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Results | Bayesian evidence supported a small beneficial effect of creatine. The creatine effect bordered significance for BDS ( | PMC10647179 | ||
Conclusions | Our study, in combination with the literature, implies that creatine might have a small beneficial effect. Larger studies are needed to confirm or rule out this effect. Given the safety and broad availability of creatine, this is well worth investigating; a small effect could have large benefits when scaled over time a... | PMC10647179 | ||
Trial registration | The trial was prospectively registered (drks.de identifier: DRKS00017250, | PMC10647179 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12916-023-03146-5. | PMC10647179 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10647179 | ||
Background | Given the important role cognition plays in daily life, enhancing cognition safely and cheaply is highly desirable. Creatine is safe, well-tolerated, and cheap [While the safety and athletic benefits of creatine are well established, its potential cognitive benefits are still unclear. A systematic review tentatively su... | PMC10647179 | ||
Methods | PMC10647179 | |||
Trial design | We conducted a randomised, placebo-controlled, double-blind, cross-over study. The primary endpoints are the scores in the cognitive tasks after 6 weeks of each supplementation. Six weeks is the duration used by Rae et al. [Participant flow through the study | PMC10647179 | ||
Participants | Participants were 18 years or older (see | PMC10647179 | ||
Interventions and similarity of treatment groups | SETTLE | Participants took the supplements daily for 6 weeks, including the day of the testing. The creatine supplement consisted of creatine monohydrate powder “CreaPure PG” produced by the company Alzchem (Trostberg, Germany). The placebo supplement consisted of maltodextrin powder “Maltodextrin 6” produced by the company Nut... | PMC10647179 | |
Outcomes | We had two primary outcomes:A standardised 10-min subtest of Raven Advanced Progressive Matrices (RAPM) [The Wechsler auditory Backward Digit Span (BDS) [RAPM is a test of abstract reasoning. Each item in the test consists of a 3 × 3 matrix with pictures of geometric forms. One of the pictures is missing and the task c... | PMC10647179 | ||
Sample size | The sample size of 123 was powered (with power = 0.8, alpha = 0.05, calculated with GPower [Block-tapping was originally performed with physical blocks and later on the website Psytoolkit [ | PMC10647179 | ||
Randomisation and blinding | The order of the two supplements was randomised with Excel by the pharmacy of the University Hospital Heidelberg. They labelled each of the cans of supplements with the participant code and “A” or “B”, corresponding to the first and second supplement. The staff members who tested participants also provided the particip... | PMC10647179 | ||
Statistical methods | For each cognitive test, we conducted a mixed ANOVA with test score after supplementation as the dependent variable, supplement (creatine vs placebo) as the within-subjects factor and supplement order (creatine-first vs placebo-first) as the between-subjects factorWe conducted a frequentist analysis, because it is wide... | PMC10647179 | ||
Confirmatory analyses | As preregistered, our two confirmatory cognitive tasks are the Backward Digit Span and Raven’s Advanced Progressive Matrices. All other cognitive tasks are analysed in an exploratory fashion. There is one deviation from our preregistered analyses. We had preregistered | PMC10647179 | ||
Robustness checks | We checked the robustness of our normality-assuming ANOVAs by performing: an ANOVA on 20%-trimmed data, an ANOVA on 5%- and 20%-winsorised data, and a robust ANOVA which uses trimming and bootstrapping (performed with the sppb functions in the WRS2 R package). The latter ANOVA provides the most robust estimate of these... | PMC10647179 | ||
Bayes factors | For the calculation of the Bayes factors, we used the estimated marginal means (EMMs) of the creatine and placebo score. The EMMs are the means weighed for the order groups (creatine-first and placebo-first), so that imbalances in the sizes of the order groups do not affect the means. So, we only had two groups for the... | PMC10647179 | ||
Exploratory analyses | In addition to the confirmatory analyses of BDS and RAPM, we analysed the other cognitive tasks in the same way in an exploratory fashion.We also looked in an exploratory fashion at the first supplementation and the second supplementation separately and at participants with a low and high baseline performance separatel... | PMC10647179 | ||
Results | PMC10647179 | |||
Participant flow | See participant flow in Fig. Drop-outs were due to supplements failing to arrive ( | PMC10647179 | ||
Recruitment | Participants were recruited through flyers and social media between 05/2019 and 05/2022 and tested between 05/2019 and 08/2022. | PMC10647179 | ||
Baseline data | MINOR | We analysed all available participant data apart from two minor exceptions (see Participant baseline characteristicsData is given as mean (standard deviation) or as percentage. The MWT-B (Mehrfach-Wahl-Wortschatztest) is a test of crystallised intelligence [ | PMC10647179 | |
Blinding, adherence, and side effects | After their final testing session, the last 73 participants were asked to guess the order of their supplements (as the idea did not occur to us before). Forty-three (59%) guessed correctly and 30 (41%) guessed incorrectly. A binomial test reveals that the probability of 43 or more correct guesses out of 73 by pure chan... | PMC10647179 | ||
Interaction with diet | There was no significant interaction between diet and supplement nor between diet, supplement, and supplement order for neither BDS ( | PMC10647179 | ||
Bayes factors | To facilitate the interpretation of the results of the confirmatory analysis, we provide Bayes factors. A Bayes factor (BFWe compare several alternative hypotheses postulating small beneficial effects of creatine to the null hypothesis. For RAPM, the data was very insensitive, very weakly favouring the alternative hypo... | PMC10647179 | ||
Robustness checks | We checked the robustness of our confirmatory analysis (the normal ANOVA) by performing an ANOVA on 20%-trimmed data, an ANOVA on 5%- and 20%-winsorised data, and an ANOVA which uses bootstrapping and 20% trimming.For RAPM, all of these methods gave overall similar results to that of the normal ANOVA (Table Results of ... | PMC10647179 | ||
Exploratory cognitive tasks | There was no indication that creatine improved the performance of our exploratory cognitive tasks. The distribution of Results for exploratory cognitive tasksCreatine effect | PMC10647179 | ||
Discussion | PMC10647179 | |||
Summary of results | This is the largest study on the cognitive effects of creatine to date. As part of our study, we aimed to replicate Rae et al. [We found Bayesian evidence for a small beneficial effect of creatine on cognition for both tasks. Cohen’s | PMC10647179 | ||
Effect of diet | Dietary creatine is primarily contained in meat, fish, and a small amount in some dairy products [Rae et al. [Observational data on the role of dietary creatine in cognition is conflicting. Ostojic et al. [Overall, observational evidence is mixed. Evidence from RCTs and brain creatine studies does not support the idea ... | PMC10647179 | ||
BDS and other short-term memory tasks | While the creatine effect for BDS in our study bordered significance, it was smaller (One reason for this could be that there might have been more noise in our study, maybe due to the COVID pandemic starting in the midst of the study. This reason might apply to all of our tests. However, the standard deviation for BDS ... | PMC10647179 | ||
RAPM and other abstract reasoning tasks | In our study, the creatine effect for Raven’s Advanced Progressive Matrices (RAPM) was much smaller (Rae et al. [In a review by Avgerinos et al. [In sum, two studies found much larger creatine effects for RAPM than that in the present study, while a third study did not find a significant effect. Possibly the real effec... | PMC10647179 | ||
Exploratory cognitive tasks other than short-term memory | We did not find a creatine effect for our exploratory tasks. Our negative finding for the verbal fluency task is in line with the only other study using the same task [In sum, for the exploratory tasks, overall the evidence does not support a creatine effect. However, as the evidence for the Stroop task shows, this mig... | PMC10647179 | ||
Effect of age | It has been claimed that creatine supplementation is more likely to benefit older adults more than younger ones [One theory behind an effect of age is that brain creatine levels might decrease with age. There is evidence that this happens with muscle creatine levels [Experimental evidence suggests an effect of age. A m... | PMC10647179 | ||
Effect of gender | In their review, Smith-Ryan et al. [There have only been three RCTs on the effect of creatine on cognition in healthy women and three in healthy men. One of the studies with women found a creatine effect and two did not find an effect (one of these with only elderly participants). Two of the studies with men (one of th... | PMC10647179 | ||
Limitations | There are a number of limitations to this study. Despite the large sample size compared to other studies, a larger sample size would be needed to be powered for effects that are smaller but still relevant. Some of the data (4%) could not be analysed because it was not labelled with the participant and timepoint. The CO... | PMC10647179 | ||
Conclusions | Supplementing creatine is safe, easy, and very cheap. The real effect of creatine on cognition is likely smaller than that reported in Rae et al. [ | PMC10647179 | ||
Acknowledgements | We thank the doctors of the University Clinic Bonn who collected blood samples. We thank Prof. Dr. Rand R. Wilcox, Dr. Lincoln Colling, Dr. Christian Stark, Jan Speller, Maximilian Meier, and David Reinstein for their feedback on statistical questions. We thank Thomas Szpejewski and Tom Lieberum for their help with ver... | PMC10647179 | ||
Authors’ contributions | JFS and JB conceived of the study. JFS, XK, SL, AP, HM, and JB designed the study. AP and HM managed staff members as the director and vice director of the hospital. JFS and JB wrote the grant proposal. XK wrote the proposal for the ethics committee. JFS preregistered the study. XK prepared the logistics of the study a... | PMC10647179 | ||
Authors’ Twitter handles | Twitter handles: @FabienneSand (Julia Fabienne Sandkühler)Twitter handles: @JanMBrauner (Jan Brauner) | PMC10647179 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. Funding was provided by the non-profit organisation Effective Ventures Foundation, 2443 Fillmore St., #380–16662, San Francisco, CA 94115, the non-profit organisation Effective Altruism Foundation, Efringerstrasse 25, CH-4057 Basel, Switzerland, and private don... | PMC10647179 | ||
Availability of data and materials | The appendix, protocol, data, code, and output of this study are openly available at the Open Science Framework, | PMC10647179 | ||
Declarations | PMC10647179 | |||
Ethics approval and consent to participate | Ethical approval was obtained from the ethics committee of the University of Bonn (060/19). Participants gave informed consent to participate before being enrolled. | PMC10647179 | ||
Consent for publication | This manuscript contains only anonymised data. Participants gave consent for the publication of this data. | PMC10647179 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10647179 | ||
References | PMC10647179 | |||
Introduction | CHF | CHF, CHRONIC HEART FAILURE | Sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardiovascular protective properties in addition to the metabolic effects and represent a cornerstone of treating patients with chronic heart failure (CHF). We hypothesised that empagliflozin reduces tissue sodium content in patients with CHF. | PMC9849317 |
Methods | CHF | CHF | In a double-blind, randomised (2:1), placebo-controlled, parallel-group, clinical trial, 74 patients with NYHA class II–III CHF and an ejection fraction of 49% or less received empagliflozin 10 mg once daily or placebo for 3 months. In each patient, tissue sodium content of the lower leg was assessed non-invasively by ... | PMC9849317 |
Results | After 1 and 3 months treatment with empagliflozin ( | PMC9849317 | ||
Conclusion | This trial showed a significant decrease in skin sodium content after 1 and 3 months of treatment with empagliflozin. The decrease in skin sodium content may reflect a decrease in subclinical micro-oedema or/and in non-osmotic bound tissue sodium, both reported to impair left ventricular function. | PMC9849317 | ||
Trial registration number | NCT03128528 ( | PMC9849317 | ||
Trial registration date | 25th April 2017.
| PMC9849317 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00392-022-02119-7. | PMC9849317 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC9849317 | ||
Introduction | hyperglycaemia, T2D, type 2 diabetes, CHF | CHRONIC HEART FAILURE, EXCESS SODIUM, CHF, HYPERGLYCAEMIA, TYPE 2 DIABETES | Sodium glucose co-transporter 2 (SGLT2) inhibitors were originally developed to treat hyperglycaemia in patients with type 2 diabetes (T2D) and became further a cornerstone of treating patients with chronic heart failure (CHF) [For years, excess of intravascular sodium (e.g. due to excessive sodium intake) has been ass... | PMC9849317 |
Material and methods | PMC9849317 | |||
Trial design | HEART | The trial was a prospective, investigator initiated, double-blind, randomised, placebo controlled, parallel-group clinical trial, performed at the Clinical Research Centre of the University Hospital Erlangen, Germany. We recruited patients with HFrEF or HFmrEF, according the 2016 ESC guidelines definition, from the Uni... | PMC9849317 | |
Trial population | diabetes, T2D, CHF | CHF, DIABETES | Patients between 18 and 85 years of age and who had a CHF with an ejection fraction below 40% (HFrEF) or an ejection fraction between 40 and 49% as well as a N-terminal pro-brain natriuretic peptide (NTproBNP) level > 125 pg/ml and at least one structural abnormality of the left atrium or ventricle (HFmrEF), in stable ... | PMC9849317 |
Endpoints | The primary endpoint of the trial was to analyse the effect of 3 months treatment with empagliflozin on change in tissue (skin, muscle, bone marrow) sodium content compared to placebo. Secondary endpoints were the effect of 1 month treatment with empagliflozin on change in tissue sodium content compared to placebo as w... | PMC9849317 | ||
Clinical parameters | At the first visit, all demographic data were recorded. At the randomisation visit, a fasting blood sample was taken in order to determine the NTproBNP level, serum sodium level, HbA1c and fasting plasma glucose as well as other biochemical safety parameters (e.g. serum creatinine, eGFR). Twenty-four-hour urine was col... | PMC9849317 | ||
Body composition measurements | overhydration | OVERHYDRATION | Fluid status of the patients was assessed by a whole-body bioimpedance spectroscopy (Body Composition Monitor (BCM), Fresenius Medical Care, Bad Homburg, Germany) at baseline, after 1 and 3 months. From the impedance data and additional clinical parameters, extracellular water, intracellular water and total water was c... | PMC9849317 |
Statistical analysis | T2D | In our trial tissue sodium, muscle water and muscle fat content in the lower leg were specially measured with a 3.0 T clinical MR system (Magnetom Skyra, Siemens Healthineers, Erlangen, Germany) using a custom-made transit/receive sodium RF birdcage knee coil (32.6 MHz, Stark Contrast, Erlangen, Germany). Reliability a... | PMC9849317 | |
Results | PMC9849317 | |||
Adherence | Adherence to trial medication (pill counting) as well as overall adherence was given with 99 ± 3%. All patients in the empagliflozin group presented significant urinary glucose excretion at 1 and 3 months follow-up visits. None of the patients in the placebo group showed urinary glucose excretion (no drop-ins). | PMC9849317 | ||
Correlations | After 1 month treatment with empagliflozin, we observed a significant correlation between the change in skin sodium content and the change in muscle sodium content (Relationship between change in skin sodium content and change in muscle sodium content No relationship was found between the change in haematocrit, 24-h ur... | PMC9849317 | ||
Discussion | hypertrophic, T2D, myocardial interstitial oedema, renal failure, cardiac dysfunction, CHF, heart failure, glucosuria, muscle inversion | CHF, RENAL FAILURE, HEART FAILURE, HYPERTROPHIC | Randomised clinical trials conducted with empagliflozin or dapagliflozin in patients with CHF have demonstrated protective effects of SGLT2 inhibitors concerning development of heart failure, incident heart failure hospitalisations, all-cause mortality and renal failure [These results are in accordance with the results... | PMC9849317 |
Conclusion | vascular dysfunction, CHF | CHF | We found a significant reduction in tissue sodium content after 1 and 3 months treatment with the SGLT2 inhibitor empagliflozin. Our data support the concept that increased skin sodium content in patients with CHF has clinically relevant pathogenic effects, leading to cardiac as well as vascular dysfunction and consequ... | PMC9849317 |
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 192 KB) | PMC9849317 | ||
Abbreviations | HEART, TYPE 2 DIABETES MELLITUS | Sodium-MRIArbitrary unitsBody composition monitorBlood pressureChronic heart failureEstimated glomerular filtration rateFlow mediated vasodilatationGlycated haemoglobinHeart failure with mid-range ejection fractionHeart failure with reduced ejection fractionN-terminal pro-brain natriuretic peptideNew York Heart Associa... | PMC9849317 | |
Acknowledgements | HYPERTENSION | We gratefully acknowledge the expert technical assistance of Dorothea Bader-Schmieder, Ingrid Fleischmann, Kerstin Fröhlich-Endress, Ulrike Heinritz, Wiebke Maurer and Simone Pejkovic (Clinical Research Centre, Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University Erlan... | PMC9849317 | |
Author contributions | JK and RES designed the study. Material preparation, data collection and analysis were performed by Julie Kolwelter and the data were reviewed by RES. The first draft of the manuscript was written by JK and all authors contributed to the discussion as well as commented on previous versions of the manuscript. All author... | PMC9849317 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. This investigator-initiated clinical trial was supported by a grant to the University Hospital Erlangen, Germany, provided by Boehringer Ingelheim. | PMC9849317 | ||
Declarations | PMC9849317 | |||
Conflict of interest | RES received speaker fees and advisory board fees and PB has received research funding (related and unrelated to the present work) from Boehringer Ingelheim Pharma GmbH & Co. KG during the conduct of the trial. All other authors declare that there is no conflict of interest. | PMC9849317 | ||
Ethical standards | The trial was approved by the Ethics Committee of the University of Erlangen. The trial was performed in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent prior to inclusion in the trial. The trial was registered at | PMC9849317 | ||
References | PMC9849317 | |||
BACKGROUND | IgE-mediated anaphylaxis, B cell malignancies | PEANUT ALLERGY, ALLERGIC REACTIONS, SYSTEMIC ALLERGIC REACTION | IgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton’s tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways and is an ideal pharmacologic target to prevent allergic reactions. In this open-labe... | PMC10425211 |
METHODS | ’ | After undergoing graded oral peanut challenge to establish their baseline level of clinical reactivity, 10 patients had a 6-week rest period, then received 4 standard doses of 100 mg acalabrutinib twice daily and underwent repeat food challenge. The primary endpoint was the change in patients’ threshold dose of peanut ... | PMC10425211 | |
RESULTS | ADVERSE EVENTS, EVENTS | At baseline, patients tolerated a median of 29 mg of peanut protein before objective clinical reaction. During subsequent food challenge on acalabrutinib, patients’ median tolerated dose significantly increased to 4,044 mg (range 444–4,044 mg). 7 patients tolerated the maximum protocol amount (4,044 mg) of peanut prote... | PMC10425211 | |
CONCLUSION | Acalabrutinib pretreatment achieved clinically relevant increases in patients’ tolerance to their food allergen, thereby supporting the need for larger, placebo-controlled trials. | PMC10425211 | ||
TRIAL REGISTRATION | ClinicalTrials.gov NCT05038904 | PMC10425211 | ||
FUNDING | LUDWIG | AstraZeneca Pharmaceuticals, the Johns Hopkins Institute for Clinical and Translational Research, the Ludwig Family Foundation, and NIH grants AI143965 and AI106043.
| PMC10425211 | |
Introduction | stinging insect venom, systemic allergic reaction, allergic, Anaphylaxis | ANAPHYLAXIS, SYSTEMIC ALLERGIC REACTION | Anaphylaxis is an acute, potentially life-threatening systemic allergic reaction that may be caused by foods, medications, or stinging insect venom in allergic individuals (Acalabrutinib (Calquence; Acerta Pharma and AstraZeneca) is a second-generation oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK), an esse... | PMC10425211 |
Results | PMC10425211 | |||
Trial design and patient characteristics. | IgE-mediated peanut allergy | This prospective, open-label trial enrolled adult patients with IgE-mediated peanut allergy (A total of 28 patients were screened, of whom 14 met eligibility criteria ( | PMC10425211 | |
Primary endpoint. | ’ | The predetermined primary endpoint was the change in patients’ threshold dose of ingested peanut protein to elicit an objective clinical reaction during OFC after acalabrutinib pretreatment compared with patients’ baseline. At baseline, patients tolerated a median of 29 mg of peanut protein (range, 1–444) before experi... | PMC10425211 | |
Secondary endpoints. | SKIN, SECONDARY | A key secondary endpoint included the change in the severity of clinical reactions during OFC, as assessed by using a modified PRACTALL scale to score symptoms (Skin puncture testing to peanut extract was included as a secondary endpoint and surrogate marker of mast cell reactivity in vivo. All patients had a positive ... | PMC10425211 | |
Exploratory endpoints. | allergy | ALLERGY | Because BTK plays an important role in B cell receptor signaling and therefore affects plasma B cell survival, exploratory endpoints included markers of humoral immunity function and allergy. Based on earlier studies ( | PMC10425211 |
Safety. | deaths, wheezing, concussions | ADVERSE EVENTS | Safety endpoints included electrocardiography and laboratory blood testing, including complete blood counts and differentials, serum chemistries, and liver function tests. A total of 15 adverse events occurred in 5 of 10 patients (50%; Among adverse events not attributed to acalabrutinib, 1 patient experienced recurren... | PMC10425211 |
Discussion | allergic, increases peanut-allergic, first-ever, ’, IgE-mediated anaphylaxis, systemic allergic reactions | FOOD-INDUCED ANAPHYLAXIS | This trial has demonstrated the first-ever treatment to achieve rapid-onset prevention of IgE-induced food reactivity. Results showed that a short course of premedication with standard dosing of the BTK inhibitor acalabrutinib can achieve marked reduction or even complete elimination of clinical reactivity to ingestion... | PMC10425211 |
Methods | PMC10425211 | |||
Study design. | The full trial protocol is available in Supplementary information. While the trial was partially supported by a research agreement from AstraZeneca, the design and conduct of the study were performed entirely by the investigators. All study procedures were conducted at a single site — Johns Hopkins University School of... | PMC10425211 | ||
Patient recruitment, screening, and eligibility. | infection, IgE-mediated allergy, hepatitis | ALLERGY, CARDIOVASCULAR DISEASE, CEREBROVASCULAR ACCIDENT, BLEEDING DISORDER, INFECTION, HEPATITIS | Eligible patients were 18 years of age or older at screening with a history of an IgE-mediated allergy to peanut. Patients were required to have a positive skin puncture test to peanut extract and an objective clinical reaction to cumulative dose of 1,044 mg of peanut protein or less during baseline OFC. Key exclusion ... | PMC10425211 |
Medical history and demographics. | atopic disorders | FOOD ALLERGIES, ATOPIC DISORDERS | Age and information about medical comorbidities including food allergies and other atopic disorders were collected at intake. Patients were asked to report their biologic sex (options included male and female) and gender identity (options included male, female, unspecified, and prefer not to answer). Patients were also... | PMC10425211 |
Endpoints. | ’ | SECONDARY | The predetermined primary endpoint was the change in patients’ threshold dose of ingested peanut protein to elicit an objective clinical reaction during OFC after acalabrutinib pretreatment compared with the patients’ baseline. A key secondary endpoint included the change in the severity of clinical reactions during OF... | PMC10425211 |
Skin puncture testing. | SKIN | End-point titration skin puncture testing was performed using whole peanut extract (Greer), undiluted and in 9 serial 1:10 dilutions (original units given by manufacturer, weight/volume). Histamine (1 mg/mL; ALK) and saline (Greer) were used as positive and negative controls, respectively. Lincoln Diagnostics Multi-Tes... | PMC10425211 | |
Oral food challenge to peanut. | ADVERSE EFFECT | All patients underwent a patient-blinded, placebo-controlled, graded OFC to peanut at visit 1 to establish their baseline level of clinical reactivity. The food challenge protocol was designed to detect the “no observed adverse effect level”, or the highest dose observed not to produce any adverse effect, for each pati... | PMC10425211 | |
Symptom score assessment. | Adapted from the PRACTALL scale ( | PMC10425211 | ||
Basophil activation testing. | MP | Whole blood samples drawn into 4 mL lithium heparin phlebotomy tubes (BD Biosciences) before food challenge at each visit were utilized for basophil activation testing. Whole blood was incubated with mouse IgM anti-human-IgE monoclonal antibody (clone 6061P, Hybridoma Labs), the indicated dilutions of peanut extract (G... | PMC10425211 |
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