Aging is a multifaceted and intricate physiological process characterized by a gradual decline in functional capacity, leading to increased susceptibility to diseases and mortality. While... Show moreAging is a multifaceted and intricate physiological process characterized by a gradual decline in functional capacity, leading to increased susceptibility to diseases and mortality. While chronological age serves as a strong risk factor for age-related health conditions, considerable heterogeneity exists in the aging trajectories of individuals, suggesting that biological age may provide a more nuanced understanding of the aging process. However, the concept of biological age lacks a clear operationalization, leading to the development of various biological age predictors without a solid statistical foundation. This paper addresses these limitations by proposing a comprehensive operationalization of biological age, introducing the “AccelerAge” framework for predicting biological age, and introducing previously underutilized evaluation measures for assessing the performance of biological age predictors. The AccelerAge framework, based on Accelerated Failure Time (AFT) models, directly models the effect of candidate predictors of aging on an individual’s survival time, aligning with the prevalent metaphor of aging as a clock. We compare predictors based on the AccelerAge framework to a predictor based on the GrimAge predictor, which is considered one of the best-performing biological age predictors, using simulated data as well as data from the UK Biobank and the Leiden Longevity Study. Our approach seeks to establish a robust statistical foundation for biological age clocks, enabling a more accurate and interpretable assessment of an individual’s aging status. Show less
Gomon, D.; Putter, H.; Fiocco, M.; Signorelli, M. 2024
During the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of care... Show moreDuring the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of care provided at each hospital is essential to improve patient outcomes. It is unclear which methods should be used to generate most informative output for the identification of potential quality issues. Our aim is to compare the commonly employed funnel plot with existing cumulative sum (CUSUM) methodology for the evaluation of postoperative survival and hospital stay outcomes of patients who underwent colorectal surgery in the Netherlands. Data from the Dutch ColoRectal Audit on 25367 patients in the Netherlands who underwent surgical resection for colorectal cancer in 71 hospitals between 2019 and 2021 is used to compare four methods for the detection of deviations in the quality of care. Two methods based on binary outcomes (funnel plot, binary CUSUM) and two CUSUM charts based on survival outcomes (BK-CUSUM and CGR-CUSUM) are considered. A novel approach for determining hospital specific control limits for CUSUM charts is proposed. The ability to detect deviations as well as the time until detection are compared for the four methods. Charts were constructed for the inspection of both postoperative survival and hospital stay. Methods using survival outcomes always yielded faster detection times compared to approaches employing binary outcomes. Detections between methods mostly coincided for postoperative survival. For hospital stay detections varied strongly, with methods based on survival outcomes signalling over half the hospitals. Further pros and cons as well as pitfalls of all methods under consideration are discussed. Methodology for the continuous inspection of the quality of care should be tailored to the specific outcome. Properly understanding how the mechanism of a control chart functions is crucial for the correct interpretation of results. This is particularly true for CUSUM charts, which require the choice of a parameter that greatly influences the results. When applying CUSUM charts, consideration of these issues is strongly recommended. Show less
Gomon, D.; Sijmons, J.; Putter, H.; Dekker, J.W.; Tollenaar, R.; Wouters, M.; ... ; Signorelli, M. 2023
During the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of... Show moreDuring the past 14 years, a clinical audit has been used in the Netherlands to provide hospitals with data on their performance in colorectal cancer care. Continuous feedback on the quality of care provided at each hospital is essential to improve patient outcomes. It is unclear which methods should be used to generate most informative output for the identification of potential quality issues. Our aim is to compare the commonly employed funnel plot with existing cumulative sum (CUSUM) methodology for the evaluation of postoperative survival and hospital stay outcomes of patients who underwent colorectal surgery in the Netherlands. Data from the Dutch ColoRectal Audit on 25367 patients in the Netherlands who underwent surgical resection for colorectal cancer in 71 hospitals between 2019 and 2021 is used to compare four methods for the detection of deviations in the quality of care. Two methods based on binary outcomes (funnel plot, binary CUSUM) and two CUSUM charts based on survival outcomes (BK-CUSUM and CGR-CUSUM) are considered. A novel approach for determining hospital specific control limits for CUSUM charts is proposed. The ability to detect deviations as well as the time until detection are compared for the four methods. Charts were constructed for the inspection of both postoperative survival and hospital stay. Methods using survival outcomes always yielded faster detection times compared to approaches employing binary outcomes. Detections between methods mostly coincided for postoperative survival. For hospital stay detections varied strongly, with methods based on survival outcomes signalling over half the hospitals. Further pros and cons as well as pitfalls of all methods under consideration are discussed. Methodology for the continuous inspection of the quality of care should be tailored to the specific outcome. Properly understanding how the mechanism of a control chart functions is crucial for the correct interpretation of results. This is particularly true for CUSUM charts, which require the choice of a parameter that greatly influences the results. When applying CUSUM charts, consideration of these issues is strongly recommended. Show less
Burg, L.L.J. van der; Wreede, L.C. de; Baldauf, H.; Sauter, J.; Schetelig, J.; Putter, H.; Böhringer, S. 2023
Advances in DNA sequencing technologies have enabled genotyping of complex genetic regions exhibiting copy number variation and high allelic diversity, yet it is impossible to derive exact... Show moreAdvances in DNA sequencing technologies have enabled genotyping of complex genetic regions exhibiting copy number variation and high allelic diversity, yet it is impossible to derive exact genotypes in all cases, often resulting in ambiguous genotype calls, that is, partially missing data. An example of such a gene region is the killer‐cell immunoglobulin‐like receptor (KIR) genes. These genes are of special interest in the context of allogeneic hematopoietic stem cell transplantation. For such complex gene regions, current haplotype reconstruction methods are not feasible as they cannot cope with the complexity of the data. We present an expectation–maximization (EM)‐algorithm to estimate haplotype frequencies (HTFs) which deals with the missing data components, and takes into account linkage disequilibrium (LD) between genes. To cope with the exponential increase in the number of haplotypes as genes are added, we add three components to a standard EMalgorithm implementation. First, reconstruction is performed iteratively, adding one gene at a time. Second, after each step, haplotypes with frequencies below a threshold are collapsed in a rare haplotype group. Third, the HTF of the rare haplotype group is profiled in subsequent iterations to improve estimates. A simulation study evaluates the effect of combining information of multiple genes on the estimates of these frequencies. We show that estimated HTFs are approximately unbiased. Our simulation study shows that the EMalgorithm is able to combine information from multiple genes when LD is high, whereas increased ambiguity levels increase bias. Linear regressionmodels based on this EM, show that a large number of haplotypes can be problematic for unbiased effect size estimation and that models need to be sparse. In a real data analysis of KIR genotypes, we compare HTFs to those obtained in an independent study. Our new EM‐algorithm‐based method is the first to account for the full genetic architecture of complex gene regions, such as the KIR gene region. This algorithm can handle the numerous observed ambiguities, and allows for the collapsing of haplotypes to perform implicit dimension reduction. Combining information from multiple genes improves haplotype reconstruction. Show less
PURPOSEThe molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value... Show morePURPOSEThe molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC).METHODSData of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests.RESULTSA total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε (POLEmut EC). In mismatch repair–deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001).CONCLUSIONThe molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control. Show less
BackgroundAs the survival of patients with rectal cancer has improved in recent decades, more and more patients have to live with the consequences of rectal cancer surgery. An influential factor in... Show moreBackgroundAs the survival of patients with rectal cancer has improved in recent decades, more and more patients have to live with the consequences of rectal cancer surgery. An influential factor in long-term Health-related Quality of Life (HRQoL) is the presence of a stoma. This study aimed to better understand the long-term consequences of a stoma and poor functional outcomes.MethodsPatients who underwent curative surgery for a primary tumor located in the rectosigmoid and rectum between 2013 and 2020 were identified from the nationwide Prospective Dutch Colorectal Cancer (PLCRC) cohort study. Patients received the following questionnaires: EORTC-QLQ-CR29, EORTC-QLQ-C30, and the LARS-score at 12 months, 24 months and 36 months after surgery.ResultsA total of 1,170 patients were included of whom 751 (64.2%) had no stoma, 122 (10.4%) had a stoma at primary surgery, 45 (3.8%) had a stoma at secondary surgery and 252 (21.5%) patients that underwent abdominoperineal resection (APR). Of all patients without a stoma, 41.4% reported major low-anterior resection syndrome (LARS). Patients without a stoma reported significantly better HRQoL. Moreover, patients without a stoma significantly reported an overall better HRQoL.ConclusionThe presence of a stoma and poor functional outcomes were both associated with reduced HRQoL. Patients with poor functional outcomes, defined as major LARS, reported a similar level of HRQoL compared to patients with a stoma. In addition, the HRQoL after rectal cancer surgery does not change significantly after the first year after surgery. Show less
Background and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We... Show moreBackground and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We investigated whetheraddition of these factors would improve the performance of prediction models for the risk ofstroke in women younger than 50 years.MethodsWe used data from the Stichting Informatievoorziening voor Zorg en Onderzoek, population-based, primary care database of women aged 20–49 years without a history of cardiovasculardisease. Analyses were stratified by 10-year age intervals at cohort entry. Cox proportionalhazards models to predict stroke risk were developed, including traditional cardiovascularfactors, and compared with models that additionally included female-specific and psychosocialfactors. We compared the risk models using the c-statistic and slope of the calibration curve at afollow-up of 10 years. We developed an age-specific stroke risk prediction tool that may helpcommunicating the risk of stroke in clinical practice.ResultsWe included 409,026 women with a total of 3,990,185 person-years of follow-up. Strokeoccurred in 2,751 women (incidence rate 6.9 [95% CI 6.6–7.2] per 10,000 person-years).Models with only traditional cardiovascular factors performed poorly to moderately in all agegroups: 20–29 years: c-statistic: 0.617 (95% CI 0.592–0.639); 30–39 years: c-statistic: 0.615(95% CI 0.596–0.634); and 40–49 years: c-statistic: 0.585 (95% CI 0.573–0.597). After addingthe female-specific and psychosocial risk factors to the reference models, the model discrimi-nation increased moderately, especially in the age groups 30–39 (Dc-statistic: 0.019) and 40–49years (Dc-statistic: 0.029) compared with the reference models, respectively.DiscussionThe addition of female-specific factors and psychosocial risk factors improves the discrimina-tory performance of prediction models for stroke in women younger than 50 years. Show less
Koster, E.A.S.; Bonneville, E.F.; Borne, P.A.V.; Balen, P. van; Marijt, E.W.A.; Tjon, J.M.L.; ... ; Wreede, L.C. de 2023
Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus... Show moreAlloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance between GvL and GvHD can be shifted by removing T-cells via T-cell depletion (TCD) to reduce the risk of GvHD, and by introducing additional donor T-cells (donor lymphocyte infusions [DLI]) to boost the GvL effect. However, the association between T-cell kinetics and the occurrence of allo-immunological events has not been clearly demonstrated yet. Therefore, we investigated the complex associations between the T-cell kinetics and alloimmune responses in a cohort of 166 acute leukemia patients receiving alemtuzumab-based TCD alloSCT. Of these patients, 62 with an anticipated high risk of relapse were scheduled to receive a prophylactic DLI at 3 months after transplant. In this setting, we applied joint modelling which allowed us to better capture the complex interplay between DLI, T-cell kinetics, GvHD and relapse than traditional statistical methods. We demonstrate that DLI can induce detectable T-cell expansion, leading to an increase in total, CD4+ and CD8+ T-cell counts starting at 3 months after alloSCT. CD4+ T-cells showed the strongest association with the development of alloimmune responses: higher CD4 counts increased the risk of GvHD (hazard ratio 2.44, 95% confidence interval 1.45-4.12) and decreased the risk of relapse (hazard ratio 0.65, 95% confidence interval 0.45-0.92). Similar models showed that natural killer cells recovered rapidly after alloSCT and were associated with a lower risk of relapse (HR 0.62, 95%-CI 0.41-0.93). The results of this study advocate the use of joint models to further study immune cell kinetics in different settings. Show less
PurposeTo determine the course of adherence to physical activity (PA) recommendation in hip/knee osteoarthritis patients before and after hip/knee arthroplasty (THA/TKA). Moreover, we explored... Show morePurposeTo determine the course of adherence to physical activity (PA) recommendation in hip/knee osteoarthritis patients before and after hip/knee arthroplasty (THA/TKA). Moreover, we explored predictors for non-adherence 12 months postoperatively.Materials and methodsPrimary THA/TKA were included in a multicenter observational study. Preoperatively and 6/12 months postoperatively, patients reported engagement in moderate-intensity PA in days/week in the past 6 months (PA-recommendation (& GE;30 min of moderate-intensity & GE;5 days/week)). We included predictors stratified by preoperative adherence: sex, age, BMI, comorbidities, smoking, living/working status, season, mental health, HOOS/KOOS subscales before and 6 months postoperatively, and 6-month adherence.Results(1005 THA/972 TKA) Preoperatively, 50% of the population adhered. Adherence increased to 59% at 6 and 12 months. After 12 months, most patients remained at their preoperative PA level, 11% of the preoperative adherers decreased, while 20% of the preoperative non-adherers increased their PA level. In all different groups, adherence to the PA recommendation at 6 months was identified as a predictor (OR-range: 0.16-0.29). In addition, BMI was identified as predictor in the THA adherent (OR = 1.07; 95%CI [1.02-1.15]) and TKA non-adherent groups (OR = 1.08; 95%CI [1.03-1.12]). THA non-adherent group not having paid work (OR = 0.53; 95%CI [0.33-0.85]), and in the TKA adherent group, lower KOOS subscale symptoms (OR = 1.03; 95%CI [1.01-1.05]) were associated with non-adherence.ConclusionsMajority of patients remained at their preoperative PA level. Non-adherence at 6 months was highly predictive for 12-month non-adherence. Show less
Antibiotic prophylaxis varies substantially between institutes. The effect of prolonged antibiotic prophylaxis seems promising, particularly in patients undergoing pancreatoduodenectomy with... Show moreAntibiotic prophylaxis varies substantially between institutes. The effect of prolonged antibiotic prophylaxis seems promising, particularly in patients undergoing pancreatoduodenectomy with contaminated bile. This systematic review and meta-analysis demonstrated a beneficial effect of prolonged antibiotic prophylaxis after pancreatoduodenectomy in patients who had preoperative biliary drainage.Background Previous studies have reported conflicting results of prolonged antibiotic prophylaxis on infectious complications after pancreatoduodenectomy. This study evaluated the effect of prolonged antibiotics on surgical-site infections (SSIs) after pancreatoduodenectomy. Methods A systematic review and meta-analysis was undertaken of SSIs in patients with perioperative (within 24 h) versus prolonged antibiotic (over 24 h) prophylaxis after pancreatoduodenectomy. SSIs were classified as organ/space infections or superficial SSI within 30 days after surgery. ORs were calculated using a Mantel-Haenszel fixed-effect model. Results Ten studies were included in the qualitative analysis, of which 8 reporting on 1170 patients were included in the quantitative analysis. The duration of prolonged antibiotic prophylaxis varied between 2 and 10 days after surgery. Four studies reporting on 782 patients showed comparable organ/space infection rates in patients receiving perioperative and prolonged antibiotics (OR 1.35, 95 per cent c.i. 0.94 to 1.93). However, among patients with preoperative biliary drainage (5 studies reporting on 577 patients), organ/space infection rates were lower with prolonged compared with perioperative antibiotics (OR 2.09, 1.43 to 3.07). Three studies (633 patients) demonstrated comparable superficial SSI rates between patients receiving perioperative versus prolonged prophylaxis (OR 1.54, 0.97 to 2.44), as well as in patients with preoperative biliary drainage in 4 studies reporting on 431 patients (OR 1.60, 0.89 to 2.88). Conclusion Prolonged antibiotic prophylaxis is associated with fewer organ/space infection in patients who undergo preoperative biliary drainage. However, the optimal duration of antibiotic prophylaxis after pancreatoduodenectomy remains to be determined and warrants confirmation in an RCT.Lay Summary Almost 40 in 100 patients develop an infection after pancreatic surgery. This study collected research that studied the effect of prolonged antibiotics after pancreatic surgery on the number of infections after surgery. Research articles were selected if patients who received antibiotics only during surgery were compared with those who had prolonged antibiotics after surgery. Prolonged antibiotics means antibiotics for longer than 24 h after surgery. Comparing patients who had antibiotics during surgery and those who received prolonged antibiotics after surgery, this study focused on the number of abdominal infections and wound infections. Ten studies were selected, and these studies included 1170 patients in total. The duration of prolonged antibiotics ranged from 2 to 5 days after pancreatic surgery. Four studies (with 782 patients) showed comparable abdominal infections in patients who had antibiotics only during surgery and those who had prolonged antibiotics after surgery (OR 1.35, 95 per cent c.i. 0.94 to 1.93). However, for patients with a stent in the bile duct (5 studies on 577 patients), fewer abdominal infections were seen in patients who had prolonged antibiotics after surgery compared with patients who received antibiotics only during surgery (OR 2.09, 1.43 to 3.07). Three studies (633 patients) showed the same rate of wound infections in patients who had antibiotics only during surgery compared with those who received prolonged antibiotics after operation (OR 1.54, 0.97 to 2.44). The number of wound infections was also the same in patients with a stent in the bile duct (OR 1.60, 0.89 to 2.88). Prolonged antibiotics after pancreatic surgery seem to lower abdominal infections in patients who have a stent placed in the bile duct. However, the best duration of antibiotics is unclear; a decent study is needed. Show less
Vuijk, F.A.; Shahbazi, S.F.; Noortman, W.A.; Velden, F.H.P. van; Dibbets-Schneider, P.; Marinelli, A.W.K.S.; ... ; Geus-Oei, L.F. de 2023
ObjectiveIn this pilot study, we investigated the feasibility of response prediction using digital [F-18]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after... Show moreObjectiveIn this pilot study, we investigated the feasibility of response prediction using digital [F-18]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial. MethodsRectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [F-18]FDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P <= 0.2, promising predictive features for response were selected. ResultsNineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Delta maximum standardized uptake value, Delta peak standardized uptake value corrected for lean body mass), were promising features. ConclusionBoth multiparametric MRI and [F-18]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT. Show less
Vuijk, F.A.; Shahbazi, S.F.; Noortman, W.A.; Velden, F.H.P. van; Dibbets-Schneider, P.; Marinelli, A.W.K.S.; ... ; Geus-Oei, L.F. de 2023
Objective In this pilot study, we investigated the feasibility of response prediction using digital [18F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after... Show moreObjective In this pilot study, we investigated the feasibility of response prediction using digital [18F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial.Methods Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [18F]FDG PET/CT before, 2 weeks into, and 6–8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P ≤ 0.2, promising predictive features for response were selected.Results Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features.Conclusion Both multiparametric MRI and [18F]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT. Show less
Tange, F.P.; Hoven, P. van den; Schaik, J. van; Schepers, A.; Bogt, K.E.A. van der; Rijswijk, C.S.P. van; ... ; Vorst, J.R. van der 2023
Contemporary quality control methods are often insufficient in predicting clinical outcomes after revascularization in lower extremity arterial disease (LEAD) patients. This study evaluates the... Show moreContemporary quality control methods are often insufficient in predicting clinical outcomes after revascularization in lower extremity arterial disease (LEAD) patients. This study evaluates the potential of near-infrared fluorescence imaging with indocyanine green to predict the clinical outcome following revascularization. Near-infrared fluorescence imaging was performed before and within 5 days following the revascularization procedure. Clinical improvement was defined as substantial improvement of pain free walking distance, reduction of rest- and/or nocturnal pain, or tendency toward wound healing. Time-intensity curves and 8 perfusion parameters were extracted from the dorsum of the treated foot. The quantified postinterventional perfusion improvement was compared within the clinical outcome groups. Successful near-infrared fluorescence imaging was performed in 72 patients (76 limbs, 52.6% claudication, 47.4% chronic limb-threatening ischemia) including 40 endovascular- and 36 surgical/hybrid revascularizations. Clinical improvement was observed in 61 patients. All perfusion parameters showed a significant postinterventional difference in the clinical improvement group (P-values <.001), while no significant differences were seen in the group without clinical improvement (P-values .168-.929). Four parameters demonstrated significant differences in percentage improvement comparing the outcome groups (P-values within .002-.006). Near-infrared fluorescence imaging has promising additional value besides clinical parameters for predicting the clinical outcome of revascularized LEAD patients. Show less
Leemkolk, F.E.M. van de; Faro, M.L. lo; Shaheed, S.; Mulvey, J.F.; Huurman, V.A.L.; Alwayn, I.P.J.; ... ; Consortium Organ Preservation Eu 2023
Hypothermic machine perfusion (HMP) provides preservation superior to cold storage and may allow for organ assessment prior to transplantation. Since flavin mononucleotide (FMN) in perfusate has... Show moreHypothermic machine perfusion (HMP) provides preservation superior to cold storage and may allow for organ assessment prior to transplantation. Since flavin mononucleotide (FMN) in perfusate has been proposed as a biomarker of organ quality during HMP of donor livers, the aim of this study was to validate FMN as a biomarker for organ quality in the context of HMP preserved kidneys. Perfusate samples (n = 422) from the paired randomised controlled COPE-COMPARE-trial, comparing HMP with oxygenation (HMPO2) versus standard HMP in kidneys, were used. Fluorescence intensity (FI) was assessed using fluorescence spectroscopy (excitation 450nm; emission 500-600nm) and validated by fluorospectrophotometer and targeted liquid chromatography mass spectrometry (LC-MS/MS). Fluorescence intensity (FI)((ex450;em500-600)) increased over time during machine perfusion in both groups (p<0.0001). This increase was similar for both groups (p = 0.83). No correlation, however, was found between FI(ex450;em500-600) and post-transplant outcomes, including day 5 or 7 serum creatinine (p = 0.11; p = 0.16), immediate graft function (p = 0.91), creatinine clearance and biopsy-proven rejection at one year (p = 0.14; p = 0.59). LC-MS/MS validation experiments of samples detected FMN in only one perfusate sample, whilst the majority of samples with the highest fluorescence (n = 37/38, 97.4%) remained negative. In the context of clinical kidney HMP, fluorescence spectroscopy unfortunately appears to be not specific and probably unsuitable for FMN. This study shows that FMN does not classify as a clinically relevant predictive biomarker of kidney graft function after transplantation. Show less
Tange, F.P.; Ferrari, B.R.; Hoven, P. van den; Schaik, J. van; Schepers, A.; Rijswijk, C.S.P. van; ... ; Vorst, J.R. van der 2023
Background: The angiosome concept is defined as the anatomical territory of a source artery within all tissue layers. When applying this theory in vascular surgery, direct revascularization (DR) is... Show moreBackground: The angiosome concept is defined as the anatomical territory of a source artery within all tissue layers. When applying this theory in vascular surgery, direct revascularization (DR) is preferred to achieve increased blood flow toward the targeted angiosome of the foot in patients with lower extremity arterial disease (LEAD). This study evaluates the applicability of the angiosome concept using quantified near-infrared (NIR) fluorescence imaging with indocMethods: This study included patients undergoing an endovascular- or surgical revascularization of the leg between January 2019 and December 2021. Preinterventional and postinterventional ICG NIR fluorescence imaging was performed. Three angiosomes on the dorsum of the foot were determined: the posterior tibial artery (hallux), the anterior tibial artery (dorsum of the foot) and the combined angiosome (second to fifth digit). The angiosomes were classified from the electronic patient records and the degree of collateralization was classified based on preprocedural computed tomography angiography and/or X-ray angiography. Fluorescence intensity was quantified in all angiosomes. A subgroup analysis based on endovascular or surgical revascularized angiosomes, and within critical limb threatening ischemia (CLTI) patients was performed. Results: ICG NIR fluorescence measurements were obtained in 52 patients (54 limbs) including a total of 157 angiosomes (121 DR and 36 indirect revascularizations [IR]). A significant improvement of all perfusion parameters in both the directly and indirectly revascularized angiosomes was found (P-values between <0.001e0.007). Within the indirectly revascularized angiosomes, 90.6% of the scored collaterals were classified as significant. When comparing the percentual change in perfusion parameters between the directly and indirectly revascularized angiosomes, no significant difference was seen in all perfusion parameters (P-values between 0.253 and 0.881). Similar results were shown in the CLTI patients subgroup analysis, displaying a significant improvement of perfusion parameters in both the direct and indirect angiosome groups (P-values between <0.001 and 0.007), and no significant difference when comparing the percentual parameter improvement between both angiosome groups (P-values between 0.134 and 0.359). Furthermore, no significant differences were observed when comparing Show less
Warmerdam, B.W.C.M.; Stevens, M.; Rijswijk, C.S.P. van; Eefting, D.; Meer, R.W. van der; Putter, H.; ... ; Schaik, J. van 2023
Background: When introducing new techniques, attention must be paid to learning curve. Be-sides quantitative outcomes, qualitative factors of influence should be taken into consideration. This... Show moreBackground: When introducing new techniques, attention must be paid to learning curve. Be-sides quantitative outcomes, qualitative factors of influence should be taken into consideration. This retrospective cohort study describes the quantitative learning curve of complex endovascu-lar aortic repair (EVAR) in a nonhigh-volume academic center and provides qualitative factors that were perceived as contributors to this learning curve. With these factors, we aim to aid in future implementation of new techniques. Methods: All patients undergoing complex EVAR in the Leiden University Medical Center (LUMC) between July 2013 and April 2021 were included (n = 90). Quantitative outcomes were as follows: operating time, blood loss, volume of contrast, hospital stay, major adverse events (MAE), 30-day mortality, and complexity. Patients were divided into 3 temporal groups (n = 30) for dichotomous outcomes. Regression plots were used for continuous outcomes. In 2017, the treatment team was interviewed by an external researcher. These interviews were reanalyzed for factors that contributed to successful implementation. Results: Length of hospital stay (P = 0.008) and operating time (P = 0.010) decreased signif-icantly over time. Fewer cardiac complications occurred in the third group (3: 0% vs. 2: 17% vs. 1: 17%, P = 0.042). There was a trend of increasing complexity (P = 0.076) and number of fen-estrations (P = 0.060). No significant changes occurred in MAE and 30-day mortality. Qualitative factors that, according to the interviewees, positively influenced the learning curve were as fol-lows: communication, mutual trust, a shared sense of responsibility and collective goals, clear authoritative structures, mutual learning, and team capabilities. Conclusions: In addition to factors previously identified in the literature, new learning curve factors were found (mutual learning and shared goals in the operating room (OR)) that should be taken into account when implementing new techniques. Show less
Bonneville, E.F.; Schetelig, J.; Putter, H.; Wreede, L.C. de 2023
Missing data are frequently encountered across studies in clinical haematology. Failure to handle these missing values in an appropriate manner can complicate the interpretation of a study's... Show moreMissing data are frequently encountered across studies in clinical haematology. Failure to handle these missing values in an appropriate manner can complicate the interpretation of a study's findings, as estimates presented may be biased and/or imprecise. In the present work, we first provide an overview of current methods for handling missing covariate data, along with their advantages and disadvantages. Furthermore, a systematic review is presented, exploring both contemporary reporting of missing values in major haematological journals, and the methods used for handling them. A principal finding was that the method of handling missing data was explicitly specified in a minority of articles (in 76 out of 195 articles reporting missing values, 39%). Among these, complete case analysis and the missing indicator method were the most common approaches to dealing with missing values, with more complex methods such as multiple imputation being extremely rare (in 7 out of 195 articles). An example analysis (with associated code) is also provided using hematopoietic stem cell transplantation data, illustrating the different approaches to handling missing values. We conclude with various recommendations regarding the reporting and handling of missing values for future studies in clinical haematology. Show less
Background Prediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to... Show moreBackground Prediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to develop prediction models for first-ever cardiovascular event risk in men and women aged 30 to 49 years.Methods and Results We included patients aged 30 to 49 years without cardiovascular disease from a Dutch routine care database. Outcome was defined as first-ever cardiovascular event. Our reference models were sex-specific Cox proportional hazards models based on traditional cardiovascular predictors, which we compared with models using 2 predictor subsets with the 20 or 50 most important predictors based on the Cox elastic net model regularization coefficients. We assessed the C-index and calibration curve slopes at 10 years of follow-up. We stratified our analyses based on 30- to 39-year and 40- to 49-year age groups at baseline. We included 542 141 patients (mean age 39.7, 51% women). During follow-up, 10 767 cardiovascular events occurred. Discrimination of reference models including traditional cardiovascular predictors was moderate (women: C-index, 0.648 [95% CI, 0.645-0.652]; men: C-index, 0.661 [95%CI, 0.658-0.664]). In women and men, the Cox proportional hazard models including 50 most important predictors resulted in an increase in C-index (0.030 and 0.012, respectively), and a net correct reclassification of 3.7% of the events in women and 1.2% in men compared with the reference model.Conclusions Sex-specific electronic health record-derived prediction models for first-ever cardiovascular events in the general population aged <50 years have moderate discriminatory performance. Data-driven predictor selection leads to identification of nontraditional cardiovascular predictors, which modestly increase performance of models. Show less
BackgroundPrediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to... Show moreBackgroundPrediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to develop prediction models for first‐ever cardiovascular event risk in men and women aged 30 to 49 years.Methods and ResultsWe included patients aged 30 to 49 years without cardiovascular disease from a Dutch routine care database. Outcome was defined as first‐ever cardiovascular event. Our reference models were sex‐specific Cox proportional hazards models based on traditional cardiovascular predictors, which we compared with models using 2 predictor subsets with the 20 or 50 most important predictors based on the Cox elastic net model regularization coefficients. We assessed the C‐index and calibration curve slopes at 10 years of follow‐up. We stratified our analyses based on 30‐ to 39‐year and 40‐ to 49‐year age groups at baseline. We included 542 141 patients (mean age 39.7, 51% women). During follow‐up, 10 767 cardiovascular events occurred. Discrimination of reference models including traditional cardiovascular predictors was moderate (women: C‐index, 0.648 [95% CI, 0.645–0.652]; men: C‐index, 0.661 [95%CI, 0.658–0.664]). In women and men, the Cox proportional hazard models including 50 most important predictors resulted in an increase in C‐index (0.030 and 0.012, respectively), and a net correct reclassification of 3.7% of the events in women and 1.2% in men compared with the reference model.ConclusionsSex‐specific electronic health record‐derived prediction models for first‐ever cardiovascular events in the general population aged <50 years have moderate discriminatory performance. Data‐driven predictor selection leads to identification of nontraditional cardiovascular predictors, which modestly increase performance of models. Show less