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3. Results | PMC10637569 |
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3.1. Participants | cedar pollinosis | Ninety-one people consented to inclusion after explanation of this study, all of whom lived nearby. Eleven people were excluded because they did not meet inclusion criteria. Forty healthy subjects were allocated to placebo (n = 21) and probiotics groups (n = 19), and forty patients with Japanese cedar pollinosis were allocated to placebo (n = 20) or probiotics groups (n = 20) (Fig. Background of subjects.Flow chart of participant inclusion in this study. | PMC10637569 |
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3.3. Plasma JCP-specific IgE | JCP | In Japan, JCP are released into the air during the spring, and the peak of this release is in March and April. This trial was begun from late January to early February. The average JCP abundance in air was 4.1/mConcentration of serum JCP-specific IgE relative to baseline are shown in Table Concentration of serum JCP-specific IgE (relative to baseline).95% CI indicated difference of IgE concentration between placebo and probiotics groups (Probiotics—Placebo). | PMC10637569 |
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3.4. Change of allergic rhinitis symptoms during JCP season | allergic rhinitis | ALLERGIC RHINITIS | To evaluate improvement of allergic rhinitis symptoms in probiotics, we analyzed the change of scores in severity of allergic rhinitis symptoms from the start to all observation points. The severity of allergic rhinitis symptoms relative to baseline are shown in Table The severity of allergic rhinitis symptoms (relative to baseline).95% CI indicated difference of each nasal symptoms score between placebo and probiotics groups (Probiotics—Placebo). | PMC10637569 |
3.5. Effect of probiotics on intestinal flora | To evaluate the effect of probiotics in intestinal flora, we analyzed the fatty acids and organic anions, which were metabolites of intestinal bacteria. Short-chain fatty acids and organic anions in stools relative to baseline are shown in Table Short-chain fatty acid and organic anions in stool (relative to baseline).95% CI indicated difference of fatty acids and organic anions concentration between placebo and probiotics groups (Probiotics—Placebo). To confirm the increase of Occupation ratio (relative to baseline) of microbacteria in stool.95% CI indicated difference of occupation ratio of microbacteria between placebo and probiotics groups (Probiotics—Placebo). | PMC10637569 |
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3.6. Effect of probiotics on psychological conditions | mood disturbances, TMD, mood disturbance | We monitored the psychological conditions of all subjects in the trial using the POMS2 questionnaire to evaluate the condition of anger-hostility (AH), confusion-bewilderment (CB), depression-dejection (DD), fatigue-inertia (FI), tension-anxiety (TA), vigor-activity (VA), friendliness (F), and total mood disturbances (TMD). POMS2 t-scores relative to baseline are shown in Table POMS2 t-scores (relative to baseline).95% CI indicated difference of t-scores (relative to baseline) in each variable between placebo and probiotics groups (Probiotics—Placebo). AH = anger- hostility, CB = confusion-bewilderment, DD = depression- dejection, F = Friendliness, FI = fatigue-inertia, TA = tension-anxiety, TMD = total mood disturbance, VA = vigor-activity. | PMC10637569 |
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3.7. Post hoc analysis in relation to occupation ratio to | nasal blockage | Analysis of intestinal flora indicated that the occupation ratio of Changing occupation ratio of In this study, the symptom of nasal blockage was improved by NTM048 12 weeks after the start of trial. The changes of occupation ratio were affected by NTM048 for 16 weeks. The changes of occupation ratio could therefore be directly reflected in improvement of nasal blockage 12 weeks after the start of the trial. Hypothesizing that the occupation ratio was linearly increased in a time-dependent manner, we evaluated the association between improvement of nasal blockage and increasing the occupation ratio of | PMC10637569 |
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4. Discussion | cedar pollinosis, allergy, nasal blockage, JCP, eczema | ALLERGY, ECZEMA | This randomized, double-blinded, placebo-controlled trial examined whether a probiotic, NTM048, increased the amount of s-IgA in saliva of adults who took an oral dose for 16 weeks during the period when JCP are most scattered in the air in Japan. In the current study, there was no promotion of secretion of s-IgA in saliva in the probiotics group at 4, 8, 12 and 16 weeks after the start of the trial (Table s-IgA is the most abundant immunoglobulin isotype in saliva, and s-IgA protects invasion of microorganisms in oral mucosa.Probiotics reportedly prevented the IgE-associated allergy including eczema.Psychological status was measured by POMS2 following collection of saliva samples, because salivary s-IgA was reported to be affected by acute psychological stress.NTM048 increased the level of succinic acid in fecal samples of all subjects or in samples of patients with Japanese cedar pollinosis (Table This study demonstrated that NTM048 strain ameliorated the nasal blockage in the 12 weeks when JCP was most scattered in the air. Focusing on the relationship between the improvement of nasal blockage and occupation ratio of This study was performed to examine whether NTM048 promoted the secretion of total s-IgA in saliva, and whether any promotion improved Japanese cedar pollinosis. Due to this goal, healthy subjects and patients with Japanese cedar pollinosis were recruited. NTM048 could not promote secretion of total s-IgA in the saliva of either group of adult subjects. The mechanisms of improving nasal blockage in NTM048 administration remain unclear in the current study because blood cytokine levels and cytometric profiling of whole blood were not measured. Adequate dose of NTM048 to improve the psychological status was unclear because this dose (1 × 10In conclusion, NTM048 did not promote secretion of s-IgA in saliva. However, it did improve the symptom of nasal blockage associated with JCP. post hoc study indicated that the psychological status was improved in the subjects with possible increase in occupation NTM048 ratio in the stool. Future study should analyze the improvement of specific psychological status and the symptom of nasal blockage in a dose-dependent manner. | PMC10637569 |
Acknowledgments | We acknowledge editing and proofreading by Benjamin Phillis from the Clinical Study Support Center at Wakayama Medical University. | PMC10637569 |
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Supplementary Material | PMC10637569 |
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Abbreviations: | Yamagishi N | colony forming unitJapanese cedar pollenProfile of Mood States 2nd Editionsecreted IgAThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.Supplemental Digital Content is available for this article.The study was supported by funding from Noster Inc.The authors have no conflicts of interest to disclose.How to cite this article: Yamamoto Y, Sugita G, Hiraoka M, Takagi S, Yamagishi N, Kawashima S, Tanioka K, Nishi T, Yamamoto S, Kakutani C, Yanase A, Kanai Y, Kato S, Hotomi M. | PMC10637569 |
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References | PMC10637569 |
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Subject terms | stroke, cardioembolic stroke, ischemic stroke, Parkinson’s disease, CAD, PD, MR | STROKE, ISCHEMIC STROKE, DISEASES, CORONARY ARTERY DISEASE, CAD | Parkinson’s disease (PD) and cardio-cerebrovascular diseases are related, according to earlier studies, but these studies have some controversy. Our aim was to assess the impact of PD on cardiocerebrovascular diseases using a Mendelian randomization (MR) method. The data for PD were single nucleotide polymorphisms (SNPs) from a publicly available genome-wide association study (GWAS) dataset containing data on 482,730 individuals. And the outcome SNPs data is were derived from five different GWAS datasets. The basic method for MR analysis was the inverse variance weighted (IVW) approach. We use the weighted median method and the MR-Egger method to supplement the MR analysis conclusion. Finally, We used Cochran’s Q test to test heterogeneity, MR-PRESSO method and leave-one-out analysis method to perform sensitivity analysis. We used ratio ratios (OR) to assess the strength of the association between exposure and outcome, and 95% confidence intervals (CI) to show the reliability of the results. Our findings imply that PD is linked to a higher occurrence of coronary artery disease (CAD) (OR = 1.055, 95% CI 1.020–1.091, P = 0.001), stroke (OR = 1.039, 95% CI 1.007–1.072, P = 0.014). IVW analyses for stroke’s subgroups of ischemic stroke (IS) and 95% CI 1.007–1.072, P = 0.014). IVW analyses for stroke’s subgroups of ischemic stroke (IS) and cardioembolic stroke (CES) also yielded positive results, respectively (OR = 1.043, 95% CI 1.008–1.079, P = 0.013), (OR = 1.076, 95% CI 1.008–1.149, P = 0.026). There is no evidence of a relationship between PD and other cardio-cerebrovascular diseases. Additionally, sensitivity analysis revealed reliable outcomes. Our MR study analysis that PD is related with an elevated risk of CAD, stroke, IS, and CES. | PMC10665329 |
Introduction | Parkinson’s disease, PD | DISEASES | Parkinson’s disease (PD) is one of the most common senile diseases | PMC10665329 |
Methods | PMC10665329 |
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Mendelian randomization data and process | PD, cardio-cerebrovascular diseases | To investigate the causal link between PD and cardio-cerebrovascular diseases, we used a two-sample MR research. Figure Flow chart of Mendelian stochastic analysis, The study satisfies the three main assumptions of Mendelian randomization: Assumption 1: The solid line indicates that the instrumental variants directly affects the incidence of PD. Assumption 2: Dashed lines indicate that instrumental variables are not related to any potential confounders. Assumption 3: The instrumental variables affect the outcome only through the exposure, and not through any other causal pathways. | PMC10665329 |
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Instrumental variables selection | The SNPs included in the study must meet the three main hypotheses of MR: (i) genetic variation is strongly associated with exposure (correlation hypothesis); (ii) genetic variation is independent of known or unknown confounders (independence hypothesis); (iii) genetic variation is only associated with the outcome of exposure (exclusion hypothesis). To meet the above assumptions we developed the following inclusion criteria: The SNPs incorporated into the study were highly correlated with a significance threshold ( | PMC10665329 |
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SNPs associated with PD | The PD-related SNPs were selected from the publicly available GWAS database from International Parkinson’s Disease Genomics Consortium, which included data from a total of 482,730 European individuals, with 33,647 in the ncase group and 449,056 in the ncontrol group | PMC10665329 |
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SNPs associated with cardio-cerebrovascular diseases | cardio-cerebrovascular diseases, HF, artery stroke, stroke, cardioembolic stroke, ischemic stroke, CAD, heart failure | ATRIAL FIBRILLATION (AF), STROKE, ISCHEMIC STROKE, HEART FAILURE, CORONARY ARTERY DISEASE, CAD | The cardio-cerebrovascular diseases included in the study were coronary artery disease (CAD), myocardial infarction(MI), atrial fibrillation (AF), heart failure (HF), stroke, ischemic stroke (IS), large artery stroke (LAS), cardioembolic stroke (CES). We show the outcome data in detail in Table The basic characteristics of outcomes.The SNPs for CAD were obtained from an open study by Ishigaki et al. | PMC10665329 |
Mendelian randomization analysis | PD, MR, cardio-cerebrovascular diseases | To determine whether there is a causal association between PD and cardio-cerebrovascular diseases, we mostly employ the inverse variance weighted (IVW) approach for MR analysis. An IVW estimate is a measure of the combined overall effect size of Wald ratio estimates for individual SNPs. The IVW method is highly effective and reliable when all the SNPs included in the analysis are valid and uncorrelated | PMC10665329 |
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Sensitivity analysis | To analyze horizontal pleiotropy, the intercept for MR-egger analysis was employed, and the test’s intercept does exist (The results of the MR sensitivity analysis. | PMC10665329 |
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Ethics statement | Ethical review and approval are not required for research with human participants per local legislation and institutional requirements. Written informed consent to participate is not required for this study in accordance with national legislation and institutional requirements. | PMC10665329 |
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Results | PMC10665329 |
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Results of the two-sample mendelian randomization analysis | PD, CAD, stroke | STROKE, CAD | In the analysis, we used 23 SNPs that had substantial associations with PD (By utilizing the merging tool to find 20 SNPs in the CADs GWAS data, we then eliminated two palindromic SNPs (rs10451230, rs823106) so that only 18 SNPs were included in the final MR analysis. According to our primary IVW analysis, PD is linked to a higher incidence of CAD (OR = 1.055, 95% CI 1.020–1.091, Forest plot for MR detection.((We found 23 SNPs in the stroke and its subgroups GWAS date by using the merge function and then removed one palindromic SNP (rs10451230), such that 22 SNPs were included in the final MR analysis. According to the MR test scatter plots shown in Fig. In our study, 20 SNPs, 22 SNPs, 16 SNPs, and 22 SNPs were included in the MR analysis of MI, AF, HF, and LAS, respectively, and the results of the IVW analyses suggested that there was no causal relationship between PD and the incidence of MI (OR = 0.984, 95% CI 0.950–1.020, | PMC10665329 |
Reverse Mendelian randomization analysis | stroke, CAD, PD | STROKE, CAD | We used reverse MR to see if there was a known causal association between CAD, stroke, IS, CES, and PD. The results of the IVW analyses suggested that there was no causal relationship between CAD (OR = 0.969, 95% CI 0.903–1.039,Forest plot for reverse MR detection.We performed a sensitivity analysis on the results of the reverse MR analysis (Table The results of the reverse MR sensitivity analysis. | PMC10665329 |
Discussion | stroke, Alzheimer’s disease, PD, CAD, Lewy body diseases, Lewy | CVD, STROKE, LEWY BODY DISEASE, DISEASES, PATHOGENESIS, CAD | Our study reveals a potential relationship between PD and CAD and stroke (including subtypes IS, CES), which is consistent with the results of previous small cohort studies, but past cohort studies were smaller and had a lower level of evidencePD is the second most common neurodegenerative condition after Alzheimer’s disease in terms of prevalenceWe explored the relationship between PD and CAD by five MR methods, and all findings consistently suggested an association between PD and increased incidence of CAD. For the effect of PD on the increased incidence of CAD, we believe that the following mechanisms exist: First, PD is a Lewy body diseases, and excessive deposition of Lewy bodies in PD patients was clarified and reported in 1997, and excessive deposition of Lewy bodies leads to cardiac sympathetic denervationThe relationship between PD and stroke has been studied more in the past, some studies have suggested that PD causes an increased risk of stroke, mainly related to abnormalities in α-synuclein metabolism, α-synuclein is a 14.5 kDa protein located predominantly in the presynaptic terminals of the mammalian brain, and over-accumulates in Lewy bodies upon gene expressionThis MR study also have some limitations, first, due to racial differences in GWAS data, its test results may be affected by population stratification bias. Second, since most of the population in this study originated in Europe, we are not sure if the same conclusions can be drawn in other populations. Third, the potential pleiotropy of some SNPs may affect the detection results. Fourth, there were some sample duplications in the included studies, which could have led to biased MR estimates, but the F-statistic we detected were all greater than 10, and the assessment of this bias should be small.In conclusion, we explored the relationship between PD and cvd at the genetic level for the first time using MR analysis, an approach that excludes environmental confounders and reverse causality bias that have been seen in previous observational studies, and provides additional clues to the pathogenesis of PD and cardio-cerebrovascular diseases as well as to therapeutic regimens. The results suggest that PD may be a potential pathogenetic factor for CAD and stroke, which is consistent with previous animal and clinical observations studies. This suggests that it is more important to achieve early screening and treatment of CAD and stroke in patients with PD. | PMC10665329 |
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-47708-2. | PMC10665329 |
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Acknowledgements | We thank researchers such as Ishigaki K, Nielsen JB, Shah S, CARDIoGRAMplusC4D Consortium, MEGASTROKE Consortium, for providing the publicly available GWAS data for this study. | PMC10665329 |
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Author contributions | Z.Z. and J.H. designed the methods and carried out the statistical analyses. Z.Z., M.Z., and Q.F. made substantial contributions to the acquisition and analysis of the data and the interpretation of data. All the authors contributed to the data extraction, drafted the article, and approved the final version of the manuscript. | PMC10665329 |
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Funding | The study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82170445). | PMC10665329 |
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Data availability | PD | DISEASES | The original contribution presented in this study is included in the article/supplementary material, further inquiries can be made to the corresponding author. All the datasets related to PD and cardio-cerebrovascular diseases are freely available from IEU OpenGWAS project, the link for PD is ( | PMC10665329 |
Competing interests | The authors declare no competing interests. | PMC10665329 |
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References | PMC10665329 |
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KEYWORDS | PMC10269629 |
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INTRODUCTION | hyperlipidemia | HYPERLIPIDEMIA | The rapid development of the world economy has dramatically changed people's living standards and diet structure, and the fast-food diet structure has also led to an obvious increase in the proportion of high-fat foods in the daily diet (Several studies have found a link between hyperlipidemia and human gut microbiota, for example, significant differences in the gut microbiota profile between hyperlipidemic and healthy individuals (including animals) (Wang et al. found that feeding animals with high-fat diets disrupted both the host’s antioxidant capacity and gut microbiota balance, ultimately leading to the exacerbation of hyperlipidemic symptoms (This study hypothesized that probiotics could regulate the gut microbiota balance in hyperlipidemic patients and improve hyperlipidemic symptoms via modulating the host lipid metabolism. In this 3-month intervention trial, a total of 56 hyperlipidemic patients were recruited and randomized into the placebo and probiotic (receiving a mixed probiotic formulation) groups. The fecal microbiome and serum lipids of these patients were analyzed using metagenomics and liquid chromatography–mass spectrometry (LC-MS), respectively. Meanwhile, changes in patients’ physiological and biochemical parameters were recorded. This study confirmed the beneficial effect of Probio-X in managing hyperlipidemia. | PMC10269629 |
RESULTS | PMC10269629 |
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Probio-X improved blood lipid indexes in a hyperlipidemia population. | hyperlipidemia | HYPERLIPIDEMIA | Body weight, height, and work employment were collected and analyzed (Information of patientsThere were no significant differences in all blood biochemistry between the placebo and probiotic groups at baseline. The blood analysis of hyperlipidemic patients showed that the total cholesterol (TC) and low-density lipoprotein (LDL-C) levels decreased significantly after probiotic consumption (paired Probio-X improved blood lipid indexes in hyperlipidemia patients. (A) Comparative analysis of (A) blood indicators; (B) body weight and composition; (C) gut mucosa indicators. (D) Number of patients that were responsive toward probiotic treatment, evaluated by changes in four key blood lipid indicators. Chi-square test was performed to evaluate the overall difference between two groups. LDL-C, low-density lipoprotein; TC, total cholesterol; HDL-C, high-density lipoprotein; TG, triglyceride; *, We further analyzed changes in the four main blood lipid indicators in the placebo and probiotic groups ( | PMC10269629 |
Probio-X improved dietary and exercise habits in hyperlipidemic patients. | hyperlipidemia | REMISSION, HYPERLIPIDEMIA | A self-administered questionnaire was applied to record the dietary and exercise habits of the hyperlipidemic patients during the trial intervention. We thus analyzed changes in dietary and exercise habits in patients showing improvements in TC, LDL-C, and HDL-C. Interestingly, patients in the probiotic group that showed a significant decrease in TC (Probio-X improved dietary and exercise habits and gastrointestinal wellness in hyperlipidemia patients. Comparative analysis of habits of vegetables/dairy product consumption and weekly exercise in (A) patients with normal total cholesterol (TC); (B) low-density lipoprotein (LDL-C) populations; and (C) high-density lipoprotein (HDL-C) remission populations. (D) Comparative analysis of patients’ feelings of gastrointestinal wellness. Pla_0M and Pla_3M indicate before and 3 months after the placebo intervention, respectively, and Pro_0M and Pro_3M before and 3 months after the probiotic intervention, respectively. | PMC10269629 |
Changes in patients’ fecal microbiota after Probio-X intervention. | HYPERLIPIDEMIA | Although numerous studies in recent years have observed a strong association between the gut microbiota and onset/progression of hyperlipidemia, our microbial alpha diversity analysis (Shannon and J indexes) of subjects’ fecal microbiota revealed no significant intra-/intergroup differences (paired Wilcoxon test, Changes in fecal microbiota after Probio-X intervention. (A) Shannon index. (B) J index. (C) Relative abundance of dominant species. (D) Principal coordinate analysis (Bray-Curtis distance). (E) Linear discriminant analysis effect size (LEfSe) analysis. Distribution of (F) dominant metagenome-assembled genomes (MAGs) in each subject; (G and H) the MAG, B14_32, and the applied probiotic strains (Probio-M8, This study also analyzed the profile of metagenome-assembly genomes (MAGs) in the fecal microbiota ( | PMC10269629 |
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Changes in patients’ serum lipid profile after Probio-X intervention. | ’ lipid blood metabolic | It is known that gut microbiota interacts with the host metabolism and influences the blood metabolome. Therefore, patients’ lipid blood metabolic profile was analyzed by principal-component analysis (Changes in serum lipid profile after Probio-X intervention. (A and B) Principal-component analysis of serum lipid metabolomes of subjects. Each dot represents the serum lipid metabolome of each subject. (C) Volcano map showing detected serum lipid metabolites. Non-SIG represented metabolites without significant increase after probiotic intervention, UP represented metabolites with significant increase after probiotic intervention. Significantly increased metabolites are shown in red. (D) Relative abundance heatmap of differential metabolites. The color scale represents the relative abundance of metabolites. (E) Box plots showing the normalized amounts of acetyl-carnitine and free carnitine after probiotic intervention. (F) Violin plots showing differences in various lipid metabolites after probiotic intervention. G, monoglyceride; CAR, acyl carnitine; CE, cholesterol lipids; FFA, free fatty acids; LPI, lysophosphatidylinositol; PI, phosphatidylinositol; PS, phosphatidyl serine. Pla_0M and Pla_3M indicate before and 3 months after the placebo intervention, respectively, and Pro_0M and Pro_3M before and 3 months after the probiotic intervention, respectively. | PMC10269629 |
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Changes in predicted gut metabolites after Probio-X intervention. | hyperlipidemia | HYPERLIPIDEMIA | The probiotic treatment did not seem to drastically modulated patients’ fecal microbiota structure and composition; thus, we further investigated the mechanisms of regulation of hyperlipidemia by analyzing probiotics-driven changes in predicted gut metabolites from the MAGs. A total of 41 gut metabolites were predicted across 337 MAGs (selection criteria: integrity greater than 80, contamination less than 10, and relative abundance greater than 1%; data not shown). The gut metabolite, MGB043, was common to the majority of MAGs, while MGB034, MGB055, MGB056, and MF0059 were predicted to be present exclusively in only one MAG. A total of 20 gut metabolites were predicted from the MGB database, including the major metabolites MGB011 and MGB043 (Predicted gut metabolites. (A and B) Relative abundance of predicted gut metabolites. (C) Violin plots showing differential gut metabolites. Correlation heatmap of (D) metagenome-assembly genome (MAGs) and gut metabolites; (E) MAGs and blood indicators. Red indicates positive correlation, blue indicates negative correlation, and the color intensity is the strength of correlation. *, Correlation analysis revealed significant positive correlations between three predicted differential gut metabolites (cortisol degradation, glycolysis, and pentose phosphate pathway) and almost all differential MAGs (Spearman's test, | PMC10269629 |
DISCUSSION | asthmatic, dyslipidemia, hyperlipidemia | ASTHMATIC, HIGH TRIGLYCERIDES, DYSLIPIDEMIA, HYPERLIPIDEMIA | Gut microbiota are associated with the host metabolism and may influence the onset and development of hyperlipidemia (Our data supported that the intake of the probiotic mix could effectively reduce the serum levels of TC and LDL-C, while increasing serum HDL-C levels, in patients with hyperlipidemia. Such results supported that probiotic application could regulate hosts’ lipid metabolism. There are different subtypes of dyslipidemia (e.g., high cholesterol and/or high triglycerides), which would require different treatment approaches. For example, Yan et al. found that oryzanol could reduce the TC of serum in rats (The results of the self-administered questionnaire revealed interesting and desirable lifestyle habit changes (such as increased daily vegetable consumption, regular dairy consumption, and increased weekly exercise time) in hyperlipidemic patients that showed significant improvement in blood lipid indexes (TC, LDL-C, and HDL-C) after probiotic consumption. Indeed, there was a strong association between the desirable changes in patients’ lifestyle habits and lowering of these indexes. Wastyk et al. believe that diet and gut microbiota are interacting bidirectionally. In other words, diet regulates the gut microbiota, and vice versa (Although a large body of study has supported that the gut microbiota serve as an important mediator of lipid metabolism, our study did not observe drastic probiotic-driven changes in the fecal microbiota structure and composition, which could be related to the high complexity of the human gut microbiota. Similar observation was made by Liu et al., where the authors investigated effects of probiotics on the gut microbiome of asthmatic patients (The blood lipid metabolome of subjects did not change significantly regardless of probiotic intervention, but further analysis of lipid metabolites identified two differential metabolites, i.e., acetyl-carnitine and free carnitine, that were significantly increased after the mixed probiotic intervention. The human body, as an extremely complex microecosystem, has a strong capacity to maintain organismal stability by self-regulation, which may be one of the reasons for the nonsignificant change in the overall blood metabolome and low number of differential metabolites. However, it is worth noting that acetyl-carnitine plays an integral role in lipid metabolism by participating in the β-oxidation of long-chain fatty acids (Our further analysis found that | PMC10269629 |
Conclusions. | HYPERLIPIDEMIA | We performed a 3-month intervention trial and confirmed the beneficial effects of application of a probiotic mix in alleviating hyperlipidemia, at least in part, by regulating the blood lipid indexes (lowering serum TC, LDL-C, and HDL-C), lipid metabolism, and gut microbiota. Although insignificant changes were observed in the lipid metabolome and gut microbiota structure, some interesting fecal bacteria (e.g., | PMC10269629 |
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MATERIALS AND METHODS | PMC10269629 |
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Probiotic administration. | Probio-X (3 × 10 | PMC10269629 |
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Trial design and subject recruitment. | diabetes, cancer, kidney disease, mental illness, hyperlipidemia | DIABETES, GASTROINTESTINAL DISEASES, DISEASES, HYPERLIPIDEMIA | This study was a 3-month randomized controlled double-blind trial. A total of 112 patients with hyperlipidemia were recruited. All patients were recruited by the Inner Mongolia People's Hospital and Inner Mongolia Agricultural University. The inclusion criteria were as follows: (i) male or female aged between 18 and 65 with diagnostic criteria for hyperlipidemia; and (ii) willingness to commit throughout the trial. In contrast, the exclusion criteria were as follows: (i) a history of major diseases, such as cancer, kidney disease, gastrointestinal diseases, mental illness, or type I diabetes; (ii) takin antibiotics, probiotics, prebiotics, postbiotics, and immunosuppressive agents within 1 month before the intervention or during the intervention; (iii) irregular eating habits during the intervention and follow-up period; and (iv) failure to collect stool and blood samples twice. Forty-three subjects were excluded after the first round of screening; sixty-nine patients were randomly assigned to probiotic ( | PMC10269629 |
Collection and processing of stool and blood samples. | STERILE | The study was conducted for 3 months, and feces and blood were collected from all participants at days 0 and 90 after the start of the study. Stool samples were self-collected by each subject at the specified time point at home using a uniformly provided sterile stool sampler with DNA protection solution (Guangdong Longhai Biomedical Co., Ltd., Guangzhou, China). All patients were given prior training in the fecal collection procedure to prevent fecal contamination during the collection process. Collected samples were transported to the hospital at low temperature and were stored in a −80°C freezer before the next steps of sample processing for deep metagenomic sequencing.All patients were asked to visit the hospital after stool sample collection, when blood samples (after a 12-h fast) were taken. All collected blood samples were stored in sterile centrifuge tubes, before centrifuging at 4°C for 15 min at 3,000 The study was approved by the Ethics Committee of the Inner Mongolia People's Hospital (no. 201811002) and was registered on the Chinese Clinical Trial Registry ( | PMC10269629 |
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Analysis of biochemical indicators. | TG | BLOOD | Blood samples were used for monitoring physiological and biochemical changes in the subjects. The analyzed physiological/biochemical parameters mainly focused on lipid metabolism, namely, LDL-C, TC, HDL-C, high-sensitivity C-reactive protein [hsCRP], fasting serum glucose, TG, serum uric acid, diamine oxidase, | PMC10269629 |
Statistical analysis and data visualization. | All statistical analyses were performed using the R software (v 4.0.3), and data were expressed as mean ± SD. Wilcoxon test and | PMC10269629 |
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ACKNOWLEDGMENTS | This research was supported by the Inner Mongolia Science and Technology Major Projects (2021ZD0014), the National Natural Science Foundation of China (31720103911), the Health Science and Technology Planning Project of Inner Mongolia (202202026), and the earmarked fund for CARS36.We declare no conflicts of interest. | PMC10269629 |
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REFERENCES | PMC10269629 |
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Background | HIV antibody, infectious disease, acute HIV infection, HIV (PWH | INFECTIOUS DISEASE, ACUTE HIV INFECTION, DISEASE, SECONDARY | Integration of a sensitive point-of-care (POC) HIV viral load (VL) test into screening algorithms may help detect acute HIV infection earlier, identify people with HIV (PWH) who are not virally suppressed, and facilitate earlier referral to antiretroviral therapy (ART), or evaluation for pre-exposure prophylaxis (PrEP). This report describes a randomized clinical trial sponsored by the Centers for Disease Control and Prevention (CDC): “Ending the HIV Epidemic Through Point-of-Care Technologies” (EHPOC). The study’s primary aim is to evaluate the use of a POC HIV VL test as part of a testing approach and assess the impact on time to linkage to ART or PrEP. The study will recruit people in Baltimore, Maryland, including patients attending a hospital emergency department, patients attending an infectious disease clinic, and people recruited via community outreach. The secondary aim is to evaluate the performance characteristics of two rapid HIV antibody tests approved by the United States Food and Drug Administration (FDA). | PMC10474693 |
Methods | PWH | The study will recruit people 18 years or older who have risk factors for HIV acquisition and are not on PrEP, or PWH who are not taking ART. Participants will be randomly assigned to either the control arm or the intervention arm. Participants randomized to the control arm will only receive the standard-of-care (SOC) HIV screening tests. Intervention arm participants will receive a POC HIV VL test in addition to the SOC HIV diagnostic screening tests. Follow up will consist of an interim phone survey conducted at week-4 and an in-person week-12 visit. Demographic and behavioral information, and oral fluid and blood specimens will be collected at enrollment and at week-12. Survey data will be captured in a Research Electronic Data Capture (REDCap) database. Participants in both arms will be referred for either ART or PrEP based on their HIV test results. | PMC10474693 |
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Discussion | The EHPOC trial will explore a novel HIV diagnostic technology that can be performed at the POC and provide viral assessment. The study may help inform HIV testing algorithms and contribute to the evidence to support same day ART and PrEP recommendations. | PMC10474693 |
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Trial registration | NIH ClinicalTrials.gov NCT04793750. Date: 11 March 2021. | PMC10474693 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12879-023-08459-7. | PMC10474693 |
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Keywords | PMC10474693 |
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Background | undiagnosed infection, PWH, HIV infection, viral suppression, HIV (PWH) [A 2019, infection, human immunodeficiency virus (HIV) infection | INFECTION, HIV INFECTION | Diagnosis of acute human immunodeficiency virus (HIV) infection followed by early antiretroviral therapy (ART) initiation serves both individual and public health, as it has health benefits for the person receiving treatment [Point-of-care (POC) testing which is defined as near-patient testing performed at home, clinic, doctor’s office, or a hospital has a fast turnaround time [POC HIV VL tests can also play an important role in the clinical management of HIV. Using these tests has the potential to improve VL monitoring, increase treatment efficacy, and reduce emergence of drug resistance. The adoption of POC HIV VL tests may improve individual health and also reduce transmission to others by facilitating viral suppression in people with HIV (PWH) [A 2019 review of 32 publications examined the performance and clinical utility of POC HIV VL tests [Another study, conducted between October 2014 to April 2016 in South Africa, compared the performance of POC Cepheid Xpert HIV-1 Qualitative test to the standard-of-care (SOC) Roche COBAS TaqMan HIV-1 Qualitative test for neonatal HIV diagnosis. The study demonstrated 100% sensitivity [95% Confidence Interval (CI): 88.4–100) and 99.9% specificity (95% CI: 99.7–100). The median time to result return for the POC test was 1 day (IQR: 0–1) as compared to 10 days (IQR: 9–13) for the comparator test (P < 0.0001) [Studies using the Cepheid GeneXpert HIV-1 Qualitative POC HIV VL test to assist with early infant HIV diagnosis in Kenya demonstrated a sensitivity of 94.1% and specificity of 99.8% compared to the SOC Roche CAP/CTM HIV-1 qualitative polymerase chain reaction assay [To assess new HIV testing technologies, it is necessary to evaluate their performance during the acute and early stages of infection and compare their performance with rapid HIV Ag/Ab tests and the gold-standard reference laboratory algorithm. Results of these tests can also help in timely identification of persons with undiagnosed infection, PWH who are not virally suppressed or may need reengagement in care, and those without HIV infection who may benefit from PrEP. This study can also measure the impact of POC HIV VL test results on key clinical decisions including immediate treatment decisions and linking patients to appropriate treatment and/or prevention services. | PMC10474693 |
Objectives | The primary objective of this trial is to evaluate whether the use of a POC HIV VL test, in addition to SOC HIV testing, for HIV screening increases the proportion of persons linked to ART or PrEP. Secondary objectives are: [ | PMC10474693 |
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Methods/design | ® | Ending the HIV Epidemic Through Point-of-Care Technologies (EHPOC) is an unblinded randomized clinical trial that will compare a standard-of-care (SOC) HIV testing algorithm to the SOC algorithm with the addition of POC HIV screening with the Xpert® HIV-1 VL test (Cepheid, Sunnyvale, CA). | PMC10474693 |
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Study sites | INFECTIOUS DISEASES, EMERGENCY | Sites planned as part of the study are the Johns Hopkins Hospital Emergency Department (JHHED), the Johns Hopkins Bayview Medical Center, the John G. Bartlett Specialty Practice (JGBSP) Infectious Diseases Clinic, and the Baltimore City Health Department (BCHD) Sexual Health Clinics, all located in a high HIV burden area [The study will recruit participants from the community using social media outreach by using social media adverts (Facebook and Instagram) and more traditional methods such as flyers. Community outreach using social media will be critical for access to disproportionately affected populations who are unwilling or unable to engage in traditional healthcare services. Potential participants from community outreach who make contact with research coordinators will be invited to visit the Clinical Research Unit (CRU) of the Institute for Clinical and Translational Research (ICTR) located at the Johns Hopkins Hospital (JHH) where eligibility will be determined, and study visits will be completed. In addition, participants recruited from clinical sites will complete follow-up visits at the CRU. | PMC10474693 |
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Recruitment, consent, and randomization | After identification by study coordinators, a clinician will ask potential participants if they are interested or willing to participate in the study. Those who are interested in the study will be introduced to a research coordinator to discuss the study and assess eligibility. Those who do not agree to participate will continue with their routine clinical care. Potential participants who become aware of the study through social media, adverts or peers, will call or email the research coordinators at the phone number or email address provided in the advertisements or posts. If the person is eligible, they will be invited to the CRU.Informed consent and all other study procedures will be obtained and performed in accordance with the relevant guidelines and regulations of the Johns Hopkins University (JHU) and the Declaration of Helsinki [After obtaining written informed consent, the participant will be randomly assigned, by the study manager or principal investigator, to either the control or the intervention arm and notified of their assignment by the research coordinator. Randomization will be determined using the online software, Sealed Envelope Ltd©, and will be overseen by the study manager. | PMC10474693 |
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Participant removal criteria | Participants may withdraw voluntarily from study participation at any time and those who do not complete all study procedures at enrollment (e.g., do not have blood drawn during visit) will be classified as early withdrawals. Participants who withdraw will continue their care with the appropriate clinical service. | PMC10474693 |
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Enrollment visit | ®, HIV, human immunodeficiency virus, HIV antibody tests- 20, human immunodeficiency virus, TATHIV, ® HIV combi | EVENTS, DISEASE, HUMAN IMMUNODEFICIENCY VIRUS | At the enrollment visit, study participants in both arms will provide blood and oral fluid specimens for HIV testing. The sequence for enrollment visit procedures is presented in Fig.
OraQuick ADVANCEDPPElecsysGeenius
Sequence for enrollment visit procedures in the EHPOC study, Baltimore, MD, 2023–2024Abbreviations: CDC, Centers for Disease Control and Prevention; EDTA, Ethylenediamine Tetra acetic Acid; HIV, human immunodeficiency virus; mL, milliliter; SOC, standard-of-care; VL, viral load
HIV Laboratory and POC tests performed in the EHPOC study, Baltimore, MD, 2023–2024This test will be in addition to the SOC algorithm as an HIV screening test- 90 min TATHIV screening in the SOC algorithm- Variable TAT (mostly within 24 h)HIV confirmation in the SOC algorithm- Variable TAT (mostly within 24 h)HIV confirmation in the SOC algorithm and comparator to the Xpert® HIV-1 VL test- Variable TAT (mostly within 48 h)HIV screening and Comparison of rapid HIV antibody tests- 20 min TATHIV screening and Comparison of rapid HIV antibody tests- 20 min TATAbbreviations: Ag: antigen; Ab, antibodies; CA, California; HIV, human immunodeficiency virus; IN, Indiana; NY, New York; FDA: Food and Drug Administration; PA, Pennsylvania; RNA ribonucleic acid; SOC, standard-of-care; TAT, turnaround time; VL, viral load; WA, Washington.Oral fluid samples and plasma aliquots will be processed and frozen for storage in a biorepository for future HIV test evaluation purposes (Fig. 1).The SOC HIV testing algorithm will be performed at the Immunology Laboratory at JHH. The current SOC HIV testing algorithm consists of the following tests: a laboratory-based, instrumented, Elecsys® HIV combi PT (Roche Diagnostics, Indianapolis, IN), the Geenius™ HIV-1/2 Supplemental Assay (Bio-Rad Laboratories, Inc., Redman, WA), with reflex, when appropriate, to the cobas® HIV-1 test (Roche Molecular Systems, Inc, Pleasanton, CA) (See Table The study will collect participants’ demographic data, as well as sexual, and drug use behaviors. Additionally, their medical records will be examined to document physical exam findings.In addition to the procedures described previously, participants assigned to the intervention arm will be tested using a research use only POC HIV VL test (Xpert® HIV-1 VL) during the enrollment visit. This will be supplemented by the cobas® HIV-1 test, which will be available for clinical use (Table
Schedule of events in the EHPOC study, Baltimore, MD, 2023–2024Abbreviations: Ab, antibody; Ag, antigen; C, Control arm; HIV, human immunodeficiency virus; I, Intervention arm; SOC, standard of care; POC, point-of-care1) Participants whose POC VL or rapid test result is discordant with laboratory-based test results will be offered additional study follow-up visits. The additional follow-up schedule will include return visits at Days 3, 7, 10, 14, 21, 28, 42, 56, and 70 after the enrollment visit. The participants with discordant results will remain in the study until one of the following events occurs:a) Participant tests reactive/positive for HIV for all tests being evaluated, orb) Participant has two consecutive study visits with non-reactive/negative results for all tests (indicating that they had a prior false-reactive/positive result) | PMC10474693 |
Week-4 and week-12 visits | All participants will be followed-up post enrollment (Table | PMC10474693 |
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Discordant result visits | ® HIV combi, ® | HIV INFECTION, EVENTS | Participants who have discordant results between (a) the POC HIV VL test or (b) the rapid HIV tests compared with the laboratory-based HIV tests will be offered additional study follow-up visits to evaluate the sensitivity of different HIV tests for detection of early HIV infection.The participants with discordant results will remain in the study until one of the following events occurs:
Participant tests reactive/positive for HIV for all tests being evaluated,Participant has two consecutive study visits with non-reactive/negative results for all tests (indicating that they had a prior false-reactive/positive result), orParticipant completes follow-up of 70 days after the enrollment visitThe follow-up schedule for those with discordant results will include return visits at Days 3, 7, 10, 14, 21, 28, 42, 56, and 70 post-enrollment visits. At each follow-up visit, participants will provide blood and oral fluid specimens for storage and testing along with the rapid HIV tests under evaluation (e.g., OraQuick ADVANCE® Rapid HIV-1/2 Antibody test, DPP® HIV-Syphilis System); other laboratory HIV diagnostics where applicable (Elecsys® HIV combi PT, Geenius™ HIV-1/2 Supplemental Assay), and the cobas® HIV-1 test (Table | PMC10474693 |
Follow up after the enrollment clinic visit and test results | HIV infection | HIV INFECTION, DISEASE, PCP | Within 24 h of results being available, research coordinators will communicate HIV test results to the participants and share the results with the participant’s primary care provider. Key clinical decisions that are impacted by having the results of the POC HIV VL test will be recorded based on participant interviews and medical chart review. If the participant is still in the clinic when the POC HIV VL test results are obtained, study coordinators will initiate LTC activities. Participants with confirmed HIV infection will be referred by the research coordinators to their preferred clinician. Those with newly diagnosed HIV infection will be referred to the local Disease Intervention Specialist team for additional LTC and partner services. Participants with non-reactive (negative) test results will be referred to their preferred clinician for consideration of HIV PrEP and prevention counseling (Fig.
Follow up activities after a participant’s enrollment visit in the EHPOC study, Baltimore, MDAbbreviations: ART, antiretroviral therapy; PCP, primary care provider; PrEP, preexposure prophylaxis; REDCap, Research Electronic Data Capture1) Participants will be referred to the following sites for Linkage-to-Care: Baltimore City Health Department, the John G. Bartlett Specialty Practice, Johns Hopkins Bayview Medical Center. These sites are located in Baltimore, Maryland and will be accessible to study participants2) REDCap is Research Electronic Data Capture software used to store study data | PMC10474693 |
Specimen and data collection | ADVERSE EVENTS, EVENTS | Two biospecimens will be collected: oral (swab and fluid), and blood via venipuncture. The research coordinators will be trained in phlebotomy by the ICTR and follow Good Clinical Practice (GCP). In addition, trained phlebotomists will be available for venipuncture for participants attending the CRU. Samples will be transported and delivered to JHH laboratories for testing, processing, and storage using standard operating procedures.Survey questionnaires will be conducted using an iPad and answers will be stored in Research Electronic Data Capture (REDCap). The data will be accessed by the research coordinators and team members of the study only using JHU workstations or other computers using the JHU SAFE Desktop feature. The SAFE Desktop is a secure cloud-based platform, which is fully Health Insurance Portability and Accountability Act (HIPAA) compliant and managed by JHU. Examination of participant medical charts will be conducted using JHU workstations or using the SAFE Desktop feature. A group of designated JHU faculty will have responsibility for monitoring, oversight of adverse events and other protocol events. | PMC10474693 |
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Outcome measures | PWH | SECONDARY | The primary outcome for this trial is the proportion of participants that are linked either to ART or PrEP. Linkage is defined as having at least one interaction (a telehealth or in-person conversation about HIV PrEP or ART) with a healthcare provider during the 12-week follow up period after enrollment. After the Week-12 visit, participants will continue to receive SOC services as appropriate. The secondary outcomes include time to linkage to care for HIV ART or PrEP; HIV case identification; proportion of PWH started on ART; proportion of PWH who are on ART and are virally suppressed at 12 weeks, and self-reported behavioral change since the time of diagnosis. | PMC10474693 |
Power calculation and analysis plan | POC HIV VL | REGRESSION | Using data from prior studies, we observed an LTC rate of 22% for the JHHED patients who are living with HIV but not in care or who are HIV-negative and PrEP-eligible, and an LTC rate of 50% for PrEP-eligible patients attending STI services or recruited via social media, resulting in an overall aggregate LTC rate of 32.5% (with 63% patient enrollment in the JHHED and 37% in the STI clinics/participants recruited via social media). To detect an increase of LTC rate from 32.5 to 52.5% within the intervention arm, with 80% power and a two-sided significance level of 0.05, a total of 95 participants are required in each arm at the end of the study if the same proportion of participants are enrolled from JHHED. Factoring in a 15% lost-to-follow-up, 112 participants will be enrolled into each arm.We will use a bivariate analysis to explore the potential association between the independent variable (POC HIV VL test) and other covariates with the outcome variable of interest. A multivariate regression is planned to determine the association between having a POC HIV VL test and linkage to PrEP or ART, with adjustment for covariates and confounders. A survival analysis will be performed (Cox proportional hazard model) to model the time to linkage to ART or PrEP by study arm, with adjustment of covariates and confounders.The performance of the OraQuick ADVANCE® Rapid HIV-1/2 Antibody Test and the DPP® HIV-Syphilis System will be evaluated by calculating the positive percent agreement, negative percent agreement, positive predictive value (PPV), and negative predictive value (NPV) compared to the standard laboratory HIV testing algorithm. | PMC10474693 |
Reporting unanticipated problems or study deviations | ADVERSE EVENT | Any protocol deviation or adverse event that meets reporting requirements of the Institutional Review Board (IRB) will be reported to the Johns Hopkins IRB, and a de-identified report will be submitted to the CDC. All deviations from the protocol will be addressed in the study participant source documents. The documentation will include the reason(s) for the deviation and all attempts made to prevent or correct the deviation. The study team will complete a Protocol Deviation Form documenting each protocol deviation. A complete copy of the Protocol Deviation Form will be maintained in the regulatory file as well as in the participant’s source documents. | PMC10474693 |
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Benefits of participation | infection | INFECTION | Participants may benefit from earlier diagnosis of HIV, which should facilitate earlier treatment and avoidance of the sequalae of untreated infection. Participants will have the opportunity to learn more about their sexual health and will be referred for rapid initiation of HIV treatment and prevention services, as well as risk reduction counselling with a clinician. There will be no cost to the participants for study-related activities or tests conducted, participants will receive a reimbursement of $40 for each in-person study visit completed.Society may benefit through (a) the reduction of transmission of HIV in the community; (b) findings may inform CDC HIV testing guidelines for clinical settings. | PMC10474693 |
Discussion | PWH, POC HIV VL, HIV infection, acute HIV infection, EHE, HIV infections | HIV INFECTIONS, HIV INFECTION, ACUTE HIV INFECTION | This clinical trial may demonstrate that HIV testing algorithms using a POC HIV VL screening test has the potential to facilitate same-day initiation of ART or PrEP and improve the diagnosis of acute HIV infection, which may be missed using existing HIV testing algorithms. Detection of acute HIV infection is especially important, since persons with acute HIV infection often have high viral loads which are associated with high transmission risk. Accurately diagnosing HIV infections with POC HIV VL screening tests could facilitate counseling and LTC while the patient is still in the clinical encounter. Having accurate real-time information on the HIV VL in PWH may also impact key treatment decisions, particularly in acute and episodic care settings. Further, having real-time results has the potential to reduce delays in ART initiation and reduce loss to follow up. Finally, assessment of HIV status among those at risk for HIV infection using a POC HIV VL test could also expedite referral for care and initiation of PrEP.Same-day ART recommendation has the potential to improve patient health outcomes. In a prior Haitian study, 347 participants were enrolled in the same-day ART group and 356 participants were enrolled in standard ART group. The results of the study showed that the probability of remaining in care 12 months post enrollment for participants in the same-day ART group was higher (risk ratio 1.21) than for those in the standard ART group (p = 0.015) [In high-income settings like the US, more evidence supporting same day ART initiation is needed. The Panel on Antiretroviral Guidelines for Adults and Adolescents [Same-day PrEP initiation may encourage engagement in care, reduce loss to follow-up, and reduce linkage barriers by eliminating the need for multiple visits to a healthcare facility. A barrier to same-day PrEP initiation is the possibility of prescribing PrEP for individuals with undiagnosed, acute HIV infection based on the results of rapid tests with imperfect sensitivity. This may lead to antiretroviral resistance. To minimize this risk, and to provide reassurance to patients and providers, sensitive HIV VL tests can be used to provide a definitive HIV test result before prescribing PrEP [EHPOC study sites, located in a high HIV burden area and an EHE jurisdiction, serve historically socio-economically disadvantaged populations and are ideal locations to serve the Baltimore City community members, including individuals who have no insurance or are underinsured, and marginalized populations that often do not have equity of access to research. | PMC10474693 |
Trial Status | RECRUITMENT | Recruitment of participants is planned to begin in Spring, 2023. | PMC10474693 |
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Acknowledgements | We acknowledge in-kind contribution (non-monetary support); Roche Diagnostics and Cepheid have agreed to provide test kits (cartridges) for this study. | PMC10474693 |
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Authors’ contributions | SE, KPD, HHM | HHM | MMH and YCM formulated the research question, and designed the study. MHB authored the first draft of the manuscript. YHH devised the data analysis plan. MHB, TS, AB, and CP oversaw the collection of clinical data. MMH, YCM, RER, YHH, SE, HHM, PRC, BE, NGJ, KPD, DD, and RJM contributed to study design. MMH, YCM, AM, and ZD provided general oversight of the study. YCM provided general oversight of this work. All authors reviewed this manuscript, provided feedback, and approved the manuscript in its final form. | PMC10474693 |
Funding | Funding for this clinical trial is provided by the CDC. The current study protocol was designed in collaboration with the CDC. Grant number: U01PS005204-01-00. | PMC10474693 |
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Data Availability | Not applicable. | PMC10474693 |
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Declarations | PMC10474693 |
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Competing interests | SE, KPD, HHM | HHM | HHM has research collaborations with Roche and Bio-Rad and serves on the advisory board for SeeGene. YCM has received research grant support to Johns Hopkins University from Hologic, Cepheid, Roche, ChemBio, Becton Dickinson, miDiagnostics, and has provided consultative feedback to Abbott on one occasion. MMH has received honoraria from Roche and GSK. All other authors, MHB, TS, AB, AM, CP, ZD, RER, YHH, SE, NGJ, PRC, BE, KPD, DD, and RJM, declare no competing interests. | PMC10474693 |
Ethics approval and consent to participate | All study procedures will be performed in accordance with the relevant guidelines and regulations of the Declaration of Helsinki. Study participants will only engage in research activities after providing signed informed consent. The informed consent process will include the research coordinators explaining all study procedures to the potential participants and allowing sufficient time for reading the consent form and asking any questions the potential participants might have. This clinical trial will not enroll anyone under the age of 18. This clinical trial has been approved, and any future amendments will be approved, by the JHU institutional review board after discussion with the funder. The reference number is IRB00274090. | PMC10474693 |
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Consent for publication | Not applicable. | PMC10474693 |
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Disclaimer | DISEASE | The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. | PMC10474693 |
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Abbreviations | TRANSMITTED, DISEASE, EMERGENCY, IMMUNODEFICIENCY | AntibodyAntigenAnti-Retroviral TherapyThe Baltimore City Health DepartmentControl armCaliforniaConfidence IntervalCenters for Disease Control and PreventionClinical Research UnitDisease Intervention SpecialistEthylenediamine Tetraacetic AcidEnding the HIV EpidemicEnding the HIV Epidemic Through Point-of-Care TechnologiesFood and Drug AdministrationGood Clinical PracticeHealth Insurance Portability and Accountability ActHuman Immunodeficiency VirusIntervention armIndianaInstitute for Clinical and Translational ResearchInterquartile RangeInstitutional Review BoardThe John G. Bartlett Specialty PracticeJohns Hopkins HospitalThe Johns Hopkins Hospital Emergency DepartmentJohns Hopkins Universitylinkage to careMarylandNew YorkPennsylvaniaPrimary care providerPoint of CarePre-Exposure ProphylaxisPeople with HIVQuantitativeResearch Electronic Data CaptureRibonucleic AcidSexually Transmitted InfectionsStandard of CareTurnaround timeUnited StatesViral LoadWashington | PMC10474693 |
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References | PMC10474693 |
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Background | infection | RESPIRATORY INFECTIONS, INFECTION | Coughing caused by tracheal extubation is common following general anaesthesia. Heavy aerosol production by coughing during recovery from general anaesthesia in patients with respiratory infections (especially COVID-19) may be one of the highest risk factors for infection in healthcare workers. The application of local anaesthetics to the endotracheal tube is an effective method to reduce coughing. The most commonly used anaesthetics are compound lidocaine/prilocaine cream and tetracaine spray. However, coughing still occurs when the two anaesthetics are used alone. We speculated that the application of compound lidocaine/prilocaine combined with tetracaine spray would better prevent coughing caused by tracheal extubation. | PMC9807976 |
Methods | postoperative pharyngeal pain, agitation, postoperative cough | Patients scheduled for laparoscopic cholecystectomy or cholecystectomy combined with common bile duct exploration under general anaesthesia were randomly assigned to Group C (saline spray), Group L (2 g compound lidocaine/prilocaine cream contains 5 mg of lidocaine and 5 mg prilocaine)), Group T (tetracaine) and Group F (compound lidocaine/prilocaine cream combined with tetracaine). The incidence of coughing, the endotracheal tube tolerance assessment, the incidence of agitation, the active extubation rate, the incidence of postoperative pharyngeal pain and the incidence of postoperative cough were recorded and analysed. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and the plasma concentrations of epinephrine and norepinephrine were measured immediately before extubation and 1 min after extubation. | PMC9807976 |
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Results | cough | A total of 211 patients were randomly assigned to Group C (53 cases), Group L (52 cases), Group T (52 cases) and Group F (54 cases). The primary result is assessment of the incidence of cough. The patients emerged from general anaesthesia, 96% of Group C had cough, which was significantly reduced in Group L (61.5%, | PMC9807976 |
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Conclusions | respiratory infectious diseases | Compound lidocaine/prilocaine cream combined with tetracaine may be a more effective approach for preventing coughing and stabilising circulation during extubation following general anaesthesia. This may play an important role in preventing medical staff from contracting respiratory infectious diseases. | PMC9807976 |
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Trial registration | Chinese Clinical Trial Registry: ChiCTR2200058429 (registration date: 09–04-2022) “retrospectively registered”. | PMC9807976 |
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Keywords | PMC9807976 |
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Introduction | Coughing caused by endotracheal tubes in general anaesthesia is one of the most common reflexes in clinical medicine, especially when the trachea is extubated and the incidence is between 38 and 96% [ | PMC9807976 |
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Methods | PMC9807976 |
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Trial design | The Affiliated Hospital of Yan’an University, China organised this RCT. The trial was performed according to the CONSORT-2010 guidelines. The Ethics Committee of The Affiliated Hospital of Yan’an University approved the study protocol (NO. 2020042), and all subjects provided written informed consent before participating in the trial. | PMC9807976 |
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Participants and setting | sore throat, intraoperative bleeding, upper respiratory tract lesions, cough, allergies, hypertension, tube tolerance cough | SORE THROAT, CHRONIC PHARYNGITIS, ALLERGIES, HYPERTENSION, INTRAOPERATIVE BLEEDING, BRONCHOSPASM | Patients were included in the trial when they were 18 ~ 64 years old and scheduled for laparoscopic cholecystectomy or cholecystectomy combined with common bile duct exploration under general anaesthesia using endotracheal tube intubation. The following major exclusion criteria were used: American Society of Anaesthesiologists (ASA) grade greater than III; preoperative chronic pharyngitis, cough or other upper respiratory tract lesions; concurrent hypertension with or without drug therapy; difficult airway; allergies to lidocaine, tetracaine, or any other ingredients in the test product; intraoperative bronchospasm; operation time greater than 2.5 h; intraoperative bleeding (> 300 ml). We randomly assigned the patients to placebo (normal saline), compound lidocaine/prilocaine cream, tetracaine spray, or compound lidocaine/prilocaine cream combined with tetracaine treatment at a 1:1:1:1 ratio. The primary end points included the overall incidence of cough, the endotracheal tube tolerance cough and cardiovascular reactions during extubation after anaesthesia during the recovery period, the sore throat within the first 24 h after extubation. Figure Consolidated Standards of Reporting Trials flow diagram A total of 236 patients were included in the study. 25 patients were excluded according to the exclusion criteria. A total of 211 patients were randomly divided into 4 groups, 53 patients in group C, 52 patients in group L, 52 patients in group T and 54 patients in group F | PMC9807976 |
Randomisation and blinding | A total of 236 random numbers were generated by IBM SPSS Statistics 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. IBM Corp, Armonk, NY, USA), and the software randomly divided the 236 numbers into four groups. Cases were enrolled according to the order of enrolment time corresponding to random numbers from small to large, and a random number corresponded to the admission ID number of the patient. A full-time anaesthesiologist (Investigator A) performed these assignments. The patient entered the operating room, and investigator A induced general anaesthesia according to the conventional method. Tracheal intubation was performed after smearing and/or spraying the tracheal tube according to the enrolment information. After completion of tracheal intubation, another anaesthesiologist (Investigator B) performed anaesthesia management according to conventional methods and collected data until the end of the study. All of the collected data were handed over to Investigator A for sorting into different groups, and Investigator C performed statistical analyses. The patients and Investigators B and C were all blinded to the grouping information. | PMC9807976 |
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Intervention | Anaesthesiologist A treated the surface of the tip of the endotracheal tube according to the random number table. In Group C, normal saline (2 ml) was evenly sprayed onto the front end of the tracheal tube up to the two black marked lines near the cuff. In Group L two grams of compound lidocaine/prilocaine cream (compound lidocaine/prilocaine cream, 10 g, containing 25 mg each of lidocaine and prilocaine, Tongfang Pharmaceutical Group Co., Ltd. Beijing China) was evenly applied onto the front end of the tracheal tube up to the two black marked lines near the cuff. In Group T, 2 ml of 10% tetracaine (tetracaine hydrochloride for injection, 50 mg, Chengdu Zhengkang Pharmaceutical Co., Ltd. Chengdu, China) was evenly sprayed onto the front end of the tracheal tube up to the two black marked lines near the cuff. In Group F, two grams of compound lidocaine/prilocaine cream were first applied onto the front end of the tracheal tube up to the two black marked lines near the cuff then a small container with a spray function was used to evenly spray 2 ml of 10% tetracaine injection onto the front end of the tracheal tube where compound lidocaine adhered. The method of applying compound lidocaine/prilocaine cream onto the front end of the tracheal tube up to the two black marked lines near the cuff was performed according to a previous study [ | PMC9807976 |
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Parameter measurement | coughing, cough, agitation, coughs, coughing reaction | The primary outcome measure was the incidence of induced coughing due to endotracheal extubation. The definition of induced cough was patients with coughing induced by extubation during recovery from anaesthesia. Secondary outcome measures were the incidence of agitation and active extubation, endotracheal tube tolerance ranking and cardiovascular reactions prior to extubation and postoperative cough and postoperative pharyngeal pain. The degree of endotracheal tube tolerance was scored as follows: 0 = no response during breathing, including spontaneous and mechanical ventilation conditions; 1 = no response during breathing, including spontaneous and mechanical ventilation conditions, but slight action response to aspiration of sputum (inconspicuous coughing reaction); 2 = tolerance to mechanical ventilation, but moderate action response to aspiration of sputum (single coughing); 3 = tolerance to ventilation, severe coughing reaction (multiple coughs that lasted shorter than 5 s) caused by sputum aspiration; 4 = could not tolerate mechanical ventilation, severe coughing reaction caused by sputum aspiration; and 5 = extubation behaviour. Coughing was scored as follows: 0 = no cough; 1 = mild cough; 2 = moderate cough, multiple coughs that lasted shorter than 5 s; and 3 = severe cough, multiple coughs that lasted longer than 5 s. The definition of agitation was patient showed thrashing or violent behaviour with removal of tubes and tracheal tube during recovery from anaesthesia according to previous report [ | PMC9807976 |
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Conditions of endotracheal tube extubation | The following conditions were used for tracheal tube extubation: 1) spontaneous breathing tidal volume greater than 6 ml/kg; 2) breathing of air for at least 5 min with saturation of pulse oximetry (SPO | PMC9807976 |
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Sample size calculation | cough | According to our previous pilot studies, the incidence of cough induced by extubation was 95% in Group C, 45% in Group L, 60% in Group T, and 15% in Group F. We set α = 0.05 and β = 0.25, with a sample drop-out rate of 15%. Using PASS 15, we calculated a minimum sample size of 59 cases in each group (a total of 236 cases). | PMC9807976 |
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