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Clinical outcomes | TG | SECONDARY | The primary clinical outcome was a change in the level of HbA1c over 84 days in the two treatment groups. The secondary clinical outcomes included the changes in the levels of FBG, 2hPBG, the area under curve of OGTT blood glucose, fasting insulin (FINS), 2-hour post-meal insulin (2hPINS), the area under curve of insulin release test, fasting C- peptide (FCP), 2-hour post-meal C-Peptide (2hPCP), the area under curve of C-peptide release test, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), BW, WC, WHR, BMI, SBP, and DBP. | PMC10246770 |
Gut microbiome, short-chain fatty acids and bile acids analysis | The stool samples were immediately transferred to the -80°Cfreezer for storage after collection on day 0 and day 84. Then the stool samples were used for bacterial 16sRNA gene sequencing, and SCFAs as well as BAs analysis. The detailed information was shown on | PMC10246770 | ||
Safety assessment | The liver function (the total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and renal function (serum creatinine (Scr) and blood urea nitrogen (BUN))of all participants was assessed on day 0 and day 84. | PMC10246770 | ||
Fecal microbiota transplantation in pseudo-sterile mice | STERILE | The animal experimental protocol was approved by the animal ethics committee of Jinan University (20190821-02). A total 50 of C57BL/6J mice (weight, 25.00 ± 2g; age, 10 weeks) were purchased from Biotechnology Company Limited (Beijing, China). The mice were raised in the specific pathogen-free animal experiment center at Jinan University, with constant temperature (24 ± 2°C), constant humidity of 55 ± 10% and a 12-h light/dark cycle. All mice received adaptive feeding for 7 days, and then were randomly divided into a control group (NC, n=10) and an antibiotic treatment group (AT, n=40). Within the next 4 weeks, the mice in AT group were fed with antibiotic-containing sterile water and then divided into 4 groups. More detailed information was shown in | PMC10246770 | |
Statistical analysis | Outcomes were calculated on a strict intention-to-treat (ITT) basis. The raw data of Day 84 – the raw data of Day 0 represented the changes in all variables. The Kolmogorov-Smirnov Test was used to detect whether the continuous data conform to normal distribution. If normally distributed, paired T-test was used for intra-group comparison and independent T-test was used for inter-group comparison, and the data were expressed as mean and standard deviations. If not normally distributed, non-parametric two-tailed Wilcoxon matched-pairs signed-ranks was used for intra-group comparison and non-parametric K-independent Wilcoxon signed-ranks were used for inter-group comparison, and the data were expressed as the median and inter-quartile ranges. Fold changes of diabetes-induced markers after treatments of CP & G were calculated as (the raw data of day 84/the raw data of day 0). Statistical Package for Social Science (SPSS) 28.0 was used to analyze all data and we defined | PMC10246770 | ||
Results | PMC10246770 | |||
Phytochemical characterization of CP | Phytochemical compositions of the CP were clarified by using high performance liquid chromatography (HPLC). The 5 components in the CP were identified in the chromatogram with peaks at 17.19 min to3-cafeoylquinic acid, 20.19 min to isoquercitrin, 22.19 min to kaempferol-3-glucoside, 23.43 min to kaempferol 3-rhamnoside, 27.56 min to quercetin by the comparison to external standards ( | PMC10246770 | ||
Clinical baseline characteristics and physical activity of participants | T2DM | According to the inclusion and exclusion criteria, a total of 38 participants with T2DM were randomly divided into the G group (n=13) and CP group (n=25) in the study. During the intervention, 6 participants dropped out (1 participant in the G group and 5 participants in the CP group). Finally, a total of 32 participants completed the intervention ( | PMC10246770 | |
CP alleviates HbA1c level in T2DM patients | fasting blood glucose×, T2DM, fasting blood glucose, post-meal blood glucose | INSULIN RESISTANCE | Compared with Day 0, the level of HbA1c, the primary clinical outcome, was significantly decreased both in the G group and in the CP group on Day 84. At the end of intervention, there was no significant difference in the reduction of HbA1c between the two groups (The changes in glucose metabolism phenotypes in T2DM patients. Comparison of metabolic parameters in T2DM patients.The data are shown as the mean ± SD for normal variables or median (IQR) for non-normal variables. Paired T-test or non-parametric two-tailed Wilcoxon paired sign rank test was used for intra-group comparisons. P-value, comparison between Day 0 and Day 84 at the same group. Independent T-test and non-parametric K independent Wilcoxon signed-ranks was used for comparisons of the changes between the two groups. P, comparison of the fold changes between the CP group and the G group.CP group, cyclocarya paliurus leaves extracts group; G group, Glipizide group; SD, standard deviation; IQR, interquartile range; HbA1c, hemoglobin A1c; FBG, fasting blood glucose; 2hPBG, 2-hour post-meal blood glucose; FINS, fasting insulin; 2hPINS, 2-hour post-meal insulin; HOMA-IR, homeostasis model assessment for insulin resistance = (fasting blood glucose×fasting insulin/ 22.5); 2hPCP, 2-hour post-meal C-Peptide; OGTT, oral glucose tolerance test; AUC, area under curve; TG, triglycerides; TC, total cholesterol; LDL-c, low-density lipoprotin cholesterol; HDL-c, high-density lipoprotein cholesterol; BW, body weight; WC, waist circumference; WHR, waist to hip ratio; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TBIL, total bilirubin; DBIL, direct bilirubin; IBIL, indirect bilirubin; ALB, albumin;ALT, alanine aminotransferase; AST, aspartate aminotransferase; Scr, serum creatinine; BUN, blood urea nitrogen. | PMC10246770 |
CP ameliorates several other metabolic phenotypes in T2DM patients | T2DM | BLOOD | From Day 0 to Day 84, the significant improvement in blood glucose homeostasis (FBG, 2hPBG, OGTT glucose AUC) (The changes in OGTT glucose AUC, insulin release test, and C-Peptide release test in T2DM patients. Blood lipid homeostasis in T2DM patients. | PMC10246770 |
CP redresses gut microbiota dysbiosis in T2DM patients | T2DM | To explore the potential role of the gut microbiota in CP-induced metabolic phenotypes improvement in T2DM patients, 16S rRNA gene sequencing was performed in the fecal samples from the patients on Day 0 and Day 84. At the phylum level, the overall microbial compositions were shown in The abundances of the gut microbiota at the phylum level in T2DM patients. At the genus level, the top 10 dominant genera was presented in The abundances of the gut microbiota at the genus level in T2DM patients. Then we conducted a spearman correlation analysis to explore the potential relationships between bacterial abundance and metabolic phenotypes. We found that Faecalibacterium, which was enriched in the participants on Day 84 in the CP group, had a negative correlation with several metabolic phenotypes (HbA1c, FBG, 2hPBG, SBP and TC). Akkermansia, which was also enriched in the participants on Day 84 in the CP group, was negatively related to a few metabolic markers (HbA1c, FBG and TC). Prevotella_9 had a positive relationship with several metabolic markers (FBG, OGTT Glucose AUC, 2hPBG and TC) ( | PMC10246770 | |
CP induces metabolites alteration in T2DM patients | CP-induced T2DM, T2DM | GCA | To reveal metabolites alteration, related to the gut microbiota, which is potentially involved in CP-induced T2DM improvement, we performed metabolic profiling of feces from the participants. From Day 0 to Day 84, a significant increase was observed in total SCFAs, propionic acid (PA) and butyric acid (BA), while the levels of acetic acid (AA), isobutyric acid (IBA), valeric acid (VA), isovaleric acid (IVA) and hexanoic acid (HA) had no significant change in the CP group. In the G group, the level of total SCFAs, AA, PA, BA, IBA, VA, IVA and HA were not affected over the 84-day period (The levels of SCFAs in T2DM patients. To explore the potential effect of CP on BA metabolism, a total of 20 species of BAs were detected. Compared to Day 0, the levels of unconjugated BAs (chenodeoxycholic acid (CDCA), 12-ketolithocholic acid (12-KLCA) and β-muricholic acid (β-MCA)) were significantly increased and the levels of conjugated BAs (taurodeoxycholic acid (TDCA),glycochenodeoxycholic acid (GCDCA) were significantly reduced, while no significant differences were found in other BAs in the CP group on Day 84. From Day 0 to Day 84, the levels of BAs showed no significant changes in the G group (The levels of BAs in T2DM patients. Correlation analyses were performed to determine the potential relationships between metabolites and gut microbiota. Coincidently, we observed that Faecalibacterium enriched in the CP group on Day 84 was positively related to SCFAs (total SCFAs, BA and PA) and unconjugated BAs (CDCA, 12-KLCA, β-MCA and LCA), but negatively correlated with conjugated BAs (GCA). Akkermansia, which was also enriched in the CP group on Day 84, showed a positive relationship with SCFAs (total SCFAs, BA, HA, IBA and PA), and unconjugated BAs (CDCA, 12-KLCA and β-MCA), but had a negative correlation with conjugated BAs (GUCDA, GCA, TDCA and TCDCA). Prevotella_9, which was depleted in the CP group on Day 84, was negatively correlated with SCFAs (total SCFAs, IBA and PA) and unconjugated BAs (CDCA and β-MCA), but positively associated with conjugated BAs (GCA, GLCA and TLCA). Megamonas was negatively correlated with conjugated BAs (GCA and GLCA), but positively associated with SCFAs (HA) and unconjugated BAs (β-MCA and CA) ( | PMC10246770 |
FMT ameliorates the glucose metabolism in pseudo-sterile mice | Experimental design for animal study for microbiota transplantation (FMT improves glucose metabolism in pseudo-sterile mice. | PMC10246770 | ||
Discussion | T2DM-associated glucose, T2DM-associated metabolic, T2DM, TG | GCA | In this pilot clinical randomized trial, we demonstrated for the first time that CP, like glipizide, significantly improved HbA1c level and other T2DM-associated glucose metabolism parameters, independent of physical activity and body weight and with no significant effects on liver and kidney function in the patients with T2DM. Moreover, CP also resulted in the improvement in the levels of blood lipid and blood pressure. These results indicate that CP displays a more beneficial effect in the alleviation of T2DM-associated metabolic phenotypes than Glipizide.The improvements in T2DM-associated metabolic phenotypes induced by CP in the study may be explained in part by multiple chemical components in the CP, such as3-caffeoylquinic acid, isoquercitrin and kaempferol-3-glucoside. It has been shown that 3-caffeoylquinic acid is associated with a wide range of biological activities, such as antioxidation, antibacterial, antiparasitic, neuroprotective, anti-inflammatory, anticancer, antiviral, and antidiabetic effect (There is mounting evidence that gut microbiota involves the etiology and progression of T2DM, which has attracted the attention of researchers (On the other hand, our results showed that Glipizide did not significantly affect the composition of intestinal flora during the intervention, which was consistent with the report by Wamg et al (In addition to gut microbiota, metabolites including SCFAs, amino acid catabolites, and BAs produced by gut microbiota play an important role in T2DM development. These metabolites alleviate or exacerbate T2DM via their homologous receptors-mediated signaling (The results of BAs profiling indicated that the regulation of BA signal might be involved in the effect of CP on T2DM patients. On Day 84 of intervention, unconjugated BAs (CDCA, 12-KLCA and β-MCA) levels were increased, while conjugated BAs (GCDCA and TDCA) levels were reduced in the CP group compared with Day 0. Mantovani et al. reported that T2DM was significantly associated with the higher levels of conjugated BAs (TCDCA, TDCA, GCDCA, GDCA and GCA) as well as the lower level of unconjugated BAs (CA) (Collectively, our results indicate that CP increases the levels of SCFAs and unconjugated BAs and decreases the levels of conjugated BAs, thus leading to the improvements in HbA1c and other metabolic indicators.At last, FMT in pseudo-sterile mice was conducted to confirm the causal relationship between the gut microbiota and the effect of CP on host glucose metabolism. The results showed that glucose metabolism parameters (FBG and OGTT glucose AUC) had a significant improvement in the mice transplanted with the post-intervention microbiota from the CP group compared with the mice transplanted with pre-intervention microbiota. Zhang et al. Reported that transplanted fecal bacteria from individuals with normal glucose tolerance altered gut microbiota composition and improved FBG, 2hPBG, TC, TG, and LDL-c in db/db mice ( | PMC10246770 |
Strengths and limitations | There were several strengths in our study. First, all existing studies on CP were based on animals or | PMC10246770 | ||
Conclusion | T2DM-associated metabolic, T2DM | In conclusion, this 84-day clinical randomized controlled trial in T2DM patients demonstrates that CP displays a more beneficial effect in the alleviation of T2DM-associated metabolic phenotypes than Glipizide by regulating gut microbiota and metabolites, with no significant effects on liver and kidney function. However, these results should be considered preliminary, and large-scale clinical controlled studies are required to confirm these findings. | PMC10246770 | |
Data availability statement | The original contributions presented in the study are included in the article/ | PMC10246770 | ||
Ethics statement | The studies involving human participants were reviewed and approved by ethical approval department No. KY-20181226001. The patients/participants provided their written informed consent to participate in this study. The animal study was reviewed and approved by Jinan University (20190821-02). | PMC10246770 | ||
Author contributions | The authors’ responsibilities were as follows—XP, SC, LuZ, YL, CW and ST contributed to the conception and design of this study. XP, SC, LuZ, YL, CW, LiZ, WC, JZ and JY were involved in the acquisition and analysis of the data. XP, LiZ and LuZ interpreted the results. XP, SC and ST drafted the manuscript. All authors read and approved the final manuscript. | PMC10246770 | ||
Acknowledgments | The authors appreciate all staff who participates in this study. | PMC10246770 | ||
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10246770 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10246770 | ||
Supplementary material | T2DM | LIVER, RECRUITMENT | The Supplementary Material for this article can be found online at: Business License of Chenzhou Mingrun biological products Co. LTD, Hunan, China and cyclocarya paliurus leaves extracts. Click here for additional data file.HPLC fingerprinting of cyclocarya paliurus leaves extracts. HPLC chromatogram of standard mixture Click here for additional data file.The flow chart of participant recruitment and withdrawal.Click here for additional data file.Anthropometric markers in T2DM patients. Click here for additional data file.Liver and renal function in T2DM patients. (A-H) The changes in the levels of TBIL Click here for additional data file.Click here for additional data file.Click here for additional data file. | PMC10246770 |
References | PMC10246770 | |||
Glossary | PMC10246770 | |||
Abstract | PMC10028524 | |||
Background | MERS | MIDDLE EAST RESPIRATORY SYNDROME, DISEASE, RESPIRATORY VIRAL INFECTION | Type I interferons (IFNs) are essential antiviral cytokines induced upon respiratory exposure to coronaviruses. Defects in type I IFN signaling can result in severe disease upon exposure to respiratory viral infection and are associated with worse clinical outcomes. Neutralizing autoantibodies (auto‐Abs) to type I IFNs were reported as a risk factor for life‐threatening COVID‐19, but their presence has not been evaluated in patients with severe Middle East respiratory syndrome (MERS). | PMC10028524 |
Methods | particle‐based, MERS | We evaluated the prevalence of type I IFN auto‐Abs in a cohort of hospitalized patients with MERS who were enrolled in a placebo‐controlled clinical trial for treatment with IFN‐β1b and lopinavir‐ritonavir (MIRACLE trial). Samples were tested for type I IFN auto‐Abs using a multiplex particle‐based assay. | PMC10028524 | |
Results | critically ill | CRITICALLY ILL | Among the 62 enrolled patients, 15 (24.2%) were positive for immunoglobulin G auto‐Abs for at least one subtype of type I IFNs. Auto‐Abs positive patients were not different from auto‐Abs negative patients in age, sex, or comorbidities. However, the majority (93.3%) of patients who were auto‐Abs positive were critically ill and admitted to the ICU at the time of enrollment compared to 66% in the auto‐Abs negative patients. The effect of treatment with IFN‐β1b and lopinavir‐ritonavir did not significantly differ between the two groups. | PMC10028524 |
Conclusion | critically ill, MERS | CRITICALLY ILL, MIDDLE EAST RESPIRATORY SYNDROME | This study demonstrates the presence of type I IFN auto‐Abs in hospitalized patients with MERS.
King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
This research is funded by the King Abdullah International Medical Research Center, Riyadh, Saudi Arabia, Grant No. RC15/142/R/CT.
Approximately 25% of hospitalized patients with Middle East respiratory syndrome (MERS) have type I interferons (IFNs) autoantibodies. These autoantibodies were more prevalent in critically ill patients. 90‐day mortality and other clinical outcomes were similar between patients who were auto‐Abs positive and negative. The effect of treatment with IFN beta‐1b and lopinavir‐ritonavir did not significantly differ between patients who were auto‐Abs positive and those who were auto‐Abs negative.
Mohammed | PMC10028524 |
INTRODUCTION | deaths, MERS | MIDDLE EAST RESPIRATORY SYNDROME | The Middle East respiratory syndrome (MERS) was first reported in Saudi Arabia in 2012, and as of January 2023, it has caused 2603 cases and 935 associated deaths.Type I interferons (IFNs) are essential antiviral cytokines induced upon human exposure to respiratory viruses such as MERS‐CoV.In this study, we evaluated the presence of type I IFN auto‐Abs, including IFN‐α2, β, and/or IFN‐ω in hospitalized patients with MERS; examined their association with mortality and other clinical outcomes; and evaluated whether the presence of type I IFN auto‐Abs affected the response to treatment with IFN beta‐1b and lopinavir‐ritonavir. | PMC10028524 |
MATERIALS AND METHODS | PMC10028524 | |||
The study design | This is a follow‐up study of the MIRACLE trial ( | PMC10028524 | ||
Subjects and samples | infection | BLOOD, INFECTION | Blood samples were collected from enrolled patients from three recruiting sites in Riyadh, Saudi Arabia, between November 2016 and April 2020. MERS infection was confirmed by real‐time reverse transcriptase–polymerase chain reaction (RT‐PCR) assay. For this study, we used plasma samples that were collected in heparin tubes on Study Day 1, before the administration of study drugs. | PMC10028524 |
Detection of auto‐abs against type I IFNs | particle‐based, MERS | Plasma samples from patients with MERS were tested at King Abdullah International Research Center laboratory, Riyadh, Saudi Arabia, for auto‐Abs against IFN‐α2, β, and IFN‐ω using a multiplex particle‐based assay that uses magnetic beads with differential fluorescence that covalently coupled to recombinant human proteins (2.5 μg/reaction) as provided by the National Institutes of Health (NIH), Bethesda, Maryland, United States. | PMC10028524 | |
MERS pseudotyped viral particles (MERSpp) neutralization assay | viral infections, infection | INFECTION, VIRUS, VIRAL INFECTION | Although type I IFNs are thought to be beneficial against viral infections, only IFN‐α2 controls early viral dissemination and prevents virus entry into the cell at the early stage of infection. | PMC10028524 |
Statistical analysis | Continuous data are presented as medians and interquartile ranges. Categorical data are presented as numbers and percentages. Statistical differences between samples were assessed using chi‐square, Fisher's exact test, Student's t‑test, or Mann–Whitney test as appropriate. Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC) and GraphPad Prism 8.2.1 (GraphPad, San Diego, CA). Statistical tests for variables were performed using a two‐sided alpha value of 0.05 to denote a significant level. | PMC10028524 | ||
RESULTS | PMC10028524 | |||
Auto‐abs against IFN‐α2, IFN‐β, and/or IFN‐ω in hospitalized patients with MERS | MERS | MIDDLE EAST RESPIRATORY SYNDROME | Among the 62 enrolled patients with laboratory‐confirmed MERS, 15 patients (24.2%) were positive for immunoglobulin G auto‐Abs for at least one subtype of type I IFNs, including IFN‐α2, IFN‐β, and/or IFN‐ω (Figure Multiplex particle‐based assay for autoantibodies (auto‐Abs) against interferon (IFN)‐α2, IFN‐β, and IFN‐ω in hospitalized patients with Middle East respiratory syndrome (MERS) ((A) Distribution of the number of positive samples for patients with immunoglobulin G autoantibodies (auto‐Abs) for more than one subtype of type I interferons (IFNs) (IFN‐α2, IFN‐ω, and IFN‐β) and (IFN‐α2 and IFN‐ω) and patients with immunoglobulin G auto‐Abs for only one subtype of type I IFNs. (B) Distribution of auto‐Ab titers of patients with positive auto‐Abs samples and mortality. | PMC10028524 |
The auto‐abs neutralization IFN‐α2 in vitro | infection | INFECTION | Overall, samples from patients with auto‐Abs against IFN‐α2 have neutralizing activity to IFN‐α2 and limit the antiviral activity of IFN‐α2 against MERSpp (Figure Increased MERS pseudotyped viral particles' (MERSpp) infection, despite the presence of interferon (IFN)‐α2, in the presence of plasma with autoantibodies (auto‐Abs) targeting IFN‐α2. MERSpp infection measured 48 h after infection in Huh7.5 cells treated with IFN‐α2 in the presence of plasma from patients with auto‐Abs or without auto‐Abs. Samples from patients with positive auto‐Abs for IFN‐α2 ( | PMC10028524 |
Clinical characteristics of patients with or without auto‐Abs for type I IFNs | death | CORONAVIRUS | In this study, the median age of the auto‐Abs positive patients was 56 years and 60 years for the auto‐Abs negative patients, and males represented 80% and 83%, respectively (Table (A) Baseline characteristics of patients in the trial and (B) study interventions and co‐interventions during the trial period.
Student's t‑test.Mann–Whitney test.Chi‑square test.Fisher's exact test.Patients without type I IFN auto‐Abs showed similar favorable responses to treatment interventions compared to patients with type I IFN auto‐Abs as shown in the forest plot (Supporting information Figure Outcomes in patients enrolled in the trial.
Abbreviation: MERS‐CoV, MERS coronavirus.Calculations of days free from supplemental oxygen, renal replacement therapy, mechanical ventilation, vasopressors, extracorporeal membrane oxygenation, organ support, and days outside the ICU were based on 28 days of observation.Days to MERS‐CoV RNA clearance censored by death or hospital discharge.Data on Karnofsky performance status score at Day 90 were not available for one patient in the placebo group. Otherwise, there were no missing values in the variables in this table. | PMC10028524 |
DISCUSSION | MERS | VIRAL INFECTION, DISEASE, CRITICALLY ILL | In this study, we found that 24.2% of hospitalized patients with MERS were positive for auto‐Abs against at least one type I IFN. Although patients with auto‐Abs were more likely to be critically ill, the presence of auto‐Abs against at least one type I IFN was not associated with different clinical outcomes or with a difference in the response to treatment with IFN‐β1b and lopinavir‐ritonavir. These observations are similar to those of Abers et al.The neutralizing activity of these type I IFN auto‐Abs was also tested using a neutralizing assay in vitro, which indicates an ability to hinder IFN responses to viral infection and results in increased disease severity.The baseline characteristics of patients with or without type I IFN auto‐Abs were similar in terms of age, gender, body mass index (BMI), and comorbidities. It has been shown previously that auto‐Abs against type I IFNs significantly increased the COVID‐19 mortality rate at all ages.In conclusion, auto‐Abs against at least one type I IFNs were common among hospitalized patients with MERS. Patients with type I IFN auto‐Abs were more likely to be critically ill. The presence of type I IFN auto‐Abs was not associated with clinical outcome or with a difference in the response to treatment with IFN‐β1b and lopinavir‐ritonavir. | PMC10028524 |
AUTHOR CONTRIBUTIONS | Faizah Alotaibi and Yaseen M. Arabi conceived and designed the study, analyzed the results, and wrote the manuscript. All other authors conducted the study, collected data, revised the manuscript, and approved the final version. | PMC10028524 | ||
CONFLICT OF INTEREST STATEMENT | Infection | INFECTION | YA provided nonpaid consultations on therapeutics for MERS for Gilead Sciences and SAB Biotherapeutics, and he is a board member of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). All other authors declare no financial or commercial conflict of interest. | PMC10028524 |
ETHICS STATEMENT | The study was approved by the IRB of the Ministry of National Guard Health Affairs (MNG‐HA), Riyadh, Saudi Arabia. | PMC10028524 | ||
PEER REVIEW | The peer review history for this article is available at | PMC10028524 | ||
Supporting information |
Click here for additional data file. | PMC10028524 | ||
ACKNOWLEDGEMENTS | We thank the patients and their families for their collaboration. We thank King Abdullah International Medical Research Center, Riyadh, Saudi Arabia for funding the study. Hanan H. Balkhy's participation was during her tenure at King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia. | PMC10028524 | ||
DATA AVAILABILITY STATEMENT | The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request once all planned analyses have been completed and published or presented and after signing sharing agreement in accordance with the policies of KAIMRC for 3 years after the publication of this paper. | PMC10028524 | ||
REFERENCES | PMC10028524 | |||
Objectives | NSCLC | NON-SMALL CELL LUNG CANCER, NSCLC | This study aimed to build and validate a prediction model that can predict progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) after image-guided microwave ablation (MWA) plus chemotherapy. | PMC10598089 |
Methods | Data from a previous multi-center randomized controlled trial (RCT) was used and assigned to either the training data set or the external validation data set according to the location of the centers. Potential prognostic factors were identified by multivariable analysis in the training data set and used to construct a nomogram. After bootstraps internal and external validation, the predictive performance was evaluated by concordance index (C-index), Brier Score, and calibration curves. Risk group stratification was conducted using the score calculated by the nomogram. Then a simplified scoring system was built to make risk group stratification more convenient. | PMC10598089 | ||
Results | In total, 148 patients (training data set: | PMC10598089 | ||
Conclusions | tumor, weight loss | TUMOR | We found weight loss, histology, clinical TNM stage, clinical N category, tumor location, and tumor size were prognostic factors of progression after receiving MWA plus chemotherapy and constructed a prediction model that can predict PFS. | PMC10598089 |
Clinical relevance statement | The nomogram and scoring system will assist physicians to predict the individualized PFS of their patients and decide whether to perform or terminate MWA and chemotherapy according to the expected benefits. | PMC10598089 | ||
Key Points | PMC10598089 | |||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00330-023-09804-9. | PMC10598089 | ||
Keywords | PMC10598089 | |||
Introduction | lung cancer, cancer, NSCLC | LUNG CANCER, CANCER, NSCLC | According to GLOBOCAN 2020, lung cancer, the second most common cancer for both sexes and the most common for men, ranked first in the cause of cancer mortality in 2020 [Thermal ablation has recently been considered to be an optional therapy for advanced NSCLC. Microwave ablation (MWA), radiofrequency ablation (RFA), and cryoablation are the three most commonly used ablation categories, in which MWA has lots of advantages over the other techniques, such as less “heat‑sink” effect and better convection [At present, there is no prediction model focusing on the prognosis of patients with advanced NSCLC that received MWA and chemotherapy. Two former prediction models, which targeted predicting the local progression-free survival and overall survival (OS) of NSCLC patients treated with MWA, failed to limit the stage of NSCLC and clarify whether to combine chemotherapy with MWA [In this study, we built and validated a prediction model to predict the 1-year PFS of patients with advanced NSCLC who received MWA and chemotherapy and published a nomogram and a simplified scoring system for clinical application. | PMC10598089 |
Materials and methods | PMC10598089 | |||
MWA procedure and chemotherapy | tumor, tumors, opacity | TUMOR, OPACITY, TUMORS, COLD, COMPLICATIONS | The MWA procedures were conducted by 15 chief physicians with ≥ 5 years of experience in tumor ablation. To guide MWA, computed tomography (CT) was applied. MWA were operated with several common microwave ablation systems. The maximal output power we utilized was 70 W. Before the procedure, planning of the puncture point and the “target skin distance” for the target lesion was conducted. Once adequate anesthesia was achieved, an incision was made at the puncture point and the microwave antenna was inserted into the target lesion under CT guidance in accordance with the previous plan. If tumors were larger than 3.5 cm, two antennae would be utilized. Prior to initiating MWA, the cold circulating pipes, and pumps were connected to the antennae and machine. Technical success was determined by the attainment of post-ablation ground glass opacity measurements that exceeded the target lesion by a range of 5 to 10 mm. After 24–48 h of MWA, CT scans without enhancement were employed to screen whether there were ablation-related complications that required proper intervention.The chemotherapy was generally conducted 7 days after the MWA procedure. Pemetrexed, paclitaxel, docetaxel, gemcitabine, or vinorelbine were administrated for chemotherapy. Cisplatin, nedaplatin, or carboplatin were applied as the corresponding platinum. The chemotherapy was performed by intravenous administration and repeated every 3 weeks and at most 6 cycles. Chemotherapy response was assessed every 6 weeks amid the therapy. Contrast-enhanced CT scans of the chest were conducted at 1-, 3-, 6-, 12-, 18-, 24-, and 36-month during the follow-up and repeated every 3 months after treatment was completed. All the detailed therapy-related product information can be found in eTable | PMC10598089 |
Assessments | death | DISEASE PROGRESSION, SECONDARY | The key endpoint was progression-free survival (PFS) and the main secondary endpoint was overall survival (OS). In this study, PFS refers to the time from the beginning of therapy to disease progression or death, and OS refers to the time from the start of therapy to death. For patients who did not meet the endpoints, the censoring date was the date when their last clinical assessment was conducted. Other endpoints such as objective response rate (ORR) and time to local progression (TTLP) were recorded in the RCT but were excluded for the construction of this prediction model. | PMC10598089 |
Data processing | tumor | TUMOR, COMPLICATIONS | Continuous variables were transformed into categorical variables according to proper cutoff values. Age was cut at 65 years old to determine whether the patients belonged to the elderly. The cutoff value was set at 3.5 cm for tumor size as a tumor with a diameter larger than 3.5 cm has a high probability of failing to be completely ablated, thus two antennae were used. We chose 70 W and 10 min to cut off the ablation power and time respectively because ablation ≥ 70 W or 10 min can lead to more ablation-related complications. Three missing values have been filled up by single imputation. If there were more than 10% of values were missing, this variable would be excluded from data analysis.To build the model and conduct the validation, data collected from the hospitals located in Jinan City (Shandong Provincial Hospital; Shandong Academy of Medical Sciences; Jinan Military Region General Hospital) was made as the training data set, while the data from hospitals located in other cities was made as the external validation data set, which is completely distinct from the training data. | PMC10598089 |
Construction of the model | Statistical analysis was proceeded by R 4.2.1 for Windows (R Project for Statistical Computing; | PMC10598089 | ||
Validation and calibration of the model | The final model was subjected to 100 bootstraps resamples of the training data set and the external validation data set for internal and external validation respectively. The results of both internal and external validation were shown by the receiver operating characteristic (ROC) curve, concordance index (C-index), and Brier Score. The value of the C-index, which infers the area under the curve (AUC), ranges from 0.5 to 1.0. As 0.5 means a random chance and 1.0 means the model had a fully correct differentiating ability, it can be applied to assess the predicting ability of the final model. The value of the Brier Score ranges from 0 to 1.0, with higher values indicating better accuracy of the predicting model. To perform the calibration of the model for 1-year PFS, the predicted survival was compared with the observed survival. | PMC10598089 | ||
Risk group stratification | Risk group stratification was conducted using the score calculated by the nomogram to divide the entire data set into three risk groups. The high-, medium-, and low-risk groups included individuals whose scores were higher than the score of 30%, between the scores of 30 and 70%, and lower than the score of 70% 1-year PFS probability, respectively. Then the progression-free survival curves of each group were created by K-M estimates to compare the PFS. A simplified scoring system was built to provide a more convenient approach to evaluating the risks without decreasing the prediction accuracy of the original model. Moreover, a typical case was used to show the practicability of this system. | PMC10598089 | ||
Results | PMC10598089 | |||
Characteristics of patients | deaths | EVENTS | After selection, 148 patients (112 in the training data set and 36 in the validation data set) who were enrolled in the MWA and chemotherapy group in the RCT were included to build and validate the prediction model. There were 85 events (progression or deaths) over a median follow-up time of 13.1 months (95% confidence interval (CI), 10.2 to 16.5 months). The median progression-free survival time was 10.3 months (95% CI, 8.0 to 13.0 months). The detailed characteristics of included patients in the training and external validation data sets are presented in Table | PMC10598089 |
Prognostic predictors of PFS in the training data set | REGRESSION | As there were more than 10% of values of EGFR and ALK status in the training data set were described as unknown, both of them were excluded from data analysis. The results of LASSO regression were displayed in Fig. Results of LASSO regression. | PMC10598089 | |
Development of the prognostic nomogram for PFS | NSCLC | NSCLC | After the step-down process, a prognostic nomogram was built based on the selected predictors to determine the estimated probability of 1-year progress-free survival of patients who received MWA plus chemotherapy by calculating the total points (Fig. Nomogram for predicting PFS of advanced NSCLC patients treated with MWA plus chemotherapy. Usage: Above each variable axis locates a variable value. To calculate the score corresponding to each variable value, you need to draw a perpendicular line upward to read the number on the “Points” axis. The sum of the numbers needs to be found on the “Total Point” axis, then another perpendicular line needs to be drawn downward to acquire the 1-year progression-free survival probability | PMC10598089 |
Validation and calibration of the prognostic nomogram | In the internal validation, the C-index for this nomogram to predict PFS was 0.77 (95% CI, 0.65–0.88), while in the external validation, this index was 0.64 (95% CI, 0.43–0.85) (Fig. Statistical evaluation plots. | PMC10598089 | ||
Risk-stratifying ability of the nomogram and the simplified scoring system | NSCLC | NSCLC | According to the nomogram, 152 and 252 corresponded to 70% and 30% 1-year PFS probability respectively and thus were selected as the cutting points to conduct risk group stratification. As shown in Fig. PFS of high-, medium-, and low-risk groups in the entire data setSimplified scoring system for evaluating PFS risks in advanced NSCLC patients treated with MWA plus chemotherapyUsage: Each variable value corresponds to a point. You need to add the points based on the patient’s characteristics and find the risk group according to the sum. Patients with points < 14, 14~25, and > 25 will be considered as low risk (1-year PFS > 70%), medium risk (1-year PFS 30%~70%), and low risk (1-year PFS < 30%), respectivelyImaging data of a typical case. | PMC10598089 |
Discussion | NSCLC, tumor, lung tumors, weight loss, Lung Cancer | TUMOR, METASTASIS, LUNG TUMORS, NSCLC, LUNG CANCER | According to previous studies and clinical practice guidelines, combining thermal ablation and chemotherapy has manifested some gratifying advancements, such as improving local control rates of lung tumors and prolonging the survival of advanced NSCLC patients [The data was obtained from a multi-center, randomized, controlled, phase III clinical trial. The centers involved are all tertiary A-level hospitals located in Shandong province, China, which provided excellent medical conditions to perform such trials. This guaranteed the data used to construct the prediction model was of good quality and representativeness.From the model, we found that clinical TNM stage, tumor size, and weight loss are the three significant factors of PFS after MWA and chemotherapy in advanced NSCLC. According to The Eighth Edition IASLC Lung Cancer Stage Classification, the main difference between stage IIIB and stage IV is whether there is distant metastasis [In the model, clinical N stage, histology, and tumor location are the three predictors with relatively lower predictive efficiency. The Clinical N stage is an acknowledged risk factor for NSCLC. According to the IASLC database, a higher clinical N stage can lead to a worse prognosis [To build and validate the model, we divided the original data into two sets based on the center’s location where patients were engaged and treated in the RCT. It ensured the external validation data set conformed to the requirement of regional validation and improved the reliability of the validation. As the C-index of 0.7–0.8 and Brier Score of 0–0.25 is considered acceptable [To our knowledge, this is the first prediction model as well as the first published nomogram and scoring system for predicting the progression-free survival of advanced NSCLC patients who received MWA and chemotherapy. However, our study still has several limitations. First, due to the deficiency of original data, we failed to incorporate some potential prognostic factors (e.g., tumor cell differentiation, EGFR mutation, ALK-EML4 fusion) in variable analysis. Second, as the sample size of the external validation is relatively small, more data sets are warranted to better validate the reproductivity of the nomogram. Third, as the median follow-up time was 13.1 months, we failed to build a model that could predict 3- and 5-year PFS.In conclusion, we found weight loss, histology, clinical TNM stage, clinical N category, tumor location, and tumor size were prognostic factors of progression after receiving MWA plus chemotherapy in advanced NSCLC patients. After building and validating, we published a nomogram that can predict 1-year PFS and a simplified scoring system for risk-group stratification. Hopefully, this model will assist physicians to predict the individualized PFS of their patients and decide whether to perform or terminate MWA and chemotherapy according to the expected benefits. | PMC10598089 |
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (PDF 28 KB) | PMC10598089 | ||
Acknowledgements | The first author thanks Professor Xin Ye and Zhigang Wei for providing data. We would like to thank Editage ( | PMC10598089 | ||
Funding | The authors state that this work has not received any funding. | PMC10598089 | ||
Declarations | PMC10598089 | |||
Guarantor | The scientific guarantors of this publication are all three co-corresponding authors. | PMC10598089 | ||
Conflict of interest | The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. | PMC10598089 | ||
Statistics and biometry | Fanhao Kong has significant statistical expertise. | PMC10598089 | ||
Informed consent | Written informed consent was obtained in the original trial. | PMC10598089 | ||
Ethical approval | Institutional Review Board approval was obtained from all centers. | PMC10598089 | ||
Study subjects or cohorts overlap | NON-SMALL CELL LUNG CANCER | Some study subjects or cohorts have been previously reported in Wei Z, Yang X, Ye X et al (2020) Microwave ablation plus chemotherapy versus chemotherapy in advanced non-small cell lung cancer: a multicenter, randomized, controlled, phase III clinical trial. Eur Radiol 30:2692-2702. | PMC10598089 | |
Methodology | • prospective• randomized controlled trial• multicenter study | PMC10598089 | ||
References
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1. Introduction | inflammation, atopic dermatitis, cutaneous inflammation, pruritus, chronic eczematous skin, eczematous, eczema, trauma | INFLAMMATION, ATOPIC DERMATITIS, ECZEMA, ADVERSE EFFECTS, INFLAMMATORY CELL INFILTRATION, SKIN DISEASES, SKIN INFLAMMATION | Long-term treatments for inflammatory skin diseases like atopic dermatitis or eczema can cause adverse effects. Super Protein Multifunction (SPM) was investigated as a potential treatment for managing skin inflammation by monitoring the expression of pro-inflammatory cytokines induced using LPS and poly(I:C)/TNFα in HaCaT keratinocytes and Hs27 fibroblasts as measured via RT-PCR. SPM solution was also assessed for its effect on cytokine release, measured using ELISA, in a UVB-irradiated 3D human skin model. To evaluate the efficiency of SPM, 20 patients with mild eczematous skin were randomized to receive SPM or vehicle twice a day for three weeks in a double-blind controlled trial. In vitro studies showed SPM inhibited inflammation-induced IL-1β, IL-6, IL-33, IL-1α, TSLP, and TNFα expression or release. In the clinical study, the SPM group showed significant improvements in the IGA, PA, and DLQI scores compared to the vehicle group. Neither group showed significant differences in VAS (pruritus). Histological analysis showed reduced stratum corneum thickness and inflammatory cell infiltration. The results suggest that SPM may reduce inflammation in individuals with chronic eczematous skin.The skin serves as the body’s outermost layer, protecting it from physical trauma, toxins, and microbes. The integrity of the skin tissue is maintained by proliferating basal keratinocytes, which give rise to an epithelial layer of differentiated keratinocytes, which then transforms into the outermost cornified layer composed of dehydrated cells and keratin filaments, forming a mechanical barrier against the entry of foreign agents, and protecting the body from loss of hydration [SPM, or Super Protein Multifunction, is a composite formulation that consists of essential components required by cells to grow and survive in vitro, enhancing their recovery capability [Additionally, certain amino acids have been shown to curtail cutaneous inflammation. Glycine can activate glycine-gated chloride channels to hyperpolarize keratinocytes and reduce inflammatory output [ | PMC10454735 |
2. Results | PMC10454735 | |||
2.1. SPM Treatment Suppresses Inflammatory Response Induced by LPS | inflammation, tumor necrosis, TNF-α | INFLAMMATION, TUMOR NECROSIS | LPS induces inflammation in human skin cells and stimulates a robust immune response by inducing inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1 family (IL-1), and interleukin-6 (IL-6) [To investigate the effect of SPM on inflammation, we assessed the IL-1β mRNA expression in HaCaT cells after a 24 h stimulation with LPS, followed by treatment with 10% or 20% SPM. The objective was to compare the optimal dose (20%) with the lowest dose (10%) of SPM to determine whether even the lowest dose exhibits an anti-inflammatory effect. First, cells were stimulated with 0 (control), 25, or 50 μg/mL LPS for 24 h. The expression of IL-1β was significantly increased by LPS at the concentration of 50 μg/mL (In human epithelium-derived fibroblasts, LPS induces the production and secretion of cytokines IL-1α and IL-6 [These results indicate that SPM supplementation suppresses cytokine expression from inflamed skin-derived epithelial and fibroblast cultures. | PMC10454735 |
2.2. SPM Treatment Downregulates the Expression of Cytokines Induced by Poly (I:C)/TNFα in HaCaT Cells | We evaluated SPM’s anti-inflammatory effects by measuring the cytokine levels (IL-1β, IL-6, IL-33, and TSLP; Thymic stromal lymphopoietin) in HaCaT cells stimulated by poly(I:C)/TNFα ( | PMC10454735 | ||
2.3. SPM Suppresses the UVB-Induced Production of Inflammatory Cytokines in a Human Epidermis Model | inflammation | INFLAMMATION | We also investigated the anti-inflammatory effect of SPM on UVB-induced inflammation in a 3D human skin model; higher doses of SPM (50% and 100%) were tested to ensure a measurable response within the model. After exposure to 250 mJ/cm | PMC10454735 |
2.4. SPM Ameliorates Symptoms and Signs of Eczematous Dermatitis | dermatological ailments, eczematous skin diseases, atopic dermatitis | ATOPIC DERMATITIS, CHRONIC ECZEMA | Unmitigated cutaneous immune responses are integral to local and systemic inflammatory processes that manifest in dermatological ailments [Twenty subjects with eczematous skin diseases such as chronic eczema or atopic dermatitis ( | PMC10454735 |
3. Discussion | eczematous skin lesions, inflammation, atopic dermatitis, cutaneous lesions, AD, eczema | PROLIFERATION, INFLAMMATION, DISEASE, ECZEMATOUS DERMATITIS, ATOPIC DERMATITIS, CUTANEOUS INFLAMMATION, DYSFUNCTION, PROLIFERATIVE, SKIN DISEASES, ECZEMA | In this combined in vitro and clinical study, we have shown the regenerative and anti-inflammatory effects of SPM. Cutaneous inflammation contributes to progressive symptoms of eczema and chronic atopic dermatitis (AD) [In our in vitro studies, SPM supplementation suppressed IL-1β, IL-6, IL-33, and TSLP transcription in inflamed human keratinocytes (In our clinical study, 3 weeks of topical SPM treatment on eczematous skin lesions ameliorated the signs and symptoms of eczema and atopic dermatitis (SPM comprises numerous components with potential or reported bioactivity in the skin tissue. Among the active components of SPM is an array of amino acids; these can activate specific amino acid receptors to influence signal transduction, proliferation, and inflammation [In addition to immunological dysfunction, disturbed skin barrier also plays a role in developing AD and eczema [In our UV-irradiated 3D epidermis model, an increased level of p63 in the presence of SPM was observed p63, a keratinocyte stem cell marker [One could speculate that SPM inhibits inflammation and increases regeneration by promoting stem cell proliferative potential and activation. However, how SPM relates to stem cell activation requires further exploration. Future studies of topical SPM treatment on eczema or atopic dermatitis with various degrees of disease, longer treatment durations, and in combination with other treatments such as steroids will help us determine the best practice for incorporating SPM to treat inflammatory skin diseases.In conclusion, SPM supplementation significantly reduces the expression and release of inflammatory cytokines in human skin cells in vitro and in a 3D epidermis model. When applied topically, SPM limits the symptoms of eczema and atopic dermatitis for at least three weeks. Our findings suggest that SPM may be developed as a potentially effective topical agent for managing inflammation in case of mild or moderate cutaneous lesions such as eczematous dermatitis. | PMC10454735 |
4. Materials and Methods | A detailed description of the materials and methods is provided in | PMC10454735 | ||
4.1. Cell Culture | HaCaT cells were obtained from CLS Cell Lines Service GmbH (Cat # 300493), and Hs27 cells were purchased from ATCC, American Type Culture Collection (CRL-1634). Dulbecco’s Modified Eagle’s Medium (DMEM) was purchased from Gibco (Cat # 11996-065) and ATCC (Cat # 30-2002). HaCaT cells were grown in DMEM (Gibco, Waltham, MA, USA) supplemented with 10% fetal bovine serum (Cat # 16000-044, Gibco), 100 U/mL penicillin, and 100 mg/mL streptomycin (Cat # P4458, Gibco) in 5% CO | PMC10454735 | ||
4.2. Cell Viability Assay | The viability of HaCaT cells was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (Thermo Fisher, Waltham, MA, USA). The viability of Hs27 fibroblasts was determined via automated time-course imaging using Incucyte (Sartorius, Göttingen, Germany). | PMC10454735 | ||
4.3. Cell Stimulation | To induce inflammatory stimulation, we seeded HaCaT and Hs27 cells in 6-well plates and cultured them for 24 h to reach 50% confluency. The culture medium was removed and replaced with serum-free DMEM supplemented with LPS or 10 μg/mL poly(I:C) and 20 ng/mL TNFα. Cells were incubated with LPS for 24 h. After washing with PBS twice, they were treated with SPM or vehicle (distilled water in serum-free DMEM) for another 24 h. Cells were incubated together with poly(I:C)/TNFα cocktail and SPM for 24 h. | PMC10454735 | ||
4.4. Human Skin Model | The growth and differentiation of KeraSkin | PMC10454735 | ||
4.5. Enzyme-Linked Immunosorbent Assay (ELISA) | ELISA kits (R & D systems, Santa Clara, CA, USA) were utilized to measure IL-1α, TSLP, and TNFα in a culture medium. The content was measured following the provided protocol. | PMC10454735 | ||
4.6. Statistical Analysis | GraphPad 10.0.1(218) software was used to analyze statistical analyses of in vitro studies. All data points were presented as means and standard deviations. One-way ANOVA followed by Tukey’s multiple comparison tests was used to determine statistical differences between groups. The statistical significance was determined by | PMC10454735 | ||
4.7. Clinical Study | itch, edema, IGA, erythema, itchiness, skin lesion, excoriation | LICHENIFICATION, ADVERSE REACTIONS, EDEMA, MINOR, ERYTHEMA, SKIN LESION, BLIND, SKIN LESIONS | The study was a three-week, randomized, double-blinded, placebo-controlled clinical trial conducted at Yonsei University Severance Hospital (Seoul, Republic of Korea) from October 2018 to February 2019. The protocol was approved by the Yonsei University Severance Hospital Institutional Review Board (IRB protocol no. 4-2018-0124). A total of 23 subjects were screened, and 20 subjects (16 females, 4 males) with Fitzpatrick skin types II-IV enrolled in the study after their written informed consent was approved by the IRB. Inclusion criteria included the following (Subjects were randomly assigned to either a vehicle or an SPM solution. Study subjects were instructed to topically apply either the SPM test solution or the placebo (with vehicle only) exclusively to each randomly designated skin lesion with 1 mL dosage volume per single palm area of skin lesion twice daily (once in the morning and once in the evening). Subjects were also instructed to refrain from local treatments, such as skin peeling and laser treatment, and from using cosmetics containing growth factors or stem cell culture fluids on the application area during this study. The test and vehicle agents were randomly coded, and the subjects and the clinical research staff carrying out the administration, training, and distribution were blind to the contents of the test agents. During self-administration, the subjects returned to the clinic twice: 1 week (±3 days) after treatment initiation for mid-treatment evaluation and 3 weeks (±3 days) after treatment initiation for end-of-treatment evaluation. A dermatology specialist evaluated the skin lesions to which SPM or vehicle had been applied by Investigator Global Assessment (IGA) by scoring the changes in signs or symptoms (erythema, scaling, excoriation, edema, lichenification, and papules) as follows: 1, no improvement; 2, 1–25%; 3, 26–50%; 4, 51–75%; or 5, 76–100% at the end of the study, and via photographic assessment (PA). For PA, two investigators independently evaluated the severity of skin lesion symptoms on a scale of 1 to 5 as they appeared in digital photographs of the skin lesions taken at the beginning and the end of the 3-week treatment. Subject-reported impact on quality of life from the skin symptoms was evaluated from the Dermatological Life Quality Index (DLQI), in which a lower score correlates with a more minor impact at the end of the 3-week application. The degree of itchiness for the SPM or vehicle-applied skin lesion was evaluated using VAS (0–10 scale, lower score correlates to less itch) within the last 24 h from the time of reporting. DLQI and VAS questionnaires were conducted at the beginning and the end of the 3-week treatment. The investigators, board-certified dermatologists, were kept blind to the treatment groups until the end of the study.Outside of subject visits, any adverse reactions during the treatment or within 30 days from the end of treatment were to be reported by the subjects within 24 h of occurrence, and causality between the adverse reactions and the treatment was assessed by the investigator. | PMC10454735 |
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