Sensitivity of an AI method for [18F]FDG PET/CT outcome prediction of diffuse large B-cell lymphoma patients to image reconstruction protocols.

BACKGROUND: Convolutional neural networks (CNNs), applied to baseline [18F]-FDG PET/CT maximum intensity projections (MIPs), show potential for treatment outcome prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study is to investigate the robustness of CNN predictions to different image reconstruction protocols. Baseline [18F]FDG PET/CT scans were collected from 20 DLBCL patients. EARL1, EARL2 and high-resolution (HR) protocols were applied per scan, generating three images with different image qualities. Image-based transformation was applied by blurring EARL2 and HR images to generate EARL1 compliant images using a Gaussian filter of 5 and 7 mm, respectively. MIPs were generated for each of the reconstructions, before and after image transformation. An in-house developed CNN predicted the probability of tumor progression within 2 years for each MIP. The difference in probabilities per patient was then calculated between both EARL2 and HR with respect to EARL1 (delta probabilities or ΔP). We compared these to the probabilities obtained after aligning the data with ComBat using the difference in median and interquartile range (IQR). RESULTS: CNN probabilities were found to be sensitive to different reconstruction protocols (EARL2 ΔP: median = 0.09, interquartile range (IQR) = [0.06, 0.10] and HR ΔP: median = 0.1, IQR = [0.08, 0.16]). Moreover, higher resolution images (EARL2 and HR) led to higher probability values. After image-based and ComBat transformation, an improved agreement of CNN probabilities among reconstructions was found for all patients. This agreement was slightly better after image-based transformation (transformed EARL2 ΔP: median = 0.022, IQR = [0.01, 0.02] and transformed HR ΔP: median = 0.029, IQR = [0.01, 0.03]). CONCLUSION: Our CNN-based outcome predictions are affected by the applied reconstruction protocols, yet in a predictable manner. Image-based harmonization is a suitable approach to harmonize CNN predictions across image reconstruction protocols.

Preventability of unplanned readmissions within 30 days of discharge. A cross-sectional, single-center study.

OBJECTIVES: To identify the preventability, determinants and causes of unplanned hospital readmissions within 30 days of discharge using a multidisciplinary approach and including patients' perspectives. DESIGN: A prospective cross-sectional single-center study. SETTING: Urban teaching hospital in Amsterdam, the Netherlands. PARTICIPANTS: 430 patients were included. Inclusion criteria were: age ≥ 18 years, discharged from one of seven participating clinical departments and an unplanned readmission within 30 days. METHODS: Residents from the participating departments individually assessed whether the readmission was caused by healthcare, the preventability and possible causes of readmissions using a tool. Thereafter, the preventability of the cases was discussed in a multidisciplinary meeting with residents of all participating departments and clinical pharmacists. The primary outcome was the proportion of readmissions that were potentially preventable. Secondary outcomes were the determinants for a readmission, causes for preventable readmissions, the change in the final decision on preventability after the multidisciplinary meeting and the value of patient interviews in assessing preventability. Differences in characteristics of potentially preventable readmissions (PPRs) and non-PPRs were analyzed using multivariable logistic regression. RESULTS: Of 430 readmissions, 56 (13%) were assessed as PPRs. Age was significantly associated with a PPR (adjusted OR: 2.42; 95%, CI 1.23-4.74; p = 0.01). The main causes for PPRs were diagnostic (30%), medication (27%) and management problems (27%). During the multidisciplinary meeting, the final decision on preventability changed in 11% of the cases. When a patient interview was available, it was used as a source of information to assess preventability in 26% of readmissions. In 7% of cases, the patient interview was mentioned as the most important source. CONCLUSION AND IMPLICATIONS: 13% of readmissions were potentially preventable with diagnostic, medication or management problems being main causes. A multidisciplinary review approach and including the patient's perspective could contribute to a better understanding of the complexity of readmissions and possible improvements.

Abnormalities and erythroblasts in peripheral blood of multiple sclerosis patients treated with natalizumab.

BACKGROUND: In natalizumab treated patients several hematopoietic abnormalities including erythroblasts, myeloblasts and neutrophilic precursors in peripheral blood have been described. So far, long term effects of the hematopoietic changes have not been reported. OBJECTIVE: To describe hematopoietic abnormalities in longitudinally monitored MS patients treated with natalizumab. Patients treated with dimethyl fumarate, teriflunomide and fingolimod served as controls. Secondly, the relation between natalizumab serum levels and the occurrence of hematopoietic abnormalities was explored. METHODS: 212 natalizumab treated patients were included, 91 patients with available baseline samples (998 follow-up samples) were compared with patients with dimethyl fumarate (n = 166, 1154 samples), teriflunomide (n = 38, 228 samples) and fingolimod (n = 114, 853 samples). One hundred twenty one patients without baseline samples (1952 follow-up samples) were included in the follow-up group. RESULTS: More than half of all natalizumab treated patients developed hematopoietic abnormalities, almost a quarter had erythroblasts. Natalizumab use was associated with an increased risk of developing abnormalities in comparison to oral treatment, with a corrected hazard ratio of 2.3, 10.0 and 8.1 in comparison to fingolimod, dimethyl fumarate and teriflunomide respectively. No difference in developing abnormalities was observed in relation to natalizumab serum concentrations. None of the patients developed a hematologic malignancy during follow up. CONCLUSION: Hematopoietic abnormalities are common during natalizumab treatment. Given the lack of consequences of this finding during long-term follow-up, it is generally justifiable to refrain from further diagnostic procedures when observing hematopoietic abnormalities in patients using natalizumab.

Fluid balance-adjusted creatinine at initiation of continuous venovenous hemofiltration and mortality. A post-hoc analysis of a multicenter randomized controlled trial.

INTRODUCTION: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is associated with high mortality. The creatinine-based stage of AKI is considered when deciding to start or delay RRT. However, creatinine is not only determined by renal function (excretion), but also by dilution (fluid balance) and creatinine generation (muscle mass). The aim of this study was to explore whether fluid balance-adjusted creatinine at initiation of RRT is related to 28-day mortality independent of other markers of AKI, surrogates of muscle mass and severity of disease. METHODS: We performed a post-hoc analysis on data from the multicentre CASH trial comparing citrate to heparin anticoagulation during continuous venovenous hemofiltration (CVVH). To determine whether fluid balance-adjusted creatinine was associated with 28-day mortality, we performed a logistic regression analysis adjusting for confounders of creatinine generation (age, gender, body weight), other markers of AKI (creatinine, urine output) and severity of disease. RESULTS: Of the 139 patients, 32 patients were excluded. Of the 107 included patients, 36 died at 28 days (34%). Non-survivors were older, had higher APACHE II and inclusion SOFA scores, lower pH and bicarbonate, lower creatinine and fluid balance-adjusted creatinine at CVVH initiation. In multivariate analysis lower fluid balance-adjusted creatinine (OR 0.996, 95% CI 0.993-0.999, p = 0.019), but not unadjusted creatinine, remained associated with 28-day mortality together with bicarbonate (OR 0.869, 95% CI 0.769-0.982, P = 0.024), while the APACHE II score non-significantly contributed to the model. CONCLUSION: In this post-hoc analysis of a multicentre trial, low fluid balance-adjusted creatinine at CVVH initiation was associated with 28-day mortality, independent of other markers of AKI, organ failure, and surrogates of muscle mass, while unadjusted creatinine was not. More tools are needed for better understanding of the complex determinants of "AKI classification", "CVVH initiation" and their relation with mortality, fluid balance is only one.

Putative novel mediators of acute kidney injury in critically ill patients: handling by continuous venovenous hemofiltration and effect of anticoagulation modalities.

BACKGROUND: Novel putative mediators of acute kidney injury (AKI) include immune-cell derived tumour necrosis factor-like weak inducer of apoptosis (TWEAK), angiopoietin-2 (Ang-2) and protein pentraxin-3 (PTX3). The effect of continuous venovenous hemofiltration (CVVH) and different anticoagulation regimens on plasma levels were studied. METHODS: At 0, 10, 60, 180 and 720 min of CVVH, samples were collected from pre- and postfilter blood and ultrafiltrate. No anticoagulation (n = 13), unfractionated heparin (n = 8) or trisodium citrate (n = 21) were compared. RESULTS: Concentrations of TWEAK, Ang-2 and PTX3 were hardly affected by CVVH since the mediators were not (TWEAK, PTX3) or hardly (Ang-2) detectable in ultrafiltrate, indicating negligible clearance by the filter in spite of molecular sizes (TWEAK, PTX3) at or below the cutoff of the membrane. Heparin use, however, was associated with an increase in in- and outlet plasma TWEAK. CONCLUSION: Novel AKI mediators are not cleared nor produced by CVVH. However, heparin anticoagulation increased TWEAK levels in patient's plasma whereas citrate did not, favouring the latter as anticoagulant in CVVH for AKI.

Coagulation, Fibrinolysis and Inhibitors in Failing Filters during Continuous Venovenous Hemofiltration in Critically Ill Patients with Acute Kidney Injury: Effect of Anticoagulation Modalities.

INTRODUCTION: The mechanisms of early filter failure and clotting with different anticoagulation modalities during continuous venovenous hemofiltration (CVVH) are largely unknown. METHODS: Citrate, heparin and no anticoagulation were compared. Blood was drawn pre- and post filter up to 720 min. Concentrations of the thrombin-antithrombin (TAT), activated protein C-protein C inhibitor (APC-PCI), and type I plasminogen activator inhibitor (PAI-1) were determined. RESULTS: In case of early filter failure (<24 h), inlet concentrations of TAT and APC-PCI were higher over time, irrespective of anticoagulation. There was more production of APC-PCI and platelet-derived PAI-1 in the filter after 10 min in the heparin group than in other groups. In clotting filters, production of APC-PCI and PAI was also higher with heparin than citrate. CONCLUSION: Coagulation activation in plasma and inhibition of anticoagulation in plasma and filter may partly determine early CVVH filter failure due to clotting, particularly when heparin is used. Regional anticoagulation by citrate circumvents the inhibition of anticoagulation and fibrinolysis by platelet activation following heparin.

Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial.

INTRODUCTION: Because of ongoing controversy, renal and vital outcomes are compared between systemically administered unfractionated heparin and regional anticoagulation with citrate-buffered replacement solution in predilution mode, during continuous venovenous hemofiltration (CVVH) in critically ill patients with acute kidney injury (AKI). METHODS: In this multi-center randomized controlled trial, patients admitted to the intensive care unit requiring CVVH and meeting inclusion criteria, were randomly assigned to citrate or heparin. Primary endpoints were mortality and renal outcome in intention-to-treat analysis. Secondary endpoints were safety and efficacy. Safety was defined as absence of any adverse event necessitating discontinuation of the assigned anticoagulant. For efficacy, among other parameters, survival times of the first hemofilter were studied. RESULTS: Of the 139 patients enrolled, 66 were randomized to citrate and 73 to heparin. Mortality rates at 28 and 90 days did not differ between groups: 22/66 (33%) of citrate-treated patients died versus 25/72 (35%) of heparin-treated patients at 28 days, and 27/65 (42%) of citrate-treated patients died versus 29/69 (42%) of heparin-treated patients at 90 days (P = 1.00 for both). Renal outcome, i.e. independency of renal replacement therapy 28 days after initiation of CVVH in surviving patients, did not differ between groups: 29/43 (67%) in the citrate-treated patients versus 33/47 (70%) in heparin-treated patients (P = 0.82). Heparin was discontinued in 24/73 (33%) of patients whereas citrate was discontinued in 5/66 (8%) of patients (P < 0.001). Filter survival times were superior for citrate (median 46 versus 32 hours, P = 0.02), as were the number of filters used (P = 0.002) and the off time within 72 hours (P = 0.002). The costs during the first 72 hours of prescribed CVVH were lower in citrate-based CVVH. CONCLUSIONS: Renal outcome and patient mortality were similar for citrate and heparin anticoagulation during CVVH in the critically ill patient with AKI. However, citrate was superior in terms of safety, efficacy and costs. TRIAL REGISTRATION: Clinicaltrials.gov NCT00209378. Registered 13th September 2005.

The plasma level and biomarker value of neutrophil gelatinase-associated lipocalin in critically ill patients with acute kidney injury are not affected by continuous venovenous hemofiltration and anticoagulation applied.

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI), and levels reflect severity of disease in critically ill patients. However, continuous venovenous hemofiltration (CVVH) may affect plasma levels by clearance or release of NGAL by activated neutrophils in the filter, dependent on the anticoagulation regimen applied. We therefore studied handling of NGAL by CVVH in patients with AKI. METHODS: Immediately before initiation of CVVH, prefilter blood was drawn. After 10, 60, 180, and 720 minutes of CVVH, samples were collected from pre- and postfilter (in- and outlet) blood and ultrafiltrate. CVVH with the following anticoagulation regimens was studied: no anticoagulation in case of a high bleeding tendency (n = 13), unfractionated heparin (n = 8), or trisodium citrate (n = 21). NGAL levels were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: Concentrations of NGAL at inlet and outlet were similar, and concentrations did not change over time in any of the anticoagulation groups; thus no net removal or production of NGAL occurred. Concentrations of NGAL at inlet correlated with disease severity at initiation of CVVH and at the end of a CVVH run. Concentrations of NGAL in the ultrafiltrate were lower with citrate-based CVVH (P = 0.03) and decreased over time, irrespective of anticoagulation administered (P < 0.001). The sieving coefficient and clearance of NGAL were low and decreased over time (P < 0.001). CONCLUSIONS: The plasma level and biomarker value of NGAL in critically ill patients with AKI are not affected by CVVH, because clearance by the filter was low. Furthermore, no evidence exists for intrafilter release of NGAL by neutrophils, irrespective of the anticoagulation method applied.

Citrate confers less filter-induced complement activation and neutrophil degranulation than heparin when used for anticoagulation during continuous venovenous haemofiltration in critically ill patients.

BACKGROUND: During continuous venovenous haemofiltration (CVVH), regional anticoagulation with citrate may be superior to heparin in terms of biocompatibility, since heparin as opposed to citrate may activate complement (reflected by circulating C5a) and induce neutrophil degranulation in the filter and myeloperoxidase (MPO) release from endothelium. METHODS: No anticoagulation (n = 13), unfractionated heparin (n = 8) and trisodium citrate (n = 17) regimens during CVVH were compared. Blood samples were collected pre- and postfilter; C5a, elastase and MPO were determined by ELISA. Additionally, C5a was also measured in the ultrafiltrate. RESULTS: In the heparin group, there was C5a production across the filter which most decreased over time as compared to other groups (P = 0.007). There was also net production of elastase and MPO across the filter during heparin anticoagulation (P = 0.049 or lower), while production was minimal and absent in the no anticoagulation and citrate group, respectively. During heparin anticoagulation, plasma concentrations of MPO at the inlet increased in the first 10 minutes of CVVH (P = 0.024). CONCLUSION: Citrate confers less filter-induced, potentially harmful complement activation and neutrophil degranulation and less endothelial activation than heparin when used for anticoagulation during continuous venovenous haemofiltration in critically ill patients.

Effect of anticoagulation regimens on handling of interleukin-6 and -8 during continuous venovenous hemofiltration in critically ill patients with acute kidney injury.

OBJECTIVE: During continuous venovenous hemofiltration (CVVH) to replace renal function in acute kidney injury (AKI), anticoagulation of the filter is routinely required. A survival benefit for citrate has been reported, possibly due to reduced proinflammatory effects of the filter (bioincompatibility). We hypothesized that the type of anticoagulation modulates the immune response to, and clearance by CVVH of interleukin-6 (IL-6) and -8 (IL-8). METHODS: Three anticoagulation regimens were compared: trisodium citrate (n=17), unfractionated heparin (n=8) and no anticoagulation in case of bleeding tendency (n=13). Immediately before initiation of CVVH (cellulose triacetate membrane) pre-filter blood was drawn. Thereafter, at 10, 60, 180 and 720 min, samples were collected from the pre- and postfilter blood and from ultrafiltrate. IL-6 and IL-8 were determined by ELISA. RESULTS: High inlet levels of IL-6 and IL-8, particularly in the no anticoagulation group, were associated with non-survival. The inlet concentrations and mass rates of IL-6 and IL-8 decreased during CVVH. The course of fluxes across the filter were similar for the groups, however. Although increasing in time for IL-6 in the no anticoagulation group, mass removal and adsorption of IL-6 and IL-8 were low and did not differ among the anticoagulation groups. CONCLUSIONS: Blood to membrane contact, adsorption/clearance and anticoagulation do not increase nor attenuate high circulating levels of IL-6 and IL-8 during CVVH for AKI. This renders the hypothesis that the reported survival benefit for citrate anticoagulation is based on a reduction of bioincompatibility unlikely.