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cGMP induces cardioprotection. | ( | PMC10471167 |
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RBCs release a cardioprotective factor dependent on sGC following nitrate administration and hypoxia. | Percentage recovery of LVDP during reperfusion ( | PMC10471167 |
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The nitrate-mediated protective effect of RBCs is dependent on sGC and transport by MRP. | Percentage recovery of LVDP during reperfusion ( | PMC10471167 |
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RBCs mediate cardioprotection via activation of cardiac PKG. | ( | PMC10471167 |
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Inhibition of cardiac protein kinase G abolishes cardioprotection induced by RBCs from nitrate-treated mice. | Percentage recovery of LVDP during reperfusion following administration of RBCs from ( | PMC10471167 |
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Increased expression of phosphorylated VASP in cardiomyocytes by hypoxic RBCs. | ( | PMC10471167 |
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Dietary nitrate in humans enables RBCs to mediate cardioprotection. | ischemia | ISCHEMIA | RBCs collected from 2 groups of subjects randomized to high nitrate intake in the form of nitrate pills or nitrate-rich vegetables and 1 group subjected to low dietary intake of nitrate were given to isolated rat hearts subjected to ischemia reperfusion. The RBCs were investigated ( | PMC10471167 |
Subject terms | neuroinflammation, ALS | AMYOTROPHIC LATERAL SCLEROSIS, PATHOGENESIS | In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/mNeuroinflammation and autophagy are two pillars of ALS pathogenesis targeted by rapamycin. Here, in a randomized, double-blind, phase 2 clinical trial, the authors find rapamycin to be safe and well tolerated in ALS patients, supporting further studies. | PMC10435464 |
Introduction | ALS | AMYOTROPHIC LATERAL SCLEROSIS 1, NEURODEGENERATIVE DISEASE | With a life-long risk of 1:400, Amyotrophic Lateral Sclerosis (ALS) is the 3rd most common neurodegenerative disease, holding an estimated increase of 69% in the upcoming yearsRapamycin, a drug used to prevent renal transplantation rejection, inhibits mammalian Target of Rapamycin Complex 1, leading to regulatory T lymphocytes (Treg) expansion and autophagy enhancement. In fact, mTOR inhibits the induction of Tregs, a specific cell population that down-regulates immune system activation and is found to be reduced and dysfunctional in ALS patientsFurthermore, several in vitro and in vivo studies also suggest that inhibition of mTOR by rapamycin may target autophagy, which is crucial not only for cell-autonomous clearance mechanisms, but also for limiting detrimental and uncontrolled activation of inflammasomesIn preclinical ALS studies, rapamycin reduced TDP-43 fragments accumulation and restored TDP-43 nuclear localization in cell linesHere we report the results of RAP-ALS, a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial (RCT), that evaluates safety, biological and clinical effects of oral rapamycin in persons with ALS | PMC10435464 |
Results | PMC10435464 |
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Participants and follow-up | ALS | From 05/10/2017 to 02/01/2020 a total of 70 patients with ALS were screened for eligibility, of whom 63 were randomly assigned to a trial group: 21 to rapamycin 2 mg/m | PMC10435464 |
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Treatment impact on blood cell subpopulations | We next examined the change from baseline to each time point (week 8, 18, 30, 54) of the activation and homing capabilities of different T, B, NK cell subpopulations, comparing treatment and placebo arms (Fig. | PMC10435464 |
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changes from baseline in blood cells population and inflammasome across treatment arms (P = placebo, R1 = rapamycin 1 mg/m | The figure displays only a selection of the most interesting outcomes (55 cell subpopulation were examined and 11 inflammasome/cytokines, without accounting for multiple outcomes). In detail from left to right: changes from baseline to week 18 (At week 18 patients treated with rapamycin 1 mg/m | PMC10435464 |
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Rapamycin effect on inflammasome | Patients treated with rapamycin showed lower mRNA relative expression of pro-inflammatory cytokine IL-18, which is a readout of inflammasome activation (MD −0.45, 97.5%CI −1.09 to 0.18; | PMC10435464 |
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Longitudinal assessment of neurofilament | In the placebo arm an overall decrease in neurofilament levels was observed since the first follow-up by serial measurements in the serum (MD from baseline in serum pNfH at week 8: −174.95 ± 602.19; week 18: −289.35 ± 788.33; week 30: −482.29 ± 927.19; MD from baseline of serum NfL at week 8: −11.61 ± 96.07; week 18: −25.76 ± 93.46; week 30: −33.21 ± 101.57) (Tables | PMC10435464 |
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Other biological outcome measures | Monthly changes of selected biological outcome measures during and after treatment, across arms confirmed an increase of classical monocytes/CD14+ (MD 5.42, 97.5%CI 2.19 to 8.65, | PMC10435464 |
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Mean rates of decline in Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) total score (Intention to Treat population) of patients enrolled in RAP-ALS over the study (baseline to week 54) based on treatment arm allocation (red = R1, rapamycin 1 mg/m | Source data are provided as a Correlation analyses was performed on changes in ALSFRS-r and neurofilament levels to investigate whether a relation existed between clinical and biological outcomes. In the placebo arm, an inverse correlation was found between the change (week 18–baseline) in serum and CSF neurofilament light levels and the change (baseline – week 18) in ALSFRS-R (Pearson’s r coefficient: −0.41, 95% CI 0.09 to −0.74, | PMC10435464 |
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Changes from week 18 to baseline in serum Neurofilament Light (NfL) and phosphorylated Neurofilament Heavy (pNfH) in relation to progression rate across treatment arms. | In detail from left to right, upper panels: changes from week 18 to baseline in serum pNfH in rapamycin (There were no statistically significant differences between patients treated with rapamycin and placebo as far as PEG (19.0% in the placebo group, 14.3% in the rapamycin group, A post-hoc analysis on tracheostomy-free survival with last observation set on 31st December 2021, showed that 52.4% of patients treated with rapamycin and 61.9% of patients in the placebo group had died or underwent tracheostomy, not a statistically significant difference ( | PMC10435464 |
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Safety and drug adherence | erythema, Treatment-emergent adverse, rash, pruritus, psychiatric, headache, dermatitis, injuries, eczema | RESPIRATORY DISORDERS, ERYTHEMA, SKIN AND SUBCUTANEOUS TISSUE DISORDER, GASTROINTESTINAL DISORDERS, DISORDERS, ACUTE HEPATITIS, CONJUNCTIVITIS, EVENTS, DERMATITIS, ECZEMA | A total of 23 over 42 individuals (55%) in the rapamycin group and 11 over 21 individuals (52%) in the placebo group had one or more AEs during the trial (Table Individuals with SAEs were 19% both in the placebo and in the rapamycin groups (Table Events occurring at a greater frequency in the rapamycin group were primarily skin and subcutaneous tissue disorders (erythema, pruritus, rash, conjunctivitis, dermatitis, eczema), then gastrointestinal disorders, injuries, respiratory disorders, headache and psychiatric disorders (Table Treatment-emergent adverse eventsOf note, there was a case of acute hepatitis probably related to the study drug, that occurred in a subject allocated to the rapamycin 2 mg/mA total of 11% of the participants dropped out during the study treatment, 5% in the placebo group and 14.3% in the rapamycin group. During follow up time, 24% of patients in each group abandoned the study. Events leading to discontinuation of the treatment are presented in Table | PMC10435464 |
Drug dosage assessment | Plasma levels of rapamycin at different time points for each treatment arm are displayed in Fig. | PMC10435464 |
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Discussion | ALSFRS-R, neuroinflammation, ALS | DISEASE PROGRESSION, CHRONIC INFLAMMATION, DISEASE, SECONDARY, EVENTS | This clinical trial measured the biological, clinical and safety effects of rapamycin on patients affected by ALS. Unfortunately, the primary outcome measure could not be satisfied also due to the reduced number of samples that could be analyzed at week 18, to which the COVID-19 pandemic significantly contributed. Notwithstanding our expectations for an inevitable loss in samples at treatment end, this led to a final sample size of 50 on which the primary endpoint was assessed. Therefore, we could not demonstrate a significant effect of the study drug on Treg lymphocytes, and the question as to why some subjects did not show the expected Tregs increase in response to rapamycin remains.Inter-individual variation amongst ALS patients in the ability to increase Tregs in response to treatment have been recently observed in other RCTsFurthermore, increased expression of the mTOR-interacting Raptor protein, increased phosphorylation of Akt, and activation of growth-related transcriptional factor AP-1 may induce rapamycin resistanceAmong secondary biological outcome measures we observed changes on B and T cell subpopulations, monocytes, and on IL-18, which could be suggestive of a rapamycin-mediated effect on neuroinflammation in ALS, where misfolded protein aggregates may activate a cascade of events that drives chronic inflammation and secretion of proinflammatory cytokines, among which IL-18, that finally leads to tissue damage and cell deathTogether with the above mentioned limitation, the increase in classical monocytes and the reduction in intermediate monocytes in patients treated with rapamycin, is even more difficult to interpret because of the uncertainty on their role in ALS, and if monocyte subsets and activation profiles are altered depending on the stage of the disease (i.e., the changes are a response to disease and their changes suggest that the immune system becomes more activated as the disease progresses) or if they are instead pathogenetic deserves further studiesSerial measurements of neurofilament showed a constant decrease in placebo-arm patients, not observed in the treatment arms, where we found stable neurofilament levels. The different behavior of neurofilament in treatment and placebo arms may have several explanations since longitudinal behavior of neurofilament during ALS and/or in clinical trials is still being studied with conflicting results. Some studies found fast disease progression to be associated with neurofilament decrease over timeThis is a non-profit, exploratory study on rapamycin action in ALS patients, that was designed to investigate if this drug warrants further research in patients with ALS, considering also its safety profile. Rapamycin in combination with riluzole, was safe and well tolerated by ALS patients. AEs and SAEs were equally distributed between treatment and placebo arms, reassuring about safety, provided that a drug plasma dosage monitoring was performed. It is also reassuring that ~24% of the participants discontinued the trial, that is in line with recent data from other clinical studiesThis study was not powered to test an effect on clinical measures, but we could not observe a slowing in the ALSFRS-R decline nor an effect on quality of life, even after excluding SOD1 patients from enrollment. If the effect on Treg cells and other immunological outcome measures was more evident for patients treated with rapamycin 1 mg/mGiven the reported detrimental effects in SOD1-ALS miceThe main potentiality of this trial stands on immediate availability of the drug for patients use, should an effect be found by larger trials, and by the existence of newer and interesting molecules i.e., rapalogs, who offer the possibility to cross the blood brain barrier perhaps deserving further properties towards autophagy and neuroinflammation. In fact, we could not find the drug in the CSF of patients treated for 18 weeks, and although we cannot exclude rapamycin free fraction values below the detection limit of LC-MS/MS, it is probable that rapamycin cannot cross blood brain barrier. If this may be of secondary importance for the drug immunological effects, the concentration at which rapamycin or any rapalog are found able to penetrate the blood-brain barrier might be a matter of uttermost relevance for the sake of fostering autophagyLimitations of this early trial of rapamycin in ALS were the small number of participants and the short duration of treatment, that were mainly due to safety concerns. Furthermore, the expected effect size of the primary outcome measure was perhaps too optimistic and, together with the difficulties in obtaining blood samples at treatment end, this led to miss the primary outcome. The choice of the primary outcome measure, as a binary response, has to be acknowledged as the main drawback of this study, together with the fact that Treg function, rather than their number would have been relevant for treatment effect. Indeed, we did not plan to study Treg suppressive function instead of their number alone and we were not able to assess Treg suppressor function as a post-hoc analysis due to lack of available samples. Before further studies in ALS, assessment of Treg suppressor function in response to different doses of rapamycin would be critical. In addition, some data on the primary outcome were not measured due to the COVID-19 pandemic, which may introduce a risk of bias into the results. However, the double-blind design of the study and the random missing mechanisms should have limited this risk. Other drawbacks are represented by the imbalance of some factors at baseline (such as in edaravone treatment), and the exploratory nature of the clinical outcomes. Finally, the results on biological outcomes should be interpreted cautiously and require confirmation in larger studies, considering that we did not apply corrections for multiple tests.In conclusion, this trial demonstrated that treatment with a low dose of rapamycin is safe in patients with ALS, but it failed to demonstrate an effect of the drug on Treg cells. Further trials focused on different outcome measures are necessary to better understand rapamycin biological and clinical effects in ALS. | PMC10435464 |
Methods | PMC10435464 |
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Study design | ICH | MAY, APPENDIX, DEL | A randomized, double-blind, placebo-controlled trial was conducted at seven Italian ALS referral centers from 2017 through 2020. The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and the ethical principles of the Declaration of Helsinki, as amended by the 64th WMA General Assembly, Fortaleza, Brazil, in October 2013. The study complies with ICMJE guidelines on reporting.Protocol (EUDRACT 2016-002399-28 registration: 31st May 2016) approval was provided for the coordinating center and all trial sites by Ethical Committee of the coordinating center (Comitato Etico Provinciale di Modena) on 23th May 2017 (file number 95/17) and by AIFA (Agenzia Italiana del Farmaco) on 14th July 2017. All the participants provided written informed consent before screening (first and last patient enrollment: 05/10/2017 to 02/01/2020). The trial was a non-profit trial, financed by ARISLA (Fondazione Italiana di Ricerca per la SLA) with the “2015 AriSLA Ice Bucket Call for Clinical Projects”. Pfizer Inc. provided the active drug. Participants received no compensation.The study promoter was Azienda Ospedaliero-Universitaria (AOU) di Modena. The trial design, data analysis, and manuscript development were shared by the Steering Committee of the Study represented by all the local PIs (Supplementary Appendix, Section An independent data and safety monitoring board was established at trial beginning and periodically reviewed unblinded safety data during the trial (Acknowledgements section). Statistical analyses were performed by the Unit of Statistical and Methodological Support to Clinical Research, AOU, Modena, Italy. All the authors guarantee for data completeness and accuracy, and for adherence to RAP-ALS study protocol (available at | PMC10435464 |
Trial participants | FALS, ALS | DISEASES | The trial enrolled patients diagnosed with definite, clinically probable or probable with laboratory support ALS according to revised El Escorial criteria who presented ALS symptoms onset not earlier than 18 months before screening. Inclusion criteria encompassed age between 18 and 75 years old, a forced vital capacity (FVC) exceeding 70% of the predicted value for sex, age, height, and weight, a Body Mass Index above 18 and a body weight over 50 kg, use of riluzole at a stable dose for at least 30 days before screening. Exclusion criteria covered a wide range of diseases and conditions that would make rapamycin use or immunosuppression contraindicated. Patients with known SOD1 mutation or with FALS and family members carrying SOD1 mutation were to be excluded as well, based on contrasting evidence of Rapamycin action in SOD1 models of ALS, | PMC10435464 |
Randomization and masking | Eligible participants were randomly assigned in three treatment arms with a 1:1:1 ratio to receive rapamycin 1 mg per square meter (m | PMC10435464 |
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Procedures | ADVERSE EVENTS | Treatment was administered orally, in the morning, at fast. Patients received 4 bottles, each containing 15 tablets of active drug or placebo depending on the assigned treatment arm, every 2 weeks, for a planned duration of 18 weeks. Rapamycin plasma levels were regularly measured by high-performance liquid chromatography with tandem mass spectrometry (LC–MS/MS) and made known only to an independent monitor, who input rapamycin levels on a separate eCRF, allowing dose reduction if rapamycin plasma levels exceeded 12 ng/mL. A dose reduction could be asked also by caring neurologist directly through eCRF in case of adverse events (AEs) or reactions that, on clinical judgment, could be attributed to the study drug. After treatment end patients had to be followed up for further 36 weeks ( | PMC10435464 |
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Outcomes | death, ALS | DISEASE PROGRESSION, APPENDIX | The primary efficacy outcome was the proportion of positive response (Tregs number increase of at least 30%) at treatment end (18 weeks) with respect to baseline, in patients treated with rapamycin compared to the placebo arm. This difference was established based on a previous study demonstrating that slowly progressing ALS patients presented a number of Tregs that was equal to healthy controls, whereas fast progressors had 31% fewer TregsSecondary outcomes were:Assessment of rapamycin safety and tolerability through documentation of the occurrence of any AEs, changes on clinical examination including vital signs and weight, and laboratory examinations (biochemistry, hematology and urinalysis) that were registered throughout the study duration. Symptoms consistent with disease progression, were recorded as AEs.Biological outcomes, assessed as the change from baseline to week 8, 18, 30, 54, comparing rapamycin and placebo arms, of the following biological variables: a) activation and homing capabilities of different T, B, NK cell subpopulations; b) relative expression of inflammasome genes and its activation status; c) phosphorylation of the S6 ribosomal protein (S6RP); d) plasma/CSF neurofilament heavy/light chain protein; e) creatinine and albumin, CK, vitamin D; f) the assessment of rapamycin in CSF samples at week 18 by LC-MS/MS.Laboratory methods are explained in Supplementary Appendix, Section Clinical outcomes through comparison between placebo and treatment arms of: a) the changes in ALSFRS-R from baseline to weeks 4, 8, 12, 18, 30, 42, 54; b) overall survival from randomization to date of documented death or tracheostomy; c) survival rate at weeks 18, 30, 42, and 54; d) respiratory muscle function as assessed by FVC score from baseline to weeks 4, 8, 12, 18, 30, 42, 54 (Supplementary Appendix, Section Quality of life, measured through absolute and relative change from baseline in ALSAQ-40 at week 4, 8, 12, 18, 30, 42 and 54 comparing treatment and placebo arms. | PMC10435464 |
Statistical analysis | death, ICH, ALS, Treg%, ALSFRS-R | REGRESSION, DISEASE | Sample size was calculated using data from an Italian study showing that ALS patients have a decreased number of circulating Treg% (mean ± SD: 2.1 ± 0.7) if compared to healthy controls (2.6 ± 0.6), except for slow progressorsSafety analyses were performed including all patients who received at least one tablet of rapamycin or placebo. All AEs, SAEs, and AEs leading to treatment discontinuation were recorded according to ICH Guidelines, listed, and compared in the treatment arms at any follow-up visit and at the end of the study.The primary population for analyses was the ITT population, which included all the participants who received at least one tablet of the investigation drug. PP analysis was performed after excluding patients as per major protocol deviations (i.e., patients who took <80% therapy) from the above-mentioned population. Descriptive statistics comparing the two groups of rapamycin treatment and placebo was performed using mean and standard deviation for continuous variables, counts and percentages for categorical variables. Immune response to rapamycin was analyzed as the difference in positive response to rapamycin (mean Tregs increase exceeding 30%) between the placebo group and the rapamycin groups Results were expressed as the relative risk (RR) comparing treatment arms. The comparison was carried out with a chi-square test without any correction. Mean absolute differences from baseline to week 18 and other time points among treatment arms for S6RP phosphorylation, of different T, B, NK cell subpopulations, of biomarkers, inflammasome, cytokines, were calculated and compared using linear regression models that include indicator variables for treatment arms as the independent variables. Results were expressed as the mean difference (MD) comparing treatment arms. Correlations between numerical variables were calculated with the Pearson’s linear correlation coefficient. The time to death, tracheostomy or permanent ventilation, were compared by using the log-rank test. Adjustment for main prognostic or unbalanced factors (namely sex, months from symptoms onset, ALSFRS-R slope at baseline and edaravone treatment) has also been performed using logistic or linear regression models. Results of logistic models were expressed as the OR comparing treatment arms.A segmented repeated measures linear mixed model analysis was carried out to assess whether the average monthly variation from baseline in selected numerical outcomes was different amongst treatment arms in two segments of time: during the treatment (after baseline and up to week 18), or after the treatment (after week 18). The dependent variables were the raw measurements of the outcomes, whereas the independent variables were: arm, time (months from baseline) × period (during or after treatment) interaction, and arm × time × period interaction. A random intercept term was also used to account for repeated measurements over the same individual, as well as a random slope term was used to account for individual linear variations over time. Random intercept and random slope terms were kept if they improved the overall goodness-of-fit of the models (assessed using the Akaike information criterion). Results of this analysis were expressed as: the monthly variation of outcomes in the placebo group; the MD in the monthly variations, comparing treatments arms vs placebo. Both these quantities were reported for the two segments of time (during and after treatment). In the analysis of average monthly variation of ALSFRS-R, three segments of time were analyzed: before, during and after treatment, by considering two additional timepoints such as the prebaseline screening visit and the disease onset. At disease onset, the ALSFRS-R was assumed to be equal to 48 for all patients. The repeated measures linear mixed model for ALSFRS-R included arm, time (months from baseline), period (before, during or after treatment), and all their pairwise and three-way interactions. The intra-group differences comparing ALSFRS-R monthly variations in the periods during and after treatment with those occurred before treatment were also reported for each arm, as well as the comparison between treatment arms and placebo in these quantities. A post hoc analysis on tracheostomy-free survival from baseline to 31st December 2021 was performed.For the comparisons between Rapamycin 1 mg/mAnalyses were performed using STATA software, version 15 (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC) and R software, version 3.6.3 (The R Foundation for Statistical Computing, Wien). | PMC10435464 |
Reporting summary | Further information on research design is available in the | PMC10435464 |
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Supplementary information |
Supplementary InformationPeer Review FileReporting Summary | PMC10435464 |
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Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-40734-8. | PMC10435464 |
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Acknowledgements | NEUROMUSCULAR DISEASES | We thank all the RAP-ALS investigators group (see supplementary material). We thank the participants in the RAP-ALS trial and their families and caregivers, without whom this trial would have not been possible; Dr. Graziella Filippini, Dr. Ettore Beghi, Dr. Lawrence Korngut and Dr. Paola Minghetti, members of the data and safety monitoring board; Neurobiobank of Modena; Telethon Genetic BioBank (GTB12001D) and the Eurobiobank network; European Reference Network for Neuromuscular Diseases (ERN EURO-NMD); CRO High Research- Evidenze Group. | PMC10435464 |
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Author contributions | SECONDARY, RECRUITMENT | J.M., A.Co., R.D.A., M.P. had the idea for the study, did the literature searches and designed the study. E.Z., I.M., N.F., G.G., C.L., F.G., C.T., L.M., F.D.M., A.S., G.S., A.F., G.L., E.D.B., C.C., G.M., A.Ch., and A.Ca. were co-investigators, were responsible for patients recruitment, treatment, biological samples collection, data input in eCRF. Clinical oversight of the study was undertaken by J.M. and supported by R.D.A. The RAP-ALS Investigators provided feedback on the protocol and oversaw site recruitment and data collection for their respective sites. J.M., R.D.A., A.Co., E.Z., I.M., R.V., F.B. were responsible for development of protocols, site training, and validation and creation of the eCRF and database. The study conduct was overseen by J.M. and R.V., supported by R.D.A. and a local management team comprising I.M., E.Z., N.F. A.Co., S.D.B., M.P. developed standard operating procedures for immunological analyses. S.D.B., C.S., D.L.T., M.P., under the supervision of A.Co., performed immunological analysis of biological samples. Acquisition of the financial support for the project leading to this publication was performed by J.M., A.Co. and R.D.A. with participation of A.C., C.C., C.L., G.S., E.D.B., L.M. Project administration was performed by J.M., R.D.A. and A.Co. The final analysis of all the primary and secondary outcomes was undertaken by F.B. under the supervision of R.D.A., and both veri fied the raw data. The manuscript was drafted by J.M., E.Z., F.B., S.D.B. All authors had access to all the study data and read, contributed to, reviewed and approved the submission of the manuscript for final publication. | PMC10435464 |
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Peer review | PMC10435464 |
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Funding | AMYOTROPHIC LATERAL SCLEROSIS | The study was supported by ARISLA (Fondazione Italiana di Ricerca per la SLA) (FGCR02/2015 to J.M.) and Pfizer Inc. (Pfizer provided the drug free of charge) (grant no. 53232941, program title: “Wi211892 Rapamycin treatment for Amyotrophic Lateral Sclerosis” to J.M.). The funders of the study were not involved in protocol design, data collection, statistical analysis, data interpretation, writing of the report and the decision to submit this article. | PMC10435464 |
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Data availability | The data that support the findings of this study are available from the corresponding author ([email protected]) to external researchers who provide methodologically sound scientific proposals and whose proposed use of the data has been approved by an independent review committee identified for this purpose. All requests will be reviewed by corresponding author and Steering Committee of the Study and response to requests will be given in 2 months. A materials transfer and/or data access agreement with the study promoter will be required for accessing shared data. However, individual participant data will not be available because informed consent did not explicitly include this. Source data are provided as Source Data files with this paper. The study protocol, including the statistical analysis plan has been uploaded in the Supplementary Information file. | PMC10435464 |
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Competing interests | J.M. reports receiving advisory board fees from Biogen, Amylix and Italfarmaco, grant support from Roche, and grant support from Pfizer (active study drug for this study by grant number Wi211892 to J.M.). ACh received consulting fees from Biogen, Cytokinetics, Amylyx. ACa reports receiving advisory board fees from Biogen and Amylix, and grant support from Cytokinetics. GL reports scientific advisory for CSL Behring, Biogen Inc, Vertex Pharmaceuticals Incorporated, Chromocell Corporation, Janssen Pharmaceuticals, Inc, Lilly, and the Bracco Group. C.L. has served as a scientific consultant for Mitsubishi Tanabe Pharma Europe, Cytokinetics, Neuraltus, and Italfarmaco. R.D.A., E.Z., S.D.B., F.B., I.M., C.S., D.L.T., R.V., N.F., G.G., M.P., F.G., C.T., L.M., F.D.M., A.S., G.S., A.F., E.D.B., C.C., G.M., A.Co. declare no competing interests. Disclosure forms provided by the authors are available with the full text of this article. | PMC10435464 |
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References | PMC10435464 |
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Introduction | comorbidity, fatigue, neurological disorders | TTP, NEUROLOGICAL DISORDERS | Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.B vitamins play a crucial role in maintaining fundamental cellular functions and various essential metabolic pathways in the body. Although they do not directly provide energy, each B vitamin acts as a cofactor in energy metabolism processes. Based on the evidence presented above, we hypothesized that a 28-day supplementation of vitamin B would enhance physical performance and reduce physical fatigue. The objective of this study was to evaluate the anti-fatigue effect of vitamin B supplementation, specifically vitamin B1, B2, B6, and B12, and its potential to improve exercise performance. We employed a randomized double-blind crossover design with a 28-day supplementation period. Sixteen male and sixteen female subjects, aged 20-30 years, were divided into two groups: the placebo group (n=16, equal gender distribution) and the Ex PLUSFatigue, defined as the inability to maintain power output and strength, is a symptom or comorbidity of neurological disorders In addition to specific efficacy properties, many foods contain essential nutrients, including vitamins and minerals, which play an important role in maintaining essential cellular functions and various essential metabolic pathways Vitamin B1 (thiamine) is rapidly absorbed by the small intestine into three phosphorylated forms: thiamine monophosphate (TMP), thiamine pyrophosphate (TPP), and thiamine triphosphate (TTP) While food intake is the main source of energy, vitamins B act as catalysts, helping to convert energy into better uses to more efficiently supply what the body needs | PMC10542023 |
Materials and methods | PMC10542023 |
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Vitamin B complex and placebo preparation | The supplement in this study was provided by Prince Pharmaceutical Co. Ltd. (New Taipei City, Taiwan). One vitamin B complex tablet (Ex PLUS | PMC10542023 |
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Participants | asthma | METABOLIC DISEASE, HYPERTENSION, ASTHMA, CARDIOVASCULAR DISEASE | This study was conducted in accordance with the Declaration of Helsinki and was approved and reviewed by the Institutional Review Board of Landseed International Hospital (Taoyuan, Taiwan; LSHIRB number 20-037-A2). The trial is first registered with clinicaltrials.gov as NCT05586295 (09/12/2022). Sixteen male and sixteen female healthy adult non-athletes aged 20-30 were included. Exclusions were made based on smoking, cardiovascular disease, hypertension, body mass index (BMI) >27, metabolic disease, asthma and sports injury (nerve, muscle, bone). After a detailed explanation of all the risks and benefits of the experimental procedure, the consenting participants signed the informed consent form in person before starting the experiment. Subjects were required to cooperate by maintaining a normal diet during the experiment and not taking nutritional supplements such as alcohol or vitamin-B-related products. The participant flow chart was shown on | PMC10542023 |
Experimental design | fatigue | Based on previous testing periods of animal and human B-vitamin supplementation, a duration of 28 consecutive days was chosen as the supplementation period Before each phase of intervention, we measured the subjects' body composition, common blood biochemical parameters, and exercise tolerance. After consecutive 28 days of supplementation, we re-measured the subjects' exercise fatigue biochemical values, exercise endurance performance, and body composition. In addition, we asked all subjects to record their diet before and after the intervention, and a professional nutritionist analyzed the daily nutrient intake to ensure that the relevant sports performance was not affected by diet ( | PMC10542023 |
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Maximal oxygen uptake (VO2max) | VO | PMC10542023 |
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Endurance performance test and exercise fatigue-related indicators | fatigue | REGRESSION | According to the heart rate and speed recorded during the maximum oxygen uptake test, a regression calculation is performed to obtain the heart rate and speed corresponding to 60% and 85% of the maximum oxygen uptake, and the speed is adjusted according to the heart rate value. The detailed formula for intensity adjustment was based on a previous study On the other hand, to assess changes in indicators of fatigue, all subjects were asked to fast for at least 8 hours before the test. On the test day, we set a personal 60% VO | PMC10542023 |
Body composition | Subjects underwent body composition measurements before and after each phase of the intervention. All subjects were required to fast for 8 hours before the measurement. During the test, all subjects stood on the bottom electrode with arms extended at a 30° angle to the torso, held the induction handle with both hands, and did not move or speak. Measurements were performed within 60 s at 1, 5, 50, 260, 500, and 1000 kHz using a bioelectrical impedance analyzer (BIA) (InBody 570, In-body, Seoul, Korea) with the multi-frequency principle. | PMC10542023 |
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Clinical biochemistry and hematology analysis | high-density lipoprotein, TG | BLOOD | Blood was collected from each subject before each phase of supplementation for clinical biochemical and hematological analysis to confirm the basic biochemical indicators and health status. All the subjects were asked to fast for 8 hours the night before blood was drawn. After blood collection, the serum was obtained by centrifugation, and aspartate transaminase (AST), alanine aminotransferase (ALT), albumin (ALB), blood urea nitrogen (BUN), creatinine (CREA), uric acid (UA), total protein (TP), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) indicators were measured using an automatic analyzer (Hitachi 7060, Hitachi, Tokyo, Japan). In addition, the complete blood count (CBC) profiles were also analyzed (MindrayBC-2800 Vet, Shenzhen, China). | PMC10542023 |
Statistical analysis | All data are expressed as the mean ± SD. Statistical analyses were performed in IBM SPSS Statistics ver. 24.1 (IBM Co., Armonk, NY, USA). Differences within groups before and after the intervention were analyzed using a Bonferroni-adjusted paired | PMC10542023 |
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Results | PMC10542023 |
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Subjects' dietary analysis and Body composition changes | fatigue | In order to ensure that subjects' exercise performance and fatigue biochemical values were not affected by differences in dietary intake and energy, 3 days dietary record analysis was performed before and after Ex PLUS | PMC10542023 |
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Effects of Ex PLUS® supplementation on biochemical parameters and hematology | Table | PMC10542023 |
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Effects of Ex PLUS® supplementation on fatigue biochemical parameters during exercise and rest | Both lactate and NH3 levels gradually increased during exercise and gradually decreased after rest and recovery. As shown in | PMC10542023 |
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Effects of Ex PLUS® supplementation on endurance performance | Before intervention, the exhaustion test times were 12.57 ± 2.03 and 12.59 ± 2.06 (min) for the placebo and Ex PLUS | PMC10542023 |
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Discussion | In humans, nutrients and energy are primarily used by the body through food intake. Although the accompanying vitamins or minerals do not act as a primary energy source, they play a vital role in energy metabolism. In the current study, we found that consecutive 28 days of Ex PLUSB vitamins are involved in the regulation of energy metabolism and in the synthesis and degradation of carbohydrates, proteins, and fats Among other B vitamins, vitamin B6, folic acid, and vitamin B12 all contribute to the metabolism of homocysteine and are involved in the metabolism of proteins and amino acids, which, in turn, play a role in important pathways used during physical activity In the current study, we demonstrated that consecutive 28 days of vitamin B complex supplementation significantly improved exercise endurance performance. In addition to helping the metabolism of nutrients to produce energy through the B vitamins, other elements may be involved. Taurine is an important free amino acid that, although not fully involved in protein synthesis, has multiple physiological effects, including regulation of osmotic pressure, membrane stability and calcium kinetics, as well as the enhancement of systemic anti-inflammatory responses and total antioxidant capacity In the current study, we demonstrated that B-complex vitamin supplementation (Ex PLUS | PMC10542023 |
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Conclusions | In conclusion, in the current study, we demonstrated that 28 consecutive days of supplementation with Ex PLUSThe authors are grateful to the graduate students at the Sport Nutrition Laboratory, National Taiwan Sport University, for their technical assistance in conducting the analysis experiments. | PMC10542023 |
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Funding | This study was supported by Prince Pharmaceutical Co. Ltd. and the Ministry of Science and Technology of Taiwan (application type: academia-industry collaboration project). The grant number is MOST-109-2622-H-179-001. | PMC10542023 |
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Authors' contributions | Mon-Chien Lee, Sih-Yu Shen and Chi-Chang Huang designed the study. Mon-Chien Lee, Chin-Shan Ho and Chi-Chang Huang carried out the experiments. Mon-Chien Lee, Sih-Yu Shen and Chin-Shan Ho analyzed the data and interpreted the results. Mon-Chien Lee and Chi-Chang Huang wrote the manuscript.Participant flow chart.Experimental design.Effects of Ex PLUSEffects of Ex PLUSSubjects' basic information.Data are presented as mean ± SD. The same superscript letters (a) indicate no significant difference between groups at Subjects' dietary intake and body composition.Data are presented as mean ± SD. The same superscript letters (a) indicate no significant difference between groups at Biochemical analysis and blood count profiles of the subjects before and after the intervention.Data are shown as the mean ± SD. Statistical significance between the Placebo and Ex PLUS | PMC10542023 |
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Introduction | Edited by: Ingo Drexler, Heinrich Heine University, GermanyReviewed by: Kai Wu, Moderna Inc., United States; Nawamin Pinpathomrat, Prince of Songkla University, Thailand; Gyanendra Gongal, World Health Organization - Regional Office for South-East Asia, IndiaThis article was submitted to Viral Immunology, a section of the journal Frontiers in ImmunologyThis phase I study explored the immunogenicity and reactogenicity of accelerated, Q7 fractional, intradermal vaccination regimens for COVID-19. | PMC9886662 |
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Methods | SARS-COV-2 INFECTION | Participants (n = 60) aged 18-60 years, naïve to SARS-CoV-2 infection or vaccination, were randomly allocated into one of four homologous or heterologous accelerated two-dose, two-injection intradermal regimens seven days apart:(1) BNT162b2-BNT162b2(n= 20),(2) ChAdOx1- BNT162b2 (n = 20), (3) CoronaVac-ChAdOx1 (n = 10), and (4) ChAdOx1-ChAdOx1 (n = 10). CoronaVac and ChAdOx1 were 20%, and BNT162b2 17%, of their standard intramuscular doses (0.1 mL and 0.05 mL per injection, respectively). Humoral immune responses were measured through IgG response towards receptor binding domains (RBD-IgG) of ancestral SARS-CoV-2 spike protein and pseudovirus neutralization tests (PVNT50). Cellular immune responses were measured using ELISpot for ancestral protein pools. | PMC9886662 |
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Results | ADVERSE EVENT | Immunogenicity was highest in regimen (2), followed by (1), (4), and (3) 2 weeks after the second dose (P < 0.001 for anti-RBD-IgG and P= 0.01 for PVNT50). Each group had significantly lower anti-RBD IgG (by factors of 5.4, 3.6, 11.6, and 2.0 for regimens (1) to (4), respectively) compared to their respective standard intramuscular regimens (P < 0.001 for each). Seroconversion rates for PVNT50 against the ancestral strain were 75%, 90%, 57% and 37% for regimens (1) to (4), respectively. All participants elicited ELISpot response to S-protein after vaccination. Adverse events were reportedly mild or moderate across cohorts. | PMC9886662 |
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Discussion | We concluded that accelerated, fractional, heterologous or homologous intradermal vaccination regimens of BNT162b2 and ChAdOx1 were well tolerated, provided rapid immune priming against SARS-CoV-2, and may prove useful for containing future outbreaks. | PMC9886662 |
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Introduction | ADVERSE EVENTS | Intradermal (ID) injection, or the administration of drugs into the dermis, is an alternative method of vaccination to conventional intramuscular (IM) or subcutaneous (SC) routes (Fractional dosing also reduces reactogenicity and systemic adverse events (AEs) due to dose-dependency (Accelerated, dose-sparing approaches towards mass immunization broadens vaccine coverage and population immunity, preventing the spread of SARS-CoV-2 (CoronaVac and ChAdOx1-nCov19 were introduced into Thailand early on during the pandemic; BNT162b2 quickly followed thereafter. This study explored the immunogenicity and reactogenicity of accelerated, fractional, ID dosing regimens of homologous and heterologous COVID-19 vaccines within a Thai population. | PMC9886662 |
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Material and methods | PMC9886662 |
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Study design and participants | COA, substance abuse, allergies | DISEASES, SARS-COV-2 INFECTION, ALLERGIES | This single-center, randomized, prospective, open-labelled, pilot cohort study enrolled healthy adults aged 18-60 years during September to December of 2021. Participants naïve for SARS-CoV-2 infection, capable of adhering to scheduled fractional dosing regimens, with an ability to understand Thai, and to self-report digitally were included in the study. Exclusion criteria included those that: were previously infected with SARS-CoV-2; received prophylactic or investigational COVID-19 treatment; received blood, plasma, immunoglobulins, or antibodies within 90 days of the study; had a history of severe drug or vaccine allergies, pre-existing comorbidities, underlying diseases, drug, or substance abuse; were pregnant; and were immunocompromised or receiving immunosuppressive agents. These study protocols were approved by the Human Research Protection Unit, Faculty of Medicine Siriraj Hospital, Mahidol University (COA: MU-MOU 704/2021) and registered under Thailand’s Clinical Trial Registry (registration number: TCTR20210904004, | PMC9886662 |
Study procedure | -20 | Initially, 10 participants were randomly assigned into 4 groups each to receive two homologous or heterologous ID doses of CoronaVac (Sinovac), ChAdOx1 nCoV-19 (AstraZeneca), or BNT162b2 (Pfizer-BioNTech) 7 days apart. The vaccine regimens (first-second dose) for each arm were: BNT162b2-BNT162b2 (Group 1), ChAdOx1-BNT162b2 (Group 2), CoronaVac-ChAdOx1 (Group 3), and ChAdOx1-ChAdOx1 (Group 4). Participants received two injections of each vaccination, one in each arm within the deltoid region. The dosage for each injection was 10-20% of conventional IM doses based on previously published literature (Preliminary analyses of anti-RBD IgG were performed for all regimens and participants. Evidence of positive anti-NP or anti-RBG IgG at baseline were excluded. In the extended phase, additional participants were recruited to the two groups (10 per regimen) with the highest anti-RBD IgG measured 2 weeks after the second vaccination to meet statistical power. Additional blood sample were collected 12 weeks after the second dose for these two groups to evaluate the persistence of anti-RBG IgG. | PMC9886662 |
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Chemiluminescent microparticle assay for anti-SARS-CoV-2 RBD IgG and anti-NP of ancestral strain | Plasma samples were isolated using sodium citrate and stored at -80°C. A chemiluminescent microparticle assay (CMIA) was used to determine anti-RBD and anti-NP through SARS-CoV-2 IgG II Quant (Abbott Laboratory System, Illinois, US) on the ARCHITECT i System. Antibody levels were linearly measured between 21.0-40,000.0 arbitrary units per mL (AU/mL), and subsequently converted to binding antibody units per mL (BAU/mL) per WHO’s International Standards and an equation provided by the manufacturer (BAU/mL = 0.142 × AU/mL). Seropositivity was defined by cutoff values ≥ 50 AU/mL (7.1 BAU/mL). Antibody response against SARS-CoV-2 NP protein was determined using baseline plasma samples through CMIA SARS-CoV-2 IgG (Abbott, List No. 06R86) on the ARCHITECT i System. | PMC9886662 |
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Pseudovirus neutralization test for ancestral Wuhan strain and omicron subvariants | PVNT was carried out as described previously at the National Center of Genetic Engineering and Biotechnology, Thailand ( | PMC9886662 |
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Cell-mediated immune response by ELISpot assay to ancestral Wuhan strain | T-cell responses were assessed using human interferon-gamma (IFN-γ) ELISpot kits according to the manufacturers’ instruction (Mabtech AB, Nacka Strand, Sweden – as previously described ( | PMC9886662 |
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Statistical analysis | anti-SARS-CoV-2 RBD | Participants positive for anti-NP and anti-RBD at baseline were excluded from the analysis. Immunological endpoints (anti-SARS-CoV-2 RBD IgG, PVNT | PMC9886662 |
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Results | 55 participants were screened during the initial phase of the study, and 40 were enrolled. Following the preliminary analysis of this initial phase, Groups 1 and 2 induced the highest immunogenic responses (highest anti-RBD IgG). An additional 26 participants were screened, and 20 subsequently enrolled in these two groups for the extended phase of this study. This amounted to a total of 60 participants enrolled in the study, with 3 excluded from its analysis due to positive baseline anti-NP or anti-RBD IgG antibody values (see Consort diagram. 55 participants were assessed for eligibility in the initial phase, and 40 were included and randomized (1:1:1:1) to receive accelerated intradermal regimens in the study. An additional 26 participants were assessed for eligibility in the extended phase, and 20 were included and randomized (1:1) into two of the four accelerated intradermal vaccine regimens. Participants were assessed thereafter at baseline (n = 57), 1 week after the first dose (n = 57), 2 weeks after the second dose (n = 55), and 12 weeks after the second dose (n =30).Baseline characteristics of the participants receiving accelerated regimens of intradermal COVID-19 vaccinations.Chi-square and Kruskal-Wallis tests were used to determine p-value among those who received any of the four vaccination regimens. ID, Intradermal. | PMC9886662 |
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Anti-SARS-CoV-2 RBD IgG response to ancestral Wuhan strain | None of the participants were seropositive for anti-RBD IgG 7 days after the first dose. All were seropositive after the second dose. Anti-SARS-CoV-2 RBD IgG geometric mean concentrations (GMCs) 2 weeks after the second dose had significantly increased (SARS-CoV-2 humoral immune responses against the ancestral Wuhan strain following accelerated regimens of fractional, ID administration. | PMC9886662 |
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PVNT | The PVNT | PMC9886662 |
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Cell-mediated immune response by ELISpot to ancestral Wuhan strain | All participants, except one, had negative responses at baseline. One participant had a low ELISpot response to S-protein (24 SFU). 2 weeks after the second dose, all participants across the four regimens had significant increases in IFN-γ response against S-protein. The highest GM SFU for S-protein 2 weeks after the second dose was observed in Group 2 (441.34; 95% CI 271.10, 718.47), followed by Group 1 (373.80; 95% CI 246.12, 567.72), Group 4 (224.99; 95% CI 136.63, 370.50), and Group 3 (85.88; 95% CI 42.22, 174.70) (see SARS-CoV-2 antigen-specific T-cell responses by ELISpot at baseline and 2 weeks after the second dose following accelerated regimens of fractional, ID administration. | PMC9886662 |
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Adverse events | ADVERSE EVENTS | Many reported AEs were mild, some moderate, but none severe. All AEs fully resolved before the end of the study (see Self-reported adverse events (AEs) in days 0-7 following the first and second ID doses. | PMC9886662 |
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Discussion | infection | INFECTION, RABIES | This pilot study explored the immunogenicity and reactogenicity of accelerated schedules of fractional, homologous or heterologous, ID COVID-19 immunization. Accelerated two-dose ID regimens, administered 7 days apart, as fractions of 17% (for BNT162b2) and 20% (for CoronaVac and ChAdOx1) of their standard IM dosages were immunogenic against the ancestral strain. Homologous regimens of BNT162b2-BNT162b2 and heterologous ChAdOx1-BNT162b2 induced higher humoral and cellular immune responses against the ancestral Wuhan strain than homologous ChAdOx1-ChAdOx1 and CoronaVac-ChAdOx1. However, they induced lower antibody responses than their respective conventional IM dosing (two doses, 4 weeks apart). Heterologous regimens also induced higher measurable neutralizing antibody titers than their homologous regimens. However, fractional ID dosing regimens induced poor neutralizing antibody responses against omicron subvariants, comparable to two-dose IM regimens.Vaccine administration Accelerated schedules provide rapid vaccine-induced immunity and have been widely used in post-exposure prophylaxis against rabies. The WHO recommends an accelerated schedule on days 0, 3, 7, and 14-28 to rapidly achieve the immune induction required to prevent rabies infection (Low or negligible antibody responses against omicron subvariants were observed. This was consistent with earlier findings in primary series administered as two doses IM, where boosters were required to generate robust cross immunity against omicron due to its immune evasion properties (Additionally, as observed in other studies, homologous and heterologous fractional ID regimens were well-tolerated, with low incidences of systemic AEs and no severe local reactions (Our study has some limitations. First, this is a pilot study and our sample size is small. However, we could still observe significant differences between the four vaccine groups with reference to their IM regimens. Second, we were not able to compare our data with an IM primary series within the same cohort. We minimized the variability of our findings somewhat by using reference data from the same setting, and testing methods as the previous cohort. Third, we did not have a reference IM group for ELISpot analysis. Therefore, we were unable to compare cellular immune responses between IM and ID administration directly. Fourth, there are no accelerated IM schedules with similar vaccination regimens 7 days apart for comparison. Lastly, our data may not be generalizable to other populations (To conclude, we found that accelerated fractional COVID-19 vaccines administered ID are immunogenic against the ancestral strain but insufficient for omicron subvariants. Our regimens were able to prime immunity, as demonstrated by humoral and cellular immune responses. With the appropriate vaccine, such strategies may be useful for containing future outbreaks, particularly in cases of vaccine shortages. Further studies on accelerated schedules warrants research on booster dose responses. | PMC9886662 |
Data availability statement | The original contributions presented in the study are included in the article/ | PMC9886662 |
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Ethics statement | COA | The studies involving human participants were reviewed and approved by The Human Research Protection Unit, Faculty of Medicine Siriraj Hospital, Mahidol University (COA: MU-MOU 704/2021). The patients/participants provided their written informed consent to participate in this study. | PMC9886662 |
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Author contributions | SN and KC conceptualized the study; SN, SA, PW, KS, and KC devised the methodology; SN and KC acquired funding; SN, LJ, ZT, PL, and KC carried out the formal analysis of its findings; SN, SA, PW, KS, and KC conducted the study’s clinical investigation; SN and LJ curated the data; KKC, ZT, and KC wrote and prepared the original draft; and all authors assisted with its review and editing. All authors contributed to the article and approved the submitted version. | PMC9886662 |
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Acknowledgments | We would also like to acknowledge Chevron Thailand and Health Systems Research Institute, Thailand for their support. | PMC9886662 |
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Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC9886662 |
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Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC9886662 |
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Supplementary material | The Supplementary Material for this article can be found online at: Click here for additional data file. | PMC9886662 |
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References | PMC9886662 |
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Background | diabetes | TYPE 1 DIABETES, DIABETES | The transition from paediatric to adult care for young adults with type 1 diabetes poses unique challenges. Virtual diabetes clinics using smartphone applications offer a promising approach to support self-management and enhance communication with healthcare providers. The primary objective of this study was to evaluate the effects of a virtual diabetes clinic on glycaemic control, treatment satisfaction, and quality of life among young adults diagnosed with type 1. | PMC10664359 |
Methods | diabetes | TYPE 1 DIABETES, DIABETES | 79 participants with type 1 diabetes aged 18–25 years were included in a prospective, single-centre, randomised, wait-list controlled trial. Participants were randomly assigned to either the intervention group or the wait-list control group. The intervention group received instant access to a virtual care platform called Vista Dialog, which facilitated real-time communication between patients and healthcare providers. Glycosylated haemoglobin (HbA1c) levels, time in range (TIR), time below range (TBR), diabetes treatment satisfaction, and quality of life were assessed at baseline and after 6 months. | PMC10664359 |
Results | diabetes | DIABETES | Baseline characteristics were similar between the intervention and control groups, except for education level, where there was a skewed distribution between the groups (the intervention group had a lower education level). At the 6-month follow-up, there were no significant differences in HbA1c levels, TIR, TBR, or diabetes treatment satisfaction between the two groups. However, the intervention group demonstrated a significant decrease in the burden on physical health compared with the control group, indicating an improved quality of life. | PMC10664359 |
Conclusions | diabetes | TYPE 1 DIABETES, DIABETES | The implementation of a virtual diabetes clinic using the Vista Dialog platform did not result in significant improvements in glycaemic control or treatment satisfaction compared with usual care. However, it did show potential benefits in terms of reducing the burden on physical health and improving quality of life in young adults with type 1 diabetes. Further research is needed to explore the long-term effects and optimal use of virtual clinics in diabetes management. | PMC10664359 |
Trial registration | ISRCTN number: 73,435,627 (registration date: 23/10/2019): 10.1186/ISRCTN73435627. The performance and results of this trial adhere to the guidelines outlined in the CONSORT 2010 (Consolidated Standards of Reporting Trials) recommendations. | PMC10664359 |
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Keywords | Open access funding provided by Uppsala University. | PMC10664359 |
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Background | diabetes, premature death, chronic disease, Diabetes | TYPE 1 DIABETES, CHRONIC DISEASE, DIABETES, COMPLICATIONS, DIABETES | Diabetes is a chronic disease that poses a significant health risk, with potentially severe complications, including premature death [Sweden has one of the highest percentages of children with type 1 diabetes in the world [Advanced treatment technologies, such as pumps and sensors, have created additional demands regarding care, education, and support for patients with type 1 diabetes and their families [Younger individuals are accustomed to using advanced technology such as insulin pumps and continuous or rapid glucose monitoring systems, which provide detailed information that can be used for online consultation with healthcare providers. This technology enables distance diabetes care with detailed analyses and recommendations. Virtual diabetes clinics via smartphone apps can be a way to support self-management of diabetes. Such clinics enable patients to communicate with healthcare providers, diabetes nurses or doctors, which can create security for the patients.Past studies have suggested that it is crucial to evaluate additional health parameters alongside HbA1c and to strengthen the methodological rigor of future investigations [Furthermore, young adults who have type 1 diabetes make up a population that is hard to reach and often have deteriorated HbA1c levels. Curiously, there is currently a lack of virtual RCTs evaluating young adults with type 1 diabetes, despite the potential benefits and increasing use of virtual trials in other areas of research. | PMC10664359 |
Study aim | diabetes | TYPE 1 DIABETES, DIABETES | This study aims to assess the effect of a virtual diabetes clinic on glycaemic control, treatment satisfaction, and quality of life in a specific population of young adults between the ages of 18 and 25 diagnosed with type 1 diabetes. | PMC10664359 |
Method | PMC10664359 |
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Study design | The study design and methods of the present study have been described in detail in a previously published study protocol [
Flowchart of the trial | PMC10664359 |
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Participants and recruitment | depression, eating disorder, diabetes | TYPE 1 DIABETES, RECRUITMENT, COMPLICATIONS, DIABETES | All participants had type 1 diabetes, were registered at a single hospital in Stockholm, Sweden, and were identified in the diabetes clinic’s patient register by hospital HCPs. The inclusion criteria of the study were access to a smartphone or computer, duration of diabetes for more than 1 year and an age of 18–25 years. Participants who met any of the following criteria were excluded from the study: diagnosis of severe depression, eating disorder, or other significant mental illness, history of alcohol or drug abuse, or presence of severe complications related to diabetes. The diabetes nurse and/or physician made the decision on whether each diabetes patient had the compliance required to participate in the study. All individuals received verbal and written information about the study before inclusion. Originally, our intention was to include 100 participants in the study. However, the widespread development of Covid-19 within society presented obstacles that hindered the recruitment of study subjects. | PMC10664359 |
Randomisation and intervention | The nurses at the clinic were responsible for including individuals in the study. Once informed consent was obtained from the participants, they were randomly assigned to either the intervention group or the wait-list control group. The randomization process involved the use of sealed envelopes containing randomized cards. The sealed envelopes were assembled by an impartial individual with no involvement in either the process of patient inclusion or their subsequent care.All materials were coded with consecutive numbers and the code list was kept in a locked fireproof cabinet at the hospital. After inclusion, a first data collection was performed in both groups. The intervention group got immediate access to the virtual clinic (Fig. | PMC10664359 |
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Vista dialog | diabetes | DIABETES | Vista Dialog is a virtual care platform, managed via secure login, delivered via a smartphone app for patients and a web interface/portal for HCPs. The platform facilitates seamless real-time communication for participants, enabling them to engage in text message exchanges, schedule online appointments with diabetes specialist nurses, and initiate impromptu video meetings if the situation necessitates further discussion related to their ongoing text message conversations with the nurses. The patient can also upload data from their insulin pump and continuous glucose monitoring (CGM) system for review and discussion. This invites and enables patients to put forward their needs when they arise. | PMC10664359 |
Measures and data collection | diabetes | DIABETES | Data collection for both clinical variables and psychometric measures was conducted exclusively at the diabetes clinic. Baseline assessments were carried out prior to the intervention, and outcome measurements were collected at both the baseline and 6-month follow-up time points. At baseline, comprehensive data encompassing sociodemographic information, including sex, age, living arrangements (whether living at home or in independent living), and education level, were collected to provide a descriptive profile of the participants. Furthermore, diabetes duration, age at onset of diabetes, and type of treatment such as multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Moreover, height (m) and weight (kg) were measured by trained HCPs and used to calculate body mass index (BMI). | PMC10664359 |
Clinical variables | diabetes | DIABETES | At the standard clinic appointments, the following data were collected:
HbA1c (Afinion 2™ [Abbott, USA]) level was used to reflect the average plasma glucose level over the preceding 8–12 weeks.Time in range (TIR), the percentage of time that a person spends with their glucose levels in a targeted range (3.9–10 mmol/L), and time below range (TBR), the percentage of time that a person spends with their glucose levels at < 3.9 mmol/L. TIR and TBR were measured through real-time CGM (rtCGM)/intermittently scanned CGM (isCGM).The insulin dosage information was extracted and recorded using diabetes management software, such as Diasend®, which allows for data downloading and analysis.Daily insulin dose (collected where possible). | PMC10664359 |
Diabetes treatment satisfaction questionnaire | ’, hypoglycemia, hyperglycemia, Diabetes, diabetes | HYPERGLYCEMIA, HYPOGLYCEMIA, DIABETES, BRADLEY, DIABETES | Diabetes Treatment Satisfaction Questionnaire, status version (DTSQs), was used to evaluate patients’ satisfaction with diabetes treatment interventions and developed and validated by Clare Bradley. This questionnaire is well-established for use in diabetes research [The DTSQs consists of three areas with a total of eight questions. The first area includes six questions covering aspects of treatment satisfaction, such as ‘satisfaction with current treatment,‘ ‘flexibility,‘ ‘convenience,‘ ‘understanding of diabetes,‘ ‘recommend treatment to others,‘ and ‘willingness to continue.‘ These questions are rated on a 7-point scale from ‘very dissatisfied’ to ‘very satisfied,‘ with a maximum score of 36, indicating higher treatment satisfaction. The second and third areas consist of single questions each, related to experiences of hyperglycemia and hypoglycemia in the weeks leading up to the assessment. Each question is rated on a 7-point scale from 0 to 6 [In summary, the DTSQs provides insights into treatment satisfaction, hyperglycemia and hypoglycemia experienced by patients in diabetes research studies. | PMC10664359 |
Check your health questionnaire | The validated questionnaire ‘Check your health’ consists of vertical scales (0–100 points) intended to screen for perceptions and experiences of physical and emotional health, social relationships and general quality of life [ | PMC10664359 |
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