High-dose carfilzomib achieves superior anti-tumor activity over lowdose and recaptures response in relapsed/refractory multiple myeloma resistant to low-dose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex

The optimal carfilzomib dosing is a matter of debate. We analyzed the inhibition profiles of proteolytic proteasome subunits β5, β2 and β1 after low-dose (20/27 mg/m2) versus high-dose (≥36 mg/m2) carfilzomib in 103 pairs of peripheral blood mononuclear cells from patients with relapsed/refractory (RR) multiple myeloma (MM). β5 activity was inhibited (median inhibition >50%) in vivo by 20 mg/m2, whereas β2 and β1 were co-inhibited only by 36 and 56 mg/m2, respectively. Co-inhibition of β2 (P=0.0001) and β1 activity (P=0.0005) differed significantly between high-dose and low-dose carfilzomib. Subsequently, high-dose carfilzomib showed significantly more effective proteasome inhibition than low-dose drug in vivo (P=0.0003). We investigated the clinical data of 114 patients treated with carfilzomib combinations. High-dose carfilzomib demonstrated a higher overall response rate (P=0.03) and longer progression-free survival (PFS) (P=0.007) than low-dose carfilzomib. Therefore, we escalated the carfilzomib dose to ≥ 36 mg/m2 in 16 patients who progressed during low-dose carfilzomib-containing therapies. High-dose carfilzomib recaptured response (≥ partial remission) in 9 (56%) patients with a median PFS of 4.4 months. Altogether, we provide the first in vivo evidence in RRMM patients that the molecular activity of high-dose carfilzomib differs from that of low-dose carfilzomib by co-inhibition of β2 and β1 proteasome subunits and, consequently, high-dose carfilzomib achieves a superior anti-MM effect than low-dose and recaptures response in RRMM being resistant to low-dose carfilzomib. The optimal carfilzomib dose should be ≥ 36 mg/m2 to reach a sufficient anti-tumor activity, while the balance between efficacy and tolerability should be considered in each patient.Bio-organic Synthesi

Pre-PCI versus immediate post-PCI Impella initiation in acute myocardial infarction complicated by cardiogenic shock

BACKGROUND: In selected patients with an acute myocardial infarction (AMI) complicated by Cardiogenic shock (CS), mechanical circulatory support with Impella may be beneficial, although conclusive evidence is still lacking. Nevertheless, it has been suggested that Impella initiation prior to primary PCI might improve survival. OBJECTIVE: To investigate the effect pre-PCI versus immediate post-PCI Impella initiation on short term mortality. METHODS: A prospective, single center, observational study, was performed including all patients with STEMI complicated by CS, treated with primary PCI and Impella. Thirty day mortality was compared between patients with Impella initiation pre-PCI and immediately post-PCI. RESULTS: A total of 88 patients were included. In the pre-PCI group (n = 21), admission heart rate was lower (84 versus 94 bpm, p = 0.04) and no IABP was implanted before Impella initiation, versus 17.9% in post-PCI group (n = 67), p = 0.04. Total 30-day all-cause mortality was 58%, and was lower in pre-PCI group, 47.6% versus 61.2% in the post-PCI group, however not statistically significant (HR 0.7, 95% CI 0.3-1.3, p = 0.21). Thirty-day cardiac mortality was significantly lower in the pre-PCI group, 19% versus 44.7% in the post-PCI group (HR 0.3, 95% CI 0.09-0.96, p = 0.042). CONCLUSION: Pre-PCI Impella initiation in AMICS patients was not associated with a statistically significant difference in 30-day all-cause mortality, compared to post-PCI Impella initiation

Early extracorporeal CPR for refractory out-of-hospital cardiac arrest

BACKGROUNDExtracorporeal cardiopulmonary resuscitation (CPR) restores perfusion and oxy-genation in a patient who does not have spontaneous circulation. The evidencewith regard to the effect of extracorporeal CPR on survival with a favorable neu-rologic outcome in refractory out-of-hospital cardiac arrest is inconclusive.METHODSIn this multicenter, randomized, controlled trial conducted in the Netherlands, weassigned patients with an out-of-hospital cardiac arrest to receive extracorporealCPR or conventional CPR (standard advanced cardiac life support). Eligible patientswere between 18 and 70 years of age, had received bystander CPR, had an initialventricular arrhythmia, and did not have a return of spontaneous circulationwithin 15 minutes after CPR had been initiated. The primary outcome was sur-vival with a favorable neurologic outcome, defined as a Cerebral PerformanceCategory score of 1 or 2 (range, 1 to 5, with higher scores indicating more severedisability) at 30 days. Analyses were performed on an intention-to-treat basis.RESULTSOf the 160 patients who underwent randomization, 70 were assigned to receiveextracorporeal CPR and 64 to receive conventional CPR; 26 patients who did notmeet the inclusion criteria at hospital admission were excluded. At 30 days, 14 pa-tients (20%) in the extracorporeal-CPR group were alive with a favorable neuro-logic outcome, as compared with 10 patients (16%) in the conventional-CPR group(odds ratio, 1.4; 95% confidence interval, 0.5 to 3.5; P = 0.52). The number of seri-ous adverse events per patient was similar in the two groups.CONCLUSIONSIn patients with refractory out-of-hospital cardiac arrest, extracorporeal CPR andconventional CPR had similar effects on survival with a favorable neurologic out-come. (Funded by the Netherlands Organization for Health Research and Develop-ment and Maquet Cardiopulmonary [Getinge]; INCEPTION ClinicalTrials.govnumber, NCT03101787.)Cardiolog

Mensbeelden en moreel handelen in de zorg voor verstandelijk gehandicapten. Een empirisch-ethisch onderzoek.

Contains fulltext : 19383.pdf (publisher's version ) (Open Access)Although 'full citizenship' of mentally handicapped persons is strongly advocated in views on care and in policy plans, its practical application is not at all a matter of course. Looking at the course of history, it can be concluded that a long period of comparative indifference was followed by a quick succession of various views on mental deficiency and the mentally handicapped. The mentally handicapped person as an incurable patient developed into a person with possibilities, a full citizen who participates in society, has rights and duties and is certainly not the least among his equals. But ideals are confronted with the reality. The propagated equality is immediately denied through patronising, protective measures and special facilities and privileges that have been assigned. It is not easy to find a balance in this and it can be concluded that reflections and proceedings with regard to the mentally handicapped are characterised by continual doubts. The hypothesis of this study is that not only the scientific domains have been overcome by ambivalent doubts; everyday practice of care for the mentally handicapped is also characterised by moral ambivalence. This ambivalence leads to diffidence with regard to proceedings, to being unsure of the legitimacy of the proceedings, which in turn influences the quality of care in a negative way. This study discusses possibilities of dealing with this moral ambivalence.Through researching and describing the moral demands of public ideas of man and from their personal interpretations in everyday practice, an insight will be given into the extent of interaction between the two. Suggestions are made to create facilities for the development of the moral competence of the employeesKUN, 12 januari 2004Promotor : Have, H.A.M.J. ten343 p

Simulations Predict Increased Brain Antenna Performance Robustness by Adding Biocompatiblility Layer

The goal of this paper is to study the effects of the simulated reflection coefficient of a cortical UWB antenna in a planar multilayered head model. This study shows that the reflection in these deeply implanted antennas can be heavily influenced by the presence of cerebrospinal fluid. However, when coating the antenna with a thin biocompatible layer of alumina having a thickness of 0.1mm, the reflection coefficient shows much more robustness to interpersonal differences in head geometry and to small variations in antenna placement. This stable behavior to these uncontrollable parameters suggest that direct high-speed brain communication using untethered implants could be feasible. This topology could more elegant than a conventional tethered, subcutaneous approach, as this wire-free option eases surgical implantation and can prevent tissue damage created by the mechanical interaction between the body and the tether cables

Can concept mapping support the quality of reflections made by undergraduate medical students? A mixed method study

BackgroundStudents perceive reflective writing as difficult. Concept mapping may be an alternative format for reflection, which provides support while allowing students to freely shape their thoughts. We examined (1) the quality of reflection in reflective concept maps created by first-year medical students and (2) students' perceptions about concept mapping as a tool for reflection.MethodsMixed-method study conducted within the medical curriculum of Maastricht University, The Netherlands, consisting of: (1) Analysis of the quality of reflection in 245 reflective concept maps created by 40 first-year students. Reflection quality was analysed by assessing focus of reflection (technical/practical/sensitising) and depth of reflection (description/justification/critique/discussion). (2) Semi-structured interviews with 22 students to explore perceived effectiveness of reflective concept mapping.ResultsDepth of reflection reached at least the level of critique in 82% of maps. Three factors appeared to affect the perceived effectiveness of concept mapping for reflection: (1) reflective concept map structure; (2) alertness to meaningful experiences in practice and (3) learning by doing.ConclusionThese results yielded supportive evidence for concept mapping as a useful technique to teach novice learners the basics of effective reflection. Meaningful implementation requires a delicate balance between providing a supportive structure and allowing flexibility for the student

Skin lesions in a patient with head and neck cancer

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