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Statistical analysis | SD | After testing for normality (Shapiro–Wilk test), the data were expressed as means ± SD and non-normally distributed data as median [interquartile range] or mean [95% CI], as appropriate. Measurements were calculated as means (± standard deviation). ANOVA was used to compare different groups. Non-parametric one-way ANOVA (Kruskal–Wallis test) was used for rating data. Pearson's chi-squared test was used to compare the categorised data in the groups. We set | PMC9807976 |
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Results | PMC9807976 |
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Patients | intraoperative bleeding, allergies | HYPERTENSION, CHRONIC PHARYNGITIS, INTRAOPERATIVE BLEEDING, ALLERGIES | A total of 236 patients at the Affiliated Hospital of Yan'an University were enrolled in the randomised trial. Twenty-five patients were excluded from this study, including 6 cases in Group C (difficult airway: 2 cases; patients with concurrent hypertension: 4 cases), 7 cases in Group L (difficult airway: 2 cases; preoperative chronic pharyngitis: 2 cases; allergies to compound lidocaine/prilocaine cream: 1 case; patients with concurrent hypertension: 2 cases), 7 cases in Group T (difficult airway: 3 cases; allergies to compound lidocaine/prilocaine cream: 1 case; patients with concurrent hypertension: 2 cases; operation time longer than 2.5 h: 1 case), and 5 cases in Group F (difficult airway: 1 case; operation time longer than 2.5 h: 1 case; intraoperative bleeding > 300 ml: 1 case; patients with concurrent hypertension: 2 cases). The study started on March 1, 2020 and ended on December 31, 2020. There were no significant differences in the baseline characteristics (such as age, weight, BMI, sex, smoking, operation time, anaesthesia time and BIS) of the patients among the groups (Table Patient characteristics | PMC9807976 |
Discussion | coughing, postoperative cough, anxiety, coughing, laryngeal injury, postoperative cough and sore, throat, cough, agitation, airway complications, DBP increase, bladder irritation, postoperative sore throat, cough reaction, postoperative pharyngeal pain | BLADDER IRRITATION | The current study compared the application of compound lidocaine/prilocaine cream, tetracaine spray or compound lidocaine/prilocaine cream combined with tetracaine to the front end of the surface of the tracheal tube and demonstrated a significant reduction in the incidence of induced coughing, agitation caused by sputum aspiration and extubation and the active extubation rate, which suggest significantly improved tolerance to the tracheal tube in patients during emergence from general anaesthesia. At least 65.1% and 75.0% of patients had induced coughing in the lidocaine/prilocaine cream and tetracaine group, respectively. However, the incidence of induced coughing was significantly reduced to 22.2% by the combination of compound lidocaine/prilocaine cream with tetracaine. The incidence of emergence agitation and active extubation rate were also significantly reduced to 16.7% and 5.6% in the compound lidocaine/prilocaine cream combined with tetracaine group, respectively. Compound lidocaine/prilocaine cream combined with tetracaine was also the most effective method to prevent extubation-induced increases in SBP, DBP, HR, E and NE plasma concentrations in patients emerging from general anaesthesia. These findings demonstrated that compound lidocaine/prilocaine cream combined with tetracaine had a better airway surface anaesthesia effect and significantly increased tolerance to the tracheal tube in patients under general anaesthesia.Endotracheal intubation-related mechanical stimulation is clinically common and associated with airway complications including, severe coughing, laryngeal injury and postoperative sore throat [During emergence from general anaesthesia, sputum aspiration and tracheal tube extubation are the strongest stimulators of the tracheal mucosa, which is the most likely to induce cough. Our study showed that compound lidocaine/prilocaine cream combined with tetracaine significantly reduced the incidence of induced coughing caused by sputum suction and extubation by approximately 39% compared to the use of lidocaine/prilocaine cream alone. Although the spraying of tetracaine alone also significantly reduced the incidence of cough, the reaction was lowest in the lidocaine/prilocaine cream combined with tetracaine group. One systematic review and meta-analysis of dexmedetomidine, remifentanil, fentanyl, lidocaine i.v., intracuff lidocaine, and lidocaine via tracheal or topical route, demonstrated that in pair-wise comparisons all study medications were equivalent in reducing moderate and severe emergence coughing incidence, and were better than placebo or nothing [During emergence from general anaesthesia, the patient may exhibit emergence agitation. The main factor of emergence agitation is delayed extubation. Study showed that patients with delayed extubation developed a cough reaction was 16.7 times higher than patients without delayed extubation [Therefore, we though that compound lidocaine/prilocaine cream combined with tetracaine inhibited the airway reflexes caused by the tracheal tube and further enhanced the body's tolerance to the tube. Our results showed that compound lidocaine/prilocaine cream or tetracaine significantly improved tracheal tube tolerance. The tracheal tube tolerance scores were reduced to 2 (0, 1) and 3 (0, 1.25), respectively. Compound lidocaine/prilocaine cream combined with tetracaine further significantly increased tracheal tube tolerance, and the tracheal tube tolerance score was reduced to 1 (0, 0). Study showed that remifentanil 0.025–0.05 microg.kg(-1).min(-1) achieves satisfactory tracheal tube tolerance in awake and spontaneously breathing patients performed under general anaesthesia, the respiratory response subscore of comfort scale of patients is all 3 [These findings may induce beneficial effects on cardiovascular reactions during the course of extubation. The current study found that hemodynamic changes (blood pressure and/or HR) exceeded 20% of the baseline at 1 min after extubation. Compound lidocaine/prilocaine cream or tetracaine significantly reduced the SBP increase from baseline (△SBP), the DBP increase from baseline (△DBP) and the HR increase from baseline (△HR) about 8% ~ 12% compared to the use saline. However, compound lidocaine/prilocaine cream combined with tetracaine significantly reduced the average values of △SBP, △DBP and △HR about 30% ~ 50% compared to the use saline.When the endotracheal tube is removed, this stimulates the receptors of the airway mucosa, which results in the release of catecholamines [We also assessed the incidence of postoperative cough and postoperative pharyngeal pain. We found that the use of local anaesthetic significantly reduced these incidences compared to saline. The incidence of postoperative cough in the compound lidocaine/prilocaine cream (13.5%), tetracaine (21.2%) and compound lidocaine/prilocaine cream combined with tetracaine (13.0%) groups were not significantly different from each other. However, the incidence of postoperative pharyngeal pain was higher in the tetracaine group than in the compound lidocaine/prilocaine cream combined with tetracaine group. Soltani, H.A. and O. Aghadavoudi suggested that the use of lidocaine to inflate the endotracheal tube cuff at the end of surgery decreased the frequency of postoperative cough and sore throat by approximately 41.4% and 17.7% respectively, compared to the use of saline to inflate the endotracheal tube cuff [There are some potential risks in the application of local anaesthetics to the airway of a patient who is under general anaesthesia: 1) if the operation time is too long, the effect of the local anaesthetic will insufficient to suppress the cough response caused by extubation; 2) the local anaesthetic effects may extend to block part of the vocal cords and affect vocalisation; 3) compound lidocaine includes prilocaine, although we used safe doses, prilocaine may increase blood methemoglobin levels, which should be monitored in clinical practice.And there are some limitations to our study. 1) This study did not observe the duration of the continuous effect of compound lidocaine combined with tetracaine on airway topical anaesthesia. 2) This study did not consider the patient's anxiety state, which will affect the release of catecholamines during awakening, and may affect the evaluation of catecholamines released during tracheal tube extubation. 3) During recovery from general anaesthesia, the patient exhibits emergence agitation due to poor tolerance to the tracheal tube, which could not be well revealed in this study based on other factors, such as preoperative anxiety or bladder irritation caused by urine retention. | PMC9807976 |
Acknowledgements | We would like to thank all the doctors, nurses, technicians, and patients involved in this study for their cooperation. Thanks to Prof. Hu Bin (Xi'an International Medical Center) and Prof. Hou Lichao (Xiang'an Hospital Affiliated to Xiamen University) for their guidance on this research project. | PMC9807976 |
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Authors’ contributions | RECRUITMENT | Jie gao was responsible for the recruitment, randomization and tracheal tube anesthetic. Hailiang Zhang, Ying li, Lei Zhang, Taiyang Li and Min Wang performed anesthesia management and data collection. Erfei zhang, Xiaoying Zhao and Ting Li analyzed data and wrote manuscript. Erfei zhang reviewed/edited manuscript. The author(s) read and approved the final manuscript. | PMC9807976 |
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Funding | This work was supported by the 2020 Yan'an Science and Technology Plan Project (No. SL2020ZCSY-001). | PMC9807976 |
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Availability of data and materials | The datasets generated and/or analysed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on reasonable request.The corresponding author: Prof. Tel: + 86 0911 2,881,264, e-mail: [email protected]) on reasonable request. | PMC9807976 |
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Declarations | PMC9807976 |
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Ethics approval and consent to participate | This study has been performed in accordance with the Declaration of Helsinki and has been approved by the Ethics Committee of The Affiliated Hospital of Yan’an University (NO. 2020042) and all subjects provided written informed consent before the trial by each participant or legal guardian. | PMC9807976 |
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Consent for publication | Not applicable. | PMC9807976 |
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Competing interests | The authors declare that they have no competing interests. | PMC9807976 |
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References | PMC9807976 |
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Subject terms | HER2-overexpressing metastatic breast cancer, tumors, breast cancer | TUMORS, BREAST CANCER | The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2–drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (Trastuzumab deruxtecan, an anti-HER2–drug conjugate, exhibits the highest objective response rate in patients with HER2-overexpressing metastatic breast cancer, but clinical activity is also observed in patients with HER2-low or non-expressing tumors, potentially pointing to additional determinants of drug efficacy. | PMC10427426 |
Main | Breast cancer, HER2-overexpressing and HER2-low mBC, cancer mortalityAlthough T-DXd, tumor | DISEASE PROGRESSION, BREAST CANCER, TUMOR | Breast cancer is the fifth leading cause of cancer mortalityAlthough T-DXd provides some clinical benefit in patients with HER2-overexpressing and HER2-low mBC, most of them will ultimately experience disease progression and die. Although the overall structure of T-DXd is well defined, several questions remain regarding its mechanisms of action and resistance. These include the impact of HER2 expression and its spatial distribution on drug efficacy; the distribution of T-DXd in the tumor; the potential impact on the tumor microenvironment; and the molecular mechanisms of resistance. Understanding these mechanisms of action and resistance could lead to improved treatment selection for patients and the potential development of more effective combinatorial treatment strategies. To address these questions, we designed DAISY, a phase 2 trial that evaluated T-DXd efficacy in patients with mBC according to HER2 expression levels and explored treatment response and resistance through biomarker analyses of tumor samples at different timepoints. | PMC10427426 |
Results | PMC10427426 |
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Study design | tumor, tumors, Tumor, HER2-overexpressing mBC | TUMOR, TUMORS, TUMOR | Patients with mBC were eligible if they had received at least one line of chemotherapy in the metastatic setting and had at least one non-bone metastatic site easily accessible to biopsy. Patients with HER2-overexpressing mBC had to be pretreated with taxanes and to be resistant to trastuzumab and TDM-1. Patients with HER2-low or HER2 immunohistochemistry (IHC) 0 tumor had to be pretreated with anthracyclines and taxanes. Patients with tumors expressing hormone receptors (estrogen and/or progesterone) had to be resistant to endocrine therapy and CDK4/6 inhibitors. Tumor biopsy was mandatory at baseline and at resistance and was optional during treatment. Additional details about patient selection and the trial design are provided in the In total, 186 patients were enrolled into the DAISY trial between 4 November 2019 and 3 March 2021 (Extended Data Fig. | PMC10427426 |
CONSORT diagram. | IHCPatient characteristics in the safety populationComparison among cohorts was performed using chi-square test or Fisher’s exact test for qualitative variables and Kruskal–Wallis test for continuous variables.NA, not applicable. | PMC10427426 |
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Primary outcome results | In total, 177 patients were included in the full analysis set (FAS) (Fig. | PMC10427426 |
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Secondary outcome results | toxicity | DISEASE PROGRESSION, SECONDARY, ADVERSE EVENT | The secondary endpoints were duration of response, PFS, OS, clinical benefit rate and safety. In 93 patients with a confirmed or unconfirmed objective response, the median duration of response was 9.7 months (95% CI 6.8–13) in cohort 1, 7.6 months (95% CI 4.2–9.2) in cohort 2 and 6.8 months (95% CI 2.8–not reached) in cohort 3. After a median follow-up of 15.6 months (95% CI 12.6–16.7), the median PFS was 11.1 months (95% CI 8.5–14.4) in cohort 1, 6.7 months (95% CI 4.4–8.3) in cohort 2 and 4.2 months (95% CI 2.0–5.7) in cohort 3. In the multivariable analysis adjusted for clinical characteristics, cohort 1 was associated with longer PFS (adjusted HR: 0.53, 95% CI 0.34–0.84, In total, 145 patients (81%) permanently discontinued treatment: 49 (72.1%) in cohort 1, 61 (83.6%) in cohort 2 and 35 (92.1%) in cohort 3. The reason for discontinuation was disease progression in 125 (86.2%) patients and toxicity in 13 (9%) patients. Adverse events were consistent with previous data | PMC10427426 |
HER2 expression patterns and treatment response | We further examined HER2 expression patterns in the three cohorts as an exploratory objective. We first assessed whether HER2 spatial distribution predicts drug response in patients from cohort 1 (HER2-overexpressing mBC; | PMC10427426 |
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T-DXd mechanisms of action | We further explored T-DXd distribution (exploratory objective) in seven paired biopsies obtained at baseline and during treatment (Extended Data Fig. | PMC10427426 |
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Mechanisms of resistance to T-DXd | tumor | SECONDARY, TUMOR | To identify mechanisms of primary and secondary resistance (exploratory objective), we performed whole-exome sequencing (WES) of frozen tumor tissue obtained at baseline ( | PMC10427426 |
Discussion | cancer, tumor, HER2-overexpressing mBC | CANCER, TUMOR | We report converging evidence that HER2 expression is a determinant of T-DXd efficacy. Specifically, the PFS rates were significantly different across the three cohorts of patients; T-DXd uptake was different according to HER2 levels; and HER2 expression decreased at resistance. A previous study suggested that HER2 quantitative continuous score (QCS) could potentially predict outcome to T-DXd in patients with HER2-low mBCAlthough T-DXd anti-tumor activity increased when HER2 expression was high, modest anti-tumor activity was also observed in patients with HER2 IHC 0. This suggests that very low levels of HER2 could allow uptake of T-DXd and/or that drug efficacy could be partially mediated by HER2-independent mechanisms. A study that involved 18 pathologists showed a low level of concordance (26%) to score HER2 IHC 0 and 1+ (ref. Although numbers are small and should be interpreted cautiously, the confirmed objective response was slightly lower in patients with HER2-overexpressing mBC who became HER2-low after baseline biopsy. This finding could be relevant to interpret the DB-02 and DB-03 studies where patients received multiple lines of prior anti-HER2 therapies.While efficacy of second-generation ADCs, such as T-DM1, was strongly associated with target expressionWe observed a lower median PFS in the DAISY trial than in previously reported studies testing the efficacy of T-DXd. PFS was longer in the DB-02 (ref. The safety profile of T-DXd in our study was similar to previous reportsPreclinical data showed that T-DXd increased tumor-infiltrating dendritic cells and CD8Although HER2 expression substantially decreased at the time of resistance to T-DXd, there is no robust evidence that a reduction of T-DXd uptake is the dominant mechanism of resistance in the present study. Indeed, T-DXd was still distributed in the cancer cells in four of six patients at the time of resistance. Unfortunately, no quantitative comparison of T-DXd uptake could be done during treatment and at resistance. In a case report, resistance to sacituzumab govitecan, an ADC targeting TROP2, was associated with Our trial has several limitations. We did not include negative controls for HER2 expression assessment at resistance; the number of samples analyzed was small; and there was no validation cohort for several of the translational objectives.The present study suggests that HER2 is a determinant of sensitivity to T-DXd, although modest anti-tumor activity was also observed in a small subset of patients whose cancer did not express HER2, suggesting other mechanisms of action. Resistance to T-DXd may occur at different levels, potentially involving decrease of HER2 expression, alterations of the cytotoxic effect of DXd and the tumor microenvironment. These data indicate that precision medicine approaches based on molecular analyses will be necessary to optimize treatment after resistance to T-DXd. | PMC10427426 |
Methods | PMC10427426 |
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Patients and study design | DAISY ( | PMC10427426 |
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Treatments and follow-up | After signature of the informed consent, patients were treated with T-DXd intravenously 5.4 mg kg | PMC10427426 |
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IHC | tumor | TUMOR | For cohort allocation, HER2 status was determined by a GEFPICS trained pathologistRegarding T-DXd distribution during treatment, 10 paired baseline and on-treatment tumor biopsies were initially selected. Three pairs were not analyzed owing to the lack of tumor cells. Seven pairs of tumor biopsies, four from cohort 2 and three from cohort 3 (days 2–4 cycle 1, Multiplex immunofluorescence was performed with the Ultivue kit containing the Immuno8 FixVUE panel composed of eight pre-diluted antibodies (twice four barcoded markers) + DAPI ready to use. The antibodies were directed against CD3 (clone BC33), CD4 (clone SP35), CD8 (clone C8/144B), CD68 (clone KP-1), FoxP3 (clone 236A/E7), PD-1 (clone CAL20), PD-L1 (clone 73-10) and PanCK/SOX10 (clone AE1/AE3/BC34). Thirty-one paired FFPE tumor biopsies obtained at baseline and on days 22–43 after cycle 1 were stained (18 cohort 1, 10 cohort 2, three cohort 3; Extended Data Fig. | PMC10427426 |
HER2 spatial distribution analysis by machine learning | Slides stained for HER2 expression collected at baseline from cohort 1 were digitalized and analyzed through an unsupervised clustering algorithm (The clusters were further analyzed on the ground of nuclei statistics toward the design of interpretable markers using an unsupervised nuclei segmentation algorithmThe association between the confirmed objective response and clusters was assessed through statistical analysis based on each cluster’s relative percentage in each slide. We used a Mann–Whitney | PMC10427426 |
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RT–PCR | tumor, Tumor | TUMOR, TUMOR | Tumor samples obtained at baseline from cohort 3 (HER2 IHC 0) were qualified for RT–PCR if the sample contained ≥30% tumor cells ( | PMC10427426 |
Genomic analyses | tumor | BLOOD, TUMOR | The tumor samples were qualified for WES if the sample contained ≥30% tumor cells. In total, 89 frozen tumor biopsies at baseline (38 cohort 1, 37 cohort 2, 14 cohort 3) and 21 (5 cohort 1, 11 cohort 2, 5 cohort 3) at resistance were analyzed. Eighty-four blood samples were used as germline control. Genomic DNA was isolated from biopsy and blood of patients using the QIAamp DNA Mini Kit and DNeasy Blood and Tissue Kit (Qiagen), respectively, according to the manufacturer’s guidelines. DNA concentration was measured using QubitTM dsDNA Broad Range Assay (Invitrogen). A quantity of 30–100 ng of DNA was used for preparing the WES libraries. For the WES, the DNA was sheared with the Covaris E220 system (LGC Genomics/KBioscience). SureSelect Low Input Target Enrichment was used. In brief, DNA fragments were end-repaired, extended with an ‘A’ base on the 3′ end, ligated with paired-end adaptors with the Bravo Platform (Agilent Technologies) and amplified to generate libraries (10 cycles). Hybridization-based exome enrichment was performed using the Agilent SureSelect Low Input Clinical Research Exome V2 target enrichment system (Agilent Technologies). The final libraries were indexed, pooled and sequenced using the onboard cluster method, as paired-end sequencing (2 × 100-bp reads) on an Illumina NovaSeq 6000 sequencer at Gustave Roussy.Statistical analyses of association with efficacy were done with the confirmed objective response. | PMC10427426 |
Bioinformatic analyses | tumor, TCGA | TUMOR, POINT MUTATION | Point mutations, small indels and CNAs were detected using an end-to-end pipeline described previouslyCNAs, tumor purity and average tumor ploidy were identified with the FACETS R package version 0.5.14 (ref. Patient and sample attributes for the TCGA cohort were downloaded from the GDC data portal (gdc-tcga-phs000178-controlled) using the R package GenomicDataCommons version 1.18.0 and from the supplementary tables publicly available on the PanCanAtlas page ( | PMC10427426 |
In vitro experiments | MCF-7 and SK-BR-3 cells were purchased from the German Collection of Microorganisms and Cell Cultures. MCF-7 cells were grown in DMEM (Gibco) supplemented with 1% GlutaMAX (Gibco) and SK-BR-3 in McCoy’s 5A medium (Gibco) in standard incubation conditions at 37 °C with 5% CO | PMC10427426 |
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Statistical analyses | tumor | TUMOR, LIVER METASTASES, PRIMARY TUMOR, EVENT, METASTATIC DISEASE, SECONDARY, REGRESSION | The primary endpoint was the confirmed ORR evaluated by investigator assessment using RECIST 1.1. The secondary endpoints included duration of response, PFS, OS and clinical benefit rate evaluated on the FAS and per cohort. Safety was evaluated on the safety population and per cohort. The required number of assessable patients for cohort 1 (The primary endpoint was reported for each cohort, and comparisons were considered exploratory. Comparison between cohorts was performed using the chi-square test or Fisher’s exact test for qualitative variables and the Kruskal–Wallis test for continuous variables; and multivariable analysis was performed using logistic regression model adjusted for hormone receptor status of primary tumor (hormone receptor-positive versus hormone receptor-negative), time from initial diagnosis to metastatic disease (0–3 months versus >3 months), time from diagnosis of metastatic disease to inclusion (0–24 months versus 24–60 months versus >60 months), number of metastatic sites (<3 versus ≥3 sites), presence of liver metastases (yes versus no) and ECOG performance status (0 versus 1) at inclusion. ORs were estimated with corresponding 95% CI. The best tumor shrinkage of target lesions was plotted on a waterfall plot and compared between cohorts using the Kruskal–Wallis test. Time to event endpoints (PFS and duration of response) were estimated using the Kaplan–Meier method, and comparison between groups was performed using the log-rank test. Multivariable analysis was performed using Cox proportional hazards model adjusted for the same variables used for the confirmed objective response. HRs were estimated with corresponding 95% CI. In the exploratory objective of modulation of tumor microenvironment, comparisons of each biomarker at baseline and on-treatment were performed using the Wilcoxon matched-pairs signed-rank test. Cell distance analysis | PMC10427426 |
Reporting summary | Further information on research design is available in the | PMC10427426 |
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Online content | Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02478-2. | PMC10427426 |
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Supplementary information |
Supplementary Table 1 and Supplementary Figs. 1–8Reporting SummarySupplementary Data 1Supplementary Data 2 | PMC10427426 |
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Extended data |
Study Design.
Determination of HER2 status by standard immunohistochemistry before DAISY inclusion and for cohort allocation.
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Waterfall plot of the best change from baseline in target lesions according to the best objective response of patients from cohort 2 in FAS population ( | On the left, patients with HER2 IHC 1+ (
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Kaplan-Meier plot of PFS in the FAS population from cohort 2 ( | The median PFS was 6.9 months (95% CI 4.1-11.7) in patients with IHC 1+ (
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Identifying an optimal number of clusters in cohort 1. | The Davies-Bouldin index was computed from Mini-Batch K-Means clustering using a number of clusters ranging from 7 to 12. This index represents how the clusters are similar to each other, with a lower value pointing toward a better segmentation. Minimum is highlighted on the graph at 8 clusters.
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Tissue and blood samples per time point and cohort used for translational analyses. | Cohort 1: HER2-overexpressing (HER2 IHC 3+ or
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Extended data | is available for this paper at 10.1038/s41591-023-02478-2. | PMC10427426 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02478-2. | PMC10427426 |
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Acknowledgements | PATHOLOGY | We thank the patients and their families as well as the investigators and staff involved in the DAISY trial. This study was supported by Unicancer and PRecISion Medicine institute in oncology (PRISM), funded by the France 2030 program and the French National Research Agency (ANR) under grant number ANR-18-IBHU-000, and Daiichi Sankyo. We are grateful to Unicancer for promoting the clinical trial and especially to M.J. who was in charge of the DAISY clinical trial and all the members of their team that led the monitoring of the clinical data and sample shipment. We are also grateful to Daiichi Sankyo, which supported T-DXd supply to the study sites, to T. Shibutani, R. Yoshimoto and H. Takahashi for pathology experiment and support, and to N. Corcos for support with graphics. | PMC10427426 |
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Author contributions | RECRUITMENT | F.M. coordinated the translational axis of the study and contributed to the writing. L.L.B. performed the artificial intelligence analyses. A.L. and T.F. ran all statistical analyses of the study. E.D., A.D., B.P., T.B., F.V. and C.L. were involved in recruitment, clinical care and data returns. Y.P., B.J. and M.D. performed bioinformatics analyses. V.M., N.S. and A.A. did the Multiplex IF analyses. I.J.G. participated in artificial intelligence analyses. H.T., S.C. and M.V. supervised the artificial intelligence analyses. D.T.N.T., N.D. and A.S. performed the genomic analyses of the trial. M.K. and T.K. performed the T-DXd distribution experiments at Japan. L.L. and P.S. did the RT–PCR analyses. M.J. and C.M. are the project managers of the DAISY trial and centralized the collected samples and data. V.B., P.L. and P.K. performed the in vitro experiments for | PMC10427426 |
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Peer review | PMC10427426 |
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Data availability | ’ | All data used in the present study are available within the manuscript and its Clinical data are available for access upon external requests. Applicants should contact the following email address ‘[email protected]’ to request access to clinical data. The request will be discussed internally in the joint steering committee of the study. The decision will be communicated within 1 month from the request. Applicants must complete specific documents to be granted a user license.Whole-exome sequencing data generated in this study have been deposited to the European Genome-phenome Archive (EGA) under accession number Databases used in the study include gnomAD ( | PMC10427426 |
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Code availability | The source code to reproduce the analyses presented in this paper is available at | PMC10427426 |
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Competing interests | F.M. received consultant fees from Novartis and Pegascy. E.D. received personal fees and non-financial support from Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eli Lilly and Merck Sharp & Dohme. T.F. received consultant fees outside the submitted work and compensation to the institution from Cellectis, Roche and Eli Lilly. B.P. received fees as advisor/consultant from Pierre Fabre (self), Daiichi Sankyo (self), Merck Sharp & Dohme (institution), Seattle Genetics (institution), Eli Lilly (institution) and Novartis (institution); funding to institution for research support from Daiichi Sankyo and AstraZeneca; and travel expenses from AstraZeneca, Pfizer and Gilead. T.B. reports receiving grants and personal fees from Daiichi Sankyo, AstraZeneca, Pfizer and Seattle Genetics and personal fees from Novartis and Roche outside the submitted work. M.K. and T.K. are employees of Daiichi Sankyo RD Novare. M.L.T. received consultant fees as speaker and consultant from AstraZeneca and Daiichi Sankyo. V.D. received travel expenses from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, Daiichi Sankyo, Seagen and Gilead; honoraria as consultant/advisor from Roche, Genentech, Novartis, Eli Lilly, Pfizer, AstraZeneca, AbbVie, Merck Sharp & Dohme, Daiichi Sankyo, Seagen, Gilead, Eisai and Pierre Fabre Oncologie; and honoraria for symposia from Roche, Novartis, Pfizer, Eli Lilly, Astra Zeneca, Daiichi Sankyo, Seagen and Gilead. F.A. received research funding and served as speaker/advisor (compensated to the hospital) from Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis and Eli Lilly. The following authors have no disclosures: A.L., L.L.B., Y.P., A.D., F.V., C.L., N.S., A.A., D.T.N.T., I.J.G., H.T., S.C., M.V., N.D., A.S., L.L., P.S., J.B., M.D., M.J., C.M., V.B., P.L., P.K. and V.M. | PMC10427426 |
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References | PMC10427426 |
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Supplementary information | fluency, cognitive flexibility |
This study aimed to develop new equations to estimate cardiorespiratory fitness specifically for older adults and, secondly, to analyze the associations of cardiorespiratory fitness, both objectively measured and estimated using new equations, with cognitive performance. Ninety-two older adults (41 females, 65–75 years) from baseline data of a randomized controlled trial were analyzed (“ClinicalTrials.gov” Identifier: NCT03923712). Participants completed 4 measurement sessions including (i) physiological and health indicators in a laboratory setting, (ii) field-based fitness tests, (iii) sociodemographic and physical activity questionnaires, and (iv) a battery of neuropsychological tests to evaluate cognitive performance. The main findings were as follows: (i) a set of new equations with good predictive value for estimated cardiorespiratory fitness were developed (74–87%), using different scenarios of complexity and/or equipment requirements, and (ii) higher estimated cardiorespiratory fitness, even using its simplest equation (eCRF = − 1261.99 + 1.97 × 6 min walking test (m) + 1.12 × bioimpedance basal metabolic rate (kcal/day) + 5.25 × basal heart rate (bpm)), was associated with better cognitive performance evaluated by several neuropsychological tests (i.e., language, cognitive flexibility, fluency, attention, and working memory), similar to using objectively measured cardiorespiratory fitness. In summary, a new set of estimated cardiorespiratory fitness equations have been developed with predictive values ranging from 74 to 87% that could be used based on necessity, availability of equipment, resources, or measurement context. Moreover, similar to objectively measured cardiorespiratory fitness, this measure of estimated cardiorespiratory fitness was positively associated with performance on language, fluency, cognitive flexibility, attention, and working memory, independently of sex, age, and education level.The online version contains supplementary material available at 10.1007/s11357-022-00718-w. | PMC10400484 |
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Keywords | Funding for open access publishing: Universidad de Cádiz/CBUA | PMC10400484 |
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Introduction | CRF | CRF | Life expectancy of the population around the world is increasing, especially in developed countries; thus, addressing the aging of the population pyramid has become an issue of global concern [CRF is the gold standard for exercise capacity [Nevertheless, few studies have developed equations to predict CRF in older people. The limited existing evidence has shown that these equations overestimate CRF [Previous literature has shown positive associations of objectively measured CRF with brain health in older adults [Therefore, the aims of this study were (i) to analyze the accuracy of existing equations in predicting CRF in older adults and to develop new equations to predict CRF (eCRF) in this specific population group and (ii) to analyze the associations of CRF (objectively measured by a laboratory-based test, and estimated by the equations) with a complete set of cognitive performance tests (i.e., screening to cognitive status, language, memory, cognitive flexibility, fluency, inhibition, attention, and working memory). | PMC10400484 |
Material and methods | PMC10400484 |
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Study participants | loss of consciousness, unstable cardiovascular disease, chronic depression, head injury | TERMINAL DISEASE | The present study used baseline data from the total sample of a randomized controlled trial (RCT registered in “ClinicalTrials.gov,” Identifier: NCT03923712). Ninety-two older adults 41 women were recruited in 13 public health care centers from Cádiz. The inclusion criteria were as follows: between 65 and 75 years, being able to speak, understand and write Spanish properly, not suffering any disease/injury that prohibits engagement in physical activity, and not engaging in supervised physical activity for more than 20 min/day. Exclusion criteria were as follows: suffering from an acute or terminal disease, chronic depression and/or unstable cardiovascular disease, and having a medical history of head injury with loss of consciousness or ictus.Participants were informed about the study procedures, potential risks, and benefits. If they met the inclusion criteria and agreed to participate, they signed the informed and photo/video consent form. This study was approved by the Human Ethics and Research Committee of the research in Cádiz and the Andalusian Coordinating Committee on Biomedical Research Ethics (codes: 0667-M1-17 and 04/2018, respectively) and conducted in accordance with the Declaration of Helsinki. | PMC10400484 |
Measurements | There were four different assessment days for the measurements of the following: (i) physiological and health indicators in a laboratory setting, (ii) field-based fitness tests, (iii) sociodemographic and physical activity questionnaires, and (iv) a neuropsychological evaluation. | PMC10400484 |
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Physiological and health indicators in the laboratory setting | Participants performed a set of laboratory tests and were instructed to follow several considerations previous to the evaluation. These standardized considerations included refraining for the 24 h prior to the assessment from (i) strenuous physical exercise, (ii) intake of alcohol, caffeine and energetic drinks, and (iii) to control hydration status during the previous week. In addition, on the evaluation day, participants were instructed to fast for at least 4 h before the scheduled session [ | PMC10400484 |
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Body composition | Body weight, fat mass, fat-free mass, and estimated basal metabolic ratio (eBMR) were obtained using a multifrequency bioimpedance (TANITA-MC780MA) [ | PMC10400484 |
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Pulmonary capacity | A forced spirometry in a standing position was performed using Jaeger MasterScreen CPX | PMC10400484 |
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Basal metabolic rate (BMR) | BMR was assessed by indirect calorimetry using a gas analyzer of open circuit (Jaeger MasterScreen CPX | PMC10400484 |
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Cardiopulmonary exercise test (CPET) | CRF | BRUCE, CRF | An incremental CPET until exhaustion using the modified Bruce protocol to determine objectively CRF was performed on a treadmill (Lode Valiant, Groningen, Netherlands) [ | PMC10400484 |
Field-based fitness tests | Two tests of the senior fitness test battery [ | PMC10400484 |
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Aerobic endurance | Aerobic endurance was assessed by the 6-min walking test which consists of walking as fast as possible (without running) between two cones 30 m apart. The test was performed only once at the end of the evaluation session, and the total of walked meters during 6 min was registered and used for analyses. | PMC10400484 |
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Muscle strength | A handgrip test was performed to assess upper body strength using a digital dynamometer (TKK 5101 Grip-D, Tokyo, Japan) [ | PMC10400484 |
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Sociodemographic and physical activity questionnaires | A modified sociodemographic questionnaire based on the Spanish national health survey [ | PMC10400484 |
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Neuropsychological evaluation | dementia | A comprehensive neuropsychological test battery measured cognitive performance including eight internationally well-known and gold-standard and validated instruments for older adults [The Mini-Mental State Examination (MMSE) is a valid test widely used to evaluate cognitive status [The Boston Naming Test (BNT) is a valid and widely used test for assessing language dimension [The Clock Drawing Test (CDT) is a valid cognitive test used for dementia screening [The Rey Auditory Verbal Learning Test (RAVLT) is a valid test to assess learning and verbal episodic memory [The Trail Making Test (TMT) is a valid test used to assess cognitive flexibility and alternating attention [The Controlled Oral Word Association Test (COWAT) is a valid instrument for assessing verbal and semantic fluency [The Stroop Color and Word Test (Stroop) is a valid and widely applied test for examining cognitive flexibility, selective attention, and cognitive inhibition [The Digit Span task is a subtest of the Wechsler Adult Intelligence Scale (WAIS)-III scale [Raw scores of each test were transformed into | PMC10400484 |
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Statistical analyses | CRF | REGRESSION, CRF | The normality of the variables was checked using both graphical and statistical procedures. To test sex for differences, a Then, multiple linear regression analyses were applied to analyze the association of objectively measured CRF and eCRF with cognitive performance. The unadjusted model (model 1) and the adjusted model (model 2) including sex, age, BMI, and/or education level as covariates were used for the regression analysis. This model 2 was based on scientific criteria, where both the individual association of potential confounders and its modifying effects over the coefficient (> 10%) were analyzed. Moreover, the interaction was also verified for the included confounders by generating virtual dummy variables in STATA code (independent × confounder) and checking its significance. This process of building the adjusted model was done for each independent variable (CRF and eCRF). The full process was performed for all neuropsychological tests as dependent variables and an overall Finally, additional sensitivity analyses were performed only for those participants achieving maximal criteria in CPET or using relative CRF instead of absolute CRF. Moreover, the normality of the residuals and the collinearity of the regression models were verified (command.All analyses were performed using the STATA software for Windows version 13.0. The level of significance was set at | PMC10400484 |
Results | PMC10400484 |
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Participants | RECRUITMENT | Figure Flow chart of participants recruitment. CPET, cardiopulmonary exercise test | PMC10400484 |
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Prediction equations for cardiorespiratory fitness | PMC10400484 |
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Examining the accuracy of existing equations in predicting CRF | eCRF equation characteristics of the previously published equations can be found in Supplementary Table | PMC10400484 |
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Discussion | CRF | CRF | The main findings of this study were as follows: (i) to provide new equations with good predictive value for eCRF (74%-87%), specifically developed for older adults and using different scenarios of complexity (laboratory-based test and field-based test) and/or equipment requirements, and (ii) higher eCRF, even using its simplest equation, was associated with better performance on several cognitive dimensions (i.e., language, cognitive flexibility, fluency, attention, and working memory), similar to using objectively measured CRF. | PMC10400484 |
Prediction equations for cardiorespiratory fitness | The present study developed new equations specifically for older adults using both non-maximal exercise information (the basic and extended equations) and adding several complementary variables from CPET but without gas exchange (maximal equation). All the equations achieved high prediction values (74–87% of variance explained) above the average of equations previously reported and based on larger sample sizes and different population age groups [The number and type of variables included in the calculation of eCRF are also relevant as they could affect the feasibility of these equations at different settings (clinical, epidemiology, etc.). Our In this line, the equation proposed by Jurcal et al. [The observed differences in the predictive values found across studies could be due to the methodological variability identified. The different age ranges and sample sizes of age groups could be plausible reasons for the variability observed in the accuracy of non-maximal exercise prediction equations in previous studies [ | PMC10400484 |
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Associations of CRF and eCRF with cognitive performance | fluency, cognitive flexibility, CRF | CRF | Another main finding from our study was the association of the eCRF with key cognitive domains such as language, fluency, cognitive flexibility, attention, and working memory, independently of confounders. In line with our results, the study of McAuley et al. [Our findings did not show associations of eCRF levels with cognitive status, inhibition, and processing speed in accordance with previous studies [Altogether, these findings indicate that eCRF is a useful approach for monitoring aerobic capacity when other methods are not available. Indeed, Tari et al. [This study has some limitations that should be taken into consideration when interpreting its results. Firstly, the age range included only older adults between 65 and 75 years; thus, this homogeneity in age limits the generalization to other ages among older adults; however, the present work has provided a new specific set of eCRF equations for older people with high predictive values. Moreover, the cross-sectional nature of the analyses does not allow to determine the causality between fitness and cognitive performance. However, we have proposed a large number of equations with a good prediction of CRF level, despite the limited sample size used. Other studies with larger samples have also generated equations to predict CRF in adults, the elderly, or both [ | PMC10400484 |
Conclusions | fluency, cognitive flexibility, deterioration of cognitive function, CRF | CRF | A new specific set of eCRF equations for older people have been developed with predictive values ranging from 74 to 87% that could be used based on needs, availability of equipment, resources, or measurement context (i.e., clinical setting or nursing home). Moreover, the eCRF is positively associated, similarly with objectively measured CRF, with performance on language, fluency, cognitive flexibility, attention, and working memory, independently of sex, age, and education level. This suggests that the new eCRF equations are useful as a proxy of CRF but also relate to cognitive performance. Thus, increasing CRF could be a protective factor against the deterioration of cognitive function associated with aging in older adults.
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Acknowledgements | We thank the participants for their cooperation and engagement in this study. In addition, we would like to thank all the institutions and researchers that have collaborated in the development of this study. | PMC10400484 |
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Funding | Frailty | Funding for open access publishing: Universidad de Cádiz/CBUA This study was supported by the Spanish Ministry of Science and Innovation - State Research Agency and European Regional Development Fund (FEDER) (grant number: DEP2016-76123-R); FEDER/Junta de Andalucía-Consejeria de Salud y Familias (grant number PI-0002–2017). Biomedical Research Networking Center on Frailty and Healthy Aging (CIBERFES) and FEDER funds from the European Union (CB16/10/00477). D.V.D is funded by the Margarita Salas Postdoctoral Program from European Union Next GenerationEU and University of Cádiz. | PMC10400484 |
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Declarations | PMC10400484 |
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Conflict of interest | The authors declare no competing interests. | PMC10400484 |
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References | PMC10400484 |
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Background | fermented milk | The effects of fermented food consumption on the small intestine microbiome and its role on host homeostasis are largely uncharacterised as our knowledge on intestinal microbiota relies mainly on faecal samples analysis. We investigated changes in small intestinal microbial composition and functionality, short chain fatty acid (SCFA) profiles, and on gastro-intestinal (GI) permeability in ileostomy subjects upon the consumption of fermented milk products. | PMC9990280 |
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Results | We report the results from a randomised, cross-over, explorative study where 16 ileostomy subjects underwent 3, 2-week intervention periods. In each period, they consumed either milk fermented by | PMC9990280 |
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Conclusions | The ingested bacteria are the main drivers of the intervention effect on the small intestinal microbiota composition. Their transient abundance level is highly personalised and influenced by the energy metabolism of the ecosystem that is reflected by its microbial composition (
Video Abstract | PMC9990280 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s40168-023-01491-4. | PMC9990280 |
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Keywords | PMC9990280 |
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Introduction | stoma, diseases like colorectal cancer, Crohn’s disease | INTESTINAL DISEASE, ULCERATIVE COLITIS | The human body hosts a multitude of microbial communities that occupy different body niches forming complex host-microbial ecosystems. There is increasing evidence of the importance of these microbial communities for host health and homeostasis [Contrary to the colonic microbiota, the human SI microbiota is poorly characterised, due to the invasive sampling technologies required to obtain material from the SI tract in healthy subjects. This can in part be overcome by sampling from individuals who underwent colectomy to remedy diseases like colorectal cancer, ulcerative colitis, or Crohn’s disease. In some of these surgical interventions the ileum is connected to a stoma in their abdominal wall (ileostoma), allowing non-invasive sampling from the SI tract. Despite their history of intestinal disease, and provided that comorbidities are absent, these ileostomists do not need maintenance medication and their SI is considered to function similarly as that of a healthy individual [Most of the SI is a harsh environment for bacteria due to high concentrations of digestive enzymes, bile salts, and antimicrobial peptides. Microbial density and diversity are relatively low [Several food products are rich in viable bacteria that may transiently dominate the SI ecosystem. For example, yogurt is a commonly consumed fermented dairy product containing more than 10The aim of the present study was to investigate how fermented dairy products could (transiently) impact the small intestinal microbiota in human subjects. To this end, 16 ileostomists were recruited that underwent 3 randomised, cross-over interventions of 2 weeks, during which they consumed dairy products fermented with | PMC9990280 |
Materials and methods | PMC9990280 |
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Subjects | Adult ileostomy patients without comorbidities were recruited for this interventions study, using specific in- and exclusion criteria (see Due to a lack of reliable prior art in the investigation of the impact of food-derived bacteria on the small intestinal microbiota, no effect size could be estimated or a priori power calculation could be performed. Therefore, the study was designed as an explorative study, aiming for the inclusion of 15 to 20 subjects fulfilling the inclusion criteria. We recruited 15 subjects with a standard ileostoma, and a single subject with a continent-ileostoma (i.e. Kock pouch). During data analysis, the SI microbiota of the latter individual was drastically different from the rest of the ileostomists and was therefore considered to be a biological outlier that was excluded from further analyses (see “ | PMC9990280 |
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Study design | gastrointestinal symptoms | MINOR | In this randomised, double-blinded placebo-controlled crossover study, ileostomy patients consecutively received three different interventions (one serving per day, at breakfast 100 ml of intervention product) for 14 consecutive days each (± 1 day) with a 2-week wash-out in between. Moreover, the study started with a 2-week run-in period and ended with a 2-week run-out period. In both periods, study subjects did not follow a specific diet a part from to not be allowed to consumed products that could influence the study (described above). At the first and last day of each intervention period (referred to as “test days” and labelled V1–V2, V3–V4, and V5–V6 for the first, second and third intervention respectively), subjects were asked to visit the testing facility (Fig. Study design. All the subjects participated in 3 intervention periods, each encompassing 14 consecutive days (± 1 day) separated by a 2-week wash-out period and preceded by a run-in period of 14 days and followed by a 14-day run-out period. Three sampling schemes overlay the timeline of the study. Microbial composition scheme indicates the days at which subjects collected ileal effluent samples at home. SCFA and microbial activity indicates the days at which subjects will participate in test days, where they filled in VAS scales to assess gastrointestinal symptoms, received standardised meals and collected urine and ileal effluent samples. Sugar permeability test scheme indicates the days at which intestinal permeability was assessedAll intervention products were manufactured by Danone (Danone Nutricia Research, Palaiseau, France) with the intention to minimise their distinction on basis of appearance and taste, including the use of similar packaging and the use of the same flavour compounds, and fully blinded. Intervention products were 100 mL of milk fermented by Subjects participated in an approximately 100-day-long trial with 3 intervention periods (Fig. Compliance to dietary interventions and to the restrictions was checked by asking whether subjects consumed the products and whether they were able to abstain from food on the forbidden food list on every test day, revealing only a few minor deviations (Additional file | PMC9990280 |
Intestinal microbiota composition | Baseclear (Leiden, The Netherlands) performed the DNA extraction from the ileostomy effluents, using DNA Fecal/Soil Microbe Kits (Zymo, CA, USA) according to manufacturer’s instruction and also generated and Illumina-sequenced (MiSeq) the 16S rRNA gene amplicon libraries (V3–V4 region, primer 341F and 805R). The results were analysed using CLC Genomics Workbench version v7.5.1 and the CLC Microbial Genomics Module version 1.5 (CLC bio, Arhus, Denmark). Briefly, the paired end reads were merged into one by CLC Workbench with default setting, and CLC pipeline was used for primer and quality trimming. The remaining high-quality sequences were clustered into operational taxonomic units (OTU) using the SILVA 16S v132 97% database as mapping reference database. A total number of paired-end, unique reads of ~ 14 M, with an average of 36,309 reads/samples, were clustered in 11,939 operational taxonomic units (OTUs) of which 10218 with more than 2 counts. After removal of the outlier samples the reads were clustered in 9270 OTUs. When investigating the interventions’ effect on the endogenous microbial community, the PDB-related OTUs were removed followed by recalculation of the relative abundances of the remaining OTUsOTUs representing Correlation analysis between the qPCR estimated copies of its genome and Unfortunately, similar analysis could not be performed for the OTUs assigned to | PMC9990280 |
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Metatranscriptomics | Ileostomy effluent samples collected for this analysis (see above) were thawed and homogenised while remaining cooled on ice using Ultra-Turrax t50 (IKA, Germany). Ten millilitres of the homogenised samples was transferred to a tube and larger debris was removed by low-speed centrifugation (3’, 500× | PMC9990280 |
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Data mining and statistics | Kock’s pouch | Descriptive statistics were calculated for age, BMI and gender (Supplementary Table SIntervention effects on SCFA and GI permeability were assessed by mixed model analysis on baseline-corrected data. A Following removal of the biological outlier (Kock’s pouch subject; see “Multivariate association with linear models (MaAsLin2) analysis with default setting was used for the association of PDB with bacterial pathways. Differential expression and abundance analysis were performed by Empirical Analysis of Digital Gene Expression (EdgeR) [ | PMC9990280 |
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Results | PMC9990280 |
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Study population, compliance, adverse events, and secondary outcomes | For this study, 18 ileostomy subjects were screened of which 16 (Fig. The primary aim was to determine the impact of the consumption of fermented dairy products on the small intestine microbiota composition and activity. In addition, intestinal permeability and SCFA levels in ileostoma effluent samples were determined at the start and end of each of the intervention periods. Notably, neither permeability nor SCFA amount or composition was significantly affected by any of the interventions (Additional file | PMC9990280 |
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Longitudinal metataxonomic analysis of the small intestinal microbiota | Longitudinal microbial composition in ileostomy effluent was analysed by metataxonomic analysis, which was successful in 390 (> 90%) of the 432 collected effluent samples (27 per individual). The samples obtained from two subjects had the lowest success rate, which for at least one of the subjects appeared to be due to the low DNA recovery in the samples (Additional file The majority of the sequences were assigned to Firmicutes (78.6%) and Proteobacteria (11.9%), followed by Actinobacteria (6.3%) and Bacteroidetes (3.1%). The average microbiota composition per subject revealed a high degree of variation among the subjects (Supplementary Figure S | PMC9990280 |
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Impact of fermented dairy product consumption on the SI microbiota composition | The fermented milk products consumed during the study contained either In samples obtained during the intervention periods, PDB corresponding to the intervention product were detected while they were consistently absent in samples collected during the rest of the study (Fig. Microbiota impact of the consumption of fermented products. PDB could be detected in the samples obtained during the corresponding intervention period. Despite the large impact of the PDB in some samples, the alpha diversity of the effluent microbiota remained unchanged during the intervention periods as compared to the run-in, although alpha diversity varied substantially between the subjects (Additional file | PMC9990280 |
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Interventions’ negligible effects on the SI endogenous microbiome | The predominant effect of the product interventions on the small intestine microbiota composition appears to be the presence of PDB in samples collected during the intervention period. To investigate the possible effect of the interventions on the endogenous microbial community, the PDB-related OTUs were removed followed by recalculation of the relative abundances of the remaining OTUs. The resulting dataset was used for subject corrected RDA analysis demonstrating that samples could still be significantly separated on basis of the intervention period in which they were taken (Fig. | PMC9990280 |
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Endogenous Peptostreptococcaceae abundance is correlated with the relative abundance of PDB during intervention | The analyses above indicated that the average relative abundance of the PDB during the intervention periods differed substantially per subject (Fig. Association of Peptostreptococcaceae abundance with PDB and alpha diversity. Notably, despite substantial variation within and between subjects, we could not detect a correlation between the microbial concentration of the ileostoma effluent samples and | PMC9990280 |
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Colonisation efficiency of | The microbial activity in ileostomy effluent was analysed by metatranscriptome analysis in the samples obtained on the first and last days of the intervention periods. Functional metatranscriptome mapping (FMM) of the small intestine microbiome were obtained for each sample by genome, protein and pathway mapping. To understand how well the microbial composition identified by 16S rRNA reflected the taxonomic distribution within the metatranscriptome, a detrended correspondence analysis (DCA plot) was used and it revealed a substantial overlap between the compositional profiles (Supplementary Figure SInter subject FMM differences was the predominant source of variation, explaining almost 25% of the overall FMM variance (Additional file | PMC9990280 |
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