Publications by authors named "Thomas Aagaard"

11 Publications

  • Page 1 of 1

Peptide Vaccination Against PD-L1 With IO103 a Novel Immune Modulatory Vaccine in Multiple Myeloma: A Phase I First-in-Human Trial.

Front Immunol 2020 9;11:595035. Epub 2020 Nov 9.

National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.

Background: Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793).

Methods: Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described.

Results: All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations.

Conclusion: Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy.

Clinical Trial Registration: clinicaltrials.org, identifier NCT03042793.
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http://dx.doi.org/10.3389/fimmu.2020.595035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680803PMC
June 2021

Benefits and Harms of Exercise Therapy for Patients With Diabetic Foot Ulcers: A Systematic Review.

Int J Low Extrem Wounds 2020 Sep 14:1534734620954066. Epub 2020 Sep 14.

Department of Orthopaedic Surgery, Zealand University Hospital, Koege, Denmark.

Aim: Exercise therapy is a core element in the treatment of diabetes, but the benefits and harms for patients with a diabetic foot ulcer (DFU) are unknown. We therefore aimed to systematically review the benefits on health-related quality of life (HRQoL) and harms of exercise therapy for patients with DFU.

Methods: We searched 6 major databases. We performed citation and reference searches of included studies and contacted authors of ongoing trials. We included randomized controlled trials (RCTs) to assess potential benefits on HRQoL and harms of exercise therapy. Observational studies were included to identify potential harms of exercise therapy.

Results: We included 10 published publications of 9 trials and results from 2 unpublished trials including a total of 281 individuals with DFUs receiving various forms of exercise therapy. Due to lack of HRQoL measurements and high heterogeneity, it was not possible to perform meta-analyses. Results on HRQoL was present in one unpublished study. Harms reported ranged from musculoskeletal problems, increased wound size, to amputation; however, no safe conclusions could be drawn from the available data due to high heterogeneity and risk of bias in the trials.

Conclusions/interpretation: Protective strategies are often preferred over therapeutic exercise that might have unforeseen consequences for patients over time. Based on the current literature, no evidence-based recommendations can be provided on the benefits and harms of exercise therapy for patients with DFUs. Well-conducted RCTs are needed to guide rehabilitation including detailed description of adverse events and an exercise program in a semisupervised or fully supervised setting.
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http://dx.doi.org/10.1177/1534734620954066DOI Listing
September 2020

[Monoclonal gammopathy of undetermined significance].

Ugeskr Laeger 2020 03;182(10)

This review summarises the work-up of patients with monoclonal gammopathy of undetermined significance (MGUS). In persons above 70 years of age, around 5% have MGUS, a premalignant state with a monoclonal plasma immunoglobulin or light chain (M protein) in blood and/or urine. Continuous follow-up is recommended due to a risk of malignant progression of around 1% per year. Immunoglobulin M MGUS primarily progresses to Waldenström's macroglobulinaemia, whereas non-immunoglobulin M MGUS typically progresses to multiple myeloma or amyloid light-chain amyloidosis. Treatment is unnecessary unless in rare cases of severe non-malignant complications. Screening is not advised.
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March 2020

Interrater Reliability of Dynamic Muscle Testing After Breast Cancer Surgery in Women at High Risk of Lymphedema: To Improve Quality in Clinical Practice.

Integr Cancer Ther 2020 Jan-Dec;19:1534735420903801

Danish Research Center for Equality in Cancer (COMPAS), Zealand University Hospital, Naestved, Denmark.

The purpose of this study is to determine the interrater reliability of dynamic muscle tests in the early rehabilitation phase in women after breast cancer surgery with axillary lymph node dissection (ALND) based on the "preventive intervention against lymphedema after breast cancer" (LYCA) randomised controlled trial. Fifteen women treated with breast cancer surgery including ALND were recruited from participants in the LYCA trial. In this interrater reliability study, women were tested in 4 dynamic muscle tests by 2 physiotherapists at a Capital Hospital in Denmark. Intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs) was used to assess the relative reliability between raters. A Bland-Altman plot and limits of agreement were calculated to describe the absolute reliability. All 6 subtests displayed high interrater reliability. ICC values were: leg press 0.96 (95% CI = 0.87-0.99), elbow flexion (contralateral) 0.94 (0.83-0.98), elbow flexion (affected arm) 0.93 (0.80-0.98), elbow extension 0.80 (0.41-0.93), shoulder abduction (contralateral) 0.89 (0.68-0.96), and shoulder abduction (affected arm) 0.91 (0.74-0.97). Cumulated interrater reliability for the test battery was very high (ICC = 0.99, 95% CI = 0.990-1.0). The absolute reliability of this study was considered high, and the absence of large shifts between mean and the line of 0 difference suggest no systematic bias that could influence clinical interpretation. The dynamic muscle tests evaluated in this study had high interrater reliability and can be used reliably in women in the postoperative phase after breast cancer surgery with ALND.
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http://dx.doi.org/10.1177/1534735420903801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052446PMC
March 2021

Optimizing literature search in systematic reviews - are MEDLINE, EMBASE and CENTRAL enough for identifying effect studies within the area of musculoskeletal disorders?

BMC Med Res Methodol 2016 11 22;16(1):161. Epub 2016 Nov 22.

Research Unit for Musculoskeletal Function and Physiotherapy, Institute for Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.

Background: When conducting systematic reviews, it is essential to perform a comprehensive literature search to identify all published studies relevant to the specific research question. The Cochrane Collaborations Methodological Expectations of Cochrane Intervention Reviews (MECIR) guidelines state that searching MEDLINE, EMBASE and CENTRAL should be considered mandatory. The aim of this study was to evaluate the MECIR recommendations to use MEDLINE, EMBASE and CENTRAL combined, and examine the yield of using these to find randomized controlled trials (RCTs) within the area of musculoskeletal disorders.

Methods: Data sources were systematic reviews published by the Cochrane Musculoskeletal Review Group, including at least five RCTs, reporting a search history, searching MEDLINE, EMBASE, CENTRAL, and adding reference- and hand-searching. Additional databases were deemed eligible if they indexed RCTs, were in English and used in more than three of the systematic reviews. Relative recall was calculated as the number of studies identified by the literature search divided by the number of eligible studies i.e. included studies in the individual systematic reviews. Finally, cumulative median recall was calculated for MEDLINE, EMBASE and CENTRAL combined followed by the databases yielding additional studies.

Results: Deemed eligible was twenty-three systematic reviews and the databases included other than MEDLINE, EMBASE and CENTRAL was AMED, CINAHL, HealthSTAR, MANTIS, OT-Seeker, PEDro, PsychINFO, SCOPUS, SportDISCUS and Web of Science. Cumulative median recall for combined searching in MEDLINE, EMBASE and CENTRAL was 88.9% and increased to 90.9% when adding 10 additional databases.

Conclusion: Searching MEDLINE, EMBASE and CENTRAL was not sufficient for identifying all effect studies on musculoskeletal disorders, but additional ten databases did only increase the median recall by 2%. It is possible that searching databases is not sufficient to identify all relevant references, and that reviewers must rely upon additional sources in their literature search. However further research is needed.
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http://dx.doi.org/10.1186/s12874-016-0264-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120411PMC
November 2016

[Positive results with haematology webcasting for junior doctors].

Ugeskr Laeger 2016 Jan;177(2):V12140747

Webcasting is an educational activity where the teacher and the participants are separated in space and time when using modern information technology. It is widely used for all learning levels and in all educational forms of haematology training in Europe. A working group in the Education Council of internal medicine, haematology in the eastern part of Denmark initiated a project with webcasting from local haematological departments. The aim of the education project was to contribute to spreading knowledge and support the training of specialist in haematology. Our experience is hereby reported.
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January 2016

[Severe haemolysis caused by Mycoplasma pneumoniae].

Ugeskr Laeger 2015 Oct;177(43):V03150207

Mycoplasma pneumoniae is naturally resistant to betalactamase antibiotics but is sensitive to macrolides. Occasionally, infections with M. pneumoniae can lead to severe anaemia due to its ability to cause haemolysis when cold agglutination occurs. Increasing bacterial resistance to macrolid antibiotics is a growing concern worldwide. We present two cases where infection with M. pneumoniae caused severe haemolysis, one of which was macrolide-resistant.
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October 2015

Vitellogenin as biomarker for estrogenicity in flounder Platichthys flesus in the field and exposed to 17α-ethinylestradiol via food and water in the laboratory.

Mar Environ Res 2013 Dec 17;92:79-86. Epub 2013 Sep 17.

Institute of Biology, University of Southern Denmark, Odense, Campusvej 55, DK-5230 Odense M, Denmark.

The ability of 17α-ethinylestradiol (EE2) to elevate vitellogenin levels were investigated in male flounder Platichthys flesus and vitellogenin concentrations in flounders from the Danish coastal environment were determined. Male flounders were exposed to 17α-ethinylestradiol (EE2) via food or water. Average vitellogenin concentrations in the control fish ranged between 25 and 100 ng mL(-)(1). Exposure to 5.1, 8.1 and 16.8 ng EE2 L(-)(1) in water and 500 and 5000 ng EE2 kg(-)(1) body weight (bw) every second day in the food increased the plasma vitellogenin concentration in a concentration and time dependent manner, whereas exposure to 2.7 ng EE2 L(-)(1) in water for 21 d and 5 and 50 ng EE2 kg(-)(1) bw for 12 days in the food did not. EE2 could be detected in liver and testes (but not in muscle) after exposure to 8.1 and 16.8 ng EE2 L(-)(1) in the water and 5000 ng EE2 kg(-)(1) bw in the food; the highest concentration was 6 ng g(-)(1) wet weight in liver. The majority of the male flounders collected from nine coastal Danish sites from 1999 to 2004 had vitellogenin concentrations below 100 ng mL(-)(1), and only at two sites moderate estrogenic inputs were indicated.
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http://dx.doi.org/10.1016/j.marenvres.2013.09.002DOI Listing
December 2013

Small-angle neutron scattering study of the ultrastructure of chloroplast thylakoid membranes - periodicity and structural flexibility of the stroma lamellae.

Biochim Biophys Acta 2012 Aug 28;1817(8):1220-8. Epub 2012 Jan 28.

Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark.

The multilamellar organization of freshly isolated spinach and pea chloroplast thylakoid membranes was studied using small-angle neutron scattering. A broad peak at ~0.02Å(-1) is ascribed to diffraction from domains of ordered, unappressed stroma lamellae, revealing a repeat distance of 294ű7Å in spinach and 345ű11Å in pea. The peak position and hence the repeat distance of stroma lamellae is strongly dependent on the osmolarity and the ionic strength of the suspension medium, as demonstrated by varying the sorbitol and the Mg(++)-concentration in the sample. For pea thylakoid membranes, we show that the repeat distance decreases when illuminating the sample with white light, in accordance with our earlier results on spinach, also regarding the observation that addition of an uncoupler prohibits the light-induced structural changes, a strong indication that these changes are driven by the transmembrane proton gradient. We show that the magnitude of the shrinkage is strongly dependent on light intensity and that the repeat distance characteristic of the dark state after illumination is different from the initial dark state. Prolonged strong illumination leads to irreversible changes and swelling as reflected in increased repeat distances. The observed reorganizations are discussed within the frames of the current structural models of the granum-stroma thylakoid membrane assembly and the regulatory mechanisms in response to variations in the environmental conditions in vivo. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial.
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http://dx.doi.org/10.1016/j.bbabio.2012.01.012DOI Listing
August 2012

Effect of mechanical brushing on survival and hemodynamic characteristics of tunneled hemodialysis catheters.

J Vasc Access 2012 Apr-Jun;13(2):226-30

Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark.

Purpose: Tunneled catheters used for hemodialysis treatment often become dysfunctional due to deposition of clotting material within the catheter lumen. In a retrospective study design we investigated the effect of mechanical brushing of dysfunctional tunneled catheters using a metal guide wire with simultaneous installation of urokinase.

Materials And Methods: During a period of 26 months all together 24 different catheters in 21 chronic hemodialysis patients were brushed due to insufficient blood flow or increased arterial or venous line pressures resulting in repeated alarms during dialysis treatments.

Results: Median functional survival after brushing was 45 days with 8 catheters being exchanged (n=5) or rebrushed (n=3) within 10 dialysis sessions (4 weeks). After 2 months all together 13 (54%) catheters were exchanged due to repeated dysfunction and by 3 months functional survival was only about 35%. The catheters needing exchange were characterized by low flow and high arterial line resistance already in the dialysis sessions immediately following the brushing procedure. Median survival of the exchanged catheters was considerably longer (>400 days) as compared to the brushed catheters.

Conclusions: In conclusion mechanical brushing of dysfunctional tunneled hemodialysis catheters can prolong short term function but only affects long term catheter survival in a minority of the patients.
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http://dx.doi.org/10.5301/jva.5000045DOI Listing
October 2012

Packing properties of 1-alkanols and alkanes in a phospholipid membrane.

Biophys Chem 2006 Jan 11;119(1):61-8. Epub 2005 Oct 11.

Department of Life Science and Chemistry, Roskilde University PO Box 260, DK-4000 Roskilde, Denmark.

We have used vibrating tube densitometry to investigate the packing properties of four alkanes and a homologous series of ten alcohols in fluid-phase membranes of dimyristoyl phosphatidylcholine (DMPC). It was found that the volume change of transferring these compounds from their pure states into the membrane, DeltaV(m)(pure-->mem), was positive for small (C4-C6) 1-alkanols while it was negative for larger alcohols and all alkanes. The magnitude of DeltaV(m)(pure-->mem) ranged from about +4 cm3/mol for alcohols with an alkyl chain about half the length of the fatty acids of DMPC, to -10 to -15 cm3/mol for the alkanes and long chain alcohols. On the basis of these observations, previously published information on the structure of the membrane-solute complexes and the free volume properties of (pure) phospholipid membranes, we suggest that two effects dominate the packing properties of hydrophobic solutes in DMPC. First, perturbation of the tightly packed interfacial zone around the ester bonds and first few methylene groups of DMPC brings about a positive contribution to DeltaV(m)(pure-->mem). This effect dominates the volume behavior for alcohols like 1-butanol, 1-pentanol and 1-hexanol. More hydrophobic solutes penetrate into the membrane core, which is loosely packed. In this region, they partially occupy interstitial (or free-) volume, which bring about a denser molecular packing and generate a negative contribution to DeltaV(m)(pure-->mem).
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http://dx.doi.org/10.1016/j.bpc.2005.09.003DOI Listing
January 2006
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