Introduction: The coronavirus disease 2019 (COVID-19) pandemic has led to the death of almost 7 million people, however, with a cumulative incidence of 0.76 billion, most people survive COVID-19.... Show moreIntroduction: The coronavirus disease 2019 (COVID-19) pandemic has led to the death of almost 7 million people, however, with a cumulative incidence of 0.76 billion, most people survive COVID-19. Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms including fatigue, dyspnea, headache, musculoskeletal symptoms, and pulmonary functional-and radiological abnormalities. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated. Aims: The Precision Medicine for more Oxygen (P4O2) consortium COVID-19 extension aims to identify long COVID patients that are at risk for developing chronic lung disease and furthermore, to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study aims to describe the study design and first results of the P4O2 COVID-19 cohort. Methods: The P4O2 COVID-19 study is a prospective multicenter cohort study that includes nested personalized counseling intervention trial. Patients, aged 40-65 years, were recruited from outpatient post-COVID clinics from five hospitals in The Netherlands. During study visits at 3-6 and 12-18 months post-COVID-19, data from medical records, pulmonary function tests, chest computed tomography scans and biological samples were collected and questionnaires were administered. Furthermore, exposome data was collected at the patient's home and state-of-the-art imaging techniques as well as multi-omics analyses will be performed on collected data. Results: 95 long COVID patients were enrolled between May 2021 and September 2022. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in post-COVID patients at 3-6 months post-COVID. The most commonly reported symptoms included respiratory symptoms (78.9%), neurological symptoms (68.4%) and fatigue (67.4%). Female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptom categories. Conclusions: The P4O2 COVID-19 study contributes to our understanding of the long-term health impacts of COVID-19. Furthermore, P4O2 COVID-19 can lead to the identification of different phenotypes of long COVID patients, for example those that are at risk for developing chronic lung disease. Understanding the mechanisms behind the different phenotypes and identifying these patients at an early stage can help to develop and optimize prevention and treatment strategies. Show less
Suijker, J.; Blok, Y.L.; Vries, R. de; Tol, M.P. van den; Krekel, N.M.A. 2022
Excision of the pectoral fascia (PF) is routinely performed in oncological mastectomies. Preservation of the PF may, however, decrease postoperative complication rates for bleeding, infections, and... Show moreExcision of the pectoral fascia (PF) is routinely performed in oncological mastectomies. Preservation of the PF may, however, decrease postoperative complication rates for bleeding, infections, and seroma. It may also improve reconstructive outcomes by better prosthesis coverage, thereby reducing implant extrusion rates and improving cosmetic outcomes.Methods: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis principles was performed. Studies describing PF preservation were searched in 3 databases. All studies including more than 10 patients were included. The main outcomes were oncological safety (local recurrence, regional and distant metastases, and mortality rates), complication rates (bleeding, infections, seroma), loss of the prosthesis after reconstructive surgery, and cosmetic outcomes following reconstruction.Results: Five studies were included. Three reported on 2 different randomized controlled trials (n = 73, and n = 244), and 2 studies were retrospective case series (n = 203 and n = 256). PF preservation did not affect oncological outcomes in terms of local recurrences, regional and distant metastases, or mortality rates. One study described a significantly lower incidence of seroma in the PF preservation group. No differences were found for bleeding complications and infections. No objective data were provided for reconstructive complications or cosmetic outcomes.Conclusions: The literature on PF preservation is scarce. Based on the current evidence, PF preservation seems oncologically safe while potentially reducing postoperative complication rates. It is expected that reconstructive outcomes will benefit from PF preservation, but these studies lack evidence on this topic. Future studies should provide insight into all aspects of PF preservation. Show less
Objectives: Exhaled breath analysis by electronic nose (eNose) has shown to be a potential predictive biomarker before start of anti-PD-1 therapy in patients with non-small cell lung carcinoma ... Show moreObjectives: Exhaled breath analysis by electronic nose (eNose) has shown to be a potential predictive biomarker before start of anti-PD-1 therapy in patients with non-small cell lung carcinoma (NSCLC). We hypothesized that the eNose could also be used as an early monitoring tool to identify responders more accurately at early stage of treatment when compared to baseline. In this proof-of-concept study we aimed to definitely discriminate responders from non-responders after six weeks of treatment. Materials and Methods: This was a prospective observational study in patients with advanced NSCLC eligible for anti-PD-1 treatment. The efficacy of treatment was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. We analyzed SpiroNose exhaled breath data of 94 patients (training cohort n = 62, validation cohort n = 32). Data analysis involved signal processing and statistics based on Independent Samples T-tests and Linear Discriminant Analysis (LDA) followed by Receiver Operating Characteristic (ROC) analysis. Results: In the training cohort, a specificity of 73% was obtained at a 100% sensitivity level to identify objective responders. The Area Under the Curve (AUC) was 0.95 (CI: 0.89-1.00). In the validation cohort, these results were confirmed with an AUC of 0.97 (CI: 0.91-1.00). Conclusion: Exhaled breath analysis by eNose early during treatment allows for a highly accurate, non-invasive and low-cost identification of advanced NSCLC patients who benefit from anti-PD-1 therapy. Show less
Disselhorst, M.J.; Vries, R. de; Quispel-Janssen, J.; Wolf-Lansdorf, M.; Sterk, P.J.; Baas, P. 2021
IntroductionRecent clinical trials with immune checkpoint inhibitors (ICIs) have shown that a subgroup of patients with malignant pleural mesothelioma (MPM) could benefit from these agents. However... Show moreIntroductionRecent clinical trials with immune checkpoint inhibitors (ICIs) have shown that a subgroup of patients with malignant pleural mesothelioma (MPM) could benefit from these agents. However, there are no accurate biomarkers to predict who will respond. The aim of this study was to assess the accuracy of exhaled breath analysis using electronic technology (eNose) for discriminating between responders to ICI and non-responders.MethodsThis proof-of-concept prospective observational study was part of an intervention study (INITIATE) in patients with recurrent MPM who were treated with nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4). At baseline and after six weeks of treatment, breath profiles were collected by an eNose. Modified Response Evaluation Criteria in Solid Tumors were used to assess efficacy at 6-month follow-up. For data processing and statistics, we used independent t-test analyses followed by linear discriminant and receiver-operating characteristic (ROC) analysis.ResultsExhaled breath data of 31 MPM patients who received nivolumab plus ipilimumab were available at baseline. There were 16 with and 15 without a response after 6 months of treatment. At baseline, breath profiles significantly differed between responders and non-responders, with a cross validation value of 71%. The ROC-AUC after internal cross-validation was 0.90 (confidence interval: 0.80–1.00).ConclusionAn eNose is able to discriminate at baseline between responders and non-responders to nivolumab plus ipilimumab in MPM, thereby potentially identifying a subgroup of patients that will benefit from ICI treatment. Show less
Colafella, K.M.M.; Neves, K.B.; Montezano, A.C.; Garrelds, I.M.; Veghel, R. van; Vries, R. de; ... ; Versmissen, J. 2020
Aims Although effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up... Show moreAims Although effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro- or antihypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria.Methods and results Male Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of similar to 25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib- than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan.Conclusions Our results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury. Show less
Helmer, L.M.L.; Weijenberg, R.A.F.; Vries, R. de; Achterberg, W.P.; Lautenbacher, S.; Sampson, E.L.; Lobbezoo, F. 2020
Background Vocalization is often used to assess pain, sometimes combined with other behaviours such as facial expressions. Contrary to facial expressions, however, for vocalization, there is little... Show moreBackground Vocalization is often used to assess pain, sometimes combined with other behaviours such as facial expressions. Contrary to facial expressions, however, for vocalization, there is little evidence available on the association with pain. The aim of this systematic review was to critically analyse the association between vocalization and pain, to explore if vocalizations can be used as a "stand-alone" indicator for pain. Methods The search was performed according to the Prisma Guidelines for systematic reviews and meta-analysis. The following terms were used: "Pain Measurement," "Vocalization" and "Verbalization." The study population included verbal and non-verbal individuals, including older people and children. The search was performed in three different databases: PubMed, Embase and CINAHL. A total of 35 studies were selected for detailed investigation. Quality assessments were made using two grading systems: Grading of Recommendations Assessment Development and Evaluation system and the Newcastle-Ottawa scale. Results An association between vocalization and pain was found in most studies, particularly when different types of vocalizations were included in the investigation. Different types of vocalization, but also different types of pain, shape this association. The association is observed within all groups of individuals, although age, amongst others, may have an influence on preferred type of vocalization. Conclusions There is an association between vocalization and pain. However, vocalization as a "stand-alone" indicator for pain indicates only a limited aspect of this multifactorial phenomenon. Using vocalization as an indicator for pain may be more reliable if other pain indicators are also taken into account. Significance Vocalizations are frequently used in pain scales, although not yet thoroughly investigated as a "single indicator" for pain, like, e.g. facial expression. This review confirms the role of vocalizations in pain scales, and stresses that vocalizations might be more reliable if used in combination with other pain indicators. Show less
Leenaars, C.; Stafleu, F.; Jong, D. de; Berlo, M. van; Geurts, T.; Coenen-de Roo, T.; ... ; Ritskes-Hoitinga, M. 2020
Increased awareness and understanding of current practices in translational research is required for informed decision making in drug development. This paper describes a systematic review of... Show moreIncreased awareness and understanding of current practices in translational research is required for informed decision making in drug development. This paper describes a systematic review of methotrexate for rheumatoid arthritis, comparing trial design between 147 animal and 512 human studies. Animal studies generally included fewer subjects than human studies, and less frequently reported randomisation and blinding. In relation to life span, study duration was comparable for animals and humans, but included animals were younger than included humans. Animal studies often comprised males only (61%), human studies always included females (98% included both sexes). Power calculations were poorly reported in both samples. Analyses of human studies more frequently comprised Chi-square tests, those of animal studies more frequently reported analyses of variance. Administration route was more variable, and more frequently reported in animal than human studies. Erythrocyte sedimentation rate and c-reactive protein were analysed more frequently in human than in animal studies. To conclude, experimental designs for animal and human studies are not optimally aligned. However, methotrexate is effective in treating rheumatoid arthritis in animal models and humans. Further evaluation of the available evidence in other research fields is needed to increase the understanding of translational success before we can optimise translational strategies. Full article(This article belongs to the Special Issue Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?) Show less
Vessem, M.E. van; Beeres, S.L.M.A.; Wilde, R.B.P. de; Vries, R. de; Berendsen, R.R.; Jonge, E. de; ... ; Palmen, M. 2019
