title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
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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 ANOV... | PMC9807976 | |
Results | PMC9807976 | |||
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; preo... | 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 sput... | 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 | ||
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... | PMC9807976 | |
Funding | This work was supported by the 2020 Yan'an Science and Technology Plan Project (No. SL2020ZCSY-001). | PMC9807976 | ||
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: zhangerfei09@... | PMC9807976 | ||
Declarations | PMC9807976 | |||
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 | ||
Consent for publication | Not applicable. | PMC9807976 | ||
Competing interests | The authors declare that they have no competing interests. | PMC9807976 | ||
References | PMC9807976 | |||
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 o... | 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 regardin... | PMC10427426 |
Results | PMC10427426 | |||
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 ... | 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 | ||
Primary outcome results | In total, 177 patients were included in the full analysis set (FAS) (Fig. | PMC10427426 | ||
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 ... | 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 | ||
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 | ||
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 qua... | PMC10427426 |
Methods | PMC10427426 | |||
Patients and study design | DAISY ( | PMC10427426 | ||
Treatments and follow-up | After signature of the informed consent, patients were treated with T-DXd intravenously 5.4 mg kg | PMC10427426 | ||
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 a... | 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 assoc... | PMC10427426 | ||
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 iso... | 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-... | 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 | ||
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 ... | PMC10427426 |
Reporting summary | Further information on research design is available in the | PMC10427426 | ||
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 | ||
Supplementary information |
Supplementary Table 1 and Supplementary Figs. 1–8Reporting SummarySupplementary Data 1Supplementary Data 2 | PMC10427426 | ||
Extended data |
Study Design.
Determination of HER2 status by standard immunohistochemistry before DAISY inclusion and for cohort allocation.
| PMC10427426 | ||
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+ (
| PMC10427426 | ||
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+ (
| PMC10427426 | ||
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.
| PMC10427426 | ||
Tissue and blood samples per time point and cohort used for translational analyses. | Cohort 1: HER2-overexpressing (HER2 IHC 3+ or
| PMC10427426 | ||
Extended data | is available for this paper at 10.1038/s41591-023-02478-2. | PMC10427426 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02478-2. | PMC10427426 | ||
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... | PMC10427426 | |
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. per... | PMC10427426 | |
Peer review | PMC10427426 | |||
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 ‘mariafernanda.mosele@gustaveroussy.fr’ to request access to clinical data. The request will be discussed internally in the ... | PMC10427426 | |
Code availability | The source code to reproduce the analyses presented in this paper is available at | PMC10427426 | ||
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 Cellect... | PMC10427426 | ||
References | PMC10427426 | |||
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 year... | PMC10400484 | |
Keywords | Funding for open access publishing: Universidad de Cádiz/CBUA | PMC10400484 | ||
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 peop... | PMC10400484 |
Material and methods | PMC10400484 | |||
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, bei... | 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 | ||
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 (i... | PMC10400484 | ||
Body composition | Body weight, fat mass, fat-free mass, and estimated basal metabolic ratio (eBMR) were obtained using a multifrequency bioimpedance (TANITA-MC780MA) [ | PMC10400484 | ||
Pulmonary capacity | A forced spirometry in a standing position was performed using Jaeger MasterScreen CPX | PMC10400484 | ||
Basal metabolic rate (BMR) | BMR was assessed by indirect calorimetry using a gas analyzer of open circuit (Jaeger MasterScreen CPX | PMC10400484 | ||
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 | ||
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 | ||
Muscle strength | A handgrip test was performed to assess upper body strength using a digital dynamometer (TKK 5101 Grip-D, Tokyo, Japan) [ | PMC10400484 | ||
Sociodemographic and physical activity questionnaires | A modified sociodemographic questionnaire based on the Spanish national health survey [ | PMC10400484 | ||
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 val... | PMC10400484 | |
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 mo... | PMC10400484 |
Results | PMC10400484 | |||
Participants | RECRUITMENT | Figure Flow chart of participants recruitment. CPET, cardiopulmonary exercise test | PMC10400484 | |
Prediction equations for cardiorespiratory fitness | PMC10400484 | |||
Examining the accuracy of existing equations in predicting CRF | eCRF equation characteristics of the previously published equations can be found in Supplementary Table | PMC10400484 | ||
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 it... | 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 e... | PMC10400484 | ||
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 ... | 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 ob... | PMC10400484 |
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 | ||
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-0002–2... | PMC10400484 | |
Declarations | PMC10400484 | |||
Conflict of interest | The authors declare no competing interests. | PMC10400484 | ||
References | PMC10400484 | |||
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 fa... | PMC9990280 | |
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 | ||
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 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s40168-023-01491-4. | PMC9990280 | ||
Keywords | PMC9990280 | |||
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 char... | PMC9990280 |
Materials and methods | PMC9990280 | |||
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 pow... | PMC9990280 | ||
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... | 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 result... | PMC9990280 | ||
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 | ||
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 (M... | PMC9990280 | |
Results | PMC9990280 | |||
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 ... | PMC9990280 | ||
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... | PMC9990280 | ||
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 ferm... | PMC9990280 | ||
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 follow... | PMC9990280 | ||
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 corr... | PMC9990280 | ||
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 un... | PMC9990280 |
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