37 research outputs found
Understanding the molecular and intracellular function of vitamin D in the immune system: Implications for translation.
No full textVitamin D is a hormone that can be obtained from food (e.g. fatty fish and dairy products), but is mainly made in the skin where sunlight exposure converts it into its biologically active metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The widespread expression of the vitamin D receptor (VDR) and vitamin D3-metabolizing enzymes in almost all cells of the immune system indicates a role for 1,25(OH)2D3 as a modulator of immune responses. In dendritic cells (DCs), 1,25(OH)2D3 interferes with the differentiation and maturation process resulting in the induction of a tolerogenic state. Tolerogenic DCs (tolDCs) are characterized by downregulated antigen-presentation, reduced costimulation and low pro-inflammatory cytokine production. As a result, tolDCs are poor T cell stimulators and induce T cell hyporesponsiveness. In addition, tolDC mediate a shift in T cell polarization from Th1/17 responses to more tolerogenic responses, with the induction of regulatory T cells (Tregs). On the other hand, 1,25(OH)2D3 are also able to directly modulate activated T cells. In these cells, 1,25(OH)2D3 decreases the production of pro-inflammatory cytokines and induces Tregs.
An important role for 1,25(OH)2D3 and its nuclear receptor in the development of type 1 diabetes (T1D) has been suggested by the discrepancy observed between absence of ligand and absence of receptor. Vitamin D3 deficiency in early life is associated with elevated risk for T1D, while the VDR null mouse model, lacking a functional VDR, do not present with aggravated disease. This difference indicates an important role for the unliganded VDR in the immune response. In the first part of this project, we investigated whether an unliganded VDR could affect the phenotype and function of murine bone marrow-derived DCs (BMDCs). Therefore, we studied myeloid BMDCs generated ex vivo from bone marrow precursors of VDR null, with a truncated, non-functional VDR, and VDR ∆AF-2 mice, with a mutated C‑terminal activation factor AF-2 domain thus rendering ligand-induced gene transcription impossible. To our surprise, the unliganded VDR did not affect BMDC phenotype or their T cell stimulatory capacity compared to VDR null BMDCs. These data indicate that an unliganded VDR does not elicit a more inflammatory phenotype in BMDCs.
Currently, no therapies for T1D are established which tackle the underlying immune attack. In general, immunotherapies focus on the inhibition of pathogenic immune cell activation and the (re-)establishment of self-tolerance against autoantigens. Given the interesting characteristics of Tregs and tolDCs to induce antigen-specific protection, cellular immunotherapies like adoptive T cell transfer and tolDC-based vaccines provide promising strategies for autoimmune diseases. In this regard, 1,25(OH)2D3 or its low‑calcemic analog TX527 are ideal for ex vivo modulation of autologous T cells and DCs.
Previously, our group showed successful ex vivo modulation of T cells isolated from healthy donors by 1,25(OH)2D3 as well as its analog TX527. However, for the clinical applicability of autologous adoptive T cell therapy, validation in samples from patients with T1D is required, especially as a defect in Treg function has been shown in T1D. Therefore, we further explored whether autologous T cells obtained from patients with T1D could be ex vivo modulated by 1,25(OH)2D3 and its analog TX527. Indeed, treatment with 1,25(OH)2D3 and TX527 increased the frequency of CD4+CD25highCD127low Tregs, with elevated CTLA-4 expression in this population. Moreover, exposure to 1,25(OH)2D3 and TX527 imprinted a unique homing signature and reduced the production of effector cytokines in the T cells isolated from T1D patients. In addition, both 1,25(OH)2D3 and TX527 promoted the formation of a stable Treg phenotype, which is essential for their possible clinical application as they will be reintroduced in an inflammatory microenvironment.
For the third part of this PhD project, we build further on a previous finding in our lab that demonstrated that the induction of the tolDC profile by 1,25(OH)2D3 is accompanied by an early and transcriptionally mediated metabolic reprogramming. We previously showed that glucose availability and glycolytic metabolism are crucial to induce and maintain tolDCs. This observation strokes with the emerging concept of immunometabolism which states that intracellular metabolism determines the phenotype and function of immune cells. In this regard, we aimed to find a primary target of vitamin D3 that could act as a metabolic switch in tolDCs. We identified the glycolytic enzyme PFKFB4 as strongly and directly upregulated by 1,25(OH)2D3 in differentiating monocytes. Pharmacological inhibition of PFKFB4 activity by the small molecule inhibitor 5-MPN could interfere with the increase in glucose metabolism, and more specifically glucose oxidation, which are hallmark features of tolDC. Moreover, PFKFB4 inhibition altered tolDC phenotype and their ability to induce functional Tregs. A better understanding of the metabolic pathways influenced by 1,25(OH)2D3 in human tolDCs will aid the development and improve the efficacy of tolDC-based immunotherapies.status: Publishe
Initiative pour la promotion de la qualité et epidémiologie chez les enfants et les adolescents atteints du diabète sucré (IPQE-EAD)- Résultats 2019
No full textLe présent rapport décrit les résultats du septième audit auquel ont participé les centres de diabétologie pédiatrique (dénommés ci-après CDP) agréés. Cet audit a permis de collecter les données de 3 365 patients atteints de diabète de type 1 âgés de moins de 19 ans et traités dans 15 CDP. Les données se rapportaient aux soins prodigués en 2019. Ce rapport explore les tendances concernant la qualité des soins et étudie les caractéristiques de la population au cours de la période 2008-2019. L’audit n’a pas permis de collecter de données de patients atteints d’un diabète de type 2.
Voici les principaux résultats :
• Certains aspects de la qualité des soins, mesurés par une large série d’indicateurs de processus et de résultats, se sont améliorés entre 2008 et 2019 : le nombre de déterminations de l’IMC et de la tension artérielle et la proportion de patients ayant atteint l’objectif thérapeutique de l’HbA1c de 7,0, 7,5 et 9,0 % ont augmenté, tandis que le nombre de déterminations de l’HbA1c (une ou trois) et du dépistage de la coeliaquie et de l’auto-immunité thyroïdienne se sont maintenus à un niveau élevé (> 80 %) pour tous les audits.
• L’amélioration de l’HbA1c a été constatée dans 11 CDP sur 15, en grande partie indépendamment des caractéristiques des patients (sexe, statut de famille nucléaire, etc.). Notez que parmi les CDP où l’amélioration n’a pas été constatée, trois comptaient parmi les centres présentant la valeur HbA1c la plus faible en 2008 et un a débuté sa participation en 2017.
• Le dépistage annuel de la rétinopathie a baissé de façon significative tant dans la population générale que dans la population cible au cours de la période 2008-2019.
• Les résultats ont montré que la proportion de patients en surpoids a légèrement augmenté depuis 2008. Toutefois, cette tendance a également été observée dans la population générale selon le rapport 2019 de l’OCDE.
• Les taux de complications aiguës et chroniques et les niveaux de facteurs de risque cardiovasculaire (à l’exception de l’IMC) sont restés stables au cours de la période 2008-2019.
En conclusion, malgré les limites inhérentes à la nature transversale de l’étude et son suivi limité, le septième audit du projet IPQE-EAD a mis en lumière la poursuite de l’évolution favorable de l’HbA1c, l’un des indicateurs essentiels de la qualité des soins. Grâce à la collecte de données supplémentaires depuis 2013 (obtenues par l’échantillonnage de tous les patients éligibles au lieu de seulement 50 %), il sera désormais possible d’analyser l’évolution de l’HbA1c de chaque patient individuellement et ses déterminants, et ainsi de repérer les facteurs auxquels nous devons apporter une attention accrue afin d’améliorer la qualité des soins de diabétologie pédiatrique.</p
Initiatief voor kwaliteitsbevordering en epidemiologie bij kinderen en adolescenten met diabetes (IKEKAD)- Resultaten 2019
No full textIn dit rapport worden de resultaten beschreven van de zevende audit bij de erkende pediatrische diabetescentra (hierna PDC’s genoemd). De audit verzamelde gegevens van 3365 patiënten met type 1 diabetes jonger dan 19 jaar die werden behandeld in 15 PDC’s. De gegevens hadden betrekking op de zorg in 2019. Het rapport focust zich op trends in de zorgkwaliteit en kenmerken van de onderzoekspopulatie in de periode 2008-2019. Er werden deze audit geen gegevens van patiënten met type 2 diabetes geregistreerd.
De belangrijkste bevindingen waren:
• Sommige aspecten van de zorgkwaliteit, gemeten door een brede set van proces- en uitkomstindicatoren, verbeterden in de periode 2008-2019: er was een toename van de BMI- en bloeddrukbepaling en een toename van het percentage patiënten dat de HbA1c-therapiedoelstellingen van 7,0%, 7,5% en 9,0% haalt, terwijl de cijfers voor HbA1c-bepaling (één of drie keer), en screening op coeliakie en schildklierauto-immuniteit waren over alle audits heen constant hoog (> 80%).
• De verbetering van het HbA1c werd waargenomen in 11 van de 15 PDC’s en was grotendeels onafhankelijk van de kenmerken van de patiënt (geslacht, kerngezinstatus, …). Merk op dat van de PDC’s waar een verbetering niet werd waargenomen, drie tot de centra met de laagste HbA1c-waarde in 2008 behoorden en één slechts in 2017 met zijn deelname is gestart.
• De jaarlijkse screening op retinopathie nam in de periode 2008-2019 zowel bij de algemene als de doelpopulatie significant af.
• Uit de resultaten blijkt dat het percentage patiënten met overgewicht sinds 2008 licht is toegenomen. Echter, deze trend werd volgens het OESO-rapport van 2019 ook waargenomen bij de algemene bevolking.
• De cijfers in verband met acute en chronische complicaties en de niveaus van de cardiovasculaire risicofactoren (behalve BMI) bleven in de periode 2008-2019 stabiel.
Tot besluit kunnen we stellen dat ondanks de beperkingen van het cross-sectionele karakter van het onderzoek en de beperkte follow-up, uit de zevende IKEKAD-audit is gebleken dat de gunstige evolutie op het vlak van HbA1c, een belangrijke indicator voor de zorgkwaliteit, zich voortzet. Aangezien er sinds 2013 meer gegevens worden verzameld (doordat alle patiënten die in aanmerking komen in de steekproef worden opgenomen in plaats van slechts 50%), zal het ook mogelijk worden het HbA1c-traject van individuele patiënten en de bepalende factoren te analyseren, wat ons meer aanwijzingen zal geven over de factoren waarop we ons moeten richten om de zorgkwaliteit bij pediatrische diabetespatiënten te verbeteren.</p
Evidence-based quality indicators in diabetic foot care: the Belgian multidisciplinary expert panel opinion
No full text
Validation of the Flemish-Dutch diabetic foot ulcer scale short form (DFS-SF) questionnaire for diabetic foot ulcers
No full textBackground/Aims: Diabetic foot ulcers (DFU) negatively affect the quality of life (QoL) of people with diabetes. The DFU Scale Short Form (DFS-SF) is a validated disease-specific patient-reported outcome measure (PROM) for measuring health-related quality of life among DFU patients. It consists of 29 items in 6 subscales: leisure, physical health, dependence/daily life, negative emotions, worried about ulcers and bothered by ulcer care. This study aimed to validate the DFS-SF questionnaire for Flemish Dutch-speaking patients with DFU in Belgium.
Methods: This observational cohort study included 100 patients with DFU from the multidisciplinary diabetic foot clinic of Onze-Lieve-Vrouw Hospital Aalst, Belgium. DFS-SF items were reverse-coded so that high DFS-SF scores indicate better quality of life. Reliability was assessed through the test-retest reliability (intraclass correlation coefficient (ICC)), internal consistency (Cronbach’s alpha) and measurement error (agreement). Spearman’s correlations and known-group comparisons were conducted to examine construct validity. Correlation with EQ-5D-5L was used to test criterion validity. The full study protocol has been published earlier (Rezaie et al. 2019. doi:10.1136/bmjopen-2019-034491).
Results: The majority of the patients were men (71.1%), with a mean age of 67.7±10.3 years and mean diabetes duration of 20.1±12.5 years. 81 patients (83.5%) had type 2 diabetes. Ischemia was present in 31.7% of the patients, neuropathy in 88.5%. Most DFU were deep (93.2%) and showed signs of infection (60,6%). ICC of the different DFS-SF subscales ranged from 0.36 to 0.84. Cronbach’s alpha was between 0.70 and 0.92 for all subscales. Agreement varied between 2.83 and 14.52. A ceiling effect was observed in the subscales leisure, dependence/daily life, negative emotions and bothered by ulcer care. None of the 6 predefined hypotheses to determine the construct validity was confirmed. The different DFS-SF subscales showed a moderate to strong correlation with the EQ-5D-5L index value. The DFS-SF subscales were not sensitive to ulcer changes over time.
Conclusions: The psychometric properties of the Flemish-Dutch version of the DFS-SF questionnaire were not confirmed nor showed a good sensitivity to ulcer changes in our patient population. The disease-specific DFS-SF provided no relevant additional information on quality of life beyond the general EQ-5D-5L.</p
A multidisciplinary Delphi consensus to define evidence-based quality indicators for diabetic foot ulcer care.
No full textBackground: Valid measures to assess quality of care delivered to patients with diabetes suffering from diabetic foot ulcer (DFU) are scarce. This study aimed to achieve consensus on relevant and feasible quality indicators (QIs) among stakeholders involved in DFU care, and was conducted as the second part of a Belgian quality indicator selection study that sought to identify QIs for DFU care.
Methods: A stakeholder panel, including caregivers from primary care and specialized disciplines active in diabetic foot care as well as a patient organization representative, was recruited. By using the RAND/UCLA Appropriateness Method, stakeholders were asked to rate a list of 42 candidate evidence-based indicators for appropriateness through a 9-point Likert scale. QIs were classified based on the median ratings and the disagreement index, calculated by the inter-percentile range adjusted for symmetry.
Results: At the end of a 3-phase process, 17 QIs were judged as appropriate. Among them, five were not previously described, covering the following topics: integration of wound care specialty in the multidisciplinary team, systematic evaluation of the nutritional status of the patient, administration of Low Density Lipoprotein (LDL)-cholesterol lowering medication and protocolized care (implementation of care and prevention management protocols).
Conclusions: The identified evidence-based QIs provide an assessment tool to evaluate and monitor quality of care delivered to DFU patients. Future research should focus on their complementarity with the existing QIs and their implementation in clinical practice.</p
CREATION OF A ‘PRECISION PROGNOSTIC CLASSIFICATION’ FOR DIABETIC FOOT ULCER HEALING WITH THE USE OF A BOTTOM-UP APPROACH
No full textValidation of the Flemish-Dutch Lower Extremity Functional Scale (LEFS) questionnaire for diabetic foot ulcers
No full textBackground/Aims: Diabetic foot ulcers (DFU) negatively affect the quality of life (QoL) of people with diabetes. The Lower Extremity Functional Scale (LEFS) is a patient-reported outcome measure (PROM) for measuring physical functioning in patients with lower extremity disorders. It consists of 20 items and can distinguish between pain and function. To date, the LEFS is not yet validated for assessing functional impairment of foot and ankle in diabetic foot conditions. This study aimed to validate the LEFS questionnaire for Flemish Dutch-speaking patients with DFU in Belgium.
Methods: This observational cohort study included 100 patients with DFU from the multidisciplinary diabetic foot clinic of Onze-Lieve-Vrouw Hospital Aalst, Belgium. Reliability was assessed through the test-retest reliability (intraclass correlation coefficient (ICC)), internal consistency (Cronbach’s alpha) and measurement error (agreement). Spearman’s correlations and known-group comparisons were conducted to examine construct validity. Correlation with EQ-5D-5L was used to test criterion validity. The full study protocol has been published earlier (Rezaie et al. 2019. doi:10.1136/bmjopen-2019-034491).
Results: The majority of the patients were men (71.1%), with a mean age of 67.7±10.3 years and mean diabetes duration of 20.1±12.5 years. 81 patients (83.5%) had type 2 diabetes. Ischemia was present in 31.7% of the patients, neuropathy in 88.5%. Most DFU were deep (93.2%) and showed signs of infection (60,6%). ICC of the LEFS questionnaire was 0.85 (95% CI 0.75-0.91). Cronbach’s alpha equaled 0.95. Agreement was 4.55. No floor or ceiling effect was observed. Only 1 of the 6 predefined hypotheses to determine the construct validity of LEFS was confirmed (17%). The LEFS score showed a strong correlation with the EQ-5D-5L index value (p<0.0001) and a moderate correlation with the EQ-5D-5L visual analytical scale (p<0.0001). The LEFS score was not sensitive to ulcer changes over time.
Conclusions: The Flemish-Dutch version of the LEFS questionnaire has good reliability properties and criterion validity could be confirmed. However, the construct validity was not optimal and the scale was not sensitive to ulcer change during follow-up in our patient population. The LEFS provided only minor relevant additional information on quality of life beyond the general EQ-5D-5L.</p
Evolution of patient characteristics and outcomes concerning diabetic foot ulcer care in Belgium between 2008 and 2020
No full textBackground/Aims: Since 2005, recognized Belgian multidisciplinary diabetic foot clinics (MDFCs) participate to biennial audit-feedback cycles, allowing to study the epidemiology of diabetic foot ulcers (DFU) and monitor/improve quality of care. We investigated how patient and foot characteristics, treatment and outcome evolved between 2008 and 2020.
Methods: Data were cross-sectionally collected between 2008 and 2020. Recognized MDFCs included the first 52 patients with a new DFU of Wagner 2 or higher during the audit period. Person and ulcer characteristics were recorded at baseline together with treatment and outcome during a 6-month follow-up period. A neutral weighting was applied to all variables. Evolution over time was studied in a repeated cross-sectional way using Generalized Estimating Equations (SAS9.4).
Results: The number of people with a new DFU included were 985 in 2008 (20 MDFCs) and increased to 1.579 in 2020 (35 MDFCs). Patients became older (2008: 68.2±0.4 years; 2020: 70.1±0.3 years; p<0.0001), had a longer median (P25-P75) diabetes duration (2008: 14.2 (7.5-23.4) years; 2020: 16.3 (9.5-24.5) years; p=0.0002) and more often type 2 diabetes (2008: 87.8%; 2020: 91.2%; p=0.0013). Comorbidity rates were high. Presentation to the MDFC on the patient’s own initiative strongly elevated over time (collected since 2011: 20.6%; 2020: 35.1%; p<0.0001). Moreover, median (P25-P75) patient-reported presentation delay reduced significantly from 4 (2-8) weeks in 2008 to 3 (1-8) weeks in 2020 (p=0.0134). Proportion of severe DFU (SINBAD≥3) diminished across the audits (2008: 91.6%; 2020: 82.3%; p=0.0115). Proportion of patients receiving offloading (collected since 2011: 74.6%; 2020: 63.2%; p=0.4750), undergoing a revascularization when having critical limb ischemia (2008: 66.4%; 2020: 67.0%; p=0.7860), minor amputation (2008: 16.8%; 2020: 21.1%; p=0.1636) or major amputation (2008: 3.6%; 2020: 2.9%; p=0.5882) remained unchanged over time. Nonetheless, healing after 6 months follow-up decreased slightly from 47.2% in 2008 to 43.8% in 2020 (p=0.0296). Inter-center variability remained high throughout time.
Conclusions: Despite the positive evolution of faster presentation to the MDFC with less severe DFU, the outcome did not change over time and even a slight decrease in healed DFU after 6 months could be observed. A negative trend towards less offloading might be an underlying cause.</p
