Objective: To develop prediction models for individual patient harm and benefit outcomes in elderly patients with RA and comorbidities treated with chronic low-dose glucocorticoid therapy or... Show moreObjective: To develop prediction models for individual patient harm and benefit outcomes in elderly patients with RA and comorbidities treated with chronic low-dose glucocorticoid therapy or placebo. Methods: In the Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis (GLORIA) study, 451 RA patients >= 65 years of age were randomized to 2 years 5 mg/day prednisolone or placebo. Eight prediction models were developed from the dataset in a stepwise procedure based on prior knowledge. The first set of four models disregarded study treatment and examined general predictive factors. The second set of four models was similar but examined the additional role of low-dose prednisolone. In each set, two models focused on harm [the occurrence of one or more adverse events of special interest (AESIs) and the number of AESIs per year) and two on benefit (early clinical response/disease activity and a lack of joint damage progression). Linear and logistic multivariable regression methods with backward selection were used to develop the models. The final models were assessed and internally validated with bootstrapping techniques. Results: A few variables were slightly predictive for one of the outcomes in the models, but none were of immediate clinical value. The quality of the prediction models was sufficient and the performance was low to moderate (explained variance 12-15%, area under the curve 0.67-0.69). Conclusion: Baseline factors are not helpful in selecting elderly RA patients for treatment with low-dose prednisolone given their low power to predict the chance of benefit or harm. Show less
Noorduyn, J.C.A.; Graaf, V.A. van de; Willigenburg, N.W.; Scholten-Peeters, G.G.M.; Mol, B.W.; Heymans, M.W.; ... ; ESCAPE Res Grp 2022
Purpose Marker-by-treatment analyses are promising new methods in internal medicine, but have not yet been implemented in orthopaedics. With this analysis, specific cut-off points may be obtained,... Show morePurpose Marker-by-treatment analyses are promising new methods in internal medicine, but have not yet been implemented in orthopaedics. With this analysis, specific cut-off points may be obtained, that can potentially identify whether meniscal surgery or physical therapy is the superior intervention for an individual patient. This study aimed to introduce a novel approach in orthopaedic research to identify relevant treatment selection markers that affect treatment outcome following meniscal surgery or physical therapy in patients with degenerative meniscal tears. Methods Data were analysed from the ESCAPE trial, which assessed the treatment of patients over 45 years old with a degenerative meniscal tear. The treatment outcome of interest was a clinically relevant improvement on the International Knee Documentation Committee Subjective Knee Form at 3, 12, and 24 months follow-up. Logistic regression models were developed to predict the outcome using baseline characteristics (markers), the treatment (meniscal surgery or physical therapy), and a marker-by-treatment interaction term. Interactions with p < 0.10 were considered as potential treatment selection markers and used these to develop predictiveness curves which provide thresholds to identify marker-based differences in clinical outcomes between the two treatments. Results Potential treatment selection markers included general physical health, pain during activities, knee function, BMI, and age. While some marker-based thresholds could be identified at 3, 12, and 24 months follow-up, none of the baseline characteristics were consistent markers at all three follow-up times. Conclusion This novel in-depth analysis did not result in clear clinical subgroups of patients who are substantially more likely to benefit from either surgery or physical therapy. However, this study may serve as an exemplar for other orthopaedic trials to investigate the heterogeneity in treatment effect. It will help clinicians to quantify the additional benefit of one treatment over another at an individual level, based on the patient's baseline characteristics. Show less
Ali, M.; Os, H.J.A. van; Weerd, N. van der; Schoones, J.W.; Heymans, M.W.; Kruyt, N.D.; ... ; Wermer, M.J.H. 2022
Background and Purpose: Women have worse outcomes than men after stroke. Differences in presentation may lead to misdiagnosis and, in part, explain these disparities. We investigated whether there... Show moreBackground and Purpose: Women have worse outcomes than men after stroke. Differences in presentation may lead to misdiagnosis and, in part, explain these disparities. We investigated whether there are sex differences in clinical presentation of acute stroke or transient ischemic attack. Methods: We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Inclusion criteria were (1) cohort, cross-sectional, case-control, or randomized controlled trial design; (2) admission for (suspicion of) ischemic or hemorrhagic stroke or transient ischemic attack; and (3) comparisons possible between sexes in >= 1 nonfocal or focal acute stroke symptom(s). A random-effects model was used for our analyses. We performed sensitivity and subanalyses to help explain heterogeneity and used the Newcastle-Ottawa Scale to assess bias. Results: We included 60 studies (n=582 844; 50% women). In women, headache (pooled odds ratio [OR], 1.24 [95% CI, 1.11-1.39]; I-2=75.2%; 30 studies) occurred more frequently than in men with any type of stroke, as well as changes in consciousness/mental status (OR, 1.38 [95% CI, 1.19-1.61]; I-2=95.0%; 17 studies) and coma/stupor (OR, 1.39 [95% CI, 1.25-1.55]; I-2=27.0%; 13 studies). Aspecific or other neurological symptoms (nonrotatory dizziness and non-neurological symptoms) occurred less frequently in women (OR, 0.96 [95% CI, 0.94-0.97]; I-2=0.1%; 5 studies). Overall, the presence of focal symptoms was not associated with sex (pooled OR, 1.03) although dysarthria (OR, 1.14 [95% CI, 1.04-1.24]; I-2=48.6%; 11 studies) and vertigo (OR, 1.23 [95% CI, 1.13-1.34]; I-2=44.0%; 8 studies) occurred more frequently, whereas symptoms of paresis/hemiparesis (OR, 0.73 [95% CI, 0.54-0.97]; I-2=72.6%; 7 studies) and focal visual disturbances (OR, 0.83 [95% CI, 0.70-0.99]; I-2=62.8%; 16 studies) occurred less frequently in women compared with men with any type of stroke. Most studies contained possible sources of bias. Conclusions: There may be substantive differences in nonfocal and focal stroke symptoms between men and women presenting with acute stroke or transient ischemic attack, but sufficiently high-quality studies are lacking. More studies are needed to address this because sex differences in presentation may lead to misdiagnosis and undertreatment. Show less
Noorduyn, J.C.A.; Teuwen, M.M.H.; Graaf, V.A. van de; Willigenburg, N.W.; Schavemaker, M.; Dijk, R. van; ... ; Escape Res Grp 2021
Purpose Although physical therapy is the recommended treatment in patients over 45 years old with a degenerative meniscal tear, 24% still opt for meniscal surgery. The aim was to identify those... Show morePurpose Although physical therapy is the recommended treatment in patients over 45 years old with a degenerative meniscal tear, 24% still opt for meniscal surgery. The aim was to identify those patients with a degenerative meniscal tear who will undergo surgery following physical therapy. Methods The data for this study were generated in the physical therapy arm of the ESCAPE trial, a randomized clinical trial investigating the effectiveness of surgery versus physical therapy in patients of 45-70 years old, with a degenerative meniscal tear. At 6 and 24 months patients were divided into two groups: those who did not undergo surgery, and those who did undergo surgery. Two multivariable prognostic models were developed using candidate predictors that were selected from the list of the patients' baseline variables. A multivariable logistic regression analysis was performed with backward Wald selection and a cut-off of p < 0.157. For both models the performance was assessed and corrected for the models' optimism through an internal validation using bootstrapping technique with 500 repetitions. Results At 6 months, 32/153 patients (20.9%) underwent meniscal surgery following physical therapy. Based on the multivariable regression analysis, patients were more likely to opt for meniscal surgery within 6 months when they had worse knee function, lower education level and a better general physical health status at baseline. At 24 months, 43/153 patients (28.1%) underwent meniscal surgery following physical therapy. Patients were more likely to opt for meniscal surgery within 24 months when they had worse knee function and a lower level of education at baseline at baseline. Both models had a low explained variance (16 and 11%, respectively) and an insufficient predictive accuracy. Conclusion Not all patients with degenerative meniscal tears experience beneficial results following physical therapy. The non-responders to physical therapy could not accurately be predicted by our prognostic models. Show less
Background:One in four patients with primary Clostridioides difficile infection (CDI) develops recurrent CDI (rCDI). With every recurrence, the chance of a subsequent CDI episode increases. Early... Show moreBackground:One in four patients with primary Clostridioides difficile infection (CDI) develops recurrent CDI (rCDI). With every recurrence, the chance of a subsequent CDI episode increases. Early identification of patients at risk for rCDI might help doctors to guide treatment. The aim of this study was to externally validate published clinical prediction tools for rCDI.Methods:The validation cohort consisted of 129 patients, diagnosed with CDI between 2018 and 2020. rCDI risk scores were calculated for each individual patient in the validation cohort using the scoring tools described in the derivation studies. Per score value, we compared the average predicted risk of rCDI with the observed number of rCDI cases. Discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUC).Results:Two prediction tools were selected for validation (Cobo 2018 and Larrainzar-Coghen 2016). The two derivation studies used different definitions for rCDI. Using Cobo's definition, rCDI occurred in 34 patients (26%) of the validation cohort: using the definition of Larrainzar-Coghen, we observed 19 recurrences (15%). The performance of both prediction tools was poor when applied to our validation cohort. The estimated AUC was 0.43 [95% confidence interval (CI); 0.32-0.54] for Cobo's tool and 0.42 (95% CI; 0.28-0.56) for Larrainzar-Coghen's tool.Conclusion:Performance of both prediction tools was disappointing in the external validation cohort. Currently identified clinical risk factors may not be sufficient for accurate prediction of rCDI. Show less
Koppel, M. ten; Onwuteaka-Philipsen, B.D.; Block, L. van den; Deliens, L.; Gambassi, G.; Heymans, M.W.; ... ; PACE 2019
BackgroundFoot orthoses (FOs) are prescribed as an important conservative treatment option in patients with foot problems related to rheumatoid arthritis. However, a broad variation in FOs is used,... Show moreBackgroundFoot orthoses (FOs) are prescribed as an important conservative treatment option in patients with foot problems related to rheumatoid arthritis. However, a broad variation in FOs is used, both in clinical practice and in research. To date, there is no overview on the outcomes of the treatment with different kinds of FOs in patients with rheumatoid arthritis and a specific foot problem. The objectives of the present study were to summarize the comparative effectiveness of FOs in the treatment of various foot problems in patients with rheumatoid arthritis, on the primary outcomes foot function and foot pain, and the secondary outcomes physical functioning, health related quality of life, compliance, adverse events, the costs of FOs and patient satisfaction.MethodsStudies comparing different kinds of FOs, with a presumed therapeutic effect, in the treatment of foot problems related to rheumatoid arthritis were included. A literature search was conducted in The Cochrane Central Registry for Controlled Trials (CENTRAL), PubMed, EMBASE and PEDro up to May 18th, 2018. Data was meta-analyzed, when this was not possible qualitative data analysis was performed.ResultsTen studies were identified, with a total number of 235 patients. These studies made a comparison between different materials used (soft versus semi-rigid), types of FOs (custom-made versus ready-made; total-contact versus non-total contact), or modifications applied (metatarsal bars versus domes). Also, different techniques to construct custom-made FOs were compared (standard custom-molding techniques versus more sophisticated techniques). A medium effect for (immediate) reduction of forefoot plantar pressure was found in favor of treatment with soft FOs compared to semi-rigid FOs (SMD 0.60, 95% CI 0.07-1.14; P=0.03; 28 participants). Other comparisons between FOs resulted in non-significant effects or inconclusive evidence for one kind of FOs over the other.ConclusionsFoot orthoses made of soft materials may lead to more (immediate) forefoot plantar pressure reduction compared to foot orthoses constructed of semi-rigid materials. Definitive high quality RCTs, with adequate sample sizes and long-term follow-up, are needed to investigate the comparative (cost-) effectiveness of different kinds of foot orthoses for the treatment of foot problems related to rheumatoid arthritis. Show less
Patients with irresectable locoregional recurrent breast cancer en cuirasse (BCEC) do not have effective curative treatment options. Hyperthermia, the elevation of tumor temperature to 40-45 A... Show morePatients with irresectable locoregional recurrent breast cancer en cuirasse (BCEC) do not have effective curative treatment options. Hyperthermia, the elevation of tumor temperature to 40-45 A degrees C, is a well-established radio- and chemotherapy sensitizer. A total of 196 patients were treated with reirradiation and hyperthermia (reRT+HT) at two Dutch institutes from 1982-2005. The palliative effect was evaluated in terms of clinical outcome and toxicity.All patients received previous irradiation to a median dose of 50 Gy. In all, 75% of patients received 1-6 treatment modalities for previous tumor recurrences. ReRT consisted of 8 x 4 Gy given twice a week or 12 x 3 Gy given four times a week. Superficial hyperthermia was added once or twice a week. Tumor area comprised >= A 1/2 of the ipsilateral chest wall.Overall clinical response rate was 72% (complete response [CR] 30%, partial response [PR] 42%, stable disease [SD] 22%, progressive disease [PD] 6%). The local progression-free rate at 1 year was 24%. Median survival was 6.9 months. Forty-three percent of our patients with CR, PR, SD after treatment remained infield progression-free until death or last follow-up. Acute >= grade 3 toxicity occurred in 33% of patients, while late >= grade 3 toxicity was recorded in 14% of patients. Tumor ulceration prior to treatment had a negative impact on both clinical outcome and toxicity.ReRT+HT provides sustainable palliative tumor control, despite refractory, extensive tumor growth. Compared to currently available systemic treatment options, reRT+HT is more effective with less toxicity. Show less
Rauh, S.P.; Heymans, M.W.; Mehr, D.R.; Kruse, R.L.; Lane, P.; Kowall, N.W.; ... ; Steen, J.T. van der 2016
Background/purpose: Treatment options for irresectable locoregional recurrent breast cancer in previously irradiated area are limited. Hyperthermia, elevating tumor temperature to 40-45 degrees C,... Show moreBackground/purpose: Treatment options for irresectable locoregional recurrent breast cancer in previously irradiated area are limited. Hyperthermia, elevating tumor temperature to 40-45 degrees C, sensitizes radio-and-chemotherapy. Four hundred and fourteen patients treated with reirradiation + hyperthermia (reRT + HT) in the AMC((n=301)) and the BVI(n=113), from 1982 to 2005 were retrospectively analyzed for treatment response, locoregional control (LC) and prognostic factors for LC and toxicity.Patients/methods: All patients received previous irradiation (median 50 Gy). reRT consisted of 8 x 4 Gy-2/week (AMC) or 12 x 3 Gy-4/week (BVI). Hyperthermia was added once (AMC)/twice (BVI) a week.Results: Overall clinical response rate was 86%. The 3-year LC rate was 25%. The number of recurrence episodes, distant metastases (DM), tumor site, tumor size, time to recurrence and treatment year were significant for LC. Acute >= grade 3 toxicity occurred in 24% of patients. Actuarial late >= grade 3 toxicity was 23% at 3-years. In multivariable analysis reRT fraction dose was significantly related to late >= grade 3 toxicity.Conclusion: reRT + HT is an effective curative and palliative treatment option for patients with irresectable locoregional recurrent breast cancer in previously irradiated area. Early referral, treatment of chest wall recurrences <= 5 cm in the absence of distant metastases, provided the highest local control rates. The cumulative effects of past and present treatments should be accounted for by adjusting treatment protocol to minimize toxicity. (C) 2015 Elsevier Ireland Ltd. All rights reserved. Show less
Background: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and... Show moreBackground: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM. Methods: We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma. Results: T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure-and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist. Conclusions: OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities. Show less