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Preparation of capsules. | STERILE, SEPARATION | Fresh stool was collected from donors in a sterile plastic container. The dry weight of the stool needed to be more than 100 g. Fresh fecal samples (25%) were mixed with saline (60%) and pharmaceutical-grade glycerol (15%) in a semiautomatic extraction instrument (Treatgut TG-01; Anjiezhishan Company, China). The instrument was launched to start the process of gradual separation. After the extraction process was performed using sterile tubes, the supernatant was collected and centrifuged to obtain the precipitate containing fecal microbiota. The precipitate was mixed thoroughly, and the capsules (DrCaps; 19504907) were filled. Each capsule contained an average of 0.9 g of precipitate of fecal microbiota and was immediately frozen at −80°C. | PMC10269780 | |
Interventions. | ADVERSE EFFECTS | We obtained informed consent from patients prior to their inclusion in this study. Authorized physicians administered FMT under monitored clinical settings. Before taking capsules orally, patients were required to fast overnight for at least 8 h. All patients received FMT in the morning. Capsules stored at −80°C were returned to room temperature before they were administered orally. Patients took the capsules with warm saline. Patients were kept under observation for 6 h after receiving FMT in the hospital to determine any adverse effects. Capsulized FMT was administered in three separate procedures (30 capsules every 2 days) within 1 week, and follow-up was performed for up to 12 weeks. The total weight of stool administered over the three FMT procedures was about 90 g. Stool samples of patients were collected for microbiome analysis at weeks 0, 1, 4, and 12, and blood samples of patients were collected for laboratory examination and metabolomic analysis. A colonoscopy assessment was conducted at the baseline (week 0, before FMT) and week 12. The time points for weekly assessment were W0 (baseline, week 0), W1 (week 1), W4 (week 4), and W12 (week 12). | PMC10269780 | |
Medication during enrollment. | UC | UC maintenance therapy was provided to patients during FMT. Because patients had a poor response to mesalazine, SASP, or prednisone, stable doses of drugs were used during follow-up after FMT. A subject treated with 5-ASA or SASP continued to receive the same dose of drugs administered during the study. A subject who was treated with prednisone would continue to receive it after a mandatory tapering of the dose: prednisone at >10 mg/day had a mandatory taper of 5 mg per week until the administration of 10 mg/day, and prednisone at ≤10 mg/day had a mandatory taper of 2.5 mg per week. | PMC10269780 | |
Outcomes. | Clinical response at week 12 was defined as a reduction of ≥3 points in the total Mayo score and a decrease of ≥30% from the baseline score ( | PMC10269780 | ||
The 16S rRNA gene in fecal microbiota and shotgun metagenomic sequencing. | Fresh fecal samples were collected and frozen at −80°C until DNA extraction. According to the manufacturer's protocol, total fecal DNA was extracted from 0.25 g of each homogenized sample using the QIAamp PowerFecal DNA kit (Qiagen). The DNA yield and quality were then checked with a Multiskan GO spectrophotometer (Thermo Fisher Scientific, USA). To identify bacterial communities, 16S rRNA gene V3-V4 amplicon libraries were generated in a 20-μL reaction mixture containing 10 μL KAPA HiFi HotStart ReadyMix (KAPA Biosystems, USA), 2 μL DNA (60 ng), and 1 μL of each of the barcoded primers (10 μM). The forward and reverse primers used were 5′- | PMC10269780 | ||
Microbial bioinformatic analyses. | Raw V3-V4 sequencing reads were assembled to generate high-quality reads using FLASH ( | PMC10269780 | ||
Serum sample collection and metabolomics. | Serum samples were collected and immediately frozen at −80°C until metabolite extraction. Total metabolite content was extracted from 0.05 g of each of the serum samples, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses, performed using the ultrahigh-performance liquid chromatography (UHPLC) system (1290, Agilent Technologies) with an ultraperformance (UPLC) HSS T3 column (2.1 mm by 100 mm, 1.8 μm) coupled to the Q Exactive system (Orbitrap MS; Thermo). MS raw data were filtered if the following criteria were met: (i) metabolites present in less than 50% of all samples in a group were removed, and (ii) missing values were replaced by half of the minimum values found by default in the data set. Peaks were annotated against an in-house MS/MS database constructed using HMDB, Metlin, and Mona. Finally, the relative content of each peak was determined by the normalization method of peak area to generate percentage value for each metabolite. | PMC10269780 | ||
Statistical analyses and visualization. | Microbial α-diversity indexes, including richness (Observed and Chao1), Shannon diversity (Shannon), and Pielou's evenness (Evenness), were computed using the vegan package ( | PMC10269780 | ||
Data availability. | The accession numbers of raw sequences have been deposited in the NCBI Sequence Read Archive under BioProject accession no. | PMC10269780 | ||
REFERENCES | PMC10269780 | |||
Keywords | PMC10570927 | |||
Introduction | Young women in sub-Saharan Africa are at a high risk of unintended pregnancies [ | PMC10570927 | ||
Methods | PMC10570927 | |||
Study design | Within the ECHO trial ( | PMC10570927 | ||
STI and BV testing | Women were tested for | PMC10570927 | ||
RNA-Seq library preparation and quality control analysis of data | Cervical cytobrush samples collected at baseline and at one-month follow-up visit from 188 matched participants ( | PMC10570927 | ||
Differential expression analysis | A paired differential expression analysis, i.e. post-vs-pre (one-month vs. baseline) comparison, was carried out for each study arm. For the paired analyses, only protein-coding probe-target genes were retained: hg19 probe coordinates from the Illumina RNA Exome kit were cross-mapped to hg38 genome assembly using cross-map, an assembly converter tool. Genes which are classified as ‘protein-coding’ by the gene biotype field in the hg38 GTF file and for which the exon coordinates showed an overlap of at least one base with any of the probe coordinates, were included in the set of protein-coding probe-target genes (19,543 genes). The overlap across the exon coordinates and probe coordinates was computed using the ‘closest’ tool from bedtools. DESeq2 (version 1.22.1) in Bioconductor/R platform was used to perform the differential expression analysis within the study arms, with a single-factor experimental design formula, design = ∼assigned_contraceptive [ | PMC10570927 | ||
Defining Lactobacillus-dominant versus Lactobacillus-depleted vaginal microbiota at baseline in DMPA-IM study arm | To investigate if the cervicovaginal transcriptomic changes observed in women using DMPA-IM were associated with a | PMC10570927 | ||
Deconvolution of immune cell types using RNA-seq data of women assigned to cu-IUD | The normalized gene counts of samples in Cu-IUD study arm ( | PMC10570927 | ||
Cell culture and luminex | REGRESSION | Human Endocervical Epithelial cells (END1/E6E7) were purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA) and cultured in keratinocyte serum-free medium (KSFM; Gibco Life Technologies, Grand Island, NY, USA) with 0.1 ng/ml human epidermal growth factor, 0.05 mg/ml bovine pituitary extract, 0.4 mM CaClSupernatants were assessed for the concentrations of IL-1b, IL-6, IP-10 and VEGF via a BioRad Bioplex Pro custom kit as per the manufacturer's protocol. All data were acquired on a Luminex 200 instrument and analyzed within the BioPlex Manager Software, where a 5 Parameter Logistic regression formula was used to interpolate unknown cytokine concentrations from standard curves. Student's | PMC10570927 | |
Statistical analysis | All downstream statistical analyses were performed in RStudio. Differences in study population characteristics according to study arm were tested using Pearson's Chi-squared test or Fisher's exact test (when the expected value was <5) for count data and unpaired Student's | PMC10570927 | ||
Results | PMC10570927 | |||
Cohort characteristics | For this nested mucosal sub-study of the ECHO trial, we included a total of 188 women with matched endocervical cytobrush samples obtained prior to, and one month after contraceptive initiation (DMPA-IM, Demographics and metadata of ECHO subjects recruited to substudy of mucosal transcriptomics.BMI; body mass index, KEMRI; Kenya Medical Research Institute (Kisumu; Kenya), sd, standard deviation, Wits RHI; (Johannesburg; South Africa). *Median and interquartile range. A retrospective power analysis of each study arm helped to demonstrate that for majority of transcripts detected at a reasonable level above background (>10 reads counts), at | PMC10570927 | ||
Cu-IUD, LNG implant and DMPA-IM initiation induce distinct patterns of endocervical gene-expression | To assess the impact of initiation of contraception on the endocervical transcriptome, we identified DEGs induced after one month of contraception usage relative to baseline within each study arm in a longitudinal intention-to-treat (ITT) analysis (Supplementary Table 2). A total of 151 DEGs were induced by DMPA-IM (60 upregulated, 91 downregulated), 82 by LNG-implant (69 upregulated, 13 downregulated) and 907 DEGs by Cu-IUD initiation (542 upregulated, 365 downregulated) (DMPA-IM, LNG implant and Cu-IUD initiation induce distinct patterns of endocervical gene-expression. The results of the statistical analyses on differential expression of post-vs-pre comparisons, i.e. DMPA-IM vs. baseline, LNG implant vs. baseline, and Cu-IUD vs. baseline, have been shown by the different panels (DMPA-IM: | PMC10570927 | ||
DMPA-IM initiation induced an enrichment of T cell gene signatures in the FGT | RECRUITMENT | The use of DMPA-IM has been reported to induce a diverse array of biological effects in the FGT. A closer examination of the 151 DEGs identified in DMPA-IM arm (Supplementary Table 2) showed significant alterations in a handful of genes that function in T cell activation (PRF1, TNFSF18, MAF) and tissue recruitment of immune cells (CXCL5, VCAM1). As a more sensitive approach to identify enriched gene pathways associated with contraceptive initiation, we performed Gene Set Enrichment Analysis (GSEA) using various well-defined gene-set/pathway collection databases from the Molecular Signatures Database (MSigDB) (DMPA-IM initiation induced an enrichment of T cell gene signatures in the cervicovaginal tract (nominal | PMC10570927 | |
DMPA-IM induced transcriptomic alterations are not strongly driven by microbial composition | We performed a sub-analysis to investigate whether the transcriptomic changes observed within the DMPA-IM arm were specific to the vaginal microbiota of participating women, i.e. | PMC10570927 | ||
Growth factor signaling and epithelial barrier pathways enriched in women assigned to LNG implant | PROLIFERATION, ADHESION | Within the LNG implant arm, several pathways associated with cell proliferation and growth including growth factor signaling by epidermal growth factor (EGF) and transforming growth factor (TGF)-β, Notch signaling, and WNT signaling, as well as cell-cell adhesion pathways were positively enriched, whereas pathways associated with cell cycle control and DNA repair were downregulated (Growth factor signaling and epithelial barrier pathways enriched in women assigned to LNG implant | PMC10570927 | |
Cu-IUD usage causes significant perturbations to the cervicovaginal transcriptome | Cu-IUD treatment, with 907 DEGs identified, had a dramatic impact on gene expression (Immune activation pathways enriched in women assigned to Cu-IUD (nominal p-value < 0.1). Important pathways enriched in Cu-IUD study arm, were selected. (A) A dot plot to represent the gene set enrichment analysis (GSEA) statistics for these pathways, across the longitudinal comparisons in the three study arms. The statistical significance of the enrichment (1-ln (nominal p-value)) is shown by the size of the dots and the normalized enrichment score (NES) is represented by a blue-to-red color-gradient, blue for negative scores and red for positive scores. (B-G) Breakout enrichment line plots and leading-edge gene heatmaps for a few of these enriched pathways. (B,D,F) In the line plots, the running enrichment score (y-axis) is indicated for each gene ordered by their rank in the whole data set for that specific comparison, shown by the vertical bars below the x-axis. (C,E,G) Heatmaps for the leading-edge genes of the indicated pathways. The gene-expressions are log-transformed, further normalized by mean of baseline samples in the Cu-IUD. The color gradient goes from blue to red color in representing the lowest to the highest gene-expression across all samples in the comparison. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)Metallothioneins and Chemokines pathways' enriched in women assigned to Cu-IUD (nominal p-value < 0.1). (A-D) Breakout enrichment line plots and leading-edge gene heatmaps for the pathways shown in the fig. (A,C) In the line plots, the running enrichment score (y-axis) is indicated for each gene ordered by their rank in the whole data set for that specific comparison, shown by the vertical bars below the x-axis. (B,D) Heatmaps for the leading-edge genes of the indicated pathways. The gene-expressions are log-transformed, further normalized by mean of baseline samples in the Cu-IUD. The color gradient goes from blue to red color in representing the lowest to the highest gene-expression across all samples in the comparison. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)We also observed highly significant enrichment of gene sets comprising ISGs and innate immune signaling (Lastly, we observed widespread induction of genes in the metallothionein (MT) family in mucosal samples post Cu-IUD initiation, including eight isoforms of MT1 genes (MT1A, MT1B, MT1H, MT1M, MT1G, MT1X, MT1E, MT1F). MT1A and MT1B had the highest fold-change of all DEGs detected, at >1000-fold and 60-fold, respectively. MT2A was also significantly elevated. Similarly, genesets including metallothionein and metal stress responses were determined to be significantly enriched ( | PMC10570927 | ||
Cu-IUD initiation recruits innate immune cells into the endocervix | Cu-IUD initiation | Since Cu-IUD initiation resulted in the highest significant changes in the FGT gene expression as compared to LNG implant and DMPA-IM, its influence on the immune cell populations was further investigated using digital flow cytometry methods (Cu-IUD initiation induces significant changes in the elements of innate immunity in endocervical tissue. (A) Workflow of in silico flow cytometry on RNA-seq data of women assigned to Cu-IUD. (B) Relative abundance of immune cell types in baseline and one month Cu-IUD samples using CIBERSORTx algorithm. (C) Hierarchical followed by k-means clustering of Cu-IUD samples according to the top significantly differentially abundant immune cell types. (D—F) The violin plots show the proportion of activated dendritic cells in samples collected at baseline and at one month, computed based on xCell and CIBERSORTx deconvolution algorithms. The two proportions were compared using Wilcoxon–Mann–Whitney test. ** and *** represents q-values ≤0.01 and 0.001, respectively. | PMC10570927 | |
Copper ions do not exert inflammatory effects on endocervical epithelial cells | EVENTS | To test if the inflammatory events observed after Cu-IUD initiation in vivo were due to a direct effect of CuThe concentrations of multiple endocervical cytokines are altered by biologically relevant copper (Cu | PMC10570927 | |
Discussion | inflammation | STIS, INFLAMMATION, PROLIFERATION, INFILTRATING | Although, sub-Saharan African women are at high risk for both STIs, including HIV, and unintended pregnancies, the impact of commonly used NBC methods on the mucosal immune environment has not been studied in detail using randomized designs. In this study, we examined the effects of three common and highly effective NBCs on endocervical gene expression of Kenyan and South African women enrolled into the ECHO trial, using high throughput transcriptomics.We found that women assigned to Cu-IUD had dramatic endocervical transcriptional perturbations compared to women assigned to DMPA-IM and LNG implant and that these transcriptomic changes were associated with enrichment of immune activation pathways including inflammation and anti-viral responses. Accordingly, using data from the same ECHO cohort, we have previously reported that Cu-IUD induced significant increases in cytokine concentrations six months post-insertion compared to baseline [One of the more striking findings within the Cu-IUD arm, in addition to upregulation of inflammatory and interferon-related pathways, was the significantly upregulated MT genes,. The MT1 gene family has ten known functional genes [In this study, we found that DMPA-IM initiation was associated with an enrichment of gene pathways associated with T cell responses, consistent with an enrichment of infiltrating T cells into the cervicovaginal environment. Some observational studies have associated DMPA-IM with elevated levels of cervical immune cells, including CD4+ T-cells, and increased expression of the HIV co-receptor CCR5 on these cells [In our analysis of DMPA-treated women, we also considered if the vaginal microbiome was influencing the local transcriptome based on Published data on the influence of LNG implants on the FGT transcriptome is sparse. In this study, we found limited endocervical transcriptomic alterations in women randomized to the LNG implant arm. We did however observe an enrichment of pathways associated with cell proliferation and growth and a decrease in expression of pathways associated with cell cycle control and DNA repair. These transcriptomic changes differed from those observed in the women using DMPA-IM despite both contraceptives being progestin based, highlighting the differential impact of progestins with different pharmacokinetic and pharmacodynamic properties on the FGT milieu as have been shown in vitro [ | PMC10570927 |
Conclusions | These results illustrate the variable influence of different contraceptives on the FGT host environment with Cu-IUD insertion resulting in the highest perturbation of the endocervical transcriptome, mainly related to immune responses, as compared to DMPA-IM and LNG implant initiation. DMPA-IM use led to an enrichment of pathways associated with T cell responses and a reduction of pathways associated with growth and metabolism while LNG implant initiation was associated with enrichment of growth factor signaling.The following are the supplementary data related to this article. | PMC10570927 | ||
Table S1 | DESeq results for Chlamydia-based analysis | PMC10570927 | ||
Table S2 | DESeq results for paired-analysis (post-vs-pre) for each study-arm in a longitudinal intention-to-treat (ITT) analysis. | PMC10570927 | ||
Table S3 | Custom in-house gene-sets used for GSEA. | PMC10570927 | ||
Table S4 | DESeq results for Lacto-dominance(LD)/non lacto-dominance (nonLD) at baseline, paired-analysis | PMC10570927 | ||
Table S5 | DESeq results for Lacto-dominance(LD)/non lacto-dominance (nonLD) at baseline, paired-analysis | PMC10570927 | ||
Table S6 | MOS | Differentially expressed pathways in the DMPA-IM group, pre-treatment vs 1 mos post-treatment, separated by women with Lactobacillus-dominated vaginal microbiome (LD), Lactobacillus-depleted vaginal microbiota (non-LD) or both groups analyzed together (LD + nonLD). | PMC10570927 | |
Table S7 | Influence of Cu-IUD initiation on the population of vaginal immune cells | PMC10570927 | ||
Supplementary material | TD | Supplementary Figure 1: A schematic representation of the RNA-Seq workflow. (A) The flowchart of RNA-Seq analysis outlines the experimental and data analysis steps carried out in the study. (B) The number of samples at collection timepoints and after quality-based filtering in each study arm.Supplementary Figure 2: Quality assessment of the RNA-seq data. (A-K) Plots to identify selection thresholds for quality-based filtering of samples. The distributions of (A-C) mapping of reads, (D) the number of reads uniquely mapped to the host, (E) the median coefficient of variation (CV) of gene coverage, (F-H) RNA integrity number (RIN) scores and (I-K) relative log expression plot of normalized counts help to identify samples that are outliers with metrics lying in the extreme value ranges. The final selection thresholds were as follows: number of reads uniquely mapped to the host >5M, median coefficient of variation (CV) coverage Supplementary Figure 3: Retrospective power analysis for each study arm. (A,C,E) Line plots for power vs. average normalized gene counts for DMPA-IM, LNG Implant and Cu-IUD. The stratified power is represented by each line for a certain sample size, stratified by the average counts of genes. Sample sizes varying from 5-50 are represented in different colors as shown in the legend in panel A. For a sample size greater than 40, the power is between 0.6 and 0.8 for genes with low counts (between 0 and 10) but improves significantly for genes with counts higher than 10 reads. (B,D,F) Marginal power-related results have been shown for each pair of sample sizes (SS1 and SS2), including marginal power, true discovery (TD), false discovery (FD), and false discovery cost (FDC, defined as the number of FD divided by the number of TD).Supplementary Figure 4: Principal component analysis (PCA) on paired-data from each study arm. PCA plots shown for each study arm, (A) DMPA-IM, (B) LNG Implant and (C) Cu-IUD. In each of the three plots, circles represent baseline samples and solid triangles represent month 1 samples.Supplementary Figure 5: Pathways enriched in at least one of the three study arms (DMPA-IM, LNG Implant and Cu-IUD) after 1 month of randomized contraceptive in post-vs-pre comparisons (nominal p-value <0.1). Dot plots to represent the statistical significance (nominal p-values) and normalized enrichment scores (NES) in gene set enrichment analysis (GSEA), for several MSigDB pathway collections have been shown. The statistical significance of the enriched pathways is shown by the size of the dots (1-ln (nominal p-value)), the larger the dot, the higher is the statistical significance. The normalized enrichment score (NES) is represented by a blue-to-red color-gradient, blue for negative scores and red for positive scores. The pathways are ordered by the nominal p-value of DMPA-IM vs. baseline contrast, with the most statistically significant pathway shown at the top.Supplementary Figure 6: Analysis on DMPA-IM subsets of participants with | PMC10570927 | |
Funding | This work and the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Study were made possible by the combined generous support of the Bill & Melinda Gates Foundation (Grant OPP1032115), the American people through the United States Agency for International Development (Grant AID-OAA-A-15–00045), the Swedish International Development Cooperation Agency (Grant 2017/762965–0), the South Africa Medical Research Council, and the United Nations Population Fund. Contraceptive supplies were donated by the Government of South Africa and US Agency for International Development. Funding to support this ancillary study of biological mechanisms was from the US National Institute of Child Health and Human Development R01 HD089831 to RH and HBJ. CB was supported by bursary funds from the | PMC10570927 | ||
References | PMC10570927 | |||
Data availability | Transcriptomic data is available in the Gene Expression Omnibus (GEO) repository under accession number GSE190923. Custom R scripts and supporting documentation on the RNA-Seq analyses are available at | PMC10570927 | ||
Background | Sexting refers to the exchange of sexually explicit digital content in the form of texts, photos, or videos. In recent years, sexting has become a public health concern. Surveys in Malaysia show a high prevalence of young adults engaged in sexting. Given that sexting is associated with sexual risk behavior, cyberbullying, and mental health issues, this behavior needs intervention to alleviate the resulting public health burden. However, there is a scarcity of theory-based intervention programs on the prevention of intention and willingness to sext among young adults. | PMC10625075 | ||
Objective | SECONDARY | This study aimed to develop and implement a sexting intervention module guided by the prototype willingness model (PWM), delivered using web-based animated video, and evaluate its effectiveness among diploma students from a public higher educational institution. The primary outcomes were intention and willingness to sext, while the secondary outcomes were knowledge, attitude, perceived norms, and prototype perceptions of sexting. | PMC10625075 | |
Methods | This 2-armed, parallel, single-blinded cluster randomized controlled trial was conducted in a public higher educational institution in the state of Melaka, Malaysia. Diploma students from 12 programs were randomly allocated into intervention and control groups. Both groups answered a self-administered web-based questionnaire assessing the outcomes at the baseline. The intervention group received a newly developed intervention module based on the PWM in the form of 5 animated videos posted on a private YouTube platform, while the control group was put on the waitlist. The intervention group was encouraged to discuss any issues raised with the researchers via WhatsApp private chat after viewing the videos. All participants were observed immediately and 3 months postintervention. Data analysis was performed with SPSS (version 26; IBM Corp). A generalized linear mixed model was used to determine the effectiveness of the intervention. | PMC10625075 | ||
Results | There were a total of 300 participants with an attrition rate of 8.3% (n=25). After adjusting for age, sex, relationship status, and the amount of time spent on the web, there were significant differences in the intention to sext (β=–.12; | PMC10625075 | ||
Conclusions | In this study, the sexting intervention module using the PWM that was delivered via web-based animated videos was effective in reducing intention and willingness to sext as well as in improving knowledge of sexting, attitudes, perceived norms, and prototype perceptions. Therefore, relevant agencies involved in the promotion of sexual and reproductive health among young adults in Malaysia can consider the implementation of this module. | PMC10625075 | ||
Trial Registration | Thai Clinical Trial Registry TCTR20201010002; https://www.thaiclinicaltrials.org/show/TCTR20201002001 | PMC10625075 | ||
Introduction | PMC10625075 | |||
Background | Sexting refers to the exchange of sexually explicit digital content in the form of texts, photos, or videos [In recent years, sexting has emerged as a major public health concern in Malaysia. According to the literature, the prevalence of sexting among Malaysian youths was higher than in Western nations [Moreover, sexting has been significantly associated with sexual risk behavior, cyberbullying, and mental health problems [ | PMC10625075 | ||
Prior Work | To date, several observational studies have asserted that the behavior of sexting is preceded by an intention and willingness to sext [In this digital age, animated videos are widely acknowledged as an effective teaching tool, especially for students in higher educational institutions (HEIs) [ | PMC10625075 | ||
Objective | This study aimed to develop, implement, and evaluate the effects of the newly developed sexting intervention module (SIM) delivered via web-based animated videos on the intention and willingness to sext among diploma students. We hypothesized that the intervention would reduce the intention and willingness to sext among diploma students. Moreover, it would improve the knowledge, attitude, perceived norms, and prototype perceptions of sexting among participants. | PMC10625075 | ||
Methods | PMC10625075 | |||
Study Design | This study was a 2-armed, parallel, single-blinded, cluster randomized controlled field trial. The available program on the main campus was chosen as a cluster unit with the assumption that students from a specific program only interact with those within the same program as they only engaged in web-based learning at home and other curricular activities were restricted during the COVID-19 pandemic. The intervention arm received SIM, whereas the control arm received a standard information program provided by the HEI and was put on the waitlist. | PMC10625075 | ||
Setting and Recruitment | HIV infections | HIV INFECTIONS | This study was conducted in one of the public HEIs in Melaka state, Malaysia. Melaka state was selected as the study site as it is one of the cities in the Association of Southeast Asian Nations that has committed to achieving 0 new HIV infections by 2030 [The study was conducted on the main campus of the largest HEI in Melaka, which is situated in the Alor Gajah District. The campus offered 13 diploma programs and a bachelor’s program. The inclusion criteria were diploma students, aged 18 to 24 years, unmarried, full-time students, and Malaysian citizens. Students who were on medical leave or deferment and students without access to the internet were excluded. | PMC10625075 |
Randomization and Allocation Concealment | The 12 programs on the main campus were randomly allocated into intervention and control groups at a ratio of 1:1. All programs were number-coded, and subsequently, a simple randomization process was conducted using Random.Org software (Random.Org LLC) [ | PMC10625075 | ||
Sample Size Calculation | The sample size was calculated to detect a mean difference of 0.44 (SD 2.19) in an intention toward sexting between the intervention and control groups based on the closest variable to this study [ | PMC10625075 | ||
Intervention Module | The newly developed intervention module, SIM, used 3 constructs of PWM, including attitude, perceived norms, and prototype perceptions. It was developed in Malay, which is the local native language. The module consisted of information regarding the definition of sexting, the negative impact of sexting, the prevalence of sexting, people’s opinions about sexting, and information regarding the negative characters of a sexter (person who sexts). In addition, behavior change techniques were also incorporated in the module, including the use of prompts to identify risky situations and barriers as well as the provision of specific instruction to prevent sexting, to enhance the effectiveness of the intervention [ | PMC10625075 | ||
Outcomes | PMC10625075 | |||
Overview | SECONDARY | A validated self-administered questionnaire was used to measure the sociodemographic characteristics and the outcomes of this study. The questionnaire was divided into 2 sections. The first section captured the respondent’s age, sex, relationship status, and the amount of time spent on the web. The questions in the second section measured the primary and secondary outcomes. The primary outcomes were intention and willingness to sext, while secondary outcomes included knowledge, attitude, perceived norms, and prototype perceptions. | PMC10625075 | |
Primary Outcome Measures | The intention to sext was measured using a 15-item questionnaire with a 6-point Likert scale adapted from a previous study [ | PMC10625075 | ||
Secondary Outcome Measures | An 8-item questionnaire was used to measure the knowledge of sexting with multiple-choice responses: “yes,” no,” or “I don’t know” [ | PMC10625075 | ||
Data Collection | MAY | Data were collected at 3 different time points, namely, baseline, immediate postintervention, and 3 months postintervention starting from December 2021 to May 2022. Due to the COVID-19 pandemic, data collection was performed via a web-based Google form. The link was sent to all the participants, and they were given 1 week to submit their responses. Reminders were sent to participants who had yet to submit their responses. | PMC10625075 | |
Data Analysis | Data analysis was performed with SPSS (version 26.0; IBM Corp). The participants were analyzed based on their initial assigned group. Data cleaning and error checking were performed before analysis. Median and IQR were used to summarize the nonnormally distributed data for continuous variables, while frequencies and percentages were used to report the categorical variables. The comparison of baseline characteristics between the 2 arms was conducted using the Mann-Whitney test for continuous variables and chi-square for categorical variables. A generalized linear mixed model (GLMM) was used to assess the group, time, and group and time interaction effect on the intention and willingness to sext, knowledge, attitude, perceived norms, and prototype perceptions between the 2 groups before and after controlling for covariates (age, sex, relationship status, and the amount of time spent on the web). | PMC10625075 | ||
Ethics Approval | This study was approved by the Ethics Committee for Research Involving Human Subjects Universiti Putra Malaysia (JKEUPM-2020-321). The HEI administration and head of program approval as well as the respondents’ written consent were obtained before the study. | PMC10625075 | ||
Results | PMC10625075 | |||
Discussion | PMC10625075 | |||
Principal Findings | SECONDARY | To the best of our knowledge, this is the first RCT to evaluate the effectiveness of a theory-based SIM delivered via web-based animated videos on the intention and willingness to sext among diploma students. The secondary outcomes assessed in this study included knowledge, attitude, perceived norms, and prototype perceptions. At the end of 3 months postintervention, the intervention group demonstrated a significant decrease in the intention and willingness to sext as well as a significant improvement in knowledge, attitude, perceived norms, and prototype perceptions among the intervention group compared to the control group.The changes in the primary and secondary outcomes following the intervention were likely attributed to the PWM constructs and the web-based animated video delivered in this study. Theoretically, sexting is a complex behavior that has been explained by a few theories including PWM. The application of PWM in this intervention allowed a systematic approach to developing the intervention, thus making it easier to develop a storyboard for the animated video. The constructs of PWM, including attitude, perceived norms, and prototype perceptions that have been addressed in the animated videos, led to a significant reduction in the intention and willingness to sext. Furthermore, the use of web-based animated video could have improved the understanding of the module's content since this approach has been recognized as an effective tool for explaining and simplifying complex topics [In view of the lack of interventional research on the intention and willingness to sext and sexting-related issues, the findings of this study were compared to other relevant studies that assessed the intention and willingness of risky behaviors. Our findings on the intention to sext were consistent with a study that applied the theory of planned behavior (TPB), the theory of reasoned action (TRA), and PWM in the intervention to measure the intention to commit sexual harassment [Moreover, there was a significant effect of the intervention on the willingness to sext. This finding was consistent with a study that measured the willingness to assist individuals at risk of sexual assault [Next, a greater effect of this intervention was observed on the knowledge of sexting. This was consistent with a previous study [ | PMC10625075 | |
Strengths and Limitations | multiple-risk behaviors | To date, interventional research on sexting remains scarce. Therefore, this study represents a critical starting point for public health interventions aimed at addressing sexting-related issues in Malaysia. The use of theory-based intervention and web-based animated videos can be seen as a new direction for future public health interventions on SRH topics among young adults, particularly students in HEIs. Moreover, since this study was designed as an RCT, there was a greater internal validity to evaluate the effectiveness of the intervention. In addition, only a few previous RCTs that used a PWM-based intervention reported the effect size of the intervention. We chose to publish the effect magnitude for future comparisons and not depend solely on the There are a few limitations to this study. First, the findings were limited to the study population, and they cannot be generalized to the young adult population as a whole. Moreover, the use of the self-reported questionnaire in this study could lead to an information bias. Given the nature of the topic, which involved sexually sensitive questions, the participants might avoid revealing their actual actions or opinions. However, they were reminded that the study aimed to evaluate the effectiveness of the educational material and that no judgment would be made on them. Furthermore, this study did not measure sexting and other multiple-risk behaviors associated with sexting. It would be beneficial to assess the effect of our intervention on the actual sexting behavior, but it would involve a great deal of time and opinions of experts and stakeholders, not to mention the major ethical considerations related to the sensitive nature of the study subject and sexting being considered as punishable under Malaysian law. Finally, it was quite difficult to ensure that all participants in the intervention group adhered to and complied with the intervention, as the animated video delivered via YouTube in this study lacked any monitoring mechanisms. | PMC10625075 | |
Conclusions | SEXUALLY TRANSMITTED INFECTIONS | The PWM-based intervention module delivered via web-based animated videos in this study was effective in reducing the intention and willingness to sext apart from improving the knowledge of sexting, attitude, perceived norms, and prototype perceptions among diploma students. This intervention can be implemented by relevant agencies involved in the promotion of SRH of young adults in Malaysia. Further research can explore the best ways to increase the effect size of the outcomes, such as providing regular reminders of the contents of the intervention via other web-based approaches.The authors would like to thank the director-general of Health Malaysia and the director-general of National Population and Family Development Board Malaysia for their permission to publish this paper. The authors also would like to express their gratitude to the HIV/STI Unit of Melaka’s Health Department for sharing valuable data on sexually transmitted infections. The authors are thankful for the approval, cooperation, and commitment given by the higher education institution and the diploma students involved in this study. The authors received a grant (GPLPPKN0022) from the National Population and Family Development Board Malaysia.Conflicts of Interest: None declared.Summary of the sexting intervention module.CONSORT (Consolidated Standards of Reporting Trials)-EHEALTH checklist. | PMC10625075 | |
Abbreviations | Consolidated Standards of Reporting Trialsgeneralized linear mixed modelhigher educational institutionprototype willingness modelrandomized controlled trialsexing intervention modulesexual and reproductive healththeory of planned behaviortheory of reasoned action | PMC10625075 | ||
Data Availability | The data sets generated during and/or analyzed during this study are available from the corresponding author on reasonable request. | PMC10625075 | ||
Graphical abstract | PMC10189551 | |||
Keywords | PMC10189551 | |||
Abbreviations | SEPARATION | area under the ROC curvelogistic regressionMinamata diseasemagnetoencephalographymethylmercurymagnetic resonance imagingoversampled temporal projectionreceiver operating characteristic curvesomatosensory evoked magnetic fieldssomatosensory evoked potentialsprimary somatosensory cortexsecondary somatosensory cortexsignal-to-noise ratiosensory nerve action potentialstemporal signal space separation | PMC10189551 | |
Introduction | neurological damage, neurologic signs, damages, ataxia | CONSTRICTION, SENSORY DISTURBANCE, AUDITORY DISTURBANCES, SENSORY DISTURBANCES | Methylmercury (MeHg) is a major environmental neurotoxicant that damages the central nervous system depending on the dose and duration of exposure (MD is classified based on the onset time as acute/subacute MD (manifestation during the heavy contamination of seafood with MeHg in the Minamata Bay) and chronic MD (manifestation following the cessation of MeHg excretion). Acute or subacute MD is characterized by marked sensory disturbances in the distal parts of the extremities (“glove and stocking type” sensory disturbance), concentric constriction of visual fields, ataxia, and auditory disturbances. Except for sensory disturbance, neurologic signs are milder and less frequent in chronic MD than in acute or subacute MD (Given that chronic exposure mercury and its compounds can cause irreversible neurological damage and recent increases in environmental mercury emissions, the Minamata Convention on Mercury was held in August 2017, aiming to issue guidance on protecting human health and decreasing anthropogenic mercury emissions (The Clinically, sensory disturbance appears initially (As the “glove and stocking type” sensory disturbances frequently observed in MD (MEG can detect magnetic fields generated by neural currents with marginal distortion owing to differences in conductance at a millisecond temporal resolution (In this study, we aimed to develop a highly sensitive objective assessment for detecting central somatosensory disturbance in patients with chronic MD. We intended to perform single-trial analysis of SEFs using MEG to clarify the pathophysiological mechanisms underlying central somatosensory disturbances in chronic MD. Single-trial epochs were classified into three categories (N20m, non-response, and P20m epochs) based on the cross-correlation between average sensor SEFs and individual epochs. Further, we compared the characteristics of N20m between patients with MD and healthy controls given previous reports of stable N20m latency and amplitude in healthy participants ( | PMC10189551 |
Materials and methods | PMC10189551 | |||
Participants | ± | RECRUITMENT, MINAMATA DISEASE | Between April 2010 and October 2022, we recruited 42 patients with MD (20 women, 22 men; mean age 70.0 ± 10.6 years) and 289 healthy volunteers (131 women, 158 men; mean age 67.7 ± 9.4 years). Flowchart of participant recruitment and enrollment. MD = Minamata disease. | PMC10189551 |
MEG recording | The right and left median nerves were stimulated at the wrist in separate recordings using constant current pulses of 0.2-ms duration. Stimulus intensity determined by visual inspection was 1.5 times the motor threshold to evoke twitches of the thumb. The interstimulus interval was 3.7 s to avoid habituation to SII responses. | PMC10189551 | ||
MR image acquisition | The three-dimensional (3D) T1-weighted images were acquired using a 1.5 T MRI unit (Magnetom Symphony, Siemens Healthcare, Erlangen, Germany) or a 3 T MRI unit (Discovery MR750 3.0 T, GE Healthcare, Milwaukee, WI). | PMC10189551 | ||
Data acquisition | peripheral sensory nerve impairment | SENSORY DISTURBANCE | We recorded the SEF responses using a whole-head 306-channel sensor array (Vectorview, ELEKTA Neuromag, Helsinki) that comprises 204 planar gradiometers and 102 magnetometers. We analyzed the MEG data recorded by 204-channel planar-type gradiometers. Before the recording, three anatomical fiducial points (nasion and bilateral preauricular points) and four head position indicator coils on the scalp were digitized using a 3D digitizer. The sampling rate was set at 5,000 Hz, and the recording bandpass ranged from 0.03 to 1,500 Hz. We collected 80–91 responses per each median nerve stimulation, and 62–91 artifact-free trials were used for the analyses. Further, we recorded the orthodromic median nerve SNAPs from the surface electrodes placed on the elbow to estimate the contribution of peripheral sensory nerve impairment to the sensory disturbance in chronic MD. | PMC10189551 |
Data processing | Because this study focused on the response of N20m, we applied a band pass filter (6–200 Hz) to the preprocessed data using MNE-Python (v0.20) (We compared neural responses (P20m rate and non-response rate) and early somatosensory cortical processing (N20m amplitude, cross-correlation value, and gamma response) between patients with MD and controls. Using source waveforms obtained from equivalent current dipole modeling, we estimated the locations and activation strengths of the neural generators of N20m.We performed the following three steps to estimate the SI function accurately: First, we needed to select the MEG sensor that best reflected the SI function. This is because data analysis is significantly affected by the choice of the sensor. We selected the sensor with the highest similarity of the averaged sensor SEFs to the source waveform reflecting neural activity in the SI, using the cross-correlation between the sensor SEFs and source waveform at N20 peak latency ± 3.0 ms. N20m amplitudes of the source waveform were highly correlated with those of the sensor SEFs (Second, we analyzed the SEFs under the restricted vicinity of the N20m peak (peak latency ± 3.0 ms). This is because N20m is a very stable response and is unaffected by the conscious state (To quantify the reproducibility of N20m at single-trial responses in the selected sensor, we calculated the cross-correlation in the N20m peak latency ± 3.0 ms between the average sensor SEFs and SEFs at each single-trial epoch. Single-trial epochs were classified into three categories according to the cross-correlation of the individual epochs. For the N20m peak at SEFs, we defined cross-correlation of > 0.2, between − 0.2 and 0.2, and < − 0.2 as N20m, non-response, and P20m epochs, respectively (Analysis of SEFs. The cross-correlation was calculated between the averaged sensor SEFs and SEFs at single-trial epochs in the N20m peak latency ± 3.0 ms. Three categories of single-trial epochs based on the cross-correlation of individual epochs were determined as follows: N20m, P20m, and non-response epochs. For the N20m peak at SEFs, we defined a cross-correlation of > 0.2, −0.2 to 0.2, and < − 0.2 as N20m (green zone), non-response (yellow zone), and P20m epochs (orange zone), respectively (We estimated the N20m amplitude in the averaged sensor SEFs and gamma response at the single-trial epochs excluding non-response epochs. The positive value of the N20m amplitude was defined as the deflection of N20m from baseline. To assess the gamma response, each raw single-trial epoch was analyzed by the Morlet wavelet-based time–frequency analysis from 6 Hz to 200 Hz at 1-Hz steps ( | PMC10189551 | ||
Statistical analyses | Python machine learning library | For each MEG parameter, the non-parametric Mann–Whitney The receiver operating characteristic (ROC) curve describes a diagnostic trade-off between sensitivity and specificity with the adjustment of a discriminative threshold (All tests were two-tailed, and statistical significance was set at a p-value of 0.05. All analyses, except ROC curve analysis, were performed using GraphPad Prism version 7.0 (GraphPad Software, San Diego, California, USA). ROC curve analysis was performed using Python 3.8.3 and scikit-learn 0.23.1, a Python machine learning library ( | PMC10189551 | |
Ethical declarations | Minamata Disease, NIMD | MINAMATA DISEASE | This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of the National Institute for Minamata Disease (NIMD 10/001, 13/001, 15/001, 16/003, 22/002). Participation was voluntary. Written informed consent was obtained from all participants. | PMC10189551 |
Results | PMC10189551 | |||
Evaluation of peripheral sensory nerve function | ± | The conduction velocity of the median nerve SNAPs was significantly slower in patients with MD than in controls on either side (left side: control: 53.7 ± 4.9 m/s; MD: 50.9 ± 5.0 m/s; p = 0.0001; right side: control: 53.6 ± 5.1 m/s; MD: 50.8 ± 5.1 m/s; p = 0.0002), despite adjustments for multiple comparisons via Bonferroni correction. There were no significant differences in the amplitude of the median nerve compound SNAPs between the controls and patients with MD on either side (left side: control: 21.5 ± 13.8 µV; MD: 23.5 ± 18.1 µV; p = 0.7886; right side: control: 17.8 ± 12.4 µV; MD: 18.4 ± 13.6 µV; p = 0.9517). | PMC10189551 | |
Neural responses and N20m amplitude | MINAMATA DISEASE | The P20m rate and non-response rate were significantly higher in patients with MD than in controls on either side, despite adjustments for multiple comparisons via Bonferroni correction (p < 0.0001) (Comparisons of MEG findings between controls and patients with MD. Patients with MD demonstrate significantly higher non-response rates and P20m rates than controls on either side (p < 0.0001). The N20m amplitudes, cross-correlation value, and power strength of induced gamma oscillations were significantly lower in patients with MD than in controls on either side (p < 0.0001). Bars and error bars indicate mean and standard deviation, respectively. MEG = magnetoencephalography; MD = Minamata disease.Compared with that in the control group, the average N20m amplitude in patients with MD was decreased on either side (Amplitude and dipole direction of N20m. Compared with those in controls, the average N20m amplitudes in patients with MD were significantly decreased on either side | PMC10189551 | |
Single-trial analysis of P20m and absent N20m peak | We examined the frequency of P20m epochs, N20m amplitude of averaged SEFs in N20m epochs, and P20m amplitude of averaged SEFs in P20m epochs in controls and patients with MD with the P20m or an absent N20m peak. The controls displayed fewer P20m epochs, and the averaged sensor SEFs and averaged SEFs of the N20m epochs nearly overlapped (Single-trial analysis of P20m and absent N20m peak. Left diagrams depict the cross-correlation of each epoch. Right diagrams depict the averaged sensor SEFs (black line), averaged SEFs of N20m epochs (blue dashed line), and P20m epochs (red dashed line). The controls exhibited fewer P20m epochs (left diagram), and the averaged sensor SEFs and averaged SEFs of the N20m epochs almost overlapped (right diagram) | PMC10189551 | ||
Cross-correlation value of N20m | We observed a significant reduction of the cross-correlation value in patients with MD on either side, despite adjustments for multiple comparisons via Bonferroni correction (p < 0.0001) (Time-frequency analysis of SEFs. Compared with that in controls, the power strength of induced gamma oscillations was significantly decreased on either side in patients with MD | PMC10189551 | ||
Time-frequency analysis of SEFs | Compared with that in controls, the power strength of induced gamma oscillations decreased on either side in patients with MD ( | PMC10189551 | ||
Correlations between two SEF parameters | The cross-correlation value and power strength of induced gamma oscillations on either side exhibited the highest negative correlation with the non-response rate and P20m rate (Correlations between two SEF parameters. On either side, the cross-correlation value exhibited the highest correlation with the non-response rate or P20m rate. High correlations were observed for both SEF parameters of early somatosensory cortical processing on either side. In particular, there was a strong correlation between the cross-correlation value and power strength of the induced gamma oscillations on either side. SEFs = somatosensory evoked magnetic fields. | PMC10189551 | ||
Discrimination analysis | REGRESSION | The AUC was > 0.77 (range; 0.77–0.79) for all parameters and was the highest (0.80 [range; 0.72–0.88]) for the integrated SEF parameters using the LogReg method (Receiver operating characteristic curves and corresponding area under the curve values for SEF parameters. The AUC was > 0.77 for all parameters, and the AUC value was the highest for the integrated SEF parameters using the LogReg method (0.8). Data are presented with 95% confidence intervals. AUC = area under the receiver operating characteristic curve; SEFs = somatosensory evoked magnetic fields; LogReg = logistic regression. | PMC10189551 | |
Discussion | chronic-phase central somatosensory disturbance, neuronal synchronization, bleeding, stroke, neoplasms, Minamata disease, infarction | DISORDER, BRAIN ATROPHY, BLEEDING, STROKE, DYSPLASTIC, NEOPLASMS, DISEASES, PATHOPHYSIOLOGY, DISORDERS, BRAIN TUMORS, MULTIPLE SCLEROSIS, UNILATERAL POLYMICROGYRIA, DEMYELINATION, MINAMATA DISEASE, INFARCTION | We performed single-trial analysis of SEFs to explore the pathophysiological mechanisms of central somatosensory disturbance in patients with chronic MD. Detailed analyses of SEFs under restricted vicinity of the N20m (peak latency ± 3.0 ms) characterized the altered SI response and early somatosensory cortical processing. In this study, the non-response rate and P20m rate were significantly higher in patients with MD than in controls, thereby indicating an impaired SI response. In addition, we observed a significant reduction of the N20m amplitude, cross-correlation value, and gamma response in patients with chronic MD, reflecting a functional abnormality of early somatosensory cortical processing. Therefore, these SEF parameters may shed light on the pathophysiology of minute central somatosensory disturbance in chronic MD.Single-trial analyses have the potential to uncover meaningful brain dynamics that are obscured using the conventional method (averaging brain activity across trials) (In this study, the N20m amplitude on either side was significantly reduced in patients with chronic MD (p One may argue that it is unclear whether the strength of the correlation between the averaged sensor SEFs and SEFs at single-trial epochs results from the amplitude of SEFs or increase of the background 1/f noise in chronic MD. As shown in The P20m peak and an absent N20m peak were observed in 6 and 11 patients with MD, respectively. The latencies of N20m in the averaged SEFs of N20m and P20m epochs in the averaged SEFs of P20m epochs were almost identical (P20m is occasionally observed in unilateral polymicrogyria, a rare dysplastic disorder. Ishitobi et al. recognized P20m in two of five patients with unilateral polymicrogyria in the parietal region (Researchers have recognized the decreased variability of neural activities across trials (increased reproducibility) as a general property of sensory perception (Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory gamma-aminobutyric acid-ergic interneurons (The cross-correlation value and power strength of the induced gamma oscillations displayed the highest negative correlation with the non-response rate and P20m rate, suggesting that the reduced reproducibility of N20m and gamma oscillations played an important role in the impaired SI response in patients with chronic MD. For both SEF parameters involved in early somatosensory cortical processing, we observed a strong correlation between the cross-correlation value and power strength of the induced gamma oscillations. This finding may be attributed to their close neurophysiological actions (early neuronal synchronization in somatosensory processing).We performed an ROC analysis to evaluate the ability of each parameter to discriminate between controls and patients with MD. The AUC was > 0.7 for all parameters; therefore, each SEF parameter displayed a moderate discrimination ability. Because the confidence intervals of the AUCs overlapped with each other, each SEF parameter was considered to exhibit an approximately equivalent discrimination ability. In other words, these SEF parameters may be useful for detecting chronic-phase central somatosensory disturbance.Our study had some limitations. First, the relatively small sample size may reduce the statistical power of this study. The first patients with MD were officially identified in 1956, and the number of surviving patients is gradually decreasing (<225 survivors of confirmed Minamata disease in Kumamoto prefecture). We recruited 49 patients with MD; therefore, the current sample may be broadly representative of chronic MD. Second, we did not analyze other central somatosensory disorders, such as multiple sclerosis, stroke, and brain tumors. Organic changes in the somatosensory pathway running from the thalamus to the SI accompanied by neoplasms, demyelination, bleeding, and infarction are generally observed on brain MRI scans in patients with these diseases. In contrast, there are no organic changes other than brain atrophy in the SI in patients with MD ( | PMC10189551 |
Conclusions | Functional abnormalities in early somatosensory cortical processing (reduced N20m amplitude, cross-correlation value, and SI gamma responses) as well as impaired SI responses (increased non-response rate and P20m rate) can be clearly detected in patients with chronic MD using MEG. Single-trial neuromagnetic analysis of somatosensory function may therefore be useful for identifying central somatosensory disturbance and elucidating the relevant pathophysiological mechanisms even in chronic cases of MD. | PMC10189551 | ||
Funding | This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | PMC10189551 | ||
Declaration of Competing Interest | The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | PMC10189551 | ||
References | PMC10189551 | |||
Supplementary data | The following are the Supplementary data to this article: | PMC10189551 | ||
Supplementary data 1 | PMC10189551 |
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