ObjectivesThis review addresses the common problem of missing patient-reported outcome (PRO) data in clinical trials by assessing the current practice of their statistical handling as reported in... Show moreObjectivesThis review addresses the common problem of missing patient-reported outcome (PRO) data in clinical trials by assessing the current practice of their statistical handling as reported in publications of randomized controlled trials (RCTs) in patients with breast cancer.Study Design and SettingWe searched PubMed to identify RCTs evaluating biomedical treatments in breast cancer patients with at least one PRO endpoint published between January 2019 and February 2022. Two reviewers independently assessed the eligibility of the publications for this scoping review and extracted prespecified information on missing PRO data and related statistical practices.ResultsOf 1,598 publications identified, 118 trials met the inclusion criteria. Eighty-eight (74.6%) trials reported the extent of missing data, with 11 (9.3%) not containing any missing PRO data. Twenty-one (19.6%) trials explicitly stated the statistical approach for handling missing data, with a preference for single imputation over multiple imputation approaches (57.2%/19.0%). Only six (5.6%) trials reported a sensitivity analysis to examine the extent to the results being affected by changes in assumptions made about missing PRO data.ConclusionInternational efforts to raise awareness of the importance of accurately reporting state-of-the-art handling of missing PRO data are not yet fully reflected in the current literature of breast cancer RCTs. Show less
Wal, I. van der; Meijer, F.; Fuica, R.; Silman, Z.; Boon, M.; Martini, C.; ... ; Gozal, Y. 2023
In this pooled analysis of two randomized clinical trials, intraoperative opioid dosing based on the nociception level-index produced less pain compared to standard care with a difference in pain... Show moreIn this pooled analysis of two randomized clinical trials, intraoperative opioid dosing based on the nociception level-index produced less pain compared to standard care with a difference in pain scores in the post-anesthesia care unit of 1.5 (95% CI 0.8-2.2) points on an 11-point scale. The proportion of patients with severe pain was lower by 70%. Severe postoperative pain remains a significant problem and associates with several adverse outcomes. Here, we determined whether the application of a monitor that detects intraoperative nociceptive events, based on machine learning technology, and treatment of such events reduces pain scores in the post-anesthesia care unit (PACU). To that end, we performed a pooled analysis of two trials in adult patients, undergoing elective major abdominal surgery, on the effect of intraoperative nociception level monitor (NOL)-guided fentanyl dosing on PACU pain was performed. Patients received NOL-guided fentanyl dosing or standard care (fentanyl dosing based on hemodynamic parameters). Goal of the intervention was to keep NOL at values that indicated absence of nociception. The primary endpoint of the study was the median pain score obtained in the first 90 min in the PACU. Pain scores were collected at 15 min intervals on an 11-point Likert scale. Data from 125 patients (55 men, 70 women, age range 21-86 years) were analyzed. Sixty-one patients received NOL-guided fentanyl dosing and 64 standard care. Median PACU pain score was 1.5 points (0.8-2.2) lower in the NOL group compared to the standard care; the proportion of patients with severe pain was 70% lower in the NOL group (p = 0.045). The only significant factor associated with increased odds for severe pain was the standard of care compared to NOL treatment (OR 6.0, 95% CI 1.4 -25.9, p = 0.017). The use of a machine learning-based technology to guide opioid dosing during major abdominal surgery resulted in reduced PACU pain scores with less patients in severe pain. Show less
Honing, M.; Reijnders-Boerboom, G.; Dell-Kuster, S.; Velzen, M. van; Martini, C.; Valenza, F.; ... ; Warle, M. 2021
Background: Muscle relaxants are routinely used during anesthesia to facilitate endotracheal intubation and to optimize surgical conditions. However, controversy remains about the required depth of... Show moreBackground: Muscle relaxants are routinely used during anesthesia to facilitate endotracheal intubation and to optimize surgical conditions. However, controversy remains about the required depth of neuromuscular block (NMB) needed for optimal surgical working conditions and how this relates to other outcomes. For instance, a deep neuromuscular block yields superior surgical working conditions compared to a standard NMB in laparoscopic surgery, however, a robust association to other (safety) outcomes has not yet been established.Methods: Trial design: an international multicenter randomized controlled double-blind strategy trial. Trial population: 922 patients planned for elective, laparoscopic or robotic, abdominal surgery. Intervention: Patients will be randomized to a deep NMB (post-tetanic count 1-2 twitches) or standard care (single-dose muscle relaxant administration at induction and repeated only if warranted by surgical team). Main trial endpoints: Primary endpoint is the difference in incidence of intraoperative adverse events during laparoscopic surgery graded according to ClassIntra (R) classification (i.e., ClassIntra (R) grade >= 2) between both groups. Secondary endpoints include the surgical working conditions, 30-day postoperative complications, and patients' quality of recovery.Discussion: This trial was designed to analyze the effect of deep neuromuscular block compared to standard neuromuscular block on intra- and postoperative adverse events in patients undergoing laparoscopic surgery. Show less
Meijer, F.; Honing, M.; Roor, T.; Toet, S.; Calis, P.; Olofsen, E.; ... ; Dahan, A. 2021
Background: The majority of postoperative patients report moderate to severe pain, possibly related to opioid under-dosing or overdosing during surgery. Objective guidance of opioid dosing using... Show moreBackground: The majority of postoperative patients report moderate to severe pain, possibly related to opioid under-dosing or overdosing during surgery. Objective guidance of opioid dosing using the Nociception Level (NOL) index, a multiparameter artificial intelligence-driven index designed to monitor nociception during surgery, may lead to a more appropriate analgesic regimen, with effects beyond surgery. We tested whether NOL-guided opioid dosing during general anaesthesia results in less postoperative pain.Methods: In this two-centre RCT, 50 patients undergoing abdominal surgery under fentanyl/sevoflurane anaesthesia were randomised to NOL-guided fentanyl dosing or standard care in which fentanyl dosing was based on haemodynamics. The primary endpoint of the study was postoperative pain assessed in the PACU.Results: Median postoperative pain scores were 3.2 (inter-quartile range 1.3-4.3) and 4.8 (3.0-5.3) in NOL-guided and standard care groups, respectively (P=0.006). Postoperative morphine consumption (standard deviation) was 0.06 (0.07) mg kg(-1) (NOL-guided group) and 0.09 (0.09) mg kg(-1) (control group; P=0.204). During surgery, fentanyl dosing was not different between groups (NOL-guided group: 6.4 [4.2] mg kg(-1) vs standard care: 6.0 [2.2] mg kg(-1), P=0.749), although the variation between patients was greater in the NOL-guided group (% coefficient of variation 66% in the NOL-guided group vs 37% in the standard care group).Conclusions: Despite absence of differences in fentanyl and morphine consumption during and after surgery, a 1.6-point improvement in postoperative pain scores was observed in the NOL-guided group. We attribute this to NOL-driven rather than BP- and HR-driven fentanyl dosing during anaesthesia. Show less
Honing, M.; Martini, C.; Velzen, M. van; Niesters, M.; Dahan, A.; Boon, M. 2020
General anesthesia is obtained by administration of potent hypnotics, analgesics and muscle relaxants. Apart from their intended effects (loss of consciousness, pain relief and muscle relaxation),... Show moreGeneral anesthesia is obtained by administration of potent hypnotics, analgesics and muscle relaxants. Apart from their intended effects (loss of consciousness, pain relief and muscle relaxation), these agents profoundly affect the control of breathing, in part by an effect within the peripheral chemoreflex loop that originates at the carotid bodies. This review assesses the role of cholinergic chemotransmission in the peripheral chemoreflex loop and the mechanisms through which muscle relaxants and hypnotics interfere with peripheral chemosensitivity. Additionally, consequences for clinical practice are discussed. Show less
Infections caused by Enterococcus spp., are a major concern in the clinical setting. In Enterococcus faecalis, the capsular polysaccharide diheteroglycan (DHG), composed of ß-D-galactofuranose-(1→3... Show moreInfections caused by Enterococcus spp., are a major concern in the clinical setting. In Enterococcus faecalis, the capsular polysaccharide diheteroglycan (DHG), composed of ß-D-galactofuranose-(1→3)-ß-D-glucopyranose repeats, has been described as an important virulence factor and as a potential vaccine candidate against encapsulated strains. Synthetic structures emulating immunogenic polysaccharides present many advantages over native polysaccharides for vaccine development. In this work, we described the synthesis of a library of DHG oligomers, differing in length and order of the monosaccharide constituents. Using suitably protected thioglycoside building blocks, oligosaccharides up to the 8-mer in length built up from either Galf-Glcp or Glcp-Galf dimers were generated and we evaluated their immunoreactivity with antibodies raised against DHG. After the screening, we selected two octasaccharides, having either a galactofuranose or glucopyranose terminus, which were conjugated to a carrier protein for the production of polyclonal antibodies. Resulting antibodies were specific towards the synthetic structures and mediated in-vitro opsonophagocytic killing of different encapsulated E. feacalis strains. The evaluated structures are the first synthetic structures described to elicit antibodies that target encapsulated E. faecalis strains, and are, therefore, promising candidates for the development of a well-defined enterococcal glycoconjugate vaccine. Show less
Boon, M.; Martini, C.; Yang, H.K.; Sen, S.S.; Bevers, R.; Warle, M.; ... ; Dahan, A. 2018
The anesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low-dose ketamine produces strong analgesia in neuropathic pain states,... Show moreThe anesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low-dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short-term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (10-14 days) show long-term analgesic effects up to 3 months following infusion. Ketamine's side-effects noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation, and in a minority of patients hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult, because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side-effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, hemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain. Show less
Niesters, M.; Khalili-Mahani, N.; Martini, C.; Aarts, L.; Gerven, J. van; Buchem, M.A. van; ... ; Rombouts, S. 2012
PURPOSE To evaluate the prognostic value of multidetector computed tomographic (CT) coronary angiography in a diabetic population known to have or suspected of having coronary artery disease (CAD)... Show morePURPOSE To evaluate the prognostic value of multidetector computed tomographic (CT) coronary angiography in a diabetic population known to have or suspected of having coronary artery disease (CAD) compared with that in nondiabetic individuals. MATERIALS AND METHODS Institutional review board approval and patient informed consent were obtained. Three hundred thirteen patients with type 2 diabetes mellitus (DM) and 303 patients without DM underwent unenhanced 64-detector row CT, at which a calcium score was obtained, followed by CT angiography. Multidetector CT coronary angiograms were retrospectively classified as normal, showing nonobstructive CAD (50% luminal narrowing). During follow-up after CT angiography, major events (cardiac death, nonfatal myocardial infarction, and unstable angina requiring hospitalization) and total events (major events plus coronary revascularizations) were recorded for each patient. Cox proportional hazards analysis and Kaplan-Meier analysis were used to compare survival rates. RESULTS In the group of 313 patients with DM, there were 213 men, and the mean age was 62 years +/- 11 (standard deviation). In the group of 303 patients without DM, there were 203 men, and the mean age was 63 years +/- 11. The mean number of diseased segments (5.6 vs 4.4, P = .001) and the rate of obstructive CAD (51% vs 37%, P < .001) were higher in patients with DM. Patients were followed up for a mean of 20 months +/- 5.4 (range, 6-44 months). At multivariate analysis, DM (P < .001) and evidence of obstructive CAD (P < .001) were independent predictors of outcome. Obstructive CAD remained a significant multivariate predictor for both patients with DM and patients without DM. In both patients with DM and patients without DM with absence of disease, the event rate was 0%. The event rate increased to 36% in patients without DM but with obstructive CAD and was highest (47%) in patients with DM and obstructive CAD. CONCLUSION In both patients with DM and patients without DM, multidetector CT coronary angiography provides incremental prognostic information over baseline clinical variables, and the absence of atherosclerosis at CT coronary angiography is associated with an excellent prognosis. Multidetector CT coronary angiography might be a clinically useful tool for improving risk stratification in both patients with DM and patients without DM. Show less
Purpose: To evaluate the prognostic value of multidetector computed tomographic (CT) coronary angiography in a diabetic population known to have or suspected of having coronary artery disease (CAD)... Show morePurpose: To evaluate the prognostic value of multidetector computed tomographic (CT) coronary angiography in a diabetic population known to have or suspected of having coronary artery disease (CAD) compared with that in nondiabetic individuals. Materials and Methods: Institutional review board approval and patient informed consent were obtained. Three hundred thirteen patients with type 2 diabetes mellitus (DM) and 303 patients without DM underwent unenhanced 64-detector row CT, at which a calcium score was obtained, followed by CT angiography. Multidetector CT coronary angiograms were retrospectively classified as normal, showing nonobstructive CAD (<= 50% luminal narrowing), or showing obstructive CAD (>50% luminal narrowing). During follow-up after CT angiography, major events (cardiac death, nonfatal myocardial infarction, and unstable angina requiring hospitalization) and total events (major events plus coronary revascularizations) were recorded for each patient. Cox proportional hazards analysis and Kaplan-Meier analysis were used to compare survival rates. Results: In the group of 313 patients with DM, there were 213 men, and the mean age was 62 years +/- 11 (standard deviation). In the group of 303 patients without DM, there were 203 men, and the mean age was 63 years +/- 11. The mean number of diseased segments (5.6 vs 4.4, P = .001) and the rate of obstructive CAD (51% vs 37%, P < .001) were higher in patients with DM. Patients were followed up for a mean of 20 months +/- 5.4 (range, 6-44 months). At multivariate analysis, DM (P < .001) and evidence of obstructive CAD (P < .001) were independent predictors of outcome. Obstructive CAD remained a significant multivariate predictor for both patients with DM and patients without DM. In both patients with DM and patients without DM with absence of disease, the event rate was 0%. The event rate increased to 36% in patients without DM but with obstructive CAD and was highest (47%) in patients with DM and obstructive CAD. Conclusion: In both patients with DM and patients without DM, multidetector CT coronary angiography provides incremental prognostic information over baseline clinical variables, and the absence of atherosclerosis at CT coronary angiography is associated with an excellent prognosis. Multidetector CT coronary angiography might be a clinically useful tool for improving risk stratification in both patients with DM and patients without DM. (C) RSNA, 2010 Show less
