This study was registered at ClinicalTrials.gov, identifier NCT02415088.

Background: The reported incidence of postoperative residual curarisation (PORC) is still unacceptably high. The capacity of intraoperative neuromuscular monitoring (NMM) to reduce the incidence of PORC has yet to be established from pooled clinical studies. We conducted a meta-analysis of data from 1979 to 2019 to reanalyse this relationship. Methods: English language, peer-reviewed, and operation room adult anaesthesia setting articles published between 1979 and 2019 were searched for on PubMed, Cochrane Central Register of Controlled Trials, ISI-WoK, and Scopus. The primary outcome was PORC incidence as defined by an at-or post-extubation train-of-four ratio (TOFR) of lower than 0.7, 0.9, or 1.0. Additional collected variables included the duration of action of neuromuscular blocking agents (NMBAs) used, sugammadex or neostigmine use, and the technique of anaesthesia maintenance. Results: Fifty-three studies (109 study arms, 12 664 patients) were included. The pooled PORC incidence associated with the use of intermediate duration NMBAs and quantitative NMM was 0.115 (95% confidence interval [CI], 0.057e0.188). This was significantly lower than the PORC rate for both qualitative NMM (0.306; 95% CI, 0.09e0.411) and no NMM (0.331; 95% CI, 0.234e0.435). Anaesthesia type did not significantly affect PORC incidence. Sugammadex use was associated with lower PORC rates. The GRADE global level of evidence was very low and the refined assessment of the network metaanalysis by means of a confidence in network meta-analysis raised concerns on within-and across-study bias. Conclusions: Quantitative NMM outperforms both subjective and no NMM monitoring in reducing PORC as defined by a TOFR of <0.9.

STUDY QUESTION Is it possible to co-culture and functionally link human liver and testis equivalents in the combined medium circuit of a multi-organ chip? SUMMARY ANSWER Multi-organ-chip co-cultures of human liver and testis equivalents were maintained at a steady-state for at least 1 week and the co-cultures reproduced specific natural and drug-induced liver–testis systemic interactions. WHAT IS KNOWN ALREADY Current benchtop reprotoxicity models typically do not include hepatic metabolism and interactions of the liver–testis axis. However, these are important to study the biotransformation of substances. STUDY DESIGN, SIZE, DURATION Testicular organoids derived from primary adult testicular cells and liver spheroids consisting of cultured HepaRG cells and hepatic stellate cells were loaded into separate culture compartments of each multi-organ-chip circuit for co-culture in liver spheroid-specific medium, testicular organoid-specific medium or a combined medium over a week. Additional multi-organ-chips (single) and well plates (static) were loaded only with testicular organoids or liver spheroids for comparison. Subsequently, the selected type of medium was supplemented with cyclophosphamide, an alkylating anti-neoplastic prodrug that has demonstrated germ cell toxicity after its bioactivation in the liver, and added to chip-based co-cultures to replicate a human liver–testis systemic interaction in vitro. Single chip-based testicular organoids were used as a control. Experiments were performed with three biological replicates unless otherwise stated. PARTICIPANTS/MATERIALS, SETTING, METHODS The metabolic activity was determined as glucose consumption and lactate production. The cell viability was measured as lactate dehydrogenase activity in the medium. Additionally, immunohistochemical and real-time quantitative PCR end-point analyses were performed for apoptosis, proliferation and cell-specific phenotypical and functional markers. The functionality of Sertoli and Leydig cells in testicular spheroids was specifically evaluated by measuring daily inhibin B and testosterone release, respectively. MAIN RESULTS AND THE ROLE OF CHANCE Co-culture in multi-organ chips with liver spheroid-specific medium better supported the metabolic activity of the cultured tissues compared to other media tested. The liver spheroids did not show significantly different behaviour during co-culture compared to that in single culture on multi-organ-chips. The testicular organoids also developed accordingly and produced higher inhibin B but lower testosterone levels than the static culture in plates with testicular organoid-specific medium. By comparison, testosterone secretion by testicular organoids cultured individually on multi-organ-chips reached a similar level as the static culture at Day 7. This suggests that the liver spheroids have metabolised the steroids in the co-cultures, a naturally occurring phenomenon. The addition of cyclophosphamide led to upregulation of specific cytochromes in liver spheroids and loss of germ cells in testicular organoids in the multi-organ-chip co-cultures but not in single-testis culture. LARGE-SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION The number of biological replicates included in this study was relatively small due to the limited availability of individual donor testes and the labour-intensive nature of multi-organ-chip co-cultures. Moreover, testicular organoids and liver spheroids are miniaturised organ equivalents that capture key features, but are still simplified versions of the native tissues. Also, it should be noted that only the prodrug cyclophosphamide was administered. The final concentration of the active metabolite was not measured. WIDER IMPLICATIONS OF THE FINDINGS This co-culture model responds to the request of setting up a specific tool that enables the testing of candidate reprotoxic substances with the possibility of human biotransformation. It further allows the inclusion of other human tissue equivalents for chemical risk assessment on the systemic level. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by research grants from the Scientific Research Foundation Flanders (FWO), Universitair Ziekenhuis Brussel (scientific fund Willy Gepts) and the Vrije Universiteit Brussel. Y.B. is a postdoctoral fellow of the FWO. U.M. is founder, shareholder and CEO of TissUse GmbH, Berlin, Germany, a company commercializing the Multi-Organ-Chip platform systems used in the study. The other authors have no conflict of interest to declare.

PWID, especially active users, are underserved for DAA treatment in real life in Belgium. Reimbursement criteria based on fibrosis stage make it difficult to treat PWID. Treatment adherence is similar in PWID and the general population, even in patients with active abuse. DAA were safe and effective in PWID despite the higher prevalence of difficult-to-treat genotypes. Based on these data more efforts to treat PWID are needed and policy changes are necessary to reach the WHO targets.

Background: Considering social cognitive theory and current literature about successful advance care planning in nursing homes, sufficient knowledge and self-efficacy are important preconditions for staff to be able to carry out advance care planning in practice. Aim: Exploring to what extent nurses’ knowledge about and self-efficacy is associated with their engagement in advance care planning in nursing homes. Design: Survey study as part of a baseline measurement of a randomised controlled cluster trial (NCT03521206). Setting/participants: Nurses in a purposive sample of 14 nursing homes in Belgium. Methods: A survey was distributed among nurses, evaluating knowledge (11 true/false items), self-efficacy (12 roles and tasks on 10-point Likert-type scale) and six advance care planning practices (yes/no), ranging from performing advance care planning conversations to completing advance directives. Results: A total of 196 nurses participated (66% response rate). While knowledge was not significantly associated with advance care planning practices, self-efficacy was. One unit’s increase in self-efficacy was statistically associated with an estimated 32% increase in the number of practices having carried out. Conclusions: Nurses’ engagement in advance care planning practices is mainly associated with their self-efficacy rather than their knowledge. Further research is necessary to improve the evidence regarding the causal relationship between constructs. However, these results suggest that educational programmes that focus solely on knowledge might not lead to increasing uptake of advance care planning in nurses.

The multilevel model is increasingly used as a flexible tool in the statistical analysis of dependent behavioral research data. A drawback of this model's flexibility is that it complicates designing the study. For example, an important additional consideration in the design of a multilevel study is choosing the number and the size of the clusters to sample to ensure sufficient efficiency as quantified by precision, bias, or statistical power. To help researchers in designing their multilevel study, a user-friendly simulation tool is introduced (Multilevel Design Efficiency Using Simulation, or ML-DEs), also allowing for design questions that have not been dealt with analytically in the literature, while avoiding complex specifications of simulation studies. ML-DEs generates MLwiN macros for running the simulations and handles its output using R scripts to compare the designs' efficiencies for both fixed and random parameters, allowing for small sample sizes, unbalanced data, and more than two levels.Various designs of varying efficiency can be used to answer specific research questions. They may differ in many ways: in the amount of information they provide as quantified by, for example, the accuracy of estimation (Kelley & Maxwell, 2003) and/or the power for statistical testing (J. Cohen, 1988); or alternatively, in how many resources are required to obtain a certain amount of information. Carefully designing studies to be efficient is especially important for behavioral research, which often has to deal with small effects and considerable uncertainty about the estimates (Pillemer, 1984).Whereas it is well understood how to increase the design efficiency for simple models (Howell, 2005), for more complex models and their corresponding analyses this relation between design and efficiency becomes much less straightforward, as with, for example, multilevel data analyses (Snijders, 2005). The multilevel statistical model is increasingly used, because it elegantly takes into account dependencies among observations that exist because of multistage sampling, with sampled observations embedded within clusters; or because repeated measurements were performed, with a sequence of observations embedded within units. Similarly, meta-analyses and multivariate analyses can also be dealt with using multilevel analyses (Raudenbush, 1988;Van den Noortgate & Onghena, 2003.Multilevel design efficiency has already been studied analytically, as well as in simulation studies. Whereas the analytical studies only deal with quite simple models and imply several assumptions, the results of the simulation studies may be difficult to generalize about, because data are generated from a specific model and specific parameter values. In response to both problems, this article will present a user-friendly tool named Multilevel Design Efficiency Using Simulation (ML-DEs), which allows applied researchers to derive more efficient multilevel designs for their own research. Unlike existing programs that use analytical results, this tool will allow...

Background Brugada Syndrome is an inherited arrhythmogenic disease, characterized by the typical coved type ST-segment elevation in the right precordial leads from V1 through V3. The BrugadaDrugs.org Advisory Board recommends avoiding administration of propofol in patients with Brugada Syndrome. Since prospective studies are lacking, it was the purpose of this study to assess the electrocardiographic effects of propofol and etomidate on the ST- and QRS-segments. In this trial, it was hypothesized that administration of propofol or etomidate in bolus for induction of anesthesia, in patients with Brugada Syndrome, do not clinically affect the ST- and QRS-segments and do not induce arrhythmias. Methods In this prospective, double-blinded trial, 98 patients with established Brugada syndrome were randomized to receive propofol (2 to 3 mg/kg-1) or etomidate (0.2 to 0.3 mg/kg-1) for induction of anesthesia. The primary endpoints were the changes of the ST- and QRS-segment, and the occurrence of new arrhythmias upon induction of anesthesia. Results The analysis included 80 patients: 43 were administered propofol and 37 etomidate. None of the patients had a ST elevation greater than or equal to 0.2 mV, one in each group had a ST elevation of 0.15 mV. An ST depression up to −0.15mV was observed eleven times with propofol and five with etomidate. A QRS-prolongation of 25% upon induction was seen in one patient with propofol and three with etomidate. This trial failed to establish any evidence to suggest that changes in either group differed, with most percentiles being zero (median [25th, 75th], 0 [0, 0] vs. 0 [0, 0]). Finally, no new arrhythmias occurred perioperatively in both groups. Conclusions In this trial, there does not appear to be a significant difference in electrocardiographic changes in patients with Brugada syndrome when propofol versus etomidate were administered for induction of anesthesia. This study did not investigate electrocardiographic changes related to propofol used as an infusion for maintenance of anesthesia, so future studies would be warranted before conclusions about safety of propofol infusions in patients with Brugada syndrome can be determined. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

The MultiSCED web application has been developed to assist applied researchers in behavioral sciences to apply multilevel modeling to quantitatively summarize single-case experimental design (SCED) studies through a user-friendly point-andclick interface embedded within R. In this paper, we offer a brief introduction to the application, explaining how to define and estimate the relevant multilevel models and how to interpret the results numerically and graphically. The use of the application is illustrated through a re-analysis of an existing meta-analytic dataset. By guiding applied researchers through MultiSCED, we aim to make use of the multilevel modeling technique for combining SCED data across cases and across studies more comprehensible and accessible.