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  1. Article ; Online: Accelerating vaccine trial conduct in a pandemic with a hot spot‐based inclusion strategy using trial and epidemic simulation

    Johan L. van derPlas / Michiel J. vanEsdonk / Ingrid M. C. Kamerling / Adam F. Cohen

    Clinical and Translational Science, Vol 14, Iss 6, Pp 2391-

    2021  Volume 2398

    Abstract: Abstract Clinical development of vaccines in a pandemic situation should be rigorous but expedited to tackle the pandemic threat as fast as possible. We explored the effects of a novel vaccine trial strategy that actively identifies and enrolls subjects ... ...

    Abstract Abstract Clinical development of vaccines in a pandemic situation should be rigorous but expedited to tackle the pandemic threat as fast as possible. We explored the effects of a novel vaccine trial strategy that actively identifies and enrolls subjects in local areas with high infection rates. In addition, we assessed the practical requirements needed for such a strategy. Clinical trial simulations were used to assess the effects of utilizing these so‐called “hot spot strategy” compared to a traditional vaccine field trial. We used preset parameters of a pandemic outbreak and incorporated realistic aspects of conducting a trial in a pandemic setting. Our simulations demonstrated that incorporating a hot spot strategy shortened the duration of the vaccine trial considerably, even if only one hot spot was identified during the clinical trial. The active hot spot strategy described in this paper has clear advantages compared to a “wait‐and‐see” approach that is used in traditional vaccine efficacy trials. Completion of a clinical trial can be expedited by adapting to resurgences and outbreaks that will occur in a population during a pandemic. However, this approach requires a speed of response that is unusual for a traditional phase III clinical trial. Therefore, several recommendations are made to help accomplish rapid clinical trial setup in areas identified as local outbreaks. The described model and hot spot vaccination strategy can be adjusted to disease‐specific transmission characteristics and could therefore be applied to any future pandemic threat.
    Keywords Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
    Subject code 310
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Mitochondrial function, grip strength, and activity are related to recovery of mobility after a total knee arthroplasty

    Marcus P. J. vanDiemen / Dimitrios Ziagkos / Matthijs D. Kruizinga / Menno R. Bénard / Philip Lambrechtse / Joris A. J. Jansen / Barbara A. M. Snoeker / Maaike G. J. Gademan / Adam F. Cohen / Rob G. H. H. Nelissen / Geert Jan Groeneveld

    Clinical and Translational Science, Vol 16, Iss 2, Pp 224-

    2023  Volume 235

    Abstract: Abstract Low muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver of sarcopenia. However, it is not known whether ...

    Abstract Abstract Low muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver of sarcopenia. However, it is not known whether it relates to recovery. In this pilot study, we monitored activity after TKA using a wrist mounted activity tracker and assessed the relation of mitochondrial function on the rate of recovery after TKA. Additionally, we compared the increase in activity as a way to measure recovery to traditional outcome measures. Patients were studied 2 weeks before TKA and up to 6 months after. Activity was monitored continuously. Baseline mitochondrial function (citrate synthase and complex [CP] 1–5 abundance of the electron transport chain) was determined on muscle tissue taken during TKA. Traditional outcome measures (Knee Injury and Osteoarthritis Outcome Score [KOOS], timed up‐and‐go [TUG] completion time, grip, and quadriceps strength) were performed 2 weeks before, 6 weeks after, and 6 months after TKA. Using a multivariate regression model with various clinical baseline parameters, the following were significantly related to recovery: CP5 abundance, grip strength, and activity (regression weights 0.13, 0.02, and 2.89, respectively). During recovery, activity correlated to the KOOS‐activities of daily living (ADL) score (r = 0.55, p = 0.009) and TUG completion time (r = −0.61, p = 0.001). Mitochondrial function seems to be related to recovery, but so are activity and grip strength, all indicators of sarcopenia. Using activity trackers before and after TKA might give the surgeon valuable information on the expected recovery and the opportunity to intervene if recovery is low.
    Keywords Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
    Subject code 796
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Objective Home-Monitoring of Physical Activity, Cardiovascular Parameters, and Sleep in Pediatric Obesity

    Janine M. Knijff / Euphemia C.A.M. Houdijk / Daniëlle C.M. van der Kaay / Youri van Berkel / Luc Filippini / Frederik E. Stuurman / Adam F. Cohen / Gertjan J.A. Driessen / Matthijs D. Kruizinga

    Digital Biomarkers, Vol 6, Iss 1, Pp 19-

    2022  Volume 29

    Abstract: Introduction: Clinical research and treatment of childhood obesity is challenging, and objective biomarkers obtained in a home-setting are needed. The aim of this study was to determine the potential of novel digital endpoints gathered by a home- ... ...

    Abstract Introduction: Clinical research and treatment of childhood obesity is challenging, and objective biomarkers obtained in a home-setting are needed. The aim of this study was to determine the potential of novel digital endpoints gathered by a home-monitoring platform in pediatric obesity. Methods: In this prospective observational study, 28 children with obesity aged 6–16 years were included and monitored for 28 days. Patients wore a smartwatch, which measured physical activity (PA), heart rate (HR), and sleep. Furthermore, daily blood pressure (BP) measurements were performed. Data from 128 healthy children were utilized for comparison. Differences between patients and controls were assessed via linear mixed effect models. Results: Data from 28 patients (average age 11.6 years, 46% male, average body mass index 30.9) and 128 controls (average age 11.1 years, 46% male, average body mass index 18.0) were analyzed. Patients were recruited between November 2018 and February 2020. For patients, the median compliance for the measurements ranged from 55% to 100% and the highest median compliance was observed for the smartwatch-related measurements (81–100%). Patients had a lower daily PA level (4,597 steps vs. 6,081 steps, 95% confidence interval [CI] 862–2,108) and peak PA level (1,115 steps vs. 1,392 steps, 95% CI 136–417), a higher nighttime HR (81 bpm vs. 71 bpm, 95% CI 6.3–12.3) and daytime HR (98 bpm vs. 88 bpm, 95% CI 7.6–12.6), a higher systolic BP (115 mm Hg vs. 104 mm Hg, 95% CI 8.1–14.5) and diastolic BP (76 mm Hg vs. 65 mm Hg, 95% CI 8.7–12.7), and a shorter sleep duration (difference 0.5 h, 95% CI 0.2–0.7) compared to controls. Conclusion: Remote monitoring via wearables in pediatric obesity has the potential to objectively measure the disease burden in the home-setting. The novel endpoints demonstrate significant differences in PA level, HR, BP, and sleep duration between patients and controls. Future studies are needed to determine the capacity of the novel digital endpoints to detect effect of ...
    Keywords pediatric obesity ; home-monitoring ; smartwatch ; physical activity ; cardiovascular parameters ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Karger Publishers
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Repeatability and predictive value of lactate threshold concepts in endurance sports.

    Jules A A C Heuberger / Pim Gal / Frederik E Stuurman / Wouter A S de Muinck Keizer / Yuri Mejia Miranda / Adam F Cohen

    PLoS ONE, Vol 13, Iss 11, p e

    2018  Volume 0206846

    Abstract: INTRODUCTION:Blood lactate concentration rises exponentially during graded exercise when muscles produce more lactate than the body can remove, and the blood lactate-related thresholds are parameters based on this curve used to evaluate performance level ...

    Abstract INTRODUCTION:Blood lactate concentration rises exponentially during graded exercise when muscles produce more lactate than the body can remove, and the blood lactate-related thresholds are parameters based on this curve used to evaluate performance level and help athletes optimize training. Many different concepts of describing such a threshold have been published. This study aims to compare concepts for their repeatability and predictive properties of endurance performance. METHODS:Forty-eight well-trained male cyclists aged 18-50 performed 5 maximal graded exercise tests each separated by two weeks. Blood lactate-related thresholds were calculated using eight different representative concepts. Repeatability of each concept was assessed using Cronbach's alpha and intra-subject CV and predictive value with 45 minute time trial tests and a road race to the top of Mont Ventoux was evaluated using Pearson correlations. RESULTS:Repeatability of all concepts was good to excellent (Cronbach's alpha of 0.89-0.96), intra-subject CVs were low with 3.4-8.1%. Predictive value for performance in the time trial tests and road race showed significant correlations ranging from 0.65-0.94 and 0.53-0.76, respectively. CONCLUSION:All evaluated concepts performed adequate, but there were differences between concepts. One concept had both the highest repeatability and the highest predictability of cycling performance, and is therefore recommended to be used: the Dmax modified method. As an easier to apply alternative, the lactate threshold with a fixed value of 4 mmol/L could be used as it performed almost as well. TRIAL REGISTRATION:Dutch Trial Registry NTR5643.
    Keywords Medicine ; R ; Science ; Q
    Subject code 796
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Immunomonitoring of Tacrolimus in Healthy Volunteers

    Aliede E. in ‘t Veld / Hendrika W. Grievink / Mahdi Saghari / Frederik E. Stuurman / Marieke L. de Kam / Aiko P. J. de Vries / Brenda C. M. de Winter / Jacobus Burggraaf / Adam F. Cohen / Matthijs Moerland

    International Journal of Molecular Sciences, Vol 20, Iss 19, p

    The First Step from PK- to PD-Based Therapeutic Drug Monitoring?

    2019  Volume 4710

    Abstract: Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of ... ...

    Abstract Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell.
    Keywords immunosuppressive drugs ; transplantation ; pharmacodynamics ; pharmacokinetics ; tacrolimus ; therapeutic drug monitoring ; immunomonitoring ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2019-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test

    Rob G.J.A. Zuiker / Catherine Tribouley / Zuzana Diamant / J. Diderik Boot / Adam F. Cohen / K. Van Dyck / I. De Lepeleire / Veronica M. Rivas / Vladislav A. Malkov / Jacobus Burggraaf / Marcella K. Ruddy

    European Clinical Respiratory Journal, Vol 3, Iss 0, Pp 1-

    2016  Volume 17

    Abstract: Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. Objectives: To evaluate whether an RNA signature can be ... ...

    Abstract Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. Objectives: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study. Methods: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge. Results: Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly with lung function and sputum eosinophil counts. Conclusion: Our RNA extraction and profiling protocols allowed reproducible assessments of inflammatory signatures in sputum including quantification of drug effects on this response in allergic asthmatics. This approach offers novel possibilities for the development of pharmacodynamic (PD) biomarkers in asthma.
    Keywords allergen bronchial provocation test ; asthma ; sputum ; Th2 inflammation ; DNA microarray ; fluticasone ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2016-07-01T00:00:00Z
    Publisher CoAction
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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