risks. For participants who were unable to provide informed consent personally, verbal consent accompanied by written consent from their caregivers was obtained. Ethical considerations were of paramount importance throughout the study, with informed consent obtained from all participants directly or from their proxies when necessary, ensuring voluntary participation and understanding of the study’s objectives and procedures. The study protocol was thoroughly reviewed and approved by the School of Biomedical Sciences Research and Ethics Committee at Makerere University, with approval number SBS-2022-256 and formal approval date of May 2, 2023, guaranteeing compliance with the highest ethical standards for research involving human participants. Additionally, the study’s protocols received accreditation from the Uganda National Council for Science and Technology, with reference number HS2930ES.\n\nA team of experienced research assistants with backgrounds in community psychology, social work, and nursing oversaw the data-gathering process. The team administered questionnaires from May to July 2023, which typically took 90–120 min to complete. All sessions were conducted in Luganda, the most common local language, to ensure clear communication. Before starting the data collection, each potential participant was approached individually to explain the purpose, nature, potential benefits, and risks of the study. Participants were informed that their participation was voluntary and that they had the right to withdraw without consequences. Written informed consent was obtained from the participants who were willing and able to provide consent after confirming their understanding and comfort, which included a clause explicitly stating that the results of the study may be published. For those unable to provide written informed consent, verbal consent was secured, accompanied by written consent from their caregivers, who also acknowledged and consented to the potential publication of study findings. The data were stored securely, ensuring limited access to authorized personnel and maintaining the anonymity and privacy of the participants.\n\nSociodemographic details, including age, sex, educational background, occupation, comorbidities, marital status, previous illnesses, and concomitant medication, were collected through a brief questionnaire. A case report form was used to gather information pertaining to previous medical illnesses, concomitant medications, heart rate, blood pressure, body mass index, and musculoskeletal (MSS) examination. The Montreal Cognitive Assessment Tool (MoCA) (copyright permission to use obtained) was employed to screen for dementia and has been validated for use in an African setting (Beath, Asmal, van den Heuvel, & Seedat, 2018). A score of 23 or lower indicated normal cognition, 19–24 indicated mild cognitive impairment, and <19 indicated dementia.\n\nSeveral measures were implemented during the research process. First, purposive sampling was used to ensure a representative sample of individuals aged ≥65 years diagnosed with Alzheimer’s disease and related dementias (ADRD) within the specified sub-counties of Wakiso, Uganda. This targeted approach helped mitigate the selection bias by focusing on specific demographic and health conditions relevant to the study objectives. Additionally, collaboration with Village Health Teams and local council leaders in identifying potential participants helped achieve a more comprehensive and less biased selection of individuals with known ADRD conditions.\n\nTo further reduce information bias, experienced research assistants with backgrounds in community psychology, social work, and nursing were employed to administer the questionnaires and conduct assessments. The use of the Montreal Cognitive Assessment Tool (MoCA), a validated instrument for dementia screening in an African setting, improved the reliability and consistency of cognitive health evaluations among participants.\n\nInformed consent procedures were followed, with participants (or their caregivers in cases where individuals were unable to consent) thoroughly briefed about the study’s purpose, procedures, potential benefits, and risks. This ensured that the participants were fully informed and voluntarily agreed to participate, thus minimizing the risk of coercion or misunderstanding.\n\nMoreover, detailed collection of sociodemographic data, including age, sex, educational background, and health parameters, allowed for a comprehensive analysis of potential confounding factors. Statistical analyses, including multivariate logistic regression, were utilized to adjust for these confounders, further minimizing bias and elucidating the independent effects of age, sex, education, and heart rate on dementia and MCI risk.\n\nTo determine the sample size for our study, which focused on trends in heart rate, we adhered to the standard formula for sample size calculation in quantitative research. The key parameters defined for this calculation included the standard normal variate (Zα/2) representing the z-score at a 5% type I error rate (significance level), and absolute precision (d), set at 2 beats per minute (bpm). Furthermore, we based our estimation of the standard deviation (SD) in the existing literature, adopting a value of 11 bpm as a representative measure of heart rate variability in the target population. Incorporating these parameters into the formula yielded a minimum sample size of 106 older adults. This calculation ensured that the study was adequately powered to detect meaningful trends in heart rate within the specified error and precision limits.\n\nA formal analysis of sociodemographic attributes was conducted using frequency distributions, and gender-based differences were examined using the chi-squared test. The Mann-Whitney U test was used to investigate age-related disparities by sex. Our study examined the interplay between age, sex, education, and heart rate in relation to dementia and mild cognitive impairment (MCI) in an older adult population in Wakiso, Uganda. Wakiso. The outcome variables were age, sex, heart rate, formal education duration, previous medical illnesses, and concomitant medication use. Multivariate logistic regression analyses were performed to explore the relationships between various factors and outcomes, and both crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated to identify the strength and orientation of these associations. Statistical significance was set at p < 0.05, and all analytical procedures were performed using the Stata 17.\n\n\nResults\n\nThe study involved a sample of 106 individuals, comprised of 76 individuals with dementia, 15 with mild cognitive impairment, and 15 healthy participants. Of these, 83 were female (78.3%), with a median age of 75 years (interquartile range: 70-82). A comprehensive breakdown of the participants’ demographics can be found in Table 1. The participants’ median education level was 3 years (interquartile range: 1-6). Approximately 20 (18.9%) were taking concomitant medications, such as antidiabetic and antihypertensive drugs. Most participants had a preexisting medical condition, with 79 (74.5%) reporting such an issue. With respect to comorbidities, 15 (14.1%) had hypertension, while 19 (19.9%) had musculoskeletal diseases.\n\nTable 2 presents the results of a multivariate logistic regression analysis examining the interplay of age, gender, education, and heart rate in relation to the risk of developing MCI and dementia. The study found that for every year increase in age, the risk of developing MCI and dementia increased by 1.19 (95% CI 1.04;1.38, p=0.015) and 1.22 times (95% CI 1.07;1.40, p=0.003), respectively. In terms of gender, males had an increased risk of dementia (0.14, 95% CI 0.03;0.81, p=0.028), while male sex was associated with a reduced risk of MCI (0.17, 95% CI 0.02;1.38, p=0.097). Education was found to be a significant protective factor, reducing the risk of MCI by 28% for each additional year (a relative risk reduction of 0.28, 95% confidence interval of 0.15-0.55, p<0.001). However, the relationship between education and dementia was unclear (relative risk reduction 0.72, 95% confidence interval of 0.52-1.01, p=0.053). Individuals with high heart rates had a 13.3 times higher risk of MCI and an 11.66 times higher risk of dementia, with statistically significant results (p-values of 0.013 and 0.004, respectively). The 95% confidence intervals range from 9.72 to 19.62 and 8.16 to 15.21, respectively, indicating a strong relationship.\n\n\nDiscussion\n\nOur study, conducted in Wakiso, Uganda, offers crucial insights into the intricate relationship between age, sex, educational attainment, and heart rate in relation to the risk of Mild Cognitive Impairment (MCI) and dementia among older adults. Our analysis, which is situated within the broader context of epidemiological research on dementia, emphasizes the significant role that aging plays as a primary risk factor. Our findings align with prior studies, demonstrating a substantial increase in the risk of MCI and dementia as individuals grow older, thereby highlighting the age-related susceptibility that is embedded in the biological mechanisms of cognitive decline (Campbell, Unverzagt, LaMantia, Khan, & Boustani, 2013; Gillis, Mirzaei, Potashman, Ikram, & Maserejian, 2019)10.\n\nA notable aspect of our study is the elucidation of sex-based differences in dementia risk. Contrary to the global trend of higher dementia prevalence among females, likely due to their longer life expectancy and distinct cardiovascular risk profiles, our findings suggest a nuanced scenario in the Ugandan context (Beam et al., 2018). Males in our study exhibited a lower risk of MCI, aligning with the hypothesis that certain protective factors might be at play, possibly linked to lifestyle, genetic predispositions, or sociocultural factors specific to the region.\n\nThe protective role of education against cognitive decline, a cornerstone of the cognitive reserve hypothesis, was evident in our study, particularly in the context of MCI. Higher educational levels were associated with a significant reduction in MCI risk, reinforcing the notion that education bolsters neural resilience against neuropathological damage. However, the relationship between education and dementia risk did not achieve clear statistical significance, suggesting that the protective effects of education might wane or become less direct in the face of advanced neuropathology. This finding warrants further exploration, especially in regions like sub-Saharan Africa, where access to education and its quality can vary dramatically, potentially influencing the strength and nature of its protective effect.\n\nThe association between elevated heart rates and increased risks of MCI and dementia is particularly compelling, shedding light on the potential role of cardiovascular health as an indicator of cognitive well-being. This correlation aligns with emerging research positing heart rate variability as a reflection of autonomic nervous system dynamics, which, in turn, may influence cognitive function (Forte, Favieri, & Casagrande, 2019). The pronounced risk elevation observed in individuals with high heart rates underscores the importance of integrating cardiovascular health management into preventive strategies for cognitive decline, especially in settings with limited healthcare infrastructure.\n\nOur study’s setting in Wakiso, Uganda, underscores the unique challenges and considerations in understanding dementia in the sub-Saharan African context. The interplay of factors such as advanced age, limited educational opportunities, gender roles, and cardiovascular health presents a complex risk profile that necessitates tailored research and intervention approaches. The findings from Wakiso contribute to the global discourse on dementia, highlighting the need for culturally sensitive and region-specific research to unravel the multifaceted epidemiology of cognitive decline and inform effective, contextually relevant interventions.\n\nIn conclusion, the insights generated from our study emphasize the intricate web of factors influencing the risk of MCI and dementia among older adults in Uganda. The nuanced understanding of these relationships not only contributes to the global body of knowledge on dementia but also paves the way for targeted, evidence-based interventions in sub-Saharan Africa and beyond. Future research should delve deeper into the sociocultural, environmental, and biological underpinnings of these findings, striving for a holistic understanding of dementia that can guide comprehensive public health strategies and policy formulations aimed at mitigating the burgeoning impact of this condition on aging populations worldwide.\n\n\n\n1. Sampling Method: The use of purposive sampling to select participants diagnosed with Alzheimer’s disease and related dementias (ADRD) might limit the generalizability of the study findings to the broader population of older adults in Uganda or similar settings. This sampling method, while beneficial for focusing on a specific demographic, may not capture the full spectrum of cognitive health statuses among older adults.\n\n2. Cross-sectional Study Design: The cross-sectional nature of the study allows for the observation of associations between variables at a single point in time but does not permit the establishment of causality. Longitudinal studies would be required to ascertain the directionality of the relationships observed between age, sex, education, heart rate, and cognitive decline.\n\n3. Self-reported Data: The reliance on self-reported information for certain variables, such as educational attainment and comorbidities, may introduce recall bias, particularly among older participants or those with cognitive impairments.\n\n4. Educational and Cultural Context: The findings related to the protective role of education against cognitive decline may not be directly applicable to other regions with different educational systems, cultural backgrounds, or levels of access to education. The influence of education on cognitive health could vary significantly across different sociocultural contexts.\n\n5. Heart Rate as a Sole Cardiovascular Indicator: While elevated heart rate was found to be associated with an increased risk of MCI and dementia, heart rate alone may not fully encapsulate an individual’s cardiovascular health status. The inclusion of additional cardiovascular parameters, such as blood pressure or lipid profiles, could provide a more comprehensive understanding of the link between cardiovascular health and cognitive decline.\n\n6. Limited Exploration of Other Potential Risk Factors: The study focuses on age, sex, education, and heart rate as risk factors for cognitive decline but may not account for other potential influences such as diet, physical activity, social engagement, and environmental factors, which could also play significant roles in cognitive health.\n\n7. Regional Specificity: The study’s findings, derived from a population in Wakiso, Uganda, might not be universally applicable to other regions, even within sub-Saharan Africa, due to variations in demographics, healthcare infrastructure, and cultural practices.\n\n8. Potential Confounders: Despite efforts to adjust for confounding factors, there may still be unmeasured variables that could influence the study outcomes, such as genetic predispositions, lifestyle choices, or environmental exposures.\n\nAddressing these limitations in future research could involve implementing longitudinal study designs, expanding the range of cardiovascular and lifestyle-related variables examined, employing more diverse and representative sampling methods, and conducting similar studies in various cultural and geographical settings to enhance the generalizability of the findings.\n\n\nEthics and consent\n\nThe study protocol was thoroughly reviewed and approved by the School of Biomedical Sciences Research and Ethics Committee at Makerere University, with approval number SBS-2022-256 and formal approval date of May 2, 2023, guaranteeing compliance with the highest ethical standards for research involving human participants. Additionally, the study’s protocols received accreditation from the Uganda National Council for Science and Technology, with reference number HS2930ES. Written informed consent was obtained from the participants who were willing and able to provide consent after confirming their understanding and comfort, which included a clause explicitly stating that the results of the study may be published. For those unable to provide written informed consent, verbal consent was secured, accompanied by written consent from their caregivers, who also acknowledged and consented to the potential publication of study findings.",
"appendix": "Data availability\n\nFigshare: Deciphering the Interplay of Age, Gender, Education, and Heart Rate in Dementia among the Elderly Population of Wakiso, Uganda. https://doi.org/10.6084/m9.figshare.25205219 (Lwere et al., 2024).\n\nFigshare: STROBE checklist for ‘Interplay of age, gender, education, and heart rate in dementia among older adults in Wakiso, Uganda: a cross sectional study’. https://doi.org/10.6084/m9.figshare.25535053 (Lwere, 2024).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nWe would like to thank the Brain Health Program, Makerere University, and the Infectious Diseases Society of America (IDSA) for their assistance and support.\n\n\nReferences\n\nBeam CR, Kaneshiro C, Jang JY, et al.: Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer’s Disease. J. Alzheimers Dis. 2018; 64(4): 1077–1083. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBeath N, Asmal L, van den Heuvel L , et al.: Validation of the Montreal cognitive assessment against the RBANS in a healthy South African cohort. S. Afr. J. Psychiatry. 2018; 24: 1304. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCampbell NL, Unverzagt F, LaMantia MA, et al.: Risk factors for the progression of mild cognitive impairment to dementia. Clin. Geriatr. Med. 2013; 29(4): 873–893. PubMed Abstract | Publisher Full Text | Free Full Text\n\nForte G, Favieri F, Casagrande M: Heart Rate Variability and Cognitive Function: A Systematic Review. Front. Neurosci. 2019; 13: 710. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGillis C, Mirzaei F, Potashman M, et al.: The incidence of mild cognitive impairment: A systematic review and data synthesis. Alzheimers Dement (Amst). 2019; 11: 248–256. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLwere K, Sendagire H, Muwonge H, et al.: Deciphering the Interplay of Age, Gender, Education, and Heart Rate in Dementia among the Elderly Population of Wakiso, Uganda. [Dataset]. figshare. 2024. Publisher Full Text\n\nLwere K: Interplay of Age, Gender, Education, and Heart Rate in Dementia among Older Adults in Wakiso, Uganda: A Cross Sectional Study. figshare. 2024. Preprint. Publisher Full Text\n\nMasellis M, Sherborn K, Neto P, et al.: Early-onset dementias: diagnostic and etiological considerations. Alzheimers Res. Ther. 2013; 5(Suppl 1): S7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOjagbemi A, Okekunle AP, Babatunde O: Dominant and Modifiable Risk Factors for Dementia in Sub-Saharan Africa: A Systematic Review and Meta-Analysis. Front. Neurol. 2021; 12: 627761. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPonjoan A, Garre-Olmo J, Blanch J, et al.: Epidemiology of dementia: prevalence and incidence estimates using validated electronic health records from primary care. Clin. Epidemiol. 2019; 11: 217–228. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSharp ES, Gatz M: Relationship between education and dementia: an updated systematic review. Alzheimer Dis. Assoc. Disord. 2011; 25(4): 289–304. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShin JH: Dementia Epidemiology Fact Sheet 2022. Ann. Rehabil. Med. 2022; 46(2): 53–59. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSiepmann M, Weidner K, Petrowski K, et al.: Heart Rate Variability: A Measure of Cardiovascular Health and Possible Therapeutic Target in Dysautonomic Mental and Neurological Disorders. Appl. Psychophysiol. Biofeedback. 2022; 47(4): 273–287. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO: Determinants of health.2017. Reference Source"
}
|
[
{
"id": "303522",
"date": "07 Aug 2024",
"name": "Robert Mathew",
"expertise": [
"Reviewer Expertise Dementia"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is cross sectional study aiming at analyzing interactions among age, sex, education, and heart rate in relation to dementia and Mild Cognitive Impairment (MCI) among individuals aged 65 years and older. The article needs substantial modifications before it can be indexed.\nMany of the sections especially those dealing with methodology need to be made more concise and repetition avoided\n\nThe results section needs more elaboration. More statistic calculations can be done with the available data itself for example Differences in demographic parameters between males and females. Since the result shows significant difference in cognition between males and female this analysis may be useful.\n\nMethods\n\nThis was not a case control study. Then why is it that data of controls also was selected? Was this data used in any statistical analysis ? In the participants section it is mentioned that the criteria for participation included 'had a diagnosis of Dementia 'How was dementia diagnosed in these patients?\n\nA few sentences are repeated under Participants section and section on Data collection procedures. This ca be avoided\n\nIn the section Data source it is mentioned that ’A score of 23 or lower indicated normal cognition, 19–24 indicated mild cognitive impairment, and <19 indicated dementia.’ What is the reference for this?\n\nSample size\n\nIn calculating sample size heart rate alone was considered\n\nHowever dementia and MCI also needs to be considered\n\nStatistical Analysis\n\nIn statistical analysis correlation between variables are looked into\n\nHowever comparisons between various groups also will give important information\n\nResults\n\nMales are substantially underrepresented in the sample which may bias the observations\n\nIs there any specific reason for this?\n\nThe median education level was 3 years (interquartile range: 1-6). This is a very narrow range and hence may bias the results\n\nWhat was the education of the controls. Was the difference in education significant?\n\nWhat was the mean and range of heart rate? What was the RRR of female participants? Was there a significant difference in education between male and females?\n\nWas co relationship between MCI and dementia looked into?\n\nDiscussion\n\nThe results of this study can be compared with some other important studies done earlier\n\n‘However, the relationship between education and dementia risk did not achieve clear statistical significance’ This is an important observation and needs more discussion. The prior studies in this direction can be reviewed briefly here and will give more information and explanations on this observation\n\nLimitations of the study\n\nSome of the limitations mentioned are that of the study design per Se For example Limitations No 2 Cross-sectional Study Design The limitations of study within the study design has to highlighted for example reduced number of male participants, absence of candidates with higher education etc.\n\nThis part of the paper appears to take up too much space. This has to be made more concise and the discussion part has to be expanded\n\nEthics and consent\n\nSome of the points mentioned here are repetitions and has to be removed\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-448
|
https://f1000research.com/articles/13-105/v1
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16 Feb 24
|
{
"type": "Research Article",
"title": "The top 50 most-cited articles about COVID-19 and the complications of COVID-19: A bibliometric analysis",
"authors": [
"Tanya Singh",
"Jagadish Rao Padubidri",
"Pavanchand H. Shetty",
"Matthew Antony Manoj",
"Therese Mary",
"Bhanu Thejaswi Pallempati",
"Tanya Singh",
"Pavanchand H. Shetty",
"Matthew Antony Manoj",
"Therese Mary",
"Bhanu Thejaswi Pallempati"
],
"abstract": "Background This bibliometric analysis examines the top 50 most-cited articles on COVID-19 complications, offering insights into the multifaceted impact of the virus. Since its emergence in Wuhan in December 2019, COVID-19 has evolved into a global health crisis, with over 770 million confirmed cases and 6.9 million deaths as of September 2023. Initially recognized as a respiratory illness causing pneumonia and ARDS, its diverse complications extend to cardiovascular, gastrointestinal, renal, hematological, neurological, endocrinological, ophthalmological, hepatobiliary, and dermatological systems.\n\nMethods Identifying the top 50 articles from a pool of 5940 in Scopus, the analysis spans November 2019 to July 2021, employing terms related to COVID-19 and complications. Rigorous review criteria excluded non-relevant studies, basic science research, and animal models. The authors independently reviewed articles, considering factors like title, citations, publication year, journal, impact factor, authors, study details, and patient demographics.\n\nResults The focus is primarily on 2020 publications (96%), with all articles being open access. Leading journals include The Lancet, NEJM, and JAMA, with prominent contributions from Internal Medicine (46.9%) and Pulmonary Medicine (14.5%). China played a major role (34.9%), followed by France and Belgium. Clinical features were the primary study topic (68%), often utilizing retrospective designs (24%). Among 22,477 patients analyzed, 54.8% were male, with the most common age group being 26-65 years (63.2%). Complications of COVID-19 affected 13.9% of patients, with a recovery rate of 57.8%.\n\nConclusion Analyzing these top-cited articles offers clinicians and researchers a comprehensive, timely understanding of influential COVID-19 literature. This approach uncovers attributes contributing to high citations and provides authors with valuable insights for crafting impactful research. As a strategic tool, this analysis facilitates staying updated and making meaningful contributions to the dynamic field of COVID-19 research.",
"keywords": [
"COVID-19",
"Complications",
"Bibliometry Analysis",
"Citations",
"SARS-COV-2"
],
"content": "Introduction\n\nIn December 2019, the first outbreak of Coronavirus disease (COVID-19) was detected in Wuhan.1 On 30th January 2020, the World Health Organization (WHO) declared COVID-19 outbreak as a “public health emergency of international concern” and on 11th March 2020, COVID-19 was declared a pandemic by the WHO.2 As of September 2023, the coronavirus SARS-COV-2 (severe acute respiratory syndrome coronavirus-2) is responsible for a total of 770 million confirmed cases and 6.9 million confirmed deaths. With the start of COVID-19 vaccination, a total of 3 billion vaccine doses have been administered as per WHO.3 While, SARS-COV-2 is primarily considered as a respiratory disease known to cause pneumonia and acute respiratory distress syndrome (ARDS), there have been numerous reports about its many extra pulmonary manifestations. Literature suggests that the cardiovascular, gastrointestinal, renal, haematological, neurologic, endocrinologic, ophthalmologic, hepatobiliary and dermatologic systems can all be affected.4 This can result either due to the extrapulmonary dissemination and replication of the SARS-COV-2 or due to the widespread immunopathological sequelae of the disease.5\n\nBibliometric analysis is the application of statistical methods to evaluate the impact of a manuscript, research performance, author contribution to a particular field and to quantitatively analyse the most influential articles related to a particular field.6\n\nAccording to our literature search, no current bibliometric analysis has focused on COVID-19 complications. The purpose of this bibliometric analysis was to compile and analyse the top 50 most-cited articles regarding COVID-19 complications across all peer-reviewed scientific journals.\n\n\nMethods\n\nA bibliometric analysis of the most cited articles about COVID-19 complications was conducted in July 2021 using all journals indexed in Elsevier’s Scopus and Thomas Reuter’s Web of Science from November 1, 2019 to July 1, 2021. All journals were selected for inclusion regardless of country of origin, language, medical speciality, or electronic availability of articles or abstracts. The terms were combined as follows:\n\n(“COVID-19” OR “COVID19” OR “SARS-COV-2” OR “SARSCOV2” OR “SARS 2” OR “Novel coronavirus” OR “2019-nCov” OR “Coronavirus”)\n\nAND\n\n(“Complication” OR “Long Term Complication” OR “Post-Intensive Care Syndrome” OR “Venous Thromboembolism” OR “Acute Kidney Injury” OR “Acute Liver Injury” OR “Post COVID-19 Syndrome” OR “Acute Cardiac Injury” OR “Cardiac Arrest” OR “Stroke” OR “Embolism” OR “Septic Shock” OR “Disseminated Intravascular Coagulation” OR “Secondary Infection” OR “Blood Clots” OR “Cytokine Release Syndrome” OR “Paediatric Inflammatory Multisystem Syndrome” OR “Vaccine Induced Thrombosis with Thrombocytopenia Syndrome” OR “Aspergillosis” OR “Mucormycosis” OR “Autoimmune Thrombocytopenia Anaemia” OR “Immune Thrombocytopenia” OR “Subacute Thyroiditis” OR “Acute Respiratory Failure” OR “Acute Respiratory Distress Syndrome” OR “Pneumonia” OR “Subcutaneous Emphysema” OR “Pneumothorax” OR “Pneumomediastinum” OR “Encephalopathy” OR “Pancreatitis” OR “Chronic Fatigue” OR “Rhabdomyolysis” OR “Neurologic Complication” OR “Cardiovascular Complications” OR “Psychiatric Complication” OR “Respiratory Complication” OR “Cardiac Complication” OR “Vascular Complication” OR “Renal Complication” OR “Gastrointestinal Complication” OR “Haematological Complication” OR “Hepatobiliary Complication” OR “Musculoskeletal Complication” OR “Genitourinary Complication” OR “Otorhinolaryngology Complication” OR “Dermatological Complication” OR “Paediatric Complication” OR “Geriatric Complication” OR “Pregnancy Complication”) in the Title, Abstract or Keyword.\n\nA total of 5940 articles were accessed, of which the top 50 most cited articles about COVID-19 and Complications of COVID-19 were selected through Scopus. Each article was reviewed for its appropriateness for inclusion. The articles were independently reviewed by three researchers (JRP, MAM and TS) (Table 1). Differences in opinion with regards to article inclusion was resolved by consensus.\n\nThe inclusion criteria specified articles that were focused on COVID-19 and Complications of COVID-19. Articles were excluded if they did not relate to COVID-19 and or complications of COVID-19, Basic Science Research and studies using animal models or phantoms. Review articles, Viewpoints, Guidelines, Perspectives and Meta-analysis were also excluded from the top 50 most-cited articles (Table 1).\n\nThe top 50 most-cited articles were compiled in a single database and the relevant data was extracted. The database included: Article Title, Scopus Citations, Year of Publication, Journal, Journal Impact Factor, Authors, Number of Authors, Department Affiliation, Number of Institutions, Country of Origin, Study Topic, Study Design, Sample Size, Open Access, Non-Original Articles, Patient/Participants Age, Gender, Symptoms, Signs, Co-morbidities, Complications, Imaging Modalities Used and outcome.\n\n\nResults\n\nOf the total 50 articles that were analyzed, 48 (96%) articles were published in the year 2020, while 1 (2%) article was published in 2021 and 1 (2%) article was published in the year 2003 (Table 2).\n\nAll of the 50 (100%) articles analyzed in the bibliometric study were open access articles.\n\nOf the total 50 articles that were analyzed, the journals that published the most number of articles published were in the The Lancet (9), NEJM (7) and JAMA (4), while Eurosurveillance, Transitional Research and Annals of Internal Medicine published one each (Table 3).\n\nAmong the 50 articles that were analyzed, the most frequently cited authors contributed 4 articles each to the list (Table 4).\n\nAmong the top 50 most-cited articles, the departmental affiliations were primarily in Internal Medicine (46.9%), Pulmonary Medicine (14.5%), and Bioscience and Technology (12.1%). Conversely, the Departments of Immunology, Paediatrics, and Urology had the lowest representation (Table 5).\n\nIn the research analyzed within the top 50 COVID-19 articles, a total of 83 countries participated. Notably, China played a substantial role, contributing to 29 articles (34.9%). France and Belgium closely followed; each being involved in 10 articles (12.1%). Additional contributing nations included Canada with 3 articles (3.6%), the UK with 2 articles (2.4%), and Switzerland with 1 article (1.2%) (Table 6).\n\nAmong the 50 most-cited articles examined in this analysis, the predominant research themes were clinical features, comprising 34 articles (68%). Following closely were articles related to drug trials and interactions, accounting for 6 articles (12%). Additionally, there were 3 articles (6%) dedicated to analytical studies. Mortality studies constituted 2 articles (4%), while a single article each (2%) delved into the psychological impact and molecular mechanisms of COVID-19 (Table 7).\n\nAmong the 50 most-cited articles examined, the most common study designs were retrospective (24%), followed by prospective (16%) and correspondence (12%). Other study designs included prospective cohort (4%), randomized controlled trial (4%), and cross-sectional (2%) (Table 8).\n\nA total of 22477 patients were analyzed from the top 50 most-cited articles.\n\nOf the total 22477 patients, 12318 (54.8%) were males while 10159 (45.2%) were females (Table 9).\n\nThe most common age group among the patients was 26-65 years of age with 14255 (63.2%) patients, followed by the age of 65 years with 6018 (26.8%) patients and then 12-25 years with 2204 (9.8%) patients (Table 10).\n\nAmong the 22477 patients, the most common clinical features were fever in 6333 (28.2%) patients, tachycardia in 4022 (17.9%) patients and dry cough in 3107 (13.8%) patients. Other common features included impaired sense of smell in 412 (1.8%) patients, impaired taste sensation in 404 (1.8%) patients and headache in 330 (1.5%) patients (Table 11).\n\nA total of 22477 patients underwent RT-PCR testing and were positive for COVID-19. Out of which, 18055 (80.3) patients underwent additional laboratory investigations. CT-chest was done for 11110 (49.4%) patients, chest X-ray was done for 8327 (22.7%) patients, and ECG done for 5098 (22.7%) patients. MRI brain and EEG were done for 8 (0.04%) patients with neurological complications (Table 12).\n\nOut of the total 22477 patients, 21989 (97.8%) patients were found to have comorbidities. Of the 21989 patients with comorbidities, hypertension was present in 6720 (30.6%) patients, diabetes mellitus in 5082 (23.1%) patients and obesity in 2666 (12.1%) patients. Other comorbidities found included chronic liver disease in 74 (0.34%) patients, endocrine disorders in 53 (0.24%) patients and psychiatric disorders in 13 (0.06%) patients (Table 13).\n\nOut of the total 22477 patients, 3143 (13.9%) patients developed complications. The most common complication seen among the patients were acute kidney injury in 707 (22.5%) patients, ARDS in 576 (18.3%) patients and Sepsis in 347 (11.0%) patients. Other complications included electrolyte imbalance in 81 (2.6%) patients, acute hepatic injury in 74 (2.4%) patients and arrhythmias in 63 (2.0%) patients (Table 14).\n\nOf the total 22477 patients who tested positive with COVID-19, 12981 (57.8%) recovered without any complications, while 6998 (31.1%) patients were hospitalised, and 2498 (11.1%) patients deceased due to the illness (Table 15).\n\n\nDiscussion\n\nIn the bibliometric analysis of the top 50 most-cited COVID-19 articles, the most cited article was “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China” by Huang C et al., in The Lancet published in 2020. This article has the highest total number of citations (24775) as well as the highest average number of citations per year (8258) among the top 50 most-cited articles.\n\nThe Lancet published the greatest number of articles from the top 50 most-cited list with a total of 9 articles, followed by NEJM with 7 articles and JAMA with 4 articles published respectively. Most of the articles (n=48, 96%) were published in the year 2020 with China (n=29, 34.9%), France (n=10, 12.1%) and Belgium (n=10,12.1%) being the top contributing countries.\n\nIn this bibliometric analysis, we found that 54.8% of the total patients were males while 45.2% were female patients. An article written by Bwire, it was reported that females were more resistant to Covid-19 infection. This could be attributed to various factors such as sex hormones, higher expression of ACE-2 receptors in men and also difference in the lifestyles.7\n\nThe incidence of COVID-19 infection was highest in adults between 26-65 years (63.2%), followed by the adults over 65 years of age (26.8%), and least in 12-25 years age group (9.8%).\n\nSimilar findings were reported in a study conducted by Jakhmola S et al, with the highest incidence of Covid-19 infection in the age groups of 20-49 years and above 50 years, and the least in the paediatric age group. This could possibly be due to lesser expression of the coronavirus (ACE-2) receptors in the nasal epithelium in younger age groups, leading to reduced susceptibility to Covid 19 infection.8 Centers for Disease Control and Prevention (CDC) reported the highest incidence of COVID-19 infection among adults above the age of 80 years and in the age group of 18-24 years during 2020.9\n\nIn our analysis, the most common clinical features were fever (28.2%), tachycardia (17.9%) and dry cough (13.8%). Other common features included impaired sense of smell (1.8%), impaired taste sensation (1.8%) and headache (1.5%). Similar to the above-mentioned findings, a study by Cascella M et al, reported the most common symptoms in patients to be fever, dry cough and dyspnoea. Other lesser common symptoms included malaise and headache.10 In a study by Mullol J et al., it was concluded that most viral respiratory infections such as COVID-19 are associated with impairment of sense of smell. The incidence of olfactory and gustatory symptoms varies due to the varied methodology used in various studies.11\n\nOf the total patients analysed in our study, 97.8% patients were found to have comorbidities. Of which, hypertension (30.6%), diabetes mellitus (23.1%) and obesity (12.1%) were the commonest comorbidities found in the patients. Other comorbidities included chronic liver disease (0.34%), endocrine disorders (0.24%) and psychiatric disorders (0.06%). In a study by Sanyaolu et al, that the common comorbidities found were hypertension, diabetes mellitus and obesity, which were associated with poorer outcomes in COVID-19 patients.12\n\nOf all the patients analysed in our study, 13.9% of patients developed complications following COVID-19 infection. The common complications seen among the patients were acute kidney injury (22.5%), ARDS (18.3%) and sepsis (11.0%). Other complications included thrombosis (3.6%), acute hepatic injury (2.4%) and arrhythmias (2.0%). In the study by Cascella M et al, it was reported that ARDS was the most common pulmonary complication of COVID-19 while extra-pulmonary complications included AKI, cardiovascular complications and prothrombotic complications.10 Similarly, in another study by Isath A et al., the most common complications reported were respiratory failure, AKI, sepsis and thrombosis.13\n\nIn our analysis, 57.8% patients recovered without any complications, while 31.1% were hospitalised, and 11.1% deceased due to the illness. Similar findings were reported in a study by Isath A et al., where 51.4% patients recovered and were discharged home, and the overall inpatient mortality was reported to be 13.2%. Most of the patients with comorbidities were associated with higher number of complications and mortality.13\n\n\nConclusion\n\nAnalyzing the 50 most-cited articles in COVID-19 and the complications of COVID-19 and assessing their citations-per-year is a valuable approach for clinicians and researchers. It offers a quick overview of the most influential literature and COVID-19 research has evolved over time. Moreover, a detailed review of these articles can uncover the key attributes that make papers highly cited. This insight can be instrumental for authors, offering guidance on creating impactful research in the future. Overall, this method serves as a strategic tool for staying updated and contributing meaningfully to the field of COVID-19 research.",
"appendix": "Data availability\n\nDryad: Data of top 50 most cited articles about COVID-19 and the complications of COVID-19, https://doi.org/10.5061/dryad.tx95x6b4m. 14\n\nThis project contains the following underlying data:\n\n- Data_of_top_50_most_cited_articles_about_COVID-19_and_the_complications_of_COVID-19.xlsx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nSinghal T: A Review of Coronavirus Disease-2019 (COVID-19). Indian J. Pediatr. 2020; 87(4): 281–286. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCucinotta D, Vanelli M: WHO Declares COVID-19 a Pandemic. Acta Biomed. 2020; 91(1): 157–160. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization; 2023 Sep 21 [cited 2023 Sep 21]. Reference Source\n\nGupta A, Madhavan MV, Sehgal K, et al.: Extrapulmonary manifestations of COVID-19. Nat. Med. 2020; 26: 1017–1032. Publisher Full Text\n\nHolmes KV: SARS coronavirus: a new challenge for prevention and therapy. J. Clin. Invest. 2003; 111: 1605–1609. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoed H: New developments in the use of citation analysis in research evaluation. Arch. Immunol. Ther. Exp. 2009; 57: 13–18. Publisher Full Text\n\nBwire GM: Coronavirus: Why Men are More Vulnerable to Covid-19 Than Women? SN Compr. Clin. Med. 2020; 2: 874–876. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJakhmola S, Baral B, Jha HC: A comparative analysis of COVID-19 outbreak on age groups and both the sexes of population from India and other countries. J. Infect. Dev. Ctries. 2023; 15: 333–341. Publisher Full Text\n\nCenters for Disease Control and Prevention (CDC): 2021 Jan 1 [cited 2023 Sep 21]. Reference Source\n\nStatPearls: 2023 Aug 18 [cited 2023 Sep 21]. Reference Source\n\nMullol J, Alobid I, Mariño-Sánchez F, et al.: The Loss of Smell and Taste in the COVID-19 Outbreak: A Tale of Many Countries. Curr. Allergy Asthma Rep. 2020; 20(10): 61. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSanyaolu A, Okorie C, Marinkovic A, et al.: Comorbidity and its Impact on Patients with COVID-19. SN Compr. Clin. Med. 2020; 2(8): 1069–1076. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIsath A, Malik AH, Goel A, et al.: Nationwide Analysis of the Outcomes and Mortality of Hospitalized COVID-19 Patients. Curr. Probl. Cardiol. 2023; 48(2): 101440. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSingh T, Padubidri JR, Shetty P, et al.: Data of top 50 most cited articles about COVID-19 and the complications of COVID-19. [Dataset]. Dryad. 2023. Publisher Full Text"
}
|
[
{
"id": "253907",
"date": "03 Apr 2024",
"name": "Husnul Khuluq",
"expertise": [
"Reviewer Expertise bibliometric",
"big data",
"machine learning",
"clinical pharmacy"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe literature is up-to-date, but it is insufficient with only 14 references. Bibliometric research is a review-based study, so it requires a more extensive collection of literature than experimental or observational research. The study design is sound, utilizing two databases: Scopus and Web of Science. However, a drawback of using these two databases is the difficulty in visualization with tools like VOSviewer or Biblioshiny. Bibliometric research should display network visualizations among institutions, countries, and author collaborations. Utilizing only Web of Science might actually be sufficient due to its more comprehensive visualization capabilities. The main weakness of this article is the absence of such visualizations, as explained above. Overall, bibliometric analysis should ideally utilize applications such as VOSviewer or Biblioshiny, wherein citation counts will automatically appear. The utilization of these applications is not explicitly stated within the research methodology. This article bears closer resemblance to a review article rather than a bibliometric analysis.\nThe literature is relevant, but the discussion lacks depth due to the scarcity of literature. The discussion on complications, which is the main topic, should be more detailed with literature from various countries, as complications may vary.\nThe conclusion remains too general and is not sufficiently relevant to its title, which is complications in COVID-19 cases. Please formulate a more specific conclusion and add recommendations.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11399",
"date": "21 Jun 2024",
"name": "Matthew Antony Manoj",
"role": "Author Response",
"response": "We would like to express our gratitude to the reviewer for dedicating their time to thoroughly review our article. We have carefully examined each comment provided and have made every effort to comprehensively address each one. Q. The literature is up-to-date, but it is insufficient with only 14 references. Bibliometric research is a review-based study, so it requires a more extensive collection of literature than experimental or observational research. Ans. We have now expanded our list of references and have incorporated this additional information into our discussion section to ensure a more comprehensive discussion. QThe study design is sound, utilizing two databases: Scopus and Web of Science. However, a drawback of using these two databases is the difficulty in visualization with tools like VOSviewer or Biblioshiny. Bibliometric research should display network visualizations among institutions, countries, and author collaborations. Utilizing only Web of Science might actually be sufficient due to its more comprehensive visualization capabilities. The main weakness of this article is the absence of such visualizations, as explained above. Overall, bibliometric analysis should ideally utilize applications such as VOSviewer or Biblioshiny, wherein citation counts will automatically appear. The utilization of these applications is not explicitly stated within the research methodology. This article bears closer resemblance to a review article rather than a bibliometric analysis. Ans. Thank you for your comment. We wish to clarify that we did not employ visual representation tools such as VOSviewer or Biblioshiny. The data analysis was conducted individually by each author and subsequently verified by all authors. This approach has been acknowledged as a limitation in the discussion section of our study. Q. The literature is relevant, but the discussion lacks depth due to the scarcity of literature. The discussion on complications, which is the main topic, should be more detailed with literature from various countries, as complications may vary. Ans. Thank you for your comment. We've now enriched the discussion section of the article with additional information as mentioned previously. Furthermore, we wish to clarify that this bibliometric study does not focus exclusively on the complications of COVID-19. Instead, it broadly covers COVID-19 and its complications. Through our data analysis, we discovered that the complications of COVID-19 remained relatively consistent across the various countries we analyzed. Hence as a result of this, we had focussed the content in the discussion revolving around the most common types of complications in COVID-19 Q.The conclusion remains too general and is not sufficiently relevant to its title, which is complications in COVID-19 cases. Please formulate a more specific conclusion and add recommendations. Ans. In response to your feedback, we have now revised the conclusion to be more specific and directly relevant to the content of the article."
}
]
}
] | 1
|
https://f1000research.com/articles/13-105
|
https://f1000research.com/articles/13-446/v1
|
03 May 24
|
{
"type": "Research Article",
"title": "Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio predicting hospital length of stay and mortality in young COVID-19 patients: A retrospective study",
"authors": [
"Ayman El-Menyar",
"Naushad A. Khan",
"Mohammad Asim",
"Hassan Al-Thani",
"Mohammed Abukhattab",
"Muna Al Maslamani",
"Naushad A. Khan",
"Mohammad Asim",
"Hassan Al-Thani",
"Mohammed Abukhattab",
"Muna Al Maslamani"
],
"abstract": "Background This study investigated the utility of platelet-to-lymphocyte ratio (PLR) and Neutrophil-to-Lymphocyte ratio (NLR) in patients with COVID-19 with respect to age, early (a week) vs. delayed recovery (> a week) and mortality.\n\nMethods This was a retrospective study including 1,016 COVID-19 patients. The discriminatory power and multivariate logistic regression analysis were performed.\n\nResults The mean age of patients was 45 (± 13.9), and 75.7% were males. Older patients had elevated NLR, PLR, D-dimer, CRP, and Interleukin-6 levels and longer hospital stay than the younger group (p < 0.001). In-hospital mortality was higher in older adults (26.9% vs. 6.6%, p =0.001). On-admission NLR (5.8 vs. 3.2; P= 0.001) and PLR (253.9±221.1 vs. 192.2±158.5; p = 0.004) were higher in the non-survivors than survivors. Both PLR and NLR displayed significant discriminatory ability for mortality. NLR had a higher AUC and specificity, while PLR exhibited slightly higher sensitivity. In individuals aged ≤55, NLR showed superior discrimination (AUC=0.717) compared to PLR (AUC=0.620). Conversely, for older adults, PLR displayed enhanced discrimination (AUC=0.710), while NLR showed AUC=0.693.\n\nConclusion Higher admission NLR and PLR levels were associated with delayed recovery, whereas an enhanced NLR was associated with considerably higher mortality in older COVID-19 patients.",
"keywords": [
"COVID-19",
"Inflammation",
"Mortality",
"Neutrophil-to-lymphocyte ratio",
"platelet-to-lymphocyte ratio",
"Hospital stay",
"age"
],
"content": "Key messages\n\n\n\n- Simple, instant bedside laboratory tests on admission are of utmost value for patients’ stratification during a pandemic.\n\n- COVID-19 patients with elevated NLR and PLR levels are associated with delayed recovery, more ICU admissions, and intubation.\n\n- A greater NLR values are associated with higher mortality in older COVID-19 patients.\n\n- However, none of these two parameters alone is an independent predictor of death.\n\n\nIntroduction\n\nThe severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) causing Coronavirus disease 2019 (COVID-19) has exhausted the healthcare infrastructure worldwide by causing recurrent waves.1 The SARS-CoV-2 infection has wide clinical variations, ranging from asymptomatic infection to moderate upper respiratory tract sickness to severe viral pneumonia with respiratory failure and death.2 Of note, reliable laboratory parameters of the severity of the disease, treatment response, and outcome were not thoroughly investigated during the early phase of the pandemic due to rapid onset and spread. As a result, early identification of clinical and laboratory variables linked with poor outcomes is critical for identifying low- and high-risk patients for triage and appropriate management.\n\nInfectious diseases are associated with inflammation, and existing data supports its central contribution to the progression and pathogenesis of COVID-19.2 Because of SARS-COV-2 viral replication, cellular destruction leads to cytokines and chemokines from the activated macrophages.3 As a result, they set off immunological responses, which in turn cause cytokine storms and aggravate the situation. As a result, they elicit immune responses, which create cytokine storms and exacerbate the problem. This imbalance arises because the adaptive immune response depends on the inflammatory response’s strength.4 Therefore, patients with a pre-existing chronic inflammatory status might be vulnerable to a severe form of COVID-19 disease.\n\nThe Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are straightforwardly obtainable ratios from complete blood count (CBC) panels. Emerging evidence suggests that peripheral NLR and PLR can be used as markers of systemic inflammation in various disease processes.5–9 Several studies have reported the prognostic role of NLR in differentiating mild/moderate cases from severe COVID-19 cases and have proposed that NLR can be a reliable predictor of COVID-19 progression associated with high mortality in COVID-19.10–16 Moreover, several studies have also suggested PLR to be a promising and reliable indicator of disease severity, exhibiting good predictive values on progression and clinical outcomes in patients with COVID-19.17–22\n\nHowever, an imitating factor of these ratios is the inability to collate with ethnic differences.23 Also, they can be profoundly influenced by age and gender,24,25 whose dependence has not yet been fully explored in COVID-19 disease. Moreover, Qatar has a distinct demographic profile, with around 88% of the expatriate workforce of Qatar’s 2.8 million citizens. While the bulk of the population (75%) is male gender, the pyramid shape of population distribution is disproportionately concentrated in the 20–50-year age group.25 COVID-19 affects males disproportionately, and older adults tend to have worse outcomes.26,27\n\nWe sought to evaluate the association of NLR and PLR and the recovery and mortality in patients with COVID-19. Also, to assess age-stratified differences in these outcomes.\n\n\nMethods\n\nA retrospective observational study was conducted, including patients with COVID-19 admitted to the different affiliated Hospitals of Hamad Medical Corporation (HMC) in Qatar at the beginning of the coronavirus pandemic (from March 01 to June 01, 2020). The subjects included in the study were laboratory-confirmed cases of COVID-19 disease (>18 years old) of both genders. Patients with an inconclusive diagnosis of COVID-19 by RT-PCR testing, undefined diagnosis, and missing data were excluded from the study. Data were extracted from the electronic medical record (CERNER), which included patients’ demographics such as (age, gender, nationality); recent exposure history, clinical symptoms and signs, comorbidities (Hypertension, diabetes mellitus, cancer, renal failure, chronic obstructive pulmonary disease, and others), initial vitals (Systolic blood pressure, diastolic blood pressure, pulse, respiratory rate, blood oxygen saturation), routine laboratory findings (initial and repeated readings) including CBC, blood chemistry and C-reactive protein (CRP), chest X-ray and computed tomographic scans, treatment, mechanical ventilation, hospital and intensive critical care (ICU) length of stay, speed of recovery (within one week, and more than one week), discharge from hospital and mortality.\n\nTaqPath COVID-19 Combo KitTM (Thermo Fisher Scientific, Waltham, Massachusetts, USA) or Cobas SARS-CoV-2 Test® (Roche Diagnostics, Rotkreuz, Switzerland) were used to identify SARS-CoV-2 infection utilizing Nasopharyngeal and throat samples. All COVID-19 testing was performed at the central laboratory of the HMC, which manages over 85% of the country’s inpatient bed capacity and is responsible for delivering public healthcare.\n\n\n\n- Every patient who experienced COVID-19-like manifestations and at the same time tested positive for COVID-19 in respiratory samples using a real-time reverse-transcription polymerase chain reaction (RT-PCR) assay was deemed a confirmed COVID-19 case.\n\n- The platelet-to-lymphocyte ratio (PLR) was defined as the ratio between absolute Platelet counts to absolute lymphocyte count, and the neutrophil-to-lymphocyte ratio (NLR) was defined as the ratio between absolute neutrophil counts to absolute lymphocyte count.\n\n- Recovery referred to two negative swab tests done consecutively.\n\nThe data were collated in Microsoft Excel, and statistical analysis was performed using SPSS, version 28.0. for Windows (Armonk, NY: IBM Corp, USA). Data were expressed as proportions, means ± standard deviations, or medians as appropriate for continuous variables or as absolute counts and percentages for categorical variables. Data were compared using the student-t-test for continuous variables and the Pearson χ2 test for categorical variables. The Fisher exact test was used if the expected cell frequencies were below five. For skewed continuous data, a nonparametric Mann-Whitney test was performed. The independent predictors of mortality were identified using multivariable logistic regression analysis after adjusting for age, gender, comorbidities, complications, NLR, and PLR as covariates of interest.\n\nAreas under the curve (AUC) of ROC curves were employed to determine the ratios’ performance in age discrimination regarding NLR and PLR. The best cut-off points of the ratios were the points on the curves with the highest sensitivity and specificity. The sample size for the current study was not determined a priori as we intended to include all the laboratory-confirmed COVID-19 cases during the study period. A two-sided P-value < 0.05 was considered statistically significant.\n\nThis observational study was conducted in accordance with the STROBE principles. The study was authorized by the Institutional Review Board and Medical Research Council (MRC-01-20-672 & MRC-05-213) of Hamad Medical Corporation. A waiver of consent was granted for this retrospective study as there was no direct contact was made with the participants, and the data were collected anonymously.\n\n\nResults\n\nDuring the study period, 1016 persons tested positive for SARS-CoV-2. The mean age of the cohort was 45 ±13.9 years, and an overwhelming majority of infected persons were male (75.7 %). The most common chronic medical conditions were hypertension (40.3%), followed by diabetes mellitus (39.0%), chronic kidney disease (14.0%), cancer (5.4%) and chronic obstructive pulmonary disease (4.8%).\n\nTable 1 outlines the comparison of clinical characteristics, in-hospital complications, comorbidities, and outcomes of COVID-19 patients according to hospital length of stay. Patients in the long-stay group were older (45.9±13.9 vs.40.6±13.2), had significantly lower SpO2 (97.1±3.6 vs. 98.4±2.0), and were more likely to have significant medical comorbidities compared to ‘short stay’ group. Compared with the short-stay group, patients in the long-stay group were presented with lower lymphocyte and platelet counts and higher inflammation-related indices (CRP, IL-6). Further significant elevations in NLR [3.7 (0.3-72.0) vs. 2.8 (0.6(0.6-53.0); P=0.002] and the PLR indices was found [205.4±178.8 vs. 199.6±168.2; P=0.001). Concerning the major in-hospital complications, patients in the long-hospital stay group were more likely to have renal failure (16.7% vs. 5.1%; P=0.001) and ARDS (3.7% vs. 0.0%; P=0.009) than patients in the short-stay group. The in-hospital mortality rate was 11.9% (121/1016). Patients in the long-stay group had higher in-hospital mortality than those in the short-stay group (12.8% vs.7.9%; P<0.06).\n\nTable 2 summarizes the impact of age. Of the total COVID-19 patients, 74% were aged ≤55, and 26% were >55. Hypertension (75% vs. 8.1%), diabetes mellitus (DM) (70.8% vs. 27.8%), and chronic kidney disease (30.3% vs. 8.2%) were more evident in older subjects than in the younger group. Regarding vital signs, the older patients had significantly lower diastolic blood pressure (DBP), pulse rate, and oxygen saturation than the younger patients. The initial laboratory results showed that, compared with the younger patients, older patients had significantly higher NLR, PLR, creatinine, CRP, IL-6, and D-dimer levels. Intubation was performed more in older patients (42% vs.17.7%; P=0.001). Besides, the median length of ICU [14.1 (0.1-74.3) vs. 11.7 (0.16-83.4) days] and ventilatory days [13.7 (0.4-74.7) vs. 9.3 (0.1-87.8)] were significantly longer in the older group. The older patient group experienced a higher frequency of renal failure (29.2% vs. 9.6%), ARDS (4.2% vs.2.7%), pulmonary embolism (1.5% vs. 0.5%), and a higher mortality rate than the younger group (26.9% vs. 6.6 %, P<0.001).\n\nTable 3 compares clinical characteristics, laboratory results, and complications among COVID-19 patients stratified according to survival status. The deceased patients were significantly older than those who survived (56.4±11.4 vs. 43.5±13.25 years, respectively, P<0.001) with more comorbidities as well. Creatinine, CRP, D-dimer, ferritin, IL-6, neutrophil, troponin, PLR, and NLR were significantly higher, whereas lymphocyte and platelet counts were significantly lower in the deceased patients.\n\nFigure 1(a) and (b) show the result of the ROC analysis plotting the sensitivity and specificity of the PLR and NLR and their discriminatory ability to predict overall mortality and their performance by age categories in COVID-19 patients, respectively.\n\nThe area under the curve (AUC) for NLR was 0.710, indicating a good discriminatory performance, and for PLR, 0.614 suggesting a fair discriminatory capacity, respectively. The optimal cut-off for NLR and PLR were 5.03 (Sensitivity 66.9% and specificity 46.5%) and 150.16 (Sensitivity 61.2% and specificity 68.4%). In individuals aged ≤55 years, the PLR demonstrated moderate discrimination with an AUC of 0.620, while the NLR exhibited a higher AUC of 0.717, signifying superior discrimination compared to the PLR. Conversely, for individuals aged >55 years, PLR showed an increased higher AUC of 0.710 in comparison to those ≤55 years, implying enhanced discrimination in this age group, while NLR exhibited moderate discrimination with an AUC of 0.693 (Figure 1(b)).\n\nTable 4 shows the association of PLR and NLR in predicting mortality and delayed recovery in COVID-19 patients. The crude odd ratio for NLR was 1.078 (95% CI 1.049-1.109; P=0.001), and PLR was 1.001 (95% CI, 1.001-1.002; P=0.002) for mortality. The crude odd ratio for NLR was 1.034 (95% CI 0.996-1.072; P=0.078), and PLR was 1.002 (95% CI, 1.000-1.004; P=0.021) for delayed recovery.\n\nTable 5 depicts the results of multivariate regression analysis to determine independent predictors of mortality. After adjusting for the relevant covariates, being older than 55 years (OR 1.068; 95% CI 1.045 to 1.091; P=0.001), hypertension (OR 0.437; 95% CI 0.255 to 0.751; P=0.003), diabetes mellitus, (OR 1.730; 95% CI 1.050 to 2.851; P=0.032), CRP (OR 1.004; 95% CI 1.002 to 1.007; P=0.001), and renal failure (OR 6.620; 95% CI 3.989 to 10.989; P=0.001) were found to be independent predictors of mortality. However, NLR (OR 1.039; 95% CI 0.998 to 1.082; P=0.051) and PLR (OR 1.000; 95% CI 0.998 to 1.001; P=0.581) were not independently associated with in-hospital mortality.\n\n\nDiscussion\n\nEver since the first cases of the COVID-19 pandemic were reported, healthcare institutions have worked to develop diagnostic tools and prognostic indications. The current study investigates associations between NLR, PLR, age, duration of hospital length of stay, and mortality in COVID-19 patients. This study demonstrates that patients with higher admission NLR and PLR levels were associated with delayed recovery, more intubation, and ICU admissions. In contrast, an enhanced NLR was associated with considerably higher mortality in older COVID-19 patients than PLR.\n\nDespite a high per capita SARS-CoV-2 infection rate in the early phase of the COVID-19 pandemic, the case fatality rate in Qatar was among the lowest in the world.28 In our analysis of 1016 COVID-19 patients, the overall in-hospital mortality was 11.9 %. The mortality in our study cohort was less than in previous reports from other countries.29,30 Lower mortality was also observed in the elderly population (aged >55). Several studies and meta-analyses have concluded that the predictive value of NLR and PLR could be used to stratify COVID-19 patients, and especially high NLR at admission has been associated with poor outcomes.11,12,30–32 Previous publications included older adults but did not perform a subgroup analysis to assess the estimated mortality risk for this age group. Ciccullo et al. demonstrated that younger age and NLR below three were associated with clinical improvement, while NLR over 4 predicted the transfer to ICU.31 Based upon the ROC analysis, the cut-off value for NLR was 5.03, and PLR was 150.16 to predict mortality. This result is in concordance with previous studies, in which the proposed optimum cut-off values for NLR ranged from 3 to 6,11,32,33 and cut-off PLR values were between 140-160.32,34 Liu et al. showed that older patients (>50 years old) with NLR ≥3.13 are more likely to develop a critical illness.35 Yang et al. showed that elevated NLR and advanced age were associated with severe COVID-19 illness and independently predicted the worse clinical outcomes.36\n\nThe NLR has emerged as a potent inflammatory marker with diagnostic and prognostic utility in various clinical conditions.11–13,15,16,21,22,35,37–39 NLR represents the equilibrium of innate and adaptive immune responses.18 A High NLR implies an aberrant immune response, with increased neutrophils and decreased lymphocytes. Also, neutrophil production can be augmented by virus-induced inflammatory factors such as IL-6, Interleukin-8 (IL-8), and tumor necrosis factor α (TNF- α).4,37,40 Furthermore, it appears to be a more reliable technique than PLR, absolute neutrophils, and lymphocyte counts since confounders influence it less. The current study’s asynchronous pattern of NLR and PLR highlights that NLR and PLR are both elevated during the onset of the COVID-19 disease. Still, NLR increases afterward, especially in older individuals. This would imply that NLR offers extra information regarding the ongoing inflammatory state in COVID-19 patients, especially those with poor prognoses. Our results suggest that NLR can be a more valuable predictor of poor prognosis in the different sub-categories of patients studied in the current study.\n\nHowever, neither NLR nor PLR were shown to be independent predictors of mortality on multivariate analysis, which contrasts with previous reports.1,14,24,31,38,41,42 This discrepancy could be explained by one of two factors. First, the pathogenesis of SARS-CoV-2 infection is complicated. Secondly, this could be attributed to the small sample size reported in the previous studies.\n\nThe severity of infections, hematological derangements (NLR, PLR), and mortality rose sharply with age. This was especially true for infection criticality, in-hospital complications, and mortality, restricted for those under 50 but rapidly increased for those over 50. It has been established that patients of advanced age are more susceptible to COVID-19 mortality.43–46\n\nRegarding the clinical outcome of patients concerning early and late recovery, we found that delayed recovery (HLOS> seven days) was associated with advanced age, prolonged ICU stay and mechanical ventilation, and higher mortality. Also, a significantly higher proportion of the older population with prolonged HLOS had comorbidities, suggesting that advanced age and associated comorbidities require more extended hospitalization and have a greater risk of mortality.47 Moreover, our cohort’s higher mean PLR demonstrated a significant association with delayed recovery. While NLR showed a modest and suggestive increase in the odds of delayed recovery, the association was non-significant. Studies have shown that HLOS is age-dependent.48 We could not find studies evaluating the impact of NLR and PLR as prognostic markers of early vs. delayed recovery.\n\nSome limitations may have affected the study and warrant consideration. This retrospective analysis did not document the patient’s follow-up. Secondly, available input data were most complete at the national level, but the results’ generalizability could have been constrained by variations within Qatar’s very diversified population. Also, the selection bias and power of the study cannot be ignored; the study would have benefitted from a larger sample size to reflect better the importance of NLR/PLR in the prognosis of patients with COVID-19. The cycle threshold (cT) value has been proposed as a potential prognostic indicator in patients with COVID-19. While this information was not available in the current study, it may be more valuable in refining the prognostic evaluation of COVID-19 patients if researchers compare and combine the NLR/PLR with cT findings. Lastly, a prospective study should ideally test the predictive value of NLR and PLR longitudinally. Despite these limitations, the study, tailored to the complexity of the epidemic, reproduces the observed biochemical trends and provides profound insights into the utility of NLR and PLR as prognostic markers in COVID-19 patients.\n\n\nConclusion\n\nPatients with higher NLR and PLR levels were associated with delayed recovery, ICU admissions, and intubation, whereas an enhanced NLR was associated with considerably higher mortality in older COVID-19 patients. However, none of these two parameters was found to be an independent predictor for death.\n\n\nEthics and consent\n\nThis study was approved by the Research Ethics Committee of the Medical Research Center, Hamad Medical Corporation (HMC), Doha, Qatar (MRC-01-20-672 & MRC-05-213) on 29 Sep 2020. A waiver of consent was granted for this retrospective study as there was no direct contact was made with the participants, and the data were collected anonymously.\n\n\nAuthors’ contributions\n\nAll authors have substantially contributed to the acquisition, analysis, and interpretation of data for the work, drafting the work or revising it critically for important intellectual content, and final approval of the version to be published.",
"appendix": "Data availability\n\nAs the covid-19 data are owned by the medical research center and CDC department, I provided the email and condition by which the reader can access the de-identified data. All data are presented in the manuscript including tables and de-identified data can be accessed after a permission from the medical research center of HMC, Qatar (mrcinfo@hamad.qa), on a reasonable research request\n\n\nReferences\n\nSarkar S, Kannan S, Khanna P, et al.: Role of platelet-to-lymphocyte count ratio (PLR), as a prognostic indicator in COVID-19: A systematic review and meta-analysis. J. Med. Virol. 2022; 94: 211–221. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarcía LF: Immune Response, Inflammation, and the Clinical Spectrum of COVID-19. Front. Immunol. 2020; 11: 1441. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTay MZ, Poh CM, Rénia L, et al.: The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 2020; 20: 363–374. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMortaz E, Tabarsi P, Varahram M, et al.: The Immune Response and Immunopathology of COVID-19. Front. Immunol. 2020; 11: 2037. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZahorec R: Neutrophil-to-lymphocyte ratio, past, present, and future perspectives. Bratisl. Lek. Listy. 2021; 122: 474–488. PubMed Abstract | Publisher Full Text\n\nBuonacera A, Stancanelli B, Colaci M, et al.: Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases. Int. J. Mol. Sci. 2022; 23: 23. Publisher Full Text\n\nWang G, Mivefroshan A, Yaghoobpoor S, et al.: Prognostic Value of Platelet to Lymphocyte Ratio in Sepsis: A Systematic Review and Meta-analysis. Biomed. Res. Int. 2022; 2022: 9056363.\n\nEl-Menyar A, Mekkodathil A, Al-Ansari A, et al.: Platelet-Lymphocyte and Neutrophil-Lymphocyte Ratio for Prediction of Hospital Outcomes in Patients with Abdominal Trauma. Biomed. Res. Int. 2022; 2022: 5374419.\n\nAl-Yahri O, Saafan T, Abdelrahman H, et al.: Platelet to Lymphocyte Ratio Associated with Prolonged Hospital Length of Stay Postpeptic Ulcer Perforation Repair: An Observational Descriptive Analysis. Biomed. Res. Int. 2021; 2021: 6680414.\n\nWang W, Zhao Z, Liu X, et al.: Clinical features and potential risk factors for discerning the critical cases and predicting the outcome of patients with COVID-19. J. Clin. Lab. Anal. 2020; 34: e23547. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu Y, Du X, Chen J, et al.: Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J. Infect. 2020; 81: e6–e12. PubMed Abstract | Publisher Full Text\n\nSarkar PG, Pant P, Kumar J, et al.: Does Neutrophil-to-lymphocyte Ratio at Admission Predict Severity and Mortality in COVID-19 Patients? A Systematic Review and Meta-analysis. Indian J. Crit. Care Med. 2022; 26: 361–375. PubMed Abstract | Publisher Full Text\n\nRegolo M, Vaccaro M, Sorce A, et al.: Neutrophil-to-Lymphocyte Ratio (NLR) Is a Promising Predictor of Mortality and Admission to the Intensive Care Unit of COVID-19 Patients. J. Clin. Med. 2022; 11: 11. Publisher Full Text\n\nShahid MF, Malik A, Siddiqi FA, et al.: Neutrophil-to-Lymphocyte Ratio and Absolute Lymphocyte Count as Early Diagnostic Tools for Corona Virus Disease 2019. Cureus. 2022; 14: e22863. Publisher Full Text\n\nLa Torre G, Marte M, Massetti AP, et al.: The neutrophil/lymphocyte ratio as a prognostic factor in COVID-19 patients: a case-control study. Eur. Rev. Med. Pharmacol. Sci. 2022; 26: 1056–1064. PubMed Abstract | Publisher Full Text\n\nRose J, Suter F, Furrer E, et al.: Neutrophile-to-Lymphocyte Ratio (NLR) Identifies Patients with Coronavirus Infectious Disease 2019 (COVID-19) at High Risk for Deterioration and Mortality-A Retrospective, Monocentric Cohort Study. Diagnostics (Basel). 2022; 12. Publisher Full Text\n\nFois AG, Paliogiannis P, Scano V, et al.: The Systemic Inflammation Index on Admission Predicts In-Hospital Mortality in COVID-19 Patients. Molecules. 2020; 25. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZeng F, Deng G, Cui Y, et al.: A predictive model for the severity of COVID-19 in elderly patients. Aging (Albany NY). 2020; 12: 20982–20996. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGong J, Ou J, Qiu X, et al.: A Tool for Early Prediction of Severe Coronavirus Disease 2019 (COVID-19): A Multicenter Study Using the Risk Nomogram in Wuhan and Guangdong, China. Clin. Infect. Dis. 2020; 71: 833–840. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhu Z, Cai T, Fan L, et al.: Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019. Int. J. Infect. Dis. 2020; 95: 332–339. PubMed Abstract | Publisher Full Text | Free Full Text\n\nErdogan A, Can FE, Gönüllü H: Evaluation of the prognostic role of NLR, LMR, PLR, and LCR ratio in COVID-19 patients. J. Med. Virol. 2021; 93: 5555–5559. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFors M, Ballaz S, Ramírez H, et al.: Sex-Dependent Performance of the Neutrophil-to-Lymphocyte, Monocyte-to-Lymphocyte, Platelet-to-Lymphocyte, and Mean Platelet Volume-to-Platelet Ratios in Discriminating COVID-19 Severity. Front. Cardiovasc Med. 2022; 9: 822556. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAzab B, Camacho-Rivera M, Taioli E: Average values and racial differences of neutrophil-lymphocyte ratio among a nationally representative sample of United States subjects. PLoS One. 2014; 9: e112361. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVafadar Moradi E, Teimouri A, Rezaee R, et al.: Increased age, neutrophil-to-lymphocyte ratio (NLR), and white blood cell count are associated with higher COVID-19 mortality. Am. J. Emerg. Med. 2021; 40: 11–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAyoub HH, Chemaitelly H, Seedat S, et al.: Age could be driving variable SARS-CoV-2 epidemic trajectories worldwide. PLoS One. 2020; 15: e0237959. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWu C, Chen X, Cai Y, et al.: Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern. Med. 2020; 180: 934–943. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhou F, Yu T, Du R, et al.: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395: 1054–1062. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhatib MY, Ananthegowda DC, Elshafei MS, et al.: Predictors of mortality and morbidity in critically ill COVID-19 patients: An experience from a low mortality country. Health Sci. Rep. 2022; 5: e542. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcPadden J, Warner F, Young HP, et al.: Clinical characteristics and outcomes for 7,995 patients with SARS-CoV-2 infection. PLoS One. 2021; 16: e0243291. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBaggio JAO, Machado MF, Carmo RFD, et al.: COVID-19 in Brazil: spatial risk, social vulnerability, human development, clinical manifestations and predictors of mortality - a retrospective study with data from 59 695 individuals. Epidemiol. Infect. 2021; 149: e100. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCiccullo A, Borghetti A, Zileri Dal Verme L, et al.: Neutrophil-to-lymphocyte ratio and clinical outcome in COVID-19: a report from the Italian front line. Int. J. Antimicrob. Agents. 2020; 56: 106017. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGüneysu F, Guner NG, Erdem AF, et al.: Can COVID-19 Mortality be Predicted in the Emergency Room? J. Coll. Physicians Surg. Pak. 2020; 30: 928–932. PubMed Abstract | Publisher Full Text\n\nYildiz H, Castanares-Zapatero D, Pierman G, et al.: Validation of Neutrophil-to-Lymphocyte Ratio Cut-off Value Associated with High In-Hospital Mortality in COVID-19 Patients. Int. J. Gen. Med. 2021; 14: 5111–5117. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAsghar MS, Haider Kazmi SJ, Ahmed Khan N, et al.: Clinical Profiles, Characteristics, and Outcomes of the First 100 Admitted COVID-19 Patients in Pakistan: A Single-Center Retrospective Study in a Tertiary Care Hospital of Karachi. Cureus. 2020; 12: e8712.\n\nLiu J, Liu Y, Xiang P, et al.: Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J. Transl. Med. 2020; 18: 206. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYang AP, Liu JP, Tao WQ, et al.: The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int. Immunopharmacol. 2020; 84: 106504. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLuo H, He L, Zhang G, et al.: Normal Reference Intervals of Neutrophil-To-Lymphocyte Ratio, Platelet-To-Lymphocyte Ratio, Lymphocyte-To-Monocyte Ratio, and Systemic Immune Inflammation Index in Healthy Adults: a Large Multi-Center Study from Western China. Clin. Lab. 2019; 65. PubMed Abstract | Publisher Full Text\n\nSeyit M, Avci E, Nar R, et al.: Neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio and Platelet to lymphocyte ratio to predict the severity of COVID-19. Am. J. Emerg. Med. 2021; 40: 110–114. PubMed Abstract | Publisher Full Text | Free Full Text\n\nToori KU, Qureshi MA, Chaudhry A, et al.: Neutrophil to lymphocyte ratio (NLR) in COVID-19: A cheap prognostic marker in a resource constraint setting. Pak. J. Med. Sci. 2021; 37: 1435–1439. PubMed Abstract | Publisher Full Text\n\nSawa T, Akaike T: What triggers inflammation in COVID-19? elife. 2022; 11: 11. Publisher Full Text\n\nGrasselli G, Greco M, Zanella A, et al.: Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. JAMA Intern. Med. 2020; 180: 1345–1355. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTatum D, Taghavi S, Houghton A, et al.: Neutrophil-to-Lymphocyte Ratio and Outcomes in Louisiana COVID-19 Patients. Shock. 2020; 54: 652–658. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXu G, Ye M, Zhao J, et al.: New view on older adults with COVID-19: comments on “SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes”. Geroscience. 2020; 42: 1225–1227. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGosch M, Singler K, Kwetkat A, et al.: COVID-19 in older adults - a complex challenge. MMW Fortschr. Med. 2020; 162: 36–40. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTan X, Zhang S, Xu J, et al.: Comparison of clinical characteristics among younger and elderly deceased patients with COVID-19: a retrospective study. Aging (Albany NY). 2020; 13: 16–26. PubMed Abstract | Publisher Full Text\n\nPepe M, Maroun-Eid C, Romero R, et al.: Clinical presentation, therapeutic approach, and outcome of young patients admitted for COVID-19, with respect to the elderly counterpart. Clin. Exp. Med. 2021; 21: 249–268. PubMed Abstract | Publisher Full Text | Free Full Text\n\nda Costa Sousa V , da Silva MC , de Mello MP , et al.: Factors associated with mortality, length of hospital stay and diagnosis of COVID-19: Data from a field hospital. J. Infect. Public Health. 2022; 15: 800–805.\n\nZheng H, Tan J, Zhang X, et al.: Impact of sex and age on respiratory support and length of hospital stay among 1792 patients with COVID-19 in Wuhan, China. Br. J. Anaesth. 2020; 125: e378–e380. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "282772",
"date": "06 Jun 2024",
"name": "Lorenzo Malatino",
"expertise": [
"Reviewer Expertise Internal and Clinical Medicine",
"Cardiology",
"Neutrophil-to-Lymphocyte Ratio"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper by El Menyar et al. presents a retrospective multicenter survey conducted in a large cohort of young patients with Covid-19 disease. The key messages are: 1) elevated NLR and PLR levels are associated with longer hospitalization, increased ICU admission, and intubation rate; and 2) higher NLR values are associated with increased mortality in older COVID-19 patients. Taken together, these data suggest that NLR and PLR levels could serve as useful bedside laboratory tests for patient stratification during the Covid-19 pandemic.\nUnlike previous data by (Regolo M, et al., 2022 [Ref 1]) on NLR, the authors conclude that neither of these two parameters alone is an independent predictor of death. This finding appears to contradict the aforementioned key messages, as it raises the question of how diagnostic tools identifying both length of stay and ICU admission could fail to predict mortality. Additionally, previous data by (Regolo M, et al., 2022 [Ref 1]) , derived from a retrospective survey of older patients with Covid-19 disease, showed that NLR had better performance as compared to PLR and CRP in stratifying disease severity and outcome. These data were age- and sex-adjusted, so the differences with El Menyar et al. data cannot be attributed to older age.\nThe better prognostic performance of NLR in (Regolo M, et al., 2022 [Ref 1]) may partially depend on NLR ability to predict survival in patients with pulmonary infections, as shown by (Cataudella E, et al., 2017 [Ref 2]) in community-acquired pneumonia (Cataudella E, et al., 2017 [Ref 2]), despite the different pattern of pulmonary involvement in CAP as compared to Covid-19. It may well be that the derangement between innate and adaptive immunity (Buonacera A, et al., 2022 [Ref 3]) in Covid-19 could be similar to that involved in the pathogenesis of CAP. In this respect, the complex humoral immuno-inflammatory pathway in Covid-19 patients was elegantly dissected by mediation analysis (Regolo M, et al., 2023 [Ref 4]), demonstrating that age, neutrophils, CRP, and lymphocytes are significantly and directly linked to PaO2/FiO2 (P/F), a marker of respiratory failure. The influence of inflammation on P/F, as reflected by CRP, was also mediated by neutrophils, indicating that neutrophils play a dual role. This is an important finding, given that NLR, but not PLR and CRP, was inversely and significantly related to P/F. Unfortunately, data on P/F, the type of ventilation support, and the mean duration of hospital stay for patients are missing in El Menyar et al. paper. Moreover, it should be emphasized that the article by El Menyar et al. regards the initial period of the COVID-19 pandemic, which was characterized by the highest mortality and the most severe clinical outcome.\nIn conclusion, the study by El Menyar et al. is generally confirmatory and is based on a larger survey than previous studies, which is notable. However, its limitations include the lack of data on respiratory function, ventilation support, and the mean duration of hospitalization. Additionally, objectives of this study were not clearly focused, so making difficult understanding the pathogenetic chain linking the pattern of humoral factors to the prognosis of patients with Covid-19.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-446
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https://f1000research.com/articles/13-445/v1
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03 May 24
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{
"type": "Study Protocol",
"title": "Prospective observational study on clinical profile of congenital anomalies of kidney and urinary tract (CAKUT) in children in central India: A study protocol",
"authors": [
"Anirudh Kommareddy",
"Jayant Vagha",
"Jayant Vagha"
],
"abstract": "Background Congenital anomalies of the kidney and urinary tract (CAKUT) are a group of structural abnormalities affecting these vital organs, frequently leading to chronic kidney disease in children. This study aims to comprehensively understand the clinical profile of CAKUT in children in Central India, an area with unique socio-demographic characteristics and limited prior research on this topic.\n\nMethods A prospective observational study will be conducted over three years in the pediatric department of AVBRH, a tertiary healthcare center in Central India. Data were collected through interviews with parents or guardians of children up to 18 admitted to the hospital. Clinical symptoms, prenatal history, physical examinations, and diagnostic investigations were meticulously documented.\n\nExpected outcome The study is expected to reveal the prevalence and clinical profile of CAKUT in Central Indian children. Anticipated outcomes include insights into anomalies, clinical symptoms, and potential correlations with factors like prenatal care and consanguineous marriages. Diagnostic investigations will help assess the severity of renal impairment. The results may also uncover regional variations and have implications for public health initiatives aimed at early intervention and improved patient care. However, these are preliminary expectations that are subject to confirmation through the completion of the study.",
"keywords": [
"CAKUT",
"Congenital anomalies",
"Kidney",
"Urinary tract",
"Children",
"Central India"
],
"content": "Introduction\n\nCongenital anomalies of the kidney and urinary tract (CAKUT) encompass a spectrum of structural abnormalities affecting the kidneys, ureters, bladder, and urethra that are present at birth. These anomalies represent a significant burden of disease in the pediatric population, contributing to a substantial proportion of cases of chronic kidney disease and end-stage renal disease in children.1 This study delves into the clinical profile of CAKUT in children up to 18 years of age in Central India, where limited research exists on this topic. The investigation is crucial, as a comprehensive understanding of CAKUT in this region can inform early diagnosis, targeted management, and public health initiatives, ultimately improving the quality of life for affected children.2\n\nCAKUT encompasses various anomalies, including renal agenesis, hypoplasia, dysplasia, and structural obstructions. These anomalies can present with varying degrees of severity, from asymptomatic conditions to life-threatening renal failure.3 In children, CAKUT may manifest with symptoms such as recurrent urinary tract infections, hypertension, renal dysfunction, or developmental issues. Understanding these anomalies’ clinical presentation and severity is imperative for timely intervention and improved patient outcomes.4\n\nWhile CAKUT is a global health concern, the prevalence, presentation, and outcomes can vary significantly based on geographical and ethnic factors. There is a strong genetic etiology of CAKUT, with 10% to 25% of cases attributable to genetic disorders.5 Central India, a region marked by a unique socio-demographic landscape, has yet to be extensively studied in this context. Therefore, this study seeks to fill a critical knowledge gap by focusing on CAKUT in children in this region.\n\nCentral India, characterized by a mix of urban and rural areas, faces unique challenges related to healthcare accessibility and infrastructure. Factors like consanguineous marriages and prenatal care practices may contribute to the prevalence and presentation of CAKUT. As such, an in-depth exploration of this region is warranted to understand the interplay of various factors in the context of CAKUT.6\n\nThe anticipated outcome of this study is a richer understanding of how CAKUT presents in Central Indian children, offering insights into the prevalence of associated anomalies and the severity of renal impairment. This knowledge will not only benefit the medical community by informing early diagnosis and tailored treatment but also directly impact the quality of life for affected children and their families. Furthermore, the findings may inform public health initiatives to prevent or identify CAKUT earlier, ultimately reducing the burden of these conditions in Central India.\n\nTo study the clinical profile of congenital anomalies of kidney and urinary tract (CAKUT) in children till 18 years of age at a tertiary health care center in a rural Hospital in Central India.\n\n\n\n1. To determine the severity of renal impairment.\n\n2. To study the other associated anomalies.\n\n\nMethods\n\nThis study will be conducted as a prospective observational study, collecting data on children with CAKUT over three years.\n\nThe study will take place in the pediatric department of AVBRH (Acharya Vinoba Bhave Rural Hospital), which is affiliated with JNMC (Jawaharlal Nehru Medical College) Wardha, located in the state of Maharashtra, Central India. This tertiary healthcare center is a referral center for children with various medical conditions.\n\nInclusion criteria\n\n1. Children up to 18 years of age.\n\n2. Children diagnosed with congenital anomalies of the kidney and urinary tract (CAKUT).\n\n3. Patients admitted to the Pediatric Intensive Care Unit (PICU), wards, and Neonatal Intensive Care Unit (NICU) of AVBRH.\n\nExclusion criteria\n\n1. Children with acquired kidney diseases or non-CAKUT-related conditions.\n\nOutcomes\n\nPrimary outcome:\n\n• Incidence of CAKUT: The primary outcome is the occurrence of any congenital anomalies of the kidney and urinary tract diagnosed in the study population during the study period.\n\nSecondary outcomes:\n\n• Progression of disease: Measured by changes in kidney function over time, such as alterations in serum creatinine or estimated glomerular filtration rate (eGFR).\n\n• Morbidity related to CAKUT: Frequency of urinary tract infections, hypertension, or renal failure.\n\nDiagnostic criteria for CAKUT:\n\n• Diagnosed based on prenatal ultrasound findings or postnatal imaging (ultrasound, VCUG, MRI, etc.).\n\n• Specific anomalies include renal agenesis, kidney dysplasia, ureteropelvic junction obstruction, posterior urethral valves, etc.\n\nExposures\n\nPrimary exposure:\n\n• Genetic factors: Family history of CAKUT or genetic syndromes associated with renal anomalies.\n\nSecondary exposures:\n\n• Environmental exposures: Prenatal exposure to specific medications, toxins, or infections that have been linked to fetal renal anomalies.\n\n• Maternal health: Conditions such as diabetes or hypertension during pregnancy.\n\nPredictors\n\n• Socio-demographic factors: Age at diagnosis, gender, socioeconomic status.\n\n• Biological markers: Genetic markers or specific biomarkers associated with renal development.\n\nPotential confounders\n\n• Genetic predisposition: Family history of renal diseases or congenital anomalies.\n\n• Maternal factors: Age, health status, medication use, and lifestyle factors during pregnancy (e.g., smoking, alcohol consumption).\n\n• Access to healthcare: Frequency and quality of prenatal care, which might influence early detection and management of anomalies.\n\nEffect modifiers\n\n• Age at diagnosis: The age at which CAKUT is diagnosed may modify the effect of interventions on outcomes.\n\n• Gender: Differences in CAKUT prevalence and severity between males and females.\n\n• Socioeconomic status: May modify the relationship between exposure and outcome due to differences in nutrition, environmental exposure, and access to healthcare.\n\nStatistical considerations\n\nTo handle these variables appropriately:\n\n• Multivariable regression models will be used to adjust for potential confounders.\n\n• Stratified analyses or interaction terms in regression models will be used to explore potential effect modifiers.\n\nThe data collection process for this prospective observational study on the clinical profile of congenital kidney and urinary tract (CAKUT) anomalies in children in Central India will follow a systematic and ethical approach. Data will be collected over three years at the pediatric department of AVBRH, a tertiary healthcare center affiliated with JNMC Wardha.\n\nUpon admission of a pediatric patient to the hospital’s PICU, wards, or NICU, the first step will be to obtain informed consent from the child’s father or nearest relative. This is a crucial ethical consideration to ensure that the child’s information is collected with proper consent.\n\nStructured interviews will then be conducted with the parents or guardians of eligible children. These interviews will serve as the primary source of information. Key data points to be gathered include the child’s age, sex, family socioeconomic status, chief complaints, and prevalent clinical symptoms. The research team will also inquire about the child’s medical history, including any previous treatments they may have received. An in-depth exploration of the prenatal history will be conducted, particularly emphasizing details from the second and third-trimester scans. Researchers will also document the child’s gestational age at birth and inquire about any history of consanguinity or blood-relation marriages within the family. Finally, the interviews will seek to identify pregnancy-related risk factors for mothers, such as the presence of oligohydramnios or diabetes mellitus. Interviews were performed to collect in-depth information on family history, environmental exposures, and impacts of the condition on the family. Interviews allow for collecting nuanced information that is not always available or detailed in medical records, such as the subjective impact of CAKUT, detailed family histories, and lesser-known environmental exposures.\n\nAfter the interviews, a comprehensive physical examination will be performed on each child, focusing on vital signs and anthropometry measurements. This examination will provide valuable clinical data, helping to form a complete picture of the child’s health.\n\nA systematic, systemic examination encompassing all body systems will follow the physical examination. The clinical signs and symptoms related to CAKUT will be meticulously documented during this process. The objective is to identify any abnormalities, complications, or kidney and urinary tract anomalies.\n\nAll relevant information, including demographic details, chief complaints, prenatal history, gestational age, and physical and systemic examination findings, will be meticulously recorded throughout the data collection process. Additionally, diagnostic investigations such as complete blood count (CBC), kidney function tests (KFT), and ultrasonography (USG) of the abdomen will be performed, and the results will be incorporated into the dataset.\n\nSelection bias\n\n• Random sampling: Whenever possible, use random sampling methods to select participants from the target population to ensure that the sample represents the broader population.\n\n• Inclusion/Exclusion criteria: Clearly define and uniformly apply inclusion and exclusion criteria to avoid selective enrollment that could skew results.\n\nInformation bias\n\n• Standardization of data collection: Use standardized forms and protocols for data collection. Train all data collectors to ensure consistency in how data is gathered, recorded, and interpreted.\n\n• Blinding: While blinding can be challenging in observational studies, try to blind assessors to the study objectives or participant groupings when measuring outcomes to prevent observer bias.\n\n• Validation of instruments: Use validated measurement instruments and procedures. For example, ensure that diagnostic tests and equipment are reliable and validated for the population under study.\n\nConfounding bias\n\n• Proper study design: Design the study to include a comprehensive set of variables that might influence the outcome, such as socioeconomic status, genetic factors, and environmental exposures.\n\n• Statistical control: Use statistical methods such as stratification and multivariable regression analyses to adjust for potential confounders identified during the design phase.\n\nReporting bias\n\n• Encouraging complete reporting: Ensure that participants understand the importance of providing complete and accurate information. Reassure them about confidentiality and the non-judgmental nature of data collection.\n\n• Independent verification: Where possible, verify reported information through medical records or other objective data sources.\n\n\n\n• Population size (N): 100,000\n\n• Hypothesized percentage frequency of the outcome factor in the population (p): 7% ± 5%\n\n• Confidence limits as a percentage of 100 (absolute ± percentage) (d): 5%\n\n• Design effect (for cluster surveys - DEFF): 1\n\n• Confidence level: 95%\n\nUsing these parameters, the formula for calculating the required sample size is as follows:\n\nWhere:\n\n• DEFF (Design Effect) is 1.\n\n• N represents the population size (100,000).\n\n• p represents the hypothesized percentage frequency of the outcome factor in the population (7%).\n\n• d represents the confidence limits (5%).\n\n• Z(1−α/2)2 corresponds to the critical value from the standard normal distribution for a 95% confidence level.\n\nAfter substituting these values into the formula, the calculated sample size is 105.\n\nIn the study on congenital anomalies of the kidney and urinary tract (CAKUT), our data analysis approach is methodically structured to ensure precise interpretation across both quantitative and qualitative data sets.\n\nQuantitative analysis: Initially, we will employ descriptive statistics to review data distributions, central tendencies, and variabilities of all quantitative variables using software like R version 4.3.1. For inferential analysis, binary logistic regression will be implemented to examine the odds of developing CAKUT based on predictors such as genetic markers and environmental exposures. This method is apt for our binary outcomes (presence or absence of CAKUT) and will involve careful variable selection and multicollinearity checks using Variance Inflation Factor (VIF). In scenarios involving longitudinal data, the Cox Proportional Hazards Model will allow us to evaluate the time to CAKUT onset, adjusting for time-dependencies and censoring in the data. Confounders will be managed through multivariable adjustments to ensure the integrity of our regression models. Sensitivity analyses will further validate our findings by testing model assumptions and the impact of data anomalies.\n\nQualitative analysis: Thematic analysis will be utilized to dissect the qualitative data from interviews. This will involve the transcription of interviews, followed by the generation of initial codes which will be meticulously grouped into themes. Tools such as NVivo or ATLAS.ti will aid in this rigorous process of coding and thematic development. The resultant themes will be critically evaluated and refined to ensure they genuinely reflect the interview data and address the research questions.\n\nIntegrating findings: Both datasets will be analyzed independently and subsequently integrated using a convergent parallel design. This dual analysis allows for a nuanced understanding of how the qualitative experiences align with or differ from the quantitative data, providing a comprehensive view of the factors influencing CAKUT.\n\nThe Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (DU) approved the study protocol on 27/06/2022. Before commencing the study, we will obtain written informed consent from all participants, providing them with a comprehensive explanation of the study’s objectives. Reference Number: DMIHER (DU)/IEC/2022/1072.\n\nThis study protocol will be published in an indexed journal.\n\nThe study has not yet begun.\n\nThe expected outcome includes improved diagnostic insights, better management, and tailored treatment for these children. We anticipate identifying patterns in the severity of renal impairment and associated anomalies, ultimately leading to enhanced patient care and a potentially reduced burden of CAKUT in the region. In summary, this research can potentially improve the quality of life for affected children and inform public health initiatives.\n\n\nDiscussion\n\nCongenital anomalies of the kidneys and urinary tract (CAKUT) represent a diagnostic term encompassing a diverse array of anomalies. These anomalies encompass alterations in kidney size and positioning, dysplastic modifications within the kidney parenchyma, and irregular structures of the collecting system, ureters, bladder, and urethra.7\n\nThe etiology of CAKUT remains partially elusive. It is known that exposure to teratogens, folate, and retinoic acid contributes to a portion of the reported cases.8 A substantial genetic component underlies the etiology of CAKUT, with genetic disorders accounting for approximately 10% to 25% of the reported cases.9 The association between genetic disorders and the phenotypic manifestations of CAKUT is notably intricate. Individuals sharing identical genomic abnormalities can display a range of CAKUT variations, and conversely, similar phenotypic anomalies can result from disparate genetic disorders. This complexity underscores the multifactorial nature of CAKUT etiology.10 Genetic disorders linked to CAKUT often exhibit concurrent extrarenal manifestations, including developmental delays, congenital heart disease (CHD), immunodeficiencies, and endocrine disruptions. This points to the systemic and multi-organ impact of these genetic conditions.10 Population-based studies have reported a prevalence range for CAKUT, with estimates spanning from 4 to more than 100 cases per 10,000 individuals. This wide variation underscores the variability in CAKUT incidence across different populations and geographic regions.5\n\nInfants born prematurely face a significant burden of morbidity and early-life mortality. While certain risk factors, such as the degree of prematurity, birth weight, sex, and antenatal steroid use, have been identified, the outcomes for these infants can vary widely. Notably, recent discoveries have revealed that genetic disorders can independently contribute to perinatal disease, adding a new dimension to our understanding of these complex health challenges.5\n\n\nEthics and consent\n\nThe Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (DU) approved the study protocol on 27/06/2022. Before commencing the study, we will obtain written informed consent from all participants, providing them with a comprehensive explanation of the study’s objectives. Reference Number: DMIHER (DU)/IEC/2022/1072.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nZenodo: Interview Guide: Understanding Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) in Children. https://zenodo.org/doi/10.5281/zenodo.10983150. 11\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nHuang Z, Shen Q, Wu B, et al.: Genetic Spectrum of Congenital Anomalies of the Kidney and Urinary Tract in Chinese Newborn Genome Project. Kidney Int. Rep. 2023 Aug 14 [cited 2023 Oct 15]; 8: 2376–2384. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nSanna-Cherchi S, Westland R, Ghiggeri GM, et al.: Genetic basis of human congenital anomalies of the kidney and urinary tract. J. Clin. Invest. 128(1): 4–15. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVivante A, Kohl S, Hwang DY, et al.: Single-Gene Causes of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) in Humans. Pediatr. Nephrol. 2014 Apr; 29(4): 695–704. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChevalier RL: CAKUT: A Pediatric and Evolutionary Perspective on the Leading Cause of CKD in Childhood. Pediatr. Rep. 2023 Feb 10; 15(1): 143–153. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHays T, Thompson MV, Bateman DA, et al.: The Prevalence and Clinical Significance of Congenital Anomalies of the Kidney and Urinary Tract in Preterm Infants. JAMA Netw. Open. 2022 Sep 14; 5(9): e2231626. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeb Roy A, Das D, Mondal H: The Tribal Health System in India: Challenges in Healthcare Delivery in Comparison to the Global Healthcare Systems. Cureus. 2023 Jun 2; 15(6): e39867. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMurugapoopathy V, Gupta IR: A Primer on Congenital Anomalies of the Kidneys and Urinary Tracts (CAKUT). Clin. J. Am. Soc. Nephrol. 2020 May 7; 15(5): 723–731. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNicolaou N, Renkema KY, Bongers EMHF, et al.: Genetic, environmental, and epigenetic factors involved in CAKUT. Nat. Rev. Nephrol. 2015 Dec; 11(12): 720–731. PubMed Abstract | Publisher Full Text\n\nSanna-Cherchi S, Kiryluk K, Burgess KE, et al.: Copy-number disorders are a common cause of congenital kidney malformations. Am. J. Hum. Genet. 2012 Dec 7; 91(6): 987–997. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHays T, Groopman EE, Gharavi AG: Genetic testing for kidney disease of unknown etiology. Kidney Int. 2020 Sep; 98(3): 590–600. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKommareddy A: Interview Guide: Understanding Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) in Children. [Dataset]. Zenodo. 2024. Publisher Full Text"
}
|
[
{
"id": "288968",
"date": "12 Jun 2024",
"name": "Daniel Landau",
"expertise": [
"Reviewer Expertise Pediatric Nephrology. Genetic kidney diseases",
"childhood CKD epidemiology and pathophysiology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors suggest here to explore the clinical profile (including the extent of renal impairment and the presence of associate anomalies) of children with CAKUT in central India, based on admissions to a single tertiary care rural center in central India. This study design by itself may suffer from several potential problems that may impair the future ability to make any generalizations beyond the data collected from that single medical center. Specific critiques: 1) Introduction: the authors should quote the Global Burden of Disease articles related to pediatric CKD and CAKUT (Dr A. Bagga is a co-author in some of them) (He et al.,2024) (Ref-1), because they elaborated on these questions, specifically for India as an example of a developing country. 2) Methods: what is the exact population coverage of the pediatric department of AVBRH ? Is it the only tertiary care center for the region? How would data collected from this single pediatrics dept. be used to generalize to the area of Central India? 3) Methods: more data is needed on the AVBRH pediatrics department: What is the activity of this pediatrics department? How many newborns per year? How many pediatric admission/yr? Is there a pediatric nephrology and/or pediatric urology in the hospital? 4) How will CAKUT be exactly defined? If by ICD-9 or -10 codes, they should be specified. Will unilateral CAKUT cases (most of them mild, such as congenital mild unilateral Hydronephrosis be included? 5) For the sample size calculation, the authors assume a CAKUT prevalence of 7%. This is too high in my opinion. The numbers I know for any kidney or urinary tract abnormality are up to 2% of pregnancies (most of them with mild hydronephrosis). This is also the number found in newborns in the research article quoted in REF#5. This is crucial for the sample size calculation. 6) If population size is 100,000 (relatively small for a tertiary care center) and CAKUT prevalence will end up being no more than 1%, and only 0.1% will have CKD, then how many years should the authors devote to prospectively collect the needed sample size?\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "288960",
"date": "09 Sep 2024",
"name": "Douglas Matsell",
"expertise": [
"Reviewer Expertise CAKUT",
"kidney development",
"regression modelling",
"pediatrics"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe report submitted by Dr. Kommareddy entitled \"Prospective observational study on clinical profile of congenital anomalies of the kidney and urinary tract (CAKUT)children in central India: A study protocol\" is an outline of a proposed clinical study.\nI offer the following comments\n\n1. While the proposal sets out to define the incidence, prevalence and clinical profile of children with CAKUT in Central India in a prospective fashion, a major drawback is that the results will be limited given the proposed inclusion criteria. The investigators set out to study CAKUT only in children admitted to hospital. Most children with CAKUT do not require admission to hospital and those that do are often those with severe bilateral kidney dysplasia and/or boys with posterior urethral valves at diagnosis or later on life when they progress to end stage kidney disease. In its present form the study will miss/exclude all the other forms of CAKUT seen in outpatient pediatric and general nephrology clinics. To achieve the study objectives and aims they will need to incorporate the data from their outpatient experience and perhaps from their local antenatal datasets.\n2. The investigators also need to be clear about their study aims and objectives. The previous comment notwithstanding, studying the clinical profile of children with CAKUT, determining their kidney impairment, and identifying associated anomalies is feasible. However the protocol includes the possibility of regression modelling, identifying risk factors for the development of CAKUT. These analyses will likely not be feasible given the study population size and the low prevalence of the outcome in their included population over the course of 3 years. It is not clear from where the \"frequency of the outcome factor of 7%\" is derived.\n4. Regarding outcomes, the study protocol should provide detail on how kidney outcomes will be defined and measured and how and when the associated anomalies will be defined and measured.\n4. The study protocol also needs to clarify exactly which conditions they are considering to be CAKUT and how these are diagnosed and defined. For example do they intend to include children with isolated hydronephrosis, or with vesicoureteral reflux?\n5. Structured interviews are proposed to enable detailed data collection. It seems however that most of the data should already be included in the standardized hospital admission record. This should be clarified.\n6. The section defining the various forms of bias appears generic. It should include the specifics of and reference to the details of the proposed study.\n7. Biological markers or risk factors such as \"genetic markers\" and \"specific biomarkers\" should be defined clearly.\n8. In effect modifiers, by \"gender\" do the investigators mean \"sex\"?\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? No\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-445
|
https://f1000research.com/articles/13-444/v1
|
03 May 24
|
{
"type": "Study Protocol",
"title": "Assess The Workload Management Model and Enhanced Quality Control in The Central Sterile Supply Department: A Study Protocol.",
"authors": [
"Prachi Pralhad Supare",
"Deepika Kanyal",
"Deepika Kanyal"
],
"abstract": "Introduction The Central Sterile Supply Department (CSSD) plays a crucial role in ensuring the safety and efficacy of medical instruments and equipment used in healthcare settings. Effective workload management and quality control are essential for maintaining high standards of patient care and minimizing the risk of healthcare-associated infections. This study protocol aims to assess the implementation and impact of a new workload management model and enhanced quality control measures in a CSSD setting.\n\nMethods The study will employ a mixed-methods approach, including quantitative analysis of workload data, qualitative interviews with CSSD staff, and observational assessments of workflow and quality control procedures. The workload management model under investigation involves the allocation of resources based on demand patterns and the implementation of scheduling algorithms to optimize staff efficiency. Enhanced quality control measures include the implementation of advanced sterilization technologies, rigorous inspection protocols, and continuous staff training initiatives.\n\nResults The study expects to provide insights into the effectiveness of the workload management model in optimizing resource allocation and improving staff productivity. Additionally, it aims to evaluate the impact of enhanced quality control measures on the reliability and safety of instrument sterilization processes. Findings from this study will inform recommendations for further improvements in CSSD operations and contribute to the advancement of best practices in sterile supply management.\n\nConclusion The successful implementation of an effective workload management model and enhanced quality control measures in the CSSD is crucial for maintaining patient safety and ensuring the efficient functioning of healthcare facilities. By systematically evaluating the implementation and impact of these interventions, this study protocol seeks to contribute to the ongoing improvement of CSSD operations and the enhancement of healthcare quality.",
"keywords": [
"Central Sterile Supply Department",
"workload management",
"quality control",
"healthcare-associated infections",
"sterilization",
"mixed-methods study."
],
"content": "Introduction\n\nThe central sterile supply department (CSSD) is maintaining a sterile and safe environment for patient care. CSSD ensuring that all the medical equipment is properly cleaned, sterilized, and ready for use in medical procedure and help to control the infection. Inadequate management of CSSD to show the hospital acquired infection and economic harm. Numerous operating devices are complicated to clean because of different type structure in devices. Mismanagement and technology may affect the improper cleaning and reduce the hospital acquired infections. It adopts a continual improvement process to accomplish the target. By the way of cycle are plan do, check, action (PDCA).1\n\nThe traditional concept of Central Sterile Supply Department (CSSD) often involves a decentralized approach to managing the disinfection and cleaning of medical devices. This decentralized model may not provide comprehensive and systematic coverage, leading to potential gaps or oversights in the process, which can compromise patient safety. Moreover, decentralized management can be prone to inefficiencies and inconsistencies across different departments or units within a healthcare facility. In recent years, there has been a shift towards adopting a centralized management model for medical devices within CSSD. This shift represents an advancement in the approach to device management, aiming to address the limitations of the traditional decentralized method. Centralized management allows for greater standardization, control, and efficiency in the sterilization and cleaning processes.2\n\nEnsuring the quality control of the sterilization process within the Central Sterile Supply Department (CSSD) is indeed crucial for maintaining the reliability of sterile supplies and, ultimately, ensuring patient safety. As medical technology advances and devices become more complex and specialized, the challenges faced by CSSDs in handling and sterilizing these devices increase significantly. Mishandling or inadequate sterilization of advanced medical devices can lead to compromised patient care and safety. One of the key challenges in CSSD management is adapting to the diverse needs of sub-specialty clinics within the healthcare facility. As the practice of medicine becomes increasingly specialized, each specialty clinic may have unique requirements and preferences regarding medical device sterilization and handling. A one-size-fits-all approach may not be sufficient to meet the specific needs and standards of each specialty. Establishing a management model for the CSSD that considers the needs of sub-specialty clinics can help address these challenges more effectively. Supply Department (CSSD) is indeed crucial for maintaining the reliability of supplies and, ultimately, ensuring patient safety. As medical technology advances and devices become more complex and specialized, the challenges faced by CSSDs in handling and sterilizing these devices increase significantly. Mishandling or inadequate sterilization of advanced medical devices can lead to compromised patient care and safety.3\n\nThe quality of work life for nursing staff in the Central Sterile Processing Department (CSPD) is influenced by various factors, and managing human resources and materials effectively is paramount to optimizing results and meeting institutional demands. Here are some key challenges faced by nursing staff in CSPD: Human Resource Management: Ensuring adequate staffing levels, managing schedules, and addressing staffing shortages or turnover are common challenges. Material Management: Proper inventory management, procurement of supplies, and equipment maintenance are critical for ensuring the smooth functioning of CSPD. Workload and Time Management: Balancing workload demands with available resources is essential for preventing burnout and maintaining staff morale. Compliance and Quality Assurance, Compliance and Quality Assurance, Professional Development and Recognition, Psychological and Physical Well-being, addressing these challenges requires a holistic approach to human resource management, material logistics, and organizational culture within CSPD. By prioritizing staff engagement, professional development, and well-being, healthcare institutions can create a conducive work environment that promotes employee satisfaction, productivity, and ultimately, the delivery of high-quality patient care.4\n\nRecordkeeping is indeed a critical aspect of operations within a Central Sterile Supply Department (CSSD). The meticulous documentation of sterilization processes and related activities serves several essential purposes, including: patient safety, Regulatory compliance and Audits, legal documentation, traceability and accountability, quality improvement resources managements. Effectiveness, safety, and regulatory compliance of sterilization processes within CSSDs. By maintaining accurate and comprehensive documentation, CSSDs can uphold high standards of patient care, minimize risks, and demonstrate accountability in their operations. Overall, robust recordkeeping practices are indispensable for ensuring the effectiveness, safety, and regulatory compliance of sterilization processes within CSSDs. By maintaining accurate and comprehensive documentation, CSSDs can uphold high standards of patient care, minimize risks, and demonstrate accountability in their operations.5\n\nThe Central Sterile Supply Department (CSSD) plays a crucial role in ensuring patient safety and the success of surgical procedures by providing properly processed and sterilized instruments and equipment. Despite its importance, CSSD has historically been undervalued and stigmatized within the hospital setting. This lack of recognition can be attributed to various factors, including historical precedents, organizational structures, and perceptions of its role within the healthcare system. Initially, the tasks of instrument preparation and sterilization were often relegated to personnel working in the operating room, with little autonomy or recognition as a distinct department. As a result, CSSD was not viewed as a vital component of patient care, and its significance was often overlooked. However, as healthcare standards evolved and the importance of infection control became increasingly recognized, the role of CSSD in ensuring patient safety became more apparent. Despite this recognition, CSSD still faces challenges in gaining full recognition and appreciation for its essential role within the hospital. Stigmatization may persist due to misconceptions about the nature of CSSD work or a lack of understanding of its critical contributions to patient care. By promoting a culture of appreciation and respect for CSSD and its contributions to patient safety, hospitals can enhance the quality of surgical care and uphold their commitment to patient-centred excellence.6\n\nWith the increasing use of sophisticated medical equipment in healthcare settings, ensuring comprehensive cleaning and disinfection of instruments has become increasingly challenging. Recent outbreaks or incidents associated with inadequate reprocessing of endoscopes have highlighted the urgent need to maintain stringent standards in sterilization or reprocessing departments.7\n\nAim: Assess The Workload Management Model and Enhanced Quality Control in The Central Sterile Supply Department.\n\n\n\n1). To observe the workload management structure in the central sterile supply department\n\n2). To study the enhanced quality control in the central sterile supply department\n\nAt Acharya Vinoba Bhave Rural Hospital, the central sterile supply department shall carry out the study and the department will be used to directly gather the data. This study aimed to understand the challenges faced by end users of processed CSSD content as well as their understanding of CSSD workflow.\n\n\nMethods\n\nControl approach\n\nThe CSSD had three working zones for control treatment (routine management): unsterile, clean, and sterile. Each zone was assigned a team leader who assisted the CSSD in completing all of the zone’s work. The CSSD’s working professionals were assigned to different work zones at random.\n\nObservation approach\n\nobservation approach (i.e., workload management structure) To enhance quality control, the staff in the Central Sterile Supply Department (CSSD) were categorized into various groups according to their professional title, years of experience in the CSSD, skill level, highest level of education attained, and individual areas of interest.\n\nStudy design: this study is an observational study comparing management structure in our hospital daily work (quality control) will be applied in our hospitals and this will be set as a control approach.\n\nThe observational management structure will be applied based on the workload management structure that will be enhanced.\n\nStudy setting: The study will be conducted in a tertiary care hospital, sawangi meghe, Wardha.\n\nParticipants: Healthcare personnel will be randomly selected from the following department: Gynaecology, orthopaedics, surgery, and paediatric.\n\nData sources/measurement: google scholar, Scopus, PubMed.\n\nBias: The overall workload damage in medical instrument during the observation and control periods. After implementing the workload management model, the CSSD staff’s theoretical and practical knowledge improved.\n\nStudy size: In this study, we shall use random sampling of more than 88 participants.\n\n\n\nGroup 1=44, Group2=44\n\nSample size:88\n\nZ=1.96б\n\nPrimary data:14 staff in the central sterile supply department, by observation and question base survey.\n\nSecondary data: a survey on a question base for other departments that include (Gynaecology, orthopaedics, surgery, and paediatric).\n\nInclusion criteria: Technicians and In-charge, ANM, GNM Inclusion criteria: This study will encompass ANMs (Auxiliary Nurse Midwives), GNMs (General Nursing Midwives), Technicians, and In-charges who are currently on duty at their Central Sterile Supply Department. Additionally, the survey will be conducted among randomly selected personnel from other departments, including Gynaecology, Orthopaedics, Surgery, and Paediatrics, based on a set of predefined questions.\n\nExclusion criteria: Doctor and attendant from the department will be excluded.\n\nDissemination: This protocol is intended for publication in an indexed journal.\n\nStudy status: Not yet started\n\n\nDiscussion\n\nObservational study to observe the workload and quality indicators in the central sterile supply department. The study compared the concentration of bioaerosols in two different Central Sterile Supply Departments (CSSDs) – one without negative pressure and the other with negative pressure. In the Central Sterile Supply Department (CSSD), bioaerosol concentrations were measured at 273.15 and 206.71 CFU/m3 in areas without negative pressure, while those with negative pressure exhibited lower concentrations at 116.96 CFU/m3 and 131.10 CFU/m3. The number of isolated colonies was significantly lower in the CSSD with negative pressure (P = .01541). These results indicate that the implementation of a negative pressure system in the CSSD cleaning area led to a notable reduction in bioaerosol levels. However, it is important to note that the concentrations of bioaerosols in both CSSDs remained below the established guidelines for indoor air quality in many countries. Therefore, it cannot be definitively concluded that CSSDs lacking a negative pressure system in their cleaning area pose an occupational risk.8\n\nThe satisfaction level of respondents with CSSD services saw a substantial rise from 54% in 2012 to 89% in 2019, a statistically significant improvement (95% CI: 0.56 to 0.25) with a p-value of 0.001. This indicates a notable enhancement in service quality over the years. this endeavor contributed to the formation of a cohesive team and fostered an environment of transparency within the CSSD. Improvement strategies were informed by data analysis, encouraging other departments such as Radiology and Laundry to adopt similar approaches to understand and meet user expectations. The study underscores the efficacy of internal user satisfaction surveys as a valuable mechanism for continual quality enhancement. It unequivocally demonstrates that consistent monitoring leads to an improvement in service quality.9,10\n\nA total of 101 adverse incidents were documented, with the primary reason identified as insufficient cleaning quality (34, 33.66%), followed by mistakes in instrument assembly (25, 24.75%), and issues related to marking (7, 6.93%). Variables such as the role of the accountable individual, educational attainment, years of experience, structural aspects of the device, quantity of instruments in the set, and set dimensions were discovered to potentially impact the occurrence of adverse incidents (P < 0.05). Additionally, integrating a standardized grading system in accordance with the Central Sterile Supply Department's protocols can ensure effective handling of adverse incidents and uphold consistency in service quality.10\n\nWorkload management plays a vital role in maintaining optimal performance levels and preventing burnout among CSSD staff. By implementing a structured workload management model, the CSSD can better allocate resources, streamline processes, and prioritize tasks based on their importance and urgency. This can lead to improved workflow efficiency, reduced turnaround times, and enhanced overall productivity.11\n\nFurthermore, effective quality control measures are essential for ensuring the safety and sterility of medical equipment and supplies processed within the CSSD. By integrating enhanced quality control protocols, such as regular audits, standardized operating procedures, and staff training programs, the CSSD can minimize the risk of contamination, infection, and equipment failure. This ultimately contributes to the delivery of high-quality patient care and promotes patient safety.12\n\nThe ethical approvalwas obtained from the Institutional Ethics Committee (IEC), Datta Meghe Institute of Higher Education and Research (DHIIMER) Wardha.\n\nApproval number: DMIHER (DU)/IEC/2023/1176, dated 01/07/2023\n\nConsent to participate written informed consent will be taken from study participants for participation in study and publication for data.",
"appendix": "Data availability\n\nNo Data collection is associated with this article.\n\nReporting guidelines\n\nFigshare, checklist for “Assess the workload management model and enhanced quality control in the Central Sterile Supply Department: A Study Protocol, DOI: 10.6084/m9.figshare.25650975\n\n\nAcknowledgments\n\nI shall thank you for the technical support received from the research house at DMIMS University and also thank my guide for giving me support for the protocol.\n\n\nReferences\n\nJing W, Mu Y, Cai Y: Central sterile supply department (CSSD) management quality sensitive index constructed by management mode under the guidance of key point control theory and its effect on CSSD management quality: a retrospective study. Ann. Palliat. Med. 2022 Jun; 11(6): 2050–2060. PubMed Abstract | Publisher Full Text\n\nYang L, Xun Q, Xu J, et al.: Application of the defect management improvement mode under Joint Commission International standard to improve the instrument cleaning and disinfection effect and management quality in the central sterile supply department: a randomized trial. Ann. Transl. Med. 2022 Feb; 10(3): 137. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang L, Cai X, Cheng P: Application of a sub-specialties management model improves quality control in a central sterile supply department. BMC Health Serv. Res. 2018 May 30; 18(1): 385. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRego GMV, Rolim ILTP, D'Eça Júnior A, et al.: Quality of life at work in a central sterile processing department. Rev. Bras. Enferm. 2020 Mar 9; 73(2): e20180792. English, Portuguese. PubMed Abstract | Publisher Full Text\n\nBasu D, Bag SC, Das A, et al.: The importance of paper records and their preservation period in a Central Sterile Supply Department: An experience from a oncology center in eastern India. J. Infect. Public Health. 2017 Sep-Oct; 10(5): 685–687. Epub 2017 Feb 7. PubMed Abstract | Publisher Full Text\n\nXavier RS, Vigário PDS, Faria ACD, et al.: The Perception of Nursing Professionals Working in a Central Sterile Supplies Department regarding Health Conditions, Workload, Ergonomic Risks, and Functional Readaptation. Adv. Prev. Med. 2022 Apr 13; 2022: 1023728–1023728. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLing ML, Ching P, Widitaputra A, et al.: APSIC guidelines for disinfection and sterilization of instruments in health care facilities. Antimicrob. Resist. Infect. Control. 2018 Feb 20; 7: 25. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSantos RKD, Pozzer CE, Rabaioli CM, et al.: Central sterile services department: screening of automated cleaning in liposuction cannulae. Rev. Gaucha Enferm. 2022 Nov 4; 43: e20210057. English, Portuguese. PubMed Abstract | Publisher Full Text\n\nAlmeida AGCDS, Bruna CQM, Moriya GAA, et al.: Impact of negative pressure system on microbiological air quality in a Central Sterile Supply Department. J. Occup. Health. 2021 Jan; 63(1): e12234. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJoseph L, Rabindranath B, Ponnie F, et al.: Achieving Continuous Improvement in CSSD Management through Performance Measurements using User Satisfaction Surveys and Interventions. Glob. J. Qual. Saf. Healthc. 2021 Jul 12; 4(4): 123–130. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTrbovich P, Prakash V, Stewart J, et al.: Interruptions during the medication administration process in an intensive care unit: A direct observational study. J. Patient Saf. 2015; 11(3): 128–133. Publisher Full Text\n\nDonà D, Di Chiara C, Sharland M, et al.: Implementation of evidence-based infection prevention and control policies in European hospitals: An ESPIAP study. Antimicrob. Resist. Infect. Control. 2020; 9(1): 1–9. Publisher Full Text"
}
|
[
{
"id": "276048",
"date": "11 Jun 2024",
"name": "Withaya Chanchai",
"expertise": [
"Reviewer Expertise Specialist in Healthcare Innovation",
"Ergonomics",
"Occupational Health",
"Medical device innovation",
"Sales skills",
"infectious disease",
"Central sterilization for medical devices",
"and Human Health Behavior."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear author, I found your article to have several inconsistencies and incoherence divided into Abstract:\nClarify the Objective: State the main objective of the study clearly and succinctly. Highlight the Importance: Emphasize the significance of the study in the broader context of healthcare. Detail the Methods: Provide more specific details about the mixed-methods approach to underline the rigor of the study. Preview Key Results: If possible, hint at the anticipated results or potential findings to engage readers. Emphasize the Impact: Highlight how the study’s findings could influence future CSSD practices and healthcare outcomes.\nIntroduction:\nEstablish the Importance Clearly: Start by making a strong statement about the CSSD's critical role in patient safety and healthcare efficacy. Define the Problem and Gap: Clearly outline the problems associated with inadequate CSSD management, including the risk of hospital-acquired infections and economic consequences. Provide a Clear Transition: Smoothly transition from discussing the current issues to introducing the new model being studied. Use Concise and Focused Language: Avoid repetitive statements and ensure each paragraph adds distinct value to the introduction. Highlight Advancements and Innovations: Emphasize the advancements and potential improvements that the new workload management and quality control measures bring. Summarize the Study’s Purpose: Clearly state the purpose of the study at the end of the introduction.\nMethods:\nCombine Aim and Objective: Integrate the aim and objectives to create a more coherent and streamlined introduction. Clarify Methods: Summarize the methods clearly and concisely, focusing on the key aspects without unnecessary detail. Highlight Anticipated Results: Indicate the expected outcomes or potential findings to give readers a sense of the study's direction. Emphasize Significance: Highlight the importance of the study and its potential impact on CSSD practices and patient care. Integrate Study Details: Combine primary and secondary data sources smoothly to provide a coherent overview. Clarify Study Design: Clearly state the study design and methodology. Highlight Key Findings: Emphasize any significant findings or expected outcomes. Focus on Impact: Highlight the study's significance and potential impact on CSSD practices and healthcare outcomes.\n\nUse Concise Language: Avoid redundant information and keep the information concise.\nResult & Discussion\nStreamline the Information: Summarize key findings and their implications without excessive detail. Highlight the Importance: Emphasize the significance of addressing adverse incidents, workload management, and quality control in CSSD. Clarify Methodology and Findings: Clearly state the methods used and the main findings, ensuring they are easy to understand. Emphasize Impact and Recommendations: Highlight how the findings can influence CSSD practices and improve patient care. Use Clear and Concise Language: Avoid redundancy and ensure each sentence adds value.\nOthers:\nYou should include more references both in the introduction and in comparisons to other works. If workload is mentioned, the purpose should be more clearly stated. Workload management strategies include task list prioritization, effective delegation, setting realistic deadlines, conducting regular team meetings, and adopting agile methodologies. These strategies collectively contribute to optimizing team efficiency and enhancing project management. 2. Should review more about the criteria for inclusion and exclusion of other research studies 3. Discussion of the results was not consistent with the study objectives.\"\n\nIs the rationale for, and objectives of, the study clearly described? No\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? No",
"responses": []
},
{
"id": "280612",
"date": "14 Jun 2024",
"name": "Dr. Munaza Bibi",
"expertise": [
"Reviewer Expertise Human Health behavior",
"AI execution in healthcare",
"HRM",
"Individual and Patient wellbeing."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Author, I appreciate your efforts but a few changes are required for improvement. Abstract Mention the study's purpose by emphasizing its importance in the healthcare context. Moreover, the method needs to be mentioned clearly along with the results for better understanding. Present implications about how CSSD practices affect healthcare prospects. Introduction Focus what was the main gap addressed in your study by specifying the CSSD's critical role in patient safety and healthcare efficacy leading toward defining the problem. Avoid reluctance in the elaboration of the problem. Furthermore, mention the purpose after defining the problem that has been addressed in your study. Method Mention the method being employed in your study with justifications to provide a coherent overview of primary and secondary data. Result & Discussion Focus on presenting key findings and their link with the fulfillment of the study objectives. Compare your results with prior literature.\n\nElaborate how the findings of your study can be helpful for managers or practitioners. Use Clear and Concise Language\n\nIs the rationale for, and objectives of, the study clearly described? No\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-444
|
https://f1000research.com/articles/13-442/v1
|
03 May 24
|
{
"type": "Study Protocol",
"title": "Cognitive dysfunction and its relationship with psychopathology and quality of life in patients with schizophrenia: a protocol for a cross sectional study",
"authors": [
"Imyarila Longkumer",
"Ragini Patil",
"Ragini Patil"
],
"abstract": "Background One central characteristic of schizophrenia is cognitive dysfunction, which typically has modest to severe effects on a variety of cognitive areas. Evidence suggests that cognitive impairment may occur far sooner than the clinical symptoms. The connection between cognitive deficiencies and functional outcome indicators has attracted increasing attention in recent years. Cognitive deficits are widely known to affect overall functioning, In India, few studies have been conducted to determine the profile of cognitive abnormalities in individuals in the chronic phase of schizophrenia as well as those in remission. Research from developing nations is crucial because schizophrenia prevalence in these nations is thought to be lower than that in industrialized nations. The aim of this study will be to assess the prevalence of cognitive dysfunction in individuals with schizophrenia and examine the relationship between cognitive dysfunction with psychopathology and quality of life in individuals with schizophrenia.\n\nProtocol This will be a cross sectional hospital-based study. After ethical clearance, all patients in the Psychiatry Department meeting the criteria of Schizophrenia, according to the ICD-10, will be part of the study. The expected number of participants is 228. All participants within the age group of 18 to 65 years who are clinically diagnosed to have schizophrenia using ICD-10 and who are able to give written informed consent will be included in the study. The patient’s sociodemographic data will be collected in Outpatient or inpatient basis and then the following questionnaires will be applied to them: i) Socio-demographic Proforma; ii) The Positive and Negative Syndrome Scale (PANSS); iii) The World Health Organization Quality of Life-BREF scale (WHOQOL-BREF); and iv) Addenbrooke’s cognitive examination III (ACE). Once the aforementioned questionnaires are completed, the prevalence of cognitive dysfunction in patients with schizophrenia will be assessed, and its relationship with psychopathology and quality of life will be studied.",
"keywords": [
"cognition",
"cognitive dysfunction",
"schizophrenia",
"pathophysiology",
"quality of life"
],
"content": "Introduction\n\nCognitive dysfunction is considered a “central characteristic” of schizophrenia.1 Schizophrenia typically has a modest-to-severe effects on various cognitive areas. Evidence suggests that cognitive impairment may occur far sooner than the clinical symptoms.2,3 Patients have cognitive impairments throughout their lives, with evidence of cognitive abnormalities observable before the development of any symptoms during the prodromal phase, at the beginning of the first psychotic episode, and throughout the course of schizophrenia.4 A patient with cognitive impairment typically struggles with daily tasks, including paying attention, processing information quickly, retaining it and recalling it, responding quickly to information, using critical thought, and solving issues. Such limitations frequently impede the patient’s capacity to attain and maintain success in the workplace; they interfere with community participation and, more crucially, prevent participation in rehabilitation and therapeutic activities.5\n\nProgressive decline over time has been associated with cognitive deficiencies.6,7 Cognitive deficiencies significantly influence how the illness progresses and how it turns out in the end. Although alertness is linked to the capacity to deal with social issues, cognitive abilities such as verbal memory are associated with social functioning.8 These cognitive deficiencies affect the quality of life, including employment performance, community involvement, social problem-solving, and the development of social skills.9–11\n\nThe connection between cognitive deficiencies and functional outcome indicators has attracted increasing attention in recent years. This has motivated others to look for therapeutic options to help cognitive impairments, particularly in the early stages of the illness, to minimize or limit functional disability, which is problematic in the treatment of schizophrenia.12–15\n\nCognitive deficits are widely known to affect overall functioning,16,17 yet so far not many studies have been conducted analyzing individuals in the chronic phase of schizophrenia18–22 as well as those in remission23–25 to determine the profile of cognitive abnormalities in patients from India. Research from developing nations is crucial because schizophrenia prevalence in these nations is thought to be lower than that in industrialized nations.26 Compared to emerging nations such as India, the results have proven to be worse in wealthy countries.27 It is claimed that patients’ cognitive profiles, which are key indicators of how their sickness would turn out, are comparable across economies.28 However, the number of studies on this topic is still limited.\n\nThe evaluation of cognitive functioning is crucial for understanding the neurobiological correlates of this complex illness, as well as for creating cutting-edge therapies and rehabilitation plans. While researching this issue, we would be able to evaluate cognitive impairment in people with schizophrenia and examine how it relates to psychopathology and quality of life.\n\nTo study cognitive dysfunction and its relationship with quality of life in patients with schizophrenia.\n\n\n\n1. To assess the prevalence of cognitive dysfunction in patients with schizophrenia.\n\n2. To examine the relationship of cognitive dysfunction with psychopathology and quality of life in patients with schizophrenia.\n\n\nMethods\n\nWe will perform a cross sectional hospital-based study.\n\nPatients diagnosed with schizophrenia being treated in the inpatient and outpatient departments of Psychiatry, Acharya Vinoba Bhave Rural Hospital, Sawangi (M), Wardha-442001 will be taken as the study population. The type of sampling done will be convenience sampling.\n\nThe sample size will be calculated using the following formula:\n\nWhere n is the sample size to be calculated and Z1-α ̸2 is the level of significance at 5% i.e. at 95% confidence level that is 1.96. σ is the estimated standard deviation i.e. 7.88 and d is the estimation error i.e. 1.023.\n\nd = estimation error = 1.023\n\nthe number of participants needed in the study (n) is calculated to be 228.\n\nAfter ethical committee clearance, all patients admitted to the Psychiatry Department of Acharya Vinoba Bhave Rural Hospital, Sawangi (M), Wardha-442001 who meet the criteria of Schizophrenia according to the International Classification of Diseases 10th Revision (ICD-10), will be included in the study. Informed consent of the patients will be obtained. The patient’s sociodemographic data will be collected using the sociodemographic proforma and then the following questionnaires will be administered i) Socio-demographic Proforma; ii) The Positive and Negative Syndrome Scale (PANSS) (copyright has been obtained); iii) The World Health Organization Quality of Life-BREF scale (WHOQOL-BREF) (copyright has been obtained); and iv) Addenbrooke’s cognitive examination III (ACE).\n\nThe Institutional Ethics Committee provided ethical approval for the study on 31/03/2023 (IEC no. – DMIHER (DU)/IEC/2023/873). Patients who are targeted for this study will be asked to provide written informed consent.\n\n\n\n1. Patients who are clinically diagnosed with Schizophrenia using the ICD-10 criteria.\n\n2. Patients in the age group of 18 to 65 years.\n\n3. Patient should be fit to provide written informed consent. Firstly, the patient would be informed about the study and that the patient should be competent to make a decision. The patient should have the capacity to understand the purpose of the study that is being conducted, that it is their decision in participating in the study.\n\n\n\n1. Subjects who are not willing to give written informed consent.\n\n2. Patients who are medically not fit or are not able to cooperate with the study.\n\n3. Patients with a history of delayed developmental milestone or any other major organic brain disease.\n\n4. Patients having a history of head injury.\n\n\n\n1. Socio-demographic data: This proforma is semi-structured and contains information regarding sociodemographic variables such as age, sex, marital status, education, religious background, occupation, and domicile background. The clinical data sheet contains variables such as age of onset, illness duration, precipitating factors, and treatment history, if available. The proforma was created by our team.\n\n2. PANSS: The PANSS includes 30 items, with a seven point rating scale.29 It was devised as an operationalized method that evaluates positive, negative, and other symptoms based on a formal semi-structured clinical interview. Of the 30 items, seven items are under a positive scale assessing features that are super added to a normal mental status, seven items are grouped into a negative scale that assesses features that are absent from a normal mental status, and the remaining 16 items contain a general psychopathology scale that measures the overall severity of schizophrenic disorder by summation of 16 items. It has an internal reliability ranging from 0.73 to 0.83.\n\n3. WHOQOL-BREF SCALE: This questionnaire has 26-items, with a five-point Likert scale that was developed by WHO to assess the quality of life over the past 2 weeks.30 Four domains are assessed here: physical health includes seven items, psychological health includes six items, social relationships includes three items, and environmental health includes eight items. Two items are also included for overall quality of life and general health. Each item on the scale has a rating from 1 to 5, where each domain score is added to obtain a raw score for each domain. A high rating on a scale implies a high quality of life. The WHOQOL-BREF domain scores demonstrate good divergent validity, content validity, internal consistency, and test-retest reliability.\n\n4. ACE III: Five cognitive domains tested in this screening exam: attention, memory, language, fluency, and visuospatial skills.31 It is useful for the detection of cognitive impairment and can differentiate between patients with and without cognitive impairment. It takes 20 minutes to complete. The total score is 100, with higher scores indicating stronger cognitive functioning.\n\nSPSS version 28.0 software will be utilized to analyze descriptive statistics. Continuous variables will be presented as mean ± SD. Categorical variables will be expressed as frequencies and percentages. For the comparison of means, the Student’s t-test or Mann–Whitney U test will be used. If two categorical variables are associated, it will be determined using Pearson’s chi-square test or the chi-square test of association. Spearman/Pearson’s correlation will be used to compare cognitive dysfunction with psychopathology and quality of life in patients with schizophrenia. Statistical significance will be set at p value<0.05.\n\nThrough this study we will be able to assess the prevalence of cognitive disfunction in schizophrenia and learn about its relationship with negative and positive symptoms of schizophrenia and the quality of life of the patients living with schizophrenia who have cognitive dysfunction.\n\n\n\n1. The confidentiality of every participant will be guaranteed, and written consent will be required before participating in this study. They will be notified that they can withdraw their consent at any time, after which they will be excluded from the study.\n\n2. The purpose of the study will be explained to the participants and samples will be selected on a voluntary basis.\n\nA simple random sampling will be followed for the selection of the study participants to prevent selection bias. To avoid measurement bias, an open ended questionnaire will be used.\n\nThis study will be presented in the National Conference Proceedings and published in an indexed journal.\n\nParticipant recruitment has not yet begun.\n\n\nDiscussion\n\nA meta-analysis conducted by Schaefer et al., in 2013 of 100 studies involving 9,048 patients with schizophrenia and 8,814 healthy controls found that there were significant generalized cognitive impairments in patients with schizophrenia, with moderate to severe impairments compared to controls across all neuropsychological measures examined and somewhat larger cognitive differences in the domains of processing speed and episodic memory.32\n\nBy applying the ACE-R SCALE i.e., Addenbrooke Cognitive Examination-Revised Scale, Talreja et al. (2013) evaluated individuals living with schizophrenia.33 It revealed that cognitive failure in the areas of attention, language, memory, focus, and executive function existed in 70% of the patients. Patients who lived in urban environments and had illnesses that lasted longer than two years had increased cognitive impairment. Masculine gender has been linked to impairment in language and memory.\n\nCross-sectional studies have demonstrated a link between negative symptoms and cognitive deficits in patients with schizophrenia. A link was studied between cognitive domains and four symptom dimensions (positive, negative, depressed, and disorganized) in a meta-analysis by Dominguez et al.34 The strongest correlations between negative symptoms and verbal fluency, verbal learning and memory, and IQ were discovered.\n\nA total of 100 individuals suffering from chronic schizophrenia and 100 matched normal controls in a study titled “Cognitive impairment and associated factors in patients with chronic schizophrenia” were compared by Srinivasan et al. (2005)35 who found that patients with schizophrenia performed poorly on all cognitive tests when compared to controls without schizophrenia. Patient cognitive impairments were associated with sex, education level, age, disease duration, and the presence of both positive and negative symptoms.\n\nAddington et al., examined the cognitive functioning of a patient population experiencing their first episode of schizophrenia with that of people who had previously had the illness. A total of 111 patients who experienced their first episode of schizophrenia and 76 outpatients with a history of illness were included in the study. The two categories did not substantially differ from one another with regard to cognitive performance. Although the patients from the first episode scored higher, their performance was subpar.36 They concluded that people who experienced their first episode exhibited cognitive abnormalities similar to those of patients who had been diagnosed with schizophrenia.\n\nIn 2020, a study on “cognitive dysfunction and impairment in persons living with schizophrenia” was conducted by Srisudha et al., with 82 adult individuals who had been diagnosed with schizophrenia.37 Overall, 93.9% had at least one mild cognitive symptom. Being married was linked to greater cognitive performance. Cognitive impairment was not linked to any other sociodemographic variable. Cognitive deficits and disability were substantially correlated, indicating that a greater cognitive deficiency in schizophrenia is associated with a greater risk of disability. They concluded that cognitive remediation treatments supported by scientific data should be part of schizophrenia treatment plans.\n\nIn their hospital-based study on “Disability among patients with schizophrenia” published in 2019, Fakorede et al., found that 78% of 300 patients had some form of impairment, 77% of which were mild to moderate, and 1% of whom had severe disability. They discovered that impairment is particularly common among patients with schizophrenia, and is linked to a more severe form of the condition.38\n\nAccording to Harvey et al., several factors contribute to disability, such as negative symptoms, impairments in daily functioning and social skills, and cognitive and social cognitive impairments.39 These deficits are linked to many aspects of disability, and neither disability nor the factors that predict it have a single universal dimension.\n\nAccording to a study by Tonmoy et al. (2003) cognitive impairment in patients with schizophrenia invariably affects the functional outcomes of the illness (i.e., a person’s capacity for social engagement, employment, and self-care).40\n\n\n\n1. The study design is a cross sectional based study.\n\n2. Adults with other medical co-morbidities will not be included.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nZenodo: STROBE checklist for ‘Cognitive dysfunction and its relationship with psychopathology and quality of life in patients with schizophrenia: a protocol for a cross sectional study’. https://zenodo.org/doi/10.5281/zenodo.8402804. 41\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nGreen MF, Harvey PD: Cognition in schizophrenia: Past, present, and future. Schizophr. Res. Cogn. 2014 Mar; 1(1): e1–e9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCaspi A, Reichenberg A, Weiser M, et al.: Cognitive performance in schizophrenia patients assessed before and following the first psychotic episode. Schizophr. Res. 2003 Dec 15; 65(2-3): 87–94. Publisher Full Text\n\nEastvold AD, Heaton RK, Cadenhead KS: Neurocognitive deficits in the (putative) prodrome and first episode of psychosis. Schizophr. Res. 2007 Jul; 93(1-3): 266–277. PubMed Abstract | Publisher Full Text | Free Full Text\n\nO’Donnell BF: Cognitive impairment in schizophrenia: a life span perspective. Am. J. Alzheimers Dis. Other Dement. 2007 Oct-Nov; 22(5): 398–405. PubMed Abstract | Publisher Full Text\n\nTrivedi JK: Cognitive deficits in psychiatric disorders: Current status. Indian J. Psychiatry. 2006 Jan; 48(1): 10–20. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRund BR, Melle I, Friis S, et al.: The course of neurocognitive functioning in first-episode psychosis and its relation to premorbid adjustment, duration of untreated psychosis, and relapse. Schizophr. Res. 2007 Mar; 91(1-3): 132–140. PubMed Abstract | Publisher Full Text\n\nTownsend LA, Norman RM: Course of cognitive functioning in first episode schizophrenia spectrum disorders. Expert. Rev. Neurother. 2004 Jan; 4(1): 61–68. Publisher Full Text\n\nGreen MF, Kern RS, Braff DL, et al.: Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr. Bull. 2000; 26(1): 119–136. PubMed Abstract | Publisher Full Text\n\nBrekke JS, Levin S, Wolkon GH, et al.: Psychosocial functioning and subjective experience in schizophrenia. Schizophr. Bull. 1993; 19(3): 599–608. Publisher Full Text\n\nGreen MF: What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J. Psychiatry. 1996 Mar; 153(3): 321–330. Publisher Full Text\n\nMilev P, Ho BC, Arndt S, et al.: Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am. J. Psychiatry. 2005 Mar; 162(3): 495–506. PubMed Abstract | Publisher Full Text\n\nEack SM, Hogarty GE, Greenwald DP, et al.: Cognitive enhancement therapy improves emotional intelligence in early course schizophrenia: preliminary effects. Schizophr. Res. 2007 Jan; 89(1-3): 308–311. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHegde S, Rao SL, Raguram A, et al.: Addition of home-based cognitive retraining to treatment as usual in first episode schizophrenia patients: a randomized controlled study. Indian J. Psychiatry. 2012 Jan; 54(1): 15–22. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUeland T, Rund BR: Cognitive remediation for adolescents with early onset psychosis: a 1-year follow-up study. Acta Psychiatr. Scand. 2005 Mar; 111(3): 193–201. PubMed Abstract | Publisher Full Text\n\nWykes T, Reeder C, Landau S, et al.: Cognitive remediation therapy in schizophrenia: randomised controlled trial. Br. J. Psychiatry. 2007 May; 190: 421–427. Publisher Full Text\n\nEvans JD, Heaton RK, Paulsen JS, et al.: The relationship of neuropsychological abilities to specific domains of functional capacity in older schizophrenia patients. Biol. Psychiatry. 2003 Mar 1; 53(5): 422–430. PubMed Abstract | Publisher Full Text\n\nGreen MF, Kern RS, Heaton RK: Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr. Res. 2004 Dec 15; 72(1): 41–51. PubMed Abstract | Publisher Full Text\n\nAnanthanarayanan CV, Janakiramaiah N, Gangadhar BN, et al.: Visual information processing deficits clinical remitted outpatient schizophrenics. Indian J. Psychiatry. 1993 Jan; 35(1): 27–30. PubMed Abstract | Free Full Text\n\nBhatia T, Garg K, Pogue-Geile M, et al.: Executive functions and cognitive deficits in schizophrenia: comparisons between probands, parents and controls in India. J. Postgrad. Med. 2009 Jan-Mar; 55(1): 3–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJohn JP: Fronto-temporal dysfunction in schizophrenia: A selective review. Indian J. Psychiatry. 2009 Jul-Sep; 51(3): 180–190. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSabhesan S, Parthasarathy S: Executive functions in schizophrenia. Indian J. Psychiatry. 2005 Jan-Mar; 47(1): 21–26. Publisher Full Text\n\nSrinivasan L, Thara R, Tirupati SN: Cognitive dysfunction and associated factors in patients with chronic schizophrenia. Indian J. Psychiatry. 2005 Jul; 47(3): 139–143. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKrishnadas R, Moore BP, Nayak A, et al.: Relationship of cognitive function in patients with schizophrenia in remission to disability: a cross-sectional study in an Indian sample. Ann. General Psychiatry. 2007 Jul 30; 6: 19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaravanan B, Jacob KS, Johnson S, et al.: Outcome of first-episode schizophrenia in India: longitudinal study of effect of insight and psychopathology. Br. J. Psychiatry. 2010 Jun; 196(6): 454–459. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTrivedi JK, Goel D, Sharma S, et al.: Cognitive functions in stable schizophrenia & euthymic state of bipolar disorder. Indian J. Med. Res. 2007 Nov; 126(5): 433–439. PubMed Abstract Reference Source\n\nSaha S, Chant D, Welham J, et al.: A systematic review of the prevalence of schizophrenia. PLoS Med. 2005 May; 2(5): e141. Epub 2005 May 31. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHopper K, Wanderling J: Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: results from ISoS, the WHO collaborative followup project. International Study of Schizophrenia. Schizophr. Bull. 2000; 26(4): 835–846. PubMed Abstract | Publisher Full Text\n\nAyres AM, Busatto GF, Menezes PR, et al.: Cognitive deficits in first-episode psychosis: a population-based study in São Paulo, Brazil. Schizophr. Res. 2007 Feb; 90(1-3): 338–343. PubMed Abstract | Publisher Full Text\n\nKay SR, Fiszbein A, Opler LA: The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 1987; 13(2): 261–276. Publisher Full Text\n\nSkevington SM, Lotfy M, O’Connell KA, et al.: The World Health Organization’s WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual. Life Res. 2004 Mar; 13(2): 299–310. PubMed Abstract | Publisher Full Text\n\nNoone P: Addenbrooke’s Cognitive Examination-III. Occup. Med. (Lond.). 2015 Jul; 65(5): 418–420. Publisher Full Text\n\nSchaefer J, Giangrande E, Weinberger DR, et al.: The global cognitive impairment in schizophrenia: consistent over decades and around the world. Schizophr. Res. 2013 Oct; 150(1): 42–50. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTalreja BT, Shah S, Kataria L: Cognitive function in schizophrenia and its association with socio-demographics factors. Ind. Psychiatry J. 2013 Jan; 22(1): 47–53. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDominguez Mde G, Viechtbauer W, Simons CJ, et al.: Are psychotic psychopathology and neurocognition orthogonal? A systematic review of their associations. Psychol. Bull. 2009 Jan; 135(1): 157–171. PubMed Abstract | Publisher Full Text\n\nSrinivasan L, Thara R, Tirupati SN: Cognitive dysfunction and associated factors in patients with chronic schizophrenia. Indian J. Psychiatry. 2005 Jul; 47(3): 139–143. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAddington J, Addington D: Cognitive functioning in first-episode schizophrenia. J. Psychiatry Neurosci. 2002 May; 27(3): 188–192. PubMed Abstract | Free Full Text\n\nSrisudha B, Kattula D, Devika S, et al.: Cognitive dysfunction and disability in people living with schizophrenia. J. Family Med. Prim. Care. 2022 Jun; 11(6): 2356–2362. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFakorede OO, Ogunwale A, Akinhanmi AO: Disability among patients with schizophrenia: A hospital-based study. Int. J. Soc. Psychiatry. 2020 Mar; 66(2): 179–187. PubMed Abstract | Publisher Full Text\n\nHarvey PD, Strassnig MT, Silberstein J: Prediction of disability in schizophrenia: Symptoms, cognition, and self-assessment. J. Exp. Psychopathol. 2019; 10: 204380871986569. Publisher Full Text\n\nSharma T, Antonova L: Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment. Psychiatr. Clin. North Am. 2003 Mar; 26(1): 25–40. Publisher Full Text\n\nLongkumer I: Cognitive dysfunction and its relationship with psychopathology and quality of life in patients with schizophrenia: a cross sectional study. Zenodo. 2023. Publisher Full Text"
}
|
[
{
"id": "279936",
"date": "12 Jun 2024",
"name": "Cristina Delgado Sallent",
"expertise": [
"Reviewer Expertise Neuroscience"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper aims to deepen the understanding of the prevalence of cognitive deficits and their relationship with the psychopathology of schizophrenia in India. The study adopts a cross-sectional design and intends to recruit 228 patients to perform four different assessments covering sociodemographic data, schizophrenia-related symptom severity, quality of life, and cognitive dysfunction. The study’s approach is commendable, particularly for its focus on quantifying cognitive deficits in schizophrenia and examining their prognostic significance in a developing country context like India. This could provide valuable insights given the unique socio-cultural and healthcare environment. However, it is important to acknowledge that similar research has been extensively conducted across various populations globally. Moreover, the paper would benefit from a more detailed description of the selection criteria. For instance, specifying whether patients are chronically treated or detailing the stage of their disease would enhance the study’s clarity and rigor. This information is crucial for interpreting the results and understanding their applicability to different patient subgroups. Additionally, including another specific cognitive deficits test could strengthen the study’s design. A more comprehensive assessment battery might provide deeper insights into the cognitive impairments experienced by individuals with schizophrenia and their relationship with other symptom severity and disease prognosis. Overall, while the research question and general approach are promising, addressing these suggestions could enhance the study’s robustness and potential impact.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-442
|
https://f1000research.com/articles/13-441/v1
|
02 May 24
|
{
"type": "Case Report",
"title": "Case Report: A rare renal manifestation of Acute intermittent porphyria",
"authors": [
"Bhushan C Shetty",
"Arun S",
"Deepak R Madi",
"Sheetal M Raj",
"Arun S",
"Deepak R Madi",
"Sheetal M Raj"
],
"abstract": "Acute porphyria is a group of metabolic disorders characterized by a deficiency in enzymes involved in heme biosynthesis. A 21-year-old female with abdominal pain and an altered sensorium, eventually leading to a diagnosis of acute porphyria. Glucose treatment and other supportive measures were given and her general condition improved. Renal biopsy was done in view of persistent renal dysfunction, which revealed acute tubulointerstitial nephritis with 5-10% interstitial fibrosis and tubular atrophy. This Case highlights a unique manifestation of acute porphyria involving the kidney and emphasizes the importance of considering acute tubulointerstitial nephritis as a cause of renal dysfunction in acute porphyria.",
"keywords": [
"Acute porphyria",
"Acute tubulointerstitial nephritis",
"Renal dysfunction",
"Renal biopsy",
"Interstitial fibrosis and tubular atrophy"
],
"content": "Introduction\n\nAcute porphyria is a group of rare metabolic disorders characterized by enzyme deficiencies in heme biosynthesis.1,2 Acute porphyria primarily affects the nervous system and renal involvement is uncommon. Porphyrins are highly reactive to ultraviolet rays; in urine, they turn a reddish hue upon exposure to sunlight.3 There are various causes of renal failure in acute porphyria with acute interstitial nephritis (AIN), an infrequent manifestation characterized by interstitial inflammation and tubular injury. To our knowledge, this is the first case report of acute tubulointerstitial nephritis secondary to acute intermittent porphyria in India.\n\n\nCase\n\nA 21-year-old female born to non-consanguineous parents presented with complaints of abdominal pain and altered sensorium. She had hypertension at presentation, neck stiffness, and a fundus within normal limits. All other systemic examination results were normal. Laboratory tests (Table 1) revealed normocytic normochromic anemia with deranged renal function tests and bland urine. Sepsis markers were standard, and the cultures were sterile. The ultrasonography results were within normal limits. ECG, 2 D Echo, and neuroimaging were performed, which was expected. Urine color provided a clue to evaluate the lines of porphyria, leading to the diagnosis of acute porphyria. Treatment included glucose administration and other supportive measures to improve the patient’s overall clinical condition. No nephrotoxic agents were used before admission, during the hospital stay, or after discharge from the hospital. She had persistent renal dysfunction for approximately six weeks following her acute episode. Hence, renal biopsy was done which revealed acute tubulointerstitial nephritis with early tubular chronicity (Figure 1 and Figure 2). She received oral steroids (0.5 mg/kg of prednisolone) for four weeks, after which she had normalization of renal function and was normotensive.\n\n\nDiscussion\n\nRenal lesions in patients with acute intermittent porphyria are attributed to hypertension but are not certain.3 Increased porphyrin metabolism during an attack is a plausible cause of renal impairment. During an acute episode, excess amounts of porphyrin metabolites that are produced can cause cytotoxic or vasospastic renal vascular lesions, inducing high blood pressure and later progressing to chronic hypertension.4 Other factors such as vasopressin and angiotensin may also be additives that cause kidney injury.\n\nIn a study by Andersson et al., 9 patients with acute intermittent porphyria who underwent renal biopsy had hypertension.5 Biopsies from these patients showed varying (slight to extensive) degrees of nephrosclerosis, with a mean of 50% globally sclerotic glomeruli, moderate tubular atrophy, and interstitial fibrosis with vessel wall thickening. Acute porphyria rarely presents as acute interstitial nephritis. The precise mechanism underlying the development of acute tubulointerstitial nephritis remains unclear; however, it is postulated that metabolic intermediates or porphyrin precursors may contribute to this. Therefore, interstitial fibrosis and tubular atrophy in renal biopsy imply an advanced phase of initial acute tubulointerstitial nephritis, which ultimately culminates in chronic interstitial nephritis and, thus, persistent renal dysfunction. Therefore, our case demonstrates that the metabolic intermediates/porphyrin precursors ignited the process of tubulointerstitial nephritis, which eventually led to early tubular chronicity, as seen in renal biopsy.\n\n\nConclusion\n\nThis case highlights the unique renal presentation of acute intermittent porphyria, thus emphasizing that clinicians should consider acute tubulointerstitial nephritis as a possibility in patients with acute porphyria presenting with unexplained renal dysfunction. Through this report, the literature includes acute intermittent porphyria as a possible cause of acute tubulointerstitial nephritis.\n\n\nConsent to participate\n\nThe patient gave written informed consent.\n\n\nConsent to publish\n\nWritten consent was obtained from the patient for publishing the case after de-identifying and anonymizing all patient identifiers.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nBissell DM, Anderson KE, Bonkovsky HL: Porphyria. N Engl J Med. 2017 Aug 31; 377(9): 862–872. Publisher Full Text\n\nSouza PVS, Badia BML, Farias IB, et al.: Acute hepatic porphyrias for the neurologist: current concepts and perspectives. Arq Neuropsiquiatr. 2021 Jan; 79(1): 68–80. PubMed Abstract | Publisher Full Text\n\nRicci A, Guida CC, Manzini P, et al.: Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications. Diagnostics (Basel). 2021 Dec 10; 11(12): 2324. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChurch SE, McColl KE, Moore MR, et al.: Hypertension and renal impairment as complications of acute porphyria. Nephrol Dial Transplant. 1992; 7(10): 986–990.\n\nAndersson C, Wikberg A, Stegmayr B, et al.: Renal symptomatology in patients with acute intermittent porphyria. A population-based study. J Intern Med. 2000 Oct; 248(4): 319–325. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "275721",
"date": "22 May 2024",
"name": "Petro E Petrides",
"expertise": [
"Reviewer Expertise acute porphyrias"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAcute interstititial nephritis (AIN) accounts for about 3% of injuries detected by kidney biopsy. It is an immune mediated condition which responds to steroids. HLA genotypes are related to acute nephritis (Ref -1) Acute intermittent porphyric (AIP) is a metabolic disease caused by PBG-deaminase deficiency. Renal function changes occur in patients with AIP either caused by the disease or/and drug therapy. There is no evidence that acute interstitial nephritis is caused by AIP. Otherwise it should have been reported more frequently. The patient responded well to steroid therapy. My conclusions are: This patient illustrates COINCIDENCE of AIN and AIP. The recommendation would be to carry out real biopsy in patients with AIP and renal dysfunction since they may also have AIN which can be treated efficiently. In Table 1: Platelets 1.5 - 4 lakh = ??\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
},
{
"id": "287833",
"date": "01 Jul 2024",
"name": "Ulrich Stölzel",
"expertise": [
"Reviewer Expertise porphyrias",
"internal medicine"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMajor point\nThe causal relationship between AIP and AIN is not plausible. Suggest to include a review from nephrologists and nephropathologists.\nAIN is demonstrated in 1 to 3 percent of all kidney biopsies. When analysis is restricted to biopsies performed in the setting of acute kidney injury, the percentage rises to approximately 13 to 19 percent.\nRef [1-3]\nMinor points\nAre there any trigger factors that precipitated the attack?\nLow sodium concentration in serum should be reflected and discussed as characteristic sign of an acute porphyria attack.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
},
{
"id": "287825",
"date": "09 Jul 2024",
"name": "Paulo Sgobbi",
"expertise": [
"Reviewer Expertise Inborn Errors of Metabolism. Neurodegenerative Disease. Clinical Trials"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors described a classical case of \"acute hepatic porphyria\" in a female patient that developed persistent kidney injury.\n\nKidney injury and chronic kidney disease is a common long-term medical complication in patients with Acute Hepatic Porphyria and a lot of knowledge has been provided in the last years.\nSome patients can present with kidney dysfunction during an attack (and this is the best point of the case) and poorly is understood about the pathology and physiopathology of kidney injury during an attack and the authors provided a good clinical investigation about this point.\n\nJust to improve the quality of the article, I suggest one single paragraph describing if the patient had any clinical condition or drug that can explain acute tubulointerstitial nephritis and how the investigation for porphyria was done.\n\nI also suggested 3 article references that can be useful to improve the discussion.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-441
|
https://f1000research.com/articles/13-437/v1
|
02 May 24
|
{
"type": "Study Protocol",
"title": "Clinical profile, visual outcome and quality of life in patients undergoing pan retinal photocoagulation for proliferative diabetic retinopathy",
"authors": [
"Meghavi Pandya",
"Shashank Banait",
"Sachin Daigavane"
],
"abstract": "Introduction Visual outcomes and quality of life of individuals with proliferative diabetic retinopathy following pan-retinal photocoagulation (PRP) have only been briefly documented in a few publications. Improved quality of life experienced by patients as a result of PRP is directly associated with a positive impact on visual outcomes.\n\nAim To determine whether visual outcomes and quality of life after PRP in diabetic patients would result in a better predictive image of the patient as a whole, thus boosting the success rates and efficacy of this treatment method.\n\nMethods P.R.P. was performed under topical anesthesia as defined by the early treatment diabetic retinopathy study (E.T.D.R.S.) guidelines.\n\nConclusion This evidence-based analytical observational prospective study could aid in exploring the prognostic value of pan-retinal photocoagulation in proliferative diabetic retinopathy.",
"keywords": [
"Pan-retinal Photocoagulation",
"Proliferative Diabetic Retinopathy",
"Diabetes",
"Vision"
],
"content": "Introduction\n\nDamage to the retina from diabetes can cause vision loss due to a condition known as diabetic retinopathy (DR), a microvascular abnormality caused by the long-term effects of diabetes mellitus. It is the leading cause of severe vision impairment among working-age adults in western countries. Avoiding diabetic retinopathy-related vision loss requires1 prompt diagnosis and easy treatment.\n\nThe non-proliferative retinopathy (NPDR) and proliferative retinopathy (PDR) stages of diabetic retinopathy are clinically distinguished from one another.\n\nThe most severe form of diabetic eye disease in both type 1 and type 2 diabetes is proliferative diabetic retinopathy (PDR). Neovascularization occurs when new blood vessels develop in the retina. These new fine blood arteries often leak through the epithelium and mold scar tissue. Tractional retinal detachment may result from scar tissue.2,3 The ETDRS classification system further divides proliferative diabetic retinopathy into its first, second, and third stages. Neovascularization of the Disc (NVD) or neovascularization elsewhere (NVE) is a sign of mild to moderate PDR. Conversely, high-risk PDR denotes NVD larger than about a third of the disc area, any NVD with vitreous hemorrhage or preretinal hemorrhage, and NVE larger than about half the circle area with vitreous hemorrhage or preretinal hemorrhage.3\n\nPatients with inadequate or ineffective treatment often develop high-stage diabetic eye disease, which is a severe form of diabetic retinopathy that impairs vision. Hemorrhages preretinal, intragel, or both), tractional retinal detachment, and rubeosis iridis are all included in this pathological category.4,5\n\nFocal or pan-retinal photocoagulation is the cornerstone of treatment for proliferative diabetic retinopathy. In a normal retina, 1200–1600 laser spots (approximately 500 m in size) are distributed or diffuse uniformly across the retina, not involving the macula, centrally obliterating the retinal pigment epithelium and external photoreceptors. Neovascularization of the outer retinal layer is rarely performed. Instead, the effect of the treatment is recalled as the elimination of pigment epithelial cells and the retinal tissue above them. The laser light is absorbed by the pigmented cells, and the resulting intensity destroys the outer retinal cells.5 The inner retinal areas that had been oxygen-depleted due to unfavorable perfusion of inward retinal arteries showed an improvement in oxygen supply after percutaneous panretinal photocoagulation (PRP).\n\nThe choriocapillaris (the vein supply to the cones, pigment epithelium, and rods) now becomes physically close to the internal retina, and there are not enough highly metabolically active rods and cones in the area of the consumes to hold oxygen from the choriocapillaris. Therefore, there is a decline in the number of viable hypoxic cells in the inner retina, which produce VEGF and other developmental factors. Due to the lack of VEGF production, the new vessels regress and may also disappear completely; however, adaptation of neovascularization without further growth is also possible. When neovascularization progresses despite laser treatment, it might cause vitreous hemorrhage or retinal detachment, and vitrectomy could be essential to maintain or improve vision.5\n\nDiabetic retinopathy is the primary cause of vision and visual deficiencies. The annual frequency of diabetic retinopathy went from 2.2% to 12.7%. The progression to proliferative diabetic retinopathy was higher in people with systemic illness than in those with no sickness.\n\nStudies on aesthetic outcomes and patient satisfaction following PRP have been conducted. The concomitant increase in patients’ personal satisfaction following PRP is directly related to the advantageous effect of PRP on visual outcomes. Consequently, distinguishing the visual results and personal satisfaction after PRP in diabetic patients would result in a better prognostic image of the patient in general, subsequently expanding the achievement rates and viability of this treatment framework.\n\nAccordingly, detailed examinations of all diabetic patients leading to the early detection of diabetic retinopathy changes and noting the progression of diabetic retinopathy based on the clinical profile of the patient will help in early intervention and maintain the visual outcome.\n\nAim: To study the clinical profile, visual outcome, and quality of life of patients undergoing pan-retinal photocoagulation for proliferative diabetic retinopathy.\n\nObjectives:\n\n• To study Clinical Profile of patients undergoing Pan Retinal Photocoagulation for PDR.\n\n• To study Visual outcome of patients undergoing Pan Retinal Photocoagulation for PDR.\n\n• To study Quality of life in patients undergoing Pan Retinal Photocoagulation for PDR.\n\n\nMethods\n\nPlace of study: Outpatient Department of Ophthalmology, AVBRH, Sawangi (Meghe), Wardha.\n\nStudy design: An analytical observational prospective study.\n\nThis will be 2 years study for data collection from September 2022 to September 2024.\n\nAfter considering the inclusion and exclusion criteria, diabetic patients hospitalized or registered at the Acharya Vinoba Bhave Rural Hospital were selected will be chosen for the study.\n\n\n\n• Patients having diabetes type 1 or diabetes type 2 having Proliferative diabetic retinopathy.\n\n• Patients of age 40 years or above.\n\n• Patients willing to undergo and fit for pan retinal Photocoagulation Procedure.\n\n• Patients consenting to follow-up visits at 1, 6, and 1 year.\n\n\n\n• Patients with non-proliferative diabetic retinopathy (NPDR)/severe NPDR.\n\n• Patients receiving additional ocular intervention such as intravitreal injection or cataract surgery.\n\n• Patients with gestational diabetes.\n\n• Patients with corneal opacities deleteriously affecting their visual acuity.\n\n• Patient below age of 40 years.\n\n\n\n• Subject withdrawal occurs when an individual decides to stop participating in the study, either during the screening or treatment phases.\n\n• Any condition, including those listed under the convention’s avoidance measures or individual conditions, which, in the opinion of the specialist, expose the subject to significant risk.\n\n• Any clinically significant adverse incident or substantial hostile event requires premature removal in the opinion of the physician.\n\n• If a subject did not show up for their final scheduled appointment or the end of the study, they were lost to follow-up.\n\nEthical committee approval from the DMIHER was issued DMIMS (DU)/IEC/2022/201on 28 August 2022: (IEC No.- ECR/440/Inst/MH/2013/RR-2019). There was no involvement of animals Considering all the ethical values, informed consent was taken from all the subjects involved. The aim of the research will be explained to each participant. The lead investigator will obtain both written and verbal informed consent from each participant before the intervention. The Helsinki Declaration of 1975, mentioned in 2008, shall be followed for all procedures in this investigation.\n\nPatients will provide their consent after being briefed on the purpose of the study and any potential drawbacks. The study documentation will be treated as confidential information and safely archived with only the principal investigator having access. Incase of any adverse effect, reporting will be done to the investigator and the subject will be treated accordingly and will be considered as drop out from the study.\n\nEach participant will be given a unique number to use as a pseudonym during the evaluation and in any member-specific contact between the specialist and the support staff. The primary investigator will be responsible for maintaining the strict confidentiality of all enrollment files.\n\nSample size estimation was carried out using the following formula, taking into consideration the findings of Fu et al 2022 study\n\nWhere,\n\nα = 0.10;\n\nβ = 0.8;\n\nProportion before (πA) = 0.44;\n\nProportion after (πB) = 0.6739\n\nSample size = 57\n\nStatistical analyses were performed using GraphPad Prism 7.0 version. Non-parametric data were analyzed using the chi-square test, and the Student’s unpaired t-test was used to analyze Parametric data. The level of significancewas set at p < 0.05.\n\nAudit\n\nThe recorded data will be reviewed for quality by a supervisor once a month. The quality evaluator will have access to all clinical records, preliminary relevant documents and communications, and the archive of informed consent.\n\nDetailed ocular examinations included best-corrected visual acuity on LogMAR (ETDRS chart), intraocular pressure measurement with automated tonometry, anterior segment evaluation using a slit-lamp, and fundus examination with direct ophthalmoscopy, indirect ophthalmoscopy, and a slit-lamp biomicroscopy setup with a +90D lens.\n\nPatients selected via the inclusion criteria set for the study will undergo the following procedure.\n\nIn accordance with the early treatment diabetic retinopathy study recommendations, PRP will be conducted with an automated pattern delivery system employing a spot size of 400–500 m on the retinal surface, 532 nm, 0.2 ms, 150–200 mW, and 1200–1500 spots split among three to four treatments.\n\nPatients underwent a thorough eye examination (using indirect ophthalmoscopy) at one month, six months, and yearly checkups to record any changes or complications. Best-corrected visual acuity on LogMAR (ETDRS chart) will be recorded, and a +78D/90D slit-lamp lens will be used for the macula examination. At the start of the experiment and again at the end, patients were asked to fill out a quality-of-life questionnaire, the National Eye Institute Visual Function Questionnaire (NEI VFQ-25).\n\nAccording to the protocol, all patients were reviewed until the end of the study period. In situations where the patient could not follow up, he or she communicated telephonically to review their status. In case of any adverse events, patients will be managed accordingly.\n\nThe findings from this study will be submitted to good impact factor journals.\n\nThe study is still recruiting the subjects and the patients are under review.\n\nThe prevalence of proliferative diabetic retinopathy is higher in patients aged 40 years or older than in those younger than 40 years.\n\nCompared to alternative forms of treatment, pan-retinal photocoagulation significantly improves the quality of life and visual results of patients with proliferative diabetic retinopathy.\n\nA study observing and analyzing the clinical characteristics, visual outcomes, and general well-being of proliferative diabetic retinopathy individuals undergoing pan-retinal photocoagulation.\n\n\nDiscussion\n\nIn this 2 year study, before and after undergoing pan-retinal photocoagulation, the clinical features, visual results, and quality of life of proliferative diabetic retinopathy patients before and after undergoing pan-retinal photocoagulation were assessed.\n\nThis research which was published by Rema M, et al.6 at 1 year follow-up, found 73% eyes that had good visual acuity (6/9) at baseline still had it; among the 53 eyes only 31 eyes had baseline visual acuity of 6/12-6/36 retained the same level of vision, while 18% (10 eyes) showed improvement. Twelve of the 17 eyes that had a baseline visual acuity of 6/60 maintained that level of clarity, while the vision of the other five improved. Twenty patients had vision loss due to vitreous hemorrhage (31.7%), nineteen had vision loss due to cataract progression (30%), fifteen had vision loss due to chronic macular edema (23.8%), six had vision loss due to macular preretinal hemorrhage (9.5%), and three had vision loss due to macular preretinal fibrosis (4.7%).\n\nThe likelihood of vision loss of at least five Early Treatment Diabetic Retinopathy Study (ETDRS) letters in treatment-naive PDR was found to be 50% 3.32 years after the first stabilization following PRP, as reported by Fu et al. 2022.7\n\nResults from the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), found by Vasilijevi JB et al. (2022),8 showed an improvement in patients’ vision from a baseline score of 65.4 17.4 to a post-PRP score of 63.3 19.5. Fewer laser burns were a significant predictor of a lower VFQ-25 composite score.\n\nIn our pilot study, we aimed to evaluate the clinical, visual, and quality-of-life profiles of patients with PDR.\n\nSmall study population.\n\nShort follow up period.\n\nThis analytical observational prospective study based on quality of life and visual outcome for patients undergoing pan-retinal photocoagulation for proliferative diabetic retinopathy would inform us about the prognostic value of pan-retinal photocoagulation for proliferative diabetic retinopathy.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nEisma JH, Dulle JE, Fort PE: Current knowledge on diabetic retinopathy from human donor tissues. World J. Diabetes. 2015 Mar 15; 6(2): 312–320. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRomero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A, et al.: Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. J. Diabetes Res. 2016; 2016: 2156273.\n\nChaudhary, et al.: 2021 - Proliferative diabetic retinopathy (PDR).pdf.[cited 2023 Jul 29]. Reference Source\n\nKanski’s Clinical Ophthalmology - 9th Edition: [cited 2023 Jun 6]. Reference Source\n\nBressler N, Beck R, Ferris F: Panretinal Photocoagulation for Proliferative Diabetic Retinopathy. N. Engl. J. Med. 2011 Oct 20; 365: 1520–1526. Publisher Full Text\n\nVasilijević JB, Kovačević IM, Bukumirić ZM, et al.: Vision-Related Quality of Life and Treatment Satisfaction Following Panretinal Photocoagulation in Diabetic Retinopathy—A Panel Study. Medicina. 2022; 58(12): 1741. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRema M, Sujatha P, Pradeepa R: Visual outcomes of pan-retinal photocoagulation in diabetic retinopathy at one-year follow-up and associated risk factors. Indian J. Ophthalmol. 2005; 53: 93–99. PubMed Abstract | Publisher Full Text\n\nFu DJ, Thottarath S, Faes L, et al.: Visual acuity outcome of stable proliferative diabetic retinopathy following initial complete panretinal photocoagulation. BMJ Open Ophthalmol. 2022 Sep 1; 7(1): e001068. Publisher Full Text"
}
|
[
{
"id": "277767",
"date": "22 Jul 2024",
"name": "Youxin Chen",
"expertise": [
"Reviewer Expertise retina"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article clearly outlines the study's objective, which is to investigate the impact of pan retinal photocoagulation (PRP) on the clinical characteristics, visual outcomes, and quality of life in patients with proliferative diabetic retinopathy (PDR). The study employs a prospective, observational design, following the guidelines of the Early Treatment Diabetic Retinopathy Study (ETDRS) to ensure methodological rigor and standardization. However, several issues need clarification:\nThe exclusion criteria eliminate individuals under the age of 40. What is the rationale behind this specific age cutoff? Many PDR patients also suffer from diabetic macular edema (DME), or may develop DME during follow-up. The exclusion criteria mention excluding patients who have undergone intravitreal injections. How does the study protocol address the emergence of DME in enrolled patients?·\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-437
|
https://f1000research.com/articles/13-435/v1
|
02 May 24
|
{
"type": "Research Article",
"title": "Analyzing a series of ligands against malaria through the application of molecular docking, molecular quantum similarity, and reactivity indices",
"authors": [
"Alejandro Morales-Bayuelo",
"Ricardo Vivas-Reyes",
"Savas Kaya",
"Ricardo Vivas-Reyes",
"Savas Kaya"
],
"abstract": "Background The primary goal of this research is to underscore the significance of molecular docking in the context of malaria drug discovery. Molecular docking plays a crucial role in comprehending the interactions between prospective drugs and the target proteins found in Plasmodium parasites. The study delves into the docking interactions of various compounds, emphasizing the necessity of stabilizing the active site to formulate potent and selective drugs.\n\nMethods The research focuses on highlighting compound-specific interactions with residues, stressing the importance of stabilizing the active site to design drugs tailored to specific target proteins. Inhibiting the function of these target proteins disrupts the life cycle of the malaria parasite. Quantum Similarity Analysis, utilizing Overlap and Coulomb operators, is employed to identify electronic similarities. The resulting quantum similarity values guide subsequent chemical reactivity analysis. Global reactivity indices such as chemical potential, hardness, softness, and electrophilicity contribute to drug design by showcasing compound-specific indices that underscore the significance of stability and electrophilicity. Fukui functions are utilized to visualize regions for stabilization, providing insights crucial for potential malaria treatment.\n\nResults The enhancement of drug-target binding affinity is observed through stabilizing interactions in the active site. Understanding electrophilicity at the active site emerges as a critical factor in drug design and selectivity. The rational manipulation of electrophilic interactions holds promise for developing potent and selective drugs against malaria. Consequently, the integration of molecular docking, quantum similarity analysis, and chemical reactivity indices offers a comprehensive approach to malaria drug discovery.\n\nConclusions The study identifies potential lead compounds, emphasizing the crucial role of stabilizing the active site. Additionally, it sheds light on electronic considerations vital for the design of effective and resistance-resistant drugs. The insights provided by Fukui functions into regions susceptible to -H bond formation make these compounds promising candidates for malaria treatment.",
"keywords": [
"Malaria treatment",
"drug design",
"molecular docking",
"molecular quantum similarity",
"chemical reactivity indices",
"Density Functional Theory."
],
"content": "Introduction\n\nMalaria remains a substantial global health challenge, particularly in numerous tropical and subtropical regions. The disease is endemic in various countries, especially in sub-Saharan Africa, Southeast Asia, and parts of Central and South America,1–3 where it imposes the highest disease burden. Plasmodium parasites, transmitted through the bites of infected female Anopheles mosquitoes, cause malaria. Among the Plasmodium species infecting humans, P. falciparum is the most lethal. In 2020, the global tally of malaria cases, as reported by the World Health Organization (WHO), stands at approximately 241 million, with 627,000 recorded deaths, with a disproportionate impact on Africa.3–6 At-risk demographics, including infants and expectant mothers, bear a significant burden, with pregnant women facing heightened risks, including maternal anemia and low birth weight. Control and prevention measures encompass the use of insecticide-treated bed nets, indoor residual spraying, antimalarial drugs, and initiatives targeting mosquito breeding sites.6,7 While Artemisinin-based combination therapies (ACTs) are extensively employed for treating uncomplicated malaria, other antimalarial drugs may be utilized for specific cases or regions. The emergence of drug resistance, particularly in the Greater Mekong Subregion, presents a formidable challenge to malaria control efforts.7–10 Additionally, concerns about insecticide resistance in mosquitoes underscore the importance of exploring new alternatives for malaria treatment.11–14\n\nCurrent research is dedicated to advancing the development of novel antimalarial medications, vaccines, and inventive vector control strategies. The objective is to enhance the arsenal of tools for preventing, treating, and ultimately eradicating malaria. Global malaria control initiatives are actively supported by international organizations, governments, and non-governmental organizations, with pivotal roles played by the WHO's Global Malaria Program and the Roll Back Malaria Partnership in orchestrating collaborative endeavors to diminish the worldwide impact of malaria.15–18\n\nFurthermore, the challenges posed by the COVID-19 pandemic have impacted malaria control efforts, redirecting resources and straining health systems. For the most recent and accurate information, it is advisable to refer to recent reports from health organizations and institutions actively engaged in malaria control.19–22 Protein kinases play pivotal roles in diverse cellular processes, encompassing signal transduction, cell cycle regulation, and gene expression.23,24 Within the context of the malaria parasite, Plasmodium spp., protein kinases are indispensable for the parasite's survival and proliferation within the host.25–29 Understanding the role of protein kinases in the malaria parasite holds significance for the development of targeted therapeutic strategies. Here are key insights into protein kinases in the malaria parasite:\n\nAbundance of Protein Kinases: The genome of Plasmodium spp., including the human malaria parasite Plasmodium falciparum, encodes a multitude of protein kinases. P. falciparum, exemplarily, boasts over 80 putative protein kinases.30–33 Diverse Functions: Protein kinases in Plasmodium participate in a spectrum of cellular processes, including signal transduction, cell cycle progression, host cell invasion, and immune evasion.33,34 They play a crucial role in regulating the parasite's life cycle, spanning the invasion of host cells by the sporozoite stage to the replication within hepatocytes (liver stage) and erythrocytes (blood stage).35–37 Unique Kinases: Some protein kinases in the malaria parasite exhibit uniqueness or distinct features compared to their counterparts in the host.38–40 This distinctiveness presents opportunities for developing drugs that selectively target the parasite without affecting host cell kinases.40–42\n\nDruggability and Therapeutic Targets: Protein kinases have been identified as potential drug targets for antimalarial therapies. Inhibiting specific kinases can disrupt essential cellular processes in the parasite, leading to its demise. Ongoing efforts aim to identify and characterize specific protein kinases critical for the parasite's survival and development.43 Inhibitors targeting these kinases could serve as the foundation for developing new antimalarial drugs. Examples of Protein Kinases in Plasmodium: Notable examples include PfCDPK1 (Calcium-Dependent Protein Kinase 1), involved in the invasion of host erythrocytes; PfPKA (Protein Kinase A), with a role in the regulation of the cell cycle; and PfPKG (Protein Kinase G), significant for the development of sexual stages of the parasite in the mosquito vector.40–43\n\nProgress in antimalarial drug discovery has been notable, but challenges such as drug resistance and the intricate life cycle of the malaria parasite persist, driving ongoing research efforts.38–41 Key aspects and approaches in antimalarial drug discovery include:\n\nTargeting the Parasite's Life Cycle: Malaria, caused by Plasmodium parasites, involves a complex life cycle in both the mosquito vector and human host. Antimalarial drug discovery aims to target various stages, including the liver stage, blood stage, and transmission-blocking interventions to disrupt the life cycle.30–35 Artemisinin-Based Combination Therapies (ACTs): Artemisinin and its derivatives are potent antimalarial drugs that rapidly reduce parasite biomass. ACTs, combining artemisinin compounds with other antimalarials, have proven highly effective in treating uncomplicated malaria.39–42 However, concerns arise over the emergence of artemisinin resistance in some regions. Drug Resistance Monitoring and Surveillance: The development of resistance to antimalarial drugs is a significant challenge. Ongoing efforts focus on monitoring and surveillance, utilizing molecular techniques to identify resistance markers in the parasite's genome.40–43 New Target Identification: Researchers continually identify potential drug targets within the malaria parasite. This includes enzymes in essential metabolic pathways, proteins crucial for invasion and egress from host cells, and unique features of the parasite's biology exploitable for drug development.25–30 High-Throughput Screening (HTS): HTS techniques rapidly test large compound libraries to identify molecules with antimalarial activity, expediting the drug discovery process.30–35 Fragment-Based Drug Design: This methodology involves screening small molecular fragments for their ability to bind to a target, leading to the design of more potent and specific compounds.35–38 Repurposing Existing Drugs: Cost-effective repurposing of drugs developed for other diseases has shown promise. Some drugs, initially designed for different purposes, exhibit antimalarial activity, expediting the development process. Vaccines and Transmission-Blocking Strategies: Malaria vaccine development, while not conventional, is integral to the broader strategy against the disease.40–43 Additionally, transmission-blocking drugs aim to reduce mosquito transmission of the parasite, contributing to malaria control efforts. Public-Private Partnerships: Collaboration among academic institutions, pharmaceutical companies, and public health organizations is crucial for advancing antimalarial drug discovery. Public-private partnerships facilitate pooling resources, expertise, and funding to accelerate research and development.38–43\n\nIn this manuscript is used an approach based in molecular docking, Molecular quantum similarity and Chemical reactivity indices. A comprehensive approach could involve integrating molecular docking, molecular quantum similarity, and chemical reactivity indices. For example, molecular docking can be used to predict the binding mode of a ligand to a target protein, while molecular quantum similarity and reactivity indices can help understand the electronic and chemical properties governing the interaction. We Started with molecular docking to identify potential ligands, validating the results using quantum similarity methods, and then analyze the reactivity indices to gain insights into the chemical behavior of the molecules.\n\nIntegrating these approaches allows us to leverage the strengths of each method, providing a more holistic understanding of molecular interactions and properties. However, it's important to note that these computational techniques are complemented by experimental validation for robust results. In this sense, the ligand studied has been analyzed by the Zhang group.44 In this sense, in this manuscript these ligands will be analyzed using new reported protein kinases with the aim of obtaining new considerations on the antimalarial activity of these ligands.\n\n\nMethod\n\nDuring the docking experiment, the receptor structure was generated in adherence to specific protocols, drawing inspiration from the crystal structure of the co-crystallized ligand located at the core of PDB entries 1ob3 and 2pmn. Structural adjustments were implemented employing the protein preparation wizard module from the Schrödinger suite 2017-1. These adjustments included optimizing the hydrogen bond (H-bond) network and refining the protein structure. The PropKa (https://github.com/schrodinger/propka-3.1) utility was utilized to determine protonation states at physiological pH. Additionally, restrained molecular minimization was executed through the Impact Refinement (Impref, https://newsite.schrodinger.com/platform/products/maestro/) module, with heavy atoms constrained to a low root-mean-square deviation (RMSD, https://newsite.schrodinger.com/platform/products/maestro/) from the initial coordinates.45–47\n\nIn contrast, the molecular structures of the compounds were fashioned using the Maestro Editor (Maestro, version 11.1, Schrödinger, LLC). Subsequently, 3D conformations were generated employing the LigPrep module, and ionization/tautomeric states were predicted under physiological pH conditions using Epik. Finally, energy minimization was carried out using the Macro model and the OPLS2005 force field.\n\nFor the molecular docking investigations, Glide48,49 was employed with default parameters and the Standard Precision (SP) model. The docking grid was established using default settings, positioning the co-crystallized ligands from PDB entries 1ob3 and 2pmn at the center. To enhance the binding of larger ligands, a scaling factor of 0.8 for the van der Waals radii of nonpolar protein atoms was applied. Extra precision (XP) was also employed to accommodate alternate receptor conformations suitable for binding ligands with unconventional orientations through induced fit docking (IFD). This approach allows for potential side-chain, backbone, or combined movements in the protein structure upon ligand docking. Redocking was performed for all results, and subsequent RMSD calculations were conducted. The binding pocket was identified using Glide.48,49\n\nThe docking procedure comprised four meticulous steps, leveraging Glide's scoring function and Prime's advanced conformational refinement for precision:\n\ni. Initial docking was conducted using Glide on the rigid receptor to generate a set of poses.\n\nii. The side-chain prediction module of the Prime tool was utilized to sample the protein, followed by structural minimization for each pose of the protein/ligand complex.\n\niii. Redocking of the ligand into the low-energy induced-fit structures from the previous step was carried out using Glide's default parameters, without van der Waals scaling.\n\niv. The binding energy (IFDScore) was estimated, taking into account the docking energy (GScore), receptor strain, and solvation terms (Prime energy).\n\nTo further evaluate ligand interactions in the active site, the extent of residue movement induced by the induced-fit docking (IFD) computation was considered. For both the most and least active ligands, all poses were compared within the molecular set. Molecular dynamics calculations spanning 30 ns were employed to predict the best poses and analyze their stabilization in the active site.\n\n\nQuantum similarity study\n\nThe Molecular Quantum Similarity Measure (MQSM), represented as ZAB, is utilized to compare two systems, A and B, by evaluating molecules generated using their respective Density Functions (DFs). The DFs are multiplied and integrated over electronic coordinates, incorporating weighting by a pre-established positive operator Ω(r1, r2)50–52:\n\nThe selection of the operator in Equation 1 holds significance, as it shapes the information under comparison and functions as a similarity measure between the two systems. For example, the Dirac delta function (Ω(r1, r2) = δ(r1 - r2)) proves effective for functions characterized by high peak values, such as electronic density, resembling a charge or point mass.\n\nCommonly utilized similarity metrics include the overlapping Molecular Quantum Similarity Measure (MQSM) and the Coulomb operator (Ω(r1, r2) = |r1 - r2|−1). Additionally, a self-similarity measure (ZAA for molecule A) can be applied, even when comparing two equivalent molecules.52\n\nFor a group of N molecules, a similarity measure is computed for each molecule concerning others, resulting in a symmetric matrix. Each column in this matrix represents the similarity measurements between the molecule and every constituent in the group, generating discrete N-dimensional representations for each structure. These vectors serve as unique chemical descriptors extending beyond traditional molecular descriptors.51–58 They are universal, derived from any collection of molecules. They are impartial, determined solely by density functions and similarity measurements.\n\nCarbó's similarity index (Equation 2) for two molecules, I and J, relies on the cosine of the angle formed by their density functions when treated as vectors. This index varies between 0 and 1, signifying the degree of similarity between the two molecules.50–55\n\nCarbó's similarity index between two molecules, I and J, is obtained from Equation 2. Also known as the cosine similarity index, it aligns with the cosine of the angle formed by the density functions treated as vectors. The Carbo QSI for any pair of compared molecules spans from 0 to 1, indicating the extent of similarity between the two molecules (approaching 1 when I equals J).50–55\n\nEquation 3 introduces a similarity measure expressed as the Euclidean distance index (Equation 4). This index represents the distance or dissimilarity between two quantum objects, allowing geometric interpretation based on the norm of the differences in density functions:\n\nIt is simplified to the so-called Euclidean distance index when k = x = 2. Index 3 of the form can also be defined as follows:\n\nThis Equation 4 forms the distance index of infinite order.50–55\n\nThe Dirac delta distribution, Ω (r1, r2) = δ (r1, r2), stands out as the most common and intuitive option for a positively defined operator in this context. Such choices refine the broad definition of MQSM, resulting in the computation of the overlap MQSM, which gauges the volume measurements covered by both electronic density functions when superimposed.56–60\n\nDerived from its physical definition, the Dirac delta function is computationally manageable. The Molecular Quantum Similarity Measure (MQSM) gauges the degree of overlap in molecular comparisons by incorporating information about the electron concentration within the molecule.61–63\n\nWhen the operator (Ω) is replaced with the Coulomb operator, Ω (r1, r2) = 1│r1−r2│, the coulomb MQS is generated, which defines the electrostatically repellent coulomb energy between two charge densities64–67:\n\nThe Coulomb operator plays a role in influencing the overlap of density functions. When molecular density functions are considered as electron distributions in space, this equation essentially extends the Coulomb operator for continuous charge distribution. In certain cases, it can be used as electrostatic potential descriptors. This operator is associated with electrostatic interactions and measures the electrostatic repulsion between electronic distributions.68\n\nAnother major transformation that can be expressed in terms of the classical distance is:\n\nHere Δxj=xaj−xbj is the distance between a and b, and k = 2 is the definition of distance, respectively. Subsequently, the Euclidean distance between A and B as two quantum objects are defined by68–70:\n\nOccasionally it is written as: DAB=ZAA+ZBB+ZZAB, where DAB has values in the range of [0,∞) but for earlier circumstances where the compared items are identical, it converges to zero between them70–72:\n\nThe norm of the differences in the density functions of the compared objects can be used to interpret this index geometrically. The distance or dissimilarity index can be used to define the Euclidean distance index, which can also be represented as73:\n\nIn this investigation, the TGSA is employed for data alignment, aligning molecules based on a common skeleton using atomic types and interatomic bonding interactions. TGSA functions through the scrutiny of atomic pairs, forming triangles, and evaluating atomic triads. This approach offers a distinctive and chemically intuitive alignment, even in cases where molecular structures exhibit limited flexibility.73–76\n\n\nChemical reactivity context\n\nResearch in this domain has unveiled a firmly established correlation between quantum similarity and descriptors associated with chemical reactivity.77,78 Both quantum similarity and Density Functional Theory (DFT) make use of the density function as a fundamental component in the analysis of similarity indices. Specifically, the Coulomb index can be correlated with electronic factors influencing chemical reactivity. In the computation of global reactivity indices, such as chemical potential (μ),77 hardness (ɳ),78 and electrophilicity (ω),79,80 Frontier Molecular Orbitals (FMO) and the energy gap will be employed. These indices, represented by Equations 11-13, offer valuable insights into system stability. Chemical potential gauges the tendency of electrons to deviate from the equilibrium system,81 while chemical hardness assesses a chemical species' resistance to altering its electronic configuration.\n\nThe mathematical definition of the electrophilicity index (ω) is related to the stabilization energy of a system when it becomes saturated by electrons from the external environment.39,40:\n\nIn this study, the focal descriptors of reactivity under examination were the Fukui functions. Equation (14) depict how the electronic density of the system responds to changes in the global charge, representing the derivative of the electronic density with respect to the electron count under a uniform external field.\n\nThe terms f+(r→) and f−(r→) and are utilized to represent nucleophilic and electrophilic attacks, respectively.81–83\n\nThis approach integrates both global and local reactivity descriptors to evaluate quantum similarity within the molecular set. All calculations were conducted using the B3LYP method84 with the 6-311xxG(d,p) basis set,84 which represents an improvement over the 6-311G(d) basis set. This enhancement facilitates the computation of electronegativity, hardness, reactivity indices, and frontier molecular orbitals at a level of quality comparable to larger basis sets like Aug-cc-pVQZ and Aug-cc-pV5Z. The Gaussian 16 package85 was employed in conjunction with this method/basis set combination.\n\n\nResults and Discussion\n\nMolecular docking plays a crucial role in drug discovery for malaria treatment. Malaria, caused by the Plasmodium parasites, A potentially fatal illness that impacts millions of individuals globally. Developing effective drugs to combat malaria requires a deep understanding of the interactions between potential drug molecules and target proteins within the Plasmodium parasites.\n\nThe compound 1 has interaction with the residue MET120 (-H, 1,125 Å) (Figure 1). In Figure 2 is shows the interaction with the compound 2 with the residues ASP123 (-H, 1,148 Å) and SER (-H, 1,358 Å).\n\nIn Figure 3, the compound 3 has interaction with the residue ASP123 (-H, 1,2561 Å).\n\nMolecular docking helps identify and validate potential drug targets within the Plasmodium parasites. By simulating the interaction between small molecules and target proteins, researchers can prioritize which proteins are most promising for drug development. The three-dimensional structures of target proteins involved in the malaria-causing parasites are essential for designing drugs that specifically interact with these proteins. Molecular docking aids in the rational design of drug candidates by predicting the binding modes and affinities of small molecules to target proteins. Figure 4 has the interactions with the residues MET120 (-H, 1,1961 Å).\n\nIn Figure 5 is shows the interaction with the residue SER176 (-H, 1,256 Å).\n\nThe importance of stabilization on the active site of proteins involved in malaria lies in the context of drug discovery and the development of therapeutics. The active site of a protein is a region where interactions with other molecules, such as substrates or ligands, occur. In the case of proteins associated with malaria, targeting the active site is crucial for designing drugs that can disrupt or modulate the function of these proteins. The active site of a protein is often the functional region where the protein interacts with its substrates or other molecules. By stabilizing the active site, researchers can design drugs that specifically bind to and modulate the activity of the protein involved in the malaria-causing parasite. Stabilizing the active site allows for the design of drugs that are specific to the target protein. This specificity is crucial to avoid unintended interactions with other proteins in the host organism, minimizing side effects and improving the selectivity of the drug.\n\nMany drugs work by inhibiting the function of a target protein. Stabilizing the active site facilitates the design of molecules that can bind tightly to the protein, disrupting its normal function. This inhibition is essential for interfering with the life cycle of the malaria parasite or preventing its ability to infect and survive within the host. Some proteins involved in malaria may rely on interactions with other proteins for their function. Stabilizing the active site can disrupt these protein-protein interactions, leading to the inhibition of essential pathways or processes required for the survival of the parasite. Figure 6 shows the interaction with the residues ASP123 (-H, 1,356 Å), SER124 (-H, 1,568 Å) and SER176 (-H, 1,239 Å), respectively.\n\nMolecular docking provides insights into the strength of the interactions between drug candidates and target proteins by predicting binding affinities. This information is crucial for selecting lead compounds with high binding affinity and therapeutic efficacy. On the other hand, Malaria parasites can develop resistance to drugs over time. Molecular docking helps researchers understand the structural basis of drug resistance by predicting how mutations in target proteins might affect drug binding. This information is vital for designing drugs that are less prone to resistance.\n\nFigure 7 shows the interaction with the residue ASP123 (-H, 1,569 Å) and PHE128 (-H, 1,4265 Å). In Figure 8, we can see the interactions with the residues ASP123 (-H, 1,4569 Å) and PHE128 (-H, 1,3569 Å).\n\nIn Figure 9, we can see the interaction with the residue ASP123 (-H, 1,319 Å).\n\nStabilizing the active site contributes to enhancing the binding affinity between the drug and the target protein. A strong and stable interaction is crucial for the drug to exert its therapeutic effects at lower concentrations, improving the efficacy of the drug. Malaria parasites can develop resistance to drugs over time. By targeting the active site and stabilizing interactions, researchers can design drugs that are less prone to resistance, as mutations in the active site that confer resistance may have a higher fitness cost to the parasite.\n\nKnowledge of the three-dimensional structure of the active site is essential for structure-based drug design. Stabilizing interactions within the active site allows for the rational design of drug candidates that fit precisely into the binding pocket of the target protein. In these sense, stabilizing the active site of proteins involved in malaria is crucial for designing effective and specific drugs. This approach allows for the development of therapeutics that selectively target the parasite, disrupt essential processes, and minimize the risk of resistance. Structure-based drug design techniques, including molecular docking and computational simulations, often play a significant role in understanding and optimizing the stabilization of the active site.\n\nQuantum Similarity Analysis in drug design provides a powerful tool for understanding molecular similarity at a deep, electronic level, contributing valuable insights into the development of new pharmaceutical agents. It integrates quantum mechanical principles into the drug discovery process, offering a more nuanced perspective on molecular interactions and reactivity.\n\nIn Table 1 the Higher similarity using the Overlap operator is between the compounds 3 and 4 with 0,8576 and an euclidean distance of 2,0743 (see Table 2). The lowest similarity value is between the compounds 3 and 6 with 0,2666 and an euclidean distance of 4,9818.\n\nIn Table 3. The higher similarity using the Coulomb operator is between the compounds 5 and 6 with 0,9389 and an euclidean distance of 21,8492 (see Table 4). On the other hand, the lowest similarity value is between the compounds 4 and 8 with 0,5758 and an euclidean distance of 43,5506.\n\nBecause the highest values of electronic quantum similarity were obtained, we have performed an analysis of chemical reactivity to obtain new electronic considerations in the molecular set.\n\nLocal reactivity indices guide the introduction of specific functional groups at strategic positions to enhance or modify the biological activity of a molecule. In these sense, global and local chemical reactivity indices play a crucial role in drug design by providing valuable information about the electronic structure and reactivity of molecules. These indices guide the selection of molecular modifications to optimize the pharmacological properties of drug candidates.\n\nIn Table 5, the compound with higher chemical potential is the compound 5 with μ = -5,4916 eV, Hardness, (ƞ = 4,5876 eV), Softness, (S = 0,2180 eV)−1 and electrophilicity, (ω = 3,6480 eV). Another compound with good stability is the compound 3 with μ = -4,4106 eV, Hardness, (ƞ = 5,3315 eV), Softness, (S = 0,1876 eV−1) and Electrophilicity, (ω = 1,8243 eV).\n\nThe compound with higher electrophilicity is 4 with ω = 4,5777eV. Understanding electrophilicity at the active site of a protein is essential in drug design and medicinal chemistry. The active site is a region within a protein where specific interactions occur with ligands, substrates, or inhibitors. Electrophilicity in this context refers to the propensity of a molecule or a functional group to accept electrons, and it plays a crucial role in the binding of ligands to the protein. Certain amino acid residues in the active site of a protein may exhibit electrophilic characteristics. Common electrophilic residues include positively charged amino acids such as lysine (LYS) and arginine (ARG), which can form electrostatic interactions with negatively charged ligands.\n\nAssessing electrophilicity in the active site of proteins is a fundamental aspect of drug design. It involves considering both the electrophilic nature of ligands and the nucleophilic properties of the protein's active site residues. Strategic control of electrophilic interactions has the potential to yield enhanced efficacy and selectivity in the creation of drugs for Malaria. In Figures 10 and 11, we can see the local regions involved in the stabilization into the protein pocket for the compound with higher experimental IC50.\n\nFigures 10 and 11 show good regions for the stabilization into the active site. These regions offers susceptibilities to form -H bond and consequently can be good candidates for the malaria treatment.\n\n\nConclusions\n\nMolecular docking is an indispensable tool in malaria drug discovery, providing insights into the interaction between potential drug molecules and target proteins within Plasmodium parasites. The study focused on the docking interactions of various compounds, emphasizing their specific interactions with residues. Stabilizing the active site of proteins associated with malaria is crucial for designing effective and selective drugs. The docking results, shows interactions with specific residues. Stabilizing the active site enhances binding affinity, a critical factor for drug efficacy. The specificity achieved by targeting the active site minimizes unintended interactions, reducing side effects and improving drug selectivity.\n\nQuantum Similarity Analysis, incorporating the Overlap and Coulomb operators, offers a deep electronic perspective on molecular interactions. The study presents tables indicating the electronic quantum similarity between different compounds. The analysis provides insights into chemical reactivity and potential resistance issues. The highest electronic quantum similarity values were observed between specific compound pairs, influencing the subsequent analysis of chemical reactivity. These findings prompted an exploration of global and local chemical reactivity indices to further guide drug design.\n\nGlobal reactivity indices, such as chemical potential, hardness, softness, and electrophilicity, were computed for each compound. These indices play a crucial role in guiding molecular modifications to optimize drug candidates' pharmacological properties. The results identified compounds with higher chemical potential and electrophilicity, essential considerations in drug design. Understanding electrophilicity at the active site is crucial for drug design, as shown by the compound with the highest electrophilicity. The assessment involves considering the electrophilic nature of ligands and the nucleophilic properties of the active site residues. Fukui functions were employed to visualize regions involved in stabilization within the protein pocket. Figures 10 and 11 highlight specific regions susceptible to -H bond formation, making them potential candidates for malaria treatment.\n\nIn this sense, the combination of molecular docking and quantum similarity analysis, coupled with an exploration of chemical reactivity indices, provides a comprehensive approach to drug discovery for malaria.\n\nThe research identifies prospective lead compounds, underscores the significance of stabilizing the active site, and elucidates electronic considerations crucial for designing drugs that are both effective and resistant-resistant.",
"appendix": "Data availability\n\nHarvard Dataverse: Replication Data for: Analyzing of a serie of ligand against malaria using Molecular docking, Molecular Quantum Similarity and reactivity indices whitin Density Functional Theory frame-work, https://doi.org/10.7910/DVN/DLWULB. 86\n\nData are available under the terms of the Creative Commons Zero (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nConsulted 20-12-2023. http\n\nGriffith KS, Lewis LS, Mali S, et al.: Treatment of Malaria in the United States: A Systematic Review. JAMA. 2007; 297(20): 2264–2277. Publisher Full Text\n\nLalloo DG, Shingadia D, Bell DJ, et al.: UK malaria treatment guidelines. J. Infect. 2016; 72(6): 635–649. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCathcart SJ, Lawrence J, Grant A, et al.: Estimating unreported malaria cases in England: a capture-recapture study. Epidemiol. Infect. 2010 Jul; 138(7): 1052–1058. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nRemarque EJ, Faber BW, Kocken CH, et al.: Apical membrane antigen 1: a malaria vaccine candidate in review. Trends Parasitol. 2008; 24(2): 74–84. PubMed Abstract | Publisher Full Text\n\nBoddey JA, Cowman AF: Plasmodium nesting: remaking the erythrocyte from the inside out. Ann. Rev. Microbiol. 2013; 67: 243–269. PubMed Abstract | Publisher Full Text\n\nSpillman NJ, Beck JR, Goldberg DE: Protein export into malaria parasite-infected erythrocytes: mechanisms and functional consequences. Annu. Rev. Biochem. 2015; 84: 813–841. PubMed Abstract | Publisher Full Text\n\nYuthavong Y, Tarnchompoo B, Vilaivan T, et al.: Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc. Natl. Acad. Sci. USA. 2012; 109(42): 16823–16828. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang VM, Chavchich M, Waters NC: Targeting Protein Kinases in the Malaria Parasite: Update of an Antimalarial Drug Target. Curr. Top. Med. Chem. 2012; 12: 456–472. PubMed Abstract | Publisher Full Text\n\nBurley SK, Berman HM, Bhikadiya C, et al.: RCSB Protein Data Bank: Biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic Acids Res. 2019; 47(D1): D464–D474. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHalgren JJ, Klicic DT, Mainz MP, et al.: Glide: A New Approach for Rapid, Accurate Docking and Scor- ing. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004; 47: 1739–1749. Publisher Full Text\n\nFriesner RA, Banks JL, Murphy RB, et al.: Glide: A New Approach for Rapid, Accurate Docking and Scor- ing. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004; 47: 1739–1749. PubMed Abstract | Publisher Full Text\n\nMadhavi Sastry G, Adzhigirey M, Day T, et al.: Protein and ligand preparation: parameters, protocols, and influence on virtual screen- ing enrichments. J. Comput. Aided Mol. Des. 2013; 27: 221–234. PubMed Abstract | Publisher Full Text\n\nJorgensen WL, Maxwell DS, Tirado-Rives J: Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. J. Am. Chem. Soc. 1996; 118: 11225–11236. Publisher Full Text\n\n[(a)] Carbó-Dorca R, Amat L, Besalú E, et al.: Quantum Similarity. Adv. Molec. Simil. 1998; 2: 1–42. JAI Press. 0-7623-0258-5. Publisher Full Text\n\n[(b)] Carbó-Dorca RE: Besalú A general survey of Molecular Quantum Similarity Huzinaga symposium, Fukuoka. J. Mol. Struct. (THEOCHEM). 1998; 451: 11–23. Publisher Full Text\n\n[(c)] Solá M, Mestres J, Carbó R, et al.: A Comparative analysis by means of Quantum Molecular Similarity Measures of Density Distributions derived from conventional ab initio and Density Functional Methods. J. Chem. Phys. 1996; 104: 636–647. Publisher Full Text\n\n[(d)] Carbó R, Besalú E: Theoretical Foundation of Quantum Similarity in “Molecular Similarity and Reactivity: From Quantum Chemical to Phenomenological Approaches”.Carbó R, editor. Understanding Chemical Reactivity. Amsterdam: Kluwer Academic Publishers; 1995; Vol. 14. , pp. 3–30.\n\n[(a)] Morales-Bayuelo A, Matute RA, Caballero J: Understanding the comparative molecular field analysis (CoMFA) in terms of molecular quantum similarity and DFT-based reactivity descriptors. J. Mol. Model. 2015; 21: 156. PubMed Abstract | Publisher Full Text\n\n[(b)] Morales-Bayuelo A: Ricardo Vivas-Reyes. J. Quant. Chem. 2014; 2014: 1–12. Article ID 850163. Publisher Full Text\n\n[(c)] Morales-Bayuelo A: Ricardo Vivas-Reyes. J. Math. Chem. 2013; 51: 125–143. Publisher Full Text\n\n[(d)] Morales-Bayuelo A, Vivas-Reyes R: Theoretical model for the polarization molecular and Hückel treatment of PhosphoCyclopentadiene in an external electric field: Hirschfeld study. J. Math. Chem. 2013; 51: 1835–1852. Publisher Full Text\n\n[(e)] Morales-Bayuelo A: Verónica Valdiris, Ricardo Vivas-Reyes. J. Theor. Chem. 2014; 14: 1–13.\n\n[(f)] Morales-Bayuelo A, Torres J, Baldiris R, et al.: Theoretical study of the chemical reactivity and molecular quantum similarity in a series of derivatives of 2‐adamantyl‐thiazolidine‐4‐one using density functional theory and the topo‐geometrical superposition approach. Int. J. Quantum Chem. 2012; 112: 2681–2687. Publisher Full Text\n\n[(g)] Morales-Bayuelo A, Torres J, Vivas-Reyes R: Quantum molecular similarity analysis and quantitative definition of catecholamines with respect to biogenic monoamines associated: Scale alpha and beta of quantitative convergence. Int. J. Quantum Chem. 2012; 112: 2637–2642. Publisher Full Text\n\n[(h)] Morales-Bayuelo A, Baldiris R, Vivas-Reyes R: J. Theor. Chem. 2013; 13: 1–13.\n\nTe Velde G, te Velde G , Bickelhaupt FM, et al.: Chemistry with ADF. J. Comput. Chem. 2001; 22: 931–967. Publisher Full Text\n\nVan Lenthe E: Relativistic total energy using regular approximations. J. Chem. 1994; 101: 9783–9792. Publisher Full Text\n\nPerdew JP, Wang Y: Accurate and simple analytic representation of the electron-gas correlation energy. Phys. Rev. B. 1992; 45: 13244–13249. PubMed Abstract | Publisher Full Text\n\nPye CC, Ziegler T, van Lenthe E , et al.: An implementation of the conductor-like screening model of solvation within the Amsterdam density functional package — Part II. COSMO for real solvents. Can. J. Chem. 2009; 87: 790–797. Publisher Full Text\n\nSchipper PRT, Gritsenko OV, van Gisbergen SJA , et al.: Molecular calculations of excitation energies and (hyper)polarizabilities with a statistical average of orbital model exchange-correlation potentials. J. Chem. Phys. 2000; 112: 1344–1352. Publisher Full Text\n\nCarbó-Dorca R, Leyda L, Arnau M: How similar is a molecule to another? An electron density measure of similarity between two molecular structures. Int. J. Quantum Chem. 1980; 17: 1185–1189. Publisher Full Text\n\nCarbó-Dorca R, Gironés X: Foundation of quantum similarity measures and their relationship to QSPR: Density function structure, approximations, and application examples. Int. J. Quantum Chem. 2005; 101: 8–20. Publisher Full Text\n\nBultinck P, Gironés X, Carbó-Dorca R: Molecular Quantum Similarity: Theory and Applications. Rev. Comput. Chem. 2005; 21: 127. Publisher Full Text\n\nConstans P, Amat L, Carbó-Dorca R: Toward a global maximization of the molecular similarity function: Superposition of two molecules. J. Comput. Chem. 1997; 18: 826–846. Publisher Full Text\n\nCarbó-Dorca R, Mercado LD: Commentaries on quantum similarity (1): Density gradient quantum similarity. J. Comb. Chem. 2010; 31: 2195–2212. Publisher Full Text\n\nGironés X, Carbó-Dorca R: Modelling Toxicity using Molecular Quantum Similarity Measures. QSAR Combinator. Sci. 2006; 25: 579–589. Publisher Full Text\n\nCarbó-Dorca R, Besalú E, Mercado LD: Communications on quantum similarity, part 3: A geometric‐quantum similarity molecular superposition algorithm. J. Comb. Chem. 2011; 32: 582–599. Publisher Full Text\n\nCarbó-Dorca R, Gironés X: Foundation of quantum similarity measures and their relationship to QSPR: Density function structure, approximations, and application examples. Int. J. Quantum Chem. 2005; 101: 8–20. Publisher Full Text\n\nCarbó-Dorca R, Besalú E: Communications on quantum similarity (2): A geometric discussion on holographic electron density theorem and confined quantum similarity measures. J. Comput. Chem. 2010; 31: 2452–2462. PubMed Abstract | Publisher Full Text\n\nMorales-Bayuelo A, Ayazo H, Vivas-Reyes R: Europ. J. Med. Chem. 2010; 45: 4509.\n\nMorales-Bayuelo A, Torres J, Vivas-Reyes R: Quantum molecular similarity analysis and quantitative definition of catecholamines with respect to biogenic monoamines associated: Scale alpha and beta of quantitative convergence. Int. J. Quantum Chem. 2012; 112: 2637–2642. Publisher Full Text\n\nMorales-Bayuelo A, Torres J, Baldiris R, et al.: Theoretical study of the chemical reactivity and molecular quantum similarity in a series of derivatives of 2‐adamantyl‐thiazolidine‐4‐one using density functional theory and the topo‐geometrical superposition approach. Int. J. Quantum Chem. 2012; 112: 2681–2687. Publisher Full Text\n\nMorales-Bayuelo A, Torres J, Vivas-Reyes R: HÜCKEL TREATMENT OF PYRROLE AND PENTALENE AS A FUNCTION OF CYCLOPENTADIENYL USING LOCAL QUANTUM SIMILARITY INDEX (LQSI) AND THE TOPO-GEOMETRICAL SUPERPOSITION APPROACH (TGSA). J. Theo. Comp. Chem. 2012; 11: 223–239. Publisher Full Text\n\nMorales-Bayuelo A, Vivas-Reyes R: Topological model to quantify the global reactivity indexes as local in Diels–Alder reactions, using density function theory (DFT) and local quantum similarity (LQS). J. Math. Chem. 2013; 51: 125–143. Publisher Full Text\n\nMorales-Bayuelo A: Quantifying the distortion by spin–orbit and spin–spin coupling in molecular clusters using Molecular Quantum Similarity. J. Math. Chem. 2024; 62: 591–605. Publisher Full Text\n\nMorales-Bayuelo A, Baldiris R, Vivas-Reyes R: Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment using Density Functional Theory (DFT). J. Theor. Chem. 2013; 13: 1.\n\nMorales-Bayuelo A, Vivas-Reyes R: Theoretical Calculations and Modeling for the Molecular Polarization of Furan and Thiophene under the Action of an Electric Field Using Quantum Similarity. J. Quant. Chem. 2014; 2014: 1–10. Article ID 585394. Publisher Full Text\n\nMorales-Bayuelo A, Vivas-Reyes R: Topological Model on the Inductive Effect in Alkyl Halides Using Local Quantum Similarity and Reactivity Descriptors in the Density Functional Theory. J. Quant. Chem. 2014; 2014: 1–12. Article ID 850163. Publisher Full Text\n\nMorales-Bayuelo A, Valdiris V, Vivas-Reyes R: Mathematic analysis on a series of 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines: a simple way to relate quantum similarity with local chemical reactivity using the Gaussian orbitals localized theory. J. Theor. Chem. 2014; 14: 1–13.\n\nMorales-Bayuelo A, Vivas-Reyes R: Understanding the Polar Character Trend in a Series of Diels-Alder Reactions Using Molecular Quantum Similarity and Chemical Reactivity Descriptors. J. Quant. Chem. 2014; 2014: 1–19. Article ID 239845. Publisher Full Text\n\nParr RG, Pearson RG: Absolute hardness: companion parameter to absolute electronegativity. J. Am. Chem. Soc. 1983; 105: 7512–7516. Publisher Full Text\n\nGeerlings P, De Proft F, Langenaeker W: Conceptual density functional theory. Chem. Rev. 2003; 103: 1793–1874. Publisher Full Text\n\nChattaraj PK, Sarkar U, Roy DR: Electrophilicity index. Chem. Rev. 2006; 106: 2065–2091. Publisher Full Text\n\nParr RG, Szentpaly L v, Liu S: Electrophilicity Index. J. Am. Chem. Soc. 1999; 121: 1922–1924. Publisher Full Text\n\nGalván M, Pérez P, Contreras R, et al.: Condensed-to-atoms electronic Fukui functions within the framework of spin-polarized density-functional theory. Chem. Phys. Lett. 1999; 30: 405.\n\nMortier WJ, Yang W: The use of global and local molecular parameters for the analysis of the gas-phase basicity of amines J. Am. Chem. Soc. 1986; 108: 5708–5711. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFuentealba P, Pérez P, Contreras R: On the condensed Fukui function. J. Chem. Phys. 2000; 113: 2544–2551. Publisher Full Text\n\nZhao Y, Truhlar DG: The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, non-covalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Accounts. 2008; 120: 215–241. Publisher Full Text\n\nFrisch MJ, Trucks GW, Schlegel HB, et al.: Gaussian Inc., Wallingford CT.2009.\n\nMorales-Bayuelo A: Replication Data for: Analyzing of a serie of ligand against malaria using Molecular docking, Molecular Quantum Similarity and reactivity indices whitin Density Functional Theory framework. [dataset]. Harvard Dataverse. 2023; 123. Publisher Full Text"
}
|
[
{
"id": "275858",
"date": "05 Jun 2024",
"name": "Tawanda Zininga",
"expertise": [
"Reviewer Expertise Protein biochemistry",
"malaria drug discovery",
"and drug screening"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Editor\nThe manuscript by Morales-Bayuelo on analysing the series of ligands using molecular docking, molecular quantum similarity, and reactivity indices highlights the use of these techniques in malaria drug discovery efforts. The main findings are that the stabilisation of active site interactions as observed through electrophilicity is a critical factor in the design of selective ligands. However, there are some adjustments that need to be made to improve the quality of this manuscript. The main issue is lack of clear interpretation of the data in the context of the focus of malaria drug design. As this study is focused on malaria, a human disease, there is a need to include screening for ligands with minimal toxicity to the host. For example, a comprehensive predictive ADMET analysis could be included, of which there are several predictive analytical tools available. The information to justify how the selectivity profiles of the ligands were confirmed is missing, which affects the impact of this study. This could be done by highlighting evidence from electronic information on current drugs that the malaria parasite has developed resistance to. I hereby provide point-by-point comments below:\nIntroduction This needs to be reworked to improve coherence, be relevant to this current study, and introduce relevant concepts in a broad sense. Page 3 minimise the use of bullet points and instead write it as one coherent body of text.\n\nMethods Briefly, state the principles for the protocols used, or, in short, why that procedure was conducted in this manuscript. The molecular docking procedure should be converted to a flow diagram to replace the bullet points. On page 4, explain how the compounds used as ligands were designed. Increase the simulation duration to show the stability of the active site after more than 250 ns as this study is based on stability analysis.\nResults and discussion Describe the findings from each of the figures and tables in this manuscript. Increase the font size for the residue labels and specify all the bonds formed between ligand and receptor that contribute to the stated binding affinities. Add an additional table with distances and relative affinities. In all the figures, the legends should summarise the main findings from each of the figures, at times with a general description of the protocol to minimise the need to go back to the methods section/main text to understand the figure. Page 8 second from last paragraph is a repetition from sections above. On Page 9, add the drug like properties of these compounds, such as the drug like ADMET properties of the compounds, to justify selectivity between host and parasite and the relative binding energies. In general, the result and discussion section should be specific to describe and interpret the findings from this study. However, as noted throughout this MS, the main text on page 9 is not relevant in addressing the findings from this study and their implications thereof. On Page 10, add a comparison of ligand and substrate binding affinities at the active site to validate the binding and interactions predicted in this study. Page 12, explain what the values in the table mean, both in terms of the magnitude of the value and in the context of a potential drug against malaria. This is lacking throughout the manuscript and should be done to show the relevance of this study in the fight against malaria. On page 13, paragraph 4, explain what these values mean in the context of ligand-active site stability and how that relates to the ADMET of the ligand. Page 13, paragraph 5, be specific and refer to the protein whose active site is being investigated.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-435
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https://f1000research.com/articles/13-433/v1
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01 May 24
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{
"type": "Case Report",
"title": "Case Report: A comprehensive rehabilitation protocol in a post-operative case of ASD closure along with PAPVC",
"authors": [
"Vishnu Vardhan",
"Chitrakshi Choubisa",
"Vishnu Vardhan"
],
"abstract": "An array of congenital cardiac disorders known as partial anomalous pulmonary venous connections (PAPVC) occur when pulmonary veins, abnormally drain into the right atrium. This can happen directly into the right atrium or via draining into systemic veins. A 10 year old female patient had chief complaints of difficulty in breathing and frequent fever hence she visited rural hospital where 2D echo was done which reviled PAPVC associated with 16 mm ASD (Atrial Septal Defect). She underwent ASD closure along with pulmonary valvotomy as a part of surgical management after which a well-planned cardiac rehabilitation has been ingrained through several breathing methods such as breathing exercises, respiratory muscle strength and home exercise program, helping the patient to carry out her activities of daily living. The Visual Analog Scale (VAS), Respiratory Muscle Strength using MicroRPM device, 6 Minute Walk Distance (MWD), Borg Scale and Fatigue Severity Scale (FSS). In this present instance, carefully thought-out physical therapy rehabilitation has been shown to be successful in enhancing functional capacity, respiratory muscle strength, optimizing functional capacity, and lowering fatigue.",
"keywords": [
"PAPVC",
"congenital heart diseases",
"open heart surgery",
"physiotherapy management",
"cardiac rehabilitation",
"case report"
],
"content": "Introduction\n\nThe atypical drainage of pulmonary veins into the right atrium leads to a variety of congenital cardiac conditions known as partial anomalous pulmonary venous connections (PAPVC). This can occur by draining directly into the right atrium or through systemic veins.1 PAPVCs, which frequently coexist with atrial septal defect (ASD) and manifest as a left-to-right shunt, have negative consequences on cardio-pulmonary physiology.2\n\nIn 0.4-0.7% of autopsies, PAPVC are discovered. Most frequently, the right pulmonary veins that drain into the right atrium or superior vena cava (SVC) are involved in the aberrant venous connection. Less commonly, abnormal pulmonary veins flow into the coronary sinus, innominate vein, or inferior vena cava.2,3\n\nVarious transcathater or surgical approaches have been proven to improve the competency of the patient’s having anomalous venous connections, which includes balloon angioplasty and surgical repair of associated anomalies.4 To facilitate flow of blood from pulmonary veins to left atrium, the wall between the coronary sinus and left atrium is excised. The coronary sinus opening is then sealed off. ASD is also closed, if it is present.2 An anastomosis between the left atrium and the pulmonary venous confluence is made in infracardiac and supracardiac PAPVC. Unless there is severe pulmonary hypertension, the vertical vein is mostly ligated in the same surgical setting. In complicated and mixed type PAPVC, a number of other procedures, such as intra-atrial rerouting, have also been employed.2,5\n\nFollowing heart surgery, there are a number of issues that call for specialised treatment, particularly in the respiratory system. These issues can extend a patient’s stay in the hospital, raising hospital expenses and playing a significant role in morbidity and death. Recent research has demonstrated that early mobilisation, such as getting out of bed and walking, improves the patient’s functional state and shortens the period of hospitalisation. Patients should receive physical treatment regularly to ensure their rehabilitation of their motor skills.6\n\nThese studies show that inspiratory muscle re-training (IMRT) is possibly beneficial in improving breathing mechanics and decreasing exercise-induced dyspnea. It is also likely useful in enhancing respiratory muscle strength and lowering airway closure (i.e., greater FVC). These mechanistic alterations reflect our developing understanding of the function of IMRT in paediatric patients and can be used to explain improvements in symptomology and clinical outcomes.7\n\n\nCase report\n\nA 10-year-old female patient presented to our hospital with a complaint of insidiously developing and increasingly worsening breathlessness which increases while walking uphill along with frequent episodes of fever. Following assessment she was admitted to the hospital. 2D Echo was done which reviled PAPVC along with 16 mm ASD. She underwent ASD closure along with pulmonary valvotomy.\n\nPrior to the examination, the patient’s caretaker provided informed permission, and the patient was then placed in a supine posture. The patient was conscious and following instructions. The patient’s BMI was 16.1 kg/m2, making her ectomorphic. Prior to surgery, the patient had gradual, insidious dyspnea that worsened as she walked uphill and subsided with rest. The patient is currently having discomfort at the suture site (Figure 1), which she rates 5/10 on a VAS (visual analogue scale). The pain was abrupt in start and dull aching in character. The pain aggravates on coughing and while inhaling deeply and she rated it 7/10 on VAS. Foley’s catheter, central line and drain were present in situ.\n\nAn examination of the cardiovascular and respiratory systems revealed a normal pericardium that was bilaterally symmetrical, had an apex beat at the level of the fifth intercostal space, and had sutures on the midsternal area. The heartbeat was regular and rhythmic at 89 beats per minute, and all of the peripheral pulsations were present. The middle and lower zones of the chest expanded less than usual, and the respiratory rate was 18 beats per minute.\n\nTimeline: Table 1 included a timeline of the occurrences. It depicts series of incidence from the patient’s hospital admission until the commencement of the physiotherapy treatment.\n\nDiagnostic assessment: 2D ECHO revealing 14×16 mm of Atrial septal defect along with PAPVC along with grade 1 pulmonary arterial hypertension with interstitial edema.\n\nTherapeutic intervention: Table 2 represents a comprehensive rehabilitation protocol post cardiac surgeries in paediatric population. The protocol includes education of the patient’s care taker and family members about the condition and post-operative care. Pain control: using chest binder to support suture line and decrease pain. Promote bronchial hygiene: nebulization and initiating with active cycle of breathing technique for effective expectoration. Improving inspiratory hold and vital capacity by giving incentive spirometer (Figure 2) and diaphragmatic breathing exercises. Facilitation of normal chest movements by asking the patient to perform thoracic expansion exercises. Improving inspiratory muscle strength: making use of Powerbreathe medic plus device (Figure 3) which is exclusively used for re-training of inspiratory muscles. Hallway ambulation to improve functional capacity (Figure 4). Incorporating home exercise programme to promote functional independence and improving level of activities of daily living.\n\n\n\n• Thoracic expansion exercises and diaphragmatic breathing (2 sets of 10 repetitions twice a day)\n\n• Incentive Spirometer with 3-5 second holds that are increased to 10 second holds twice day in sets of 10.\n\n\n\n• Strengthening of upper and lower extremities with half kilogram weight cuff progressing to 1 kilogram weight cuff (2 sets of 10 reps twice a day)\n\n• Bed mobility training\n\nFollow-up and outcome measures: Preoperatively and on the first day of physical therapy rehabilitation, the outcome measures were evaluated. A follow-up was done after one week and two weeks of the physiotherapy intervention. The outcomes were listed in Table 3.\n\n\nDiscussion\n\nAndré Luiz Lisboa Cordeiro et al. in their studies have stated that Surgery for a coronary artery bypass graft (CABG) is linked to longer hospital stays, pulmonary problems, and reduced functional ability. Patients who are at a high risk for post-operative (PO) pulmonary problems prior to CABG experience these adverse effects to a greater degree. The healing phase for CABG patients has been demonstrated to be aided by inspiratory muscle training (IMT). However, there is insufficient evidence to support the use of IMT post-operatively to promote speedier recovery in high-risk patients.6 According to Tamires Daros Dos Santos et al. Patients undergoing CABG experienced additional advantages from short-term moderate-to-high intensity IMT combined with aerobic and resistance training in terms of exercise capacity, inspiratory muscle strength, QoL, and antioxidant profile.8 Studies conducted by Balbino Rivail Ventura Nepomuceno Jr et al. suggest that early implementation of inspiratory muscle training on hospitalised patients without established respiratory deficits may prevent adverse outcomes that are either directly or indirectly related to the loss of respiratory muscle mass inherent to a prolonged hospital stay. Training the respiratory muscles can prevent endotracheal intubation, muscular wasting, and death.9 According to Rhoia Neidenbach et al. Respiratory training is known to improve exercise capacity and cardiopulmonary function showing significant improvement in oxygen saturation and maximum workload capacity.10 In this current case we have found significant improvement in PIMax and functional capacity.\n\n\nConsent\n\nAn informed written consent was taken from patients parents before assessment and implementing rehabilitation protocol. Written informed consent was taken from the patient and her parents for sharing clinical details and images for the publication.",
"appendix": "References\n\nMounir R, Nya F, Mohammed B, et al.: Adults forms of scimitar syndrome. J. Card. Surg. 2020 Jul; 35(7): 1697–1699. PubMed Abstract | Publisher Full Text\n\nSahay S, Krasuski RA, Tonelli AR: Partial Anomalous Pulmonary Venous Connection and Pulmonary Arterial Hypertension. Respirol. Carlton Vic. 2012 Aug; 17(6): 957–963. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang H, Kalfa D, Rosenbaum MS, et al.: Scimitar Syndrome in Children and Adults: Natural History, Outcomes, and Risk Analysis. Ann. Thorac. Surg. 2018 Feb; 105(2): 592–598. PubMed Abstract | Publisher Full Text\n\nGao YA, Burrows PE, Benson LN, et al.: Scimitar syndrome in infancy. J. Am. Coll. Cardiol. 1993 Sep; 22(3): 873–882. Publisher Full Text\n\nEarly Outcomes for In Situ Pericardial Roll Repair for Distant Anomalous Pulmonary Venous Return - PubMed.[cited 2023 Jul 17]. Reference Source\n\nCordeiro ALL, Carvalho BSCD, Silva EGD, et al.: Inspiratory muscle training and functional capacity following coronary artery bypass grafting in high-risk patients: A pilot randomized and controlled trial. J. Clin. Transl. Res. 2022 Jun 17; 8(4): 266–271. PubMed Abstract\n\nBhammar DM, Jones HN, Lang JE: Inspiratory Muscle Rehabilitation Training in Pediatrics: What Is the Evidence? Can. Respir. J. 2022 Aug 18; 2022: 1–18. Publisher Full Text\n\nDos Santos TD, Pereira SN, Portela LOC, et al.: Moderate-to-high intensity inspiratory muscle training improves the effects of combined training on exercise capacity in patients after coronary artery bypass graft surgery: A randomized clinical trial. Int. J. Cardiol. 2019 Mar 15; 279: 40–46. PubMed Abstract | Publisher Full Text\n\nNepomuceno BRV, Barreto MS, Almeida NC, et al.: Safety and efficacy of inspiratory muscle training for preventing adverse outcomes in patients at risk of prolonged hospitalisation. Trials. 2017 Dec 28; 18(1): 626. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNeidenbach R, Freilinger S, Stöcker F, et al.: Clinical aspects and targeted inspiratory muscle training in children and adolescents with Fontan circulation: a randomized controlled trial. Cardiovasc. Diagn. Ther. 2023 Feb 28; 13(1): 11–24. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "330526",
"date": "24 Oct 2024",
"name": "Babar Hasan",
"expertise": [
"Reviewer Expertise Pediatric Cardiology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe introduction should be short and crisp and should mention\n\n- What is known about the topic - What are the gaps in knowledge - Which gap is this case report addressing.\n\nThe uniqueness of this case report is not coming through. What the authors are describing is quite standard of care and routinely done as part of post CHD cardiac rehab.\n\nGoing into details of surgery in the introduction is distracting and doesn't help define which knowledge gap this case report strives to address.\n\nTable 1 and the figures are not adding much to the the case discussion.\n\nCrux is in table 2 where they define their rehab protocol. The effectiveness of this protocol cannot be judged by just one case report and for a post-op simple cardiac lesion. Publishing the utility of their protocol in a systematic manner on more patients may be a worthy contribution to the literature.\n\nDiscussion is around CABG patients which is a totally different population than the patient in the case study. It is important to mention previously published work which addresses a similar patient population.\n\nIs the background of the case’s history and progression described in sufficient detail? No\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
},
{
"id": "334941",
"date": "08 Nov 2024",
"name": "Ayoola Awosika",
"expertise": [
"Reviewer Expertise Cardiology",
"Clinical Exercise physiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAuthor should consider the following: - Add the full meaning of PAPVC in the topic - In line 3 of your abstract you can reword it as: \"A 10-year-old female presents with concerns of difficulty in breathing and frequent fever hence she visited rural hospital where 2D echo was done which revealed PAPVC.\nConsider rewriting the clinical presentation section to be better articulated. This will ensure readers of the article can follow the thought process from admission to discharge of the patient.\n\n- You can start with Patient chief concern, followed by 3 - 4 line details about the history of present illness. Followed by other pertinent past medical history (is this the first time seeing the patient or has this been an ongoing concern with the patient). Followed by patient physical examination findings (especially Cardiovascular and Respiratory systems). Followed by patient vital signs at presentation/admission and laboratory testing. Followed by the hospital course of events, treatment, and intervention.\nUnder the Clinical presentation; this statement seems to be incorrect. Physical examination cannot reveal what the pericardium looks like. \"An examination of the cardiovascular and respiratory systems revealed a normal pericardium that was bilaterally symmetrical\"\nThe discussion section is very scanty, consider discussing your Cardiopulmonary rehab data points here. How did it help the patient? What was the initial workload used and how did that progress? With the incentive spirometry, how did you increase this over time, etc and other interventions done as well.\n\nOverall, this is an interesting case and it adds to the body of scholarly knowledge. All claims and conclusions made are consistent with existing literature.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-433
|
https://f1000research.com/articles/13-431/v1
|
01 May 24
|
{
"type": "Research Article",
"title": "Regulatory gaps and research waste in clinical trials involving women with metastatic breast cancer in Germany",
"authors": [
"Till Bruckner",
"Daniel Sanchez",
"Tarik Suljic",
"Okan Basegmez",
"Tungamirai Ishe Bvute",
"Carolina Cruz",
"Dominic Grzegorzek",
"Fabiola Karely Lizárraga-Illán",
"Themistoklis Paraskevas",
"Aminul Schuster",
"Mayra Velarde",
"Ronak Borana",
"Shreya Ramakrishnan",
"Daniel Sanchez",
"Tarik Suljic",
"Okan Basegmez",
"Tungamirai Ishe Bvute",
"Carolina Cruz",
"Dominic Grzegorzek",
"Fabiola Karely Lizárraga-Illán",
"Themistoklis Paraskevas",
"Aminul Schuster",
"Mayra Velarde",
"Ronak Borana",
"Shreya Ramakrishnan"
],
"abstract": "Background Non-publication, incomplete publication and excessively slow publication of clinical trial outcomes contribute to research waste and can harm patients. While research waste in German academic trials is well documented, research waste in Germany related to a specific disease area across non-commercial and commercial sponsors has not previously been assessed.\n\nMethods In this cohort study, we used public records from three clinical trial registries to identify 70 completed or terminated clinical trials involving women with metastatic breast cancer with trial sites in Germany. We then searched registries and the literature for trial outcomes and contacted sponsors about unreported studies.\n\nResults We found that 66/70 trials (94.3%) had made their results public. Only 13/70 (18.6%) trials had reported results within one year of completion as recommended by the World Health Organisation (WHO). The outcomes of 4/70 trials (5.7%) had not been made public at all, but only one of those trials had recruited a significant number of patients.\n\nConclusions Discussions about research waste in clinical trials commonly focus on weakly designed or unreported trials. We believe that late reporting of results is another important form of research waste. In addition, a discussion regarding the appropriate ethical and legal rules for reporting the results of terminated trials might add value. German legislation now requires sponsors to upload the results of some clinical trials onto a trial registry within one year of trial completion, but these laws only cover around half of all trials. Our findings highlight the potential benefits of extending the scope of national legislation to cover all interventional clinical trials involving German patients.",
"keywords": [
"clinical trials",
"publication bias",
"research waste",
"germany",
"metastatic breast cancer",
"breast cancer",
"Clinical Trial Regulation",
"Medical Device Regulation"
],
"content": "Background\n\nNon-publication of clinical trial results violates medical research ethics as set out by the Declaration of Helsinki,1 leaves gaps in the medical evidence base, can harm patients, and contributes to research waste.2,3 The World Health Organisation recommends that the results of every interventional clinical trial should be made public on a trial registry within one year of trial completion.4 Trial registries offer a way to audit shortcomings in the reporting of trial outcomes in the academic literature.2,5–8\n\nA recent study found that 30% of clinical trials run by German university medical centres had never made their results public, neither on trial registries nor in the academic literature. Only 43% of trials had published results within two years of completion.9 A subsequent study followed up a subset of those trials for more than nine years and found that 29% had still not reported results. In addition, for trials that did publish, the median time to publication was 3.4 years, far in excess of the one-year timeframe recommended by the WHO.10 Similar reporting gaps and reporting timelines have been documented across the five Nordic countries.11\n\nWhile research waste in German academic trials is thus well documented, research waste in Germany related to a specific disease area across non-commercial and commercial sponsors has not previously been assessed.\n\nOne in eight women in Germany develop breast cancer in their lifetimes, and around one in four of those cancers eventually metastasises.12 Metastatic breast cancer is currently nearly always incurable; 74% of German patients die within 5 years of being diagnosed.13 Many existing treatment options carry significant harms.12 Therefore, there is an urgent need to develop more effective and less harmful treatment options.\n\nThis study seeks to fill a gap in the literature by assessing the publication status and publication speed of clinical trials involving German women with metastatic breast cancer across all sponsor types and regulatory categories.\n\n\nLegal framework for clinical trial reporting in Germany\n\nCurrent German laws pertaining to clinical trial outcome reporting differentiate cover only investigative drug trials and (some) medical device trials. All other clinical trials are not required to report results under federal law. According to a recent estimate, around half of clinical trials run in Germany are not subject to any legal reporting requirements14 (Table 1)\n\nSince 2014, sponsors have been obliged to disclose the results of Clinical Trials of Investigative Medicinal Products (CTIMPs) on the European EudraCT trial registry within one year of trial completion. This long-standing regulatory guidance became legally binding under German national law when the EU Clinical Trials Regulation became fully applicable in the wake of the launch of Europe’s successor registry CTIS during 2022-2023.15 With minor exceptions, sponsors of CTIMPs are legally obliged to disclose the results of all CTIMPs registered on CTIS within one year of trial completion at most.16 Under German law, sponsors that fail to do so risk a fine of up to 25,000 Euros.17 Depending on the type of CTIMP, either BfArM or Paul-Ehrlich-Institut (PEI) is the responsible German regulator, with BfArM regulating the large majority of CTIMPs. Thanks to strong engagement by both regulators, future compliance with CTIMP reporting requirements is likely to be very strong.14\n\nThe EU Medical Device Regulation requires the results of certain trials of medical devices to be made public within one year of study completion on the new Eudamed database.18 This provision has been integrated into German law.17 However, the European Commission has repeatedly delayed the full launch of Eudamed, leaving sponsors in Germany and elsewhere in Europe confused about regulatory expectations. German device studies falling within the scope of the European regulation are overseen by BfArM, which seems likely to face an uphill struggle in securing compliance in coming years.\n\nFor the purpose of this study, ‘other trials’ are defined as interventional studies listed on a clinical trial registry that fall outside the scope of European drug and medical device regulations. Examples include trials of surgical techniques, physiotherapy, or behavioural interventions. There is no legal requirement to make public the results of such trials under European law or German federal law. Those trials are instead regulated by provisions set out individually by Germany’s 16 federal states, none of which appears to mandate or monitor results reporting.17 Therefore, it is currently completely legal in Germany for sponsors of such trials to recruit and treat patients and later not make study results public. The Working Group of Medical Ethics Committees in Germany has called for lawmakers to adopt legislation that fully reflects Declaration of Helsinki requirements.19\n\n\nMethods\n\nThis study was preregistered on OSF (https://osf.io/gc7xm). A UK Health Research Authority NHS REC ethics waiver was secured on 20 October 2022. The study protocol, dataset, literature search guide, ethics waiver and sponsor responses are publicly available on GitHub (https://github.com/TillBruckner/GermanMBC). Outcomes are reported in line with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guideline for cohort studies.20 This study did not receive external funding. The authors have no conflicts of interest to declare.\n\nGerman sponsors commonly use three WHO primary trial registries. CTIMPs are directly registered on EudraCT (which is now being replaced by CTIS) by the responsible German regulator. All other trials, including device trials, are commonly registered by sponsors or by individual investigators either on the American ClinicalTrials.gov or the German DRKS registries. Double and triple registrations of the same trial on different trial registries are discouraged by the WHO but are common.\n\nIn October 2022, a team member (DG) searched all three trial registries for interventional studies with at least one study site in Germany that had been completed or terminated between 01 January 2016 and 31 December 2020 that contained the term “metastatic breast cancer” in either the condition/disease, trial title, or ‘other terms’ field in their registry entries. He then downloaded all available trials that matched these criteria and removed duplicates, generating a cohort of 358 trials (flowchart in the protocol). We manually reviewed all 358 trials and removed those that had not enrolled women with metastatic breast cancer inside Germany, arriving at a final study cohort of 70 trials.\n\nWe (DS,TJ,OB,TIB,CC,KL,TP,AS,MV,RB,SR) then performed two rounds of systematic registry and literature search for the results of these 70 trials during November and December 2022. The first round involved: 1) checking ClinicalTrials.gov records for native tabular results and any linked journal articles either uploaded by the sponsor or automatically linked to the registry; 2) searching Google Scholar for the ClinicalTrials.gov NCT ID; and 3) searching Google Scholar using the trial title and listed primary investigators. A team member not involved in the original search (TB) reviewed the data and followed up on selected publications, including all that had been marked as difficult to classify. We then conducted a second round of systematic literature searches using PubMed covering all trials for we had not located any results. The search strategies used are described in detail in the study protocol.\n\nIn December 2022, a team member (TS) contacted the sponsors of all trials for which we had been unable to locate outcomes on the registry or in the scientific literature to check whether relevant publications had been overlooked. We used sponsors’ press offices as point of contact whenever possible. In January and February 2023, we sent reminder emails to those sponsors who had not responded to our initial outreach. All sponsors we contacted eventually responded.\n\nIn February 2023, a team member (DS) double-checked all data points against registry data and updated our dataset in line with recent changes. We double-checked all DRKS trial numbers and removed those no longer available on the DRKS registry due to a recent decision by the registry to remove legacy double registrations. On 08 March 2023, a team member (TB) performed a final search for the outcomes of the 4 trials that remained listed as unreported.\n\nAs per study protocol, we documented whether and when the 70 trials in our cohort had made their results public either on trial registries or in the scientific literature. For all trials, we tabulated the number of enrolled patients based on registry data as of February 2023.\n\n\nResults\n\nOur final cohort consists of 70 interventional clinical trials that had enrolled women with metastatic breast cancer within Germany, and that had been completed or terminated between 2016 and 2020.\n\nOut of the 70 trials in our cohort, 66 (94.3%) had made their results public either on a trial registry or in the scientific literature by March 2023. The outcomes of the remaining 4/70 trials (5.7%) remained completely unreported.\n\nThe average time from trial completion to results publication was 584 days (median: 406 days). Only 13/70 trials (18.6%) of trials had published results within one year as recommended by the WHO. In two cases, results had only been made public after more than five years.\n\nIn total, 22,907 women participated across all 70 clinical trials. Results for 3,657 participants (16.0%) had been made public within one year as recommended by the WHO. Results for 19,120 participants (83.5%) were made public after a delay of more than one year. Results for 130 participants (0.6%) remained unpublished (Table 2).\n\n* Outcome measure not pre-specified in protocol.\n\n\nDiscussion\n\nWe identified 70 clinical trials involving 22,907 women with metastatic breast cancer with study sites within Germany. Of those 70 trials, only 13 trials (18.6%) involving 3,657 trial participants (16.0%) had made their results public within one year of trial completion as recommended by the WHO.\n\nThe nonpublication rate of 5.7% that we found in this cohort is significantly lower than that found in other recent large-scale studies of German academic trials.9,10,21 Our study does not call these previous findings into question. Our far smaller cohort of only 70 trials is dominated by commercial sponsors and includes a higher proportion of drug trials; both factors are associated with higher reporting rates. We did not disaggregate reporting performance by type of sponsor, funding source or trial within our small cohort because we did not pre-specify such an analysis.\n\nWe located only 4 unreported trials. The sponsor of 1 trial (Merrimack Pharmaceuticals, NCT02213744 and 2014-003159-73, 133 participants) pledged to attempt to recover and report its results. As of 02 March 2024, Merrimack has yet to publish those results. The sponsors of the other 3 trials stated that they did not plan to make results public due to low recruitment numbers (3-11 patients); all 3 trials had been terminated early. In the latter 3 cases, the potential scientific value added by uploading the results onto a registry arguably does not justify the investment of finite researcher time. However, neither the Declaration of Helsinki nor current European and American reporting laws make any exceptions for terminated trials, and waiving reporting requirements for all terminated trials seems inappropriate considering that some trials may enrol hundreds of participants before being terminated. Going forward, a discussion regarding the appropriate ethical and legal rules for terminated trials might add value.\n\nDiscussions about research waste in clinical trials commonly focus on weakly designed or unreported trials. We believe that late reporting of results is another important form of research waste. Delays in making clinical trial results public can slow down the development and adoption of new or improved medical interventions. Late reporting lengthens the intervals between successive trials of the same intervention, and makes it impossible to for guideline developers, systematic reviewers, meta-analysts, and other medical researchers to access and integrate recent scientific evidence. Arguably, the value added of any given clinical trial result progressively depreciates over time. The one-year registry reporting timeframe recommended by the WHO is already a legal requirement for some trials in the United States and across all European Union member states, including Germany. In Europe, the reporting timeframe for paediatric drug trials is only six months. The largest commercial sponsors and many large non-commercial sponsors now comply with these rules, demonstrating that faster reporting of results is feasible. At least one European non-commercial sponsor has voluntarily committed to reporting all trial results within 12 months, regardless of the trials’ legal status.22\n\nThere is currently no legal or regulatory requirement to register or make public the results of around half of all clinical trials run in Germany, probably over 1,000 trials per year.14 Only 33/70 (47.1%) trials in our cohort were CTIMPs. From a patient, clinician and scientific perspective, the current regulatory approach of limiting reporting requirements to only drug and certain device trials is irrational, as ‘other trials’ for the same indications can be of equal or greater clinical and scientific importance. The UK has adopted a national strategy that sets out to ensure that every clinical trial in the country is prospectively registered and rapidly makes its results public.23 German policy makers should put into place a similar system.\n\nOur use of a methodology standardised across multiple projects and cohorts of clinical trials24 enabled us to increase the efficiency of protocol development, project management and results reporting. We urge other researchers in this field to integrate outreach to trial sponsors into their methodologies, both to improve the quality of their own data25 and to drive improvements in actual reporting performance. Our small project may yet lead to the publication of trial data for 133 women with metastatic breast cancer that would otherwise have been lost forever.\n\nThis study provides the first overview of the publication status and speed of clinical trials involving German women with metastatic breast cancer. The study was pre-registered and the underlying materials and datasets made public. Data quality was safeguarded through two independent rounds of structured literature searches combined with direct outreach to sponsors that generated a 100% response rate. We verified the reporting status of every unreported trial in our cohort with responsible parties.\n\nOur cohort is limited to 70 trials. Our methodology was unable to capture trials that were not registered on one of the three registries commonly used by German researchers. Trial recruitment figures are taken from registry data, which aggregates recruitment numbers over multiple countries and in some cases may be inaccurate. We may have failed to locate the earliest publication for a minority of trials whose outcomes were reported more than once.\n\n\nConclusion\n\nLess than one in five clinical trials involving German women with metastatic breast cancer made its results public within one year as recommended by the WHO. Late reporting of results constitutes research waste. Major European and American sponsors’ strong compliance with legal reporting timeframes of one year for drug trials (Europe) and some medical device and drug trials (United States)26 illustrates that sponsors can set up systems that ensure rapid outcome reporting. German policy makers should enshrine this requirement in law for all interventional clinical trials and use the approval documentation of medical ethics committees to monitor compliance, as the UK is already doing.23\n\nThe lead author thanks Elisabeth Kerler for pointing out a mistake in the data analysis in an earlier draft of this manuscript.\n\n\nEthics statement\n\nThis study was based on publicly available data and did not require NHS REC ethics approval. A UK Health Research Authority NHS REC ethics waiver was secured on 20 October 2022.",
"appendix": "Data availability\n\nOSF Repository - “New German MBC Trials Project.” OSF. April 2. DOI: 10.17605/OSF.IO/YXUK8. 27\n\nThis project contains following data: This study was preregistered on OSF (https://osf.io/gc7xm). The study protocol, dataset of all clinical trials and their reporting status, literature search guide, ethics waiver and sponsor responses are publicly available on OSF. 27\n\nData are available on the OSF repository under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nOutcomes are reported in line with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guideline for cohort studies.\n\n\nReferences\n\nWorld Medical Association: World Medical Association Declaration of Helsinki. JAMA. 2013; 310(20): 2191. Publisher Full Text\n\nGlasziou P, Altman DG, Bossuyt P, et al.: Reducing waste from incomplete or unusable reports of biomedical research. Lancet. 2014; 383(9913): 267–276. Publisher Full Text\n\nChan AW, Song F, Vickers A, et al.: Increasing value and reducing waste: addressing inaccessible research. Lancet. 2014; 383(9913): 257–266. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: Joint statement on public disclosure of results from clinical trials.May 18, 2017. Accessed February 25, 2022. Reference Source\n\nGoldacre B, Drysdale H, Dale A, et al.: COMPare: a prospective cohort study correcting and monitoring 58 misreported trials in real time. Trials. 2019; 20(1): 118. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTang E, Ravaud P, Riveros C, et al.: Comparison of serious adverse events posted at ClinicalTrials.gov and published in corresponding journal articles. BMC Med. 2015; 13(1): 189. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchmucker C, Schell LK, Portalupi S, et al.: Extent of Non-Publication in Cohorts of Studies Approved by Research Ethics Committees or Included in Trial Registries. PLoS One. 2014; 9(12): e114023. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRosati P, Porzsolt F, Ricciotti G, et al.: Major discrepancies between what clinical trial registries record and paediatric randomised controlled trials publish. Trials. 2016; 17(1): 430. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRiedel N, Wieschowski S, Bruckner T, et al.: Results dissemination from completed clinical trials conducted at German university medical centers remained delayed and incomplete. The 2014 –2017 cohort. J. Clin. Epidemiol. 2022; 144: 1–7. PubMed Abstract | Publisher Full Text\n\nJansen MS, Dekkers OM, Groenwold RHH, et al.: Publication rates in small German trials remained low five years after trial completion. Contemp. Clin. Trials. 2022; 121: 106899. PubMed Abstract | Publisher Full Text\n\nNilsonne G, et al.: Results reporting for clinical trials led by medical universities and university hospitals in the Nordic countries was often missing or delayed. MedRxiv. 2024.\n\nKrebshilfe D: Patientinnenleitlinie: Metastasierter Brustkrebs.2018.\n\nIQWIG: Metastasierter Brustkrebs.\n\nStrech D: Transparenz in der klinischen Forschung: Welchen Beitrag leistet die neue EU-Verordnung 536/2014? Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2023; 66(1): 52–59. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEuropean Medicines Agency: Clinical Trials Information System reaches major milestone towards go-live and application of the Clinical Trial Regulation. Press Release. April 21, 2021.\n\nEuropean Parliament: Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use.May 27, 2014.\n\nBruckner T: Clinical Trial Regulation in Europe: Legal Reporting Requirements and Regulatory Strategies in Seven Countries.2022.\n\nEuropean Parliament: EU Medical Device Regulation.April 5, 2017.\n\nArbeitskreis Medizinischer Ethik-Kommissionen in der Bundesrepublik Deutschland e.V. Positionspaper: Notwendigkeit einer Pflicht zur Studienregistrierung.2012.\n\nvon Elm E , Altman DG, Egger M, et al.: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007; 370(9596): 1453–1457. Publisher Full Text\n\nWieschowski S, Riedel N, Wollmann K, et al.: Result dissemination from clinical trials conducted at German university medical centers was delayed and incomplete. J. Clin. Epidemiol. 2019; 115: 37–45. PubMed Abstract | Publisher Full Text\n\nFrench Cooperative Thoracic Intergroup (IFCT): Setting new standards for medical research transparency in France: IFCT. TranspariMED.\n\nUK Health Research Authority: Make it Public: transparency and openness in health and social care research.\n\nBruckner T, Yerunkar S, Basegmez O, et al.: Most clinical trials involving American children that violated FDAAA legal reporting requirements had not published outcomes in the scientific literature. medRxiv. Publisher Full Text\n\nBergen H: Har undersøkt status på registrering av forskningsresultat.\n\nNational Library of Medicine: FDAAA 801 and the Final Rule.2017. Accessed January 13, 2023. Reference Source\n\nBruckner T: New German MBC trials project. OSF data repository.2024, April 2. Publisher Full Text"
}
|
[
{
"id": "276565",
"date": "03 Jul 2024",
"name": "Merle-Marie Pittelkow",
"expertise": [
"Reviewer Expertise I have a background in (clinical) psychology but have since moved on to meta-research in (bio)medical sciences. I also have a strong interest in open and transparent research practices and have done some work in that area as well. While I have not published about clinical trial transparency",
"I now work in a research group which (partly) focuses on this topic and strongly support the notion that results of clinical trials need to be made public in a timely manner. While I did not have contact with the first author",
"I know that colleagues of mine did and have heard them talk positive about the person and collaboration. While I will try and remain reflective during my review",
"these positive reports might influence my judgement."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for giving me the opportunity to review this interesting piece. The authors present a thorough description of the state of results publication for interventional studies enrolling women with metastatic breast cancer inside Germany completed or terminated between 01 January 2016 and 31 December 2020.\nPositionality Statement:\nTo enable the authors and readers of this review to better understand and reflect on my comments, I would like to begin with a positionality statement.\nI have a background in (clinical) psychology but have since moved on to meta-research in (bio)medical sciences. I also have a strong interest in open and transparent research practices and have done some work in that area as well. While I have not published about clinical trial transparency, I now work in a research group which (partly) focuses on this topic and strongly support the notion that results of clinical trials need to be made public in a timely manner. While I did not have contact with the first author, I know that colleagues on mine did and have heard them talk positive about the person and collaboration. While I will try and remain reflective during my review, these positive reports might influence my judgement.\nReview:\nIs the work clearly and accurately presented and does it cite the current literature?\nI believe the work is presented clearly and cites the relevant, current literature.\nIs the study design appropriate and does the work have academic merit?\nWhile the authors do not explicate what the merit of focusing on a specific disease area is, I believe there is academic and societal merit in the work. I suggest that the authors add some information why focusing on a specific disease area is important as well as a paragraph on the specific aim of the paper to the Background section (see also the next comment).\nAre sufficient details of methods and analysis provided to allow replication by others?\nThe methods are clearly described in the manuscript and the study protocol on OSF provides great detail for how to replicate the manual search.\nHowever, I noticed discrepancies between the manuscript and the pre-registration that are not communicated in the manuscript. 1. While the pre-registration includes a somewhat exploratory hypothesis: “The study hypothesis is that the results of some clinical trials in the cohort are not made public at all, and that the results of the remaining trials are sometimes only made public in the academic literature more than 12 months post primary completion date.”, this hypothesis (which I believe is more of an aim) is not stated in the manuscript. Instead, the authors state “This study seeks to fill a gap in the literature by assessing the publication status and publication speed of clinical trials involving German women with metastatic breast cancer across all sponsor types and regulatory categories”. I believe that a short paragraph regarding the clear aim of the paper is currently missing.\n2. I also noticed one discrepancy between the preregistration and the manuscript. In the preregistration the authors speak of “the final cohort consists of 358 interventional clinical trials involving potential treatments for metastatic breast cancer conducted during 2016-2020 that involved at least one study site in Germany”. The manuscript however includes an additional screening step that I could not find in the preregistration, namely the manual review to check whether trials had enrolled women with metastatic breast cancer in Germany. I think it would be more transparent to highlight that this eligibility criteria was added post-registration and explain why.\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\nAre all the source data underlying the results available to ensure full reproducibility?\nThe authors provide two datasets on OSF https://osf.io/e5yn8. When downloading German_MBC_trials_DG20220909.xlsx, I noticed that the rows after row 77 appear scrambled. I would urge the authors to provide a clean dataset for reproduction.\nGerman_MBC_clinical_trials_TB20230311.xlsx seems to be the dataset containing the data needed to reproduce the results (a Readme file might help the user to navigate this). With this dataset and the information provided in the manuscript, I was able to reproduce the results manually.\n\nAre the conclusions drawn adequately supported by the results?\nYes, however there are a few open questions to me. Given that the authors argue that there is merit in investigating specific disease areas, I was wondering whether the authors would expect similar results for other specific disease areas (say other cancer types for example) or do they believe this to be a unique situation to metastatic breast cancer? If the reporting rate is so high in this specific area, what might be other areas with low reporting that might drive the results we see in similar publications? I would be interested in seeing the authors add some nuance to this discussion.\nAdditional comments:\n- the sentence “Current German laws pertaining to clinical trial outcome reporting differentiate cover only investigative drug trials and (some) medical device trials.” Includes a redundant “differentiate” - Table 1: depending on the targeted audience, it might be worthwhile to spell out the acronyms. - In general, the authors are using a lot of acronyms without first spelling them out. E.g., CTIS, BfArM.\nOverall, I think this is an important and well designed, and well reported piece of work and I understand my comments as relatively minor. I still hope that the editor and authors will find them useful in improving the manuscript.\nI sign all my reviews for transparency.\nSincerely, Merle-Marie Pittelkow\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-431
|
https://f1000research.com/articles/11-1221/v1
|
27 Oct 22
|
{
"type": "Software Tool Article",
"title": "CircSeqAlignTk: An R package for end-to-end analysis of RNA-seq data for circular genomes",
"authors": [
"Jianqiang Sun",
"Xi Fu",
"Wei Cao",
"Xi Fu",
"Wei Cao"
],
"abstract": "RNA sequencing (RNA-seq) technology has now become one of the standard tools for studying biological mechanisms at the transcriptome level. Advances in RNA-seq technology have led to the emergence of a large number of publicly available tools for RNA-seq data analysis. Most of them target linear genome sequences although it is necessary to study organisms with circular genome sequences. For example, by studying the infection mechanisms of viroids which comprise 246–401 nucleotides circular RNAs and target plants, tremendous economic and agricultural damage may be prevented. Unfortunately, using the available tools to construct workflows for the analysis of circular genome sequences is difficult, especially for non-bioinformaticians. To overcome this limitation, we present CircSeqAlignTk, an easy-to-use and richly documented R package. CircSeqAlignTk performs end-to-end RNA-seq data analysis, from alignment to the visualization of circular genome sequences, through a series of functions. Additionally, it implements a function to generate synthetic sequencing data that mimics real RNA-seq data obtained from biological experiments. CircSeqAlignTk not only provides an easy-to-use analysis interface for novice users but also allows developers to evaluate the performance of alignment tools and new workflows.",
"keywords": [
"R package",
"alignment",
"visualisation",
"small RNA-seq",
"circular genome sequence",
"viroid."
],
"content": "Introduction\n\nRNA sequencing (RNA-seq) technology can offer insights into various biological mechanisms, such as gene stress responses and plant-virus infection mechanisms (Vihervaara et al., 2018; Zanardo et al., 2019). The two essential processes for analysing RNA-seq data are aligning sequence reads to the genome sequence and summarising the alignment coverage. The widespread use of RNA-seq has encouraged the development of numerous tools for data analyses. For example, Bowtie2 (Langmead & Salzberg, 2012) and HISAT2 (Kim et al., 2019) are well-known tools for read alignment, whereas SAMtools (Li et al., 2009) and BEDtools (Quinlan & Hall, 2010) are for coverage calculation.\n\nThe application of RNA-seq technology to various organisms, including those with circular genome sequences, such as bacteria, viruses, and viroids, provides clues to solving important biological and social problems. For example, studying the infection mechanisms of viroids, the simplest known infectious agents containing single-stranded circular non-coding RNAs comprised of 246–401 nucleotides (Hull, 2014), on plants may prevent tremendous economic and agricultural damage (Soliman et al., 2012; Sastry, 2013). However, most existing tools are designed only for analysing RNA-seq data of organisms with linear genome sequences, such as animals and plants. Early efforts in developing tools to cater to such genomes often relied on complex workflows that involved a large number of tools written in different programming languages and were thus not user friendly, especially for non-bioinformaticians. Although several tools have recently been developed for aligning reads to circular genomes (Ayad & Pissis, 2017; Adkar-Purushothama et al., 2021), these tools often require advanced programming skills to compensate for a lack of rich documentation and example usage.\n\nHere, we present an easy-to-use R package, CircSeqAlignTk, which functions as a circular sequence alignment toolkit. It performs end-to-end analysis of RNA-seq data for circular genomes, mainly focusing on viroids. CircSeqAlignTk can be easily integrated with other R packages, enabling analysis to be accomplished in a uniform programming language environment.\n\n\nMethods\n\nCircSeqAlignTk is an R package registered in the Bioconductor repository with its source code available on the GitHub and archived in Zenodo (Sun, Fu & Cao, 2022). The package requires R (≥ 4.2) and runs on most popular operating systems (OSs) including Linux, macOS X, and Windows.\n\nThe workflow analysis with CircSeqAlignTk (Figure 1) begins with the preparation of two types of data. The first type is RNA-seq data in FASTQ format. This data can be obtained from biological experiments; for example, according to their research objectives, researchers may sequence small RNAs from plants which may be infected by pathogens using high-throughput sequencing platforms. Alternatively, data can be downloaded from public databases such as the Sequence Read Archive (Leinonen et al., 2011); usually, these data are published by other researchers worldwide and can be used for re-analysis and meta-analysis. The other type of data is organism genome sequence data (e.g., the circular RNA sequence of a viroid) in FASTA format, which can be obtained from public databases such as GenBank (Benson et al., 2013).\n\nAfter the preparation step, the build_index function implemented in CircSeqAlignTk builds two types of reference sequences from the input genome sequence for alignment: (i) type 1, the input genome sequence itself, and (ii) type 2, generated by restoring the type 1 reference sequence to a circular sequence by opening the circle at a position opposite to that of the type 1 reference sequence. Once the two reference sequences are built, the align_reads function is used for alignment through two stages: (i) aligning reads to the type 1 reference and (ii) collecting the unaligned reads and aligning them to the type 2 reference. The align_reads function allows users to choose either Bowtie2 (Langmead and Salzberg, 2012) or HISAT2 (Kim et al., 2019) for alignment. Alignment is performed by preferentially calling Bowtie2 or HISAT2, both of which are directly installed on the OS. However, if the tools are not available, align_reads will automatically call the Bioconductor packages Rbowtie2 (Wei et al., 2018) or Rhisat2 (Soneson, 2022) for alignment, which are installed automatically as dependencies of CircSeqAlignTk. Finally, the calc_coverage and plot functions can be used to summarise and visualise the alignment coverage according to the length and strand of the aligned reads, respectively.\n\nBesides performing end-to-end RNA-seq data analysis, CircSeqAlignTk also implements a function to generate synthetic sequence reads to mimic RNA-seq data that are sequenced from circular genome sequences using the generate_reads function. This function is intended for developers to evaluate the performance of new alignment algorithms and analysis workflows. To generate synthetic reads, users can specify certain circular genome sequences for read sampling and then include adapter sequences and mismatches by adjusting arguments.\n\n\nUse cases\n\nThe goal of use cases is to briefly overview the basic usage of CircSeqAlignTk functions. Herein, we show two use case examples: (i) analysis of small RNA-seq data sequenced from a viroid infection experiment and (ii) analysis of synthetic small RNA-seq data generated by CircSeqAlignTk. Additionally, the detailed usages of CircSeqAlignTk are documented in the package vignette and can be accessed with the browseVignettes function.\n\n\n\nFor a practical CircSeqAlignTk use case, we analysed a subset of small RNA-seq data sequenced from tomato plants that were experimentally infected with the potato spindle tuber viroid (PSTVd) isolate Cen-1. Herein, we show that aligning RNA-seq reads onto the genome sequence of PSTVd isolate Cen-1 and visualising the alignment coverage with CircSeqAlignTk. The sample RNA-seq data and the genome sequence of PSTVd isolate Cen-1 are included in CircSeqAlignTk and can be accessed with the system.file function.\n\n\n\nSince most reads in this RNA-seq data contain adapters with the sequence “AGATCGGAAGAGCACACGTCTGAACTCCAGTCAC,” we used AdapterRemoval (Schubert et al., 2016), which was implemented in the R package Rbowtie2 (Wei et al., 2018), to trim the adapters before analysis with CircSeqAlignTk.\n\n\n\nAfter the adapter removal, we built indexes of PSTVd isolate Cen-1 genome sequences using the build_index function and performed alignment using the align_reads function. Thereafter, we summarised the alignment coverage using the calc_coverage function and visualised the result using the plot function (Figure 2A).\n\nA. Alignment coverage of RNA-seq data from viroid-infected tomato plants. B. Alignment coverage of synthetic RNA-seq data generated by the CircSeqAlignTk functions.\n\n\n\nOne of the notable functions of CircSeqAlignTk is generating synthetic small RNA-seq data that mimics real RNA-seq data obtained from biological experiments. Herein, we used the generate_reads function to generate 10,000 small RNA-seq reads with 150 nucleotides and the adapter sequence “AGATCGGAAGAGCACACGTCTGAACTCCAGTCAC” to mimic real RNA-seq reads from plants infected by PSTVd isolate Cen-1. Additionally, we introduced two mismatches for each read with the probabilities of 0.1 and 0.01, respectively.\n\n\n\nThe above function generates synthetic reads by repeating the following operation: randomly cutting substrings from the whole genome sequence of PSTVd isolate Cen-1, adding the adapter, and introducing two mismatches with the specified probability. The location of random cutting and the length of reads can be stored into a variable, allowing users check these information as well as visualise the ground truth of alignment coverage of these synthetic reads (Figure 2B).\n\n\n\nThe generated reads are saved in FASTQ format. Users can use these reads to evaluate the performance of the workflow analysis by calculating the root mean squared error between the ground truth and outputs by the workflow.\n\n\n\n\n\n\n\n\nConclusions\n\nThe R package CircSeqAlignTk has promising potential for end-to-end analysis of RNA-seq data for circular genomes including bacteria, viruses, and viroids. In addition, it can also be extended to other organisms and organelles with circular genomes, such as mitochondria and chloroplasts. Given its easy installation, straightforward usage, and detailed documentation, the package will dramatically reduce barriers to analysing such RNA-seq data.\n\n\nSoftware availability\n\nSoftware available from: https://doi.org/doi:10.18129/B9.bioc.CircSeqAlignTk\n\nSource code available from: https://github.com/jsun/CircSeqAlignTk\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.7218032 (Sun, Fu & Cao, 2022).\n\nLicense: MIT",
"appendix": "Data availability\n\nZenodo: CircSeqAlignTk. https://doi.org/10.5281/zenodo.7218032 (Sun, Fu & Cao, 2022).\n\n- The datasets analysed in this manuscript are stored in the inst/extdata directory of CircSeqAlignTk package.\n\n\nAcknowledgements\n\nWe thank Yosuke Matsushita for insightful discussions and inputs.\n\n\nReferences\n\nAdkar-Purushothama CR, Sridharan lyer P, Sano T, et al.: sRNA Profiler: a user-focused interface for small RNA mapping and profiling. Cells. 2021; 10(7): 1771. PubMed Abstract | Publisher Full Text\n\nAyad LAK, Pissis SP: MARS: improving multiple circular sequence alignment using refined sequences. BMC Genomes. 2017; 18: 86. PubMed Abstract | Publisher Full Text\n\nBenson DA, Cavanaugh M, Clark K, et al.: GenBank. Nucleic Acids Res. 2013; 41: D36–D42. PubMed Abstract | Publisher Full Text\n\nHull R: Plant Virology (fifth edition). Plant virology. Cambridge, Massachusetts, US:Academic Press;2014. Publisher Full Text\n\nKim D, Paggi JM, Park C, et al.: Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 2019; 37: 907–915. PubMed Abstract | Publisher Full Text\n\nLangmead B, Salzberg S: Fast gapped-read alignment with Bowtie 2. Nat. Methods. 2012; 9: 357–359. PubMed Abstract | Publisher Full Text\n\nLeinonen R, Sugawara H, Shumway M: and on behalf of the International Nucleotide Sequence Database Collaboration. The sequence read archive. Nucleic Acids Res. 2011; 39: D19–D21. PubMed Abstract | Publisher Full Text\n\nLi H, Handsaker B, Wysoker A, et al.: The sequence alignment/map format and SAMtools. Bioinformatics. 2009; 25(16): 2078–2079. PubMed Abstract | Publisher Full Text\n\nQuinlan AR, Hall IM: BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010; 26(6): 841–842. PubMed Abstract | Publisher Full Text\n\nSastry KS:Impact of virus and viroid diseases on crop yields. Plant virus and viroid diseases in the tropics. Springer;Dordrecht:2013. Publisher Full Text\n\nSchubert M, Lindgreen S, Orlando L: (2016) AdapterRemoval v2: rapid adapter trimming, identification, and read merging. BMC. Res. Notes. 2016; 9: 88. PubMed Abstract | Publisher Full Text\n\nSoliman T, Mourits MCM, Oude Lansink AGJM, et al.: Quantitative economic impact assessment of an invasive plant disease under uncertainty – A case study for potato spindle tuber viroid (PSTVd) invasion into the European Union. Crop Prot. 2012; 40: 28–35. Publisher Full Text\n\nSoneson C: Rhisat2: R wrapper for HISAT2 aligner. R package version 1.12.0. GitHub.[October 6, 2022 accessed].Reference Source\n\nSun J, Fu X, Cao W:CircSeqAlignTk. Zenodo. [Dataset].2022. Publisher Full Text\n\nVihervaara A, Duarte FM, Lis JT: Molecular mechanisms driving transcriptional stress responses. Nat. Rev. Genet. 2018; 19: 385–397. PubMed Abstract | Publisher Full Text\n\nWei Z, Zhang W, Fang H, et al.: esATAC: and easy-to-use systematic pipeline for ATAC-seq data analysis. Bioinformatics. 2018; 34(15): 2664–2665. PubMed Abstract | Publisher Full Text\n\nZanardo LG, de Souza GB , Alves MS: Transcriptomics of plant–virus interactions: a review. Theor. Exp. Plant Physiol. 2019; 31: 103–125. Publisher Full Text"
}
|
[
{
"id": "228243",
"date": "13 Feb 2024",
"name": "Eric Soler",
"expertise": [
"Reviewer Expertise Genomics",
"epigenetics",
"bioinformatics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript titled “CircSeqAlignTk: An R package for end-to-end analysis of RNA-seq data for circular genomes” by Jianqiang Sun, Xi Fu, and Wei Cao describes a new tool dedicated to circular genome mapping in deep sequencing applications. While this tool could be of interest to scientists dealing with (small) circular genome sequencing, its accessibility to non-bioinformaticians/non-specialists could be improved (see comments below). We provide several suggestions to enhance the content of the manuscript.\nMinor comments:\nComparative Analysis: A comparative analysis of CircSeqAlignTk with existing tools would greatly enhance the manuscript. This comparison could focus on performance metrics, user-friendliness, and specific advantages of CircSeqAlignTk. Such analysis would provide a clearer picture of the tool’s place in the current landscape of bioinformatics software. Discussion of Limitations: A balanced discussion of any potential limitations of CircSeqAlignTk, or scenarios where it might not be the optimal choice, would provide a more comprehensive view of the tool. This discussion could guide users in making informed decisions about when to use this package. Future Work and Enhancements: Suggestions for future enhancements would be beneficial. This could include potential areas of expansion or integration with other bioinformatics tools and workflows. Implementation of an R Shiny Interface: Lastly, we strongly recommend the implementation of an R Shiny interface for CircSeqAlignTk completed by Docker integration. An R Shiny interface would significantly enhance the accessibility of the tool, especially for researchers who are not bioinformaticians. This user-friendly interface would allow a broader range of scientists to engage with and benefit from the tool, making it not just a powerful resource but also an accessible one. The ability to interact with CircSeqAlignTk through a graphical interface would streamline the analysis process and potentially increase the adoption and impact of the tool in the research community. Incorporating Docker into this solution would offer several advantages. It would not only make CircSeqAlignTk more accessible but also ensure its robustness, reproducibility, and compatibility with diverse computational environments. This approach could significantly expand the user base of CircSeqAlignTk and enhance its overall utility in the scientific community.\nIn conclusion, the manuscript presents a valuable tool for the analysis of RNA-seq data from circular genomes. The implementation of the suggested enhancements would, in our opinion, greatly increase the manuscript’s impact and the utility of CircSeqAlignTk to a broader scientific community.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "11464",
"date": "20 Jun 2024",
"name": "Jianqiang Sun",
"role": "Author Response",
"response": "Thank you for reviewing our manuscript and for your constructive comments. We have largely revised the manuscript according to your and other reviewers’ comments. Please check the revised manuscript. Additionally, below are our responses to the individual comments. Thank you for the constructive comments. Although many alignment tools have been developed for circular genomes, few specialise in viroid expression analysis. Among these, the sRNA Profiler (Adkar-Purushothama et al) is an alignment tool with similar purpose to CircSeqAlignTk. However, neither by checking the manual nor by reading the code we could not find the functionality to perform alignment and visualisation from FASTQ files. Thus, comparative studies were not possible due to the lack of software on the same basis as CircSeqAlignTk. We added the discussion about the limitations of CircSeqAlignTk in the revised manuscript. In brief, although CircSeqAlignTk provides a user-friendly analysis tool and therefore offers a way to adjust important parameters that may affect the analysis results, some minor parameter adjustments are not possible. Currently, research on viroid expression profiling focuses on mapping viroid-derived sRNAs to viroids and visualising their coverage. Our package covers all these operations and is promising enough to be stand-alone at the moment. However, since CircSeqAlignTk is one of Bioconductor packages, it can easily be used together with other R/Bioconductor packages. Additionally, we intend to update the package according to the direction of development and the needs of future research. Thanks for the constructive remarks, we have implemented the Shiny interface to access CircSeqAlignTk for end-to-end data analysis. Users can now create an instance with the `build_app` function and easily start the GUI with the `runApp` function. Additionally, as you know, the size of RNA-Seq data is generally large and using Docker requires mounting the directory, which is quite inconvenient for users unfamiliar with CUI. For this reason, we decided not to provide a Docker image at this stage."
}
]
},
{
"id": "254597",
"date": "20 Mar 2024",
"name": "Xueyi Dong",
"expertise": [
"Reviewer Expertise bioinformatics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the manuscript \"CircSeqAlignTk: An R package for end-to-end analysis of RNA-seq data for circular genomes\" by Jianqiang Sun, Xi Fu and Wei Cao, the authors introduced an R package CircSeqAlignTk for RNA-seq data analysis related to circular genome, including read alignment, coverage visualization and data simulation. The authors have clearly introduced the rationale for developing this package, how the alignment to circular genome works, and how to use this package. I only have several minor comments:\nThe authors should add more details on the definition of alignment coverage and explain how it is calculated in this package. More descriptions should be added to the captions of Figure 2 to help the readers interpret this figure. While the analyses are based on circular genomes, the visualization of alignment coverage was still on linear axes. I found it a bit hard to determine the end of the sequence coordinate in Figure 2 (i.e. are the blank space on the right end of x-axis regions with no coverage, or are they outside of the range of the genome?). Have you considered using circular plots? If applicable, the performance of CircSeqAlignTk should be compared to other tools for the same or similar tasks.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "11465",
"date": "30 Apr 2024",
"name": "Jianqiang Sun",
"role": "Author Response",
"response": "Thank you for reviewing our manuscript and for your constructive comments. We have largely revised the manuscript according to your and other reviewers’ comments. Please check the revised manuscript. Additionally, below are our responses to the individual comments. The coverage is calculated separately for forward and reverse aligned-reads from the BAM file using the `IRanges::coverage` function which counts the number of reads covering each position of viroid-genome. Thank you for pointing this out. We have revised the manuscript and Figure 2. Because the expression profile of viroids’ small RNA is often visualised in linear axes, this package visualises in a linear fashion by default. However, the vignette of this package introduces an example of visualisation with circular axes (https://www.bioconductor.org/packages/release/bioc/html/CircSeqAlignTk.html). Thank you for the constructive comments. Although many alignment tools have been developed for circular genomes, few specialise in viroid expression analysis. Among these, the sRNA Profiler (Adkar-Purushothama et al) is an alignment tool with similar purpose to CircSeqAlignTk. However, neither by checking the manual nor by reading the code we could not find the functionality to perform alignment and visualisation from FASTQ files. Thus, comparative studies were not possible due to the lack of software on the same basis as CircSeqAlignTk."
}
]
},
{
"id": "267951",
"date": "28 Apr 2024",
"name": "Alexander Zelikovsky",
"expertise": [
"Reviewer Expertise Computational genomics",
"RNA-seq and DNA-seq data analysis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article provides a comprehensive overview of the urgent need for packages tailored for non-bioinformaticians, addressing the challenges in analyzing circular genome data. However, there are some minor comments:\nThe authors primarily focus on the use of Bowtie2 and HISAT2 for alignment, neglecting to mention pseudoalignment algorithms like Kalisto. Including a brief description of such tools in the introduction would enhance the readers' understanding. Additionally, a comparative analysis of different alignment algorithms, along with the option to choose between them, would augment the robustness of the tool.\n\nWhile the package utilizes SAMtools and BEDtools for coverage computation, incorporating downstream analysis tools compatible with circular genomes would enrich the utility of the tool for users.\n\nEach figure in the article requires thorough explanation to aid interpretation, as they may be challenging to decipher at first glance. For instance, the coverage plot's significance is not easy to comprehend.\n\nTo attract non-computational users, it would be advantageous for the package to feature an easy-to-use graphical user interface (GUI), aligning with the intended accessibility for this audience.\nOverall, these suggestions aim to enhance the comprehensiveness and usability of the CircSeqAlignTk package for a wider range of users.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "11486",
"date": "30 Apr 2024",
"name": "Jianqiang Sun",
"role": "Author Response",
"response": "Thank you for reviewing our manuscript and for your constructive comments. According to reviewers’ comments, we have largely revised the manuscript and updated the software. Please find our point-by-point detailed responses to the reviewers’ comments, below. We will update the software to support kallisto and update the documentation of this package in the next scheduled release. Thank you for your suggestion. We plan to add functions for downstream analysis based on future needs. We modified the captions of figures in the revised manuscript. Thank you and other reviewers’ suggestions, we have already implemented the GUI and released it."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1221
|
https://f1000research.com/articles/13-428/v1
|
30 Apr 24
|
{
"type": "Study Protocol",
"title": "An evaluation of job satisfaction levels among ASHA workers at the Raipur PHC, Nagpur",
"authors": [
"Priti Bisane",
"Swapnil Inkane",
"Sonali G. Choudhari",
"Harshal G. Mendhe",
"Swapnil Inkane",
"Sonali G. Choudhari",
"Harshal G. Mendhe"
],
"abstract": "Background ASHA (Accredited Social Health Activists) are an essential connection between the community and health care providers, these guidelines were established by The Ministry of Health and Family Welfare, Government of India. An ASHA worker’s level of job satisfaction is influenced by societal, cultural, and economic factors. An ASHA worker who does not receive a sufficient salary will find it difficult to support their family. The ASHA employee is not at all satisfied with this issue. In earlier research investigations, ASHAs voiced unhappiness with the incentives and expectations of greater or regular income.\n\nObjectives To assess the job satisfaction of the ASHA workers in the selected area of Nagpur, Maharashtra and find the association between levels of job satisfaction with selected variables.\n\nMethods The sample for the study will be conducted by using Multistage Random sampling techniques. Data will be collected by using semi- questionnaires. All responses from the questionnaires will be collated in a Microsoft Excel file, encoded, and processed using chi squared test and SPSS version 26.",
"keywords": [
"ASHA workers",
"job satisfaction",
"health worker",
"workload"
],
"content": "Introduction\n\nIn 2005, a new initiative to improve health care in India was carried out by the Ministry of Health and Family Welfare, Government of India when it introduced Accredited Social Health Activists (ASHA) workers under its National Health Mission NHM.1,2 One of the important elements of the National Rural Health Mission is the provision of a trained female community health activist, ASHA workers are chosen from the identical village and caring for an average population of 1000. In hilly and tribal areas, on the other hand, it is possible to adapt this rule in order to take account of specific circumstances. ASHA will be the first stop for any health-related needs of underprivileged populations, particularly women and children who are having challenges for accessing health care.3\n\nNHM is the government’s primary programme for achieving the Millennium Development Goals, which include MMR, IMR, the control of particular diseases, improving the nutritional status of mothers and children, and enhancing the accessibility, availability, and acceptability of health facilities, particularly in rural areas.1\n\nThe main challenges are workload, lengthy working hours, fatigue in training and much time spent under the shade of a hot sun. They also stated that they had been ill due to their work on all national health programmes. The afternoon field visit walk has been described as being extremely stressful and exhausting by some ASHA employees, who also claimed that the excessive workload had affected their dedication and level of productivity.2\n\n“In this study, we will fill a gap in existing knowledge by examining and identifying factors that contribute to ASHA employees’ job satisfaction with Raipur PHC Nagpur, which has been relatively unknown until now.” The study’s findings will be beneficial in identifying the gap in ASHAs’ work satisfaction.\n\n\nAim and objectives\n\n\n\n- The study aims to gauge job satisfaction levels among A.S.H.A. workers and examine potential associations between job satisfaction and specific demographic variables.\n\n\n\n- To assess the workload of ASHA workers in Raipur PHC Nagpur, including their responsibilities, caseload, and work hours.\n\n- To measure the job satisfaction levels of ASHA workers in Raipur PHC Nagpur.\n\nWhat are the levels of job satisfaction among ASHA workers, and are there any significant associations between job satisfaction and specific demographic variables in this study?\n\nThe rate of job satisfaction among ASHA employees will significantly correlate with the chosen demographic factors.\n\n\nMethods\n\n\n\n1) Study design\n\nStudy design: An observational cross-sectional descriptive study.\n\nStudy settings: The study will be conducted at the Raipur PHC, Hingna Taluka, Nagpur. Hingna Taluka consists has 4 Primary Health Centres, namely Adegaon, Kanholibara, Raipur, and Takalghat, of which Raipur village was selected using simple random sampling. Raipur PHC targets close to 30000 population. The data from the study participants will be collected for a period of 2 months after obtaining approval from the Institutional Ethics Committee.\n\nStudy participants: ASHA workers working under Raipur PHC, Hingna and will include all the urban and rural ASHA workers who are working for a minimum of period of 1 year and are willing to give written informed consent. Remaining ASHA workers will be excluded from the study.\n\n2) Variables: Sociodemographic attributes of ASHA workers, Daily tasks, caseload, working hours, and job satisfaction levels.\n\n3) Data sources: A semi-structured validated questionnaire will be administered to ASHA workers in Raipur PHC to collect details about their sociodemographic profile, workload, and job satisfaction. Data pertaining to each variable of study will be collected using semi-structured questionnaire.\n\n4) Bias: To address recall bias, the questionnaire did not include any questions pertaining to their employment history or work experiences.\n\n5) Study size\n\nThe findings of a study done in the Tahsil Samudrapur reported that 72% of ASHA workers felt satisfied while working in Nagpur’s rural and urban areas.4 Considering that estimates as the basis, the sample size for the present study will be calculated as\n\n[Where, P-72; Q- 28, L (allowable error) – 9]\n\nAssuming a 10% non-response rate, the final sample size is 107.\n\n6) Quantitative variables: Age, Education, Work experience\n\n7) Statistical methods: Data will be entered in Microsoft Excel and analysis will be carried out using descriptive (frequency and percentages) and inferential statistics (Chi-square test to study the association between sociodemographic attributes and job satisfaction), at a p value of <0.05. Microsoft Excel will be used for statistical analysis. https://www.ibm.com/support/pages/spss-statistics-220-available-download\n\n\n\n- Informed consent: Every participant will be asked for their written informed consent.\n\n- Privacy and confidentiality: Personal information will be kept private, and strict confidentiality will be maintained.\n\n- Minimizing harm: Measures will be implemented to minimize potential harm or distress to participants during the study, primarily focusing on prioritizing their well-being. Participants will be ensured that the findings of the study will not have any impact on their professional careers.\n\n- Fairness and equity: The research will take steps to prevent bias and discrimination in participant selection, data analysis, and reporting to uphold fairness and equity.\n\n- Ethical review: Ethical approval for this study (SMHRC/IEC/2023/1603) was provided by the ethical committee of Shalinitai Meghe Hospital and Research Centre, Wanadongri (Nagpur) on 12/April/2023.\n\nData collection will be done in the month of April and May 2024.\n\n\nDiscussion\n\nOne of the essential measures of the national rural health mission in India’s success is ASHA. Delivering the provided healthcare services to the people in rural India has taken all of their heart and soul. The primary concerns of ASHA employees are those relating to working conditions, job satisfaction, and rewards.2\n\nASHA is a female villager who has completed at least the eighth grade; however, this requirement may not be enforced in tribal regions. She is trained for 23 days over the course of a year and undergoes ongoing refresher training.5 There are currently more than a million ASHAs (1,047,324) serving everyone in the country, excluding Goa. There is about one ASHA among 879 people living in rural areas, with a wide range of interstate variations.3 As multitaskers, ASHAs played a significant role in bridging the gap between the public and the healthcare system by assuming the “social activist” responsibilities of health educators and facilitators of healthcare services. They have been shown to positively impact family planning, prenatal care, postpartum care, and healthcare-seeking behaviour.5\n\nIn addition to healthcare costs, work satisfaction strongly impacts quality, efficiency and effectiveness in healthcare workers. Professional satisfaction in health professionals is directly linked to absences from work, human relations and organizational arrangements, which also impact patients and the healthcare system as a whole.6 A survey on job satisfaction is regularly carried out in several countries, and if the data obtained are monitored, it may be possible to find that work organization still needs to be complied with.\n\nThe employment satisfaction of the ASHA workers is, in fact, a matter of economics, social conditions and culture. There will be problems for those ASHA workers who need more pay. This issue leaves the (ASHA) feeling far from satisfied.6\n\nRoles and responsibilities of ASHA\n\nASHA is an activist who aims to raise awareness on health and social determinants in a way that encourages the community to consider local health plans and encourage beneficiaries to use available healthcare services by the state. At this level, ASHA can also offer a minimal package of curative care where appropriate and practical and must promptly refer patients.7\n\nThey also have responsibility for Counselling (breastfeeding, complementary feeding, immunization, birth preparedness, safe delivery, Family Planning, breastfeeding),Escort for institutional delivery, Antenatal care, Postnatal care, Immunization, Family planning Detection, referral, confirmation, registration of cases (malaria, TB, leprosy, RTI/STI Survey of health and related events, Mobilize community and facilitate in accessing health and health-related services Organization of VHND, promotion of household toilets Depot holder of drugs such as ORS, condoms, oral pills, chloroquine, disposable delivery kit (DDK), IFA and chloroquine.8\n\nChallenges faced by ASHA workers\n\nJob satisfaction among ASHA workers is influenced by a multitude of challenges they encounter, including.\n\na. Low compensation\n\nR. Bhatnagar et al.’s9 study found that approximately 50% of ASHAs in the blocks it examined served a population of between 1000 and 1500 people. Every ASHA member routinely attends neighbourhood meetings and cooperates closely with the neighbourhood. Less incentives compared to their job were frequently cited as the source of dissatisfaction, particularly for ASHAs operating in tribal regions.\n\nb. Workload\n\nKawade A et al.,10 study conducted on 67 ASHAs from the two PHCs were studied. ASHAs worked up to 20 hours a week in their village of residence, providing services to about 800-1200 people despite a workload that left them harried and exhausted.\n\nc. Lack of training and skill development\n\nGuha I et al.’s11 study claimed that no additional education had been given, only basic training during the first stage of their time in uniform. A few people said their training was successful, but modification training was necessary. A few people also mentioned the need for training due to their need for more awareness of various national programs.\n\nLimitations – The study has a limitation: the findings may not be broadly applicable to all ASHA workers, the reliance on self-reported data introduces the potential for response bias, impacting the accuracy of job satisfaction assessments, and the finding may lack universal applicability beyond the unique circumstances of Raipur PHC.\n\n\nEthic and consent\n\nEthical approval for this study (SMHRC/IEC/2023/1603) was provided by the ethical committee of Shalinitai Meghe Hospital and Research Centre, Wanadongri (Nagpur) on 12/April/2023.\n\nInformed consent: Every participant will be asked for their written informed consent.",
"appendix": "Data availability\n\nNo data is associated with this article.\n\n\nReferences\n\nKori S, Bhatia M, Mishra A: A Cross-sectional Assessment of Knowledge of ASHA Workers. J. Krishna Inst. Med. Sci. Univ. 2015; 4(4): 57–63.\n\nBidari R, Ray S: Job satisfaction of Accredited Social Health Activist (ASHA). Eur. J. Mol. Clin. Med. 2020; 7(11): 20–26.\n\nNational Health Mission: ASHA Update July 2019.[cited 2023 Sep 16].Reference Source\n\nTaksande VD, Ashtankar PA, Bansod CR, et al.: To Assess the Job-Related Difficulties and Dissatisfaction of Asha Workers in Selected Rural Area. J. Evolution Med. Dent. Sci. 2021; 10(2): 98–101. Publisher Full Text\n\nAgarwal S, Curtis SL, Angeles G, et al.: The impact of India’s accredited social health activist (ASHA) program on the utilization of maternity services: A nationally representative longitudinal modelling study. Hum. Resour. Health. 2019; 17(1): 68. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVisser MRM, Smets EMA, Oort FJ, et al.: Stress, satisfaction and burnout among Dutch medical specialists. CMAJ. 2003; 168(3): 271–275. PubMed Abstract\n\nMishra A: The role of the Accredited Social Health Activists in effective health care delivery: evidence from a study in South Orissa. BMC Proc. 2012; 6(S1): P1. Publisher Full Text\n\nScott K, George AS, Ved RR: Taking stock of 10 years of published research on the ASHA programme: examining India’s national community health worker programme from a health systems perspective. Health Res. Policy Sys. 2019; 17(1): 29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBhatnagar R, Singh K, Bir T, et al.: An assessment of performance based incentive system for ASHA Sahyogini in Udaipur, Rajasthan. Indian J. Public Health. 2009; 53(3): 166–170. PubMed Abstract\n\nKawade A, Gore M, Lele P, et al.: Interplaying role of healthcare activist and homemaker: a mixed-methods exploration of the workload of community health workers (Accredited Social Health Activists) in India. Hum. Resour. Health. 2021; 19: 7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuha I, Raut A, Maliye C, et al.: Qualitative Assessment of Accredited Social Health Activists (ASHA) Regarding their roles and responsibilities and factors influencing their performance in selected villages of Wardha. Int. J. Adv. Med. Health Res. 2018; 5: 21. Publisher Full Text"
}
|
[
{
"id": "287138",
"date": "16 Sep 2024",
"name": "Ioannis Pantelis Adamopoulos",
"expertise": [
"Reviewer Expertise OCCUPATIONAL SAFETY AND HEALTH"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDEAR AUTHORS CONGRATULATIONS FOR THIS IMPORTANT AND FINE WORK !! It has the correct specifications, and approves : 1) Topics. 2) improve the quality of scientific paper, achieve indexing goals, and improve consistency and readability. Preserve flow of expression, Professional results, Improve structure and presentation, check plagiarism, also the Bibliographic editing, and Formatting finally improve the target of the journal. 3) All content presented in the manuscripts is perfect and follows the guidelines of journal, including opinions, abstracts, methods, statistical analysis and materials, results, images, discussions, and conclusions. The article is original research work and prototype ideas work. 4) Manuscripts using acceptable file formats use the layout options, depending on the length of the research articles, and keep the main text of the body below appropriate words. Grammar and punctuation standards should be followed when preparing the content. The international system of units should be followed in the representation of all units in the text, recommended structure of the of the manuscript follows. References: keep the proper method formatting and style guidelines. Contribution to the literature: the uniqueness and importance of this work in terms of research topics, its methodologies, and outcomes, this article enhances the scholarship in the subject. Ideas are presented clear, concise, and complete manner. Manuscript is free from any repetitions, irrelevant information, or unjustified generalizations. Theoretical framework is explicitly stated. All claims are backed up with evidence and references. Research problems’ position and significance in existing literature is emphasized. Chosen methodology is suitable for the problem. Study’s findings are well presented with sufficient discussions and comparisons to existing literature. Objective and convincing measures exist to support the validity and reliability of the methodology and results. Relevant literature is properly cited for the An evaluation of job satisfaction levels among ASHA workers at the Raipur PHC, Nagpur. And finally have completed the aims and scope of F1000 Research.\n\nI suggest: Please Accept the article as it is.\nWITH REGARDS The Reviewer\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-428
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https://f1000research.com/articles/13-427/v1
|
30 Apr 24
|
{
"type": "Research Article",
"title": "High levels of soluble P-selectin, neutrophil extracellular traps, and myeloperoxidase as risk factor of deep vein thrombosis in malignancy patients receiving platinum-based chemotherapy",
"authors": [
"Ni Made Renny Anggreni Rena",
"I Made Bakta",
"Ketut Suega",
"I Made Bakta",
"Ketut Suega"
],
"abstract": "Backgrounds Venous Thromboembolism (VTE) is a disease entity comprising Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). VTE events increase the mortality rate of patients with cancer receiving platinum-based chemotherapy. Soluble P-Selectin, Neutrophil Extracellular Traps (NET), and myeloperoxidase (MPO) are risk factors associated with DVT in malignancy patients receiving platinum-based chemotherapy. The purpose of this study was to determine the role of soluble P-selectin, NET, and MPO as risk factors for DVT in patients with malignancy receiving platinum-based chemotherapy.\n\nPatients and Methods This study used a case-control design (matched pair case-control study) based on age and gender. The case group consisted of subjects with DVT, whereas the control group consisted of subjects without DVT. The subjects were 31 in each case and control groups. Soluble P-selectin, NET, and MPO levels were measured in each group.\n\nResults The mean age of case group was 50.26±12.15 years meanwhile in control group was 52.81±11.64 years. In the case group, 71% of the subjects were female, whereas 51.6% of the control group were male. Most subjects, either in the case group (71%) or the control group (71%), used carboplatin. In the case group, cervix malignancy was the most common malignancy (32.3%), whereas in the control group, it was nasopharyngeal malignancy (25.8%). High soluble P-selectin level was a risk factor for DVT (OR 3.38, CI 1.180 – 9.780, p=0.02). A high NET level was also a risk factor for DVT (OR 2.88, CI 1.026-8.074, p=0.04). The high MPO levels in this study could not be proven as a risk factor.\n\nConclusions Soluble P-selectin and NET are risk factors that play a role in the pathophysiology of DVT through the pathomechanism of immunothrombosis induced by endothelial injury and activation of monocytes and neutrophils due to the use of platinum-based chemotherapy.",
"keywords": [
"Soluble P-Selectin",
"NET",
"MPO",
"risk factors",
"DVT"
],
"content": "Introduction\n\nVenous thromboembolism (VTE) is characterized by Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). Deep vein thrombosis (DVT) is a condition in which a thrombus forms in the venous system. Pulmonary embolism occurs when some of the thrombi released from deep vein thrombosis are trapped in the pulmonary circulation, thereby blocking blood flow to the lungs.1,2 A high prevalence of VTE, a number of related risk factors, and high mortality from VTE are global concerns. Data obtained from several studies in Western Europe, North America, Australia, and Argentina have recorded the incidence of VTE per year ranging between 1.75 and 2.69 per 1,000 individuals. Based on the IDENTIA study in 2016, which nationally recorded the incidence of Deep Venous Thrombosis (DVT) in Indonesia, the data showed that the incidence in the medically ill population was quite high at 37.1%.2\n\nVenous thromboembolism (VTE) is one of the main causes of morbidity and mortality in patients with malignancies. Approximately 20% of all VTE patients with either deep vein thrombosis (DVT) or pulmonary embolism (PE) have malignancy as the underlying disease. The risk of VTE in patients with cancer is estimated to be 5-7.5 times greater than that in the general population.1,3,4 Risk factors for VTE in patients with cancer can be grouped into three categories: patient-related factors (intrinsic and extrinsic), treatment-related factors, and cancer-related factors. The risk factors for VTE in cancer patients are the contributions of the three categories of risk factors, and the VTE risk caused by each risk factor is difficult to evaluate separately from one another.5\n\nCancer patients receiving chemotherapy have a six-fold increased risk of VTE compared with the general population. A study by Heit JA, et al. in 2005 the odds ratio was 6.5 and 4.1 for the occurrence of VTE in cancer patients receiving chemotherapy and cancer patients not receiving chemotherapy.5–7 Chemotherapy can induce a prothrombotic state through several mechanisms, including damage to the vascular endothelium by increasing the levels of procoagulant molecules and reducing endogenous anticoagulants. Chemotherapy can also induce tumor and endothelial cell apoptosis and cytokine release, leading to increased Tissue Factor (TF) expression and activity. Furthermore, chemotherapy triggers platelet activation and directly induces the expression of monocyte-macrophage TF.8\n\nPlatinum-based chemotherapy is a chemotherapeutic drug used to treat several types of malignancies. Platinum-based chemotherapy is widely used, covering about half of the patients undergoing chemotherapy.9 Platinum chemotherapy is a class of chemotherapy which is an inorganic compound that works through DNA binding and interferes with DNA repair mechanisms. In a retrospective review of VTE in patients with germ cell cancer treated with cisplatin and bleomycin-based chemotherapy, the risk of thrombosis was estimated to be 8.4%. A prospective evaluation of VTE in patients with non-small cell lung cancer (NSCLC) treated with cisplatin and gemcitabine showed a VTE incidence of 17.6%.8\n\nThe mechanism underlying platinum-class chemotherapy drugs to increase thrombosis is thought to involve several mechanisms, such as decreased protein C activity and increased von Willebrand factor. A separate in vitro investigation revealed that cisplatin induces platelet activation. Elevated von Willebrand factor (vWF) levels suggest endothelial injury, and are associated with cisplatin-induced arterial thrombosis.8\n\nIn addition, cisplatin can disrupt the balance of the cytokine profile by increasing Tumor Necrosis Factor (TNF), which is a procoagulant for endothelial cells and reduces prostacyclin synthesis, causing intravascular platelet aggregation. Endovascular damage occurs directly through free radical-induced lipid peroxidation in endothelial cells. This can lead to the thickening of the intimal tunica and platelet aggregation. in vitro evidence has shown that pharmacological doses of cisplatin increase TF activity in human blood monocytes without increasing TF expression.10\n\nCancer cells have the capacity to express specific adhesion molecules that allow for attachment to blood vessel walls and interactions with blood cells as well as activation of the procoagulant properties of stem cells, especially endothelial cells, leukocytes, and platelets. The adhesion of tumor cells to endothelial cells significantly initiates clotting in the vessel wall and subsequent thrombus formation. Several adhesion molecules have been described to have a role in the adhesion of various types of tumor cells to endothelial cells, such as P-selectin.11 Activated endothelial cells and platelets express P-selectin, which binds to cancer cells. P-selectin mediates binding to specific carbohydrate-containing ligands, such as P-selectin glycoprotein ligand-1, which is present on leukocytes and platelets. Thus, P-selectin supports the initial tethering of leukocytes to endothelial cells and activated platelets and mediates leukocyte attachment to endothelial cell surfaces.11\n\nChemotherapy also causes an increase in tissue factors and activates monocytes and macrophages, which in turn activate neutrophils. Neutrophil Extracellular Traps (NET), a histone net of DNA and proteases produced by activated neutrophils, are one of the markers of thrombosis. Its role in both venous and arterial thromboses has been demonstrated in several animal studies. Neutrophil Extracellular Traps (NETs) play a role in inducing cell interaction and activation, resulting in thrombosis. Histones from NET can activate endothelial cells and increase the release of von Willebrand factor (a glycoprotein important for platelet adhesion and aggregation). In 2018, Mauracher et al.12 found that increased histone citrullinated H3 (a biomarker for NET formation) was associated with an increased incidence of VTE in patients with cancer, whereas other NET biomarkers (DNA and nucleosomes) were associated with a higher risk of VTE during the first 3–6 months. These data demonstrate the importance of NET in the pathogenesis of cancer-associated thromboses.3\n\nMyeloperoxidase (MPO) is a heme protein secreted from activated neutrophils, monocytes, and macrophages, which mediates lipid peroxidation due to reactive processes.\n\nNeutrophil activation, degranulation, and release of MPO have been reported in arterial thrombosis, such as unstable angina and acute myocardial infarction, owing to their suspected proatherogenic nature. Therefore, MPO has been suggested as a potentially useful marker for the initial assessment of patients with acute coronary syndromes. While the role of MPO in VTE cases has not been widely revealed, several studies have reported that neutrophil-binding MPO was detected in venous thrombus on immunohistochemical examination.13\n\nDue to the high incidence of VTE and mortality in malignancy patients receiving chemotherapy, platinum is one of the most widely used chemotherapy classes in clinical practice, and is closely related to the incidence of VTE. It is very important to know the risk factors and mechanisms underlying the occurrence of VTE. Several risk factors, such as P-selectin, NETs, and myeloperoxidase, are thought to play a role. This encourages researchers to determine whether P-selectin, NET, and MPO play a role as risk factors for VTE, especially DVT, in patients with malignancies who receive platinum-based chemotherapy. This study aimed to determine the role of soluble P-Selectin, Neutrophil Extracellular Traps (NET), and myeloperoxidase (MPO) in the occurrence of Deep Vein Thrombosis, particularly as risk factors in patients with malignancy receiving platinum-based chemotherapy.\n\n\nMethods\n\nThis study used a case-control design (matched pair case-control study) based on age and gender. The study was conducted at the Polyclinic and Internal Medicine ward of Sanglah General Hospital Denpasar, which was conducted in December 2020 until the number of samples was met. Samples in the case group were cancer patients who received platinum-based chemotherapy, were treated at Sanglah General Hospital Denpasar, and experienced DVT. The control group included patients with cancer who received platinum-based chemotherapy and did not experience DVT. In each case and control group, 31 research participants were obtained by purposive sampling. Serum blood examination was performed to determine Soluble P-Selectin, NET, and MPO levels. Purposive sampling was performed on all patients with malignancy who received platinum-based chemotherapy at Sanglah Hospital who met the inclusion criteria and did not meet the exclusion criteria until the completion of the study. The explanation of the research design can be seen in Figure 1.\n\nWe then explain the benefits and objectives of the study, as well as the risks that may be experienced. If the patient voluntarily stated that they were willing to participate in the study, they were asked to sign an informed consent form. The informed consent given to research participants was written consent. This research has been ethically approved on 19 November 2020 by the Research Ethics Committee (KEP) Faculty of Medicine, Udayana University/Sanglah General Hospital Denpasar (No. 2303/UN14.2.2.VII.14/LT/2020).\n\nData on the questionnaire were collected through anamnesis, physical examination, and from the patient’s medical records, which included demographic data of the patient as well as previous medical history, surgery history, examination of vital signs, height and weight, general physical examination, signs of sepsis, heart defects, kidney disease, pregnancy, history of thrombosis, and liver disorders.\n\nSamples were determined for the case and control groups using the DVT diagnosis algorithm. The levels of Soluble P Selectin, NET, and MPO were measured in the blood. P-Selectin measurement used Human Soluble P-Selectin/CD62P Immunoassay while NET and MSO measurement used ELISA. All data obtained were statistically analyzed. Descriptive statistical analysis was used to describe the characteristics of the research subjects and the frequency distribution of several variables in this study, such as age, gender, type of malignancy, stage of malignancy, type of chemotherapy used, Well’s score, comorbid hypertension, and diabetes mellitus. Variables that scale numerical data and are normally distributed are displayed using mean and standard deviation. Categorical variables were presented as numbers and percentages. The results of the statistical analysis were presented in the form of distribution tables. Normality tests were performed using the Shapiro–Wilk test, and the data were normally distributed. To calculate the odds ratio of MPO levels, soluble P-Selectin and NET to Deep Vein Thrombosis using the Chi Square test based on a 2 × 2 table. The research protocol can be seen in Figure 2.\n\n\nResults\n\nThis study included 62 participants. Both the case and control groups included patients with malignancy who received platinum-based chemotherapy. The case group consisted of 31 patients with malignancy who received platinum-based chemotherapy and had deep vein thrombosis (DVT), while the control group consisted of 31 study subjects with malignancy who received platinum-based chemotherapy without deep vein thrombosis (DVT). The characteristics of the study participants are presented in Table 1.\n\n* Statistically significant at p < 0.05.\n\nRegarding the type of malignancy recorded in this study, the majority of cases were cervical, colorectal, or ovarian malignancies. The control group had nasopharyngeal and cervical malignancies (Table 2). Most of the samples during the study had non-metastatic clinical stages, both in the case and control groups. This is because patients with metastatic stage were mostly not administered chemotherapy due to their performance status; therefore, patients with metastatic stage were not recruited in this study.\n\n* Statistically significant at p < 0.05.\n\nAfter examining the levels of Soluble P-Selectin, Neutrophil Extracellular Traps (NET) and Myeloperoxidase (MPO) in this study, then based on the Area Under Curve ROC (Receiver Operating Characteristic) as shown in Figure 3, the cut-off point of the three variables was obtained and grouped the data into two categories, high and low.\n\nThe results of the examination of the levels of Soluble P Selectin, neutrophil extracellular traps (NET), and myeloperoxidase in this study were grouped based on the cut-off points obtained as shown in Table 3.\n\n* Statistically significant at p < 0.05.\n\n\nDiscussion\n\nBased on sex characteristics, the proportion of female subjects (74.2%) was higher than that of males (25.8%) in the case group, while in the control group, there were more males (51.6%). However, the sex difference between the two groups was not significant. A previous study in Japan found that female compared to males had a 2.32 times higher risk for VTE than men.14 A multicentre, prospective, observational registry study in 12 hospitals throughout Indonesia, including Sanglah Hospital Denpasar, showed that 54.19% of the sample was female and the remaining 45.81% were male.2 In this study, females were found more in the case group, related to the underlying malignancy, which is ovarian malignancy, cervical malignancy, and breast malignancy. Although few studies have investigated the effect of sex on the incidence of VTE and the relationship between sex and the location of VTE, a study conducted by Barco et al. in 2018 stated that even sex can have an impact on the characteristics that show symptoms and prognosis in patients with VTE.15\n\nRegarding the age limit of the research subjects, this study used adult patients (aged > 18 years) with an age range of 20–71 years. The mean ages of the two groups were not significantly different. In the case group, it was found with 50.26 ± 12.15 years, while in the control group, the mean age was 52.81 ± 11.64 years. Theoretically, advancing age increases the risk of developing VTE, and some studies have found that people over 60 years of age have a higher risk of developing VTE compared to those under 60 years of age.5 In this study, several samples obtained were patients with malignancies at a young age, such as osteosarcoma, cervical cancer, and Hodgkin’s lymphoma; therefore, the mean age of this study was less than 60 years.\n\nRegarding the type of malignancy recorded in this study, the majority of cases were cervical, colorectal, or ovarian malignancies. The control group had nasopharyngeal and cervical malignancies (Table 2). Most of the samples during the study had non-metastatic clinical stages, both in the case and control groups. This is because patients with metastatic stage were mostly not administered chemotherapy due to their performance status; therefore, patients with metastatic stage were not recruited in this study.\n\nCancer is associated with an increased risk of VTE, which in turn is associated with an increased risk of death in patients with all stages and types of cancer. Recent research on approximately one million cancer patients recorded in the University Health System Consortium database showed that 41,666 (4.1%) cancer patients experienced VTE in the hospital. A large observational cohort study showed that the types of cancer associated with the highest VTE rates were pancreatic, brain, ovarian, uterine, kidney, stomach, colon, rectal, and lung cancers. In these patients, the cancer sites associated with the highest incidence of VTE were the pancreas (8.1%), ovaries (5.6%), kidneys (5.6%), lungs (5.1%), stomach (4.9%), and brain (4.7%). The incidence of VTE is also high in patients with hematology malignancies such as leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, and myeloma, with VTE rates ranging from 4.2% to 5.0%.5,16\n\nBased on the data on the type of chemotherapy used by patients in this study, both in the DVT group and without DVT, most patients used carboplatin. A total, 71% used carboplatin chemotherapy, 19.4% used oxaliplatin, and 9.7% used cisplatin. In the group without DVT, 71% used carboplatin, 25.8% used cisplatin, and 3.2% used oxaliplatin. There was no significant difference between the two groups (p = 0.054). This retrospective study was conducted to estimate the risk of VTE development in patients receiving cisplatin chemotherapy. A total of 200 samples were treated with cisplatin chemotherapy and 200 samples were treated without cisplatin chemotherapy. The basic characteristics of the two study groups were similar. The results of this study showed that the incidence of VTE in the Cisplatin group was 2.8 times higher than that in the non-cisplatin group (95% CI 1.4 – 4.2).17\n\nThe results of this study support several previous studies regarding the role of Soluble P-Selectin in cancer patients as a risk predictor and as a diagnostic tool to detect the presence of VTE. Previous study showed 167 (93.82%) patients were suspected of having DVT and after a diagnostic examination, it was confirmed that 59 (35.33%) patients had DVT and 11 (6.18%) had pulmonary embolism. There was a significant difference in the mean levels of Soluble P-Selectin in this study (p < 0.001).5\n\nThe study by Vandy et al. reported that in a study conducted on all inpatients and outpatients for 3 years, 159 patients with confirmed DVT had statistically significant levels of Soluble P Selectin, D-dimer, CRP, and von Willebrand factor. In this study, the Soluble P-Selectin cut-off point used was > 90 ng/mL combined with Wells Score 2 as a DVT diagnostic tool with a specificity of 96%, positive predictive value of 89%, and negative predictive value of 77%.18\n\nA study conducted by Antonopaulus et al. found that Soluble P-Selectin levels increased after the occurrence of VTE (OR = 2.89, 95% CI = 2.31–3.61, p < 0.001) or DVT only (OR = 2.64, 95% CI = 1.95-3.56, P < 0.001). This study excluded patients with solid tumors and HIV-positive patients with lupus anticoagulants. The aggregated sensitivity and specificity of Soluble P-Selectin were 0.57 (95% CI = 0.30–082, p < 0.001) and 0.73 (95% CI = 0.51-0.90, p < 0.001) and the Diagnostic Odds Ratio (DOR) 4.31 (95% CI = 2.22–8.37, p < 0.01). The ROC curve showed significant Soluble P-Selectin accuracy (AUC = 0.74, p = 0.05). This indicates that Soluble P-Selectin is significantly increased in patients with DVT, with or without PE complications, with high diagnostic performance.19\n\nAnother study showed that there was a significant difference in Soluble P-Selectin levels between patients in the case and control groups, with a cut-off point of 70.5 ng/ml with a sensitivity of 98%, specificity of 100%, NPV of 96.8%, and PPV of 100%.19 Platinum-based chemotherapy induces thrombosis through several mechanisms including direct vascular endothelial damage, induction of cell apoptosis, and subsequent production of microparticles. In addition, platinum-based chemotherapy is also suspected to directly induce the activation of monocytes and macrophages that produce Tissue Factor (TF), and is able to induce an increase in von Willebrand factor.8 P-Selectin is one of a cell adhesion molecule (CAM) found on the surface of activated endothelial cells, which coat the inner surface of blood vessels and activated platelets. Soluble P-selectin is the soluble form of P-selectin in the circulation and is considered to be a key molecule in haemostasis and mediating the inflammatory process in thrombosis. Soluble P-selectin induces the production of procoagulant microparticles and increases fibrin deposition.20 Soluble P-selectin and P Selectin Glycoprotein Ligan-1 (PSGL-1) play a role in the interaction of platelets with neutrophils in the innate immune system and in the formation of Neutrophil Extracellular Traps (NET), known as NETosis, an important process in the immuno-thrombosis system.\n\nTheoretically, when viewed from the perspective of the Virchow Triad (stasis, endothelial injury, and hypercoagulability), in this study, an increase in Soluble P-Selectin levels in malignancy patients reflects a hypercoagulable (prothrombotic) condition, and the use of chemotherapy results in endothelial injury, thereby increasing the risk of thrombosis in cancer patients.5 The results of this study prove the hypothesis that high Soluble P-Selectin levels in malignancy patients using platinum-based chemotherapy can be used as a risk factor for DVT.\n\nThe administration of platinum-based chemotherapy to cancer patients increases the risk of developing DVT. Through several mechanisms that have been described, platinum-based chemotherapy mostly induces the process of thrombosis formation through endothelial injury and increased expression of tissue factors, thereby increasing activated monocytes and neutrophils as well as through platelet activation mechanism, thereby inducing the emergence of a NETosis process so that NET is formed.\n\nNeutrophil extracellular traps (NETs) are composed mostly of chromatin and neutrophil granular proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), and cathepsin G. The results of several studies have indicated that neutrophils are a major component of the intravascular immune response to circulating blood pathogens. As host protection against pathogens, neutrophils secrete neutrophil extracellular traps (NETs). In addition to the capacity of intracellular mechanisms to fight infection, neutrophils also utilize extracellular devices to protect the host from cellular damage caused by infection. Several studies have suggested a role for NETs in tumor progression, metastasis, and cancer-associated thrombosis.21,22\n\nThe role of NET in the mechanism of immune-thrombosis can occur through several pathways, such as direct activation of factor XII and binding to Von Willebrand factor in recruiting and activating more platelets. In addition, the enzymes contained in NET, such as neutrophil elastase (NE) and myeloperoxidase (MPO), are able to cause inactivation of endogenous anticoagulants, such as Tissue Factor Pathway Inhibitor (TFPI), and NET is able to bind directly to tissue factors and activate the extrinsic haemostasis system. The activation of intravascular blood coagulation and thrombus formation in microvessels (microvascular thrombosis) under certain conditions that support this intravascular immune mechanism is called immunothrombosis.21\n\nThe main player in the release of neutrophils from the chromatin nucleus, known as neutrophil extracellular traps (NET), is citrullinated histone H3 (H3Cit). The increase in plasma H3Cit reported in several studies was found to be significant in thrombotic patients compared to that in healthy individuals. Neutrophil analysis in thrombotic patients showed a greater proportion of H3Cit intracellular neutrophils than in healthy individuals. The presence of plasma H3Cit in thrombotic patients correlates strongly with the activation of the markers of neutrophil elastase (NE), myeloperoxidase (MPO), and the inflammatory cytokines IL-6 and IL-8, known as NETosis. H3Cit can be detected in the nuclei of neutrophils at the time of stimulation and released into the blood circulation at the time of NETosis.23\n\nThalin et al. suggested that H3Cit is a potential blood plasma marker for the diagnosis and prognosis of thrombosis and cancer. Examination of H3Cit in the circulating blood is crucial for diagnosis and prognosis.23 In this study, the authors used the H3Cit marker to represent NET produced in patients with malignancy undergoing platinum-based chemotherapy. The results of this study are similar to those of other studies that have been carried out, such as the cohort study by Mauracher et al., who found that high plasma NET levels, identified by the H3Cit biomarker, are a fairly specific prognostic indicator of an increased risk of VTE 2 years after diagnosis or recurrence in cancer patients. An increase in H3Cit to 100 ng/mL is known to increase the risk of VTE by 13%.12\n\nIn a cohort study followed for 2 years, it was found that cancer patients had elevated NET biomarkers, and 2.3% of them had arterial thromboembolism (ATE). An increase in H3Cit levels was also associated with an increased risk of developing ATE. This study also found that increasing H3Cit up to 100 ng/mL is known to increase the hazard ratio by 1.1 higher for mortality in patients with cancer.24\n\nThe studies were grouped into high and low, with a cut-off point of 644.14 ng/mL. High MPO levels were observed between the case and control groups with an Odds Ratio of 2.08 with a 95% Confidence Interval of 0.709 – 6.085. Myeloperoxidase (MPO) is a peroxidase enzyme that is synthesized and stored in the cytoplasm of neutrophils. MPO is mostly expressed in immune cells, such as leukocytes, polymorphonuclear neutrophils, lymphocytes, monocytes, and macrophages. MPO is secreted under certain conditions such as chronic inflammation, infection, and other conditions that involve the immune system. Activated neutrophils, monocytes, and macrophages release MPO at sites of inflammation.20 previous study examining the relationship between plasma DNA (including MPO) and DVT biomarkers (Von Willebrand Factor (VWF)), D-dimer, and P-selectin found a unidirectional relationship between plasma DNA levels compared to other DVT biomarkers.25 In the pathogenesis of VTE, it is known that one is caused by damage to the vascular endothelium, causing the induction of tissue factor and F.VII; thus, venous thrombosis is associated with the inflammatory process. Research using a murine model supports this by demonstrating the contribution of platelets, monocytes, and neutrophils to the process of thrombus initiation and propagation. Several recent studies have also shown a contribution to the formation of Neutrophil Extracellular Traps (NET) in venous thrombosis, and MPO is suspected that MPO is a component of NET.23 After inflammation due to vascular endothelial damage, endothelial cells secrete massive amounts of Von Willebrand Factor (VWF) and P-selectin. Secretion of these two components enhances platelet adhesion and leukocyte withdrawal and induces NET production. In addition, the production of cytokines by endothelial cells (IL-1β, IL-8, and ROS) accelerates NET formation.26\n\nAnother mechanism underlying the relationship between MPO and VTE is the increased consumption of Nitric Oxide (NO) that occurs as a result of the inflammatory process. MPO itself binds to NO in the process, resulting in an increase in NO consumption both through the inflammatory process and by MPO itself. This condition is thought to cause inflammation of the blood vessel endothelial cells, which worsens.26\n\nMPO is a biomarker of neutrophil activation and is involved in the pathogenesis of immune-thrombosis. Neutrophil activation, degranulation, and markers of MPO release are now widely used as biomarkers for unstable angina and acute myocardial infarction, which are thought to be proatherogenic and play a role in destabilizing atherosclerotic plaques. MPO is widely recommended as an early biomarker for patients with acute coronary syndrome. Venous thromboembolism (VTE) is a condition associated with excessive free radical production in a homeostatic system that has not shown much efficiency.26\n\nOne factor that can affect the results of the examination of MPO levels is that the MPO substrate is the same as the general peroxidase substrate. Additionally, myoglobin and haemoglobin are known to exhibit peroxidase activity, which may impair the results. Myeloperoxidase can be detected by cytometry, immunohistochemistry, or cytochemical staining. Some literature states that from existing studies comparing different levels of myeloperoxidase tests have not obtained satisfactory results, so further standardization and validation are needed.26 The results of myeloperoxidase (MPO) examination in this study were grouped into high and low, with a cut-off point of 644.14 ng/mL. High MPO levels between the case and control groups were not proven to be a risk factor for DVT in malignancy patients receiving platinum-based chemotherapy.13\n\nTherefore, Soluble P-Selectin and Neutrophil Extracellular Traps (NET) play a role in the pathophysiology of Deep Vein Thrombosis (DVT) in malignant patients who receive platinum-based chemotherapy. The pathomechanism is thought to be an immune thrombosis process, which is a new concept that is being developed. The presence of endothelial injury and activation of monocytes and neutrophils due to platinum-based chemotherapy induces the formation of NETosis, which is the initial initiation of thrombosis.\n\nThis research has been ethically approved on 19 November 2020 by the Research Ethics Committee (KEP) Faculty of Medicine, Udayana University/Sanglah General Hospital Denpasar (No. 2303/UN14.2.2.VII.14/LT/2020).",
"appendix": "Data availability\n\nFigshare: Data Tabulation.doc, https://doi.org/10.6084/m9.figshare.25398304.v1. 27\n\nFigshare: Informed Consent.docx, https://doi.org/10.6084/m9.figshare.25398298. 28\n\nFigshare: Data Collection Form.doc, https://doi.org/10.6084/m9.figshare.25398301.v1. 29\n\nFigshare: PROCEDURE AND METHODS (1).doc, https://doi.org/10.6084/m9.figshare.25398307.v1. 30\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgments\n\nThe author would like to thank all the parties who have always supported the author in conducting this research.\n\n\nReferences\n\nTambunan KL, Suharti C, Fadjari TH, et al.: Panduan Nasional Tromboemboli Vena. Jakarta: Perhimpunan Trombosis Hemostasis Indonesia (PTHI); 2018.\n\nTambunan KL, Kurnianda J, Suharti C, et al.: IDENTIA registry: incidence of deep vein thrombosis in medically ill subjects at high risk in Indonesia: a prospective study. Acta Med. Indones. 2020; 52(1): 14–24. PubMed Abstract\n\nAbdol-Razak NB, Jones G, Bhandari M, et al.: Cancer-associated thrombosis: an overview of mechanisms, risk factors, and treatment. Cancers (Basel). 2018; 10(10): 380. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRiondino S, Ferroni P, Zanzotto FM, et al.: Predicting VTE in cancer patients: candidate biomarkers and risk assessment models. Cancers (Basel). 2019; 11(1): 95. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFernandes CJ, Morinaga LTK, Alves JL, et al.: Cancer-associated thrombosis: the when, how and why. Eur. Respir. Rev. 2019; 28(151): 1–11.\n\nHeit JA: Cancer and Venous Thromboembolism: Scope and The Problem. Cancer Control. 2005; 12(Supl(1)): 5–10. PubMed Abstract | Publisher Full Text\n\nHeit JA: Epidemiology of venous thromboembolism. Nat. Rev. Cardiol. 2015; 12(8): 464–474. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHaddad TC, Greeno EW: Chemotherapy-induced thrombosis. Thromb. Res. 2006; 118(5): 555–568. Publisher Full Text\n\nJohnstone TC, Park GY, Lippard SJ: Understanding and improving platinum anticancer drugs–phenanthriplatin. Anticancer Res. 2014; 34(1): 471–476. PubMed Abstract\n\nJafri M, Protheroe A: Cisplatin-associated thrombosis. Anti-Cancer Drugs. 2008; 19(9): 927–929. PubMed Abstract | Publisher Full Text\n\nAntonopoulos CN, Sfyroeras GS, Kakisis JD, et al.: The role of soluble P selectin in the diagnosis of venous thromboembolism. Thromb. Res. 2014; 133(1): 17–24. PubMed Abstract | Publisher Full Text\n\nMauracher L, Posch F, Martinod K, et al.: Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J. Thromb. Haemost. 2018; 16(3): 508–518. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLippi G, Cervellin G, Franchini M, et al.: Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future. J. Thromb. Thrombolysis. 2010; 30: 459–471. PubMed Abstract | Publisher Full Text\n\nOhashi Y, Ikeda M, Kunitoh H, et al.: Venous thromboembolism in patients with cancer: Design and rationale of a multicentre, prospective registry (Cancer-VTE Registry). BMJ Open. 2018; 8(5): e018910–e018916. Publisher Full Text\n\nBarco S, Klok FA, Mahé I, et al.: Impact of sex, age, and risk factors for venous thromboembolism on the initial presentation of first isolated symptomatic acute deep vein thrombosis. Thromb. Res. 2019; 173: 166–171. PubMed Abstract | Publisher Full Text\n\nStreiff BM: Association between cancer types, cancer treatments and venous thromboembolism in medical oncology patients. Clin. Adv. Hematol. Oncol. 2013; 11(6): 349–357. PubMed Abstract | Publisher Full Text\n\nZahir MN, Shaikh Q, Shabbir-Moosajee M, et al.: Incidence of venous thromboembolism in cancer patients treated with cisplatin based chemotherapy - a cohort study. BMC Cancer. 2017; 17(1): 57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAnghel L, Sascău R, Radu R, et al.: From classical laboratory parameters to novel biomarkers for the diagnosis of venous thrombosis. Int. J. Mol. Sci. 2020; 21(6): 1920. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaadeldin AA, El-Sakhawy YN, Hussien HA: Soluble p-selectin level in patients with deep venous thrombosis. Egypt J. Hosp. Med. 2018; 70(9): 1529–1538. Publisher Full Text\n\nKhanna AK, Vaidya M, Khanna S: Novel biomarkers in deep vein thrombosis. Venous Disorders. United States: Springer; 2018; pp. 129–135.\n\nEngelmann B, Massberg S: Thrombosis as an intravascular effector of innate immunity. Nat. Rev. Immunol. 2013; 13(1): 34–45. PubMed Abstract | Publisher Full Text\n\nFuchs TA, Brill A, Wagner DD: Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler. Thromb. Vasc. Biol. 2012; 32(8): 1777–1783. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThålin C, Lundström S, Seignez C, et al.: Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer. PLoS One. 2018; 13(1): 1–17. Publisher Full Text\n\nGrilz E, Mauracher LM, Posch F, et al.: Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer. Br. J. Haematol. 2019; 186(2): 311–320. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDiaz JA, Fuchs TA, Jackson TO, et al.: Plasma DNA is elevated in patients with deep vein thrombosis. J. Vasc. Surg. Venous Lymphat. Disord. 2013; 1(4): 341–348.e1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQi H, Yang S, Zhang L: Neutrophil extracellular traps and endothelial dysfunction in atherosclerosis and thrombosis. Front. Immunol. 2017; 8(928): 1–9.\n\nRena NMRA: Data Tabulation.doc. Data. figshare. 2024. Publisher Full Text\n\nRena NMRA: Informed Consent.docx. figshare. Journal contribution. 2024. Publisher Full Text\n\nRena NMRA: Data Collection Form.doc. figshare. Journal contribution. 2024. Publisher Full Text\n\nRena NMRA: PROCEDURE AND METHODS (1).doc. figshare. Journal contribution. 2024. Publisher Full Text"
}
|
[
{
"id": "296985",
"date": "18 Jul 2024",
"name": "Eko Adhi Pangarsa",
"expertise": [
"Reviewer Expertise Medical Oncology",
"Hematology (B cell malignancy)",
"Thrombosis Hemostasis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n- In the reference section please add citation author by (Setiawan et al. 2024) (Ref-1)about P-selectin and von Willebrand factor with the risk of DVT in chemotherapy patient published in Thrombosis (Springer Nature) Journal 2020 year.\n\n- Please the conclusion of this study suggestion for clinician if the patient has history DVT and undergoing platinum based chemotherapy, please elaborate if possible we change the regimen chemotherapy or add anticoagulant profilaksis.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "320045",
"date": "22 Nov 2024",
"name": "Irawan Cosphiadi",
"expertise": [
"Reviewer Expertise Hematology and medical oncology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear authors,\nThis study presents valuable insights into the role of soluble P-selectin, NET, and MPO as potential risk factors for DVT in cancer patients undergoing platinum-based chemotherapy. The authors have taken a systematic approach to measurement and analysis, employing appropriate case-control matching and utilizing ROC analysis to establish a cut-off for soluble P-selectin, NET, and MPO levels. These methods provide a solid foundation for understanding the biomarker profiles related to thrombotic risk in this population. The thoughtful inclusion of matched controls based on age and gender, along with the detailed measurement procedures, strengthens the study’s contributions to current research in immunothrombosis.\nHowever, some additional details and analyses could further refine and support the study’s findings.\n\nDespite the role of MPO in promoting oxidative stress and endothelial dysfunction, both of which are implicated in thrombosis, the study notes that MPO levels could not be proven as a risk factor for DVT. The explanation of the measurement methods and use of ROC analysis to determine the MPO cut-off point is helpful. However, further clarification and analysis could strengthen the interpretation of the findings:\nIf possible, detail any cross-reactivity validation of the ELISA kit used (Quantikine® Human MPO Immunoassay) to address concerns about interference from other peroxidases that was mentioned by the authors in the discussion section. Report the AUC, sensitivity, and specificity from the ROC analysis for the chosen MPO cut-off of 644.14 ng/mL. Explore MPO as a continuous variable to offer further insights into its relationship with DVT, potentially revealing associations missed by categorizing it as high/low.\n\nIt may strengthen the study’s conclusions to include a multivariate analysis, such as logistic regression, to adjust for potential confounders. Cancer type showed a statistically significant difference between cases and controls (p = 0.038), and variables such as type of chemotherapy (p = 0.054) and gender (p = 0.07) had borderline p-values and could be clinically relevant. A multivariate model would help clarify whether these factors independently predict the outcome. Given the sample size, a simple model including only a few key variables (e.g., cancer type, type of chemotherapy, and gender) may be appropriate to avoid overfitting.\nOverall, this study makes a valuable contribution to our understanding of thrombotic risk in cancer patients receiving chemotherapy. By incorporating these additional analyses and clarifications, the authors can further enhance the robustness and clinical relevance of their findings.\nBest regards, Cosphiadi Irawan\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "276428",
"date": "13 Jan 2025",
"name": "Shinta Wardani",
"expertise": [
"Reviewer Expertise Hematologi and Medical Oncology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is my short summary report of my Review. This article addresses the link between Soluble P-selectin, neutrophil extracellular trap (NETs) and Myeloperoxidase (MPO) as risk factors of Deep Vein Thrombosis in malignancy patients receiving platinum based that would be an important contribution for our data since this is the first data for Indonesian patients.\nThere are a number of issues that need to be clarified :\n1. In introduction mentions that VTE risk factors in patients with cancer can be grouped into three categories :\nPatient-related factor (intrinsic and extrinsic) Treatment-related factors and Cancer related factors\n\nbut it has not been explained in detail whether the position of soluble P-selectin, NETs and MPO is a patient-related factor, treatment-related factor or cancer related\n\nfactor. If it is a patient-related factor it could be a novelty data specific for Indonesian people.\n2. In this study the most common type in the case group was Cervical cancer and in the control group dominated by Nasopharynx cancer. I needs authors opinion about\n\nThese different types of cancer do not affect the level of P-selectin, NETs and MPO.\n\nIf differences in cancer type affect the levels of these three biomarkers maybe the author could give a brief additional information as your research limitation.\n3. In the last paragraph of page 10 noted that haemoglobin level is known to exhibit peroxidase activity which may impair the results of MPO level and might be the\n\nreason why MPO level was not proven to be a risk factor for DVT in your study result. Perhaps researchers can review the research data to see if there is a difference\n\nin mean haemoglobin between case and control group which can explain that the difference haemoglobin is a factor causing the insignificance of MPO results as a\n\nrisk factor for DVT\nSince only need minor revision I suggest to ACCEPT this article.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-427
|
https://f1000research.com/articles/13-426/v1
|
30 Apr 24
|
{
"type": "Research Article",
"title": "Computational simulation of the effects of blood flow velocity on atherosclerosis progression in a human carotid artery",
"authors": [
"Edith Alagbe",
"Temiloluwa Amoo",
"Osejie Oriaifo",
"Augustine Ayeni",
"Temiloluwa Amoo",
"Osejie Oriaifo",
"Augustine Ayeni"
],
"abstract": "Background Atherosclerosis is a build-up of low-density lipoproteins (LDL) in the channels of blood vessels. This occludes the vessels and, occurring in the carotid arteries, portends conditions that favour stroke. This work is an attempt to mathematically represent the physiological process of atherosclerosis caused by plaques on the walls of the human arteries.\n\nAim Provide insight into the effect of blood flow velocity on wall shear stress and its implications on atherosclerosis progression in a human carotid artery via computational simulation.\n\nMethods The effect of blood velocity on plaque growth and progression is simulated using COMSOL multi-physics. The human carotid was modeled in 2-D with Stokes law for model flow. The simulation began with a plaque-free vessel with velocities of 30 m/s – 125 m/s.\n\nResults Results showed that the rate of plaque initiation dropped as the blood velocity increased from 30 m/s to 125 m/s; higher inlet velocities gave lower plaque growth; the highest degree of 30% stenosis was recorded at a blood velocity of 30 m/s. Plaque height significantly affects the Plaque wall Stress, PWS, and its distribution around the plaque and arterial wall; higher plaque heights experience higher velocity distribution around the plaque, causing a higher force associated with blood flow around the plaque, resulting in higher compression stress. More compressional stresses are localized around the root, which would encourage growth as well as possible rupture at higher velocities. These ruptured plaques potentially narrow or block the arteries and prevent blood flow. This is atherosclerosis and can lead to a heart attack.\n\nConclusion Results from this study can find significant use in the understanding, management, and treatment of atherosclerosis since the regulation of blood velocity and pressure plays a major role in the progress of atherosclerosis in the carotid artery which raises the risk of stroke.",
"keywords": [
"CVD",
"plaque progression",
"blood velocity",
"atherosclerosis",
"arterial resistance"
],
"content": "Introduction\n\nStrong et al. (2007)1 highlighted that stroke was the second leading cause of death globally and the number one reason for neurological dysfunction in adults. In 2010, the Global Burden of Disease estimated that approximately 16.9 million individuals experienced a stroke each year 2 Following Alzheimer’s disease, stroke stands as the second leading cause of dementia, and it is associated with depression and fatigue.3 It has also been observed that there is now an increased incidence of ischemic stroke in the younger population, aged 55 and below, which has surpassed the incidence of myocardial infarction.4 Cardiovascular Diseases (CVDs) are also on the rise globally, which may be connected to vessel changes with age.5 Furthermore, as the world population is projected to be an aging population, the number of stroke cases is expected to rise, and it has been projected that by 2030, today’s numbers will rise by about 50%.6\n\nAtherosclerosis is a disease that propagates in large and intermediate blood vessels, usually arteries where fatty lesions are initiated and developed in the inner surface of the arterial wall (Tunica Intima). It occurs as a result of the hemodynamic processes in the blood and its interaction with the arterial wall. Atherosclerosis is usually initiated when dysfunctional damage to the arterial endothelial cells.7 Atherosclerosis is caused by the blockage or stiffening of arteries induced by plaque growth within the tunica intima of the arterial wall. This is a frequent cause of CVD (cerebrovascular diseases) – a major cause of morbidity, worldwide.7,8\n\nDuring flow, blood exerts a tangential force, “shear stress” on the endothelial surface of the blood vessel. In laminar flow, shear stress is predominantly high and helps with alignment in the flow direction and also, facilitates endothelial cell survival. On the contrary, turbulent flow gives low-shear stress that enhances endothelial proliferation and platelet aggregation.9 The pathogenesis of atherosclerosis is connected to deviations from normal shear stress, and it is imperative to fully understand the impact of this abnormal shear stress.\n\nThe pathobiology of atherosclerosis is quite complex, being a function of multifactorial processes, and shear stress associated with blood flow has been an essential factor in the initiation and overall development of the disease.8 The control of physiological laminar shear stress is essential for normal vascular function, influencing vascular diameter regulation, inhibiting proliferation, reducing arterial wall inflammation, and preventing thrombosis.10,11 The wall shear stress on the vessel is paramount in regulating the athero-protective, normal physiology, and pathobiology, through complex molecular mechanisms that influence the initiation and progression of the diseases.11 Gibson et al. (1993)12 in their study, were able to show that shear stress is an independent local hemodynamic factor that can act independently of other known risk factors and direct correlations can be found between the disease progression and the wall shear stress, which is related to the velocity of the blood.\n\nWada and Karino (2000)13 theoretically investigated the effect of flow patterns and wall shear stress induced by the flow on LDL concentrations at endothelial boundaries which begin in childhood and advance in size and numbers over time.14 Results identified that the shear stress, among other factors, was responsible for a pile-up of LDL occurring at the vessel wall. The LDLs are laden with cholesterol that becomes fixed on arterial walls, forming plaques. The presence of plaques on the arterial wall perturbs blood flow which eventually leads to occlusion.15,16 Their work also revealed low LDL concentrations in regions of low shear stress.13,17 Plaque stenosis has been reported to present higher anterograde motion in patients with stenosed carotid arteries. This anterograde motion was found to be directly proportional to plaque severity, and blood flow patterns in stenosed carotid arteries notably gave better estimates of motion compared to non-stenosed arteries.18 Variations of blood flow within a blood vessel can lead to vessel occlusion in the presence of a thrombus. Our research attempts to give a clearer understanding of the effect of blood flow velocity on wall shear stress and its implications.\n\n\nMethods\n\nTwo domains (the arterial wall and lumen domains) were considered in the carotid artery 2-D straight model. It was assumed that the arterial wall was homogeneous, isotropic, and linear-elastic.19 The boundary conditions taken for the flow are described in Figure 1 and Table 1. Modified vessel dimensions on the carotid artery from previous work were adapted8 as indicated in Figure 1. The vessel and carotid model characteristics are presented in Table 1.\n\nThe diameter, length and thickness of the artery were taken as 6, 10 and 0.5 mm, respectively.\n\nThe assumption is that blood is Newtonian, incompressible, and viscous in carrying out Wall Shear Stress, and WSS (frictional forces exerted by the moving blood in the artery) studies in nature under the arterial conditions under investigation.23,24 Laminar flow was also assumed for the blood rheology for the conditions under investigation. That is, Reynolds number values are less than 2300. This completely rules out the turbulent considerations. In the absence of underlying risks, constant blood parameters are presumed throughout the flow process. The rheological properties and density of blood are assumed to be 0.0035 Pa.s and 1050 kg/m3 respectively.22\n\nSince arteries undergo constant deformation, a linearly elastic arterial wall was assumed during the cardiac cycle of blood flow.8 The linear elastic model has been observed to yield results that closely align with experimental data.25 The area under examination was the common carotid artery, with edge constraints implemented to ensure model stability during blood flow.26 For fluid-structure interaction between the domains, the remaining nodes were designated as free.19,27,28 The inlet velocity and traction boundary pressure were fully developed. Boundary conditions were applied at the artery’s inlet and outlet, respectively.11,20,29 A constant mean (inlet) velocity of exposure was assumed throughout time. A no-slip condition at the arterial wall was also assumed during the cardiac cycle. The distribution of velocity along the cross-section of the vessel is as defined in the work of Alagbe et al. (2022).8\n\nA fluid-solid interaction (FSI) system was taken as the arterial flow model – with a simultaneous interaction between the solid and liquid domains. Blood flow in the artery was simulated using Navier-Stokes equation, incorporating model equations of Alagbe et al. (2022)8 were used for the simulation.\n\nThe plaque’s geometry was simplified and simulated starting at the artery’s central length (5 mm). Plaque growth, forming an asymmetric blockage, extended from the arterial wall as it progressed.\n\nThe model equations by Alagbe et al. (2022)8 and Tang et al. (2008)30 for plaque initiation and development were adopted. This model gives a linear function expressed as;\n\nσ represents principal shear stress (Plaque Wall Stress, PWS) in KPa, and τ denotes flow shear stress (WSS) in Dyne/cm2. WTI measures the increase in plaque wall thickness in cm, reflecting the difference from the initial height. This model predicts the achievable plaque height relative to the initial height every 304 days, corresponding to one cycle of geometry update.\n\nFrom the modified work of Liu and Tang (2010),31 the two major stages of initiation and progression were adopted.\n\nInitiation Stage: A plaque-free artery is assumed before plaque formation. The blood flow in the plaque-free vessel is taken as the initial condition. Values of WSS and PWS are taken at plaque initiation. These values are used to obtain the WTI value. With this WTI, the plaque is now freshly initiated in a new domain.\n\nProgression Stage: Plaque growth is considered in relation to the initial plaque condition’s memory. The values for WSS and PWS are obtained from the fluid-solid interaction (FSI) model. By adding the WTI, the next plaque height was obtained. The steps are repeated and stopped at the expected time of exposure.\n\nThe stenosis severity is expected to increase with every geometry update, leading to an increase in plaque height. Stenosis severity quantifies the degree of arterial lumen blockage by the plaque, expressed in terms of luminal diameter. This obstruction limits blood flow in the axial direction.\n\nNavier-Stokes equation was solved with finite elements, quadratic velocity, linear pressure, and GMRES iteration, using COMSOL Multiphysics. The meshing used for the simulations were fine meshes as shown in Figure 2 because it guarantees an optimum between computational cost and result accuracy. For the developed carotid vessel geometry before the plaque is initiated, after implementing boundary conditions and selection of meshing protocol, the finalized geometry had 3 domains, 10 boundaries, and 8 vertices. The complete mesh consisted of 3078and 246 domain elements and 246 boundary elements respectively.\n\nThe meshing was done such that, they are more intricate around the boundaries and the wall/blood interface to ensure that the interactions between both domains are accurately computed.\n\n\nResults and discussion\n\nFrom Figure 3, it can be observed that there is a general decline in the rate of initiation of the plaque as the velocity of blood in the artery is increased from a minimum of 40 cm/s to 125 cm/s from its initial dimensions where there is no plaque (Figure 8). The variation of plaque initiation height with velocity shows a very strong linear relationship. On comparison of the change in plaque initiation height with velocity change, a 40 cm/s to 80 cm/s change in velocity (100% change) shows an approximate difference of -8.8% in plaque height, although this may seem like a small change, accumulated changes over the years could be significant in the determination of the period in time when the patient is at a high risk of stroke. Minimum and maximum stenosis within the velocity range occurred at 125 cm/s and 40 cm/s, respectively, with plaque heights 1.02 and 0.83 mm, indicating degrees of stenosis of 17 % and 13.8 %, respectively, indicating that persons with lower blood velocities would experience stroke earlier in life. The reason for this could be a result of the higher residence time usually associated with low velocities in plug flow systems; this leads to higher recirculation of blood within the region as well as more significant leaching of LDL into the permeable arterial wall within the region, at the end of this processes, the result is more stagnation and accumulation of biochemical cells.32 This buttresses the results of Liu & Tang (2010),33 where a higher flow rate was associated with lower plaque heights.\n\nLower inlet blood velocity favours a higher initiation of plaque growth.\n\nFigure 4 shows that as time progressed, the differential increase in plaque height reduced. The work of Liu & Tang (2010)33 buttresses this observation when a similar model was implemented in the coronary artery. It is also generally observed that lower blood velocity causes a higher differential increase in plaque deposition in the vessel over the years; the highest blood velocity of 45 cm/s studied produced the least amount of plaque deposition over the period. Figure 4 buttresses the initial study of Figure 3 that higher inlet velocities correspond to lower plaque growth, so also the plaque is observed to grow at a decreasing rate over the years; this is in line with the study of Stone et al. (1993)34 which showed that higher degrees of stenosis retards the rate of growth. The velocity at the neck of the stenosis is much higher compared to other parts, as indicated in the velocity band plots. This observation aligns with the earlier statement that higher velocities around the plaque do not favor plaque progression.33,35 A maximum differential plaque increase of 0.17 mm was recorded for an inlet velocity of 30 cm/s after the time-2 (604 days), and a minimum differential plaque height increase of 0.1 mm was observed for a velocity of 45 cm/s after the second year (608 days).\n\nThe plaque height is steadily higher for lower blood flow velocity over the period investigated.\n\nFigure 5 shows how the overall plaque height increases with time, causing more obstruction of the blood vessel termed “stenosis,” which is measured as the amount of the arterial lumen domain (measured as a function of diameter) the plaque has blocked. Initially, at the initiation of the plaque, there is a sharp increase in plaque height from 0 mm to around 1.0 mm (Figure 9) for all cases of inlet velocity; this is a result of the associated low WSS effect on the initiation of plaque; However, as the plaque continued to develop, as a result of diminishing differential plaque deposit (as indicated by the plaque progression curve getting dampened), the changes in height became significantly less compared to the initiation stage. After about five years, the carotid vessel that was exposed to the 30 cm/s blood velocity had the highest degree of stenosis of about 30% (Figure 10), as indicated by the overall plaque height of 1.78 mm, and the artery exposed to the 45 cm/s inlet velocity experienced the least plaque height of 1.32 mm equivalent to a stenosis degree of 22% (Figure 11). These values may not seem significant at this early stage. Still, as indicated by the curve trend, the plaque height of the 30 cm/s and 45 cm/s inlet velocities, the divergence between the two curves seems to widen as time elapsed (in this case, after each geometric update); this indicates that after a long period in time, the significance of overall plaque height would be too massive to overlook (Figures 10 and 11).\n\nFrom Figure 6, it can be observed that, on a general note, the peak WSS values are localized at the peak of the plaque. This observation is in tandem with that made by Razavi et al. (2011)22 in the study of the inlet velocity cycle in the carotid artery. It can also be observed that WSS values are relatively lower and flattened before and after the region of the plaque location. As indicated in Figures 8 to 11, velocity contour plots indicate that areas of high velocity are localized just above the stenosis neck (peak), which could have been responsible for high WSS values around that region of plaque growth. This corroborates the fact that high wall stress is caused by high flow velocity. A high difference of about 500 dyne/cm2 was observed between the far-developed stenosis of 80% and initial stenosis of 17%. Since high WSS values tend to retard plaque growth, this study gives a better insight into how high WSS values can go, depending on the level of stenosis and the probability or magnitude of plaque growth associated with these values. Taking a closer look at how WSS is distributed around the plaque, it can be seen that the lower region of the plaque tends to grow at a faster rate from lower WSS regions compared to the neck of the plaque.\n\nFigure 7 shows that the plaque height (measured in terms of the degree of stenosis) plays a significant role in PWS and its distribution around the plaque and the entire arterial wall. The higher the degree of stenosis, the more influential the PWS; 80% stenosis plaque neck experienced the maximum tensile stress of 0.3 kPa, while the initiation stage plaque neck experienced the minimum tensile stress of 0.09 kPa. Taking a holistic look at Figure 7 concerning Figures 8–11, higher plaque heights experience higher velocity distribution around the plaque, causing a higher force associated with blood flow around the plaque, resulting in higher compression stress. From the growth perspective, higher tensile stresses lead to a lower growth rate of the plaque and higher compression stresses lead to faster growth rates as indicated by the growth model in equation 1, this automatically implies that since higher plaque heights lead to higher tensile stresses around the plaque, hence, lower growths rates would be observed. However, as the plaque geometry increases in size, more compressional stresses are localized around the root, which would encourage growth as well as possible rupture at higher velocities. The PWS shock wave seen in Figure 7 at the region of arterial length 4 and 6 mm for 17.3% stenosis and 2 and 8 mm for 50% stenosis, could be a result of reflective backflow caused by the plaque obstruction.\n\nAt the plaque initiation stage, there is a sharp increase in plaque height from 0mm to 1.0 mm.\n\nSimulation for 5 years gives a 30% stenosed carotid artery at a blood velocity of 30 m/s.\n\nSimulation for 5 years gives a 22% stenosed carotid artery at a blood velocity of 45 m/s.\n\nWSS is seen to increase with plaque height.\n\nIt can be observed that blood velocity constitutes more force within the plaque as the plaque tends to resist the flow.\n\nFigure 12, shows the WSS distribution in the carotid artery model at plaque heights of 4.8 mm representing 80% of stenosis in the artery. Studies have shown that at this degree of stenosis, the plaque is usually in a very vulnerable state of rupture.34 This study gives insight into the WSS and PWS distribution at the stage of plaque development, insights for further growth of plaque would also be drawn. It can be observed that WSS values are generally extremely high with 125 cm/s inlet blood velocity showing the highest WSS of about 2800 Dyne/cm2 and 30 cm/s inlet velocity showing the lowest WSS value of about 500 Dyne/cm2. The implication for these high WSS values is that; WSS-associated growth would be unlikely around this region, WSS WSS-associated plaque growth is more likely at lower shear stress values below 400 Dyne/cm2.12,30\n\nAs earlier seen in Figure 7, which shows how PWS increases as stenosis height increases, Figure 13 also exhibits these characteristics between inlet blood velocity and the PWS. It can be conveniently inferred that blood velocity constitutes more force within the plaque as the plaque tends to resist the flow. At this 80% degree stenosis, the maximum tensile stress was experienced at the neck of the plaque with the value of about 4 kPa for a velocity inlet of 125 cm/s. This plot gives a revelation that at the root of the stenosis at vessel length 1 mm to about 4 mm for 125 cm/s to 30 cm/s respectively, relatively high compressive force is observed for 125 cm/s inlet velocity with the value of -10 kPa. This gives an insight as to how this compressive force could cause a possible rupture of the plaque at the root and also how blood flow with higher velocities in fully-developed plaques has a higher probability of rupture, hence leading to stroke. The maximum compressive PWS was higher than the maximum tensile PWS.\n\n\nConclusion\n\nThe results have shown that blood velocity is inversely related to plaque initiation rate and progression rate, although the variation of plaque growth with blood velocity in the artery is not overly significant, however, long-term exposure effects are significant, as this would determine the overall plaque height after a couple of years. It can also be concluded that WSS and PWS increased with blood velocity, at regions around the stenosis neck. Similarly, the WSS and PWS increased with the degree of stenosis. Regions farther from the point of initiation of the stenosis experience lesser WSS and PWS, therefore, as the plaque tends towards being fully developed, regions on the plaque, that are away from the neck of the plaque, that is, around the root, would tend to grow at a faster rate compared to the neck of the plaque, which could further affect the structural stability of the plaque.\n\nResults from this study can find significant use in the understanding, management, and treatment of atherosclerosis since the regulation of blood velocity and pressure significantly contributes to the onset and progression of atherosclerosis in the carotid artery, elevating the risk of stroke.",
"appendix": "Data availability\n\nMendeley Data: Dataset on blood flow velocity’s impact on atherosclerosis progression, https://doi.org/10.17632/cdx38fx5vp.1. 36\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAcknowledgements\n\nThe Team is appreciative of the publication fee support for this manuscript by the management of Covenant University and the collaborative support of the Brody School of Medicine at East Carolina University, Greenville NC.\n\n\nReferences\n\nStrong K, Mathers C, Bonita R: Preventing stroke: saving lives around the world. The Lancet Neurology. 2007; 6(2): 182–187. PubMed Abstract | Publisher Full Text\n\nFeigin VL, Forouzanfar MH, Krishnamurthi R, et al.: Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014; 383(9913): 245–255. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPinoit J-M, Bejot Y, Rouaud O, et al.: Post-stroke depression, another handicap. Presse Medicale (Paris, France: 1983). 2006; 35(12 Pt 1): 1789–1793. PubMed Abstract | Publisher Full Text\n\nGentil A, Béjot Y, Lorgis L, et al.: Comparative epidemiology of stroke and acute myocardial infarction: the Dijon Vascular project (Diva). Journal of Neurology, Neurosurgery and Psychiatry. 2009; 80(9): 1006–1011. PubMed Abstract | Publisher Full Text\n\nKomutrattananont P, Mahakkanukrauh P, Das S: Morphology of the human aorta and age-related changes: anatomical facts. Anatomy & Cell Biology. 2019; 52(2): 109–114. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJensen HA, Mehta JL: Endothelial cell dysfunction as a novel therapeutic target in atherosclerosis. Expert Review of Cardiovascular Therapy. 2016; 14(9): 1021–1033. Publisher Full Text\n\nRobinson RG, Jorge RE: Post-stroke depression: a review. 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Publisher Full Text\n\nGibson CM, Diaz L, Kandarpa K, et al.: Relation of vessel wall shear stress to atherosclerosis progression in human coronary arteries. Arteriosclerosis and Thrombosis: A Journal of Vascular Biology. 1993; 13(2): 310–315. PubMed Abstract | Publisher Full Text\n\nWada S, Karino T: Computational study on LDL transfer from flowing blood to arterial walls. Clinical Application of Computational Mechanics to the Cardiovascular System. 2000; pp. 157–173. Publisher Full Text\n\nTuran Y, Kozan A, Başkaya M: Management of lipid metabolism. Primer on Cerebrovascular Diseases. Elsevier; 2017; pp. 870–873.\n\nBouchnita A, Galochkina T, Kurbatova P, et al.: Conditions of microvessel occlusion for blood coagulation in flow. International Journal for Numerical Methods in Biomedical Engineering. 2017; 33(9): e2850. PubMed Abstract | Publisher Full Text\n\nOmonhinmin CA, Ajiboye IB: Medicinal Plants Research in Nigeria: An Output Analysis. Tropical Journal of Natural Product Research (TJNPR). 2021; 5(1): 1–6. Publisher Full Text\n\nAjanaku CO, Ademosun OT, Atohengbe PO, et al.: Functional bioactive compounds in ginger, turmeric, and garlic. Frontiers in Nutrition. 2022; 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTat J, Psaromiligkos IN, Daskalopoulou SS: Carotid atherosclerotic plaque alters the direction of longitudinal motion in the artery wall. Ultrasound in Medicine and Biology. 2016; 42(9): 2114–2122. PubMed Abstract | Publisher Full Text\n\nKumar N, Khader SA, Pai R, et al.: Fluid-structure interaction study of stenosed carotid artery considering the effects of blood pressure. International Journal of Engineering Science. 2020; 154: 103341. Publisher Full Text\n\nSaxena A, Ng E, Mathur M, et al.: Effect of carotid artery stenosis on neck skin tissue heat transfer. International Journal of Thermal Sciences. 2019; 145: 106010. Publisher Full Text\n\nStein JH: Carotid intima-media thickness and vascular age: you are only as old as your arteries look. Journal of the American Society of Echocardiography. 2004; 17(6): 686–689. PubMed Abstract | Publisher Full Text\n\nRazavi A, Shirani E, Sadeghi M: Numerical simulation of blood pulsatile flow in a stenosed carotid artery using different rheological models. Journal of Biomechanics. 2011; 44(11): 2021–2030. PubMed Abstract | Publisher Full Text\n\nJohnston BM, Johnston PR, Corney S, et al.: Non-Newtonian blood flow in human right coronary arteries: transient simulations. Journal of Biomechanics. 2006; 39(6): 1116–1128. PubMed Abstract | Publisher Full Text\n\nJohnston BM, Johnston PR, Corney S, et al.: Non-Newtonian blood flow in human right coronary arteries: Transient simulations. Journal of Biomechanics. 2006; 39(6): 1116–1128. PubMed Abstract | Publisher Full Text\n\nTorii R, Oshima M, Kobayashi T, et al.: Fluid–structure interaction modeling of blood flow and cerebral aneurysm: significance of artery and aneurysm shapes. Computer Methods in Applied Mechanics and Engineering. 2009; 198(45-46): 3613–3621. Publisher Full Text\n\nLønnebakken MT, Izzo R, Mancusi C, et al.: Aortic root dimension and arterial stiffness in arterial hypertension: the Campania Salute Network. Journal of Hypertension. 2016; 34(6): 1109–1114. PubMed Abstract | Publisher Full Text\n\nMisiulis E, Džiugys A, Navakas R, et al.: A fluid-structure interaction model of the internal carotid and ophthalmic arteries for the noninvasive intracranial pressure measurement method. Computers in Biology and Medicine. 2017; 84: 79–88. PubMed Abstract | Publisher Full Text\n\nTang D, Yang C, Ku DN: A 3-D thin-wall model with fluid–structure interactions for blood flow in carotid arteries with symmetric and asymmetric stenoses. Computers & Structures. 1999; 72(1-3): 357–377. Publisher Full Text\n\nValencia A, Villanueva M: Unsteady flow and mass transfer in models of stenotic arteries considering fluid-structure interaction. International Communications in Heat and Mass Transfer. 2006; 33(8): 966–975. Publisher Full Text\n\nTang D, Yang C, Mondal S, et al.: A negative correlation between human carotid atherosclerotic plaque progression and plaque wall stress: in vivo MRI-based 2D/3D FSI models. Journal of Biomechanics. 2008; 41(4): 727–736. PubMed Abstract | Publisher Full Text | Free Full Text\n\nComputer simulations of atherosclerotic plaque growth in coronary arteries. Molecular & Cellular Biomechanics. 2010; 7(4): 193–202. PubMed Abstract\n\nArzani A, Gambaruto AM, Chen G, et al.: Wall shear stress exposure time: a Lagrangian measure of near-wall stagnation and concentration in cardiovascular flows. Biomechanics and Modeling in Mechanobiology. 2017; 16: 787–803. PubMed Abstract | Publisher Full Text\n\nLiu B, Tang D: Computer simulations of atherosclerotic plaque growth in coronary arteries. Molecular & Cellular Biomechanics: MCB. 2010; 7(4): 193–202. PubMed Abstract\n\nStone PH, Gibson CM, Pasternak RC, et al.: Natural history of coronary atherosclerosis using quantitative angiography in men, and implications for clinical trials of coronary regression. The American Journal of Cardiology. 1993; 71(10): 766–772. PubMed Abstract | Publisher Full Text\n\nDhawan SS, Avati Nanjundappa RP, Branch JR, et al.: Shear stress and plaque development. Expert Review of Cardiovascular Therapy. 2010; 8(4): 545–556. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlagbe E, Amoo T, Oriaifo O, et al.: Dataset on blood flow velocity’s impact on atherosclerosis progression. Mendeley Data. 2024; V1. Publisher Full Text"
}
|
[
{
"id": "297728",
"date": "25 Jul 2024",
"name": "Ahmad Khairul Faizin",
"expertise": [
"Reviewer Expertise fluid mechanics",
"computational fluid dynamics",
"biofluid mechanics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAre sufficient details of methods and analysis provided to allow replication by others? comment: 1. simulation was set up with velocities of 30 m/s – 125 m/s in methods section, that's huge number for blood flow velocity, but in results and discussion, the set up of the blood velocity about 30 cm/s to 125 cm/s. So, which one is the correct? 2. please consider the non-Newtonian viscosity models can accurately describe shear-thinning nature of blood flow. 3. please add the Verification and Validation of Simulation Results, I suggest to put this section in your paper report.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "311052",
"date": "22 Aug 2024",
"name": "Hashnayne Ahmed",
"expertise": [
"Reviewer Expertise I am passionate about studying the movement of fluids",
"and I employ computational methods to gain a deeper understanding of these flows. This includes a particular focus on both atmospheric dispersed flow and the intricate dynamics of blood flow."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript investigates the impact of blood flow velocity on the progression of atherosclerosis within the human carotid artery using computational simulations. While the topic is of significant interest and relevance, the manuscript suffers from several fundamental flaws that hinder its contribution to the field.\n1. The language and overall presentation of the manuscript are poor. The manuscript contains grammatical errors, awkward phrasing, and inconsistencies that hinder the reader's ability to fully understand the content. A thorough revision is required to improve the clarity, coherence, and readability of the manuscript. 2. There is a discrepancy in the reported blood flow velocities: the methods section mentions velocities ranging from 30 m/s to 125 m/s, whereas the results section refers to velocities from 30 cm/s to 125 cm/s. 3. The manuscript assumes a Newtonian model for blood flow, which is a common simplification. However, considering that blood exhibits non-Newtonian behavior, especially in smaller vessels, the use of non-Newtonian viscosity models would provide a more accurate representation of the shear-thinning properties of blood. 4. The manuscript models blood flow as steady, but blood flow in arteries is pulsatile due to the cardiac cycle. Pulsatile flow has significant implications for wall shear stress and the development of atherosclerosis. The authors should consider including pulsatile flow in their simulations or, at the very least, discuss the limitations of using a steady flow assumption and how it might affect the results. 5. The current study models the carotid artery with a simplified geometry, but this approach may not be sufficient to capture the complexities of real arterial structures. Specifically, the carotid artery bifurcates into the external and internal carotid arteries, each with different hemodynamic properties. The lack of this bifurcation in the model could lead to inaccurate predictions of flow patterns and plaque development. 6. The approach to modifying the geometry to account for stenosis is not rigorous enough. 7. The literature review could be more comprehensive in covering recent advances in computational modeling of atherosclerosis with relevant citations and the use of non-Newtonian models. 8. The manuscript lacks a section dedicated to verifying and validating the simulation results. This is a crucial step in computational studies to ensure that the models used are accurate and that the results are reliable. 9. The discussion on how blood flow velocities affect plaque growth is informative but could be expanded. For example, the manuscript mentions that higher blood velocities are associated with lower plaque growth, but it does not sufficiently explore the physiological mechanisms behind this observation.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "311046",
"date": "30 Sep 2024",
"name": "Ebenezer Olubunmi Ige",
"expertise": [
"Reviewer Expertise Theorist",
"Biofluid Mechanics",
"Computational Mechanics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n(1)\n\nAuthors declare “Our research attempts to give a clearer understanding of the effect of blood flow velocity on wall shear stress and its implications.” The authors should clearly and specifically articulate the objective of the work, as the current statement is too generalized. (2)\n\nReference [16] and [17] do not have a direct relevance to the core subject matter discussed in this manuscript.\n\n(3)\n\nFig. 1: Simplifying the \"idealized\" carotid artery to a 2D rectangular geometry may adversely affect the accuracy of hemodynamic analysis and wall shear stress (WSS) predictions. Authors may note that key geometrical features such as bifurcation, curvature, and asymmetry are important for capturing flow separation, vortices, and secondary flows. (4)\n\nBased on (3) validating the results of the current study against established reports that employed more realistic geometries to analyze carotid arteries may strengthen the authors' use of Figure 1. (5)\n\nAuthors declare ‘ Two domains (the arterial wall and lumen domains) were considered in the carotid artery 2-D straight model’ Neither Figure 1 nor the other figures in the manuscript effectively capture the essence of this statement. (6)\n\nAuthor should support this statement with appropriate figure(s). ‘The plaque’s geometry was simplified and simulated starting at the\n\nartery’s central length (5 mm). Plaque growth, forming an asymmetric\n\nblockage, extended from the arterial wall as it progressed’ (7)\n\nSince the authors used models from Alagbe et al. (2022) and Tang et al. (2008), it would be beneficial to validate the current study against the findings of both Alagbe et al. and Tang et al. (8)\n\nThe authors are required to provide a rationale for selecting a velocity of 30 m/s and a simulation duration of 604 days.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-426
|
https://f1000research.com/articles/11-1006/v1
|
06 Sep 22
|
{
"type": "Research Article",
"title": "Automatic Vehicle Fueling System using PLC Controlled Robotic Arm",
"authors": [
"Chitra Venugopal",
"Bhuvaneswari Thangavel",
"Bhuvaneswari Thangavel"
],
"abstract": "The objective of this research is to design and develop a robotic arm for an automatic fuelling system using a PLC LogixPro simulation. The system includes the “FASS” concept, which is Fast, Accurate, Safe and Simple, to allow car users to have an efficient fuel filling system.\n\nThe design concept consists of three processes – identification of the vehicle, payment, and filling with the fuel. The first process identifies the presence of the car by the in-floor weight sensors. The weight sensor identifies the car, locks it in position, and activates the payment system. The second process activates the payment system. After payment is completed, the fuel cap will be opened to enable the system to start filling the fuel. If the payment doesn’t go through the car will be released, manual operation will be initialized, and the entire system will be reset. A timer is included in the payment section to process the payment. In the third process, the filling arm is extended to the car, the fuel cap is opened, the fuel pump is inserted into the tank, and fuel is directed into the tank. Once the tank is full, filling is stopped, the pump is ejected, the fuel cap is closed, and the arm returned back to its position. Thus, an automatic vehicle fuelling system is created to overcome the problems of poor safety and longer waiting time during peak hours.\nThe fuel cap is activated and deactivated by pressure and the sensor filler is stopped by a level sensor. The pump insert is activated and deactivated by a photosensor.",
"keywords": [
"PLC",
"LogixPro",
"Automatic Vehicle Fueling System",
"Ladder Logic",
"Pressure sensor",
"fuel pump",
"fuel cap",
"FASS"
],
"content": "1. Introduction\n\nThe COVID-19 pandemic has put a spotlight on the role of automation in businesses. Since human contact spreads the disease, machines now have a protective role. This has accelerated the number of robots in industrial applications. The number of vehicles on roads is increasing every day. As fuel stations are operated manually delays are caused and there are long queues, especially in front of gas pumps. During fuelling, drivers must expose themselves to extreme hot or cold temperatures and may also come into contact with dangerous fumes. Thus, an automatic vehicle fuelling system is proposed to overcome problems like poor safety, longer waiting times during peak hours, and the spread of COVID-19.\n\nPetroleum products are expensive. Hence the proper use and distribution of petroleum products is an important task in industries. Fuel stations are built to dispense gasoline and diesel into vehicles for commercial and non-commercial purposes.\n\nIn a study by Edward1 to automate the fuel pumping system, an RFID based automated petrol pump system was proposed. In this, the RFID system is used to implement the design tasks sequentially. In Ref. 2 an inventory management procedure is proposed by which the supervisor can find the detailed information of the entity. They can delete the record if they want. Several modules (product cost, staff management) and report forms, like daily pump reports, shift delivery reports, cumulative daily reports, and salary reports are incorporated into the proposed system. It has a password facility for each module for safety purposes.\n\nFuel stations are operated manually in Bangladesh, leading to delays. Ali Newaz Bahar et al. proposed an automated fuel management system that can maintain the account of the fuel stations to reduce corruption in transactions.3 It prints a receipt automatically after every transaction and can monitor the transactions from a remote place via the internet.4 presents an RFID technology-based fuel dispensing system. The proposed system prevents unauthorized fueling in Baghdad city. Based on the type of vehicle, each registered vehicle will have a specific amount of fuel.\n\nIn Ref. 5, a Raspberry Pi based automated fuel pumping system is analyzed. The proposed system aims to confirm the resetting of the transaction every time the fuel pump nozzle is placed back on the dispenser station. In this design, a Raspberry Pi camera and Bluetooth communication are used to reset the dispenser unit when the vehicle passes the dispenser unit. The results show the successful implementation of the automation process.\n\nM.Z.A Rashid et al. proposed an Automatic vehicle fuelling system that utilizes a positioning robot arm.6 They explored a new fuel dispensing system that allowed the robotic arm to move using its search head and extendable nozzle toward the fuel spot of the car sensors are used to identify the location and fuelling position of the vehicle.\n\nIn Ref. 7 Wavekar Asrar A et al. aims to design an electronic payment system by creating a prepaid card for petrol stations. In this design, RFID technology is used to automatically pay for petrol dispensed. In Ref. 8 a fuel filling automation process using RFID and GSM technology is discussed. This design uses an RFID card and card reader. When the user swipes the RFID card in the card reader installed in the fuel station, it reads the card information, such as the quantity of fuel to be dispensed, and calculates the amount to deduct from the card. Upon receiving confirmation from the user and the amount remaining in the card, the amount is deducted, and the fuel is dispensed. The GSM technology is used to facilitate the online recharge facility.\n\nAishwarya Jadhav et al. design a prepaid card for petrol bunk systems and also petrol dispensing systems using RFID technology.9 Use of an unmanned power pump requires less time to operate, is effective, and can be installed anywhere.\n\nSince fuel stations are operated manually, they are time-consuming and require more manpower. In Ref. 10 a self-operated petrol pump is proposed. The use of unmanned petrol pump requires less time to operate. It is effective and can be installed anywhere the customer self-going to avail the services the payment is done by electronic clearing system.\n\nM.B. pranto et al. Proposed an RFID based secure fuel monitoring method with low labour cost. The goal of this system was to avoid the dishonesty of pump labourers & car drivers toward car owners.11 This was achieved by developing a mobile application to trace a vehicle's fuel refill amount, refill cost, current and previous balance of the account & time of transaction. The users need to register themselves first to control their accounts.\n\nIn Ref. 12 an IoT-based automated petrol pump system for remote areas is proposed to advantage the petrol station owners. With this proposed smart petrol pump there is no need for a physical operator/person for the distribution of petrol. When a user needs to fill with fuel the vehicle first checks for pricing online in that specific portal designed for this petrol station. Then by selecting the nearby stations and pay for petrol amount. Then he proceeds go the station for filling.\n\n\n2. Methods\n\nThe functional diagram of the automatic fuelling system is shown in figure. The functional diagram is divided into three major sections – identification of the vehicle, payment confirmation, and fuel filling which are activated by the sensor inputs and controlled using PLC LogixPro programming.\n\nThe system is designed with a robotic arm. The armrests are in position and get activated when the car is parked in the designated space in front of the pumping station. The in-floor weight sensor is activated by the presence of the car which sends a signal to the PLC system indicating that the car has arrived at this pumping station. The PLC system activates the robotic arm and the payment system. Once the payment is successful, the robotic arm is extended to the tank position to fill the fuel. A photoelectric sensor (1) is used to track the position of the arm. When the arm is released from its position, the photoelectric sensor output sends a signal to the PLC to activate the pump insert motor. The opening of the fuel cap is identified by the photoelectric sensor (2). An ultrasonic sensor is used to identify the distance reached by the robotic arm to make sure that the arm has reached the tank position. The ultrasonic sensor and two photoelectric sensors are used to activate the pump insert motor. Once the pump is inserted into the tank, fuel filling happens until the tank level is reached. When the fuel filling is stopped, the pump eject motor is activated, to release the pump from the tank, and the fuel tank cap is closed, the arm is returned back to its original position and is ready for the next fuel filling.\n\nThe following algorithm explains the program which controls the entire automation operation.\n\n1. The built-in in-floor weight sensor senses the car and activates the payment sensor.\n\n2. Once the payment is completed, the arm is extended for fuel filling, if the payment is not completed, the system will be reset, and manual operation will be initiated.\n\n3. Fuel arm position sensor is used to activate the fuel arm motor\n\n4. Fuel arm position sensor and fuel arm and fuel arm motor activate the fuel cap opener.\n\n5. Fuel cap open sensor is used to activate the fuel pump insert motor\n\n6. A fuel pump insert sensor is used to start the fuel filling system\n\n7. The level sensor stops the filling once the tank reaches the full level\n\n8. The stop full sensor will eject the pump, the fuel cap will close, the arm will return to its position and the car will be released to move.\n\nOperation and address\n\nThe input components along with their addresses are shown in Table 1. The output components, along with their addresses, are shown in Table 2.\n\n\n3. Results and analysis\n\nThe PLC simulation program is simulated using LogixPro 500 (https://www.plclogix.com) I/O simulator switches.\n\nStep 1: Activate the system – Sensing the Car\n\n\n\nThe car sensor is activated by the limit switch. When the car sensor is activated, it activates the payment system.\n\n\n\nStep 2: The payment system activates the timer.\n\n#\n\nStep 3: When the payment is done at or before the timer bit is done, the fuel arm motor is activated.\n\n\n\nTo simulate the system, the ‘payment done’ signal is generated by using a push-button switch in the I/O simulator. To ensure the safety of the system, before activating the fuel arm motor, the fuel arm position detector, pump eject motor, fuel cap close sensor and car release sensor are disabled. Also, manual input is added to bypass the automatic system in case of any error in the automatic system.\n\n\n\nStep 4: If the payment doesn’t go through then release the car and reset the system.\n\n\n\nTo simulate this condition, the ‘payment not done’ signal is activated using a push-button switch in the I/O simulator.\n\n\n\nStep 5: Open fuel cap.\n\n\n\nTo simulate this condition, the fuel arm position sensor is simulated using a switch in the I/O simulator. For the safety of the system, the fuel cap close condition is used as normally closed in this statement. If the fuel cap is already opened, then the fuel cap opener will not operate.\n\n\n\nStep 6: Insert Pump.\n\n\n\nThe fuel cap sensor senses the opening of the fuel cap of the car tank. The fuel cap sensor and fuel cap opener activate the fuel arm insert motor. To simulate this step, the fuel cap sensor input is simulated by using a switch in the I/O simulator.\n\n\n\nStep 7: Fill Fuel\n\n\n\nOnce the pump is inserted into the tank, it will activate the limit switch which is the pump insert sensor. The full level sensor is a liquid level sensor used to identify the fuel level of the tank. It is used as a normally closed switch as a safety condition to avoid overfill. The pump insert sensor, full level sensor and pump insert motor condition activate the fuel fill start operation. To simulate this condition, the pump insert sensor input is used using a I/O simulator switch.\n\n\n\nStep 8: Pump Eject\n\nOnce the full level is reached, the pump eject motor is activated. The full level sensor is simulated using an I/O simulator switch.\n\n\n\n\n\nThis condition deactivates the pump insert motor, fuel cap opener, fuel arm motor and returns the robotic arm to its original position and releases the car. This can be seen from the deactivated output O:2/2, O:2/3, O:2/4, O:2/4, O:2/5, O:2/6.\n\n\n\nThus, the algorithm for the automatic fuelling system works in the failsafe mode and achieves the objective successfully.\n\n\n4. Conclusion\n\nThe application of PLC in industry is inevitable and is unexplored in the context of fuel filling stations so far. To avoid crimes happening in fuel filling stations due to manual operation and delays caused by manual operation, this automatic fuel filling is suggested. Also, the recent pandemic situation necessitates reducing physical distancing and exchanging of payment systems between customers due to which many fuel stations were closed during pandemic times. Also, the long waiting times during peak hours due to manual operation indicate a dire need for automatic fuel filling systems in this field of engineering. The design of the system considered for this study is explained in this paper. The programming was developed using LogixPro simulation and tested using the I/O simulator. The step-by-step test results were explained. The study shows that the algorithm was implemented successfully and is ready for hardware implementation.\n\n\nData availability statement\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "References\n\nEdward O: A research using remote monitoring technology for pump output monitoring in distributed fuel station in Nigeria. International journal of Advances in Engineering & Technology. January 2014; 6(6): 2408–2415.\n\nAmarnath MV, Bipin NN, Ajit SN, et al.: Resource Planning System for Petrol Station (Petro-Hash). International Journal of Advanced Research in Computer and Communication Engineering. February 2014; 3(2).\n\nBahar AN, Islam N, Hossain S, et al.: A New Automation Approach for Fuel Station Management System. Nevşehir Bilim ve Teknoloji Dergisi Cilt. 2015; 4(2): 99–107. Publisher Full Text\n\nAl Naima F, Hassan MM: Design and Implementation of RFID based fuel Dispensing system. International Journal of Computing & Network Technology. Sept. 2015; 3(3): 105–111. Publisher Full Text\n\nJadhav RA, Gawade M, Gawde S, et al.: A Review Paper on Automated Fuel Pump Security System. International Journal on Recent and Innovation Trends in Computing and Communication. 2015; 3(11): 6156–6158.\n\nRashid MZA, Shah HNM, Abdollah MF, et al.: Study of the Automatic Vehicle Fueling System using Robotic Arm Controlled via PLC. International Journal of Advanced Science and Technology. 2016; 89: 27–36. Publisher Full Text\n\nWavekar Asrar A, Patel Tosif N, Pathan Saddam I, et al.: RFID Based Automated Petrol Pump (IJSRD).2016; Volume 4(Issue 01). 2321-0613.\n\nRao SS, Prasad VS: Centralized automation of petrol bunk management and safety using RFID and GSM technology. 2017 International Conference on Intelligent Computing and Control (I2C2). 2017; pp. 1–5. Publisher Full Text\n\nJadhav A, Patil L, Patil L, et al.: Smart Automatic Petrol Pump System. International Journal for Science Technology and Management. April 2017; 6(04).\n\nDongarsane R, Dalavi P, Golandag S, et al.: Self-Operated Petrol Pump. International Journal of Advance Research, Ideas and Innovations in Technology. 2017; 3(2).\n\nPranto MB, Rahman MM, Zunayeed-Bin-Zahir: Vehicle Fuel Monitoring and Management using RFID authentication and Telematics Notification: An automated petrol refueling & notifying system. 2019 International Conference on Advanced Computer Science and information Systems (ICACSIS). 2019; pp. 477–482. Publisher Full Text\n\nRathod RB, Patil S, Gole A, et al.: Automatized IoT based E-Petrol Pump. International Research Journal of Engineering and Technology (IRJET). Apr 2020; 07(04)."
}
|
[
{
"id": "162216",
"date": "13 Feb 2023",
"name": "Francisco Javier Folgado",
"expertise": [
"Reviewer Expertise Microgrids",
"Hydrogen",
"PEM Electrolyzers",
"Photovoltaic",
"Renewable Energies",
"Automation",
"Internet of Things",
"Industrial IoT."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript covers an interesting R&D topic and fits the scope of the Journal. Nonetheless, the paper requires substantial modifications to its content and format to improve its quality and presentation in order to be accepted. Some considerations and recommendations are listed below.\nFirst of all, both the title of the paper and the content of the abstract do not accurately reflect the scope of the manuscript. In both, it is implied that all issues related to the development and design of the robotic arm will be addressed. However, the content of the manuscript only focuses on the development of the PLC control algorithm that will command the robot and its testing by means of a simulation. Therefore, the title of the document should be modified to clearly reflect the content of the paper.\nIn section 1. Introduction, the acronyms RFID and GSM must be defined before their use. Additionally, references used in the paper are cited in two different formats, a single format should be used for all references.\nContinuing with the Introduction section, this section reviews various articles related to automatic refueling systems. They highlight key aspects of each one or the technologies used. Following this literature review, the reviewer recommends including a paragraph expressly describing the novel aspects of the research carried out. In addition, if appropriate, authors are encouraged to include a comparative table grouping the common aspects of the reviewed works, as well as this paper. In this way, all the aspects of the literature review as well as the novelty of the article are summarized and presented in a visual and simplified way.\nA paragraph should be included detailing the objective and scope of the paper, clearly specifying that only the development of the control algorithm of the automatic refueling system by means of a PLC will be addressed, the results of which will be simulated.\nA common practice in scientific papers consists on providing a brief overview of the structure of the paper at the end of the Introduction. This reviewer suggests including such information for a better presentation.\nIn section 2. Methods, the operation of the presented algorithm is described. The heading of subsection 2.1 \"Design of the system\" should be deleted, since there is no other subsection within section 2.\nThe content of this section repeatedly describes how the algorithm works. Firstly, by means of the second paragraph of the section. Secondly, by means of a step-by-step description of the algorithm. In order to eliminate this repetition and to enhance the explanation of the algorithm, the reviewer recommends eliminating the step-by-step description and replacing it with a flowchart-like figure that shows each of these steps in a connected and orderly manner.\nThe sentence \" Operation and address\" should be deleted.\nIt is recommended to relocate the phrase \" The input components along with their addresses are shown in Table 1. The output components, along with their addresses, are shown in Table 2.\" before displaying the tables.\nSection 3. Results and analysis presents the simulation process of the developed algorithm. On the other hand, all the figures shown in this section lack a title or legend. It is required to include an individual title for each of the figures presented in the paper.\nRegarding section 4. Conclusions, it is highly recommended to include some sentences related to future work derived from the results obtained in this research.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "11355",
"date": "30 May 2024",
"name": "Chitra Venugopal",
"role": "Author Response",
"response": "The suggested reviews are implemented in the revised version"
},
{
"c_id": "11356",
"date": "30 May 2024",
"name": "Chitra Venugopal",
"role": "Author Response",
"response": "The description is modified and displayed in the first sentence of the Abstract Acronyms RFID and GSM are expanded in the first use. Objective of this research is added at the end of section 1. Section 2 Title is modified to System Design and 2.1 Design of the system is removed New figures fig.1 and 2 are added to explain the model and the algorithm Table 1 and Table 2 contents are moved after the Tables In Section 2, the figure legends are included and described in the text In Section 4, suggested future modifications are added at the end of the section."
}
]
},
{
"id": "166991",
"date": "11 Apr 2023",
"name": "S. V. Viraktamath",
"expertise": [
"Reviewer Expertise Error control coding and Image processing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper requires quite a few modifications and the manuscript should be in order to the required format to be accepted. Some recommendations are listed below:\nThe contents in the Abstract need to be as per the given format specified. Abbreviations needs to be specified along with their full forms.\n\nThe acronyms must be defined initially in the Section 1. The Literature survey carried out in the same section has various articles along with various approaches carried out doesn’t give a comparative approach thus the survey does not give a summary.\n\nIn the section 2, since there is just one subsection, no need to make a separate section 2.1. Objective of the work carried out in the manuscript is missing.\n\nThe figures in the manuscript does not have any figure numbers along with their description. Also, the figure explanation along with their numbers should be carried out in the content that is followed.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11357",
"date": "30 May 2024",
"name": "Chitra Venugopal",
"role": "Author Response",
"response": "The description is modified and displayed in the first sentence of the Abstract Acronyms RFID and GSM are expanded in the first use. Objective of this research is added at the end of section 1. Section 2 Title is modified to System Design and 2.1 Design of the system is removed New figures fig.1 and 2 are added to explain the model and the algorithm Table 1 and Table 2 contents are moved after the Tables In Section 2, the figure legends are included and described in the text In Section 4, suggested future modifications are added at the end of the section."
}
]
},
{
"id": "166988",
"date": "18 Apr 2023",
"name": "Md. Tabil Ahammed",
"expertise": [
"Reviewer Expertise Photonics",
"Optoelectronics",
"WSN",
"Renewable Energy",
"ML"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGreat work on designing and developing a robotic arm for an automatic fueling system using a PLC LogixPro simulation. Your use of the FASS concept to ensure that the system is Fast, Accurate, Safe and Simple is commendable. The three-step process you have identified for identification, payment, and fuel filling is well thought out and ensures a smooth user experience. The inclusion of safety features such as the weight sensor, pressure-activated fuel cap, level sensor for filler, and photosensor for pump insert are impressive. This automatic vehicle fueling system is an innovative solution to overcome the problems of poor safety and longer waiting times during peak hours. Overall, this is a well-written report.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11358",
"date": "30 May 2024",
"name": "Chitra Venugopal",
"role": "Author Response",
"response": "Thank you. The report is modified with 2 new figures to help reader understand the concept better."
}
]
}
] | 1
|
https://f1000research.com/articles/11-1006
|
https://f1000research.com/articles/13-425/v1
|
30 Apr 24
|
{
"type": "Research Article",
"title": "Evaluation of the administrative management model in a municipality in Peru, incorporating the Intelligent Organization Theory",
"authors": [
"José Elider Tarrillo Carrasco",
"José Humberto Becerra Santa Cruz",
"Carlos Hugo Luna Rioja",
"José Carloman Saldaña Castillo",
"Rogger Orlando Morán Santamaría",
"Francisco Eduardo Cúneo Fernández",
"Nikolays Pedro Lizana Guevara",
"Cynthia Vanessa Coronel Benites",
"José Elider Tarrillo Carrasco",
"José Humberto Becerra Santa Cruz",
"Carlos Hugo Luna Rioja",
"José Carloman Saldaña Castillo",
"Francisco Eduardo Cúneo Fernández",
"Nikolays Pedro Lizana Guevara",
"Cynthia Vanessa Coronel Benites"
],
"abstract": "Background This study begins with the analysis of the current management models and their degree of effectiveness in municipal administration. Its aim is to design an administrative management model that enables effective administration in the District Municipality of Nueva Cajamarca, Peru, based on the theory of intelligent organizations.\n\nMethod The research type employed in this study is diagnostic-propositional, utilizing both deductive and inductive methods, in alignment with a mixed-method approach and a non-experimental nature of the study. Data was collected from three distinct populations, including the 189 municipal employees engaged in administrative roles, who were subjected to a 50-question survey. This survey aimed to assess their perceptions regarding the current management model and its relationship with administrative effectiveness. Additionally, interviews were conducted with three experts to gain deeper insights into the behavior of the variables under investigation.\n\nResults Finally, documentary information about the management models currently in use was collected. This facilitated the triangulation of data collection, processing, analysis, and inferences from three sources of information. The results reveal a positive, direct, and significant correlation between the management model and administrative effectiveness. It becomes evident that the current management model is deficient, resulting in a low level of administrative effectiveness.\n\nConclusion The management model based on the theory of intelligent organizations was validated using a rubric by experts in effective management. The main pillars of this model include transformational leadership, structural change, and cultural change.",
"keywords": [
"Administrative management",
"intelligent organizations",
"systemic learning",
"management models."
],
"content": "Introduction\n\nIn a global context, elements such as technological innovation, market globalization, and social changes are causing constant dynamics in the administrative management of any organization, necessitating ongoing adaptation (Coffay & Bocken, 2023; Kashani et al., 2023; Nasir & Zhang, 2024; Huynh et al., 2023; Del Carpio, et al., 2021). Hence, the need to develop strategies and tools for building organizations that are conducive to learning (Forliano et al., 2023; Olszak, 2022; Senge et al., 2018). This implies that institutions must transition to new management models rooted in systemic thinking approaches as a foundation for personal growth, mental frameworks, the creation of shared visions, and group learning (Senge, 2019; Funke et al., 2023; Pedraza et al., 2023; Chiu & Lin, 2022).\n\nOn the other hand, an intelligent organization embarks on a process to extract the highest benefit from its experiences. These organizations resemble societies of organizations within modern society and represent complex, multidimensional systems at various levels of human activity (Chiavenato, 2014; Tian et al., 2022; Capatina et al., 2016). To effectively achieve their objectives and attain success, it is essential to focus on resource and personnel management (Banmairuroy et al., 2022; Gómez and Balkin, 2003). Furthermore, it is crucial to evolve empirically and adapt proactively, involving both expansion and strategic restraint to establish a strong foundation (Wang et al., 2023; Erazo, 2013).\n\nHowever, in these organizations, survival and adaptation are not the sole factors of importance. They must also develop the ability to create and learn, grounding their growth in five core disciplines: systemic thinking, mental models, shared vision, team learning, and personal mastery (León et al., 2003; Krskova & Breyer, 2023). In this regard, according to Senge (2019), each of these disciplines represents a path of development to acquire competencies and skills, with systemic thinking considered complementary to the others (Panagiotopoulos et al., 2023).\n\nIn Peru, among the areas of application for management models, public administration is of the greatest interest. This is because it has the mission of serving and directly and continually managing the relationships between the government and the citizenry (Rojas Palacios et al., 2023). In this regard, as stated by Criado (2016), paradigms in public administration are constantly evolving, making it necessary to improve personnel management, teams, resources, the economy, and organizational interrelations (Reyes & Castañeda, 2020). This need arises from the fact that continuous improvement is the primary objective of intelligent organizations, and it can be applied to public administration to harness and enhance the capacity for learning from each member through a systematic mechanism (Reyes & Castañeda, 2020).\n\nFurthermore, there is an observed reality of limited progress in the modernization of the state, leading to issues such as deficient designs of organizational functions, inadequate policies and human resource management, the absence of effective planning systems affecting the budget, minimal impact of evaluations on the necessary changes, and a lack of goals and efficient administration.\n\nThis reality is reflected in the District Municipality of Nueva Cajamarca, which exhibits an inadequate administrative system due to a lack of managerial competencies (Visalot, 2016). In this regard, the general question was raised: “What would the administrative management model be to enable the development of the District Municipality of Nueva Cajamarca - Peru, incorporating the theory of intelligent organizations?”\n\nThe research provides theoretical utility as it could validate a theory in the field of public management in Peru, serving as fundamental knowledge that can be replicated in all public sector entities in the Peruvian state. It also serves as a reference for future research work involving triangulation designs, new data collection instruments, processing and analysis. Additionally, it offers practical utility by enabling the implementation of a highly effective intelligent management model within the municipality, which would translate into improved governance and territorial governance. This, in turn, would lead to the provision of quality services, a reduction in social disparities, and the creation of public value, ultimately enhancing the quality of life for the population.\n\n\nMethods\n\nThe research had a descriptive-propositional. In the initial stage, the relationship between the current management model and the administrative effectiveness being implemented by the municipality was evaluated to determine the direction, intensity, and significance between these two variables (Hernández-Sampieri and Mendoza, 2018). Subsequently, a new municipal management model based on Peter Senge's theory of intelligent organizations is proposed with the aim of enhancing municipal administrative effectiveness.\n\nThe study's nature is mixed, involving the triangulation of both quantitative and qualitative information through surveys, interviews, and documentary sources. A correlational design was used for the quantitative part (surveys), and a phenomenological approach was employed for the qualitative aspect (interviews and documents), following a sequential process (first measuring quantitatively and then interpreting to deepen the characterization of the variables).\n\nThe research design is non-experimental, as variables were not manipulated; instead, events were analyzed after they occurred (Carrasco, 2017).\n\nFor the quantitative part of the study, the entire population, known as the census population, consisting of 189 municipal employees in administrative roles, was included. The formula for finite population sampling was not used. As for the qualitative part, based on the author's discretion, three individuals were considered representative of the district (1 representative from the Municipal Workers Union, 1 former mayor, and 1 municipal manager) (Hernández et al., 2014).\n\nIn terms of data collection techniques, instruments, equipment, and materials, three types were used: Surveys, interviews, and evaluation techniques - rubrics.\n\nThe survey, conducted using a questionnaire, was employed to measure the perception of municipal employees regarding the type of management model being implemented in their job performance. The survey consisted of 50 items, with 20 items related to the administrative management variable and 30 items related to intelligent organizations.\n\nInterviews are a technique that allows for detailed data collection, as the informant shares information orally with the researcher. This is a valuable tool for data collection (Fontana and Frey, 2005; Díaz et al., 2013). This is why interviews were used in the research, which served to triangulate the information provided by the interviewees with the data obtained from the survey of municipal employees.\n\nThe evaluation rubric was structured, according to its table of contents, into five (5) parts, each with a given number of items: Part 1, 2 items; Part 2, 9 items; Part 3, 3 items; Part 4, 7 items; Part 5, 2 items; making a total of 23 items to be evaluated, and, each one, was evaluated according to ten (10) indicators: clarity, objectivity, timeliness, organization, sufficiency, intentionality, consistency, coherence, relevance and feasibility.\n\nBefore the instruments were used, their validity and reliability were assessed.\n\nReliability: Reliability was assessed using the Cronbach's Alpha coefficient (α). A pilot test was conducted with employees from 7 similar municipalities, including 5 district and 2 provincial ones. The results showed very high reliability for the Administrative Management variable (0.903) and for the Intelligent Organizations variable (0.952) (Sanchez, 2022; Vara, 2015; Córdova, 2019).\n\nValidity: Validity was assessed through informed opinions of individuals with expertise and authority to provide information, tests, and judgments. Qualitative evaluation by 5 experts concluded that the instrument's validity qualifies as excellent-good, meaning it is validated. As for the quantitative assessment, a statistical analysis was conducted for each item, calculating the Aiken's V coefficient using binary ratings of 0 or 1, resulting in a validity level of 0.98 for each variable (Escobar and Cuervo, 2008; Walker and Lev, 1953; Sanchez, 2022; Córdova, 2019).\n\nEvaluation Technique with Rubric: The rubric technique was used to theoretically assess the proposed administrative management model through expert judgment. According to Menzala & Ortega (2021), a rubric is an assessment tool to communicate quality expectations. Its validity was assessed through the judgment of five experts, obtaining an Aiken's V coefficient of 1, and its reliability, evaluated through a pilot test, yielded a result of 0.643 according to the KR-20 coefficient, indicating a good level of reliability.\n\nFor processing and analyzing quantitative data, software such as Excel, SPSS (V. 26), and Atlas.ti were used. The Kolmogorov-Smirnov normality test was employed, as the sample size exceeded 50 data points, and the non-parametric Spearman's Rho correlation coefficient was used, as the significance level was less than 0.05.\n\nConsent\n\nDuring the conduct of the study, we ensured that the research population was always fully informed. This was achieved through signed informed consent, each participant, a detailed description of the study, its objectives, the procedures involved and any potential impact.\n\n\nEthical approval\n\nThe research was approved by “Resolution N°091-2023-EPG” by the “Unidad de TeleEducación de la Escuela de Posgrado de la Universidad Nacional Pedro Ruiz Gallo de Lambayeque”, on January 27, 2023.\n\n\nResults\n\nThree management models were evaluated: the 7-S Management Model (M7-S), the Results-Oriented Management Model (GpR), and the Process-Oriented Management Model (GpP). The qualitative description of the current administrative management model was based on information provided by three interviewees and processed in Atlas.ti. It yielded the following categories: intelligent organizations (15 codes), administrative management (5 codes), oversight bodies (7 codes), state structure (7 codes), deficient management (8 codes), planning area (5 codes), and deficient vision (7 codes), all of which are interconnected and coordinated. The category of intelligent organizations accumulates the highest number of codes (15), indicating an interest in their implementation but also concern about rating the current management as deficient (8 codes).\n\nThe quantitative description of the current administrative management model shows perceptions from the sample. 55%, 53%, and 38% of respondents state that actions aligning with the M7-S, GpR, and GpP models are always or nearly always implemented, respectively. Meanwhile, 45%, 47%, and 62% report that these actions are only sometimes, rarely, or never implemented. The M7-S model is the most prevalent, while the GpP model is the least applied. However, the implementation of all three models is limited, hindering the development of comprehensive management and the introduction of tools that ensure a positive impact on municipal activities and the quality of life for citizens. In other words, the pursuit of continuous improvement in activities is not being effectively pursued, with a maximum of 13% implementing it consistently.\n\nTo establish the level of effectiveness of the current management models, following Delgado & Marcos (2018) and Vásquez & Farje (2020), categories were instituted for each dimension: efficient (5), good (4), fair (3), poor (2), and deficient (1), resulting in an average of 10.17%, indicating “Efficient.” The results showed that the Results-Oriented Management model prevails with a percentage of 13.43%. On average, 38.89% falls into the “Good” category, with the 7-S model prevailing at 45.28%. On average, the categories “Fair,” “Poor,” and “Deficient” obtained percentages of 31.61%, 18.28%, and 1.04%, respectively. In this context, the current management model would be rated as having a “Fair\" level of effectiveness, which does not ensure efficient administrative management. Therefore, it is necessary to propose a management model that incorporates systemic thinking as the foundation of intelligent organizations to improve this situation (Figure 1).\n\nQualitatively, the interviewees expressed that regarding the application of the Process-Oriented Management model (GpP), it is limited, but it seeks to enhance the quality of meeting needs, as measured by service management indicators. They are unfamiliar with ISO 9000 standards that would enable them to ensure quality, and the process map is not designed, resulting in poor management and weaknesses in continuous improvement planning.\n\nBased on the obtained data, descriptive analyses, normality tests, and correlation between variables were conducted to determine the requirements needed to optimize municipal management by proposing the implementation of an administration model based on the theory of intelligent organizations. In this context, the results are presented as follows:\n\nRegarding descriptive statistics, the mean, standard deviation (SD), skewness, and kurtosis of the intelligent organization’s variable are shown. The mean of 101.57 represents the average score obtained, considering that a Likert scale has been assigned values from 1 to 5. This implies that the minimum score to obtain would be 30 (if all items received a value of 1), and the maximum would be 150 (if all items received a value of 5). Therefore, the mean (101.57) indicates that the average scores fall between 3 and 4, meaning between “almost always\" and “sometimes.\"\n\nThe normality test results suggest that the data distribution is not normal (p < 0.05). Therefore, the non-parametric statistical test Rho of Spearman was used.\n\nThe analysis also examined the relationship between administrative management and intelligent organizations, resulting in a correlation coefficient of 0.672 (p < 0.01), indicating a strong and positive direct relationship.\n\nFrom the qualitative analysis, it is evident that the application of a municipal administrative management model based on intelligent organizations is feasible. There is willingness, but it is clear that the structure must first be adjusted to prioritize technical-political commitment in order to provide quality services. To achieve this, the following conditions must be met: having an appropriate structure, an organizational climate tailored to needs, suitable office equipment, strengthening and promoting professional development, fostering a culture of attitudinal change, depoliticizing policies, guidelines, and strategies, and implementing salary improvements.\n\nIt is observed that 52%, 47%, 49%, 49%, and 46% of the surveyed individuals reported that actions consistent with the disciplines of personal mastery (DomPer), mental models (ModMen), shared vision (VisComp), team learning (AprendEq), and systems thinking (PensSist) are always or almost always implemented in administrative management. On the other hand, 48%, 53%, 51%, 51%, and 54% indicated that these actions are only performed sometimes, rarely, or never. Personal mastery is the most emphasized dimension, while systems thinking is the least emphasized.\n\nFrom the results analysis, it appears that there is little commitment among municipal employees regarding personal mastery. As for mental models, there is a need to work on improving positive aspects such as paradigms, beliefs, maps, images, assumptions, and more. This suggests that the percentage of those who share the institutional vision is low, as is the case with team learning. All of this leads to a limited connection between the various components of the organizational system to achieve desired results, with only 9% of municipal employees consistently practicing systems thinking.\n\nThe information presented was triangulated with the data acquired from the interviewees. Regarding personal mastery, they indicate that the workers lack identity and relevance, are dissatisfied, demotivated, and lack professionals with the required profiles. Concerning mental models, they express that these are generally based on personal perspectives rather than institutional ones, which is why institutional objectives and vision are not adequately shared or socialized. Team learning is primarily facilitated by leaders and is not extended to all employees, and they agree that the practice of systems thinking as a behavioral pattern aimed at learning and continuous improvement is still in its early stages (Figure 2).\n\nThe proposed model, named “Administrative Management Model for Developing an Intelligent Organization in the District Municipality of Nueva Cajamarca - Peru,\" is structured into five parts: model definition, model disciplines and continuous improvement proposal, management theories and their relation to the model, considerations for model implementation, and considerations for model evaluation. Given that in Peru, public sector organizations struggle with governance at different levels of government, according to Chanamé (2017), these difficulties generally include a deficient planning system, government failure to collect people's needs, inefficient organizational and functional structure, inadequate production of goods and services, and weak governmental and interinstitutional coordination.\n\nStarting with a baseline description of each discipline:\n\nPersonal Mastery (DomPer), as an individual discipline of growth and learning, allows for an objective observation of the context and linking work to individual and group learning. In this regard, 48% of municipal personnel state that they sometimes, rarely, or never receive actions to strengthen personal mastery. This perception aligns with the information obtained from the interviewees.\n\nMental Models (ModMen), as an individual discipline of permanent mechanisms, its practice allows for perceiving the real world from different perspectives. In this sense, 53% of municipal personnel state that they sometimes, rarely, or never receive actions to strengthen mental models. This perception aligns with the interviewees' responses, who indicate that the employees' performance is based on personal perspectives rather than institutional ones.\n\nShared Vision (VisComp), as a group and systemic discipline that proposes appropriate transformations in the real world. The obtained perception indicates that 51% of municipal personnel sometimes, rarely, or never receive actions to strengthen it. This aligns with the interviewees' opinions, who state that the socialization of the institutional vision and objectives is deficient, and only a small percentage is oriented towards implementing an intelligent organization due to employees' lack of knowledge.\n\nTeam Learning (AprendEq), as a group discipline, consists of the process of aligning and developing the group's ability to generate ideas, innovate, and improve the quality of desired results. It is reported that 51% of municipal personnel sometimes, rarely, or never receive actions to strengthen this type of learning. The interviewees indicate that this learning is primarily facilitated by leaders, referring to those in offices with greater responsibility for executing established tasks.\n\nSystemic Thinking (PensSist), as a discipline that combines others, 54% of municipal personnel state that they sometimes, rarely, or never receive actions to strengthen this discipline. This data is consistent with the interviewees' opinions, who state that behavioral patterns towards learning and continuous improvement are in their early stages.\n\nFrom the information presented for each of the disciplines, it is evident that there is a significant gap that demands the design of competency development strategies for municipal employees to set the institution on the path of intelligent organizations. Based on this, the implementation of strategies for developing the profile of municipal human talent is proposed. The proposal for continuous improvement is composed of three components: knowing how (knowledge and skills), being able to do (procedural), and wanting to do (attitudinal). The baseline is described based on the presented information, and the expected achievement level is projected at the end of the model's implementation. To execute the competency proposals for continuous improvement, three fundamental aspects are considered, namely transformational leadership, structural change, and cultural change, and the disciplines of intelligent organizations are applied to have municipal collaborators open to learning to provide the best service to the user population (Figure 3).\n\nInterviewees, regarding skills development for implementing strategies, state that it is a legal obligation, implemented in strategic areas as needed. However, information systems, production processes, control, and budgets are limited and outdated. Nevertheless, they provide transparent and timely information because they are supervised by control bodies. On the other hand, promotion is occasional, and the leadership style has a deficient vision. People are moderately oriented towards achieving objectives since they are not shared, leading to inefficient personnel.\n\nTo transform the Municipality of Nueva Cajamarca into an intelligent organization, it is necessary for the theory of transformational leadership to be applied at all levels, understanding that leaders are not necessarily only those in high positions within an entity, but that any employee can be a leader from their workspace. Leadership is the ability to mobilize people towards shared goals and objectives (Fischman, 2017). According to Hermosilla et al. (2016), transformational leadership is considered one of the most appropriate leadership styles for driving processes of change and innovation in the organization.\n\nSubsequently, a structural change is needed, which, according to Yoguel (2014), is defined as a process of qualitative and quantitative transformation that occurs in a particular production structure.\n\nLastly, the most important aspect is cultural change, which, according to Taylor (1995), allows understanding the nature of culture as a necessary element to comprehend human behavior, as presented in the model of intelligent municipal administrative management.\n\n\nDiscussion\n\nThe discussion begins by accepting the hypothesis that incorporating an administrative management model based on intelligent organizations facilitates institutional development. Romera (2016) indicates that knowledge, skills, and competencies must be continuously improved. Therefore, when describing the current administrative management, the 7-S model by McKinsey Company in 2012 was analyzed. The results showed that only 10% of employees always apply this model, and 1% never do. This is in line with Peralta (2017), who concludes that the functions of local governments are limited and do not strengthen decentralization. García & Mendoza (2018) indicate that the strategy, personnel, systems, and structure are unfavorable, while leadership styles and shared values received favorable scores. However, Ortiz (2020) disagrees and states that at UPLA-Huancayo, 77% agree, and only 17% disagree.\n\nManagement based on the results-oriented management model, which, according to Makon (2017), allows the management and evaluation of the performance of state organizations in relation to public policy, is applied by only 13%, and 1% never apply it. This aligns with Ccoa (2018), who indicates that it is not being applied or encouraged, while Cabrejos (2019) maintains that the model's application in the Municipality of San Jose has an average index of 1.56. However, this contradicts Shack & Rivera (2017) and Esparta & Paco (2017), who state that it has a positive impact on performance-based budgeting. Additionally, Bernuy (2017) asserts that 81% of the budget is aligned with results-focused programs.\n\nThe process-oriented management model, as mentioned by Aranda et al. (2018), is felt to be an obligation for the state to fulfill its commitments. However, it is not progressing at the required pace, as only 7% always apply it, and 2% never do. This is consistent with Aranda, Ordóñez, and Peralta (2018), who identified that level 0 processes in the Ministry of Agriculture are not being implemented and recommend implementing process management. Begazo & Fernandez (2017) affirm that public administration should work with process management.\n\nIn terms of the demand for intelligent organizations management models, Senge (2019) points out that it requires a constant commitment to learning. The results in individual dimensions, personal mastery and mental models, have a positive Pearson correlation of 0.723, in line with Rojas (2018) who indicates that the key to becoming an intelligent organization is to implement a business philosophy with values and employee involvement in decision-making. Martínez et al. (2017) state that intelligence and knowledge are intangible assets for the organization. Regarding the collective dimensions, systems thinking is related to shared vision, and team learning has correlation indexes of 0.639 and 0.623, respectively. These results are consistent with Lozano & Gonzalez (2016), who present a comprehensive view of the changes needed for the development of organizational intelligence. In this regard, Seminario & Seminario (2020) concluded that in intelligent organizations, achieving team learning enhances competitiveness.\n\nFurthermore, the development of learning in intelligent organizations' disciplines was evaluated. In terms of personal mastery, 11% always apply it, 41% almost always, 32% sometimes, 15% almost never, and 1% never. For mental models, 7% always practice it, 40% almost always, 35% sometimes, 16% almost never, and 2% never. This aligns with Quiroz (2017), who indicates that although the organization theoretically exhibits plans and proposals for intelligent management, in practice, it falls short of being so. However, it disagrees with Barrena (2017), who concludes that 95% of workers consider a high degree of personal mastery, and 85% consider the socialization aspect to be moderate. In terms of shared vision disciplines, 12% always apply it, 37% almost always, 30% sometimes, 19% almost never, and 2% never. For team learning, 13% always put it into practice, 36% almost always, 32% sometimes, 17% almost never, and 1% never. Finally, for systems thinking, 9% always apply it, 37% almost always, 39% sometimes, 15% almost never, and 1% never. These results are in line with López et al. (2016), Passailaigue et al. (2017), and Luza (2017), who indicate a direct link between the learning capacity and strategic decisions.\n\nIn the development of the structure of the municipal administrative management model based on the theory of intelligent organizations, the results show that only 10% always apply it, 38% almost always, 34% sometimes, 16% almost never, and 2% never. It is evident that in the criteria expected to always and almost always, they do not exceed the optimal level's average. This aligns with Guevara (2017), who indicates that the organizational climate in the Municipalidad Provincial de Chota is inadequate. Cutipa (2017) states that the organizational level is not coordinated with all workers, consistent with Arroyo (2016) and Rincón et al. (2016), who argue that changing old prevailing schemes is necessary to give way to new management by shifting from bureaucratic models to intelligent organizations.\n\nIn summary, this research contributes to the scientific community by introducing a new model of municipal administrative management based on the theory of intelligent organizations. This model will serve as a theoretical foundation for quasi-experimental application and scientific effectiveness testing, aiming to incorporate soft skills into functional tasks to achieve cultural and structural change through transformational leadership. Additionally, it provides validated instruments such as a survey questionnaire, interview questionnaire, and evaluation rubric. Finally, it demonstrates the existence of a significant correlation between municipal administrative management and intelligent organizations, thus supporting the research hypothesis.\n\n\nConclusions\n\nAccording to the research results, the study provides valuable contributions to science by designing a municipal administrative management model based on intelligent organizations. This model incorporates soft skills to achieve cultural and structural change through transformational leadership. The study also includes validated instruments such as a survey questionnaire, interview questionnaire, and evaluation rubric. Furthermore, it confirms the existence of a significant correlation between variables, thereby supporting the research hypothesis.\n\nIn the diagnostic phase, the findings revealed a positive, direct, and significant correlation (0.672, p<0.01) between the variables related to the research problem, general objective, and hypothesis, which is the model of management and administrative effectiveness. It was also demonstrated that the implementation of the dimensions is being applied moderately. Consequently, this study presents a proposal aimed at contributing to a new intelligent management model with both theoretical and practical implications.\n\nThe level of perceived administrative management effectiveness at the District Municipality of Nueva Cajamarca is considered moderate. Approximately 51% of the respondents mentioned that actions aligned with the 7-S management models, results-based management, and process-based management are implemented sometimes, almost never, or never. This perception aligns with the statements made by the interviewees regarding the moderate application of these models.\n\nThe results of the evaluation of learning development as an intelligent organization indicate that 52% of respondents working at the District Municipality of Nueva Cajamarca mentioned that actions aligned with the dimensions of personal mastery, mental models, shared vision, team learning, and systems thinking are sometimes, almost never, or never implemented. This perception is consistent with the input provided by the interviewees. Therefore, strategies need to be developed through an administrative management model that incorporates dimensions from the intelligent organizations' theoretical approach to improve the performance of municipal workers.\n\nThe municipal administrative management model for developing an intelligent organization in the District Municipality of Nueva Cajamarca, Peru, was designed and theoretically validated through expert judgment. An Aiken's content and construct validity coefficient of 0.98 was obtained, indicating a very acceptable level of content and construct. This data underscores the importance of considering these proposed considerations for an effective transition from traditional municipal administration to intelligent municipal administration, achieved through transformational leadership, structural changes, and cultural shifts.\n\nThe research was approved by “Resolution N°091-2023-EPG\" by the “Unidad de Tele Educación de la Escuela de Posgrado de la Universidad Nacional Pedro Ruiz Gallo de Lambayeque”, on January 27, 2023.\n\nDuring the conduct of the study, we ensured that the research population was always fully informed. This was achieved through signed informed consent, each participant, a detailed description of the study, its objectives, the procedures involved and any potential impact.",
"appendix": "Data availability statement\n\nZenodo. Evaluation of the administrative management model in a municipality in Peru, incorporating the Intelligent Organization Theory. https://doi.org/10.5281/zenodo.10872138 (Tarrillo et al., 2024).\n\nThis project contains the following underlying data:\n\n• COREQ_checklist.pdf\n\n• Data.xlsx\n\n• Figure 1. Results of the management models, as per the workers' perception.png\n\n• Figure 2. Management under the dimensions of intelligent organizations.png\n\n• Figure 3. Intelligent Municipal Administrative Management Model.png\n\n• Informed Consent.pdf\n\n• INSTRUMENTS.pdf\n\nCreative Commons Zero v1.0 Universal (CC0 License)\n\n\nReferences\n\nAguilar I, Pereda M, Mera C:Applying Business Process Modeling to improve IT Incident Management Processes in a Public Entity in Peru. Journal of Software and Systems Development. 2020; 2020: 1–20. 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Argentina: Granica; 2019.\n\nSenge P, Charlotte R, Ross R, et al.: La quinta disciplina en la práctica. Estrategias y herramientas para construir la organización abierta al aprendizaje. GRANICA; 2018.\n\nShack N, Rivera R: Seis años de la gestión por resultados en el Perú.2017.\n\nTarrillo J, Becerra J, Luna C, et al.: Evaluation of the administrative management model in a municipality in Peru, incorporating the Intelligent Organization Theory. [Data set]. Zenodo. 2024.\n\nTaylor F: Principios de la Administración Científica. Herrero Hnos. S. A; 1995.\n\nTian H, Li Y, Zhang Y: Digital and intelligent empowerment: Can big data capability drive green process innovation of manufacturing enterprises?Journal of Cleaner Production.2022; 377(August): 134261. Publisher Full Text\n\nVásquez K, Farje JD: Efectividad de la gestión administrativa en los gobiernos locales altoandinos, Luya, región Amazonas. Revista Científica UNTRM. 2020; 3(3): 60–66.\n\nVara A: 7 pasos para elaborar una tesis. Macro.2015.\n\nVisalot M: Percepción de la gestión administrativa y su relación con la cultura tributaria, en la Municipalidad Distrital de Nueva Cajamarca, Año 2016.2016.\n\nWalker H, Lev J: Análisis de variación. En H. Walker, & J. Lev, Inferencia estadística.1953.\n\nWang X, Liu Z, Li J, Lei X: How organizational unlearning leverages digital process innovation to improve performance: The moderating effects of smart technologies and environmental turbulence.Technology in Society.2023; 75(April): 102395. Publisher Full Text\n\nYoguel G: ¿De qué hablamos cuando hablamos de cambio estructural? Una perspectiva evolucionista-neoschumpeteriana. La estructura productiva argentina. Evolución reciente y perspectivas. Buenos Aires. Argentina: CEPAL; 1-3 de Octubre de 2014."
}
|
[
{
"id": "279219",
"date": "12 Jun 2024",
"name": "Walter Ibarra Fretell",
"expertise": [
"Reviewer Expertise Master in Finance and PhD in Accounting"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFirst and foremost, I appreciate you considering me for the work review.\nThis work is important for both practice and theory in administrative sciences, providing a solid foundation for improving public management and advancing scientific knowledge in this area.\nThe use of both qualitative and quantitative methods in the study provides a comprehensive view of administrative management in the studied municipality. This approach is critical since it allowed and will allow future studies to capture perception from a mixed perspective, which is always significant.\nThis research is significant for administrative sciences as it provides a rigorous methodology and empirical evidence to help make informed decisions and implement better practices in public management. Furthermore, it enriches scientific literature by encouraging the use of mixed approaches and introducing new conceptual frameworks that promote adaptability and innovation in organizations.\nAs a suggestion for the future, a better approach to the conclusions could be placed, although it is evident that there is support for the results, the entrepreneurial part and the opinion of the authors is always important to know the point of view of the researchers.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "303379",
"date": "04 Oct 2024",
"name": "Hugo Espinoza Rodríguez",
"expertise": [
"Reviewer Expertise As a professional with my high academic degree as a Doctor in Management",
"and my experience in business administration and as a research work evaluator",
"I can vouch that the research work meets the scientific rigours required by high impact journals."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study focuses on evaluating the current administrative management models in a Peruvian municipality and proposes a new model based on the theory of intelligent organisations.\nThe presentation on the research purpose demonstrates a well-executed systematic review of high-impact databases, which makes the information highly useful for the development of this research.\nThe theories put forward in the research align with the study’s purpose, and the methodology is highly appropriate for collecting both quantitative and qualitative data.\nIn the context of Peruvian municipalities and their deficiencies in service quality, this research contributes by proposing a new management model based on the theory of intelligent organisations, aiming to improve municipal workers' performance and transform the municipality into an intelligent organisation.\nThe conclusions are consistent with the research, highlighting a solid proposal to provide intelligent solutions within the organisations under study.\nAs a reviewer, the evaluation is acceptable, and it is certain that this study will serve as a valuable precedent for significant projects in municipalities and/or organisations. It is worth mentioning that the application of circular economy principles would contribute greatly to the reuse of materials, the creation of more sustainable management systems, and the reduction of waste through recycling and composting, as well as renewable energies.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-425
|
https://f1000research.com/articles/11-1230/v1
|
28 Oct 22
|
{
"type": "Software Tool Article",
"title": "LiftoffTools: a toolkit for comparing gene annotations mapped between genome assemblies",
"authors": [
"Alaina Shumate",
"Steven Salzberg",
"Steven Salzberg"
],
"abstract": "In 2020 we published Liftoff, which was the first standalone tool specifically designed for transferring gene annotations between genome assemblies of the same or closely related species. While the gene content is expected to be very similar in closely related genomes, the differences may be biologically consequential, and a computational method to extract all gene-related differences should prove useful in the analysis of such genomes. Here we present LiftoffTools, a toolkit to automate the detection and analysis of gene sequence variants, synteny, and gene copy number changes. We provide a description of the toolkit and an example of its use comparing genes mapped between two human genome assemblies.",
"keywords": [
"Bioinformatics",
"Genome annotation",
"Genomics"
],
"content": "Introduction\n\nLiftoff (Shumate and Salzberg, 2021) is a computational tool specifically designed for mapping gene annotations from a reference assembly to a target assembly of the same or closely related species. Liftoff uses sequence alignment software to align the complete exon-intron structure of each annotated transcript from a source to a target, and it can also map virtually any other feature specified as an interval along the genome. It also includes a method to find additional copies of genes that might be present in higher copy numbers in the target genome. After lifting genes over, one of the first questions that many researchers have is how the sets of genes compare between the reference assembly and the target, and in particular whether any of the differences are biologically consequential.\n\nHere we introduce LiftoffTools, a toolkit to compare genes mapped from one assembly to another. LiftoffTools includes three different modules. The first identifies changes in protein-coding genes and their effects on the corresponding genes, including simple amino acid changes as well as more-serious alterations. The second compares the gene synteny (e.g., the preservation of gene order along the chromosomes), and the third clusters genes into groups of paralogs to evaluate gene copy number gain and loss. While LiftoffTools is designed to analyze the output of Liftoff, it is also compatible with the output of other annotation transfer tools such as UCSC liftOver (Kuhn et al., 2013). Here we provide a description of each module as well as results comparing genes in the GRCh38 human reference genome mapped onto CHM13, the first truly complete human genome (Nurk et al., 2022).\n\n\nMethods\n\nThe inputs required for all three modules of LiftoffTools are the sequences of the reference and target assemblies (in FASTA format), and the annotations of the reference and target assemblies (in GFF3 or GTF format). The target annotation can be derived from other lift-over tools besides Liftoff, as long as the feature IDs in the reference and target annotations are the same. All three modules can be run with the following command:\n\nliftofftools all -r reference.fasta -t target.fasta -rg reference.gff3 -tg target.gff3\n\nEach module can also be run separately as detailed on GitHub.\n\nLiftoffTools is designed and implemented in Python 3 (requires 3.6 or higher) and is easily installable with PyPi (pip install liftofftools) and bioconda (conda install -c bioconda liftofftools). Details on how to run LiftoffTools are available on the GitHub page.\n\nThe variants module calculates the sequence identity between transcripts in the reference genome and the corresponding transcripts in the target genome. For protein-coding genes, the module identifies variants and their effect on the translated amino acid sequences. The first step in the module will globally align the nucleotide sequences of the reference transcripts to the target transcripts using the Needleman-Wunsch algorithm implemented by Parasail (Daily, 2016), which is a single instruction/multiple data (SIMD) C library for sequence alignment. If the transcript has an annotated protein-coding sequence (a CDS feature), we align the protein sequences again using Parasail. We then identify mismatches and gaps in the alignments and evaluate the effects on the protein sequence. The potential effects we look for are synonymous mutations, nonsynonymous mutations, in-frame deletions, in-frame insertions, start codon loss, 5′ truncations, 3′ truncations, frameshifts, and stop codon gain. For all transcripts we output the percent identity at the nucleotide level, and for protein-coding transcripts we also output the protein percent identity and the variant effect if applicable. If there is more than one variant, we report only the most severe. For example, if a transcript has a synonymous mutation and a frameshift mutation, we output ‘frameshift’ for that transcript as this would be more disruptive to gene function.\n\nThe synteny module compares the gene order in the reference annotation to the order in the target annotation. The genes present in both annotations are sorted first by chromosome and then by start coordinate in each annotation. Each gene is then plotted as a point on a 2D plot where the x-coordinate is the ordinal position (e.g., 1st, 2nd, 3rd, etc.) in the reference genome and the y-coordinate is the ordinal position in the target genome. The color of the point corresponds to the sequence identity between the corresponding genes, where green indicates higher identity and red indicates lower identity. Note this color feature is only available for target annotations created by Liftoff which have the sequence identity information in the GTF/GFF3. The plot and a file with the ordinal positions and sequence identities of each gene is output. The user also has the option to calculate the edit distance between the reference order and the target order.\n\nThis module clusters the genes into paralogous groups to evaluate gene copy number gain and loss. LiftoffTools first invokes MMSeqs2 (Steinegger and Söding, 2017) to cluster the reference gene sequences. MMSeqs2 clusters the amino acid sequences of the protein-coding genes, and the nucleotide sequences of noncoding genes. For each gene we select only the longest isoform to be included in the clustering. For genes to be considered copies and be clustered together, they must be at least 90% identical across 90% of both of their lengths, although these parameters can be adjusted by the user. After clustering the reference genes, we create the target gene clusters by first iterating through each reference cluster and removing any gene that failed to map to the target genome. Next, if Liftoff was run with the -copies option to identify extra gene copies in the target genome, we add the extra copies to the same cluster as their closest paralog. For each cluster, we output the number of reference genes and the number of target genes belonging to that cluster as well as the gene IDs of the cluster members.\n\n\nResults\n\nTo illustrate the use of these tools, we used them to compare the human annotation on the current reference genome, GRCh38, to the same annotation when mapped onto the first-ever complete human genome, CHM13 (Nurk et al., 2022). We first mapped the human annotation onto CHM13 by running Liftoff v1.6.3 (with options -copies -sc 0.95 -polish) to map genes from RefSeq release 110 (O’Leary et al., 2016) from GRCh38 onto CHM13v2.0. (This annotation is available on the Johns Hopkins Center for Computational Biology website) We then ran each module of LiftoffTools on the resulting CHM13 annotation.\n\nRunning the variants module on GRCh38 and CHM13, we found that out of 130,316 protein-coding transcripts in GRCh38, 77,109 CHM13 transcripts were identical, 421 failed to map, and 52,669 had variants with the effects shown in Table 1. The vast majority of these effects were either simple amino acid changes or insertion/deletions (indels) that preserved the reading frame; only 932 of the variants had a major effect on the translated protein sequence.\n\nIn-frame changes refer to insertions or deletions that are a multiple of 3 in length. Truncations are variants that shorten the protein sequence by removing either the 5′ or 3′ end of the transcript including the start or stop codon. Start codon loss variants are point mutations in the start codon, and stop codon gain variants are point mutations that result in a premature stop codon.\n\nWe ran the synteny module to compare the gene order of CHM13 to GRCh38. The dot plot in Figure 1 shows that the vast majority of genes were collinear and nearly identical in sequence, as expected. The small number of genes which were not collinear generally mapped with a lower sequence identity, suggesting they may have been mapped to a different (non-syntenic) copy of a gene in a multi-gene family.\n\nThe color of each point indicates the sequence identity, and the gray lines separate the chromosomes.\n\nThe clusters module found 5,213 genes in GRCh38 with at least one paralog that met the 90% sequence identity and alignment length minimums. These 5,213 genes were grouped into 1,629 clusters with copy numbers ranging from two to 66. In CHM13, 8,356 genes had at least one paralog. These copies were grouped into 2,089 clusters with copy numbers ranging from two to 228. (Note that the ribosomal DNA gene is the largest cluster, and most copies of this gene are not present in the GRCh38 assembly.) Among clusters with a copy number of at least 2 in GRCh38, 134 clusters had fewer gene copies in CHM13 resulting in a total loss of 188 gene copies. A total of 715 clusters had more copies in CHM13 resulting in a total gain of 3,035 gene copies.\n\n\nConclusions\n\nLiftoff gave us the ability to easily map genes between closely related genomes, but further analysis is required to identify similarities and differences between the genes in each assembly that may be biologically important. LiftoffTools enables this analysis by automating the comparison of protein-coding variants, gene synteny, and gene copy loss and gain. Here we provided an example demonstrating the use of LiftoffTools to compare genes mapped between two human assemblies, and we hope this set of tools will be useful for a wide diversity of assembled genomes from species across all domains of life.\n\n\nSoftware availability\n\nSource code available from: https://github.com/agshumate/LiftoffTools\n\nArchived source code as at time of publication: https://doi.org/10.5281/zenodo.6967163 (Shumate, 2022)\n\nLicense: GNU GPL v3\n\n\nData availability\n\nGRCh38 sequence: https://ftp.ncbi.nlm.nih.gov/genomes/all/GCF/000/001/405/GCF_000001405.26_GRCh38/GCF_000001405.26_GRCh38_genomic.fna.gz\n\nCHM13 sequence: https://ftp.ncbi.nlm.nih.gov/genomes/all/GCF/009/914/755/GCF_009914755.1_T2T-CHM13v2.0/GCF_009914755.1_T2T-CHM13v2.0_genomic.fna.gz\n\nCHM13 annotation: https://ccb.jhu.edu/T2T.shtml or ftp://ftp.ccb.jhu.edu/pub/data/T2T-CHM13/chm13v2.0_RefSeq_Liftoff_v3.gff3\n\n(Note: The CHM13 annotation has been updated to v4 since the submission of this manuscript)",
"appendix": "References\n\nDaily J: Parasail: SIMD C library for global, semi-global, and local pairwise sequence alignments. BMC Bioinform. 2016; 17: 1–11. Publisher Full Text\n\nKuhn RM, et al.: The UCSC genome browser and associated tools. Brief Bioinform. 2013; 14: 144–161. PubMed Abstract | Publisher Full Text\n\nNurk S, et al.: The complete sequence of a human genome. Science (1979). 2022; 376: 44–53. Publisher Full Text\n\nO’Leary NA, et al.: Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res. 2016; 44: D733–D745. PubMed Abstract | Publisher Full Text\n\nShumate A, Salzberg SL: Liftoff: accurate mapping of gene annotations. Bioinformatics. 2021; 37: 1639–1643. PubMed Abstract | Publisher Full Text\n\nShumate A: 2022, agshumate/LiftoffTools: Version 0.4.3.2 [Software], zenodo. https://doi.org/10.5281/zenodo.6967163\n\nSteinegger M, Söding J: MMseqs2 enables sensitive protein sequence searching for the analysis of massive data sets. Nat. Biotechnol. 2017; 35: 1026–1028. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "154534",
"date": "01 Dec 2022",
"name": "Adam Frankish",
"expertise": [
"Reviewer Expertise Gene annotation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript describes a set of tools to analyze gene annotation that has been mapped between one genomic sequence and another closely related genomic sequence. The methods described build on the widely adopted Liftoff annotation transfer tool developed by the same group.\nThe development of LiftoffTools is clearly relevant and timely as we enter an era of rapidly increasing numbers of high quality genome sequences suitable for comparison to species reference genome assemblies that are generally the focus of gene annotation effort. The description of the tools is sound and we were able to run the code with the instructions provided and generate the correct/expected output. The code is written entirely in Python and looks clear and well-organized.\nThere is broadly sufficient information to allow interpretation of the results, although a little more guidance might be useful, for example, adding annotated examples of real data from Variant and Cluster analysis to guide users.\nComments:\n\"...as long as the feature IDs in the reference and target annotations are the same. All three modules can be run with the following command\" - Is this somewhat inflexible? Not all transfer methods will preserve feature ID identically across different assemblies as they seek to avoid storing two or more features with identical IDs but different properties (sequence/length/etc). Is it possible to accommodate methods that take this approach?\n\nIt is not clear from the manuscript or the supporting information in https://github.com/agshumate/LiftoffTools/blob/master/README.md how LiftoffTools handles genes that are LoF on genome 1 but functional on genome 2. Can these genes and their 'rescuing' variation be identified?\n\nWhile the list of variant consequences is comprehensive for the annotated CDS, it would be useful to add other LoF consequences such as disruption of core splice site to the analysis.\n\nIt would also be useful to specifically state the ranking of consequences in the /README.md file for genes with multiple transcript-affecting variants as only the most significant is provided in the variation output file.\n\nSimilarly, as only one variant is reported, does LiftoffTools identify (and/or flag) corrective variation e.g a second frameshift that compensates for an earlier frameshift and restores the CDS with a small aa change?\n\nIn the calculation of cluster gain/loss, are haplotypic duplicated pseudogenes considered? i.e. is loss only deletion/absence of the gene or is loss (or gain) of function included as well? An example with real data in /README.md could be helpful.\n\nWhat is reported for variants in genes that are missing or partial on GRCh38 where it is used as a reference? An example with real data in /README.md could be helpful.\n\nThe CHM13 GFF and FNA (fasta) files appear to have different chromosome names, which threw an error when running the code.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "11342",
"date": "29 Apr 2024",
"name": "Alaina Shumate",
"role": "Author Response",
"response": "Comment 1 Is this somewhat inflexible? Not all transfer methods will preserve feature ID identically across different assemblies as they seek to avoid storing two or more features with identical IDs but different properties (sequence/length/etc). Is it possible to accommodate methods that take this approach? Response 1 While it would be great to accommodate all lift-over tools, without the preservation of feature IDs, identifying the reference/target gene equivalents for comparison becomes a non-trivial task. LiftoffTools was specifically designed as a post-processing toolkit for the output of Liftoff , and in our experience, other commonly used tools such as UCSC liftOver do indeed preserve feature IDs. Furthermore, the GFF3 specification states that all feature IDs must be unique. If a transfer method is changing IDs to eliminate duplicates, this is an issue of the reference annotation failing to adhere to the GFF3 specifications and should be addressed prior to mapping annotations. Comment 2 It is not clear from the manuscript or the supporting information in https://github.com/agshumate/LiftoffTools/blob/master/README.md how LiftoffTools handles genes that are LoF on genome 1 but functional on genome 2. Can these genes and their 'rescuing' variation be identified? Response 2 Currently, LiftoffTools does not identify ‘rescuing’ variants. In our particular case, we used the RefSeq annotation as a reference, which requires a valid open reading frame to annotate a coding sequence; therefore, there are no LoF coding sequences annotated in the reference to be mapped. We recognize that this is not true for all reference annotations; many include annotations of coding sequences without a valid open reading frame. There are varying schools of thought on whether this is acceptable, but regardless, we do agree that identifying rescuing or gain of function variants would be useful, and we will consider implementing that feature in the future. We have updated the manuscript to say “the module identifies variants that have a neutral or deleterious effect on the translated amino acid sequences in the target genome.” The README has also been updated. Comment 3 While the list of variant consequences is comprehensive for the annotated CDS, it would be useful to add other LoF consequences such as disruption of core splice site to the analysis. Response 3 We do agree that splice site variants would be useful to include, but we are currently only aligning and looking at variants in the mRNA due to computational limitations. Performing Smith-Waterman alignment on transcript sequences including splice-sites and introns would require significant computational resources for human and other eukaryotic genomes. Even with a very fast implementation of the Smith-Waterman alignment, aligning just the mRNA and amino acid sequences is the computational bottleneck of the LiftoffTools pipeline. While faster alignment methods could alleviate this, they would not have the same accuracy as Smith-Waterman, which we feel is necessary for accurately identifying the position and type of variants. We have edited the manuscript to specifically state that we are aligning mRNA sequences. Comment 4 It would also be useful to specifically state the ranking of consequences in the /README.md file for genes with multiple transcript-affecting variants as only the most significant is provided in the variation output file. Response 4 Thank you for the suggestion. I have updated the README.md accordingly. Comment 5 Similarly, as only one variant is reported, does LiftoffTools identify (and/or flag) corrective variation e.g a second frameshift that compensates for an earlier frameshift and restores the CDS with a small aa change? Response 5 We do not report this explicitly. The intent of the variants module is to provide high level summary information about how many genes were disrupted by variants rather than identifying every variant in every gene. We do however include the amino-acid level sequence identity information, so compensatory frameshifts can be inferred if a sequence is reported to have a frameshift but also retains a high sequence identity to the reference protein. We have added the following text to the manuscript to capture these points. “While there may be multiple variants within a transcript, the intent of this module is to summarize the functional consequences of variation; therefore, if there is more than one variant, we report only the most severe. For example, if a transcript has a synonymous mutation and a frameshift mutation, we output ‘frameshift’ for that transcript as this would be more disruptive to gene function. Combining the sequence identity information with the variant effect can provide further insights into the severity of the variant. For example, a gene with a frameshift near the 3’ end or a gene with a compensatory frameshift nearby will have a high percent identity at the amino acid level and may still retain function.” Comment 6 In the calculation of cluster gain/loss, are haplotypic duplicated pseudogenes considered? i.e. is loss only deletion/absence of the gene or is loss (or gain) of function included as well? An example with real data in /README.md could be helpful. Response 6 This is a good point. Liftoff intentionally avoids annotating extra gene copies in the target genome that are processed pseudogenes by including introns in the initial alignment step. Therefore, when working with the output of Liftoff, it is not something we need to consider. If a different annotation tool was used that does annotate pseudogenes, they will get clustered with their paralogs even if they are not functional. As previously mentioned, LiftoffTools was designed to be used in conjunction with Liftoff, so we have not considered a strategy for removing non-functional pseudogene copies from the clusters. Comment 7 What is reported for variants in genes that are missing or partial on GRCh38 where it is used as a reference? An example with real data in /README.md could be helpful. Response 7 Variants are only reported for genes that are in both GRCh38 and CHM13. We state in the manuscript “The variants module calculates the sequence identity between mRNA transcripts in the reference genome and the corresponding transcripts in the target genome…” A limitation of lifting over gene annotations is that a partial reference gene will likely also be annotated as partial in the target annotation. There are various lift-over algorithms/strategies; however, they generally rely on converting the start and end coordinates of the gene from reference to target. If the start-end range is only a partial gene, only that part of the gene will be lifted over. In these cases, they will be reported as either a 5’ truncation or a 3’ truncation based on the presence or absence of start and stop codons. Comment 8 The CHM13 GFF and FNA (fasta) files appear to have different chromosome names, which threw an error when running the code. Response 8 Thank you for bringing this to our attention. The link to the fasta file has been replaced to a file with the same chromosome names."
}
]
},
{
"id": "212791",
"date": "29 Nov 2023",
"name": "Mark Borodovsky",
"expertise": [
"Reviewer Expertise Bioinformatics",
"Genome Analysis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript is well written and presents a useful computational tool for comparison of gene annotations between genome assemblies.\nI have two minor comments for the Methods section.\nVariants\nDo transcripts include UTRs?\nIf yes, the applicability is limited to genomes with annotated UTRs, if no – the term transcript should be defined as such.\n\nClusters\nIn the sentence:\n\n“Next, if Liftoff was run with the -copies option to identify extra gene copies in the target genome, we add the extra copies to the same cluster as their closest paralog.”\n\nThe meaning of the “-copies” option, the difference with the default run, was not described.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "11343",
"date": "29 Apr 2024",
"name": "Alaina Shumate",
"role": "Author Response",
"response": "Comment 1 Variants Do transcripts include UTRs? If yes, the applicability is limited to genomes with annotated UTRs, if no – the term transcript should be defined as such. Response 1 The mRNA transcripts are aligned which we derive by concatenating all of the ‘exon’ features in the GFF3 annotation. Some annotations include UTRs in the 5’ or 3’ exons. In these cases, yes, the UTRs are included. Others annotate them separately as their own feature upstream or downstream of exons. In these cases, they are not included. While the full transcript is used to calculate sequence identity, variants are only called within the amino acid sequence, so the module can be applied to genomes with or without annotated UTRs with no effect on the number or types of variants reported. Comment 2 Clusters In the sentence: “Next, if Liftoff was run with the -copies option to identify extra gene copies in the target genome, we add the extra copies to the same cluster as their closest paralog.” The meaning of the “-copies” option, the difference with the default run, was not described. Response 2 I have updated the manuscript to include the text below for clarification: “Next, if Liftoff was run with the -copies option to identify extra gene copies in the target genome, we add the extra copies to the same cluster as their closest paralog. If Liftoff was run without the -copies option, no extra gene copies will be present in the target annotation, and thus the clusters module will only report instances of copy number loss.”"
}
]
}
] | 1
|
https://f1000research.com/articles/11-1230
|
https://f1000research.com/articles/13-422/v1
|
29 Apr 24
|
{
"type": "Study Protocol",
"title": "How cAN we grow research in community-baseD NHS and SociaL CarE Services (HANDLE)?",
"authors": [
"Gulshan Tajuria",
"Lauren Gray",
"Louise Warburton",
"Ruth Lambley-Burke",
"Christine Burt",
"Ian Maidment",
"Lauren Gray",
"Louise Warburton",
"Ruth Lambley-Burke",
"Christine Burt",
"Ian Maidment"
],
"abstract": "Background Community-based NHS and social care services offer a wide range of health and social care services, including General Practice, care homes, hospices, community pharmacies, district and community nursing, and mental health services, which provide care from birth to the end of life. However, despite being fundamental to plans for health and critical social care, community-based NHS health services are poorly understood compared to hospital-based services. A scoping exercise failed to identify any specific research examining the barriers and facilitators of community-based NHS and social care services.\n\nObjectives 1) To develop a qualitative framework using semi-structured interviews to explore the perspectives and experiences of the research staff and practitioners. 2) To explore how we can build research on community-based NHS and Social Care services using the perspectives and experiences of the research participants. 3) To make recommendations to clinicians, practitioners, policymakers, and funding organizations on how to build research in community-based NHS and Social Care Services.\n\nMethods With reference to the literature and input from the project team and key stakeholders, interviews will be conducted using a semi-structured topic guide. The interview guide will identify barriers and facilitators to researching community-based NHS health and social services.\n\nOutcomes The intended outcomes of this study could help in understanding and developing strategies to address workforce needs to increase the capacity and capability of research delivery. Further, to embed a research culture in community-based NHS and social care services by supporting collaborative work between primary, secondary, community, and social care to build research capacity and capability; reach underserved communities and increase local engagement and participation in research; and increase equality, diversity, and inclusion by adding research in community-based NHS and social care services where everyone lives.",
"keywords": [
"Community based services",
"qualitative research",
"barriers and facilitators to research"
],
"content": "Introduction\n\nThe vast majority of healthcare is delivered in the community rather than hospital settings, and they play an important role in planning the future of NHS health and care.1 The range of community-based healthcare is vast and includes general practices, care homes, hospices, community pharmacies, ambulance services, prisons, schools, opticians, district nursing, immediate care, and other community-based practices. Community health services, excluding GPs, have approximately 100 million patient contacts and account for approximately £10 billion of the total NHS funding every year, containing 20% of the NHS workforce.2\n\nCommunity services can reach large, diverse, seldom-heard patient groups who are at different stages of their illness, and the NHS Long Term Plan aims to deliver more community-based services.3 It is important to note that the National Institute for Health and Care Research (NIHR) data revealed that UK communities that experience high disease rates also have the lowest number of patients participating in research.4 The areas where this was most evident were ethnic minorities and areas where deprivation is the highest. Community NHS Trusts and social care are the services most likely and appropriate to reach these underserved communities and embed research culture among these populations. However, despite being key to plans for health and critical social care, community services are poorly understood in comparison to hospital-based services,2 with limited community-based research.\n\nCommunity healthcare providers are not viewed as obvious places for research compared with large teaching hospitals. Research may not be viewed as relevant to day-to-day community services in practice.5 However, little is known about the barriers and facilitators of community based NHS and social care services’ based research, and a scoping search had failed to identify any specific research projects on this topic.\n\n\nProtocol\n\nIn view of the above, there is a clear need to explore barriers and facilitators to engaging and delivering research in community-based NHS and social care services. By understanding these barriers and facilitators, recommendations can be made to address them. This will support the delivery of research in the community and increase research capacity and capability across local NHS trusts.\n\nThis study aims to understand how we can build research in community-based NHS and Social Care Services.\n\nObjectives\n\nTo use semi-structured interviews and develop a qualitative framework to explore the perspectives and experiences of research staff and practitioners (with or without research experience) on barriers and facilitators of community-based research, and how we can build research in community-based NHS and Social Care services.\n\nOutcomes\n\n• Developing strategies to address the workforce needs to increase the capacity and capability of delivery of research.\n\n• Support joint working between primary, secondary, community, and social care to build research capacity and capability.\n\n• Strategies to embed a research culture in the community.\n\n• Increase equality, diversity, and inclusion within research by adding research to the community in which everyone lives.\n\n• Reach underserved communities and increase local engagement and participation in research.\n\nStudy design\n\nHandle study is a qualitative study where members of research staff and other practitioners (with or without research experience) from community-based NHS and social care services will be invited to participate in a single semi-structured interview. The interviews will be conducted either face-to-face, via telephone, or using platforms such as MS Teams. The interviews will aim to explore the viewpoints and experiences of staff in engaging with research, which will help us understand the barriers and facilitators to building research in community-based NHS and social care services.\n\nThe sample\n\nThe sample will consist of research staff and practitioners with or without experience in research. People can be identified in several ways.\n\n• Creating project awareness within the professional network of the Principal Investigator (PI–Ian Maidment)\n\n• Working with the Community Healthcare Alliance of Research Trusts (CHART)\n\n• Social media\n\n\n\n• Members of research staff or practitioners working in community-based NHS or social care services with or without research experience. These may include, but are not limited to, GPs and other practice staff (e.g., practice-based pharmacy), social care staff, occupational therapists, and physiotherapists employed by an organization providing community-based NHS and social services.\n\n\n\n• Less than 18 years of age\n\n• Do not work in community-based NHS or social care services.\n\nBased on similar research projects and the study team’s experiences, the predicted sample size is up to 25 staff members, including research staff and practitioners, or until data saturation is reached.\n\nTo recruit participants for this study, professional networks and social media will be used. Potential participants expressing interest will be asked to contact the Research Associate (RA) if they would like to participate in the study. The RA will share the study documents, including the Participant Information sheets and consent form, with them via email. Participants will be given the time to read the study documents and the opportunity to ask questions. An interview will then be organised either face-to-face or telephone/MS teams, as preferred by each participant. Informed consent will be obtained from each participant by the RA before the interviews. The participants will be given an opportunity to discuss any concerns with the RA before signing a written consent form and sharing it with the RA via email (if the interview is conducted virtually) or in person (if the interview is conducted face-to-face). The RA will countersign these forms prior to the interviews. Two copies of the consent forms will be completed: one to be retained by the research team and one for the participant.\n\nA topic guide for interviews will be developed by the research team with reference to the literature, and input from the stakeholders and will change iteratively depending on ongoing data collection and analysis. The topic guide has been informed by results from a scoping review (conducted by the PI and Dr. Louise Warburton from the study team) looking at barriers to research in community-based NHS and social care services.\n\nWith the participants’ consent, the interviews will be audio-recorded and transcribed for analysis.\n\nThe interviews will be transcribed verbatim and anonymized. Qualitative framework analysis6,7 will be undertaken by the RA (GT) with support from other members of the research team. Framework analysis, which is well-suited for applied qualitative research and deductively moves from pre-specified aims and objectives, will be utilised to organize and understand the interviews by forming an analytical framework and then charting this data into a framework matrix.8,9\n\nThe initial analysis will be presented to and discussed with patient and public involvement and engagement (PPIE) members and key stakeholders to gain additional perspectives. The findings from this qualitative study will inform recommendations made to clinicians, practitioners, policymakers (local and national), and funding organizations on how to build research in community-based NHS and social care services.\n\n\n\n1. Two members of the public will be involved to inform the content of the interview topic guide, interpret the findings, and contribute to the development of key messages for dissemination from the qualitative interviews. One of the lead organizations Midlands Partnership University NHS Foundation Trust (MPFT) for the HANDLE study has an established PPIE group, the PPIE co-ordinator has been contacted by the RA to identify one member of the public to be involved as an advisor. The second advisor will be identified by linking with the lead for Birmingham’s Community Connexion (a PPIE program).\n\nUpon completion of HANDLE, a Final Study Report will be written for the funders in the form of an academic publication. This paper will be available online in Open Access. The funding body will be acknowledged according to the standard NIHR criteria. Anonymised data will be made available upon formal request.\n\nIf participants desire, they can consent to being notified about the outcome of the study by providing their e-mail address on the consent form. E-mail addresses for this purpose will be stored for up to 2 years to allow time for the research to be completed. At this point, a lay summary report will be written and sent to consenting participants alongside the publication.\n\nThis research will be used to create recommendations to address the barriers and facilitators of conducting research in community-based NHS and social services. Findings and conclusions will also be shared at appropriate conferences (e.g., Health Services Research UK and Society for Academic Primary Care).\n\nApproval committee: College of Health and Life Sciences, College Research Ethics Committee (CREC), Aston University.\n\nApproval number: #HLS21115\n\nApproval date: 1st August 2023\n\nHANDLE involves human participants, and we will adhere to the Declaration of Helsinki at all times.\n\nEthical and regulatory considerations\n\nThis study is led by Professor Ian Maidment. Members of the study team will meet fortnightly in Study Management Group meetings to oversee the study’s progress.\n\nAs data collection does not include the recruitment of NHS patients, ethical approval was sought from the College of Health and Life Sciences College Research Ethics Committee (CREC) at Aston University.\n\nAny subsequent amendments to the study design and/or process will be submitted via CREC procedures. Routine reporting will take place in line with the Aston University CREC and\n\n• All correspondence with the CREC will be retained in the study file.\n\n• The Chief Investigator will notify the CREC of the end of the study.\n\n• If the study is terminated prematurely, the Chief Investigator will notify the CREC, including the reasons for premature termination.\n\nFor any amendment to the study, the Chief Investigator in agreement with the sponsor will submit information to the appropriate body for them to issue approval for the amendment. Any amendments required for the study will be submitted to the College of Health and Life Sciences Research Ethics Committee, Aston University, for review.\n\nThe PI and RA will be responsible for the decision to amend the protocol.\n\nIf substantive changes are required, the funding body and R&D at each participating site will be notified in writing. Any amendments approved by the College of Health and Life Sciences Research Ethics Committee of Aston University will be added to an updated version of the research protocol.\n\nHANDLE is a non-interventional study that is associated with a very low risk. There is a slight possibility that the interviews might cause distress to the participants; however, this is not an emotive subject. The study team recognises that sparing time to participate in interview/travel may cause minor discomfort. To minimise the discomfort the participants will be given a choice to take part in a remote meeting interview. Also, prior to the interview, the researcher will make it clear to the participants that there are no right, or wrong answers and they have the right to ‘not answer’ any question if they wish; pause/stop the interview or withdraw from the study altogether at any point during the interview. The RA has received appropriate training, as required, to conduct the interviews and ongoing support and supervision from the PI and other members of the team throughout the project will also be provided. The safety of the RA will be protected by adhering to Aston University’s Lone Working Guidance. The NIHR Safeguarding policy will always be followed.\n\nParticipants may feel that their participation will have an impact on their work lives. To address this issue, all participants will be fully briefed about the study procedures to maintain confidentiality before participating in the study. There is also the possibility that a participant may raise concerns or safeguard issues. If this occurs, the issue will be discussed with the person making the disclosure, and if appropriate, the RA will discuss the issue with the PI and report the matter to the relevant bodies. Ensuring the safety, well-being, and confidence of participants in the research is a prime concern.\n\nThe study will be conducted in accordance with the principles of Good Clinical Practice (GCP) in research studies and the UK Policy Framework for Health and Social Care Research. Aston University as the Sponsor, has a quality management system in place containing standard operating procedures that will be adhered to in the conduct of the study. Studies may be subject to an audit by Aston University as the Sponsor for quality assurance.\n\nAny potential noncompliance event affecting the research will be promptly reported to the PI as soon as any member of the research team becomes aware of the event. The PI (or delegate), in discussion with the study management group/committee (SMG), will gather information to assess whether the event is a true noncompliance event with escalation and reporting, as outlined in the applicable HSCR standard operating procedure (SOP).\n\nThe SMG will monitor protocol compliance and recruitment during the conduct of this study, which will be discussed at fortnight meetings. Technical deviations from the protocol that do not result in harm to the study participants, do not compromise data integrity, or significantly affect the scientific value of the reported results of the study will be documented, and appropriate corrective and preventative actions will be taken by the research team with the PI responsible for these with agreement from the SMG.\n\nA “serious breach” is defined as a breach of the protocol or of the conditions or principles of GCP, which is likely to significantly affect the safety or physical or mental integrity of the study subjects, or the scientific value of the research. In the event of doubt or for further information or guidance, the investigator should contact the PI. All protocol deviations and breaches of the GCP will be recorded and reported to the Sponsor and REC according to the applicable HSCR SOP.\n\nStandard data protection procedures at Aston University will be employed to protect confidentiality and anonymity. The interviews will be audio-recorded with the permission of the participants. RA ensures that the audio files do not contain any personally identifiable information. To do so, the RA will ensure that the participants do not discuss personal information about themselves, their workplace, or any other identifying information after the recording has started. The participants will be made aware of this before starting the interview recording and will be reminded during the interview if a need arises. After the recording has started, the RA will ensure that the participants are not referred using their real name during the interview. The interview recordings will be securely transferred electronically to an Aston University-approved transcription service for transcribing.\n\nAfter receiving the transcripts, the RA will go through each transcript to check for accuracy and again ensure that there were no names or other identifiable information recorded/included in the transcription. At this stage, each participant’s transcript will be replaced with a unique participant identifier, following the procedure described by Aston University. Only the PI and RA will have access to personal information and data. The agreement with the external transcription service covers confidentiality, data transfer, and destruction (files will be deleted once the transcription is completed). At all times, the transcriber will comply with the Data Protection Act of 1998. At the end of the study, database anonymization and locking will be performed in accordance with the SOPs.\n\nAston University has robust data security systems and procedures that are regularly reviewed, and it achieves the legal obligations set by the Data Protection Act (2018) and the General Data Protection Regulation (GDPR),10 followed by the GMC Caldicott Guardian and British Computer Society standards and guidelines.11\n\nData collected from the interviews will be stored in Aston University’s secure Box, accessed by a password-protected laptop. The storage and access to the data will be in accordance with the SOPs. Data used for analysis will be kept separate from the consent forms containing participant-identifiable information. All confidentiality arrangements will adhere to relevant regulations and guidelines, and the PI has responsibility for ensuring the integrity of the data and that all confidentiality procedures are followed.\n\nAll investigators and study site staff must comply with the requirements of the Data Protection Act 2018 with regard to the collection, storage, processing, and disclosure of personal information and will uphold the Act’s core principles.\n\n1) Personal addresses or email contacts will not be used to send invitation letters, PIS, or consent forms to potential participants.\n\n2) Interviews conducted via MS Teams will be recorded on MS Teams. Telephone and face-to-face interviews will be recorded using an audio recording device. Data will be transcribed (with pseudonyms and identifying personal information removed). All participants will be aware of the audio recording and transcription processes via the PIS and the introduction to the interview. Transcription will be undertaken by an Aston University approved transcriber with a duty of confidentiality.\n\n3) Data storage and analysis will be performed by the RA with support from the PI. Files will always be password-protected when emailed. Electronic data will not contain any identifiable personal information.\n\n4) The study adheres to the General Data Protection Regulation (GDPR) 2018, which requires data to be anonymized as soon as it is practical to do so. Participants’ names will not be used instead of unique identifiers will be assigned (e.g., Participant 1).\n\n5) The PI is the custodian of the data.\n\n6) Data will be stored for 6 years in accordance with Aston University Policies.\n\nInsurance and/or indemnity to meet the potential legal liability of the sponsor for harm to participants arising from the management of the research will be covered by the Aston University insurance.\n\nInsurance and/or indemnity to meet the potential legal liability of the sponsor or employer for harm to participants arising from the design of the research will be covered by Aston University insurance.\n\nNo equipment will be provided to NHS sites for the purposes of this study.\n\nOnly members of the Project Management Team will have access to the fully anonymized dataset. The consent form will include permission to use the interview data for appropriate analysis within the overall scope of the project.\n\n\nEthics and consent\n\nApproval committee: College of Health and Life Sciences, College Research Ethics Committee (CREC), Aston University.\n\nApproval number: #HLS21115\n\nApproval date: 1st August 2023\n\nHANDLE involves human participants, and we will adhere to the Declaration of Helsinki at all times.\n\nWritten informed consent will be obtained from each participant by the RA before the interviews. Consent to publish will be obtained from all participants and all efforts to anonymise the data will be followed.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nThe King’s Fund: Community health services explained. UK.2019. Reference Source\n\nCharles A: Community health services explained. London: The King’s Fund; 2019. Reference Source\n\nNational Health Service: The NHS Long Term Plan.2019. Reference Source\n\nNational Health Service: Increasing diversity in research participation: A good practice guide for engaging with underrepresented groups. NHS Accelerated Access Collaborative » Increasing diversity in research participation: A good practice guide for engaging with underrepresented groups (england.nhs.uk).2022.\n\nMcKenna HP, Ashton S, Keeney S: Barriers to evidence-based practice in primary care. J. Adv. Nurs. 2004; 45(2): 178–189. Publisher Full Text\n\nMalterud K, Siersma VD, Guassora AD: Sample size in qualitative interview studies: guided by information power. Qual. Health Res. 2016; 26(13): 1753–1760. Publisher Full Text\n\nRitchie J, Spencer L: Qualitative data analysis for applied policy research.Bryman B, Burgess R, editors. Analyzing qualitative data. 1994; pp. 173–194.\n\nSrivastava A, Thomson SB: Framework analysis: a qualitative methodology for applied policy research.2009.\n\nGale NK, Heath G, Cameron E, et al.: Using the framework method for the analysis of qualitative data in multi-disciplinary health research. BMC Med. Res. Methodol. 2013; 13(1): 1–8.\n\nRegulation P: General data protection regulation. InTouch. 2018; 25: 1–5.\n\nDepartment of Health: The caldicott guardian manual 2010.2010."
}
|
[
{
"id": "284473",
"date": "17 Jun 2024",
"name": "David R Thomas",
"expertise": [
"Reviewer Expertise Public health and community-based health and social services. Research designs",
"survey methods",
"qualitative methods",
"evaluation research."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper’s general purpose is described as ‘…to explore barriers and facilitators to engaging and delivering research in community-based NHS and social care services.’ The proposed methods, using qualitative interviews, seem appropriate.\nThe proposed research could provide some useful information for increasing research and research capacity related to community-based health services. However, there is no indication of specific topics that might be covered in the proposed qualitative interviews. The paper could have reviewed topics that are central to research in community-based health and social care services and that might be covered in the interviews. Some examples include evaluation of health services, building research capacity, setting a research agenda, and collaborative research between research providers and service providers. Each of these is briefly described below.\nEvaluation research focuses on ways in which health services can be improved. It is distinct from general research in having a focus on assessing the effectiveness of services and providing information that could be used to improve services.\nBuilding research capacity refers to developing research competencies and resources which could be relevant to existing communities and organisations and developing capacity to use research findings (e.g., Hamel & Schrecker, 20111). In qualitative interviews participants could be asked what research resources are currently available, and organisations and community groups that might be involved in building research capacity.\nOne purpose of community-based interviews is to document what research is needed to help establish a research agenda for community-based health services.\nCollaborative research can occur between service providers needing research information and providers of research such as university public health and social science sections (e.g., Chrisman et al., 19992). It would be useful to get interview participants’ views about how such collaboration might occur.\nIn summary the paper has made a useful start but lacks a clear indication of some of the topics that could be suitable for inclusion in the interviews.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "301600",
"date": "10 Aug 2024",
"name": "Antuela A Tako",
"expertise": [
"Reviewer Expertise operations research",
"health and systems modelling",
"statistical analysis",
"survey methods",
"qualitative research methods."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper seeks outlines a study protocol for an upcoming investigation which aims to identify the barriers and facilitators to conducting research in community-based NHS health and social services. The ultimate objective of the study is to develop strategies that will enhance research in community-based health and social care services. The research team intends to conduct semi-structured interviews, and the study's design, data collection methods, and analysis protocols have been described to a satisfactory level of detail, and the study is overall suitably conceived and well-planned.\nHowever, the paper could benefit from providing further details and clarifications. Further elaboration on the research hypothesis and the specific topics that will be the focus of the investigation would enhance the scope and relevance of the research. More details the theory that will inform the selection of research topics and interview questions to be asked in the research would offer a better understanding of the rationale behind the study and its focus areas.\nThe paper notes that participants will include both research staff and practitioners, while the exclusion criteria specify that individuals who do not work in community-based NHS or social care services will be excluded. I wondered if the research team have considered the inclusion of university-based researchers who conduct health-related research. Furthermore PPIE group of the Midlands Partnership University NHS Foundation Trust will be invited to designing the study but no patients will be included in the sample. I wondered why the team has not considered interviewing members of the public, who could be potential patients.\nAdditionally, the choice of a sample size of 25 appears to be arbitrary; it would be beneficial for the authors to explain the rationale behind this decision and perhaps reference guidelines or recommendations from similar studies to support their choice.\nThe paper addresses ethical considerations, assessment and risk management, regulatory compliance, and patient confidentiality to a satisfactory level and I believe these aspects are well-planned. Ethical approval has been sought and granted by the University. A minor comment regarding the decision to ask participants to avoid providing personally identifiable information, such as their workplace, during the interviews may not be practical and could hinder the natural flow of the conversation. It might be more effective if the Research Associate removes any personally identifiable information from the transcripts after the interviews, which the research team has already planned to do.\nFurthermore, good to see that members of the public will be participating in the study design and data analysis. I am curious if the team have considered any incentives or benefits to be offered to members of the public to encourage their participation.\nAnother minor detail, the introduction of the paper mentions prisons and schools as settings where health services are delivered. It would be helpful to clarify the connection between these institutions and healthcare services, as they differ in nature from other types of community-based services mentioned, such as GPs, community pharmacies, and ambulance services.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-422
|
https://f1000research.com/articles/13-420/v1
|
29 Apr 24
|
{
"type": "Opinion Article",
"title": "Interior frontiers and highly skilled migrants' work-related challenges in Japan",
"authors": [
"Liang Morita"
],
"abstract": "In this opinion article, the author argues that highly skilled migrants in Japan face many challenges and are ineffectively used due to the existence of interior frontiers. Although interior frontiers are more subtle than the external boundaries these migrants have had to cross to enter the country, they have tremendous power over their everyday lives. Ethnocentric attitudes, influenced by Nihonjinron, have contributed to the existence of these frontiers. They emphasise homogeneity instead of flexibility and accommodation, and exist in the workplace. Employers want a homogeneous workplace and highly skilled migrants face strong pressures to assimilate. There is also an insistence on Japanese human resource practices such as seniority-based pay and promotion. An interior frontier also exists in the hiring process, and migrants are less likely to progress beyond the first round of interviews. With Japan’s rapidly aging and declining population and acute labour shortages, there is urgency in addressing these frontiers.",
"keywords": [
"Japan",
"immigration",
"highly skilled migrants",
"workplace",
"interior frontiers"
],
"content": "1. Introduction\n\nSince the end of the 20th century, many developed countries have focused on having knowledge-based economies, prompting them to participate in the race to attract highly skilled migrants (Shachar, 2006). Japan has also joined this global competition for highly skilled migrants, and frames these migrants as desirable human resources (Joppke, 2021).\n\nJapan has been selectively prioritising the highly skilled from the late 1980s (Liu-Farrer et al., 2023). In 2012, it introduced a point-based system and the category of ‘highly skilled professionals’, providing incentives for the highly skilled to live and work in the country. The government has developed increasingly attractive policies and programmes to recruit and retain these migrants, making Japan the most liberal immigration regime (Oishi, 2014). From the beginning of the 21st century, Japanese companies and recruitment agencies have tapped into foreign labour markets, setting up job fairs and collaborating with universities in Southeast Asia to recruit their graduates (Conrad and Meyer-Ohle, 2019).\n\nIn spite of lawmakers’ and policymakers’ good intentions, highly skilled migrants do not necessarily find Japan to be an attractive destination and those who have come do not necessarily integrate smoothly into the workplace or are able to find alternative employment when they wish to. In fact, research has shown that the country can be unattractive (Morita, 2017; Liu-Farrer, 2023), highly skilled migrants face challenges in the workplace (Hof and Tseng, 2021), and there is discrimination in the hiring process (Igarashi and Mugiyama, 2023). In the context of Japan’s rapidly aging and declining population and shrinking workforce, there is urgency in understanding and addressing the issues involved.\n\nThis opinion article draws on the concept of interior frontiers in Lems’ (2020a, 2020b) work on young asylum seekers in Switzerland. In spite of the fact that these young people are already physically present in the country, interior frontiers prevent them from being accepted and integrated into Swiss society. Likewise, highly skilled migrants in Japan face interior frontiers in the workplace, although they have successfully crossed the external boundary and entered the country. There are parallels between Lems’ work and the situation of these migrants in Japan that can help us better understand and address the challenges the latter face.\n\nThe next section introduces the concept of interior frontiers and ethnocentric attitudes, followed by employers’ desire for a homogeneous workplace in Section 3. Highly skilled migrants face strong pressures to assimilate into the workplace, and their unique skills and abilities are undervalued. Section 4 discusses employers’ insistence on Japanese human resource practices such as seniority-based pay and promotion. Section 5 finds discrimination in the hiring process, and the paper ends with Discussion and concluding remarks in Section 6.\n\n\n2. Interior frontiers and the ethnocentric attitudes that contribute to their existence\n\n‘Interior frontier’ (also ‘interior border’ or ‘interior boundary’) was originally a concept put forward by Johann Fichte, a German philosopher in the 19th century. It was revived by Etienne Balibar about 30 years ago, and was employed by Stoler (2017, 2018) to describe the rise of Trumpism in the US when Donald Trump was President from 2017-2021. According to Fichte, an interior frontier is a fortifying moral barricade against the erosion of the nation and self, a boundary between those who belong in the nation and those who do not (Stoler, 2017). Stoler stresses that these barricades and boundaries result in vast inequalities (Morita, 2023).\n\nLems (2020a, 2020b), in adopting the concept in her work on young asylum seekers from Eritrea, Guinea and Somalia in Switzerland, describes interior frontiers as vernacular thresholds of belonging that create unspoken distinctions between self and other, familiar and alien, and inside and outside. They are not conspicuous frontiers created by overt acts of boundary-drawing, but are put in place in much more subtle ways. In spite of the fact that interior frontiers are less visible than external ones, they have tremendous power over the life-worlds of individuals, as they determine who is allowed in and who is kept out of society (Lems, 2020a, 2020b; Morita, 2023).\n\nThere are striking parallels between the following account provided by Lems and what highly skilled migrants in Japan face at the workplace. In the school which young asylum seekers attend, these young people are taught to integrate into a system of values which is extremely alien to them. The approach used by their teachers in this process of integration is one-way, which means that the young people are required to fully submerge into Swiss society, but the Swiss do not have to show any flexibility in accommodating them. In this asymmetrical power relationship, even if the young people were to obey the rules and try to blend in, acceptance as members of Swiss society is not guaranteed (Lems, 2020a, 2020b; Morita, 2023).\n\nThe young asylum seekers studied by Lems have in fact experienced rejection in spite of their efforts in submitting to the rules and blending in. They frequently experience being excluded by the Swiss, they have difficulties in transferring from their school’s ‘integration’ stream to ‘regular’ stream, and they have trouble securing apprenticeships (Lems, 2020a, 2020b).\n\nIn the author’s opinion, ethnocentric attitudes have contributed to the existence of interior frontiers, and these attitudes have been strongly influenced by Nihonjinron (‘theories about being Japanese’). Nihonjinron has been referred to as Japan’s dominant identity discourse (Befu, 2001), and has been the subject of thousands of books and articles (Rear, 2017). Its key tenets, summarised by Rear (2017), are firstly, that Japan is a homogeneous country and its culture and people are extremely unique, to the point of its culture being superior to that of other countries. Secondly, Japan is a vertical society in which social obligations, indebtedness and shame are prioritised over Western values of individual rights, duties and conscience. Thirdly and finally, Japanese culture values harmony over conflict and emotion over rationality.\n\nHomogeneity is emphasised, along with the unique set of collectivist and harmonious social values that have built the country (Rear, 2017). Japanese values such as self-sacrifice and supposed to be truly understood only by the Japanese, because they possess a unique sensibility. If one deviates from Japanese values, for example, by behaving in a manner deemed to be individualistic or self-serving, one risks being judged as having betrayed what it truly means to be Japanese (Rear, 2017).\n\nEthnocentric attitudes influenced by Nihonjinron are unfriendly to migrants in general, to say the least. The emphasis on homogeneity translates into the thinking that Japan is for the Japanese only, and that non-Japanese do not belong. The belief that Japanese culture and customs are unique and superior encourages an insistence on doing things the Japanese way instead of openness, flexibility and accommodation in situations where non-Japanese are involved (Morita, 2022). We will see what this looks like in real life in the workplace when employers insist on Japanese practices and are unwilling or unable to accommodate highly skilled migrants.\n\n\n3. Employers want a homogeneous workplace\n\nWe begin this section with the experiences of fresh foreign university graduates who joined Japanese companies at entry level. We will see that they face pressures to assimilate culturally. A boundary between the Japanese and non-Japanese exists, although more subtle and less overt and conspicuous than the boundaries the latter have had to cross to enter the country and later the company. This is an interior frontier which has great power over the life-worlds of individuals (Lems, 2020a, 2020b), as we will see below.\n\nIn the application process, fresh foreign university graduates encounter extremely high ethnocentric cultural expectations (Liu-Farrer and Shire, 2021). In spite of the discourse of workplace diversity resulting in higher revenues and greater success, most companies expect highly skilled migrants to conform culturally and behave like Japanese employees, referred to as ‘coerced harmonisation’ by Wakisaka (2018). Companies recruit these migrants in order to assimilate them into Japanese employees (Hof and Tseng, 2021). In this process of assimilation, non-Japanese are measured against the ideal Japanese employee, assuming that non-Japanese are imperfect versions of the Japanese (Desai-Trilokekar et al., 2016) rather than ‘global talent’ they are often said to be. Some white employees feel that they are not adequately valued for their skills and abilities, and have been hired merely for their physical appearances, which serve as symbols of diversity (Hof, 2021). All of the above: pressures to conform culturally and assimilate, being thought of as of less worth than Japanese coworkers, and having one’s skills and abilities undervalued, directly impact highly skilled migrants’ everyday lives. It is widely known in business management research that employees have a need to feel unique, to maintain a distinctive and differentiated sense of self (Shore et al., 2011). For many highly skilled migrants, this need is probably not being met.\n\nWhat comes across clearly in the preceding paragraph is employers’ desire for a homogeneous workplace, which is directly related to the Nihonjonron emphasis on a homogeneous Japan. This desire is carefully detailed in Hof and Tseng’s (2021) study, which found a homogenising work culture, a sole focus on assimilation, and inflexibility towards others. Homogeneity in fact supersedes the desire for a more diverse workplace, where employees from different backgrounds can better serve customers around the world in this age of globalisation. This can be seen in the tendency of companies to hire highly skilled migrants whom they think can be ‘Japanised’ or made to behave like the Japanese (Wakisaka, 2018). This is in fact a more important criterion in the hiring process than the unique skills and abilities an applicant possesses.\n\nCox (1991) and Joshi’s (2006) model in business management can help us better understand where Japanese companies stand now and where they should be ideally. The model is made up of demographically heterogeneous organisations in three stages, each stage being different in terms of the proportion of diverse social groups, their integration, and power and status hierarchy. The stages are named ‘low’ (monolithic), ‘moderate’ (pluralistic) and ‘high’ (multicultural). ‘Monolithic’ has the lowest degree of heterogeneity and structural integration, while ‘multicultural’ has the highest.\n\nMost Japanese companies fall into the category of ‘monolithic’ (Sekiguchi et al., 2016; Ghosh et al., 2023). There are distinct in-groups and out-groups in which in-group members (Japanese) are treated preferentially while out-group members (non-Japanese) are disregarded. In monolithic organisations, employees from dominant groups possess high status and power, hold positions at higher levels, and command more respect and deference (Ghosh et al., 2023). From the point of view of non-dominant employees, the impermeability of status and power differences threatens their identity and devalues their sense of self, and their uniqueness needs are not met in this exclusionary environment. More importantly, non-dominant employees’ unique perspectives, knowledge or ideas are not considered as relevant (Shore et al., 2011). They are not treated as insiders who belong and whose uniqueness is valued.\n\nAt the other end of Cox (1991) and Joshi’s (2006) model is ‘multicultural’ organisations. These companies are heterogeneous, structurally integrated, and inclusive. All employees respect, value, and learn from one another (Ghosh et al., 2023). Employees from all social groups are treated as insiders and encouraged to retain and leverage their unique attributes. Non-dominant employees can effectively use their unique knowledge, skills and abilities, and are assured of being valued members of the organisation and that it is safe to express their identities and associated values (Ghosh et al., 2023).\n\nThe description in the preceding paragraph contrasts sharply with the situation of highly skilled migrants in Japanese companies, where they are expected to conform culturally and behave like Japanese employees. They are also measured against Japanese employees and made to feel second-rate, and their skills and abilities undervalued. Japanese companies would be far more productive if they are willing to learn from Cox (1991) and Joshi’s (2006) ‘multicultural’ organisations.\n\n\n4. Employers insist on Japanese human resource practices\n\nMany of the frequently discussed workplace practices that highly skilled migrants are dissatisfied with stem from the tradition of lifelong employment in Japan (Liu-Farrer, 2023). While it is understandable that Japan has developed its own system of human resource practices, what comes across clearly is employers’ unwillingness or inability to be flexible and accommodate their non-Japanese employees (Liu-Farrer, 2023). This suggests the existence of an interior frontier, where one-way submission to the rules is expected of outsiders, while insiders do not have to show any flexibility in accommodating them (Lems, 2020a; Lems, 2020b).\n\nJapanese companies mostly recruit fresh university graduates with a view to employing them for the rest of their working lives. Employees who join companies mid-career are relatively few, and often find that they lack the in-depth knowledge of the company possessed by coworkers who have been working there since the beginning of their careers. Many highly skilled migrants are mid-career when hired by Japanese companies, and feel left out of the unwritten rules and conventions shared by the majority of their Japanese colleagues (Morita, 2022).\n\nIn comparison with other developed countries, Japanese salaries may appear low, due to the fact that Japanese salaries are determined with the assumption that employees stay in the same company for their entire working lives. Salaries start low but gradually increase with annual increments. Highly skilled migrants are often dissatisfied with their earnings and this is exacerbated by their tendency to leave before they benefit from the yearly increments (Morita, 2022).\n\nPromotion is seniority-based, depending on the length of time employees have served the company, which contrasts sharply with performance-based promotion practised in many developed countries. Many highly skilled migrants feel that promotion is slow (Liu-Farrer and Shire, 2021), and their career development stifled.\n\nCompany-provided training is yet another practice which highly skilled migrants are dissatisfied with. This directly impacts fresh foreign university graduates who join Japanese companies alongside their Japanese counterparts. Companies typically provide three to six months’ training for their new employees, the contents of which are company-specific and not transferrable or useful should the employee choose to work for a different employer. From the point of view of highly skilled migrants, the skills gained are too specific and may hinder their mid-career moves to other companies or other countries, thereby limiting them to their initial places of employment.\n\nIn general, Western-style human resources practices such as performance-based pay and promotion have not become mainstream among Japanese companies (Haghirian, 2022). In addition to benefitting highly skilled migrants, it is in these companies’ best interests to modernise their practices, as explained below.\n\nDue to Japan’s rapidly aging and declining population, there has been an acute shortage of skilled labour (Haghirian, 2022). Skilled employees are in short supply in many new business areas (including technology-related ones, digitisation and social media), and the conventional practice of giving employees a few years to develop the necessary skills and knowledge has proven to be too slow. Employers realise that they need skilled employees in fast-moving business fields, but find it very difficult to recruit mid-career employees in the Japanese labour market. The difficulties are due to relatively low numbers of Japanese employees changing jobs mid-career, and to the traditional seniority system being an obstacle to the integration of new employees of higher rank. Experienced and skilled employees are reluctant to change employers in case they end up in a lower position than they should in the seniority hierarchy of the new company (Haghirian, 2022).\n\nIn this context of a fast-moving and everchanging business world, it would make business sense, or would even be imperative to overhaul Japanese human resource practices. The traditional training system for new employees and seniority-based pay and promotion have to adapt to changing times and circumstances.\n\n\n5. Discrimination in the hiring process\n\nCompared with studies conducted on highly skilled migrants and the challenges they encounter at the workplace, there are relatively few on discrimination in the hiring process. Igarashi and Mugiyama, 2023 is one of the most recent, which includes migrants of all skill levels and utilises the concept of taste-based discrimination. The authors found that there is taste-based discrimination in the hiring process, which suggests the existence of an interior frontier when migrants seek employment.\n\nTaste-based discrimination is defined as personal and societal (i.e. customers and coworkers) preferences for native applicants, and is due to prejudice against other ethnic groups (Igarashi and Mugiyama, 2023). Becker (1957), who first put forward this notion, stated that employers avoided hiring from other ethnic groups in order to avoid interacting with them, and they assumed that customers and coworkers are prejudiced against these groups. By not having employees from other ethnic groups, employers felt they were protecting their companies’ reputation and avoiding conflict between their employees and those from other ethnic groups that may decrease workplace productivity (Igarashi and Mugiyama, 2023).\n\nIgarashi and Mugiyama found that due to taste-based discrimination, non-Japanese applicants are less likely to progress to the next stage of the job application process (after the initial round of interviews) after controlling for human capital.\n\n‘Prejudice’ is a key word in Igarashi and Mugiyama’s work, which is generally understood as an unfair or unreasonable opinion or feeling against someone or something. It is difficult to say with certainty as the authors did not elaborate on prejudices of Japan employers, but prejudice against other ethnic groups would point to a boundary between those who belong in the nation and those who do not (Stoler, 2017), or between insiders and outsiders (Lems, 2020a; Lems, 2020b). Ethnocentric attitudes influenced by Nihonjinron also appear to be involved, since employers clearly prefer a homogeneous workplace without employees from other ethnic groups.\n\nThe preference for a homogeneous workplace is also clear in a government publication on Japan’s labour situation (JILPT, 2014). About two-thirds of employers who participated in a survey said they had no plans to hire foreign employees. This is a telling response in the context of Japan’s rapidly aging and declining population and labour shortages.\n\nIn the same publication, it is reported that in companies which are experienced in hiring foreign employees, Japanese language ability is prioritised over specialist knowledge, skills or experience (JILPT, 2014). This is justified by the explanation that work-related instructions are given in Japanese, so Japanese language skills are a precondition for employment.\n\nThe Japanese language requirement sounds commonsensical and reasonable, but it is also a fact in Japan that practically all students study English in elementary, middle and high schools. Those who attend university receive a few more years of English language instruction. With English being the global lingua franca, and provided Japanese employers are willing to make the effort, communication with non-Japanese employees should be possible to some extent. By laying down the rule that Japanese language is a precondition for employment, employers are revealing their expectations of migrants’ one-way submission to Japanese rules.\n\n\n6. Discussion and concluding remarks\n\nThe Japanese situation involving highly skilled migrants in the workplace is not unique in the world. In the literature on diversity management, lack of preparedness on the part of human resource staff members to accommodate and make efficient use of highly skilled migrants’ diversity is nothing new (van Riemsdijk and Basford, 2022). Friesen and Ingram (2013) noted managers’ lack of diversity management experience in Canadian engineering firms. Managers with limited intercultural management experience complained about the ‘deficits’ of foreign engineers vis-a-vis their Canadian counterparts initially, but in the long run, they learned that foreign engineers’ differences (not deficits) can be a strength.\n\nDiversity of experience can increase productivity and innovation for companies, and imparts new skills that enhance professional development for employees (van Riemsdijk and Basford, 2022). Openness to diversity is crucial to cross-cultural collaboration in the workplace, which requires employer commitment to diversity management (Homan et al., 2008).\n\nIn a study conducted in Sweden (Morillas and Romani, 2023), managers who have been encouraged to believe that ‘diversity is good’ conclude that although highly skilled migrants are culturally different from them, the difference is superficial. Differences are perceived as enriching and as contributing to a more sustainable society. Managers also become more open-minded and motivated to work towards inclusion, as well as see integration as a two-way process.\n\nThe present author could not agree more with Liu-Farrer’s (2023) remark that highly skilled migrants are being ineffectively used in Japan. Interior frontiers have stood in the way, and addressing and eradicating these boundaries is one way to move forward.\n\nFichte defined an interior frontier as a boundary between those that belong to the nation and those that do not, and Stoler emphasised that such boundaries result in inequalities (Stoler, 2017), which is what is happening in the hiring process in Japan. Non-Japanese applicants are less likely to be called back for a second round of interviews after controlling for human capital (Igarashi and Mugiyama, 2023). Employers’ prejudice against non-Japanese points to boundaries between insiders and outsiders (Lems, 2020a, 2020b).\n\nLems (2020a, 2020b) observed in her work that although interior frontiers are less visible than external ones, they have a great deal of power over the lives of individuals, which can be seen in Japanese workplaces when highly skilled migrants are pressurised to assimilate culturally, thought of as imperfect substitutes for Japanese employees, and have their skills and abilities undervalued. These directly impact and have tremendous power over their everyday lives.\n\nLems also noted that the process of integration for young asylum seekers is one-way, meaning that they have to submit to Swiss rules while the Swiss do not have to do anything or show flexibility in accommodating them. The same can be observed in Japanese workplaces, where highly skilled migrants are required to follow Japanese practices while their employers do little to accommodate them. In the JILPT (2014) publication which cited employers stating Japanese language skills are a precondition for employment, it is clear that they expect one-way submission to Japanese rules on the part of migrants.\n\nEthnocentric attitudes influenced by Nihonjinron manifest themselves too, especially Nihonjinron’s emphasis on homogeneity. Japan culture and customs, as well as people, are thought to be unique to the point of being superior to others, which may explain employers’ unwillingness to make exceptions for highly skilled migrants regarding Japanese workplace practices or in wanting them to behave like Japanese employees. Superiority can also result in prejudice against non-Japanese and preference for Japanese employees. The belief that Japan should be homogeneous is pervasive, as can be observed in the forced assimilation of highly skilled migrants in the workplace and the preference for Japanese employees.\n\nThe first step to take in moving forward is to challenge the discourse of Japanese homogeneity, which is inaccurate and inappropriate. Indigenous people in Hokkaido and Okinawa have lived in the country for a long time alongside the Japanese, and more recently, the Koreans and Chinese. With globalisation, more migrants are arriving. Japan is clearly not homogeneous. While there is no question that Japanese culture and customs are unique, other cultures and customs are unique too and have their strengths. Japan would benefit far more from being open, flexible and accommodating to highly skilled migrants.",
"appendix": "Data availability statement\n\nNo data are associated with this article.\n\n\nReferences\n\nBecker GS: The Economics of Discrimination. Chicago: The University of Chicago Press; 1957.\n\nBefu H: Hegemony of Homogeneity. Melbourne: Trans Pacific Press; 2001.\n\nConrad H, Meyer-Ohle H: Overcoming the ethnocentric firm? – foreign fresh university graduate employment in Japan as a new international human resource development method. Int. J. Hum. Resour. Manag. 2019; 30(17): 2525–2543. Publisher Full Text\n\nCox T: The multicultural organization. Executive. 1991; 5(2): 34–47. Publisher Full Text\n\nDesai-Trilokekar R, Thomson K, El Masri A: International Students As Ideal Immigrants: Ontario Employers’ Perspective. Toronto: York University; 2016.\n\nFriesen M, Ingram S: Advancing intercultural competency: Canadian engineering employers’ experiences with immigrant engineers. Eur. J. Eng. Educ. 2013; 38: 219–227. Publisher Full Text\n\nGhosh D, Gonzalez JA, Sekiguchi T: Different feathers embedding together: Integrating diversity and organizational embeddedness. J. Manag. Stud. 2023: 1–29. Publisher Full Text\n\nHaghirian P: Japan’s employment system and human resource management – coping with increasing adjustment pressures. Contemporary Japan. 2022; 34(1): 3–12.\n\nHof H: Intersections of race and skills in European migration to Asia: Between white cultural capital and “passive whiteness”. Ethn. Racial Stud. 2021; 44(11): 2113–2134. Publisher Full Text\n\nHof H, Tseng Y-F: When “global talents” struggle to become local workers: The new face of skilled migration to corporate Japan. Asian Pac. Migr. J. 2021; 29(4).\n\nHoman AC, Hollenbeck JR, Humphrey SE, et al.: Facing differences with an open mind: Openness to experience, salience of intragroup differences, and performance of diverse work groups. Acad. Manag. J. 2008; 51(6): 1204–1222. Publisher Full Text\n\nIgarashi A, Mugiyama R: Whose tastes matter? Discrimination against immigrants in the Japanese labour market. J. Ethn. Migr. Stud. 2023; 49: 3365–3388. Publisher Full Text\n\nJoppke C: Neoliberal Nationalism: Immigration and the Rise of the Populist Right. Cambridge: Cambridge University Press; 2021.\n\nJoshi A: The influence of organizational demography on the external networking behavior of teams. Acad. Manag. Rev. 2006; 31(3): 583–595. Publisher Full Text\n\nLems A: Being inside out: the slippery slope between inclusion and exclusion in a Swiss educational project for unaccompanied refugee youth. J. Ethn. Migr. Stud. 2020a; 46(2): 405–422. Publisher Full Text\n\nLems A: Phenomenology of exclusion: Capturing the everyday thresholds of belonging. Social Inclusion. 2020b; 8(4): 116–125. Publisher Full Text\n\nLiu-Farrer G: The logics of staying for highly skilled Asian migrants in Japan. Asian Pac. Migr. J. 2023; 32: 105–128. Publisher Full Text\n\nLiu-Farrer G, Green AE, Ozgen C, et al.: Immigration and labor shortages: Learning from Japan and the United Kingdom. Asian Pac. Migr. J. 2023; 32: 336–361. Publisher Full Text\n\nLiu-Farrer G, Shire K: Who are the fittest? The question of skills in national employment systems in an age of global labour mobility. J. Ethn. Migr. Stud. 2021; 47(10): 2305–2322. Publisher Full Text\n\nMorillas M, Romani L: Ideology, doxa and critical reflexive learning: The possibilities and limits of thinking that ‘diversity is good’. Manag. Learn. 2023; 54(4): 511–530. Publisher Full Text\n\nMorita L: Why Japan isn’t more attractive to highly-skilled migrants. Cogent Social Sciences. 2017; 3(1306952): 1–12. Publisher Full Text\n\nMorita L: Japanese norms in Japanese workplaces. F1000 Res. 2022; 11(1210): 1–10.\n\nMorita L: Interior frontiers in Japanese blue-collar workplaces. SSRN. 2023: 1–14. Publisher Full Text\n\nOishi N: Redefining the “highly skilled”: The Points-Based System for highly skilled professionals in Japan. Asian Pac. Migr. J. 2014; 23(4): 421–450. Publisher Full Text\n\nRear D: A critical analysis of Japanese identity discourses: Alternatives to the hegemony of Nihonjinron. Asian Studies. 2017; 53(2): 1–27.\n\nSekiguchi T, Froese FJ, Iguchi C: International human resource management of Japanese multinational corporations: Challenges and future directions. Asian Bus. Manag. 2016; 15(2): 83–109. Publisher Full Text\n\nShachar A: The race for talent: Highly skilled migrants and competitiveimmigration regimes. N. Y. Univ. Law Rev. 2006; 81(1): 148–206.\n\nShore LM, Randel AE, Chung BG, et al.: Inclusion and diversity in work groups: A review and model for future research. J. Manag. 2011; 37(7): 1262–1289. Publisher Full Text\n\nStoler AL: “Interior frontiers” as political concept, diagnostic, and dispositif. Society for Cultural Anthropology Editor’s Forum; 2017. Reference Source\n\nStoler AL: Interior frontiers: Diagnostic and dispositive. Political Concepts: A Critical Lexicon. 2018. Reference Source\n\nThe Japan Institute for Labour Policy and Training (JILPT): Labour Situation in Japan and its Analysis: General Overview 2013/2014. Tokyo: JILPT; 2014.\n\nvan Riemsdijk M , Basford S: Integration of highly skilled migrants in the workplace: A multi-level framework. J. Int. Migr. Integr. 2022; 23: 633–654. Publisher Full Text\n\nWakisaka D: Labyrinth of highly skilled migration in Japan. University of Bristol; 2018. PhD thesis."
}
|
[
{
"id": "270674",
"date": "13 May 2024",
"name": "Stephen R Nagy",
"expertise": [
"Reviewer Expertise I conducted research on Japan's migration policies in the past"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe author uses an interesting framework, interior frontier to discuss the challenges of highly skilled migrants. It covers the essential literature such as Liu-Farrer, Oishi and others. It is balanced and not normative, sticking to the data and academic literature. The only squabble that I have is that the problems faced by highly skilled overlap heavily with the non-skilled/ low skilled migrants. The exclusive nature of Japan's ethno-centric identity based on insider and outsider groups at all levels in society creates conditions where everyone including Japanese citizens are negotiating the interior frontier when they engage with groups that are not their insider group.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
},
{
"id": "270679",
"date": "22 May 2024",
"name": "Yunchen Tian",
"expertise": [
"Reviewer Expertise migration",
"race and ethnicity",
"border studies",
"Japan"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMorita argues that even highly skilled workers in Japan, enjoying supposedly privileged visas and migration pathways, face a variety of barriers within Japan. Deeming them internal frontiers, Morita argues that they arise from ethnocentric attitudes, antiquated human resources and managerial practices, and other organizational dynamics in Japanese corporate culture.\nMorita's argument can be simply distilled into identifying the relevance of Stoler's concept of \"interior frontiers\", itself drawn for the work of Johann Fichte, in conceptualizing the challenges faced by skilled migrants to Japan today.\nThis modest argument is suitable for an opinion piece within your journal.\nI do not take issue with any of the argumentation or evidence. However, I suggest that Morita consider the use of the term \"frontier\" versus another, such as \"border\". As Stoler admits, the translation from Fichte's original German allows for ambiguity in this regard. She herself uses \"interior border\" and \"interior frontier\" interchangeably throughout her chapter on the term.\nHowever, in contemporary academic literature, \"border\" and \"frontier\" have increasingly developed differing nuances. For example, the work of Thomas Nail on the border identifies frontier as having the connotation of (the prospect for) future (often colonial) expansion. (Nail T, 2016 [Ref 1])\nThat nuance doesn't seem to exist in Morita's use of the term, so I would suggest that Morita use the term \"internal borders\" more so than \"internal frontiers\".\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? No\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-420
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https://f1000research.com/articles/13-419/v1
|
29 Apr 24
|
{
"type": "Study Protocol",
"title": "Accuracy of chronic liver failure consortium (CLIF-C) ACLF score compared with meld, MELD-NA and CTP as a mortality predictor in acute on chronic liver failure patients admitted to tertiary rural care hospital",
"authors": [
"Nitish Batra",
"Shilpa Gaidhane",
"Sourya Acharya",
"Sunil Kumar",
"Shilpa Gaidhane",
"Sourya Acharya",
"Sunil Kumar"
],
"abstract": "Background Chronic Liver Failure Consortium (CLIF-C) ACLF score, Model for End-Stage Liver Disease (MELD), MELD-Na, and Child-Pugh (CTP) are established scoring systems for predicting mortality in Acute on Chronic Liver Failure (ACLF) patients. However, their comparative accuracy, especially in rural care settings, still needs to be explored. This study aims to assess and compare the predictive performance of these scoring systems, providing a nuanced understanding of their applicability in a tertiary rural care hospital.\n\nMethod This prospective observational cohort study will be conducted at Acharya Vinoba Bhave Rural Hospital, following approval from the institutional ethical committee. ACLF patients aged 18 and above, presenting within one week of onset, will be included. Data collection will involve comprehensive assessments, including scoring system calculations, clinical examinations, and relevant investigations. Statistical analyses, encompassing descriptive statistics, comparative analyses, survival analyses, and multivariate models, will elucidate the accuracy and independent predictors of 28-day mortality.\n\nExpected Outcome Anticipated outcomes include a comprehensive understanding of the strengths and limitations of the CLIF-C ACLF score, MELD, MELD-Na, and CTP in predicting mortality among ACLF patients in a rural care context. The study aims to identify potential correlations and independent predictors, offering valuable insights for risk stratification. These findings are expected to guide clinicians in optimising prognostic assessments and decision-making, thereby improving the care and outcomes of ACLF patients in rural healthcare settings.",
"keywords": [
"Acute on Chronic Liver Failure",
"CLIF-C ACLF Score",
"Model for End-Stage Liver Disease (MELD)",
"Rural Care Hospital",
"Mortality Prediction",
"Tertiary Healthcare"
],
"content": "Introduction\n\nChronic liver diseases represent a substantial global health burden, contributing significantly to morbidity and mortality.1 Among the various clinical manifestations of liver dysfunction, Acute Chronic Liver Failure (ACLF) is a critical syndrome characterised by acute decompensation in the setting of pre-existing chronic liver disease. ACLF is associated with high short-term mortality rates, necessitating accurate prognostication for timely and appropriate interventions.2\n\nSeveral scoring systems have been developed to assess the severity of liver disease and predict mortality, each with advantages and limitations.3 The Chronic Liver Failure Consortium (CLIF-C) ACLF score, Model for End-Stage Liver Disease (MELD), MELD-Na, and Child-Pugh (CTP) are prominent examples widely utilised in clinical practice. However, their comparative accuracy in predicting mortality, especially in the specific context of rural healthcare settings, remains an area warranting investigation.4\n\nRural healthcare facilities often need help with unique challenges, including limited resources and different demographic profiles compared to urban centres. Understanding the performance of scoring systems in these settings is crucial for tailoring prognostic strategies to the specific needs of the population.5 This study seeks to address this gap by assessing and comparing the accuracy of CLIF-C ACLF score, MELD, MELD-Na, and CTP in predicting 28-day mortality in ACLF patients admitted to a tertiary rural care hospital.\n\nThe choice of scoring system can significantly impact clinical decision-making, resource allocation, and patient outcomes. While the MELD score is widely utilised, the CLIF-C ACLF score, incorporating dynamic clinical parameters, may offer enhanced prognostic accuracy, particularly during acute exacerbations in chronic liver disease. This study aims to provide evidence-based insights into the optimal choice of scoring systems in rural care settings, contributing to the refinement of risk stratification and ultimately improving the management and outcomes of ACLF patients.\n\nThe primary aim of this study is to assess the accuracy of the Chronic Liver Failure Consortium (CLIF-C) ACLF score in predicting 28-day mortality in patients with Acute Chronic Liver Failure (ACLF) admitted to a tertiary rural care hospital. This will be compared with the widely used Model for End-Stage Liver Disease (MELD), MELD-Na, and Child-Pugh (CTP) scoring systems.\n\n\n\n• Estimation of scoring systems: To calculate and compare the CLIF-C ACLF score, MELD, MELD-Na, and CTP score in patients with ACLF.\n\n• Comparison of sensitivity and specificity: To evaluate and compare the sensitivity and specificity of the CLIF-C ACLF score against MELD, MELD-Na, and CTP as indicators of 28-day mortality in ACLF patients.\n\n\nMethods\n\nThis study will employ a prospective observational cohort design, aiming to assess and compare the predictive accuracy of the Chronic Liver Failure Consortium (CLIF-C) ACLF score with MELD, MELD-Na, and Child-Pugh (CTP) in predicting 28-day mortality in Acute on Chronic Liver Failure (ACLF) patients.\n\nThe study will focus on patients diagnosed with ACLF, presenting within one week of onset, aged 18 years and above, and providing informed consent for participation.\n\nThe study will be conducted at Acharya Vinoba Bhave Rural Hospital (A.V.B.R.H.), a tertiary care teaching hospital in the rural Wardha District area.\n\nPatients meeting the following criteria will be included in the study:\n\n• Diagnosed with Acute Chronic Liver Failure (ACLF).\n\n• Age 18 years and above.\n\n• Presentation within one week of ACLF onset.\n\n• Willingness to provide informed consent.\n\nPatients meeting any of the following criteria will be excluded from the study:\n\n• Chronic liver disease treated outside the hospital before emergency presentation.\n\n• Lack of informed consent for participation in the study.\n\nBias in a study can affect the validity and reliability of its results. In the context of this study, potential biases need to be acknowledged and addressed to ensure the robustness of the findings.\n\n\n\n• Selection bias: The inclusion criteria focus on ACLF patients presenting within one week of onset, potentially excluding patients with a delayed presentation. This could introduce bias if there are systematic differences between early and delayed presenters. Efforts will be made to minimise this bias by clearly defining and adhering to the enrollment criteria.\n\n• Volunteer bias: Patients providing informed consent may differ from those who decline participation. To mitigate this bias, efforts will be made to explain the study comprehensively, emphasising its importance and the non-invasive nature of data collection. Additionally, the potential impact of volunteer bias will be acknowledged in interpreting results.\n\n• Exclusion criteria bias: The exclusion of patients with chronic liver disease treated outside the hospital may lead to the exclusion of a subset of ACLF patients with different characteristics. This bias will be addressed by clearly justifying the exclusion criteria and considering potential implications in the discussion of results.\n\nPatient identification will commence in the Medicine ward and Intensive Care Unit (ICU) of Acharya Vinoba Bhave Rural Hospital (AVBRH). Eligible patients meeting the inclusion criteria will be approached for participation, where the research team will provide a detailed explanation of the study's purpose, procedures, and potential risks. Informed consent will be sought from willing participants, emphasising the voluntary nature of their involvement.\n\nOnce consent is obtained, comprehensive baseline information will be gathered. This will include demographic details, medical history, family history, and lifestyle factors such as smoking and alcohol intake. A thorough physical examination will be conducted, focusing on symptoms indicative of Acute or Chronic Liver Failure (ACLF), such as right upper quadrant pain, jaundice, mental status changes, and abdominal distention.\n\nCalculating various scoring systems will be a crucial component of data collection. The Chronic Liver Failure Consortium (CLIF-C) ACLF score.2 Additionally, the Child-Pugh-Turcotte Score (CTP)6 will be determined through the evaluation of prothrombin time (or INR), encephalopathy, albumin, bilirubin, and ascites. The Model for End-Stage Liver Disease (MELD) and MELD-Na scores7 will be calculated using the specified formulas.\n\nRelevant investigations will be conducted to support the diagnosis and assess liver function. These may include blood tests measuring bilirubin, INR, and creatinine, as well as imaging studies and ultrasonography of the abdomen.\n\nPatients will be followed throughout their hospital stay until discharge, death, or 28 days post-discharge, whichever occurs first. Any events, interventions, or changes in clinical status will be meticulously documented to provide a comprehensive dataset for analysis.\n\nData management will involve recording collected information in a structured electronic database, ensuring accuracy and maintaining confidentiality. Regular training sessions for data collectors will be conducted to uphold standardised data collection procedures. Periodic audits will be performed to validate data accuracy.\n\nThe study will strictly adhere to ethical guidelines, with a formal submission of the study protocol for ethical approval. Any modifications to the protocol will be communicated to the relevant authorities. Implementing a predefined timeline will guide the data collection process, ensuring efficiency and completion within the specified timeframe. Through this comprehensive and systematic approach, the study aims to gather reliable and pertinent information for the subsequent analysis of scoring system accuracy in predicting mortality in ACLF patients.\n\nCalculated by following the formula where:\n\nWere,\n\nZ alpha/2 is the level of significance at 5%, i.e., 95% confidence interval = 1.96\n\nP = Prevalence of Acute on chronic liver disease = 12% - 40%\n\nd = desired error of margin = 4 %\n\nSo, the minimum sample size required will be 386 patients.\n\nThe statistical analysis for this prospective observational cohort study will be conducted to comprehensively assess the accuracy of scoring systems in predicting mortality among patients with Acute Chronic Liver Failure (ACLF). A detailed overview of the study population's baseline demographic characteristics will be provided through descriptive statistics, including means and standard deviations for continuous variables and frequencies for categorical variables.\n\nIn the comparative analysis, the sensitivity and specificity of the Chronic Liver Failure Consortium (CLIF-C) ACLF score will be compared with the widely used Model for End-Stage Liver Disease (MELD), MELD-Na, and Child-Pugh (CTP) score in predicting 28-day mortality in ACLF patients. The discriminatory power of each scoring system will be assessed using Receiver Operating Characteristic (ROC) curve analysis.\n\nSurvival analysis will be employed to illustrate the survival distribution among patients based on different scoring systems. Kaplan-Meier survival curves will be generated, and the log-rank test will be utilized to identify significant differences in mortality rates. Multivariate logistic regression models will be used for in-depth analysis, identifying independent predictors of 28-day mortality while considering various clinical and demographic variables. Adjusted odds ratios will quantify the strength of these associations.\n\nCorrelation analysis, employing Pearson or Spearman correlation coefficients, will assess the degree of correlation between different scoring systems, providing insights into their interrelationships. Subgroup analyses will be conducted to explore the performance of scoring systems within specific patient subpopulations, accounting for factors such as age, comorbidities, and the severity of liver disease. Statistical analysis will be performed using dedicated software such as by using R studio version 4.3.1., with statistical significance set at the conventional alpha level of 0.05. The results will be interpreted in the context of clinical relevance, contributing valuable insights into predicting mortality in ACLF patients within a rural care setting.\n\nThe study anticipates providing valuable insights into the predictive accuracy of various scoring systems, including the Chronic Liver Failure Consortium (CLIF-C) ACLF score, Model for End-Stage Liver Disease (MELD), MELD-Na, and Child-Pugh (CTP), in forecasting 28-day mortality among patients with Acute on Chronic Liver Failure (ACLF) in a rural care setting. The analysis is expected to elucidate each scoring system's strengths and limitations, aiding clinicians in better assessing the prognosis of ACLF patients.\n\nFurthermore, the study aims to identify potential correlations and associations between different clinical and demographic variables, shedding light on factors that may independently predict mortality in this patient population. This information can potentially refine risk-stratification strategies and enhance clinical decision-making in managing ACLF cases.\n\nThe anticipated outcomes will contribute to the academic understanding of ACLF prognosis and have practical implications for healthcare practitioners, potentially influencing the selection and utilisation of scoring systems in real-world clinical scenarios. Ultimately, the study aspires to offer evidence-based recommendations to optimise the care and outcomes of patients experiencing Acute or Chronic Liver Failure in rural healthcare settings.\n\nEthical considerations play a paramount role in this study, as evidenced by the approval from the institutional ethical committee of Datta Meghe Institute of Medical Sciences (DU). The approval reference number is DMIMS. (DU)/IEC/2022/1095 signifies the adherence to ethical standards in the research protocol. A crucial aspect of ethical practice involves maintaining the confidentiality of participants. Stringent measures will be implemented to ensure the confidential status of all gathered data, safeguarding the privacy and rights of the individuals involved in the study.\n\nAfter the completion of the study, we will publish it in an indexed journal or conference.\n\nThe study has yet to start. After the publication of the protocol, we will start recruitment in the study.\n\n\nDiscussion\n\nThe proposed study aims to contribute valuable insights into scoring systems' predictive accuracy in Acute on Chronic Liver Failure (ACLF) patients admitted to a tertiary rural care hospital. The selection of appropriate scoring systems is crucial for effective prognostication and clinical decision-making in this patient population.\n\nThe Chronic Liver Failure Consortium (CLIF-C) ACLF score, Model for End-Stage Liver Disease (MELD), MELD-Na, and Child-Pugh (CTP) are well-established tools for assessing the severity of liver disease and predicting mortality. The proposed study compares these scoring systems, considering their applicability in rural care. This approach aligns with existing research emphasising the need for tailored prognostic tools that account for variations in patient demographics and healthcare resources.8,9\n\nExisting literature suggests that while the MELD score is widely used for liver disease severity assessment, the CLIF-C ACLF score may offer additional prognostic accuracy, particularly in acute exacerbations in chronic liver disease.10,11 This study's focus on rural care is essential, as healthcare disparities between urban and rural settings can impact the applicability and generalizability of scoring systems.12\n\nUsing a prospective observational cohort design enhances the study's credibility, enabling the examination of real-world clinical scenarios and outcomes. However, it is essential to acknowledge potential limitations, such as selection bias, which may arise from the exclusion of patients treated outside the study hospital before presentation. Efforts will be made to mitigate this bias by clearly justifying the exclusion criteria and considering its potential impact on the study's external validity.\n\nThe anticipated outcomes of the study include a refined understanding of scoring system accuracy and the identification of potential predictors for 28-day mortality in ACLF patients in a rural care context. These findings may inform clinical practice by aiding healthcare providers in selecting the most appropriate scoring system for prognosis, ultimately improving patient care and outcomes.\n\nThis study protocol has been registered with the Clinical Trials Registry – India (CTRI) - CTRI REF/2023/07/069843.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nReferences\n\nCheemerla S, Balakrishnan M: Global Epidemiology of Chronic Liver Disease. Clin Liver Dis (Hoboken). 2021; 17: 365–370. Publisher Full Text\n\nCLIF-C ACLF (Acute-on-Chronic Liver Failure): MDCalc. Accessed: November 9, 2023. Reference Source\n\nBarosa R, Roque Ramos L, Patita M, et al.: CLIF-C ACLF score is a better mortality predictor than MELD, MELD-Na and CTP in patients with Acute on chronic liver failure admitted to the ward. Rev. Esp. Enferm. Dig. 2017; 109: 399–405. Publisher Full Text\n\nRamzan M, Iqbal A, Murtaza HG, et al.: Comparison of CLIF-C ACLF Score and MELD Score in Predicting ICU Mortality in Patients with Acute-On-Chronic Liver Failure. Cureus. 12; e7087. Publisher Full Text\n\nChen X, Orom H, Hay JL, et al.: Differences in Rural and Urban Health Information Access and Use. J. Rural. Health. 2019; 35: 405–417. Publisher Full Text\n\nTsoris A, Marlar CA: Use Of The Child-Pugh Score In Liver Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.\n\nSingal AK, Kamath PS: Model for End-stage Liver Disease. J. Clin. Exp. Hepatol. 2013; 3: 50–60. Publisher Full Text\n\nChallen R, Brooks-Pollock E, Read JM, et al.: Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ. 2021; 372: n579. Publisher Full Text\n\nSmith AC, Thomas E, Snoswell CL, et al.: Telehealth for global emergencies: Implications for coronavirus disease 2019 (COVID-19). J. Telemed. Telecare. 2020; 26: 309–313. Publisher Full Text\n\nKamath PS, Kim WR: Advanced Liver Disease Study Group: The model for end-stage liver disease (MELD). Hepatology. 2007; 45: 797–805. Publisher Full Text\n\nMoreau R, Jalan R, Gines P, et al.: Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013; 144: 1426–37. 1437.e1-9. Publisher Full Text\n\nHart LG, Larson EH, Lishner DM: Rural definitions for health policy and research. Am. J. Public Health. 2005; 95: 1149–1155. Publisher Full Text"
}
|
[
{
"id": "280742",
"date": "29 May 2024",
"name": "Jonathan Soldera",
"expertise": [
"Reviewer Expertise Acute on Chronic Liver Failure and Inflammatory Bowel Disease."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study protocol aims to evaluate the accuracy of the Chronic Liver Failure Consortium (CLIF-C) ACLF score in predicting mortality among acute on chronic liver failure (ACLF) patients in a tertiary rural care hospital, compared with other established scoring systems like MELD, MELD-Na, and CTP. It is a prospective observational cohort study involving comprehensive assessments and statistical analyses to identify the best predictors of 28-day mortality in ACLF patients. Congratulations to the authors on undertaking this important study. Investigating the performance of CLIF-C ACLF, MELD, MELD-Na, and CTP scores in a rural healthcare setting is crucial for improving prognostic accuracy and patient outcomes in these environments. To enhance the robustness and depth of the study, the authors should consider reviewing the following papers:\nA systematic review on the use of these scoring systems for ACLF to provide a comprehensive background and context: (Rashed et al.,2022) (ref-5) Recent research articles that discuss advancements in liver failure prognostication tools in multiple scenarios, such as SBP and variceal bleeding: (Jonathan,2023) (ref-1) ; (Grochot et al.)(ref-2); (Terres et,al.,2020)(Ref-5) ; (Jacques et al.,2020)(Ref-6) ; (Grochot et.,2020) (Ref-10);(Jacques et al.,2021) (Ref-7); (Terres et al., 2021) (Ref-8); (Terres.,2023)(Ref-9) ; (Ndomba et al.,2023)(ref-3)\nAdditionally, improving the language clarity in the manuscript is recommended, as some sentences are challenging to understand. This will ensure the findings are communicated more effectively to a broader audience.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": []
},
{
"id": "280740",
"date": "03 Jun 2024",
"name": "Yu Chen",
"expertise": [],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n\"Acute on chronic liver failure\" and \"acute chronic liver failure\" should be uniformly referred to in this protocol.\n\nThe ACLF diagnostic criteria vary between the Asia-Pacific and EASL. As a protocol, could you mention which standard you're using to include patients?\n\nAs a comparative study of model scores, please clarify why there is no validation cohort in this study.\n\nAll participants in the study are ACLF patients, and you calculated the sample size based on ACLF incidence rates. This is methodologically or logically incorrect.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "280745",
"date": "03 Jun 2024",
"name": "Alexandra Alexopoulou",
"expertise": [
"Reviewer Expertise Cirrhosis and complications"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study protocol entitled \"Accuracy of chronic liver failure consortium (CLIF-C) ACLF score compared with meld, MELD-NA and CTP as a mortality predictor in acute on chronic liver failure patients admitted to tertiary rural care hospital\" is very interesting, aiming to compare the predictive performance of scoring systems commonly used for the estimation of acute on chronic liver failure in a rural caring environment.\nThe authors are aware of the literature, their rationale and objectives were well described and their methods are clearly presented.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-419
|
https://f1000research.com/articles/13-418/v1
|
29 Apr 24
|
{
"type": "Policy Brief",
"title": "Legal framework for AI applications",
"authors": [
"Hashim Balas",
"Reem Shatnawi"
],
"abstract": "Artificial intelligence (AI), the most widespread technological term, has become an integral part of human daily life. People are becoming increasingly dependent on AI-powered devices; thus, it is now essential to have a legal framework to oversee artificial intelligence's various uses and legal peculiarities. As artificial intelligence has entered all areas of life and into various sectors, which requires examining in detail the legal nature of artificial intelligence, determining the laws that must be applied to it, and identifying the people or entities responsible for it to determine the scope of their responsibilities for the resulting damages that may be caused to others as a result of the use of intelligence. Artificial, this research aimed to examine the adequacy of the legal rules in Jordanian legislation regulating the provisions of artificial intelligence in light of the diversity of its applications and its different legal nature. The research is divided into two chapters. The first chapter presents the concept of artificial intelligence, and the second chapter discusses the legal liability of artificial intelligence. The results of the research revealed that the Jordanian legislator did not specify the legal nature of the artificial intelligence and contented himself with stipulating it in separate texts, Legal liability resulting from utilizing artificial intelligence systems can be challenged under regulations of the defect in manufacturing, responsibility for guarding things, and the distinction between responsibilities due to the degree of independence and intelligence of artificial intelligence, In determining the liability of artificial intelligence, the legislator should consider the types of artificial intelligence systems, their different capabilities, and their independence from humans, The process of enacting special laws regulating all aspects of artificial intelligence must be expedited. This law should be characterized by flexibility that enables it to keep pace with and rapid development witnessed in this field.",
"keywords": [
"administrative liability",
"artificial intelligence",
"civil liability",
"legal nature",
"legal framework",
"science fiction",
"electronic intermediary",
"legal personhood."
],
"content": "Introduction\n\nArtificial intelligence applications are developing rapidly worldwide, with applications being used in various industries, including education, entertainment, industry, finance, security systems, and medicine. These artificial intelligence-based applications have drawbacks in addition to their countless benefits. This progress has rendered the legal systems of all countries unable to hold parties liable for damages caused by artificial intelligence and, thus, unable to demand reimbursement for such damages in many situations. This has prompted most countries and the international community to regulate artificial intelligence through a legal framework that lays out its tenets, obligations, usage controls, and liabilities arising from the potential harm it may bring. However, in Jordan, the legislator did not stipulate specific statutes for artificial intelligence; rather, he adopted texts scattered from the general rules the general rules, The problem of this study crystallizes in examining the adequacy of the general legal rules contained in Jordanian legislation to regulate the provisions of artificial intelligence in light of the diversity of its applications and its different legal nature, as the current legal rules when they were drafted did not consider in their content the accelerated application of artificial intelligence in all aspects of life and fields, and this research aimed to examine the legal framework of artificial intelligence in Jordanian legislation by extrapolating the legislative and regulatory rules that govern artificial intelligence and analyzing legal texts to determine their application to artificial intelligence. This research reviews the definition of artificial intelligence, its electronic nature, and the legal effects resulting from using it.\n\n\nPolicy outcomes and implications\n\nThe study found a set of findings that were important there is no comprehensive definition of artificial intelligence, not in jurisprudence or even legislation, due to its different applications and the difference in its legal nature. The Jordanian legislative system has inadequate regulation for artificial intelligence status. Legal liability resulting from utilizing artificial intelligence systems can be challenged under regulations of the defect in manufacturing, responsibility for guarding things, and the distinction between responsibilities due to the degree of independence and intelligence of artificial intelligence.\n\n\nActionable recommendations\n\nAnd this study also found a set of recommendations that were important the process of enacting special laws organizing all aspects of artificial intelligence should be speeded up. And this law should be characterized by the flexibility to keep pace with this field's tremendous and rapid development. In determining the liability of artificial intelligence, the legislator should consider the types of artificial intelligence systems, their different capabilities, and their independence from humans. The legislator should consider the liability of the administration for errors resulting from using AI, state the scope and limits of the administration's responsibility, and the possibility of holding it liable for the errors caused by the use of AI.\n\n\nChapter One\n\nThroughout history, humanity has been obsessed with developing devices that can mimic the cognitive processes of the human mind. The ultimate objectives have always been to improve human life, increase production in various industries, and reduce mistakes. For example, in 1872, Samuel Butler predicted that machines would be essential to human progress and the global advancement of prosperity.\n\nScience fiction was the first genre to use artificial intelligence (AI). It sometimes emphasized the predicted bad features of artificial intelligence, depicting it as a ferocious enemy of humanity that seeks to control it, and at other times referred to it as a way to improve human life. A new chapter in the history of technology began in 2018 when artificial intelligence became a reality. Its integration has spread to other areas of daily life, such as traffic control, city navigation, and virtual assistants to assist with various operations. Today, artificial intelligence is widely recognized as an instrument that could boost society (Ghaleb, 2011).\n\nArtificial intelligence has special characteristics, applications, advantages, and drawbacks like other concepts. Therefore, it is imperative to draft a law regulating all issues associated with it, such as its controls and legal liability. Therefore, the researcher has dedicated two sections to discussing these issues. The first deals with the AI concept, while the second section will discuss the legal nature of AI.\n\n\nSection One\n\nIn April 2021, the European Commission proposed an artificial intelligence (AI) regulatory framework within the EU. The draft AI legislation represents the first attempt to pass a horizontal regulation for AI. The intended legal framework is centered on the particular application of AI systems and related risks. The Commission defined Artificial intelligence as “software that is developed with one or more of the techniques and approaches listed in Annex I and can, for a given set of human-defined objectives, generate outputs such as content, predictions, recommendations, or decisions influencing the environments they interact with.”\n\nThe World Intellectual Property Organization defines artificial intelligence as: “ a discipline of computer science that is aimed at developing machines and systems that can carry out tasks considered to require human intelligence. Machine learning and deep learning are two subsets of AI.” As for the legal aspect, Robert Little Dictionary defined artificial intelligence as: “a part of computer science that aims to simulate a cognitive ability to replace humans in performing appropriate functions in a specific context that require intelligence.” John McCarthy, the father of artificial intelligence, defined it as “the science and engineering of making intelligent machines.” And that “AI involves the creation of programs and machines that can perform tasks that, when done by humans, typically require intelligence. These tasks include learning, reasoning, problem-solving, perception, and language understanding.”\n\nIn Jordanian legislation, artificial intelligence was not specifically defined. However, Article (2) of the Electronic Transactions Law defines the electronic intermediary as “The electronic program or software used to carry out a procedure or to automatically respond to a procedure for the purpose of generating, sending, or receiving information message.\" This definition is deemed the closest to AI despite excluding certain characteristics and varieties. Regretfully, the legislator in Jordan is still ignorant of the gravity of the rapidly advancing applications of artificial intelligence and the appreciable rise in their use across all sectors of the economy, society, and agriculture.\n\nBased on the definitions above, it is obvious that the variations in the concept of artificial intelligence result from the many lenses through which they are viewed. As a result, the researcher suggests the following definition of artificial intelligence: a scientific discipline focused on empowering robots to perform complex classification, specialized research, and analytical processes in various fields related to areas concerning human needs and developing machines capable of simulating the human mind, making decisions, solving problems, and providing solutions independently.\n\n\nSection Two\n\nDetermining the legal nature of artificial intelligence requires defining its legal personhood. There has been a lot of controversy around the issue of granting artificial intelligence legal personality since it comes in various forms, such as machines and software operated by humans or independent robots that can make autonomous decisions (Salam, 2022). This variation makes it difficult to determine which law shall be adopted and applied to cases where risk results from machines operated by artificial intelligence.\n\nArtificial intelligence was divided into three main categories (Salam, 2022) depending on the abilities they have such as:\n\n1. Artificial Narrow Intelligence (ANI): The simplest type of artificial intelligence used to perform specific tasks, and its narrow capabilities, such as fingerprint or facial recognition technology and drones, are operated by humans.\n\n2. Artificial General Intelligence (AGI): It uses advanced technologies. This type of AI has human-level cognitive functions, such as planning and thinking independently and logically, similar to medical robots used in surgical medicine and military and security robots.\n\n3. Artificial Super Intelligence (ASI): This type of artificial intelligence would surpass all human capabilities and adapt to external situations and all surrounding circumstances without human interference. It also has the ability to manufacture machines and equipment. ASI has large and infinite memory, enabling it to process and analyze data immediately.\n\nThe Jordanian legislator specifies in Articles (30-52) of the Civil Codes that legal personality is granted to a natural person eligible to acquire rights and obligations. It is also granted to judicial persons when they meet the specified conditions. In this context, we argue whether we can apply the rules pertaining to natural or legal personality to artificial intelligence or whether it needs special provisions; if so, a new legal amendment must be put in place (Al-Khouli, 2021).\n\nThe issue of granting legal personhood status to artificial intelligence has been widely debated. Some consider artificial intelligence to be a human product; therefore, it should be treated as property or under intellectual property rights laws, such as copyright, which should be applied to AI (Mohammad, 2021). Opposing opinions typically claim that artificial intelligence technology regularly outsmarts natural human intelligence, especially those who did not create it. This viewpoint holds that artificial intelligence (AI) arises as a separate, autonomous being that is not dependent on its human creators, making it eligible to have rights and obligations. The holder of this opinion argues that legal personhood should be granted to artificial intelligence (Badr, 2022).\n\nThe researcher claims no provision in the general rules states that legal personality is granted exclusively to natural and legal persons. Therefore, nothing is preventing artificial intelligence from being granted legal personality. However, the recognition of artificial intelligence as a legal personality as an independent entity in itself will be reflected in the prevailing legal system, as this will result in the artificial intelligence having its own independent financial liability under which it can acquire rights and bear obligations.\n\nIn this regard, the researcher suggests that legislators should urgently specify special regulations clarifying the legal personality of AI, especially in light of the tremendous development of artificial intelligence.\n\n\nChapter Two\n\nArtificial intelligence systems of all types have become a reality in our lives, and their applications are used to perform various tasks, whether in the educational, health, economic, or security fields. Since AI performs something physical, the likelihood of making an error is anticipated; therefore, whoever is responsible for this error must bear all liability and make good for any resulting damages. In the next chapter, we will discuss the civil and administrative liability resulting from using artificial intelligence.\n\n\nSection One\n\nIn Jordan, there is a dramatic gap between the slow pace of making regulations pertaining to artificial intelligence, specifically regarding legal personhood, and the breathbreaking development of artificial intelligence applications in all aspects of life. Therefore, it is necessary to establish legal texts defining the scope of AI responsibility and provide texts protecting the rights of AI and protecting individuals from harm that may be inflicted on them by AI.\n\nIn this context, two theories have emerged regarding determining the responsibility of artificial intelligence: the traditional theory and the modern theory (Salam, 2022). The traditional theory claims that artificial intelligence may take on the nature of a physical thing directed by humans. Based on this opinion, the person who owns it bears full responsibility for guarding and protecting it and ensuring that it does not inflict any harm to others (Al-Khatib, 2018). For instance, Article (291) of the Jordanian civil law has stipulated that “Any person who has things under his control which require special care to prevent their causing damage or mechanical equipment, shall be liable for any harm done by such things or equipment, save to the extent that damage could not have been averted.” As for artificial intelligence machines and tools that are independent and capable of making decisions, some jurists believe that the one who ultimately bears responsibility for the damages resulting from it is the producer who created and programmed their software in the first instance (Al-Dahiyat, 2019).\n\nRegarding protecting AI, Article (3/B/8) of the Copyright Protection Law No. (22) Of (1992) and its amendments stated that “The protection under this law includes Computer programs whether in the source language or machine language.”\n\n\nSection Two\n\nThe Supreme Court of Justice defined the administrative decision as: “a final legal act issued by the unilateral and binding will of the public administration, with the authority it has under the laws and regulations, and in the form required by the law, with the intention of establishing, amending, or abolishing a specific legal position for the public good.”\n\nThe technology revolution has greatly developed the administration sector, just like in other fields. Artificial intelligence is now a part of the administration process and may do many administrative tasks, including independent decision-making. Artificial intelligence has undoubtedly made significant progress in this area, as seen by its ability to streamline and reduce administrative procedures while guaranteeing prompt and efficient responses. Electronic administrative decision-making, which some jurists have described as “the responsible authorities' use of information systems to adopt one alternative from among the alternatives presented,” is one of the most notable examples of this evolution (Hosni, 2008).\n\nHowever, this development raises crucial issues pertaining to the legal framework of the administration's responsibility for the actions and decisions carried out by artificial intelligence instead of the public employee.\n\nFrom a technical standpoint, it is clear that artificial intelligence systems used in the administrative domain depend on a human operator who is skilled in artificial intelligence and provides the first input of data and information. Then, the system does all the instructions independently without needing a human operator. The next steps in this technological revolution are language comprehension, sound and visual fingerprint identification, and the ability to comprehend and use knowledge. The system gathers data from established laws, concepts, theories, or principles previously incorporated into the artificial intelligence program (Ahmed, 2022).\n\nHowever, entrusting administrative decisions to artificial intelligence may lead to many errors, such as making illegal decisions, refusing to grant rights, or refusing to grant a service despite the availability of all the conditions that must be met by the person applying for this service.\n\nIn this regard, some jurisprudence believes that if the administration has taken a decision based on artificial intelligence systems as a result of an illegal decision issued by it in the first place, then it will be responsible for this decision and compensation for the harm caused to individuals (Mohammad, 2021) however when the error resulted from a technical defect in the artificial intelligence systems. In that case, the administration cannot be held accountable for this error, and it is difficult to know who is responsible for this error because it is a precise technical issue (Mohammad, 2022).\n\nThis issue has received great controversy around the world. Certain judicial systems tend to associate liability with two outcomes: 1. The administration in charge of the procedures must strike a balance between all concerned interests from the outset before the program is implemented. This calls for regular testing of algorithms (artificial intelligence), particularly if they are machine learning or deep learning algorithms. It also calls for modifications and updates. 2. The justiciability of algorithms (artificial intelligence) assumes that judges and citizens understand them, and this requires that all their aspects be known, such as their authors, preparation procedures, and decision systems (Mohammad, 2021).\n\nReviewing the Jordanian law in this context, we find that the Administrative Judiciary Law stipulates in Article (8) that “The lawsuit shall be filed with the court using a written summons submitted within (60) sixty days from the date of notice of the administrative decision complained of to the plaintiff or from the date of its publication in the Official Gazette or by any other means, including electronic means if the legislation stipulates that the administrative decision shall be implemented from that date.”\n\nThe researcher argues that the Jordanian legislator has specified the use of electronic notice. At the same time, he ignores clarifying the effectiveness of this notice, indicating its legal effects or the extent to which it can be considered.\n\n\nConclusion\n\nThe researcher concluded that artificial intelligence has become integral to society's life. AI technology is seen in all areas of life. Therefore, setting detailed regulations for AI status is urgent and cannot be delayed anymore.\n\n\nEthics and consent\n\nEthical approval and written consent were not required.",
"appendix": "Data availability statement\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nAhmed R: Management Applications of Artificial Intelligence in Administrative Decision Making, Master's Thesis, Middle East University, Jordan.2022.\n\nAl-Azab IS: Artificial Intelligence in Internet Business.2021.\n\nBadr M: Civil Liability Arising from the Use of Artificial Intelligence Technologies in Jordanian Legislation, Master's Thesis, Middle East University, Jordan, (June 2022).2022; p. 24.\n\nAl-Borai AS: Applications of artificial intelligence and robots from the perspective of Islamic jurisprudence, Egyptian Dar Al-Iftaa Magazine, No. 48, Al-Azhar University, Egypt.2022.\n\nCopyright Protection Law No. (22) of: and its amendments, published in the Official Gazette No. (3821), page (684), dated (4/16/1992), and amended No. (9) of (2005), published in the Gazette. Official No. (4702), page (1101), date(3/31/2005).1992.\n\nAl-Dahiyat I: Towards a Legal Regulation of Artificial Intelligence in Our Lives. Al-Ijtihad Journal of Legal and Economic Studies, United Arab Emirates. 2019; 8(5).\n\nDecision No: chapter dated (9/26/2005), Supreme Court of Justice, published on Qastas.271/2005.\n\nElectronic Transactions Law No. (15) of: published in the Official Gazette No. (5341), page (5292), date (5/17/2015).2015.\n\nGhaleb Y: Fundamentals of Management Information Systems and Information Technology. 1st ed.Amman: Dar Al-Manhaj for Publishing and Distribution; 2011.\n\nHosni DA: The End of Administrative Decision Through the Judiciary. 2nd ed. Egypt: Dar Al-Kutub Al-Qanuni; 2008.\n\nJordanian Civil Law No. (43) of: published in the Official Gazette, No. (2645), page (2), dated (1/8/1976).1976.\n\nAl-Khatib ME: Guarantees of Rights in the Digital Age, Journal of the Kuwait International College of Law, Fifth Annual Conference, Contemporary Challenges to Legal Guarantees in a Changing World.2018.\n\nAl-Khouli AM: Civil liability resulting from the illegal use of artificial intelligence applications. The Journal of Jurisprudential and Legal Research. 2021; issue (36): p. 241. date (October 2021).\n\nMohammad A: Liability for Artificial Intelligence between Private Law and Public Law. Twentieth Annual Conference, Legal and Economic Aspects of Artificial Intelligence and Information Technology. Egypt: Mansoura University; 2021.\n\nMohammad FI: Legislative Regulation of Artificial Intelligence Applications. Journal of Legal and Economic Research. 2022; Issue (81): p. 1098. date (September 2022).\n\nMousa A, Habib A: Artificial Intelligence is a Revolution in the Technologies of the Age. 1st ed. Egypt: Arab Group for Training and Publishing; 2019.\n\nProposal for a regulation: of the European Parliament and of the Council laying down harmonized rules on artificial intelligence (artificial intelligence act) and amending certain union legislative acts, Brussels), 21.4.2021 .\n\nSalam A: Legal Regulation of Artificial Intelligence, A Comparative Study, PhD thesis, University of Karbala.2022.\n\nThe Administrative Judiciary Law No. (27) of: published in the Official Gazette, No. (7722), page (2644), dated (8/17/2014).2014.\n\nThe Supreme Court of Justice Resolution No: Chapter Date (9/26/2005), Supreme Court of Justice.271/2005."
}
|
[
{
"id": "273886",
"date": "10 May 2024",
"name": "Enas Mohammed Al-Qodsi",
"expertise": [
"Reviewer Expertise artificial intelligence",
"civil liability",
"contracts",
"environment",
"consumer protection",
"and intellectual property."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComprehensive Definition of AI: The article rightly acknowledges the absence of a comprehensive definition of AI, both in jurisprudence and legislation. However, to enhance scientific rigor, it would be beneficial to explore existing definitions proposed by scholars or international organizations and critically evaluate their applicability within the Jordanian context. This would provide clarity and context for readers and facilitate a deeper understanding of AI's legal implications.\nIn-depth Analysis of Legal Framework: While the article outlines the inadequacy of Jordanian legislation in regulating AI, it could benefit from a more detailed analysis of specific legal provisions and their relevance or limitations concerning AI applications. This includes an examination of relevant laws governing intellectual property, data protection, and liability frameworks in other jurisdictions to inform potential legislative reforms in Jordan. By providing concrete examples and comparative analyses, the article can offer actionable insights for policymakers and legal practitioners.\nExploration of Ethical Considerations: In discussing the legal implications of AI, the article primarily focuses on liability issues but overlooks broader ethical considerations surrounding AI deployment. Integrating discussions on ethical frameworks, fairness, accountability, and transparency in AI systems would enrich the analysis and contribute to a more holistic understanding of the challenges and opportunities posed by AI. This interdisciplinary approach is essential for fostering responsible AI governance and promoting public trust in AI technologies.\nEmpirical Evidence and Case Studies: To strengthen the empirical basis of the research, incorporating empirical evidence and case studies illustrating real-world instances of AI-related legal challenges or liabilities in Jordan or comparable contexts would enhance the article's credibility and relevance. By grounding theoretical discussions in practical examples, the article can provide tangible illustrations of the issues at hand and facilitate a more nuanced analysis of the legal landscape surrounding AI. Addressing these constructive critiques would enhance the scientific soundness and scholarly impact of the article, providing valuable insights for policymakers, legal practitioners, and researchers navigating the complex intersection of AI and law in Jordan and beyond.\nIn Section Two Administrative Liability Resulting From The Utilization of Artificial Intelligence\nThe paragraph effectively highlights the potential challenges in attributing liability for errors in administrative decisions made by AI systems. It distinguishes between errors stemming from illegal decisions and those arising from technical defects in the AI systems. However, it could benefit from a clearer delineation of the responsibilities of the administration versus the developers or operators of the AI systems. Providing specific examples or case studies where these distinctions have been addressed in other jurisdictions would strengthen the argument.\nNeed for Regulatory Framework: The researcher correctly emphasizes the urgency of establishing detailed regulations for AI, given its pervasive presence in society. To strengthen this argument, the paragraph could elaborate on the specific gaps or deficiencies in the existing regulatory framework in Jordan and highlight how these gaps contribute to legal ambiguities and challenges in holding parties accountable for AI-related decisions. Additionally, proposing specific provisions or amendments to existing laws that could address these issues would enhance the practical relevance of the research.\nClarification on Electronic Notice: The paragraph raises a valid point regarding the use of electronic notice in administrative procedures. To further develop this argument, the researcher could explore how electronic notices are currently implemented in Jordanian administrative practices, including any legal precedents or guidelines governing their effectiveness and legal implications. Furthermore, discussing the potential benefits and drawbacks of electronic notices in the context of AI-driven decision-making processes would provide valuable insights for policymakers and legal practitioners.\nRecommendations for Future Research: In concluding the paragraph, the researcher suggests that certain amendments or clarifications are necessary to address the identified shortcomings in the legal framework. To enhance the credibility and impact of the research, it would be beneficial to propose specific recommendations or actionable steps that policymakers can take to address these issues. This could involve advocating for legislative reforms, promoting stakeholder dialogue and collaboration, or conducting further empirical research to assess the real-world implications of AI technologies in administrative decision-making.\n\n2. The research lacks recent references, hence, there is a need to update the references and incorporate studies published in databases such as Scopus. Additionally, one of the cited studies has inaccurate documentation, which has been corrected. Furthermore, I recommend the researcher to utilize the following studies, as they would greatly benefit the research and contribute to its enrichment. I assure you that incorporating these studies will be in the best interest of the research and will lead to its enhancement.\n\nDoes the paper provide a comprehensive overview of the policy and the context of its implementation in a way which is accessible to a general reader? Yes\n\nIs the discussion on the implications clearly and accurately presented and does it cite the current literature? Partly\n\nAre the recommendations made clear, balanced, and justified on the basis of the presented arguments? Partly",
"responses": [
{
"c_id": "11753",
"date": "20 Jun 2024",
"name": "Hashim Balas",
"role": "Author Response",
"response": "Based on the feedback received on this research, we present our responses from our perspective, with appreciation and respect for the valued comments provided by the esteemed reviewer. Thank you for your understanding. :Response 1. The researchers in their study pointed to the most important global definitions of artificial intelligence. They clarified the clear stance of the Jordanian legislator regarding the definition of artificial intelligence, noting that Jordanian legislation lacks a specific definition. The researchers proposed the closest existing definitions in Jordanian legislation as a definition for artificial intelligenceThe researchers in their study pointed to the most important global definitions of artificial intelligence. They clarified the clear stance of the Jordanian legislator regarding the definition of artificial intelligence, noting that Jordanian legislation lacks a specific definition. The researchers proposed the closest existing definitions in Jordanian legislation as a definition for artificial intelligence 2. The researchers explain that the laws mentioned in the notes, such as intellectual property law and its precise application, along with other laws, are discussed in the second section, \"The Legal Nature of Artificial Intelligence 3. The researchers have studied the legal aspect of artificial intelligence and defined the scope of its legal responsibility. What is mentioned in this part of the note does not fall under this concept 4. Although this study is more theoretical than practical, the researchers, in the second section titled \"Administrative Responsibility Resulting from the Use of Artificial Intelligence,\" referenced the Supreme Court's jurisprudence on artificial intelligence. They explained how to interpret legal texts and assess their applicability to real-world scenarios References 5. Dear, Your feedback is of utmost importance to us. However, the selection of references cited in our research was made with the specificity of the study in mind and to align with the direction of our research objectives. We will consider these references in future studies. Thank you for your attention and interest"
}
]
},
{
"id": "283462",
"date": "08 Jun 2024",
"name": "Anat Lior",
"expertise": [
"Reviewer Expertise AI Liability",
"AI Policy and Regulation",
"Insurance of Emerging Technologies",
"Torts",
"Intellectual Property."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction section:\nThe article should acknowledge that there are two possible paths to regulating a new technology. First, leveraging existing legislation to ensure fast enforcement using interpretation to apply to the new technology. Second, crafting a new legislation specifically designed to address the new technology. The authors advocate for the latter. I recommend delving deeper into the question as to why existing legislation in Jordan is not sufficient. In the context of AI definition, it is highly contested whether such a definition would even help establish appropriate AI policy and regulation given the difficulty in agreeing on a legal definition that will not be over or under-inclusive. The article doesn’t explain why such a definition is necessary to achieve appropriate AI governance. Furthermore, the flexibility the authors seek in their recommendation section could be better achieved by not having a rigid AI definition but rather by building on existing technological legislation to enable enforcement as soon as possible.\nChapter one:\nIn the second paragraph, the authors claim, \"A new chapter in the history of technology began in 2018 when artificial intelligence became a reality.” It is unclear what happened that year that led to this statement. A clarification should be added. The overall premise in the third paragraph that we must have a one-stop-shop regulation for AI technology is arguable. This might even be impossible, given the fast pace of AI. Thus, attempting to achieve such legislation seems futile to begin with. The article would be more robust if there were reasoning for this approach despite its challenges. The authors only present some specific AI definitions, but other legal definitions, such as those from the US, Canada, and different US states, are missing. There should be some explanation for why the authors focused on the EU and WIPO. The third paragraph in section one claims that the Jordanian legislator is “still ignorant of the gravity of the rapidly advancing applications of artificial intelligence and the appreciable rise in their use across all sectors of the economy, society, and agriculture.” In fact, in 2020, Jordan created and published a strategy for AI. A more detailed survey of how Jordan has approached AI policy until now seems warranted in this section In section two, the statement, \"This variation makes it difficult to determine which law shall be adopted and applied to cases where risk results from machines operated by artificial intelligence,” seems inaccurate. The damages incurred, the type of risks, and the nature of the relationship between the parties will determine the applicable law. I believe the authors should clarify what this sentence means and the specific difficulty special to AI. The division in this section into three types of AI categories seems under and over-broad. A couple of concert examples per category could be helpful to better understand the classification and its value to the reader. The discussion about AI’s legal personhood seems partial. Why are these the only two options? AI can also be treated as property, agent, etc.; it doesn’t have to be a legal entity or something completely new.\n\nChapter two:\nRegarding the first paragraph, AI can cause damage even if it doesn’t perform something physical, for example, via software such as algorithms in the criminal justice systems or for making hiring decisions. The section talks about AI that “the system does all the instructions independently without needing a human operator.” Some scholars would claim that this is not accurate. AI is not fully independent from humans because humans wrote the code and gave it its agenda and task/s. Even if the authors disagree with this approach, they should acknowledge this and explain why the legal nexuses to a human being cannot be found in these cases. Some clarification is needed regarding what amounts to a “technical defect” in which the administration will not be held accountable. Who should be held responsible in this case, and why? A discussion about this will help strengthen the argument presented in the article. I agree with the comment of the first reviewer requesting more concrete clarification on the Electronic Notice.\n\nOverall, I highly recommend that the authors make a clearer and more robust connection between their review of AI definitions, legal frameworks, and Jordanian law. More concrete examples would make the article’s contribution more substantial and rigorous, given the lack of attention Jordan has received thus far in this avenue.\n\nDoes the paper provide a comprehensive overview of the policy and the context of its implementation in a way which is accessible to a general reader? Partly\n\nIs the discussion on the implications clearly and accurately presented and does it cite the current literature? Partly\n\nAre the recommendations made clear, balanced, and justified on the basis of the presented arguments? Partly",
"responses": []
},
{
"id": "283461",
"date": "16 Sep 2024",
"name": "Nasir Muftic",
"expertise": [
"Reviewer Expertise Law"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article tackles important issues in the field of law and artificial intelligence. Each of them will be important for legislators around the world. However, the text remains vague and not focused on a single issue. Due to the limitation in length, it is not easy for a reader to delve into any of them and understand author's points. The conclusion, likewise, seems vague. I suggest that the author elaborates more extensively their points.\n\nDoes the paper provide a comprehensive overview of the policy and the context of its implementation in a way which is accessible to a general reader? Partly\n\nIs the discussion on the implications clearly and accurately presented and does it cite the current literature? Partly\n\nAre the recommendations made clear, balanced, and justified on the basis of the presented arguments? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-418
|
https://f1000research.com/articles/13-417/v1
|
29 Apr 24
|
{
"type": "Study Protocol",
"title": "Analysis of prescription pattern and adverse drug reactions of drugs used in Urinary Tract Infection in reproductive age group (15-44 years) women in a Tertiary Care Hospital in Central India: An observational retrospective study",
"authors": [
"Gayatri Patil",
"Sushil Varma",
"Sushil Varma"
],
"abstract": "Background Urinary tract infection is considered a common bacterial infection. Nowadays there is an increase in the irrational and inappropriate use of drugs. Adverse drug reactions have been reported to be a main cause of morbidity, hospital admission, and sometimes death. For this, it is very important to do the analysis of prescriptions and to see the adverse drug reactions due to the prescribed drugs.\n\nObjective\n1. To determine the prescribing pattern of drugs used in urinary tract infections of the reproductive age group (15-44). 2. To identify adverse reactions due to drugs used for UTI of reproductive age group (15-44). 3. To observe the pattern of combination therapy for urinary tract patients of reproductive age group. 4. To analyze the Fixed Drug Combination.\n\nMethods It is a retrospective observational study. Data will be collected from 175 prescription papers. Data will be collected from the medical record section. The study will include prescriptions of UTI for Females of the reproductive age group (15-44 years).",
"keywords": [
"Pattern",
"Prescription",
"urinary tract infection",
"adverse drug reaction",
"reproductive."
],
"content": "Introduction\n\nUrinary tract infection occurs when microbial pathogens are present in the urinary tract. It affects both genders but it is more common in women and it affects the females of the reproductive age group (15-44 years) mostly. It may be because of their anatomy and reproductive physiology. Women get urinary tract infections more often because their urethra is shorter than men's and it may be due to delay in micturition, use of contraceptives, and sexual activity.\n\nThe kidneys and the ureter are involved in upper urinary tract infections, while the bladder and urethra are involved in lower urinary tract infections.1\n\nClinically urinary tract infection is classified into – Complicated/uncomplicated and primary/recurrent.1 organisms that are responsible for urinary tract infection are “Escherichia coli, Staphylococcus, Streptococcus, Klebsiella, Proteus, Corynebacterium, Neisseria and Pseudomonas species”.2\n\nTreatment of urinary tract infections may vary according to location, age of patient, and severity of presentation in the community. After the urine culture sensitivity test, empiric therapy for UTI should be initiated. The choice of medication should be determined by identifying the pathogen, assessing sensitivity through urine culture, and considering the patient's comorbid conditions.3\n\nUncomplicated cystitis:\n\nNitrofurantoin 100mg - 5 days is the 1st line treatment and\n\n2nd line treatment for uncomplicated cystitis: Trimethoprim/Sulfamethoxazole - 3 days,\n\noral Cephalexin 500mg - 3-7 days, or Fosfomycin 3 g -1 day.\n\nComplicated cystitis:\n\nNitrofurantoin 100mg - 7 days is the 1st line treatment and\n\nTrimethoprim/Sulfamethoxazole -7 days, or oral Cephalexin 500 mg - 7 days, or Fosfomycin 3g every 48 hours for 3 doses is the 2nd line treatment.4\n\nMost commonly Nitrofurantoin and Sulfonamides are used in the treatment of UTI in reproductive age groups and pregnant women.5\n\nRELATED ADVERSE DRUG REACTIONS:\n\n(1) Adverse drug reactions of Nitrofurantoin:\n\nNausea, loss of appetite, vomiting and diarrhea\n\nSevere adverse reactions are:\n\nPulmonary toxicity (acute, subacute, chronic pulmonary reaction)\n\nliver injuries due to nitrofurantoin\n\nPeripheral neuropathy – is rare and it is mostly seen in patients with poor renal function and on prolonged use.6\n\n(2) Adverse drug reactions of Sulfonamides:\n\nSulfonamide-induced liver injury- it can be hepatocellular or cholestatic hypersensitivity reactions include fever, facial edema, lymphadenopathy, arthralgias, rash, eosinophilia, or atypical lymphocytosis (or both).\n\ndiarrhea, nausea, headaches, and dizziness, skin rash.\n\nRare adverse reactions:\n\nsevere allergic skin rashes, aplastic anemia, pancreatitis, serum sickness, Stevens-Johnson syndrome, agranulocytosis, nephritis, confusion seizures, and ataxia.7\n\nNowadays, it is necessary to evaluate prescriptions due to the rapid changes in the prescriptions of diseases.\n\nTo analyze the irrational and inappropriate use of drugs this study is necessary.\n\nFor the improvement of patient compliance and to find out what type of adverse reactions are seen in reproductive age group female (15-44yrs) UTI patients due to prescribed drugs.\n\nTo analyze the prescription pattern and adverse drug reactions of drugs used in urinary tract infections of reproductive age group (15-44).\n\nPrimary-\n\n1. To determine the prescribing pattern of drugs used in urinary tract infections of the reproductive age group (15-44).\n\n2. To identify adverse reactions due to drugs used for UTI of reproductive age group (15-44).\n\nSecondary-\n\n1. To observe the pattern of combination therapy for urinary tract patients of reproductive age group.\n\n2. To analyze the Fixed Drug Combination.\n\n\nMethods\n\nStudy design: Retrospective Observational Study\n\nStudy population: 175\n\nStudy duration: 18 Months (February 2024 – August 2025)\n\nThe study will include prescriptions of UTI for Females of the reproductive age group (15-44 years).\n\nICU patients\n\nIncomplete case files.\n\nThis research study will be carried out in the Department of Pharmacology.\n\nDaniel Formula:\n\nZ = statistic for a level of confidence =1.96\n\nP = Prevalence of urinary tract infection =33.54% = 0.3354\n\nd = Desired error of margin = 7% = 0.07\n\n\n\nStudy reference: Pritam Pardeshi\n\nStatistical methods: Student's t-test, Chi-square Test.\n\nSoftware used: SPSS 27.0 version\n\nStudy design: Retrospective observational study.\n\nWe will collect recorded files of patients from the medical record section. And Analyze prescriptions and adverse drug reactions of patients. Table 1 details the parameters included in the study. Data will be analyzed using a suitable Statistical Test SPSS- 20.\n\nThe findings of this study will be used for metanalysis.\n\nThe study is yet to be started\n\n\nDiscussion\n\nNowadays irrational and inappropriate use of drugs is a major concern. Irrational drug use may cause adverse consequences including drug resistance and adverse drug reactions.8,9For the improvement of patient compliance, it is very important to analyze prescription patterns and adverse drug reactions (ADRs). The benefits of our research will be patient care improvement and risk assessment.\n\nThis analysis is for the use of evidence-based medicine in tertiary care centers, to fulfill the drug information needs of the physician and also for improvement in the quality of healthcare by giving feedback to prescribers. This is an observational, retrospective study that will aim at the analysis of drug patterns and adverse drug reactions due to drug prescription in urinary tract infections at tertiary health care centers.\n\n1. Ethical Committee approval is obtained.\n\nConsent to participate:\n\nAs it is a retrospective there is no requirement asked from our institutional Ethical committee for getting the data of the past patient it is waived off for this study, Also we have taken proper permission and a letter from the concerned faculty of Hospital (CMS) from the medical record section for the previous data.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\nAVBRH HOSPITAL, HMIS\n\n\nReferences\n\nMuthulakshmi M, Gopalakrishnan S: Study on urinary tract infection among females of reproductive age group in a rural area of Kancheepuram district, Tamil Nadu. Int. J. Commun. Med. Public Health. 2017 Sep 22; 4(10): 3915–3921. Publisher Full Text\n\nAlmukhtar SH: Urinary tract infection among women aged (18-40) years old in Kirkuk city, Iraq. The Open Nurs. J. 2018 Dec 31; 12(1): 248–254. Publisher Full Text\n\nFatima E, Anwar A, Dudeja M, et al.: Drug utilization pattern and adverse drug reaction monitoring in urinary tract infection patients in a tertiary care hospital. Journal of Drug Delivery and Therapeutics. 2015 Nov 15; 5(6): 23–30. Publisher Full Text\n\nBettcher CM, Campbell E, Petty LA, et al.: Proudlock AL. Urinary tract infection.\n\nMoon J, Prasad S, Egan M: Treating UTIs in reproductive-age women—Proceed with caution. J. Fam. Pract. 2010 Apr; 59(4): 220–222. PubMed Abstract\n\nSquadrito FJ, del Portal D : Nitrofurantoin.\n\nBethesda L: Clinical and research information on drug-induced liver injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012.\n\nMelku L, Wubetu M, Dessie B: Irrational drug use and its associated factors at Debre Markos Referral Hospital’s outpatient pharmacy in East Gojjam, Northwest Ethiopia. SAGE open medicine. 2021 Jun; 9: 205031212110251. Publisher Full Text\n\nOjo MA, Igwilo CI, Emedoh T: Prescribing patterns and perceptions of health care professionals about rational drug use in a specialist hospital clinic. Journal of Public Health in Africa. 2014 Jun 6; 5(2). PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "276370",
"date": "28 May 2024",
"name": "Niels Frimodt-Møller",
"expertise": [
"Reviewer Expertise Clinical microbiology",
"urinary tract infections",
"E.coli pathogenesis",
"antibiotic activity in vitro and in vivo"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe protocol by Patil et al concerns an interesting subject regarding antibiotic use in urinary tract infection (UTI) in women, but the protocol needs revision particluarly to be more strict and prescise. 1. It is not clear, whether the investigation partakes on nosocomial (hospital derived) UTI or community associated UTI, or both? Define. 2. Define how a UTI is going to be defined through the retrospective approach (symptoms, urine culture, biochemical issue etc), if it is going to be analysed, whether the antibiotic treatment was correct i.e. administered for UTI. 3. Define which adverse effects are searched for, not only for nitrofurantoin and sulfonamides? it is often the case, that hospital records do not monitor adverse effects - this is always better done in a prospective study, where such effects are defined and the investigators asked to record them. 4. The calculation of sample size is performed according to prevalence of UTI; since all subjects searched for are supposed to have UTI, this is not correct. The sample size should be based upon the theoretical prevalence of adveres effects, since this is main objective. This is usually in the range of 5-10%, why the sample size must be much larger. 5. What is meant by combination therapy and fixed combinations? describe which e.g. trimethoprim-sulphamethoxazole, amoxicilin-clavulanic acid etc. Is combination therapy meant to be two drugs both intended for UTI?\n\nIs the rationale for, and objectives of, the study clearly described? No\n\nIs the study design appropriate for the research question? No\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? No",
"responses": []
},
{
"id": "297784",
"date": "13 Jul 2024",
"name": "Vineetha Menon",
"expertise": [
"Reviewer Expertise Geriatrics",
"Medication safety management"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. Abstract: The abstract is too brief; lacks specificity and content. 2. Introduction: The introduction lacks smooth flow and transitions between sections. There is some redundancy of information, grammatical errors, and formatting issues. There is no information given on the findings from previous studies done in this area. Also, there is a lack of focus on the significance of the study. 3. Method: a. Study criteria: Study criteria is missing out on several vital elements. For example, details of treatment settings, time frame, presence of comorbidities, pregnancy status, or recurrent infections had not been addressed in the study criteria. b. What does the author mean by \"Study reference: Pritam Pardeshi\"? c. Statistical methods: There is a lack of information on how statistical methods were applied. d. Dala collection: The data collection process is not detailed enough. e. Study setting: The study setting does not mention in which institution the study was done. f. Overall there are a lot of inconsistencies in the methodology. It's also stating that the study will be done- what does that mean? 4. Results: No results are available for review. 5. Discussion: The discussion lacks depth and specificity. There is also repetition of information previously mentioned. No clear conclusion or limitations were stated.\n\nIs the rationale for, and objectives of, the study clearly described? No\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-417
|
https://f1000research.com/articles/13-414/v1
|
29 Apr 24
|
{
"type": "Study Protocol",
"title": "MRI based evaluation of carcinoma gallbladder using apparent diffusion coefficient (ADC) and diffusion weighted imaging (DWI)",
"authors": [
"Sakshi Dudhe",
"Gaurav Mishra",
"Pratapsingh Parihar",
"Dhananjay Shinde",
"Anjali Kumari",
"Gaurav Mishra",
"Pratapsingh Parihar",
"Dhananjay Shinde",
"Anjali Kumari"
],
"abstract": "Background Carcinoma of the gallbladder is a malignant neoplasm, which is associated with a poor prognosis due to its often-asymptomatic nature and late-stage diagnosis. Non-invasive imaging techniques play a key role in the early detection and characterization of gallbladder carcinoma. This thesis presents a comprehensive analysis of the utility of Diffusion-Weighted Imaging (DWI) and Apparent Diffusion Coefficient (ADC) mapping in the magnetic resonance imaging (MRI) evaluation of carcinoma of the gallbladder. The primary objective of this research was to investigate the exact diagnostic accuracy and potential clinical applications of DWI and ADC in assessing carcinoma of the gallbladder and related tumour aggressiveness. A systematic review of existing literature was conducted to establish a foundation for this study with efforts to acquire relevant imaging data. The results of this study demonstrate the efficacy of DWI and ADC in the detection of carcinoma of the gallbladder when compared to conventional MRI sequences. These advanced imaging techniques hold promise in increasing the accuracy of diagnosis, ultimately leading to improved patient outcomes and more informed clinical decision making. The potential of Diffusion-Weighted Imaging (DWI) and Apparent Diffusion Coefficient (ADC) mapping in the evaluation of gallbladder cancer using magnetic resonance imaging (MRI) is thoroughly analysed in this thesis.\n\nMethods A descriptive prospective study will be done at Acharya Vinoba Bhave Rural Hospital, Sawangi, involving 20 patients with clinically suspected carcinoma gallbladder, who are referred to the department of Radiodiagnosis. These patients will be subjected to study-purposive sampling.\n\nConclusion After an appropriate statistical analysis, we expect to assess the role of Diffusion-Weighted Imaging (DWI) and Apparent Diffusion Coefficient (ADC) mapping in the magnetic resonance imaging (MRI) evaluation of carcinoma of the gallbladder.\n\nCTRI registration This trial has been submitted to Clinical Trials Registry-India (CTRI) for Review. Registration Number: REF/2023/09/072780 Registration date:01/05/2023 URL of trial: https://www.ctri.nic.in/",
"keywords": [
"MRI",
"DWI",
"ADC",
"gallbladder carcinoma",
"b values",
"gallbladder"
],
"content": "Introduction\n\nCarcinoma of the gallbladder, although relatively uncommon, is a highly belligerent type of malignancy associated with a grim prognosis.1 It is often diagnosed at advanced stages, leading to limited treatment options leading to poor survival rates.2 This unfortunate reality underscores the critical need for improved methods of early detection, accurate staging, and precise characterization of gallbladder carcinoma. Non-invasive imaging techniques have emerged as indispensable tools in addressing these challenges, with Magnetic Resonance Imaging (MRI) at the forefront.3 This thesis aims to establish and validate a proper standard methodology for MRI based evaluation of gallbladder cancer utilizing Diffusion-Weighted Imaging (DWI) and the Apparent Diffusion Coefficient (ADC) as its key components.\n\nThe clinical significance of gallbladder carcinoma: In the field of oncology, Gallbladder carcinoma is a challenge. Often due to delay in diagnosis of this sneaky malignancy, the patient presents when the disease progresses to advanced stage with complications like local invasion and distant metastasis.4 The overall prognosis remains poor, with approximate 5-year survival rate of these patients less than 5% for advanced stage Gallbladder carcinoma.1 In such cases, early detection is paramount to improving patient outcomes.\n\nThe limitations of conventional imaging: Conventional imaging modalities like Computed Tomography (CT) and Ultrasound have been the torch bearers for diagnosis of gallbladder carcinoma. Even though used for preliminary stage scanning, they have their limitations in proper evaluation. Differentiating between gallbladder lesions can be challenging, and accurately assessing the extent of tumor invasion is often imprecise. Such diagnostic insufficiency can lead to delayed or inadequate treatment. The diagnostic potential of DWI and ADC for identifying gallbladder diseases can be of immense help.5\n\nThe potential of mri in gallbladder carcinoma: Magnetic Resonance Imaging (MRI) is becoming more and more recognized as an essential approach in differentiating pathologies related to gall bladder. MRI has an upper hand not only due to its multiparametric capabilities and superior soft tissue contrast, but also considering the absence of ionizing radiation DWI and ADC are evolving diagnostic tools as compared to conventional biliary imaging techniques.6 MRI allows detailed visualization of gallbladder and its surrounding structures. Moreover, MRI has shown promise in differentiating malignant gallbladder lesions as well.\n\nFacilitation of early detection: The primary reason for the development of a standardized MRI technique using DWI and ADC in the evaluation of carcinoma of gallbladder is for enhancing early detection. Delay in diagnosis is mainly due to the asymptomatic nature of the disease. However, tissue microstructure can be studied using DWI and ADC for the recognizing restricted water diffusion patterns, which are characteristic of malignant lesions.7 Therefore, we present this study protocol for facilitating the early detection of gallbladder carcinoma and impact patient survival rates and overall prognosis.\n\nImproving diagnostic accuracy: DWI and ADC gives a distinct advantage in analyzing gallbladder lesions by measuring water diffusion inside the tissues. Lower ADC values are seen in malignant tumors due to its altered cellular density and altered membrane integrity, in comparison to benign lesions.8 Diagnostic accuracy can be improved due to implementation of a standardized protocol for their use in gallbladder carcinoma evaluation. This can further can lead to reduced misdiagnosis or delay in diagnosis, which will guide the clinicians toward more appropriate treatment strategies.\n\nUnlocking prognostic insights: Numerous studies have shown ADC values and histopathological correlations, indicating that ADC values might be highly predictable in terms of tumor behavior.9 This study seeks to investigate the evolving importance of ADC in gallbladder carcinoma, by adopting a structured strategy of data collection and analysis, potentially guiding treatment decisions and patient management.\n\nStandardization and reproducibility: Finally, for promoting consistency and reproducibility in our clinical practice, establishing a standardized MRI protocol for gallbladder carcinoma evaluation using DWI and ADC becomes essential. Improper imaging protocols can lead to disparities in disease interpretation and its treatment decisions. A standardized strategy ensures that findings are comparable in different clinical settings, facilitating collaboration and research efforts to bring about advancements in understanding of this challenging malignancy.10\n\nAs a result, optimizing the clinical management of this aggressive malignancy will need the establishment and validation of a standardized MRI procedure utilizing DWI and ADC for the evaluation of gallbladder carcinoma.4 By addressing the limitations of conventional imaging, enhancing early detection, improving diagnostic accuracy, and potentially unlocking prognostic insights, this protocol has the potential to significantly impact patient outcomes. Furthermore, by promoting standardization and reproducibility, it contributes to the broader effort to advance research and collaboration in the field of gallbladder carcinoma evaluation.\n\n\nProtocol\n\nRegistration\n\nThis trial has been registered with CTRI for Review-Acknowledgement Number: REF/2023/09/072780.\n\nEthics and consent\n\nThe protocol got its approval from the Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research DMIMS (DU)/IEC/2023/761. All the patients that are referred to the department of radiodiagnosis, AVBRH, Sawangi with clinically suspected carcinoma gallbladder will be subjected to the study – purposive sampling. Written informed consent will be obtained from the patients after describing the complications of the procedure to the patient as approved by ethics committee. A proforma shall be filled.\n\nTo evaluate role of ADC and DWI in analyzing patients with gallbladder carcinoma.\n\nProspective cross sectional analytical study with purposive sampling.\n\nParticipants:\n\n• Inclusion criteria: Patients undergoing MRI scan for with clinically suspected carcinoma gallbladder, referred to Department of Radiodiagnosis for investigative purpose.\n\n• Patients with biopsy proven gallbladder carcinoma on HPE.\n\n• Patients of suspected gallbladder cancer within all age groups irrespective of their sex will be included.\n\nExclusion criteria:\n\n• Patients with prior surgery for gallbladder carcinoma.\n\n• Pregnant patients.\n\n• Patients with metallic implants, pacemaker/cochlear implant.\n\n• Patients with claustrophobia/another psychiatric abnormality.\n\n• Uncooperative patients and those refusing to give informed consent.\n\nSample size\n\nThe study included 20 patients who had been sent to Acharya Vinoba Bhave Rural Hospital in Sawangi (Meghe) with known or suspected gall bladder cancer. Both IPD and OPD patients are included in the sample.\n\nCochran Formula for Sample size\n\nWhere; Zα/22 is the level of significance at 5% i.e., 95% confidence interval = 1.96\n\nP = Incidence of Gall Bladder Cancer = 1.2% = 0.012\n\nn = 18.21, n = 20 patients are required for the study.\n\nDuration of study: 2 years.\n\nStudy reference: NCBI\n\nSample Size in Statistics (How to Find it): Excel, Cochran’s Formula, General Tips - Statistics How To. Accessed: April 23, 2024. https://www.statisticshowto.com/probability-and-statistics/find-sample-size/.\n\nProcedure for MRI evaluation of gallbladder cancer patients:\n\n• In our study, consent of the patient shall be filled by those willing to undergo MRI for evaluation of Gallbladder. A Proforma shall be filled by the patient following which procedure and complications shall be explained.\n\n• To evaluate ADC values at respective areas of gallbladder neoplasm for patients with suspected GB carcinoma.\n\n• To calculate the ADC values, ROI shall be selected and ADC mapping by the shall be done.\n\n• Appropriate statistical tests will be incorporated post data collection and correlation will be done between ADC values.\n\nObjectives:\n\nPrimary objective:\n\n• To evaluate role of ADC and DWI in analyzing patients with gallbladder carcinoma.\n\nSecondary objective:\n\n• To calculate the Apparent Diffusion Coefficient value at areas of gallbladder carcinoma.\n\n• To calculate mean Apparent Diffusion Coefficient value.\n\nTo correlate ADC values with b values.\n\n\nDiscussion\n\nMRI is considered helpful, noninvasive tool for diagnosing malignancies related Gallbladder, which further helps to carry out surgical treatment of the patient. DWI is helpful in measuring random Brownian motion of moving water molecules. Early diagnosis can improve clinical outcome and cure rates. Application of diffusion-weighted imaging (DWI) is one of the evolving and latest advancement in MRI. ADC values can be evaluated quantitatively for monitoring therapeutic outcomes in patients with Gallbladder cancer. With our study, we plan to use DWI sequence of MR in patients with Gallbladder cancer for calculating ADC values as a part of our research. MRI plays a critical role by helping in better delineation of Gallbladder carcinoma as compared to any other radiological scan. This further helps in proper diagnosis and better patient care.\n\nSugita et al. (2009): found out that High b-value DWI showed promise in detecting gallbladder carcinoma, suggesting its potential as a valuable diagnostic tool.11\n\nKim et al. (2013) found out that DWI plays a crucial role in diagnosing gallbladder cancer, offering valuable information for clinical assessment.12\n\nYoshioka et al. (2013) established specific ADC cut-off values, helping in the differentiation of various gallbladder lesions based on their ADC values.13 Top of Form\n\nMin et al. (2019) found that ADC was considered a potential marker for gallbladder tumor differentiation and long-term clinical outcomes.14\n\nWu et al. (2020) found out that initial clinical experiences with reduced field-of-view DWI indicated its utility in gallbladder carcinoma evaluation.15\n\nTan and Lim (2013) has reviewed the role of MRI, including DWI, in gallbladder cancer, emphasizing its importance in clinical practice.16\n\nThe protocol got its approval from the Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (Reg no.-ECR/440/Inst/MH/2013/RR-2019) with approval number DMIMS (DU)/IEC/2023/761 on 21/03/2023. All the patients that are referred to the department of radiodiagnosis, AVBRH, Sawangi with clinically suspected carcinoma gallbladder will be subjected to the study – purposive sampling. Written informed consent will be obtained from the patients after describing the complications of the procedure to the patient. A proforma shall be filled.\n\nThis study material will be considered to be confidential and will be safely stored with access only to the principal investigator.\n\nThe data collection has not been started yet.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\nZenodo: Proforma for the data collections ‘MRI based evaluation of carcinoma gallbladder using apparent diffusion coefficient (ADC) and diffusion weighted imaging (DWI) in rural Indian population’, https://doi.org/10.5281/zenodo.10973483. 17\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nHundal R, Shaffer EA: Gallbladder cancer: epidemiology and outcome. Clin. Epidemiol. 2014; 99–109.\n\nDuffy A, Capanu M, Abou-Alfa GK, et al.: Gallbladder cancer (GBC): 10-year experience at memorial Sloan-Kettering cancer centre (MSKCC). J. Surg. Oncol. 2008; 98(7): 485–489. PubMed Abstract | Publisher Full Text\n\nEsnaola NF, Meyer JE, Karachristos A, et al.: Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma. Cancer. 2016; 122(9): 1349–1369. Publisher Full Text\n\nMisra S, Chaturvedi A, Misra NC, et al.: Carcinoma of the gallbladder. Lancet Oncol. 2003; 4(3): 167–176. Publisher Full Text\n\nGoel S, Kumar R, Chattopadhyay TK, et al.: Role of imaging in the diagnosis of gallbladder carcinoma. World J. Radiol. 2014; 6(12): 840–846.\n\nGourtsoyianni S, Papanikolaou N, Karantanas A: Magnetic resonance imaging of the gallbladder: Value of T2- and diffusion-weighted imaging in diagnosing acute cholecystitis. J. Magn. Reson. Imaging. 2009; 30(1): 166–174.\n\nLe Bihan D, Breton E, Lallemand D, et al.: Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology. 1988; 168(2): 497–505. Publisher Full Text\n\nKoh DM, Collins DJ: Diffusion-weighted MRI in the body: applications and challenges in oncology. Am. J. Roentgenol. 2007; 188(6): 1622–1635. PubMed Abstract | Publisher Full Text\n\nParikh J, Selmi M, Charles-Edwards G, et al.: Changes in primary breast cancer heterogeneity may augment midtreatment MR imaging assessment of response to neoadjuvant chemotherapy. Radiology. 2014; 272(1): 100–112. PubMed Abstract | Publisher Full Text\n\nTofts PS, Brix G, Buckley DL, et al.: Estimating kinetic parameters from dynamic contrast-enhanced T1-weighted MRI of a diffusable tracer: standardized quantities and symbols. J. Magn. Reson. Imaging. 1999; 10(3): 223–232. PubMed Abstract | Publisher Full Text\n\nSugita R, Yamazaki T, Furuta A, et al.: High b-value diffusion-weighted MRI for detecting gallbladder carcinoma: preliminary study and results. Eur. Radiol. 2009; 19: 1794–1798. PubMed Abstract | Publisher Full Text\n\nKim SJ, Lee JM, Kim H, et al.: Role of diffusion-weighted magnetic resonance imaging in the diagnosis of gallbladder cancer. J. Magn. Reson. Imaging. 2013; 38(1): 127–137. PubMed Abstract | Publisher Full Text\n\nYoshioka M, Watanabe G, Uchinami H, et al.: Diffusion-weighted MRI for differential diagnosis in gallbladder lesions with special reference to ADC cut-off values. Hepato-Gastroenterology. 2013; 60(124): 692–698. PubMed Abstract\n\nMin JH, Kang TW, Cha DI, et al.: Apparent diffusion coefficient as a potential marker for tumour differentiation, staging and long-term clinical outcomes in gallbladder cancer. Eur. Radiol. 2019; 29(1): 411–421. PubMed Abstract | Publisher Full Text\n\nWu S, Zou X, Wang Q, et al.: Gallbladder carcinoma: an initial clinical experience of reduced field-of-view diffusion-weighted MRI. Cancer Imaging. 2020; 20: 1–8. Publisher Full Text\n\nTan CH, Lim KS: MRI of gallbladder cancer. Diagn. Interv. Radiol. 2013; 19(4): 312–319. PubMed Abstract | Publisher Full Text\n\nDudhe S: MRI based evaluation of carcinoma gallbladder using apparent diffusion coefficient (ADC) and diffusion weighted imaging (DWI) in rural Indian population. Published Online First: 15 April 2024. Publisher Full Text"
}
|
[
{
"id": "345047",
"date": "10 Dec 2024",
"name": "Angel Justiz-Vaillant",
"expertise": [
"Reviewer Expertise Oncology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nRelevant Topic: The study addresses an important diagnostic challenge in gallbladder carcinoma using advanced imaging techniques. The integration of DWI and ADC mapping in MRI is innovative and clinically relevant. Clear Objectives: The primary and secondary objectives are well-defined, focusing on improving diagnostic accuracy and determining ADC values. Comprehensive Background: The introduction covers essential aspects of gallbladder carcinoma, including its aggressive nature, limitations of conventional imaging, and potential of MRI techniques. This establishes a strong foundation for the study's rationale. Well-Defined Methodology: The study's design, sample size calculation, inclusion and exclusion criteria, and data collection procedures are clearly described, ensuring transparency and reproducibility. Ethical Compliance: The ethical considerations and consent procedures are adequately addressed, with relevant Institutional Ethics Committee approval.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": [
{
"c_id": "12936",
"date": "12 Dec 2024",
"name": "Sakshi Dudhe",
"role": "Author Response",
"response": "Thank you so much for completing the review. I hope the rest of the reviews will be completed in time."
}
]
}
] | 1
|
https://f1000research.com/articles/13-414
|
https://f1000research.com/articles/12-1596/v1
|
15 Dec 23
|
{
"type": "Case Report",
"title": "Case Report: Scrub Typhus manifesting as Acute Respiratory Distress Syndrome (ARDS) with corresponding radiological findings",
"authors": [
"Jay Dinesh Bhanushali",
"Babaji Ghewade",
"Ulhas Jadhav",
"Babaji Ghewade",
"Ulhas Jadhav"
],
"abstract": "Background Scrub typhus is a life-threatening infectious disease endemic in the Asia-Pacific region. It typically presents with nonspecific symptoms such as fever, headache, and myalgia, making early diagnosis challenging. Acute Respiratory Distress Syndrome (ARDS) is a severe pulmonary condition characterized by acute-onset hypoxemia, bilateral lung infiltrates on radiology, and increased pulmonary capillary permeability.\n\nCase Presentation An 18-year-old female student in central India presented with a seven-day history of recurrent fever, chills, dry cough, and severe shortness of breath, escalating to Modified Medical Research Council dyspnea grade III-IV. After unsuccessful local clinic treatment, a chest radiograph revealed bilateral pneumonia. On admission, she displayed tachycardia, tachypnea, hypotension, and hypoxia requiring non-invasive ventilation (NIV). Computed tomography confirmed scrub typhus-associated pneumonia, and serological testing was positive for scrub typhus. She was diagnosed with moderate ARDS and began treatment. Symptomatic improvement was seen in the ICU, and she was discharged on day 10 with radiological and clinical resolution.\n\nManagement and Outcomes She received intravenous doxycycline and oral azithromycin for scrub typhus and any potential concurrent lung infection. In the ICU, she required continuous NIV and supplemental oxygen, with significant symptomatic improvement, evidenced by reduced tachypnoea and oxygen requirements after 72 hours. She was weaned off NIV and monitored for an additional four days. After satisfactory oxygen saturation on room air, she was discharged on the tenth day. High-resolution CT scan demonstrated resolution of ground glass opacities and consolidation. Sequential chest radiographs exhibited gradual reduction in bilateral alveolar infiltrates over time, in parallel with clinical improvement. Laboratory findings, including reduced CRP and D-dimer values, and a normal hemogram on discharge indicated a resolution of leukopenia.\n\nConclusion This case underscores the importance of early recognition and intervention in scrub typhus-associated ARDS and highlights the utility of timely diagnostic imaging in monitoring the progress of the disease.",
"keywords": [
"Scrub typhus",
"acute respiratory distress syndrome",
"ARDS",
"computed tomography",
"CT scan"
],
"content": "Introduction\n\nScrub typhus, an infectious ailment brought on by the rickettsial microbe Orientia tsutsugamushi, presents a significant challenge to public health across the Asia-Pacific region. It’s notably prominent within the expansive domain referred to as the “tsutsugamushi triangle.”1,2 Notably, a recent study on the burden of scrub typhus in India, situated within this geographical region, unveiled its substantial impact, contributing to at least 25.3% of acute undifferentiated febrile illness (AUFI) cases. This disease typically exhibits clinical symptoms following an incubation period of 6-21 days, characterized by fever, headaches, myalgia, and various gastrointestinal issues.3\n\nThe pathophysiology of O. tsutsugamushi involves the infection of endothelial cells, leading to vasculitis, followed by the infiltration of T cells and monocytes/macrophages around blood vessels. This sets off a complex cascade of inflammatory responses, where various cytokines are produced by both endothelial and non-endothelial cells. These responses, while serving antimicrobial purposes, can also harm the host’s tissues. This dual nature of the immune response can give rise to severe complications, including hepatitis, renal failure, meningoencephalitis, acute respiratory distress syndrome (ARDS), respiratory failure, and occasionally myocarditis.1\n\nTypical clinical presentations of scrub typhus encompass fever, generalized lymph node enlargement, cough, shortness of breath, muscle pain, headaches, skin rashes, eschar formation, loss of appetite, vomiting, and abdominal discomfort. Unusual complications, although infrequent, may include meningoencephalitis, glomerulonephritis, acute renal failure (ARF), interstitial pneumonia, acute respiratory distress syndrome (ARDS), acute hepatic failure, myocarditis, pericarditis, gastrointestinal bleeding, septic shock, acute hearing loss, acute cholecystitis, and intracranial hemorrhage.4\n\nScrub typhus manifesting as Acute Respiratory Distress Syndrome (ARDS) is unique in medical literature due to the convergence of a tropical infectious disease, caused by Orientia tsutsugamushi, with a severe respiratory condition. This combination is distinctive because it involves a broad spectrum of clinical complications, which can include life-threatening ARDS, not commonly associated with tropical infections. The rarity of this manifestation and the complex interplay between vasculitis, immune responses, and tissue damage make it a subject of special interest in the medical community. Understanding this unique presentation is crucial for early diagnosis and effective management, given the potential for severe morbidity and mortality associated with scrub typhus-induced ARDS.5\n\n\nCase report\n\nOn the 9th of October 2022, an 18-year-old student hailing from Wardha, India, with recent travel history to Amravati, was urgently brought to Acharya Vinoba Bhave Hospital. She presented with a triad of fever accompanied by chills and rigors, recurring over the past week. In addition to her febrile episodes, she reported a persistent dry cough for three days and experienced a notable exacerbation of shortness of breath over the previous two days, reaching a severity classified as grade III–IV on the modified Medical Research Council (mMRC) dyspnea scale. Despite seeking initial treatment at a local clinic for two days, her symptoms showed no improvement. Subsequently, a chest radiograph revealed bilateral pneumonia, prompting her referral to the hospital for comprehensive evaluation and management.\n\nDuring her initial hospitalization, the patient continued to suffer from fever, chills, and acute shortness of breath. She experienced orthopnoea (breathlessness when lying down), and her dry cough exacerbated when supine. On admission, her vital signs included a high pulse rate of 127 beats per minute, a rapid respiratory rate of 36 breaths per minute, low blood pressure at 100/70 mmHg, and a body temperature of 98.7°C. A respiratory examination revealed diminished breath sounds bilaterally and scattered crepitations in both lung fields. No evident abnormalities were observed in her central nervous, cardiovascular, or gastrointestinal systems.\n\nArterial blood gas analysis (ABG) confirmed type I respiratory failure with severe hypoxia on room air, necessitating non-invasive positive pressure ventilation. The patient’s PF ratio of 153 mmHg suggested moderate ARDS as per Berlin’s definition. A chest CT upon admission revealed diffuse ground glass opacities with patchy consolidations in both lungs, indicative of interstitial pneumonia, along with bilateral mild pleural effusion and a CT Severity index of 21/25, illustrating disease progression. These findings were consistent with characteristic imaging manifestations of scrub typhus-associated pneumonia.\n\nA complete blood count demonstrated leukopenia with a white blood cell count of 3200 cells/mm3, and smears and antigen testing for malarial parasites were negative. Blood samples were forwarded for further analysis, and the initial treatment regimen included intravenous piperacillin and tazobactam (4.5 grams three times a day) alongside azithromycin (500 mg once daily). The patient also received nebulized bronchodilators and inhaled corticosteroids.\n\nThe diagnostic workup, focusing on the patient’s fever pattern, confirmed a positive serological test for scrub typhus while testing negative for Widal, leptospira, and dengue. Blood and sputum samples, despite being sent for culturing, showed no growth. Elevated levels of C-reactive protein and D-dimer, notably CRP 108 and D-dimer 2350, led to the initiation of low molecular weight heparin therapy. A diagnosis of scrub typhus with moderate ARDS was established, prompting the initiation of intravenous doxycycline (100 mg twice daily) and oral azithromycin (500 mg once daily) to manage any concomitant lung infection.\n\nIn the ICU, the patient required noninvasive ventilation (NIV) for the initial four days continuously, supplemented with 8-10 L of oxygen via a face mask during meals. She exhibited symptomatic improvement after 72 hours, with a gradual reduction in tachypnea and a decreased need for oxygen. Consequently, she was successfully weaned off NIV and transferred to the general ward, where she was monitored for an additional four days. Her ability to maintain oxygen saturation on room air improved, eliminating the need for external oxygen support, and she was discharged on day 10 of her hospital stay.\n\nIn Figure 1, upon admission, the high-resolution computed tomography (HRCT) of the thorax reveals bilateral extensive diffuse areas of ground glass opacification, accompanied by superimposed patchy consolidation. The CT severity score for these findings is notably high, with a recorded score of 21 out of 25. These radiological characteristics align with the typical imaging manifestations of scrub typhus-associated acute respiratory distress syndrome (ARDS). High-resolution chest CT scan conducted before discharge illustrated the satisfactory resolution of ground glass opacities and consolidations, affirming her clinical improvement (Figure 2). Sequential chest radiographs, as shown in Figures 3, 4, and 5 displayed a gradual reduction in bilateral alveolar infiltrates over time, further correlating radiological resolution with symptomatic improvement. These positive outcomes were reinforced by significant changes in diagnostic markers during her follow-up, where CRP and D-dimer values markedly reduced and her hemogram returned to normal, demonstrating the resolution of leukopenia. CRP decreased from 108 to 21, D-dimer decreased from 2350 to 430, hemoglobin slightly decreased from 11.5 to 11.2, white blood cell count increased from 3200 to 4900, and platelet count improved from 245,000 to 345,000. This comprehensive case presentation underscores the patient’s challenging journey from illness to recovery, emphasizing the vital role of early diagnosis and effective management in scrub typhus-associated ARDS.\n\nThese findings were consistent with the characteristic imaging manifestations of scrub typhus-associated ARDS.\n\n\nDiscussion\n\nScrub typhus is a prevalent infectious disease in India, with a higher susceptibility among individuals residing in rural areas, particularly agricultural workers and military personnel.6,7 The clinical spectrum of scrub typhus varies from constitutional symptoms commonly seen in acute febrile illnesses, such as fever, headache, cough, and the presence of an eschar, to severe and potentially life-threatening complications, including pneumonitis, encephalopathy, shock, and septicemia.8 The characteristic necrotic eschar associated with scrub typhus is typically observed at the site of the wound. Fatality rates are influenced by delayed presentation, diagnostic challenges, and drug resistance.8 Importantly, scrub typhus has the potential to progress into acute respiratory distress syndrome (ARDS), displaying a spectrum of lung-related symptoms ranging from bronchitis and interstitial pneumonitis to the eventual onset of ARDS.9 In a comprehensive study by Wang CC et al., which focused on ARDS among individuals afflicted with scrub typhus, a mortality rate of approximately 25% was reported. However, it’s noteworthy that this figure could be mitigated through the prompt application of appropriate interventions, such as doxycycline or chloramphenicol.10\n\nIn the presented case, the absence of a pathognomonic eschar posed a diagnostic challenge, necessitating the diagnosis of scrub typhus primarily based on ELISA results. Notably, this diagnostic approach underscores the significance of considering scrub typhus as a potential etiology for ARDS, especially in endemic regions.\n\nThe identification of diffuse bilateral ground-glass opacities with a peripheral and subpleural distribution, consolidations, and mediastinal lymphadenopathy on CT scans can contribute to the diagnosis of scrub typhus-associated pneumonia. In this case, timely recognition and the initiation of appropriate antibiotic therapy were critical for enhancing patient outcomes.\n\nThe strengths of our approach lie in the prompt recognition of scrub typhus as a potential cause of ARDS, even in the absence of a characteristic eschar. The utilization of diagnostic imaging, such as CT scans, played a pivotal role in reaching an accurate diagnosis. Additionally, the adherence to evidence-based treatment protocols, including the use of appropriate antibiotics and non-invasive positive pressure ventilation, demonstrated positive outcomes for the patient.\n\nHowever, there are some limitations to consider. The delayed presentation of the patient to the healthcare facility highlights the need for increased awareness and early diagnostic strategies for scrub typhus. This case emphasizes the significance of early diagnosis, as delays can lead to severe complications. Additionally, despite the positive outcome in this case, it is essential to acknowledge that scrub typhus-associated ARDS can be associated with high mortality, making early intervention and accurate diagnosis crucial.\n\nThe follow-up diagnostic information in this case, including the significant reduction in CRP and D-dimer values and the return to normal hemogram, indicates the resolution of leukopenia and demonstrates the effectiveness of the treatment. The patient’s perspective on the use of Bipap is noteworthy, as it reflects the importance of patient compliance and adaptation to treatment measures. The motivation and growing confidence of the patient with noticeable symptomatic improvement and reduced respiratory effort underscore the collaborative role of both clinicians and patients in achieving positive outcomes.\n\n\nConclusion\n\nIn conclusion, this case highlights the multifaceted challenges and successes in the diagnosis and management of scrub typhus-associated ARDS. It underscores the importance of early recognition, diagnostic imaging, and timely intervention in endemic regions, and the potential for positive outcomes when evidence-based treatment protocols are adhered to. Patient outcomes, as demonstrated in this case, underscore the significance of patient cooperation and adaptation to treatment measures, contributing to improved recovery and overall success in managing scrub typhus-associated ARDS.\n\n\nConsent\n\nWritten informed consent from the patient for the use and publication of patient’s data was taken.",
"appendix": "Data availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReferences\n\nSingh OB, Panda PK: Scrub Typhus. StatPearls Treasure Island. (FL): StatPearls Publishing; 2023.\n\nJanardhanan J, Trowbridge P, Varghese GM: Diagnosis of scrub typhus. Expert Rev. Anti-Infect. Ther. 2014 Dec; 12(12): 1533–1540. Publisher Full Text\n\nDevasagayam E, Dayanand D, Kundu D, et al.: The burden of scrub typhus in India: A systematic review. PLoS Negl. Trop. Dis. 2021 Jul; 15(7): e0009619. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaxena A, Khiangte B, Tiewsoh I: Scrub typhus complicated by acute respiratory distress syndrome and multiorgan failure; an unrecognized alarming entity in central India: A report of two cases. J. Family Med. Prim. Care. 2014; 3(1): 80–83. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLim H-K, Wang J-M: Scrub typhus: Seven-year experience and literature review. JACME. 2018; 8(3): 99–108. PubMed Abstract | Publisher Full Text\n\nHornick BB: Goldman: Cecil Textbook of Medicine. Ricketssial diseases. 21st ed.Bennett JC, Plum F, editors. Philadelphia, USA: WB Saunders Company; 2000; pp. 1911–12.\n\nNarvencar KP, Rodrigues S, Narvenkar RP, et al.: Scrub typhus in patients reporting with acute febrile illness at a tertiary health care institution in Goa. Indian J. Med. Res. 2012; 136: 1020–1024. PubMed Abstract\n\nMahajan SK: Scrub typhus. J. Assoc. Physicians India. 2005; 53: 954–958. PubMed Abstract\n\nChayakul P, Panich V, Silpapojakul K: Scrub typhus pneumonitis: an entity which is frequently missed. Q. J. Med. 1998; 68: 595–602. PubMed Abstract\n\nWang CC, Liu SF, Liu JW, et al.: Acute respiratory distress syndrome in scrub typhus. Am. J. Trop. Med. Hyg. 2007; 76: 1148–1152. Publisher Full Text"
}
|
[
{
"id": "243744",
"date": "22 Feb 2024",
"name": "Philippe Jouvet",
"expertise": [
"Reviewer Expertise Pediatric Intensive care"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nBhanushali and al. report a case of a 18 year-old indian female, who presented an ARDS due to scrub typhus. Scurub typhus is a frequent cause of unspecific acute undifferentiated febrile illness (fever, headaches, myalgia, and various gastrointestinal issues) in the Asia-Pacific region, due to the rickettsial microbe Orientia tsutsugamushi. O. tsutsugamushi infecte endothelial cells responsible of inflammatory cascade activation, which is involved in unusual manifestations such as hepatitis, meningoencephalitis, myocarditis or ARDS. According to authors, ARDS is a rare complication in case of tropical infectious disease, whereas its frequently observed in case of O. tsutsugamushi infection, due to this inflammatory activation. The different figures offer a useful view of lungs evolution according to time, which is often discuss and debate by clinicians. This manuscript is well written but some additional information are needed.\n\nComments.\nThe patient presents a bilateral pneumonia, observed in chest radiography and in chest CT. There was revealed diffuse ground glass opacities with patchy consolidations in both lungs, indicative of interstitial pneumonia. Authors report in the abstract and the description of the case that it is “characteristic imaging manifestations of scrub typhus-associated pneumonia”. Why non-specific interstitial pneumonia images are characteristic of scrub typhus-associated pneumonia? Can the authors further specify what are the differential diagnosis ? Authors report a “low blood pressure at 100/70 mmHg”, and a “body temperature of 98.7°C”. A blood pressure at 100/70 mmHg is in the normal range, maybe there was other shock signs such as decrease urinary output? A temperature of 98.7°C is not compatible with life. Did authors mean 38.7°C? The authors report a neutropenia but no neutrophils count is provided (only white blood cells) Authors only report the initial PaO2FiO2 ratio (at 153mmHg). They only notice the initial management with Non-Invasive Ventilation, without information in FiO2, or PEEP value, or PEEP evolution compared to chest radiography evolution. Could they had such information may be with a graph? Initial antimicrobial therapy was intravenous piperacillin and associated to azithromycin. Is it due to antimicrobial resistance profile of bacteria? Even in case of interstitial pneumonia images, which is due to other bacterias than community-acquired pneumonia? Why introduction of nebulized bronchodilators and inhaled corticosteroids treatment? There are not recommended of ARDS, may it an interesting treatment in case of O. tsutsugamushi pulmonary infection? Low molecular weight heparin therapy seems to have been introduced according to the existence of a pro-inflammatory status (Elevated levels of C-reactive protein and D-dimer). With a NIV support responsible of a bed rest in a pubescent patient, is it not the standard care? Or is it a specific treatment in case of severe O. tsutsugamushi infection? The conclusion could reinforce that Interstitial pneumonia images should make perform an ELISA test to search scrub typhus and introduce appropriate antibiotic treatment early in case of documentation and in such cases the treatment of O. tsutsugamushi is based on doxycycline or chloramphenicol, which are not the standard treatment in case of pneumonia.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "11473",
"date": "20 Jun 2024",
"name": "Jay Bhanushali",
"role": "Author Response",
"response": "Thank you for your detailed review of our case report. We appreciate you highlighting the important points and have made the necessary changes."
},
{
"c_id": "11475",
"date": "20 Jun 2024",
"name": "Jay Bhanushali",
"role": "Author Response",
"response": "The patient presents a bilateral pneumonia, observed in chest radiography and in chest CT. There was revealed diffuse ground glass opacities with patchy consolidations in both lungs, indicative of interstitial pneumonia. Authors report in the abstract and the description of the case that it is “characteristic imaging manifestations of scrub typhus-associated pneumonia”. Why non-specific interstitial pneumonia images are characteristic of scrub typhus-associated pneumonia? Can the authors further specify what are the differential diagnosis ? Changes made, Yes I agree ,scrub typhus was a serological diagnosis, cannot confirm the same of CT scan Authors report a “low blood pressure at 100/70 mmHg”, and a “body temperature of 98.7°C”. A blood pressure at 100/70 mmHg is in the normal range, maybe there was other shock signs such as decrease urinary output? A temperature of 98.7°C is not compatible with life. Did authors mean 38.7°C? Typing error, also I confirm blood pressure was normal and not low , changes made The authors report a neutropenia but no neutrophils count is provided (only white blood cells) Patient had leucopenia not neutropenia in particular. Authors only report the initial PaO2FiO2 ratio (at 153mmHg). They only notice the initial management with Non-Invasive Ventilation, without information in FiO2, or PEEP value, or PEEP evolution compared to chest radiography evolution. Could they had such information may be with a graph? Initial settings of NIV added to the report, graph is not available as data was not recorded. Initial antimicrobial therapy was intravenous piperacillin and associated to azithromycin. Is it due to antimicrobial resistance profile of bacteria? Even in case of interstitial pneumonia images, which is due to other bacterias than community-acquired pneumonia? Antibiotic choice as keeping in mind the local resistance pattern and doxycycline was initiated once scrub typhus was confirmed Why introduction of nebulized bronchodilators and inhaled corticosteroids treatment? There are not recommended of ARDS, may it an interesting treatment in case of O. tsutsugamushi pulmonary infection? Nebulised bronchodilators and ICS were used as patient had occasional wheezing, not a known case of OAD. Low molecular weight heparin therapy seems to have been introduced according to the existence of a pro-inflammatory status (Elevated levels of C-reactive protein and D-dimer). With a NIV support responsible of a bed rest in a pubescent patient, is it not the standard care? Or is it a specific treatment in case of severe O. tsutsugamushi infection? This was used as standard care and not specific to scrub typhus The conclusion could reinforce that Interstitial pneumonia images should make perform an ELISA test to search scrub typhus and introduce appropriate antibiotic treatment early in case of documentation and in such cases the treatment of O. tsutsugamushi is based on doxycycline or chloramphenicol, which are not the standard treatment in case of pneumonia. Yes I agree, with you a detailed fever profile should be done for patients presenting with interstial pneumonias."
}
]
},
{
"id": "259630",
"date": "04 Apr 2024",
"name": "Zahid Khan",
"expertise": [
"Reviewer Expertise Cardiology",
"Respiratory Medicine",
"GIM and Gastroenterology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPlease use the full terminology for all abbreviations when using first time. O. tsutsugamushi can be used in the first sentence in the introduction section after Orientia tsutsugamushi.\nThis disease typically exhibits clinical symptoms following an incubation period of 6-21 days, characterized by fever, headaches, myalgia, and various gastrointestinal issues. (Please provide frequency of these symptoms)\nTypical clinical presentations of scrub typhus encompass fever, generalized lymph node enlargement, cough, shortness of breath, muscle pain, headaches, skin rashes, eschar formation, loss of appetite, vomiting, and abdominal discomfort. Unusual complications, although infrequent, may include meningoencephalitis, glomerulonephritis, acute renal failure (ARF), interstitial pneumonia, acute respiratory distress syndrome (ARDS), acute hepatic failure, myocarditis, pericarditis, gastrointestinal bleeding, septic shock, acute hearing loss, acute cholecystitis, and intracranial hemorrhage. (Please provide frequency for these complications or clinical features)\nIn the case report section, please avoid providing specific date and time of the presentation to minimize the risk of patient identification.\nThe vitals need further clarity and I think the temperature presented is wrong. It can not be 98C. Heart rate of 127 ? sinus tachycardia?\nPlease include reference for the lab results used in the case report.\nThe patient also received nebulized bronchodilators and inhaled corticosteroids.(What was the reason for this?\nDid this patient have any ABG prior to starting on NIV? Please include the results in the case report.\n\nPlease consider using arrows to highlight findings or areas of interest in the images.\n\nThe case report is well written however needs some changes as highlighted in the report. It provides details about a health problem of significant importance.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "11474",
"date": "20 Jun 2024",
"name": "Jay Bhanushali",
"role": "Author Response",
"response": "Thank You for your repose and highlighting the important modifications. Same have been done, Please use the full terminology for all abbreviations when using first time. O. tsutsugamushi can be used in the first sentence in the introduction section after Orientia tsutsugamushi. - Changes done This disease typically exhibits clinical symptoms following an incubation period of 6-21 days, characterized by fever, headaches, myalgia, and various gastrointestinal issues. (Please provide frequency of these symptoms) - Our patient gave history of only fever with chills and rigors. Denied any other symptoms. In the case report section, please avoid providing specific date and time of the presentation to minimize the risk of patient identification. - changes made The vitals need further clarity and I think the temperature presented is wrong. It can not be 98C. Heart rate of 127 ? sinus tachycardia? - Changes made. - Tachycardia + Rhythm regular Please include reference for the lab results used in the case report. - added The patient also received nebulized bronchodilators and inhaled corticosteroids.(What was the reason for this? - patient had episodic wheezing hence bronchodilators and ICS added. No past history of OAD. Did this patient have any ABG prior to starting on NIV? Please include the results in the case report. - Yes, Details added"
}
]
}
] | 1
|
https://f1000research.com/articles/12-1596
|
https://f1000research.com/articles/13-8/v1
|
03 Jan 24
|
{
"type": "Opinion Article",
"title": "Creating cloud platforms for supporting FAIR data management in biomedical research projects.",
"authors": [
"Marcel Jentsch",
"Valentin Schneider-Lunitz",
"Ulrike Taron",
"Martin Braun",
"Naveed Ishaque",
"Harald Wagener",
"Christian Conrad",
"Sven Twardziok",
"Marcel Jentsch",
"Valentin Schneider-Lunitz",
"Ulrike Taron",
"Martin Braun",
"Naveed Ishaque",
"Harald Wagener",
"Christian Conrad"
],
"abstract": "Biomedical research projects are becoming increasingly complex and require technological solutions that support all phases of the data lifecycle and application of the FAIR principles. At the Berlin Institute of Health (BIH), we have developed and established a flexible and cost-effective approach to building customized cloud platforms for supporting research projects. The approach is based on a microservice architecture and on the management of a portfolio of supported services. On this basis, we created and maintained cloud platforms for several international research projects. In this article, we present our approach and argue that building customized cloud platforms can offer multiple advantages over using multi-project platforms. Our approach is transferable to other research environments and can be easily adapted by other projects and other service providers.",
"keywords": [
"Cloud",
"data management",
"data science",
"bioinformatics",
"platforms",
"FAIR"
],
"content": "Introduction\n\nUtilizing cloud platforms to link researchers, combine data, and manage data throughout the entire data life cycle is advantageous for biomedical research initiatives. It has become common practice to employ big data analytics to stratify and identify biomarkers in life science research ranging from biodiversity, development, and diseases such as cancer, mental health, or rare diseases. The information pertaining to biological samples from an individual donor has become incredibly complex and may comprise various scientific domains, types, and levels of biological organization.1 Examples include data from neuroimaging, genomics, proteomics, or even wearables and electronic health records. The different modalities of data can represent different aspects and levels of a complex biological system. Harmonization and integration of these diverse types of data within large research projects is a major challenge.1 Managing the flow of large datasets within a project and between different processing and analysis steps creates many technical and regulatory challenges when data is distributed across institutes, states, and countries.\n\nThe data management requirements of research projects can be represented by the different phases of the data life cycle. The research community has access to numerous definitions of the data life cycle. Here, we adhere to the ELIXIR RDMkit’s2 description, which classifies the data life cycle in research projects into the following seven phases (Figure 1). Each phase has different requirements on technical solutions:\n\n1. Plan: The planning phase involves the formalization of a data management plan. This very important and often mandatory document enables projects to organize data flows and processes within the project. Especially for larger projects, this phase requires the planning of data infrastructures that support data management during all the following phases of the data life cycle.\n\n2. Collect: The collection phase involves performing multiple experiments and generation of data by e.g., application of instruments and running measurements. This phase requires technical solutions that connect the many different involved sites and move data to further processing facilities.\n\n3. Process: Processing data sets typically requires the linking of several tools into a workflow that can transform input data into processed files.3 An example is the alignment of Next Generation Sequencing (NGS) reads to a reference sequence followed by the detection of genomic variants. Popular workflow systems such as Nextflow4 and Snakemake5 support and structure the creation of workflows. Depending on their complexity, research projects may then require environments that manage and monitor many workflow executions.\n\n4. Analyze: The analysis phase involves the use of applications, scripts, and notebooks to analyze data sets. Examples include applying machine learning methods, calculating statistics, summarizing data, or creating graphs. This task is usually performed interactively by an interdisciplinary, cross-institutional data science team. This requires an environment where different people can collaboratively access data as well as develop, share, and apply analysis scripts and notebooks.\n\n5. Preserve: Data preservation is a critical process aimed at guaranteeing the long-term safety, integrity, and accessibility of data, spanning several decades if required. This covers a range of strategies and procedures to mitigate data loss risk, corruption, or obsolescence over time.\n\n6. Share: Biomedical research projects often involve many partners from different institutes and countries. While accessing institutional computer centers is regularly restricted for external scientists, projects require solutions for sharing data between scientists. This also requires federated access functionalities.\n\n7. Re-use: Providing computational access to data facilitates integration of the project data with external data sets from the external communities and reanalysis in new approaches.\n\nThe schema describes the four phases of our platform development and project support. Starting with project initialization and selection of relevant services, we install a customized project platform in the deployment phase. In the production phase of the platform, projects use the services for data management activities covering the whole data life cycle. Finally, in the transfer phase, knowledge and experiences feed back into our service portfolio.\n\nCloud technologies offer solutions for research data management by providing scalable resources for data processing, enabling controlled access to data through federated user management, and facilitating collaborative and interactive data analyses through shared workspaces.6 There are different approaches to implement cloud platforms for biomedical research projects and a basic distinction is made between cloud types and service models.7 Centralized platforms based on the System as a Service (SaaS) model provide data processing or data management functionalities for many users and multiple research projects in parallel. Hereby the platforms offer many established tools for the end-users, which support data management and can be used to answer project-specific questions. Important examples of multi-user platforms are Galaxy-Europe8 and Anvil.9 The creation of customized platforms that are subsequently run on a cloud Infrastructure as a Service (IaaS), or Platform as a Service (PaaS) architecture is a counter design to the centralized platforms.\n\nCustomized platforms that adhere to a modular microservice design can strengthen the FAIR principles and improve the interoperability of the research data by providing Application Programming Interfaces (APIs) for access to data slices and data summaries.10 The FAIR principles are a set of guidelines for making data Findable, Accessible, Interoperable, and Reusable.11 These principles aim to improve the ability of researchers and other stakeholders to locate, understand, and (re-) use data, which is of importance within large projects as well as for sharing data with the scientific community. Although it has many advantages, creating customized cloud platforms is a complex task and requires expert knowledge, experienced technical staff, and guidelines.\n\nHere, we present our approach for creating customized cloud platforms for biomedical research projects and argue that such platforms offer many advantages for managing and processing data over the whole data life cycle and according to the FAIR principles. With similar use cases in mind, the framework is easily adaptable to various research initiatives and infrastructures. Our methodology offers a flexible framework for the management of knowledge and experiences while enabling the effective creation of cloud platforms.\n\nOur approach is based on managing a portfolio of supported services, which we have established within our cloud infrastructure. Our cloud is operated as a part of the German de. NBI network,12 but this approach applies as well to other commercial or public providers. For our portfolio services, we document best practices, deployment scripts and default settings internally using our instance of GitLab. Using git enables collaborative file editing, allows versioning, and supports integration of deployment pipelines. We also provide general guidelines and best practices for the research community in the de. NBI Cloud Wiki (https://cloud.denbi.de/wiki/). For developing our platforms, we follow a microservices architecture and manage our services as container images, which supports deploying these services in container environments. Our cloud environment mainly supports the container environments Docker and Kubernetes, which we apply depending on the requirements of the respective services.\n\nDuring project initialization (Figure 1), we consult projects, analyze which services are relevant for the respective project and design a platform framework. The consultation is generally performed in close coordination with the project management and scientists. The project-specific services are then installed on a cloud infrastructure in the deployment phase. We then maintain the project platforms throughout the whole production phase to support the data life cycle in the projects. Finally, knowledge and experiences of a project are transferred back into the portfolio and are then available for any other new project initialization. Hereby, we update deployment scripts and best practices as well as add new services, versions, and functionalities to our documentation. Applying this approach results in an evolving set of parallel running platforms over time, where any new platform profits from experiences and knowledge from all previous projects.\n\nOur service portfolio consists of a set of core services (Figure 1), which are regularly required by our collaboration partners. The selection of these services is based on our experiences and reflects the requirements of our research bubble. Anyhow, the general concepts can be easily transferred to other tools and services. Here, we describe how these services contribute to supporting the data life cycle and to the application of the FAIR principles. We generally recommend our projects to validate the application of FAIR criteria through self-assessment, as e.g., applied by de. NBI network.13\n\nOpenStack Manila\n\nIn most projects, we provide a shared network files system in our OpenStack cloud platform using the Manila service such as used in other OpenStack implementations.14 All project-relevant data can be stored, managed, and shared in such a central file system. The other services can thus access the same database. This allows files to be shared with the scientists, who can access the data via the respective other services. The central data structure also ensures that the data can be clearly identified via paths within the project, which facilitates communication, increases the reproducibility of the results, and ensures the findability of the data.\n\nLS Login\n\nLife Science Login (LS Login) is a service which is developed by EOSC-life including the ELIXIR infrastructure to provide a unified user management and authorization infrastructure for European researchers.15 It enables researchers to use their home organization credentials, community or other identities (e.g. Google, LinkedIn) to sign in and access data and services they are authorized to access. Thereby, it supports the OIDC standard which can easily be integrated by many other tools such as a user login system. By using LS Login users do not have to maintain multiple different user accounts for logging into the cloud platform services, which support the accessibility of data. By implementing LS Login, service providers don’t need to maintain their own user management system.\n\nJupyterHub\n\nJupyterHub is a multi-user platform, which allows for running Jupyter Notebook in a cloud environment.16 Data scientists can use JupyterHub for interactive data analysis, and for sharing analysis scripts and results. Within the portal, the users have access to private home storage and optionally to shared cloud data, including the results of experiments, the shared user storage space, and a common code base. Optionally, JupyterHub can be configured to provide different compute resource profiles, such as high-memory machines for extensive data analysis and processing steps. Jupyter supports specifically the explorative analysis of research data.\n\nR-Shiny server\n\nR-Shiny is a framework that allows for rapid and intuitive development of interactive data visualization applications. We support serving of R-Shiny apps using the open-source Shiny Server.17 R-Shiny apps can be used for interactive data analysis by members of a project as well as by external users. To ensure quality of services for multiple users, parallel processing over multiple servers as containers using Docker or Kubernetes is possible. A specific example of an R-Shiny app is the iSEE application,18 which provides interactive analysis of single-cell data. The iSEE app can e.g., support annotation of cell types in single-cell data for members of a consortium by displaying gene expression in selected cell clusters. Providing interactive access to data supports data analysis and increases the accessibility of data for people without programming knowledge.\n\nMinIO\n\nFindability requires registration of metadata in public data registries and assigning unique identifiers to datasets. Using an S3 (Simple Storage Service) object storage, all files are structured into buckets and further grouped into folders. Single files or groups of files can then be identified via unique URIs. We usually set up an S3 endpoint via the open-source software MinIO.19 The identifiers are globally unique since the domain name of the website is included. The unique identifier can then also be used to reference data in publications and in public data registries. An S3 server also provides an Application Programming Interface (API) access to the data, which allows access to all data that is to be published or shared with external users. The access to the S3 server can be public or protected by authentication.\n\nWESkit\n\nWESkit20 is a workflow execution service implementing the GA4GH WES API.21 It was developed to manage the execution of bioinformatics workflows at the German Cancer Research Center (DKFZ) and Charité Universitätsmedizin Berlin, but it can also be used in a cloud framework as well. The WESkit software provides features such as workflow monitoring, logging, and provenance tracking. It directly supports the processing of data. Hereby WESkit provides an interoperable environment for the execution of Snakemake5 and Nextflow4 workflows. The documentation of workflow executions supports the reusability of resulting data.\n\nOTP\n\nThe platform “One Touch Pipeline” (OTP) was initially developed by the German Cancer Research Center (Deutsches Krebsforschungszenter, DKFZ)22 as a part of the International Cancer Genome Consortium (ICGC) for management and processing of sensitive cancer genomics data. Since 2020, OTP is used at the DKFZ and Berlin Institute of Health for automatic execution of different workflows to process NGS data coming from whole genome sequencing (WGS), exome sequencing, RNA sequencing (RNA-seq), whole genome bisulfite sequencing (WGBS), and single-cell RNA sequencing (10x scRNA-seq) data. OTP has also been used for management of single-cell genomics data from COVID-19 patients.23\n\nNextcloud\n\nNextcloud is a suite of client-server software for creating and using file hosting services. It is enterprise-ready with comprehensive support options. Being free and open-source software, anyone is allowed to install and operate it on their own private server devices.21 It combines the comfort and user-friendliness of cloud solutions such as Dropbox or Google Drive with the requirements for security, data protection and control. The service runs on our infrastructure so that data does not need to leave the house. This allows users to share, for example, intermediate results and analysis scripts as part of data analysis. Access is granted to all members of a project and each user receives an initial 50 GB of storage.\n\nMultiple projects implemented the presented approach for creating customized cloud platforms to support the daily data life cycle.\n\nESPACE\n\nThe ESPACE project merged three prior Human Cell Atlas (HCA) early pilot studies to build a first version of the Human Cell Atlas of the Pancreas. The HCA project is an international effort to map all the cells in the human body and understand their functions.24 The ESPACE cloud platform consists of shared storage, a JupyterHub portal, an R-Shiny Server for providing interactive applications and MinIO as an S3 backend for providing computational access to the data. The JupyterHub portal (https://espace-cloud.bihealth.org) is actively used by more than ten data scientists throughout Europe for data processing and interactive data analysis. It is planned that the ESPACE data will soon be available to the research community via the ESPACE cloud platform.\n\nenvironMENTAL\n\nThe environMENTAL project investigates how some of the greatest global environmental challenges, climate change, urbanization, and psychosocial stress affect mental health across the lifespan. The project aims to identify underlying molecular mechanisms and develop preventions and early interventions. Cohort data of over 1.5 million EU citizens and patients, enriched with deep phenotyping data from large-scale behavioral neuroimaging cohorts, are used to identify brain mechanisms related to environmental adversity underlying symptoms of depression, anxiety, stress, and substance abuse. The Berlin Institute of Health (BIH) (https://www.bihealth.org/) provides a cloud platform to support data management in the environMENTAL project and all phases of the data life circle. The platform comprises a Nextcloud instance as a central storage for respective environmental data sets, a JupyterHub Portal as an interactive workspace and WESkit for running data processing on the integrated data sets.\n\nEASI-Genomics\n\nThe EASI-Genomics consortium aims to provide translational access to cutting-edge sequencing technologies and data analysis methodologies to researchers, adhering to ethical and legal requirements, as well as FAIR and secure data management. A JupyterHub-based cloud platform was utilized to provide users with translational access to example datasets and Jupyter notebooks to provide guidelines for data analysis for single-cell, multi-omics and spatial transcriptomics data in both R and Python programming languages (https://easi-genomics-cloud.bihealth.org).\n\nSpaceHack\n\nThe JupyterHub-based cloud platform facilitated the SpaceHack project at the ELIXIR Germany BioHackathon 2022. The project’s objective was to generate benchmarking data sets by leveraging the expertise of researchers with both biological and technical backgrounds to evaluate the performance of segmentation and cell assignment tools in the context of tissue-specific challenges.25 Over a week, the platform was utilized by more than 60 users, enabling virtual and onsite participants to collaborate effectively.\n\nOTP2EOSC\n\nThe OTP2EOSC project developed a cloud-ready data management and processing platform that sends analysis workflows to the data, avoiding transferring data between sites. This increases the efficiency of data management and data security. The project deployed a demonstration cloud platform (https://otp-demo.bihealth.org) for processing sensitive cancer-genomics data based on OTP, WESKit, and relevant ICGC cancer genomics workflows. The platform is available for interested users and to test the functionalities of the OTP software.\n\n\nDiscussion\n\nCollection, processing, analysis, storage, and access of biomedical research data require platforms for managing research data.26 For this end, the use of a cloud platform can greatly support biomedical projects. There are already many existing platforms available and important examples of central multi-project platforms include Galaxy-Europe,8 the AnVIL project,9 the Human Cell Atlas data coordination platform24 and the Cancer Genomics Cloud.27 Such platforms can be used for specific use cases like the execution of Galaxy workflows or to work on specific data types like human cells or cancer genomics data. There are also several commercial providers including DNA Nexus and Seven Bridges, which offer the development and deployment of centralized multi-project platforms. Central platforms are generally operated via the SaaS model and the costs for infrastructure and resources are usually returned to the projects.7 Alternatively, biomedical projects can also create their own customized platforms and run them using an IaaA or a PaaS approach.\n\nFrom a data management perspective, there are several advantages and disadvantages to using a central multi-project cloud platform. These platforms come with a lot of functionality already built in and provide unified environments to support all stages of the data lifecycle, making it easier to define processes and train scientists across projects. However, biomedical scientists are typically involved in several different projects at the same time, and it can be challenging for them to work in many different cloud environments.10 By using external central platforms, projects can worry less about technical infrastructure and have lower technical requirements. On the other hand, it can be a challenge to obtain funding for the use of external platforms7 and integration into the local data access regulations and processes needs to be solved. Existing platforms do not necessarily provide all the desired functionality for specific projects and customization may be required. For multi-project platforms, there is a risk that changes and updates to individual components become more difficult when the number of ongoing projects increases, making it less flexible to respond to the needs of individual projects. Monolithic platforms also tend to suffer from lock-in effects and data becoming less interoperable.10\n\nThe operation of a project-specific cloud platform based on an IaaS or PaaS model can offer several advantages over using a centralized multi-project framework. A customized cloud platform can save funding while operating on the existing resources of the institutes data centers, has greater flexibility and adaptability, and has a limited timeframe for long-term maintenance. Furthermore, long-term archiving may be easier to achieve. A local platform can be adapted to local data protection regulations such as those required by EU law with the General Data Protection Regulation (GDPR). On the technical side, copying large sets of data to a central platform can also be an issue. The features of a project-specific platform can be easily adapted to the specific needs of the users and the individual project goals. By developing self-controlled project-specific platforms, data interoperability and interconnection of platforms can be achieved more easily.\n\n\nConclusions\n\nA customized cloud platform can improve data sharing within a consortium, support data analysis and provide access to data over the whole data life cycle according to the FAIR criteria. This is particularly useful in an environment where many different partners within a consortium are analyzing a shared database. A common data structure also supports the sharing of analysis scripts and tools, making results reproducible within a project. In addition, data can be shared with external parties via a cloud platform as part of a review process, or more generally for reusing data by other researchers in new analyses. Hereby, our approach offers a structured and efficient way for developing platforms and serving multiple research projects.\n\nThe approach presented here of managing a portfolio of supported services has proven its worth in various projects at the BIH. A major benefit is the ease and speed with which new projects can be launched and supported. Due to management of know-how, existing platforms can be easily transferred to new projects within a few working days. By using existing software solutions and a microservice architecture, the individual components of the platform can be set up in a short time by a skilled cloud engineer. The microservices architecture makes the platform flexible and adaptable to individual user needs. In addition, the portfolio can be constantly updated during the transferring of services to new projects. However, this approach only makes sense if the potential projects have recurring software and service requirements. It is also a challenge to manage, update, extend and clean up the service portfolio on an ongoing basis.\n\nOur supported projects benefited greatly from the provision of the de. NBI cloud for research in Germany and its integration into the European ELIXIR network. The de. NBI cloud is a federated cloud framework operated by the de. NBI network in Germany and is available for academic projects in Germany.12 The de. NBI cloud is involved in the European Open Science Cloud (EOSC) project via the ELIXIR network with other European partners. Through EOSC, academic partners across Europe can also access cloud resources. The federated structure of the de. NBI cloud supports making platforms available where the data is stored. This has technical advantages with data transfer as well as legal advantages, e.g., if data is not allowed to leave an organization or to cross regional boundaries. It also has the advantage that local contact people are available on site. In addition, central services such as the central de. NBI project management system, established processes, and best practices as well as the LS Login can be used and accessed. The local availability of cloud technologies is of significant value for our project partners.",
"appendix": "Data availability\n\nNo data are associated with this article.\n\n\nAcknowledgements\n\nThe authors would like to thank all members of our collaborating projects and consortia including EOSC-life, EASI Genomics, ESPACE and environMENTAL for useful discussions, feedback, and insight into their specific use cases and requirements. We acknowledge financial support from the Open Access Publication Fund of Charité – Universitätsmedizin Berlin and the German Research Foundation (DFG).\n\n\nReferences\n\nCirillo D, Valencia A: Big data analytics for personalized medicine. Curr. Opin. Biotechnol. 2019; 58: 161–167. Publisher Full Text\n\nELIXIR: Research Data Management Kit. A deliverable from the EU-funded ELIXIR-CONVERGE project (grant agreement 871075).2021. Reference Source\n\nPerkel JM: Workflow systems turn raw data into scientific knowledge. Nature. 2019; 573(7772): 149–150. PubMed Abstract | Publisher Full Text\n\nDi Tommaso P, et al.: Nextflow enables reproducible computational workflows. Nat. Biotechnol. 2017; 35(4): 316–319. Publisher Full Text\n\nMölder F, et al.: Sustainable data analysis with Snakemake. F1000Res. 2021; 10: 33. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLangmead B, Nellore A: Cloud computing for genomic data analysis and collaboration. Nat. Rev. Genet. 2018; 19(5): 325. PubMed Abstract | Publisher Full Text\n\nNavale V, Bourne PE: Cloud computing applications for biomedical science: A perspective. PLoS Comput. Biol. 2018; 14(6): e1006144. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCommunity, T.G: The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2022 update. Nucleic Acids Res. 2022; 50(W1): W345–W351. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchatz MC, et al.: Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space. Cell Genom. 2022; 2(1).\n\nSheffield NC, et al.: From biomedical cloud platforms to microservices: next steps in FAIR data and analysis. Sci Data. 2022; 9(1): 553. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilkinson MD, et al.: The FAIR Guiding Principles for scientific data management and stewardship. Sci Data. 2016; 3: 160018. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBelmann P, et al.: NBI Cloud federation through ELIXIR AAI. F1000Res. 2019; 8: 842. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMayer G, et al.: Implementing FAIR data management within the German Network for Bioinformatics Infrastructure (de. NBI) exemplified by selected use cases. Brief Bioinform. 2021; 22(5). PubMed Abstract | Publisher Full Text | Free Full Text\n\nCastro León J: Advanced features of the CERN OpenStack Cloud. EPJ Web Conf. 2019; 214: 07026. Publisher Full Text\n\nHarrow J, et al.: ELIXIR: providing a sustainable infrastructure for life science data at European scale. Bioinformatics. 2021; 37(16): 2506–2511. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJupyterHub: Zero to JupyterHub with Kubernetes.2023. Reference Source\n\nShiny Server. Reference Source\n\nRue-Albrecht K, et al.: iSEE: Interactive SummarizedExperiment Explorer. F1000Res. 2018; 7: 741. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMinIO: 2022. Reference Source\n\nKensche PR, et al.: Executing workflows in the cloud with WESkit. BioHackrXiv. 2023. February 20.\n\nRehm HL, et al.: GA4GH: International policies and standards for data sharing across genomic research and healthcare. Cell Genom. 2021; 1(2).\n\nReisinger E, et al.: OTP: An automatized system for managing and processing NGS data. J Biotechnol. 2017; 261: 53–62. PubMed Abstract | Publisher Full Text\n\nTrump S, et al.: Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19. Nat Biotechnol. 2021; 39(6): 705–716. PubMed Abstract | Publisher Full Text\n\nRegev A, et al.: Science forum: the human cell atlas. elife. 2017; 6: e27041. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIshaque N, Long B, Kuemmerle L: SpatialHackathon.2022. Reference Source\n\nNavale V, von Kaeppler D , McAuliffe M: An overview of biomedical platforms for managing research data. J Data Inf Manag. 2021; 3(1): 21–27. Publisher Full Text\n\nLau JW, et al.: The Cancer Genomics Cloud: Collaborative, Reproducible, and Democratized-A New Paradigm in Large-Scale Computational Research. Cancer Res. 2017; 77(21): e3–e6. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "242781",
"date": "22 Feb 2024",
"name": "Anna Bernasconi",
"expertise": [
"Reviewer Expertise Data integration",
"Genomic data",
"Knowledge management",
"Bioinformatics",
"FAIR principles"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper describes the choice of adopting customized cloud platforms over centralized multi-project platforms in the context of biomedical research. The authors explain that, so far, the main trend has preferred the first kind of infrastructure instead of the second, bringing several limitations. I do believe that the author's experience is of great value and is worth being shared with a broader community. Therefore, I make some suggestions that should lead to improving the presentation of the work in the current manuscript.\nFigure 1 should drive the reader along the whole paper; however, it is not well-used. E.g. seven phases in the data life cycle are not connected to the other parts of the figure. The four project phases are not described in the paper. Services have been partitioned into four areas in the figures but this organization is not reflected in the paper (Services section, pages 5-6).\nSeveral parts of the Introduction and Discussion attempt to draw a line between centralized platforms based on SaaS (sometimes called central multi-project cloud platforms) and \"customized cloud platforms\" (based on IaaS/PaaS) such as the one proposed by the authors (see Page 4 and 7). This distinction is far from being well-explained and pragmatically justified. I urge the authors to better describe this, as it is fundamental for understanding their contribution.\n\nThe paper is focused on a specific experience, the one of the Berlin Institute of Health. The experience would be plausible in many other research institutes; however, the paper reads more like an experience paper/institute report rather than a research paper. This is even more evident when the author themselves speak about their research bubble (\"The selection of these services is based on our experiences and reflects the requirements of our research bubble.\"). To overcome this, a more structured discussion on competitor / alternative platforms is needed. In this way, the paper would become understandable/useful also for whom is coming from different \"bubbles\".\nThe descriptions of Services sometimes provide details that are not properly justified (e.g., why explain that 'Access is granted to all members of a project and each user receives an initial 50 GB of storage.' if further scalability is not discussed? Is 50GB a limitation in practical scenarios?)\nMINOR: - Page 5: explain OIDC acronym - don't --> do not - The adherence to FAIR principles is evaluated by \"self-assessment\". Could this be elaborated further? - Page 6, WESkit paragraph, remove 'as well' - Bibliography, please provide URLs for entries 2, 16, 17, 19, 25\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly",
"responses": [
{
"c_id": "11282",
"date": "04 Apr 2024",
"name": "Sven Twardziok",
"role": "Author Response",
"response": "Dear reviewer, Thank you very much for your constructive comments and suggestions. Our reposes to your suggestions are in detail below and changes are included in the new version. Figure 1 should drive the reader along the whole paper; however, it is not well-used. E.g. seven phases in the data life cycle are not connected to the other parts of the figure. The four project phases are not described in the paper. Services have been partitioned into four areas in the figures but this organization is not reflected in the paper (Services section, pages 5-6). Thank you very much for this comment. We adapted the description of the four project phases the text. We also We modified the figure to make a connection between the phases of the data life cycle, the FAIR principles and the services. Several parts of the Introduction and Discussion attempt to draw a line between centralized platforms based on SaaS (sometimes called central multi-project cloud platforms) and \"customized cloud platforms\" (based on IaaS/PaaS) such as the one proposed by the authors (see Page 4 and 7). This distinction is far from being well-explained and pragmatically justified. I urge the authors to better describe this, as it is fundamental for understanding their contribution. We agree that the distinction between the terms \"centralised platforms\" and \"customised platforms\" was unclear and have removed these distinctions accordingly throughout the manuscript. The manuscript now focuses more on the distinction between Iaas/PaaS and IasS at the project level, as these are common terms and projects ultimately have to choose between the models when building a cloud platform. The paper is focused on a specific experience, the one of the Berlin Institute of Health. The experience would be plausible in many other research institutes; however, the paper reads more like an experience paper/institute report rather than a research paper. This is even more evident when the author themselves speak about their research bubble (\"The selection of these services is based on our experiences and reflects the requirements of our research bubble.\"). To overcome this, a more structured discussion on competitor / alternative platforms is needed. In this way, the paper would become understandable/useful also for whom is coming from different \"bubbles\". We agree that this work reflects our own view. However, the framework of this work is an opinion paper and we believe that our experiences and the general concept in the present form will be useful for other readers as well. The descriptions of Services sometimes provide details that are not properly justified (e.g., why explain that 'Access is granted to all members of a project and each user receives an initial 50 GB of storage.' if further scalability is not discussed? Is 50GB a limitation in practical scenarios?) Thanks for the hint. We have revised the description of the services and removed unnecessary information. MINOR: Page 5: explain OIDC acronym We added an explanation of the OIDC acronym. don't --> do not done The adherence to FAIR principles is evaluated by \"self-assessment\". Could this be elaborated further? We added an additional explanation of the term “self-assessment”. The reader will find more information in the cited publication. Page 6, WESkit paragraph, remove 'as well' done Bibliography, please provide URLs for entries 2, 16, 17, 19, 25 Urls are provided as links on the article website as well as in the pdf documents"
}
]
},
{
"id": "242776",
"date": "06 Mar 2024",
"name": "Joseph Bonello",
"expertise": [
"Reviewer Expertise Bioinformatics",
"FAIR",
"Data Science"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary:\nThe project is about using a local microservice-based cloud architecture as a cost-effective solution over a per-project platform to support FAIR data management. The authors highlight the tools thay have available in their environment and who how projects can leverage this technology with the benefit of having project-specific expertise, built over several projects, available to them.\nThese are my detailed comments for the individual sections of the article.\nAbstract:\nThe abstract provides a summary of the project and highlights what the article is about sufficiently well.\nIntroduction:\nThe introduction describes the use of cloud platforms in biomedical research. In particular, reference is made to the need for the analysis of large datasets that need to adhere to strict legal and ethical frameworks. The authors adhere to the ELIXIR RDMkit definition of the data lifecycle which they summarise for the benefit of the overall narrative. The authors summarise well the problem associated with researchers' use of data and provide a good overview of the FAIR principles.\nApproach:\nThe authors describe the approach as being based on Docker and Kubernetes and how they provision services based on a core set of services that facilitate the research process based on the existing needs of their users.\nThe authors then proceed to list and describe the list of services they make available on the platform they maintain. To complement this list, they provide several examples of projects where the technologies have been implemented.\nComments:\n1. The authors mention the validation of adherence to FAIR principles through a self-assessment. It would be interesting if this self-assessment is defined better, to highlight the synergy between the provided services and adherence to the FAIR principles.\n2. The list of tools and services provided on the platform is interesting. However, how these tools relate to the FAIR principles, and to which principles they relate, is not immediately clear. I suggest that the authors explicitly link the tool to the relevant FAIR principle for added clarity.\nDiscussion:\nIn the discussion section, the authors compare the proposed solution to multi-project platform, comparing the pros and cons of the two different solutions.\nComments:\n1. In terms of costs, comparing the costs between the multi-project solution and using an in-house solution needs to consider not only the cost of purchasing and maintaining the hardware (including the salary costs, power, etc). It is important to acknowledge these costs, although I am aware that they may be difficult to quantify and compare.\n2. I think that a short mention of the performance differences offered by the two solutions merits a mention. This is in view of the fact that in order to achieve high performance locally, you must acquire the hardware to match the needs (e.g. GPUs). This can be expensive and require expertise to maintain.\nConclusion:\nIn the concluding remarks, the authors highlight the benefits of having a local data structure that supports sharing resources within the project. They highlight the benefits of the proposed solution and provide examples where the solution has been used.\nGeneral suggestions for improvement:\n- Capitalize machine learning (Machine Learning) and data science (Data Science). - Provide a figure where each of the tools that support the data lifecycle is organized under the relevant heading of the RDMKit phases. - Provide more details on the security aspects that a local solution offers, how it compares to multi-project solutions and how it helps researchers align with legal requirements. - Show more clearly (with examples) how a local solution would encourage reproducibility of scientific study and how, in reality, can project groups share their data and research within a FAIR environment.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": [
{
"c_id": "11283",
"date": "04 Apr 2024",
"name": "Sven Twardziok",
"role": "Author Response",
"response": "Dear reviewer, Thank you very much for your constructive comments and suggestions. Our reposes to your suggestions are in detail below and changes are included in the new version. The authors mention the validation of adherence to FAIR principles through a self-assessment. It would be interesting if this self-assessment is defined better, to highlight the synergy between the provided services and adherence to the FAIR principles. We added an additional explanation of the term “self-assessment”. The reader will find more information in the cited publication. The list of tools and services provided on the platform is interesting. However, how these tools relate to the FAIR principles, and to which principles they relate, is not immediately clear. I suggest that the authors explicitly link the tool to the relevant FAIR principle for added clarity. We modified the figure to make a connection between the phases of the data life cycle, the FAIR principles and the services. In terms of costs, comparing the costs between the multi-project solution and using an in-house solution needs to consider not only the cost of purchasing and maintaining the hardware (including the salary costs, power, etc). It is important to acknowledge these costs, although I am aware that they may be difficult to quantify and compare. We added a sentence to make the reader aware of acquisition and operating costs; anyhow, our approach is not focused on running on institutes data centers, but an advantage is, that such existing hardware can be used. I think that a short mention of the performance differences offered by the two solutions merits a mention. This is in view of the fact that in order to achieve high performance locally, you must acquire the hardware to match the needs (e.g. GPUs). This can be expensive and require expertise to maintain. The presented approach is not limited to the use of own hardware and therefore the purchase of own hardware is not a requirement."
}
]
}
] | 1
|
https://f1000research.com/articles/13-8
|
https://f1000research.com/articles/13-412/v1
|
26 Apr 24
|
{
"type": "Research Article",
"title": "Land deformation due to earthquake in Cianjur, West Java, Indonesia: A multisensor-multitemporal study",
"authors": [
"Putri Setiani",
"Adi Wibowo",
"Supriatna Supriatna",
"Fatwa Ramdani",
"Putri Setiani",
"Adi Wibowo",
"Supriatna Supriatna"
],
"abstract": "Background The Java Island is located in a seismically active region, which makes it vulnerable to earthquakes. On 21 November 2022, an earthquake of magnitude 5.6 struck Java, with its epicentre located in Cianjur, West Java. The earthquake caused significant damage to the buildings and infrastructure in the region, and several injuries and fatalities.\n\nMethods In this study, we used multisensor and multitemporal data to investigate the land deformation. Multi-pairs of Sentinel-1 SAR and aerial orthomosaic photos are used. Sentinel-1 SAR data were acquired from the Copernicus Data Space Ecosystem and the SNAP software was used to do inSAR analysis, while aerial orthomosaic data were acquired using DJI Drone Mavic Pro.\n\nResults Our results show that the earthquake caused significant land deformation in the area, with surface displacements of up to 9.8 cm and 11 cm for land uplift and land subsidence, respectively. We also found that deformation was primarily concentrated in the south-eastern and north-western parts of the study area. We identified the possibility of an unmapped fault that could trigger earthquakes in the future.\n\nConclusions Our findings highlight the usefulness of radar and remotely sensed optical data in studying the effects of earthquakes. This data can be used to effectively design future disaster response and recovery efforts.",
"keywords": [
"earthquake",
"land deformation",
"SAR",
"Indonesia"
],
"content": "Introduction\n\nIndonesia is situated in the so-called “Ring of Fire”, a region of high seismic activity along the Pacific Ocean. The country is particularly vulnerable to earthquakes because of its location on the Sunda megathrust, which is a major boundary between Eurasian and Australian tectonic plates (Keep and Schellart 2012), and the geostatistical distribution of historical earthquake in Indonesia with magnitude more than 7.5 and casualties over 10 people has been studied elsewhere (Ramdani and Chairunnisa 2021). In the previous decade, this region has experienced several large earthquakes, including an earthquake of magnitude 7.8 on 2 June 1994 and an earthquake of magnitude 7.7 on 17 July 2006, both of which occurred on the south of the Java Island and caused destructive tsunamis (Gunawan et al. 2017). Furthermore, an earthquake of magnitude 6.3 occurred in Yogyakarta on 26 May 2006, and was at a shallow depth within the overriding Sunda Plate. Additionally, an earthquake of magnitude 6.9 hit Java on August 2, 2019 (Pratama et al. 2022; USGS 2022a).\n\nOn 21 November 2022, an earthquake of magnitude 5.6 struck Java, with its epicentre located in Cianjur, West Java. The earthquake caused significant damage to the buildings and infrastructure in the region, and several injuries and fatalities have been reported (Sutarman et al. 2022). In this study, we geospatial data to investigate the land deformation caused by the Cianjur earthquake.\n\nIn nature, land deformation constitutes vertical and horizontal deformation. The use of interferometric synthetic aperture radar (InSAR) to detect and monitor land deformation has gained significant attention in recent years. InSAR has proven to be an effective tool for detecting and quantifying land deformation because it allows for the measurement of ground deformation with high spatial and temporal resolution (Li et al. 2019). Vertical land deformation is the vertical downward or upward movement of the Earth’s surface relative to a specific surface, such as the ellipsoidal height in Global Navigation Satellite System (GNSS) observations.\n\nMany studies have been conducted on this topic (Sneed and Brandt 2015; Liu et al. 2019; Jones, Jones, and Bekaert 2021; Deros et al. 2022). A study by monitored land subsidence in San Joaquin Valley, California using InSAR and GPS. They found that the InSAR data could accurately detect and map areas of land subsidence, and that this technique was able to provide valuable information on the spatial and temporal patterns of land subsidence. Another study by Bawden et al. (2012) used the InSAR method for ERS satellite data processing to monitor land subsidence in the Houston-Galveston region of Texas. They found that the InSAR technique could detect and map areas of land subsidence that provided valuable information on its spatial and temporal patterns. Furthermore, a study by Lai et al. (2022) used the InSAR method to monitor the land subsidence of Wuhan City, China. They found that land subsidence was caused by construction and underground subway development. Another study in Iran (Ghorbani et al. 2022) reported an average annual rate of 38 mm between 2006 and 2020 using the InSAR technique. However, the authors stated that their method could not be optimised for local deformations such as for infrastructural monitoring.\n\nOne advantage of InSAR method for land subsidence detection, is its ability to provide high-resolution measurements of ground deformation. InSAR uses radar images from multiple satellite passes to produce an interferogram, which is a map of the phase differences between the radar signals. These phase differences can be converted into displacement values, allowing for the measurement of land subsidence with sub-millimetre accuracy (Raspini et al. 2016).\n\nAdditionally, InSAR can provide continuous monitoring of land subsidence, allowing for the detection of both long-term and short-term changes in ground deformation. This can be particularly useful for detecting land subsidence events, such as those caused by underground mining (Zhang, Lu, and Kim 2017).\n\nFurthermore, InSAR can be used to detect subsidence in areas that are difficult to access or monitor using traditional methods, such as remote or urban areas (Zhang et al. 2011). This can provide valuable information for the management and mitigation of subsidence-related hazards.\n\nIn summary, InSAR applications for land subsidence have several advantages. First, InSAR provides high spatial and temporal resolution, allowing for the detection of small-scale subsidence events and monitoring of changes over time (Hooper et al. 2012). Second, InSAR can operate under all weather conditions, making it suitable for areas with variable climatic conditions (Li et al. 2019). Third, InSAR can penetrate vegetation and clouds, providing access to areas that are difficult to monitor using other traditional methods (Flores-Anderson et al. 2019).\n\nThis study aimed to accurately measure and monitor the land deformation in the study area using the InSAR method. This information can be used to identify potential hazards associated with land deformation, such as soil instability, liquefaction or the risk of landslides, and to support effective land management, disaster response, and recovery (Hidayat et al. 2020; Jiang et al. 2021; Krisnanto et al. 2021; Deros et al. 2022).\n\nCianjur is located in the south-eastern part of Indonesia’s capital Jakarta, approximately 107 km by road from Jakarta. It is located in a mountainous region, with the exception of short plains in some areas on the southern coast. The total area of Cianjur is 3,840.16 km2 with a population of 2,437,838 inhabitants (BPS 2022) and a population density of 634.82/km2.\n\nThe livelihood of the community depends predominantly on food crops, horticulture, animal husbandry, fisheries, plantations, and forestry. The majority of the population works in the agricultural, manufacturing, and service sectors. Major and small rivers, such as the Cibuni River, which drains into the Indian Ocean and is the longest river in Cianjur, are the source for crop irrigation, which supports the agricultural sector.\n\nFrom 1992 to 2022, the region has been struck by more than 200 earthquakes (USGS 2022a). One of the largest earthquakes was an earthquake with a force of seven magnitudes on the Richter scale that occurred on 2 September 2009 (Centre for Research on the Epidemiology of Disasters 2022). The earthquake occurred at a depth of approximately 50 km as a result of reverse faulting near the Australian Sunda plate boundary. The rupture occurred on north-northeast- or south-striking, moderately dipping the reverse fault according to focal mechanism solutions (USGS 2009).\n\nAs per the United States Geological Survey (USGS), the earthquake that struck on November 21, 2022, measuring 5.6 magnitude, resulted from movement along fault lines within the crust of the Sunda plate. The fault lines either slant sharply to the north with a rightward shift or to the east with a leftward shift, as indicated by seismic data. The Australian plate moves about 59 mm/year towards the north-northeast relative to the Sunda Plate, sinking beneath it at the Sunda Trench, approximately 260 km southwest of the quake’s epicenter (USGS 2022b).\n\nThe region where the Australian plate meets the Sunda plate is known for frequent seismic activity, with significant earthquakes occurring within both plates and along their boundary. Over the past three decades, there have been notable instances of seismic events in this area (see Figure 1), making it susceptible to secondary disasters like landslides and damage to infrastructure.\n\nThe layouting process was done using QGIS Desktop 3.22.8.\n\n\nMethods\n\nTo study land deformation caused by the earthquake, we used SAR data from the Sentinel-1 satellite operated by the European Space Agency (ESA). The Sentinel-1 satellite carries a C-band SAR instrument that can be used to measure ground displacement with high spatial and temporal resolution. Some studies also showed that data from Sentinel-1 images can be used to support fault line identification in the event of major earthquake (Yang et al. 2020; Li et al. 2023; Funning and Garcia 2019; Li et al. 2021). We acquired SAR data for the Cianjur region before and after the earthquake and applied interferometric techniques using The European Space Agency’s (ESA) software, called the Sentinel Application Platform (SNAP) (McGarragh et al. 2015), to calculate the surface displacement caused by the earthquake. The data were downloaded from https://scihub.copernicus.eu/dhus/#/home. Table 1 summarises the data.\n\nThe downloaded data required pre-processing. The first step was to create a new product with a selected swath and apply the orbit file using the S1-TOPS Split operator. These pre-processes were performed for both the acquired data (before and after the earthquake). The next step was to Appy-Orbit-File and Back Geocoding which allows the co-registration of both SLC products at sub-pixel accuracy for interferometry analysis. Next, we performed the joint co-registration of Sentinel-1 (obtained from the previous step) by creating a network (graph) of images and then estimating range and azimuth offsets by solving an optimisation problem using the Enhanced-Spectral-Diversity operator of SNAP. We then performed the deburst and merge using the TOPSAR Deburst operator because IW products have three swaths and EW products have five swaths. Each sub-swath image consisted of a series of bursts, where each burst was processed as a separate SLC image. The flowchart in Figure 2. shows the pre-processing steps.\n\nThe interferogram was then computed using the input data from the stack of co-registered-debursted images. We then estimated and subtracted the topographic phase from the interferogram using the TopoPhaseRemoval operator of the SNAP software. To improve image interpretability, a multilook process was then performed to reduce the speckle noise effect inherent in the original SAR data. Finally, the Goldstein phase-filtering operator (Feng et al. 2016) was used to reduce the residues from the later process in the phase-unwrapping step and enhance the phase-unwrapping accuracy. A flowchart of interferogram computation is presented in Figure 3.\n\nThe output result from the Goldstein Phase Filtering was then exported to the Statistical-Cost, Network-Flow Algorithm for Phase Unwrapping (SNAPHU) (Zebker 2023) to unwrap the phase product. The exported result contained a configuration file with a command to call SNAPHU. This command can be extracted from the configuration file and pasted into the command line to correctly run the SNAPHU process to produce an interferogram phase map. The output from this result was then used as the input for the SNAPHU import operator.\n\nThe interferogram phase map is rich in information regarding the location of land deformation as well as the strength and direction of surface deformation. The interferogram phase map can also be used as a proxy for other earthquake-related variables such as energy generation during an event and the intensity of shaking felt throughout the impacted region. The interferogram results are shown in Figure 4.\n\nThe blue arrows on the left illustrate the satellite’s antenna pointing direction. The lay outing process was done using Google Earth Pro version 7.3.6.9285 (64-bit).\n\nFinally, the displacement map was generated using the phase-to-displacement operator of the SNAP software. To reduce bias, we stacked the coherence and displacement maps. We then masked the displacement using coherence values lower than or equal to 0.2. The displacement results before masking are shown in Figure 5.\n\nThe blue arrows on the left illustrate the satellite’s antenna pointing direction. The layouting process was done using Google Earth Pro version 7.3.6.9285 (64-bit).\n\nFor the accuracy assessment, we compared the results with very high-resolution satellite images from the PlanetScope data. The PlanetScope dataset used in this study was acquired on 27 September 2022 (before the earthquake), and 29 November 2022 (after the earthquake). The data were downloaded from https://www.planet.com/explorer/. The images were then classified using a supervised classification algorithm. Classification was performed using the Random Forest algorithm, which has been widely applied for classification techniques (Breiman 2001; Purwanto et al. 2023; Gounaridis, Apostolou, and Koukoulas 2016; Tempa and Aryal 2022), with the Semi-automatic Classification Plugin in QGIS. The input data are the spectral bands of the satellite images, and the output data are the landslides as proof of land deformation due to the earthquake. Furthermore, we also utilised an aerial orthophoto product acquired using an Unmanned Aerial Vehicle (UAV) to acquire the data of damaged residential buildings at a higher spatial resolution.\n\n\nResults\n\nOur analysis of SAR data revealed significant land deformation in the Cianjur region following the earthquake. Figure 6. shows a map of the surface displacement caused by the earthquake, with the colours indicating the magnitude of the displacement. Highest displacements were observed in the south-eastern and north-western parts of the study area, with displacements of up to 9.8 cm (uplift) and 11 cm (subsidence).\n\nThe results show a high possibility of faults occurring around the study area. As shown in Figure 7, the northwest and southeast parts experienced opposite effects. The northwest part experienced land uplift, whereas the southeast part experienced land subsidence. Moreover, the fault line approximately aligns with the historical epicentre of earthquakes, forming a straight line from the South-West to the North-East, as illustrated in Figures 7 and 8. Therefore, we drew a line across the location of a possible fault which has never been mapped.\n\nColours indicate the magnitude of the displacement, with blue indicating uplift and red indicating land subsidence. The layouting process was done using QGIS Desktop 3.22.8.\n\nThe approximate fault line is illustrated within the red-dashed polygon boundary.\n\nLand displacement was observed in the northern (uplift) and southern (subsidence) part of the fault, indicating that the possible direction of the fault is east-west. Then epicentre location of historical earthquakes formed a seemingly straight east-west direction fault, as shown in Figure 7. Such method of fault line determination from interferograms have also been used in other studies (Li et al. 2021, 2023).\n\nFurthermore, we created a cross-sectional line to extract the value of land deformation. The line length was 24 km from the north-western to the south-eastern part of the study area. There was a displacement of approximately 8 cm around the fault line (Figure 8).\n\nFigure 9 shows the landslide as proof of land deformation. This was overlapped with the observed land deformation map produced using the InSAR technique. Many residential buildings and public infrastructure were damaged observed using aerial orthophotos, and the locations exactly overlapped with the land deformation map (Figure 10).\n\nThe layouting process was done using QGIS Desktop 3.22.8.\n\nThe layouting process was done using QGIS Desktop 3.22.8.\n\n\nDiscussion\n\nOur results show that the earthquake of magnitude 5.6 that struck Cianjur on 21 November 2022 caused significant land deformation in the region. The highest displacements were observed in the south-eastern and north-western parts of the study area, with some areas experiencing land uplift of up to 9.8 cm and subsidence of up to 11 cm.\n\nA report by the Center for Volcanology and Geological Hazard Mitigation of Indonesia stated that the most affected location, seeing massive damage, was the Cugenang District, especially the villages of Gasol and Sarampad. This is due to the rock layers of old volcanic products that have experienced weathering, and buildings that are not designed to be earthquake-resistant (Center for Volcanology and Geological Hazard Mitigation 2022), with additional possibility of vertical deformation. This report is consistent with our findings, where massive landslides and damaged residential infrastructure were found in the Cugenang District (Figures 11 and 12). Considering the seriousness of the impact, the use of InSAR for regular monitoring in this area is highly recommended to provide detailed information that is required for education purpose, as well as mitigation measure in time of disaster. InSAR can be used to study wider area where estimation on heavily impacted areas can be obtained, so that the use of ground radar can be more efficient as it become more directed. Then, for verification of fault line identification using images from Sentinel-1, the highest accuracy is provided by ground survey. However, the two additional datasets from PlanetScope satellites and orthophoto obtained from UAV as is discussed in this study also significantly improve the confidence level of fault lines identification.\n\nThe zonal statistic operator of QGIS was used to calculate the average values of land displacement. The algorithm calculates statistics of the land displacement raster layer of an overlapping hexagon vector layer. The layouting process was done using QGIS Desktop 3.22.8.\n\nThe old volcano products, lava, and lahar deposits (symbolized with Qot, Qyl, Qyg, respectively) that have experienced weathering led to massive collapsed buildings in the study area. The visualization was designed using QGIS Desktop 3.22.8.\n\nHowever, this study has some limitations. For example, the detected land deformation can be due to other changes not related to the earthquake, since a large part of the study area is cultivated, for example paddy fields are present in the study area. Furthermore, some densely vegetated areas may produce false positive results. Changes in these areas should not be considered as land deformation. The approximate fault line also requires further investigation using ground-based techniques.\n\nAlso, there are limitations in the use of InSAR for land subsidence mapping and monitoring. One limitation is the need for a stable reference surface, known as the “interferometric baseline”, to accurately measure subsidence (Antonova et al. 2018). This can be challenging in areas with complex topographies or large variations in the surface reflectivity. Another limitation is that atmospheric effects are one of the limiting error sources in repeat-pass InSAR measurements. InSAR is sensitive to atmospheric effects, such as changes in temperature and water vapour, which can introduce errors in the measurements of ground deformation (Ding et al. 2008).\n\nA subsequent limitation is the need for multiple satellite passes in order to generate an interferogram, which can limit the temporal resolution of InSAR measurements.\n\n\nConclusion\n\nIn this study, we used multisensor and multitemporal data to investigate land deformation in Cianjur, West Java, following an earthquake of magnitude 5.6 that occurred on 21 November 2022. Our results show that the earthquake caused significant land deformation in the area, with surface displacements of uplift of up to 9.8 cm and land subsidence of up to 11 cm in some areas.\n\nWe also found that deformation was primarily concentrated in the southeastern and northwestern parts of the study area. The earthquake led to secondary disasters such as landslides and collapsed residential buildings. This is due to a combination of geological factors and inadequate building structures.\n\nWe recommend that local and national governments conduct regular monitoring of the study area using InSAR, supported by ground-based techniques to track changes in land deformation over time and assess the effectiveness of any mitigation measures. For future research, possibility of using cloud-based processing system is important to be explored to improve the processing time, so that faster observation result can be generated to provide a timelier recommendation in time of disaster mitigation.",
"appendix": "Data availability\n\nZenodo: InSAR result of Cianjur Earthquake (November 2022), Indonesia. https://doi.org/10.5281/zenodo.10483646 (Ramdani et al. 2024).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nAntonova S, Sudhaus H, Strozzi T, et al.: Thaw Subsidence of a Yedoma Landscape in Northern Siberia, Measured In Situ and Estimated from TerraSAR-X Interferometry. Remote Sens. 2018; 10(4): 494. Publisher Full Text\n\nBawden GW, Johnson MR, Kasmarek MC, et al.: Investigation of land subsidence in the Houston-Galveston region of Texas by using the Global Positioning System and interferometric synthetic aperture radar, 1993-2000. Scientific Investigations Report. 2012; 2012–5211. Reference Source\n\nBPS: Indikator Kesejahteraan Rakyat Kabupaten Cianjur 2021. Cianjur: BPS Kabupaten Cianjur; 2022. Reference Source\n\nBreiman L: Random Forests. Mach. Learn. 2001. Publisher Full Text\n\nCenter for Volcanology and Geological Hazard Mitigation: Geologi Gempa Cianjur - 21 November 2022. Kementerian Energi dan Sumber Daya Mineral Badan Geologi. 2022. Reference Source\n\nCentre for Research on the Epidemiology of Disasters: The International Disaster Database. EM-DAT Public. 2022. Reference Source\n\nDeros SN, Mohamad NM, Din SM, et al.: Land Subsidence Susceptibility Projection for Palembang Slum Area by Complex MCDM-AHP Technique. J. Eng. Technol. Sci. 2022; 54: 220104. Publisher Full Text\n\nDing X-l, Li Z-w, Zhu J-j, et al.: Atmospheric Effects on InSAR Measurements and Their Mitigation. Sensors. 2008; 8(03): 5426–5448. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFeng Q, Huaping X, Zhefeng W, et al.: Improved Goldstein Interferogram Filter Based on Local Fringe Frequency Estimation. Sensors (Switzerland). 2016; 16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFlores-Anderson AI, Herndon KE, Thapa RB, et al.: SAR Handbook: Comprehensive Methodologies for Forest Monitoring and Biomass Estimation. Huntsville, Alabama: SERVIR Global Science Coordination Office National Space Science and Technology Center; 2019. Publisher Full Text\n\nFunning GJ, Garcia A: A Systematic Study of Earthquake Detectability Using Sentinel-1 InterferometricWide-Swath Data. Geophys. J. Int. 2019; 216(1): 332–349. Publisher Full Text\n\nGounaridis D, Apostolou A, Koukoulas S: Land Cover of Greece, 2010: A Semi-Automated Classification Using Random Forests. J. Maps. 2016; 12: 1055–1062. Publisher Full Text\n\nGunawan E, Meilano I, Hanifa NR, et al.: Effect of Coseismic and Postseismic Deformation on Homogeneous and Layered Half-Space and Spherical Analysis: Model Simulation of the 2006 Java, Indonesia, Tsunami Earthquake. J. Appl. Geod. 2017; 11: 207–214. Publisher Full Text\n\nHidayat RF, Kiyota T, Tada N, et al.: Reconnaissance on Liquefaction-Induced Flow Failure Caused by the 2018 Mw 7.5 Sulawesi Earthquake, Palu, Indonesia. J. Eng. Technol. Sci. 2020; 52(1): 51–65. Publisher Full Text\n\nHooper A, Bekaert D, Spaans K, et al.: Recent advances in SAR interferometry time series analysis for measuring crustal deformation. Tectonophysics. 2012; 514-517(01): 1–13. Publisher Full Text\n\nJiang G, Feng Z, Zhao R, et al.: Unload Pull-out Test of Full-Length Grouted Bolts in Slope Reconstruction and Expansion. Journal of Engineering and Technological Sciences. 2021; 53. Publisher Full Text\n\nJones J, Jones CE, Bekaert DP: Value of InSAR for Monitoring Land Subsidence to Support Water Management in the San Joaquin Valley, California. J. Am. Water Resour. Assoc. 2021; 58: 995–1001. Publisher Full Text\n\nKeep M, Schellart WP: Introduction to the Thematic Issue on the Evolution and Dynamics of the Indo-Australian Plate. Aust. J. Earth Sci. 2012; 59: 807–808. Publisher Full Text\n\nKrisnanto S, Rahardjo H, Kartiko RD, et al.: Characteristics of Rainfall-Induced Slope Instability in Cisokan Region, Indonesia. Journal of Engineering and Technological Sciences. 2021; 53(5): 210504. Publisher Full Text\n\nLai W, Shen Q, Hansheng Wang CK, et al.: InSAR-derived land subsidence in Wuhan between 2015 and 2020. All Earth. 2022; 34(1): 224–242. Publisher Full Text\n\nLi S, Wang X, Tao T, et al.: Source Model of the 2023 Turkey Earthquake Sequence Imaged by Sentinel-1 and GPS Measurements: Implications for Heterogeneous Fault Behavior along the East Anatolian Fault Zone. Remote Sens. 2023; 15(10). Publisher Full Text\n\nLi Y, Jiang W, Zhang J, et al.: Sentinel-1 SAR-Based Coseismic Deformation Monitoring Service for Rapid Geodetic Imaging of Global Earthquakes. Nat. Hazards Res. 2021; 1: 11–19. Publisher Full Text\n\nLi Z, Wei Y, Wei J, et al.: Time-series InSAR ground deformation monitoring: Atmospheric delay modeling and estimating. Earth Sci. Rev. 2019; 192(05): 258–284. Publisher Full Text\n\nLiu Z, Liu P-W, Massoud E, et al.: Monitoring Groundwater Change in California’s Central Valley Using Sentinel-1 and GRACE Observations. Geosciences. 2019; 9(10). Publisher Full Text\n\nMcGarragh G, Poulsen C, Povey A, et al.: SNAP (Sentinel Application Platform) and the ESA Sentinel 3 Toolbox. ESASP; 2015.\n\nPratama C, Heliani LS, Widjajanti N, et al.: Recent GPS-Based Long Wavelength Crustal Deformation Revealed Active Postseismic Deformation Due to the 2006 Yogyakarta Earthquake. J. Appl. Geod. 2022; 16: 131–141. Publisher Full Text\n\nPurwanto AD, Wikantika K, Deliar A, et al.: Decision Tree and Random Forest Classification Algorithms for Mangrove Forest Mapping in Sembilang National Park, Indonesia. Remote Sens. 2023; 15. Publisher Full Text\n\nRamdani F, Chairunnisa V: Combination of Geostatistical and Geovisualisation Techniques for Analysing 120 Year Earthquake Events in Indonesia Using Open- Source Software.2021. Publisher Full Text\n\nRamdani F, Setiani P, Wibowo A, et al.: InSAR result of Cianjur Earthquake (November 2022), Indonesia (1.0). [Dataset]. Zenodo. 2024. Publisher Full Text\n\nRaspini F, Bardi F, Bianchini S, et al.: The contribution of satellite SAR-derived displacement measurements in landslide risk management practices. Nat. Hazards. 2016; 86(11): 327–351. Publisher Full Text\n\nSneed M, Brandt JT: Land subsidence in the San Joaquin Valley, California, USA, 2007–2014. Copernicus Publications on behalf of the International Association of Hydrological Sciences. 2015; 11: 23–27. Reference Source\n\nSutarman S, Herlina H, Mulyeni S, et al.: Implementation of Human Concern in Education and Empowerment of Earthquake Victims in Cianjur Regency. Int. J. Educ. Manag. Sociol. 2022; 1(2): 1–17. Publisher Full Text\n\nTempa K, Aryal KR: Semi-Automatic Classification for Rapid Delineation of the Geohazard-Prone Areas Using Sentinel-2 Satellite Imagery. SN Appl. Sci. 2022; 4. Publisher Full Text\n\nUSGS: M 7.0-66 km SSW of Banjar, Indonesia. USGS Earthquake Hazards Program; 2009. Reference Source\n\nUSGS: Search Earthquake Catalog. USGS Earthquake Hazards Program; 2022a. Reference Source\n\nUSGS: M 5.6-18 km WSW of Ciranjang-hilir, Indonesia. USGS Earthquake Hazards Program; 2022b. Reference Source\n\nYang J, Caijun X, Wang S, et al.: Sentinel-1 Observation of 2019 Mw 5.7 Acipayam Earthquake: A Blind Normal-Faulting Event in the Acipayam Basin, Southwestern Turkey. J. Geodyn. 2020; 135: 101707. Publisher Full Text\n\nGhorbani Z, Khosravi A, Maghsoudi Y, et al.: Use of InSAR data for measuring land subsidence induced by groundwater withdrawal and climate change in Ardabil Plain, Iran. Sci. Rep. 2022; 12(08): 13998. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZebker HA: SNAPHU: Statistical-Cost, Network-Flow Algorithm for Phase Unwrapping. Stanford Radar Interferometry Research Group; 2023; vol. 2023. . Reference Source\n\nZhang A, Jason L, Kim J-W: Detecting mining-induced ground deformation and associated hazards using spaceborne InSAR techniques. Geomat. Nat. Haz. Risk. 2017; 9(1): 211–223. Publisher Full Text\n\nZhang Y, Zhang J, Hongan W, et al.: Monitoring of urban subsidence with SAR interferometric point target analysis: A case study in Suzhou, China. Int. J. Appl. Earth Obs. Geoinf. 2011; 13(5): 812–818. Publisher Full Text"
}
|
[
{
"id": "269941",
"date": "31 May 2024",
"name": "Mehmet Ali Yücel",
"expertise": [
"Reviewer Expertise Cartography",
"GIS",
"GNSS",
"Remote Sensing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article is well-prepared. The data is sufficient, and good results have been obtained. I have a suggestion regarding maps. I think adding it would be useful. I have also added a reference suggestion to the list.\nFigures 7 and 8 illustrate some fault lines in the study area. It would be beneficial to display the faults of the entire study area on the topographic location map in Figure 1 and to incorporate the fault lines into the geological map in Figure 12.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "11881",
"date": "29 Jun 2024",
"name": "Fatwa Ramdani",
"role": "Author Response",
"response": "Thank you very much for your expertise and time to review our work. We have been looking for the existing fault data in the study area, but unfortunately, the data is not available. We will update the figure when the data is available."
}
]
},
{
"id": "301157",
"date": "26 Aug 2024",
"name": "Fathoni Usman",
"expertise": [
"Reviewer Expertise Civil Engineering with Geospatial AI and Remote Sensing."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the method section, the author did not explain how they selected the pairs of the image. It is supposed to mention the temporal and spatial baselines that will affect the quality of the interferogram and displacement results. The study area was large and dominated by vegetative regions, which caused the low coherence. Since the Sentilen-1 is considered low-quality SAR data with band C. The size of the study area and considering the ratio between vegetative or water areas to fix features on the ground will become crucial. Filtering was also not mentioned clearly in the method especially the pairs of imagery taken during the rainy season between October to December. It is needed to manage the atmospheric error due to time lagging because of the atmospheric conditions.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "275596",
"date": "14 Sep 2024",
"name": "Chaoying Zhao",
"expertise": [
"Reviewer Expertise InSAR",
"geohazard monitoring related to land subsidence",
"landslide",
"glacier movement etc."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper examines land deformation caused by an earthquake in the Cianjuar area of Indonesia using the InSAR technique with SNAP software. The study aims to identify the blind fault in the region. However, I suggest making some major revisions to the manuscript:\n- The sentences are too long and should be split apart. - The figures should align with the text in the manuscript. Currently, the figures are placed before the text. - Some moderate editing of the English language is required. -What’s the difference between Figs. 6 and 7. Please give some explanation. - The InSAR results are too noisy, so the main findings are not fully supported by the deformation results.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/13-412
|
https://f1000research.com/articles/13-408/v1
|
26 Apr 24
|
{
"type": "Brief Report",
"title": "Psychometric characteristics of individuals’ intention to engage in philanthropic activities measure: An early development and tryout",
"authors": [
"Emaridial Ulza",
"Engkos Achmad Kuncoro",
"Asnan Furinto",
"Minsani Mariani",
"Engkos Achmad Kuncoro",
"Asnan Furinto",
"Minsani Mariani"
],
"abstract": "This brief article reports on the psychometric characteristics of the early development of individuals’ intention to engage in philanthropic activities questionnaire. In the innitial stage of development, the questionnaire was tried out by administering it online to a targeted sample. Out of 63 sample participants completing the questionnaire, only 43 data were appropriate for further analysis using the Rasch model. While the overall scale of the questionnaire suggested multidimensionality, subscales aligned with unidimensionality criteria. Acceptable reliability was observed in the overall scale and the Funding Philanthropic Brand Trust (FPBT) subscale, contrasting with inadequate reliability in the Philanthropic Brand Preference (PBP) and Pride of Affiliation (PoA) subscales, warranting further investigation. Specific items like Q17, Q31, Q42, and Q44 posed challenges, indicating difficulties in discussing social issues, cultural conformity in donations, valuing recognition, and seeking community support in philanthropy. Differential Item Functioning (DIF) analysis revealed demographic variations in responses, indicating diverse agreement levels based on age, gender, and education. These findings offer crucial insights for refining future questionnaire iterations, highlighting the need for a second round of development to address these limitations, with an expanded sample size to ensure robustness.",
"keywords": [
"Philanthropy",
"psychometric characteristics",
"questionnaire development",
"Rasch model"
],
"content": "Introduction\n\nResearch has highlighted the significance impact of corporate philanthropy and community wealth groups for society. Prior investigations have mainly focused on corporate philanthropy’s impact on trade credit financing (Liao, 2020; Yang et al., 2019) and firm reputation (Brammer & Millington, 2005), with less attention to personal motivations for philanthropic involvement. To bridge this gap, a preliminary study within a broader doctoral research project analyzed factors that drive individuals to participate in philanthropy. A survey questionnaire capturing the propensity for philanthropic engagement was developed and administered to a select group of samples. The psychometric properties of the survey questionnaire were evaluated using Rasch model analyses, encompassing tests of dimensionality, reliability, and item bias. This initial exploration serves as an important first step in understanding the complex factors that influence individuals’ intention to engage in philanthropy, and provides insights for further investigation in the larger doctoral research project.\n\n\nMethods\n\nIn the current preliminary study, we developed a questionnaire to measure individuals’ intention to engagement in philanthropic activities measure. The questionnaire contained 44 items and was developed using a five-point Likert scale. Those 44 items were developed using six constructs, including six items of Key Opinion Leader (KOL), eleven items of Word of Mouth (WoM), six items of Funding Philanthropic Brand Trust (FPBT), eight items of Philanthropic Intention (PI), five items of Philanthropic Brand Preference (PBP) and finally, eight items of Pride of Affiliation (PoA). The questionnaire was developed and administered to targeted samples. A total of 63 raw samples were recorded. Then, the collected data was converted into Excel format for analysis using WINSTEP to identify any outliers or invalid data. After the screening process, there were 45 responses remains to be analyzed, consisting 30 participants within range of 11-26 years old and 15 participants within range of 27-42 years old. Further Rasch modelling analysis were performed to the remaining data, including dimensionality analysis, reliability of the questionnaire, Wright map analysis, and potential item bias.\n\n\nFindings\n\nThe unidimensionality of the questionnaire was evaluated through the use of Rasch Principal Component Analysis (PCA) to scrutinize the overall scale as well as the distinct subscales. Unidimensionality refers to the extent to which items in the instrument measure a single construct (DiStefano & Jiang, 2020; Khine, 2020; Ningsih et al., 2021). Moreover, an examination of the raw variances revealed how each subscale aligned with unidimensionality criteria: the Global scale demonstrated 48.0%, the Key Opinion Leader (KOL) subscale 54.2%, Word of Mouth (WoM) 44.5%, Funding Philanthropic Brand Trust (FPBT) 60.8%, Philanthropic Intention (PI) 52.8%, Philanthropic Brand Preference (PBP) 57.2%, and Pride of Affiliation (PoA) 56.4%. The PCA analysis determined that the global scale and FPBT calculated eigenvalues of 4.6 and 2.7 logits respectively, surpassing the 2.0 logits threshold. These results suggest that the global scale could comprise multiple dimensions that extend beyond a single construct. Conversely, eigenvalues of 2.0 logits or less for the subscales suggested a reflection of unidimensionality within the subscale items.\n\nThe reliability analysis indicated that the global scale’s item separation reliability was recorded at 0.77 logit, which is below the accepted standard of 0.80. Similarly, KOL and WoM scales yielded reliabilities of 0.77 logit and 0.79 logit, respectively. These findings indicate that the reliablity of both scales shown at minimum levels. On the other hand, the FPBT scale displayed a reliability of 0.80 logit, which is considered acceptable, while the PI scale showed a reliability of 0.85 logit, classifying it as good. In contrast, the PBP and PoA scales scored lower with reliabilities of 0.57 logit and 0.35 logit, respectively, indicating that both were not reliable. Furthermore, the analysis revealed that the global scale had an item separation index of 1.85 logit, while the KOL and WoM scales were close, with indices of 1.81 logit and 1.92 logit, respectively. The FPBT scale had a separation index of 1.99 logit, and the PI scale outperformed with 2.35 logit. Although these indices suggest a differentiation into three levels of item difficulty for these scales, the PBP scale’s index at 1.15 logit implies the possibility of only two difficulty levels, and the PoA scale’s index of 0.73 logit indicates a single level of difficulty. Overall, the separation indices of the global scale and the various subscales did not surpass the 3 logit threshold, suggesting shortcomings in their ability to differentiate item difficulty effectively. These results highlight the need for further review and potential revision of these scales to enhance their reliability and discriminative capacity.\n\nWright Maps are utilized to assess the distribution of individuals’ proficiency levels and the difficulty levels of items on a common scale. Figure 1 illustrates the distribution of agreement levels for items and persons. The left side of the map illustrates the distribution of persons’ measured proficiency levels, while the right side shows the distribution of item difficulty levels, organized from the most agreed item to the most disagreed item. As suggested by Rusland et al., (2020), logit data falling within the range from the Mean (M) to one standard deviation below the mean (S) are considered to represent a moderate level of agreement. Data points above M indicate a higher level of agreement, whereas data below S are categorized as reflecting a lower level of agreement.\n\nM: Moderate Level; Mp: person mean; Sp: one standard deviation of person mean; Tp: two standard deviation of person mean; Mi: item mean; Si: one standard deviation of item; Ti: two standard deviation of item mean.\n\nFigure 1 illustrates that participants struggled with certain questions, such as Q17, Q31, Q42, and Q44, suggesting a reluctance to discuss social issues and online donations. This difficulty may point to a preference for adhering to cultural norms and valuing recognition and support from their community in donation decisions. However, the study found broad agreement on questions related to KoL, especially Q2 and Q4. Participants viewed KoL as compelling figures in the philanthropic sector and trusted their influence on donation behaviors. The survey also revealed strong affirmative responses to questions about the effectiveness of WoM, including the impact of personal discussions and stories about donations (Q12 and Q13) and the utility of donation information for social issues (Q9). Furthermore, agreement was evident on items tied to FPBT, demonstrating a belief in technology’s ability to facilitate donations (Q22) and trust in charities working for the public interest (Q18). Responses to PI items showed a strong endorsement of donating as an ethical obligation (Q28), a focus on the ethical credibility of organizations when giving (Q24), and alignment of donations with personal moral values (Q25). Such agreement highlights the importance of ethics in driving donation decisions. Finally, participants agreed on items associated with PBP and PoA, displaying a preference for well-regarded charities (Q33) and pride in affiliating with their chosen organizations (Q38). These attitudes reflect the importance of charity credibility and the personal satisfaction that motivates philanthropic actions for the good of society.\n\nThe analysis of Differential Item Functioning (DIF) using Rasch-Welch tests was conducted to assess the potential presence of item biases attributed to demographic variables (Huang et al., 2020; Lee et al., 2020; Ningsih et al., 2021; Zulaiha & Mulyono, 2020). DIF was determined when the DIF contrast value, representing the difference in item difficulty, exceeded 0.5 logits and was statistically significant (Rasch-Welch probability value < 0.05) (Chan & Subramaniam, 2020; Kreijns et al., 2020; Linacre, 2018; Mulyono et al., 2020; Suryoputro et al., 2023) Evaluation of DIF among participants’ demographic characteristics revealed that several items exhibited statistically significant DIF concerning participants’ age, gender, and educational background (see Table 1).\n\nThe DIF analysis revealed distinct age-based disparities; younger participants (aged 11 to 26) more readily acknowledged a “moral obligation to donate money” (Q26) and cultural influences on donations (Q31) compared to older respondents (27 to 42). Conversely, the latter group aligned more with statements involving tangible solutions in donation recommendations (Q11) and the need for communicative services by charities (Q17). Gender disparities emerged, with females showing higher agreement with cultural influences on donations (Q31) than males. Regarding the education background, high school graduates found cultural influences easier to agree with than master’s degree holders (Q31), while bachelor’s holders aligned more with the effectiveness of KOL items (Q1 and Q2). Master’s degree holders found it easier to support communicative charity services (Q17) and discuss support for charity campaigns (Q34) compared to bachelor’s degree holders.\n\n\nConclusions\n\nThe preliminary study aimed to assess the psychometric characteristics of a philanthropic activities engagement measure using Rasch modelling analysis. Various aspects of the questionnaire were explored, including dimensionality, item and person reliability, item bias, and their interrelations. Rasch Principal Component Analysis (PCA) suggested potential multidimensionality in the overall scale, while subscales met unidimensionality criteria. Reliability was acceptable for the overall scale and the Funding Philanthropic Brand Trust (FPBT) subscale, but inadequate for Philanthropic Brand Preference (PBP) and Pride of Affiliation (PoA) subscales, warranting further investigation. Some items (i.e. Q17, Q31, Q42, and Q44) posed challenges, indicating issues in discussing social matters, adhering to cultural norms in donations, valuing recognition, and seeking community support in philanthropy. Differential Item Functioning (DIF) analysis revealed demographic differences in response patterns concerning age, gender, and education. These findings offer valuable insights for refining the questionnaire in subsequent development cycles, albeit with acknowledgment of potential limitations due to the sample size. A follow-up study with addressed issues and larger sample coverage is thus recommended.\n\nA research evaluation panel from Doctor of Research in Management (DRM) Program BINUS Business School, Research ethics and publication center approved the current preliminary study on August 25th, 2023. The ethical approval was obtained from DRM Research Ethics committee with letter no 004/HoP.DRM/I/2024. The participants of the current study were selected on voluntary basis and written informed consent was collected prior to the study. The participants were anonymized and their identity had been removed from the dataset.",
"appendix": "Data availability statement\n\nZenodo: Dataset on the validation of individuals’ intention to engagement in philanthropic activities measure available at https://doi.org/10.5281/zenodo.10123085 (Ulza, 2023).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nBrammer S, Millington A: Corporate reputation and philanthropy: An empirical analysis. J. Bus. Ethics. 2005; 61(1): 29–44. Publisher Full Text\n\nChan M, Subramaniam R: Validation of a science concept inventory by Rasch analysis.Khine MS, editor. Rasch Measurement: Applications in Quantitative Educational Research. Singapore: Springer; 2020; Issue July: pp. 159–178. Publisher Full Text\n\nDiStefano C, Jiang N: Applying the Rasch rating scale method to questionnaire data.Khine MS, editor. Rasch Measurement: Applications in Quantitative Educational Research. Singapore: Springer; 2020; pp. 31–46. Publisher Full Text\n\nHuang F, Huang L, Oon PT: Constructs evaluation of student attitudes toward science-a rasch analysis. Rasch Measurement: Applications in Quantitative Educational Research. 2020. Publisher Full Text\n\nKhine MS: Rasch Measurement. Khine MS, editor. Singapore: Springer; 2020. Publisher Full Text\n\nKreijns K, Bijker M, Weidlich J: A Rasch analysis approach to the development and validation of a social presence measure.Khine MS, editor. Rasch Measurement: Applications in Quantitative Educational Research. Singapore: Springer; 2020; pp. 197–221. Publisher Full Text\n\nLee WL, Chinna K, Sumintono B: Psychometrics assessment of HeartQoL questionnaire: A Rasch analysis. Eur. J. Prev. Cardiol. 2020; 28(12): e1–e5. PubMed Abstract | Publisher Full Text\n\nLiao F: The effect of philanthropic activities on corporate financial performance: From the perspectives of charity donation and volunteer service. Mod. Econ. 2020; 11(1): 96–108. Publisher Full Text\n\nLinacre JM: A user’s guide to Winsteps Ministep Rasch-model computer programs (version 5.2.0). Institute for Objective Measurement; 2018.\n\nMulyono H, Saskia R, Arrummaiza VS, et al.: Psychometric assessment of an instrument evaluating the effects of affective variables on students’ WTC in face-to-face and digital environment. Cogent Psychol. 2020; 7(1): 1823617. Publisher Full Text\n\nNingsih SK, Mulyono H, Ar Rahmah R, et al.: A Rasch-based validation of Indonesian EFL teachers’ received online social support scale. Cogent Educ. 2021; 8(1): 1957529. Publisher Full Text\n\nRusland SL, Jaafar NI, Sumintono B: Evaluating knowledge creation processes in the Royal Malaysian Navy (RMN) fleet: Personnel conceptualization, participation and differences. Cogent Bus. Manag. 2020; 7(1): 1785106. Publisher Full Text\n\nSuryoputro G, Rahmanda A, Sulthonah FA, et al.: Measuring Indonesian EFL teachers’ digital creativity: Validation of Hoffmann‘s digital creativity scale. Int. J. Inf. Educ. Technol. 2023; 13(4): 763–771. Publisher Full Text\n\nUlza E: Dataset on the validation of individuals’ intention to engagement in philanthropic activities measure. Zenodo. [Dataset]. 2023. Publisher Full Text\n\nYang Y, Yao S, He H, et al.: On corporate philanthropy of private firms and trade credit financing in China. China Econ. Rev. 2019; 57: 101316. Publisher Full Text\n\nZulaiha S, Mulyono H: An Investigation into EFL teachers’ assessment literacy: Indonesian teachers’ perceptions and classroom practice. Eur. J. Contemp. Educ. 2020; 9(1): 189–201."
}
|
[
{
"id": "301354",
"date": "02 Aug 2024",
"name": "Lucia Gomez Teijeiro",
"expertise": [
"Reviewer Expertise philanthropy",
"artificial intelligence",
"finance",
"neuroscience",
"psychology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript “Psychometric characteristics of individuals’ intention to engage in philanthropic activities measure: An early development and tryout”, addresses a significant research question previously explored by scholars in the field of philanthropy (see suggested references). The methodology for constructing and evaluating the scale is well-described, indicating the promise of this work once developed to a final version. The authors position this report as an initial step and provide raw data, offering a valuable preprint resource for academics and practitioners in philanthropy and related fields. Nonetheless, substantial development is needed to convert this brief report into a sound academic contribution, particularly but not exclusively in terms of framing the contribution, increasing the sample size and diversity, and providing descriptive statistics for the sampling. A more detailed review is given below: Framing: This manuscript is not well contextualized within the research field or the question. The gap to be addressed is just suggested but not elaborated in the introduction. Unclear why to mention corporate philanthropy or its impact on trade credit financing or firm reputation. Are the authors discussing corporations or individuals? Inconsistency. Sampling and quality control on responses: Approach for sampling is not described. Rationale on target populations are not described. Descriptive statistics are needed to easily understand diversity representation. Missing information on country belonging of respondents or beliefs, known to be influencers on reasons to engage in philanthropy. Some missing values identified in raw data provided, likely discarded replies but this information is not provided. Which replies where selected and which where the specific QC criteria for each? Power analysis considering the multiple scales of the questionnaire: how many participants would ensure a robust analysis? Variable coding: age and monthly amount coding need improvement. Two very big group for age when it is know that this variable affects philanthropy engagement very nuancedly. Donated amount disregards the range between 100000 to 200000 rp. Reproducibility: methodological approach for analyzing the questionnaire results is described, but lacks details on implementation: versioning, software, packages, etc. As of now, reproducing this results is challenging. Proving the code used and versioning would be sufficient to ensure full reproducibility as data is provided. Results description: Table 1 would greatly benefit from descriptive statistics. As of now, difficult to assess whether this significance values are due to outliers or low sample size. Figure 1 does not report axis labels and the legend is insufficient to understand such a complex visual, that otherwise is very complete but for experts. Make clearer where the sd cutoffs are placed, groupings of left and right side of the plot, increase font size, detail what it means here the ordering of questions in x axis (as it is not a difficulty questionnaire). Conclusions drawn: The small sample size makes impossible to sustain any of the conclusions drawn. Problematic to understand what the authors convey as message for questions 17, 31, 42, and 44, as this questionnaire indicate motives and not performance. Rephrase “participants struggled” or “posed challenges” as this type of interpretation is not appropriate to this type of questionnaire.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Partly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-408
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https://f1000research.com/articles/13-407/v1
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26 Apr 24
|
{
"type": "Study Protocol",
"title": "Management of traumatic brain injury in India: A protocol for systematic review and meta-analysis",
"authors": [
"Gaurav Mittal",
"Roshan Prasad",
"Tangmi Djabo Eric Adrien",
"Roshan Prasad",
"Tangmi Djabo Eric Adrien"
],
"abstract": "Abstract*\n\nIntroduction This systematic review and meta-analysis protocol aims to evaluate the management of traumatic brain injury (TBI) in India, addressing a critical gap in the understanding and treatment of TBI in low- and middle-income countries (LMICs). Despite advancements in healthcare focusing primarily on communicable diseases, TBI remains a leading cause of death and disability worldwide, significantly affecting the quality of life of patients and their families. Recent interest has surged in platelet-rich plasma (PRP) as a novel treatment for TBI, necessitating a comprehensive review of its therapeutic benefits.\n\nMethodology The study will source articles from PubMed, EMBASE, SCOPUS, and the Cochrane Central Register of Controlled Trials, targeting a range of studies including randomized controlled trials (RCTs), observational studies, and cohort studies. The review will exclude case series, review articles, and studies not reported in English. The primary aim is to collate evidence-based data on TBI management, with particular focus on the Indian healthcare context, evaluating the efficacy of current treatments and the potential role of PRP in enhancing neurological function and recovery post-TBI. Data management will involve a rigorous selection process, with independent reviewers conducting initial screenings and resolving discrepancies through discussion or arbitration. A PRISMA flow diagram will illustrate the study selection procedure, and a standardized form will be used for data extraction, ensuring thoroughness and consistency.\n\nConclusion By highlighting current knowledge gaps, this systematic review and meta-analysis will guide future research directions and clinical practice, potentially revolutionizing TBI management strategies in LMICs. This protocol underscores the necessity for high-quality, evidence-based approaches to TBI treatment, aiming to improve patient outcomes through enhanced management practices.",
"keywords": [
"management",
"traumatic brain injury",
"india",
"systematic review",
"meta-analysis",
"protocol"
],
"content": "1. Introduction\n\nWhile LMICs (Low – middle income countries) have made significant improvements to their healthcare systems by concentrating on communicable diseases (CDs),1 Traumatic brain injury (TBI) is the leading cause of death and disability globally and a significant public health concern. Numerous physical, mental, and emotional impairments may result from it, which could significantly lower the quality of life for those who are affected as well as their families. Even with advances in TBI therapy, no recovery fully restores neurological function.2,3\n\nNo proven therapy completely restores neurological function, despite advancements in the management of traumatic brain injury. Recently, there has been a growing interest in platelet-rich plasma (PRP) as a potential treatment for traumatic brain injury. Platelet-rich plasma (PRP) is a blood product that contains a high concentration of platelets that are rich in growth factors and other bioactive molecules that can aid in tissue regeneration and repair. PRP has been used to reduce inflammation and speed up healing in a variety of clinical settings, and there is mounting evidence that it may also be beneficial for treating traumatic brain injury. PRP has the potential to treat traumatic brain injury (TBI), but in order to assess its efficacy and safety, a comprehensive analysis of the available data is required. A review of this kind would offer a thorough and trustworthy strength of evidence to reveal new information and direct future studies and clinical practices. This protocol describes how to carry out a thorough analysis of PRP’s therapeutic benefit in the treatment of traumatic brain injury.\n\nThe purpose of this study is to compile evidence-based data on TBI management in low- and middle-income nations like India. Building up the infrastructure that sup-ports the healthcare system is a crucial strategy for India’s healthcare system to be sustainable.4\n\nTraumatic brain injury (TBI) and its aftermath are thought to be a global health concern nowadays. They significantly affect patient function, quality of life, and social impact globally. Traumatic brain injury (TBI) can cause a variety of long-term problems, including headaches, erratic sleep patterns, psychosis, mood, behavioural, and anxiety disorders, and psychosis.5 In the coming years, there will likely be a rise in the incidence of traumatic brain injury (TBI) due to the increased use of motor vehicles, which is a major cause of traffic accidents and TBI development. There are projections that indicate both global population growth and density will contribute to this in-crease. As of 2018, an estimated 69 million people had suffered traumatic brain injury (TBI), with the majority of these cases occurring as a result of traffic accidents, which have a particularly serious effect in low- and middle-income countries (LMICs).6\n\nThe prevention of traumatic brain injury (TBI) has focused on treatment strategies that lessen the injury’s immediate to moderate-term effects in addition to surveillance systems and programs for the purpose of preventing TBI. These methods include pharmacological treatment with steroids, muscle relaxants, anticonvulsants, antidepressants, stimulants, anti-anxiety drugs, and more, as well as rehabilitation therapy.7 Treatment for traumatic brain injury (TBI) that enhances long-term functionality and quality of life by promoting neurological regeneration, restoration, and repair is more well-established than the modalities mentioned above. Novel approaches to treating a range of diseases, including traumatic brain injury (TBI), have been made possible by biotechnology breakthroughs such as platelet-rich plasma (PRP). Platelet-rich preparations, such as platelet-rich plasma (PRP), are essentially the platelet-rich fraction of blood obtained by centrifuging fresh blood. They have the potential to accelerate healing, stimulate bone and tissue regeneration, and improve bone density.8 Apart from the previously mentioned potential advantages, PRP is inexpensive, non-invasive, adaptable, has a simple preparation process, and has an excellent biosafety profile.\n\nApart from its ability to reduce inflammation, platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), transforming growth factor-N (TGF-β), endothelial growth factor (EGF), and vascular endothelial growth factor (VEGF) are among the growth factors that PRP can inhibit and stimulate locally. In addition to promoting vascularization and collagen synthesis, the growth factors mentioned above are also responsible for stimulating keratinocyte proliferation and attracting local fibroblasts and stem cells.9,10\n\nPrimary aim: To assess the management of TBI in India.\n\nSecondary aim:\n\n1. To review and summarize the existing literature on the management of TBI in India.\n\n2. To evaluate the efficacy of the management of patients with traumatic brain in-jury.\n\n3. To evaluate the neurological functional recovery post-TBI patient.\n\n4. To identify gaps in current knowledge and highlight areas for further research and investigation regarding the management of TBI in LMICs in India.\n\nProtocol\n\n\n2. Methods\n\nPatients with traumatic brain injury(ies), regardless of age or gender.\n\nFrom January 2024 to February 14, 2024.\n\nAll randomized controlled trials (RCTs), non-randomized con-trolled clinical trials, observational studies, case-control and prospective cohort studies describing the management of traumatic brain injury. Only articles reported in English will be included.\n\nCase series, case reports, abstract-only articles, letters to the editor, conference proceedings, review articles, articles with missing data in other languages, and those reporting animal studies will be excluded. Studies describing the management of traumatic brain injury and other disease conditions in animals will al-so be excluded.\n\nArticles for our study will be sourced from PubMed, EMBASE, SCOPUS, Web of Science, and Cochrane Central.\n\n2.5.1 Search strategy\n\n(“manage”[All Fields] OR “managed”[All Fields] OR “management s”[All Fields] OR “managements”[All Fields] OR “manager”[All Fields] OR “manager s”[All Fields] OR “managers”[All Fields] OR “manages”[All Fields] OR “managing”[All Fields] OR “managment”[All Fields] OR “organization and administration”[MeSH Terms] OR (“organization”[All Fields] AND “administration”[All Fields]) OR “organization and administration”[All Fields] OR “management”[All Fields] OR “disease manage-ment”[MeSH Terms] OR (“disease”[All Fields] AND “management”[All Fields]) OR “disease management”[All Fields]) AND (“brain injuries, traumatic”[MeSH Terms] OR (“brain”[All Fields] AND “injuries”[All Fields] AND “traumatic”[All Fields]) OR \"trau-matic brain injuries”[All Fields] OR (“traumatic”[All Fields] AND “brain”[All Fields] AND “injury”[All Fields]) OR “traumatic brain injury”[All Fields]) AND (“india”[MeSH Terms] OR “india”[All Fields] OR “india s”[All Fields] OR “indias”[All Fields]) AND (“systematic review”[Publication Type] OR “systematic reviews as topic”[MeSH Terms] OR “systematic review”[All Fields]) AND (“meta analysis”[Publication Type] OR “meta analysis as topic”[MeSH Terms] OR “meta analysis”[All Fields])\n\n2.5.2 Translations\n\nManagement: “manage”[All Fields] OR “managed”[All Fields] OR “management’s”[All Fields] OR “managements”[All Fields] OR “manager”[All Fields] OR “manager’s”[All Fields] OR “managers”[All Fields] OR “manages”[All Fields] OR “managing”[All Fields] OR “managment”[All Fields] OR “organization and administration”[MeSH Terms] OR (“organization”[All Fields] AND “administration”[All Fields]) OR “organization and administration”[All Fields] OR “management”[All Fields] OR “disease manage-ment”[MeSH Terms] OR (“disease”[All Fields] AND “management”[All Fields]) OR “disease management”[All Fields]\n\nTraumatic Brain Injury: “brain injuries, traumatic”[MeSH Terms] OR (“brain”[All Fields] AND “injuries”[All Fields] AND “traumatic”[All Fields]) OR “traumatic brain in-juries”[All Fields] OR (“traumatic”[All Fields] AND “brain”[All Fields] AND “injury”[All Fields]) OR “traumatic brain injury”[All Fields]\n\nIndia: “india”[MeSH Terms] OR “india”[All Fields] OR “india’s”[All Fields] OR “indias”[All Fields]\n\nSystematic Review: “systematic review”[Publication Type] OR “systematic reviews as topic”[MeSH Terms] OR “systematic review”[All Fields]\n\nMeta-analysis: “meta-analysis”[Publication Type] OR “meta-analysis as topic”[MeSH Terms] OR “meta-analysis”[All Fields]\n\nSearch results from PubMed on 11/02/2024 at 09:23:08 have been shown in Table 1.\n\n\n3. Data management\n\nTwo independent reviewers who are blinded will perform a preliminary screening of titles and abstracts after downloading and uploading the database literature search result to Rayyan (ref). This will help to avoid duplication of studies. Any disagreements that arise will be discussed and settled by the review team; if an agreement cannot be reached, an independent author will act as an arbitrator.\n\nThe selected papers will then go through a second round of full-text screening to ensure they meet our inclusion requirements, followed by a final screening to assess bi-as risk. Using a PRISMA flow diagram, this study selection procedure will be illustrated.\n\nThere will be two steps in the data extraction process. We will perform a preliminary pilot extraction. The process will entail the authors selecting ten (10) articles at random and extracting data from them according to the goals and study outcomes. The purpose of the pilot phase is to verify the consistency of the extraction process and identify any unclear or missing data. Once the pilot phase is over, a meeting of the authors will take place to decide on the right data to extract. The primary data extraction phase, which comes next, will involve a detailed review of the studies that satisfy the eligibility requirements in order to extract established data.\n\nThis section explains how the data for this systematic review and meta-analysis will be recorded and charted in order to guarantee openness and the reproducibility of the procedures involved.\n\nIn order to chart the data and find answers to our research questions and study objectives, the following procedures will be followed:\n\n3.3.1 Data extraction: A standardized extraction form will be used to extract the important data from each study that is part of the review. This data extraction will com-prise the following: the year of publication, the study design, the sample size, the severity of traumatic brain injury, the drug dosage (such as propranolol or platelet rich plasma, etc), the timing and duration, the outcome measures, and the main conclusions. At least two separate reviewers will handle the extraction process in order to guarantee accuracy and minimize bias.\n\n3.3.2 Data organization: Tabulated and standardized data format will be used to arrange the extracted data in order to facilitate comparison and analysis. We’ll use readily readable tables and graphs created by applications such as Microsoft Excel.\n\n3.3.3 Statistical analysis: The I2 statistic will be used to determine the homogeneity be-tween the studies. A fixed-effects model will be used in the meta-analysis if the results indicate a low level of heterogeneity (I2 <50%), and a random-effects model will be used in the case of high heterogeneity (I2 >50%).\n\n3.3.4 Assessment of heterogeneity: Using suitable statistical tests, such as the chi squared or I2 statistic, heterogeneity will be evaluated to make sure that variable results from various studies are taken into account when performing statistical analysis.\n\n3.3.5 Analysing and synthesizing the drug’s neuroprotective effects: Results from all of the studies on the neuroprotective effects of propranolol in the treatment of traumatic brain injury will be examined. Its effects on synaptic plasticity, neuronal regeneration, lowering neuronal damage, neuroinflammation, and oxidative stress are among these.\n\n3.3.6 Tabular and graphical representation: We will use clear tables and accurate graphical representations, such as forest plots, to present the collected data for the synthesized outcome measures. This procedure will make understanding the specific study results and the overall meta-analysis results easier.\n\n3.3.7 Quality assessment: Every study will undergo an independent evaluation to identify any potential sources of bias using the Cochrane risk-of-bias tool and overall study quality. We’ll assess the evidence’s quality using the GRADE method.\n\nWe will be able to fully comprehend the role of propranolol in treating traumatic brain injury (TBI), pinpoint knowledge gaps, and produce tangible evidence to direct clinical practice and future research by adhering to this strict and impartial system of data charting.\n\n\n4. Measurement of effect\n\nThis systematic review and meta-analysis will primarily focus on the neuroprotective effects of medications on patients who have suffered from traumatic brain injury (TBI) in terms of effect measurement. The main goals of the study will be to improve quality of life, motor function, and cognitive function. Reductions in oxidative stress, neuroinflammation, and neuronal injury will be the secondary outcome metrics.\n\nPatients with traumatic brain injury (TBI) will have the effects of propranolol assessed using validated clinical measures such as the Glasgow Outcome Scale (GOS), the Extrapyramidal Symptom Rating Scale (ESRS), and the Quality-of-Life Inventory (QOLIBRI). In addition, neuroimaging methods like magnetic resonance imaging (MRI), positron emission tomography (PET), and functional MRI will be employed to evaluate alterations in brain structure and function.\n\nWe will compare the efficacy of propranolol with other treatments for traumatic brain injury, such as corticosteroids and hyperbaric oxygen therapy. The evaluation of propranolol’s safety profile will also involve tracking adverse effects like weariness, light-headedness, and insomnia.\n\nInclude plans for dissemination of the study outcome (including the associated data) once completed.\n\nOnce this protocol is thoroughly peer reviewed by 2 peer reviewers the authors will start writing the review article keeping in mind the insights of the reviewers. Hence, the status of the article is the protocol\n\n\n5. Discussion and Conclusion\n\nThe outcomes assessed here include the frequency of complications, the death rate, cognitive function, functional recovery, and any other pertinent indicators of brain injury recovery. Primary outcome being mortality rate, the incidence of complications and cognitive function. Secondary outcomes being pain scores and mean length of hospital stay.\n\nUsing the Newcastle-Ottawa Scale (NOS), a method for estimating the risk of bias in observational studies, three authors will separately evaluate the quality of the studies. Research that receive a NOS score of 4 or higher will be deemed to have minimal bias risk and will be incorporated into reviews and meta-analyses.\n\nNumerous studies have looked into the management of traumatic brain injury (TBI) using platelet rich plasma, propranolol etc. Regarding propranolol, these studies have demonstrated that giving low-dose propranolol to TBI patients at an early stage can shorten their hospital stay and mortality rate. Propranolol improves cerebral per-fusion by lowering sympathetic discharge and catecholamine release associated with paroxysmal sympathetic hyperactivity. It does this by lowering tachycardia, hypertension, hyperthermia, cerebral oedema, metabolism, and hypoxia. Propranolol can cross the blood-brain barrier. More investigation is required to completely comprehend propranolol’s neuroprotective mechanisms in traumatic brain injury and to establish the best dosage and administration guidelines.\n\nTo reduce the possibility of bias in the event that there is a lot of heterogeneity, we will categorize the results and perform a pooled subgroup analysis.\n\nSince we are using previously published studies, no patients will be involved in this study.\n\nThe validity and applicability of the evidence that has been compiled from this review will be evaluated using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) algorithm.\n\nBecause it is a novel method of assessing the volume of literature on the topic, this systematic review of published articles on “management of traumatic brain injury in India\" will not need ethical approval because it is a secondary analysis. The Cochrane Handbook for systematic reviews and meta-analyses of diagnostic test accuracy guide-lines will be adhered to in this study.11 In order to protect human subjects and ensure responsible research practices, we have followed ethical principles and guidelines during the conduct of this study. First off, the data in this review originate from pub-lished, publicly accessible literature, suggesting that the authors of the original studies have already gotten informed consent. Our privacy policies protect patients’ and their families’ identity and we never gather personally identifiable information.12\n\nWe will follow PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines to ensure that our findings are comprehensible, thorough, and repeatable. In order to maintain scientific rigor, we make an effort to reduce bias and maintain transparency throughout the planning, gathering, analyzing, interpreting, and reporting of our review.13 In order to do this, we will adhere to a predetermined protocol that is listed in the International Prospective Register of Systematic Reviews (PROSPERO), which specifies the goals, qualifying requirements, search approach, synthesis techniques, and scheduled analyses.14 Publication of our review to enable clinicians, researchers, and policymakers to critically evaluate and apply the findings.15 Additionally, we offer an assessment of the risk of bias and a summary of findings table that employs GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) to aid readers in understanding the calibre and potency of the evidence.16\n\nAs part of the dissemination strategy, we plan to submit our study to a peer-reviewed journal in the field of neurology and neurosciences, providing open access to ensure a wider reach and impact of our findings. We also aim to present the results in conferences and meetings, targeting not only academics but also healthcare professionals, policymakers, and patient advocacy groups who can use our findings to in-form the improvement of paediatric traumatic brain injury care in LMICs.17\n\nUltimately, this section on Ethics and Dissemination highlights our dedication to carrying out a transparent and morally sound systematic review and meta-analysis that can support better clinical practices and policies to enhance patient outcomes and quality of life, as well as the evidence-based management of pediatric traumatic brain injury patients in LMICs.\n\nIt may be necessary to address certain significant limitations despite the meticulous procedures employed in this systematic review and meta-analysis. First and fore-most, there may be a bias in the publications that are published because studies with significant findings are more likely to be published than those with smaller findings.\n\nFurthermore, because we limited our search to English-language publications, we might have missed relevant research that was only available in other languages. Furthermore, there is a chance that some of the included studies in the systematic review were biased, which could affect our study’s results.\n\n\n6. Conclusion\n\nIn conclusion, the goal of this protocol for a systematic review and meta-analysis is to give a thorough understanding of how propranolol helps TBI patients by protecting their brains. By carefully analyzing the data, we hope to determine whether propranolol can help TBI patients recover better and to pinpoint any knowledge gaps.\n\n\nAuthor contributions\n\nConceptualization, Gaurav Mittal and Roshan Prasad; methodology, Tangmi Djabo Eric Adrien; software, Gaurav Mittal; validation, Roshan Prasad, Gaurav Mittal and Tangmi Djabo Eric Adrien; formal analysis, Tangmi Djabo Eric Adrien; data curation, Gaurav Mittal; writing—original draft preparation, Gaurav Mittal.; writing—review and editing, Roshan Prasad; visualization, Tangmi Djabo Eric Adrien; supervision, Tangmi Djabo Eric Adrien; project administration, Tangmi Djabo Eric Adrien. All authors have read and agreed to publish version of the manuscript and Tangmi Djabo Eric Adrien is identified as guarantor of the manuscript.”",
"appendix": "Data availability\n\nNo data is associated with this article.\n\nReporting guidelines\n\n‘PRISMA-P’ checklist for ‘Management of Traumatic Brain Injury in India: A Protocol for Systematic Review and Meta-analysis’. 10.5281/zenodo.10685436. 18\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReferences\n\nAdrien T, Mbougo J, Muili A, et al.: An E-survey study protocol for the perception of African healthcare professionals on the in-trathecal injection of antitetanic serum for the treatment of tetanus. J. Surg. Protoc. Res. Methodol. 2023; 2023. Publisher Full Text\n\nEmhemed MS, Murhega RB, Stanley AC, et al.: Evaluating the efficacy and safety of tumor treating fields versus laser interstitial thermal therapy in glioblastoma treatment: a comprehensive systematic review and meta-analysis. J. Surg. Protoc. Res. Methodol. 2023; 2023: snad015. Publisher Full Text\n\nEric D, Adrien T, Mustapha Jolayemi M, et al.: A systematic review of the therapeutic effect of platelet-rich plasma for treating traumatic brain injury: A Study Protocol. J. Surg. Protoc. Res. Methodol. 2023; 2023. Publisher Full Text\n\nMuili AO, Tangmi A, Shariff S, et al.: Exploring strategies for building a sustainable healthcare system in AFRICA: lessons from JAPAN and SWITZERLAND. Ann. Med. Surg. 86: 1563–1569. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStone JE, Fung TS, Machan M, et al.: Ultrasound-guided platelet-rich plasma injections for post-traumatic greater occipital neu-ralgia: study protocol for a pilot randomized controlled trial. Pilot Feasibility Stud. 2021; 7: 130. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHyder AA, Wunderlich CA, Puvanachandra P, et al.: The impact of traumatic brain injuries: A global perspective. NeuroReha-bilitation. 2007; 22: 341–353. PubMed Abstract | Publisher Full Text\n\nChen N-F, Sung C-S, Wen Z-H, et al.: Therapeutic Effect of Platelet-Rich Plasma in Rat Spinal Cord Injuries. Front. Neurosci. 2018; 12: 252. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLundin A, De Boussard C, Edman G, et al.: Symptoms and disability until 3 months after mild TBI. Brain Inj. 2006; 20: 799–806. PubMed Abstract | Publisher Full Text\n\nDucic I, Sinkin JC, Crutchfield KE: Interdisciplinary treatment of post-concussion and post-traumatic headaches: Post-Concussion and Post-Traumatic Headaches. Microsurgery. 2015; 35: 603–607. PubMed Abstract | Publisher Full Text\n\nGeorges A, Das MJ: Traumatic Brain Injury. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.\n\nHiggins JP, Green S: Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series.\n\nWorld Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects|Re-search, Methods, Statistics|JAMA|JAMA Network.\n\nStandards for design and measurement would make clinical research reproducible and usable|PNAS.\n\nPreferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation|The BMJ.\n\nPage MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuyatt GH, Oxman AD, Vist GE, et al.: Rating Quality of Evidence and Strength of Recommendations: GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336: 924–926. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrownson RC, Fielding JE, Green LW: Building capacity for evidence-based public health: Reconciling the pulls of practice and the push of research. Annu. Rev. Public Health. 2018; 39: 27–53. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMittal G: PRISMA-P Checklist for ‘Management of Traumatic Brain Injury in India: A Protocol for Systematic Review and Meta-analysis’. Zenodo. 2024. Publisher Full Text"
}
|
[
{
"id": "277712",
"date": "12 Jun 2024",
"name": "Jose Antonio Gonzalez",
"expertise": [
"Reviewer Expertise Statistics in clinical research",
"systematic reviews"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript under review introduces a protocol for a systematic review about management of TBI in India. Registered protocols for studies in general, or systematic reviews in particular, are essential for several reasons, which appear described in the PRISMA-P publication, already referenced in this manuscript, and I am more than satisfied that the authors include these important references among their bibliography. My first recommendation would be: please include with your paper a copy of the PRISMA-P checklist fulfilled. with indications about whether the topic was considered or not and, in case it was, the place in the text where it was addressed.\nObviously, if that task is useful to the authors to detect any point susceptible to improve, I strongly encourage them to strengthten them in order to follow the checklist as close as possible.\nI have found some sentences which are not clear to me. For instance, \"2.1 The population of study\" does not mention \"India\" especifically, neither \"2.3 Inclusion criteria\"; although the search strategy does include this word.\nMoreover, I wonder what is the purpose of Table 1 and the sentence that mentions it: \"Search results from PubMed on 11/02/2024 at 09:23:08 have been shown in Table 1\". Please clarify it.\nIn \"3.1 Study selection\", the reference in \"... uploading the database literature search result to Rayyan (ref)\" is missing.\n\"3.3\": I don't think that Charting the data is an appropriate name for this section. \"Charting\" is just a simple stage in data management. Consider PRISMA and PRISMA-P for inspiration.\n\"3.3.3 Statistical analysis\". This is, for me, one of the key items in your research, and it needs to be enhanced. First, the authors should mention which precise statistical software are planning to use. Second, I was surprised to read that \"A fixed-effects model will be used ...\" when I2 < 50%. This threshold is not just arbitrary, in my opinion it does not make sense. A value for such an indicator close to 50% reveals notable heterogeneity already, and a fixed-effects model would be a wrong decision, clearly. I would advise the authors not to employ fixed-effects models (as homogeneity is not expected in such an investigation), it could be fully justified only with I2 equal to 0 or very close to it. Third: I think that the authors should specify in this protocol which group analysis will be performed, and I would recommend at least one, separating RCT studies from observational ones.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "295523",
"date": "12 Jul 2024",
"name": "Franco Servadei",
"expertise": [
"Reviewer Expertise Traumatic brain Injury"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting paper about a systematic review of management of traumatic Brain Injury in a large LMIC (India) I do not consider the methodology of the research already well discussed by the first reviewer (Jose Antonio Gonzalez) The problem is the clinical relevance of the study and its implication. In the abstract, it is stated “The primary aim is to collate evidence-based data on TBI management, with particular focus on the Indian healthcare context, evaluating the efficacy of current treatments and the potential role of PRP in enhancing neurological function and recovery post-TBI.” It seems that the interest of the study is only focus is seeing a possible efficacy of the “treatments” (which? Surgical? medical? In the acute phase? In the late recovery phase?) and of the PRP (potential, not much is reported until now) In the discussion “The outcomes assessed here include the frequency of complications, the death rate, cognitive function, functional recovery, and any other pertinent indicators of brain injury recovery. Primary outcome being mortality rate, the incidence of complications and cognitive function. Secondary outcomes being pain scores and mean length of hospital stay” It is difficult in any country to extract from published outcomes of TBI data which are not mortality and Glasgow Outcome score. More to have data on complications (which???) and cognitive performances you will probably need a prospective study. In the conclusion section:” in conclusion, the goal of this protocol for a systematic review and meta-analysis is to give a thorough understanding of how propranolol helps TBI patients by protecting their brains.” There is the sudden appearance of the propranolol as a goal of the study\nAs far as the clinical part of the study is concerned, I invite the authors to better target the study: may be initially a study with a systematic review of epidemiology, incidence and outcomes (whenever possible) of TBI in India will be enough ….\n\nIs the rationale for, and objectives of, the study clearly described? No\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
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https://f1000research.com/articles/13-407
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