Perspectives of ICU Patients on Deferred Consent in the Context of Post-ICU Quality of Life: A Substudy of a Randomized Clinical Trial.

OBJECTIVES: Deferred consent enables research to be conducted in the ICU when patients are unable to provide consent themselves, and there is insufficient time to obtain consent from surrogates before commencing (trial) treatment. The aim of this study was to evaluate how former ICU patients reflect on their participation in a study with deferred consent and examine whether their opinions are influenced by the quality of life (QoL) following hospital discharge. DESIGN: Survey study by questionnaire. SETTING: Eight ICUs in The Netherlands. PATIENTS: Former ICU patients who participated in the ICONIC trial, a multicenter randomized clinical trial that evaluated oxygenation targets in mechanically ventilated ICU patients. INTERVENTIONS: Participants enrolled in the ICONIC trial in one of the eight participating centers in The Netherlands received a questionnaire 6 months after randomization. The questionnaire included 12 close-ended questions on their opinion about the deferred consent procedure. QoL was measured using the EQ-5D-5L questionnaire. By calculating the EQ-5D index, patients were divided into four QoL quartiles, where Q1 reflects the lowest and Q4 is the highest. MEASUREMENTS AND MAIN RESULTS: Of 362 participants who were contacted, 197 responded (54%). More than half of the respondents (59%) were unaware of their participation in the ICONIC study. In total 61% were content with the deferred consent procedure, 1% were not content, 25% neutral, 9% did not know, and 9% answered "other." Those with a higher QoL were more likely to be content ( p = 0.02). In all QoL groups, the legal representative was the most often preferred individual to provide consent. CONCLUSIONS: Former ICU patients who participated in the ICONIC study often did not remember their participation but were predominantly positive regarding the use of deferred consent. Those with a higher QoL were most likely to be content.

Conservative versus Liberal Oxygenation Targets in Intensive Care Unit Patients (ICONIC): A Randomized Clinical Trial.

Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear. Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy. Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (PaO2, 55-80 mm Hg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (PaO2, 110-150 mm Hg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included. Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved PaO2 was 75 mm Hg (interquartile range, 70-84) and 115 mm Hg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively. Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Clinical trial registered with the National Trial Register and the International Clinical Trials Registry Platform (NTR7376).

ICONIC study-conservative versus conventional oxygenation targets in intensive care patients: study protocol for a randomized clinical trial.

BACKGROUND: Oxygen therapy is a widely used intervention in acutely ill patients in the intensive care unit (ICU). It is established that not only hypoxia, but also prolonged hyperoxia is associated with poor patient-centered outcomes. Nevertheless, a fundamental knowledge gap remains regarding optimal oxygenation for critically ill patients. In this randomized clinical trial, we aim to compare ventilation that uses conservative oxygenation targets with ventilation that uses conventional oxygen targets with respect to mortality in ICU patients. METHODS: The "ConservatIve versus CONventional oxygenation targets in Intensive Care patients" trial (ICONIC) is an investigator-initiated, international, multicenter, randomized clinical two-arm trial in ventilated adult ICU patients. The ICONIC trial will run in multiple ICUs in The Netherlands and Italy to enroll 1512 ventilated patients. ICU patients with an expected mechanical ventilation time of more than 24 h are randomized to a ventilation strategy that uses conservative (PaO2 55-80 mmHg (7.3-10.7 kPa)) or conventional (PaO2 110-150 mmHg (14.7-20 kPa)) oxygenation targets. The primary endpoint is 28-day mortality. Secondary endpoints are ventilator-free days at day 28, ICU mortality, in-hospital mortality, 90-day mortality, ICU- and hospital length of stay, ischemic events, quality of life, and patient opinion of research and consent in the emergency setting. DISCUSSION: The ICONIC trial is expected to provide evidence on the effects of conservative versus conventional oxygenation targets in the ICU population. This study may guide targeted oxygen therapy in the future. TRIAL REGISTRATION: Trialregister.nl NTR7376 . Registered on 20 July, 2018.

Clinical and computed tomography characteristics of COVID-19 associated acute pulmonary embolism: A different phenotype of thrombotic disease?

INTRODUCTION: COVID-19 infections are associated with a high prevalence of venous thromboembolism, particularly pulmonary embolism (PE). It is suggested that COVID-19 associated PE represents in situ immunothrombosis rather than venous thromboembolism, although the origin of thrombotic lesions in COVID-19 patients remains largely unknown. METHODS: In this study, we assessed the clinical and computed tomography (CT) characteristics of PE in 23 consecutive patients with COVID-19 pneumonia and compared these to those of 100 consecutive control patients diagnosed with acute PE before the COVID-19 outbreak. Specifically, RV/LV diameter ratio, pulmonary artery trunk diameter and total thrombus load (according to Qanadli score) were measured and compared. RESULTS: We observed that all thrombotic lesions in COVID-19 patients were found to be in lung parenchyma affected by COVID-19. Also, the thrombus load was lower in COVID-19 patients (Qanadli score -8%, 95% confidence interval [95%CI] -16 to -0.36%) as was the prevalence of the most proximal PE in the main/lobar pulmonary artery (17% versus 47%; -30%, 95%CI -44% to -8.2). Moreover, the mean RV/LV ratio (mean difference -0.23, 95%CI -0.39 to -0.07) and the prevalence of RV/LV ratio >1.0 (prevalence difference -23%, 95%CI -41 to -0.86%) were lower in the COVID-19 patients. CONCLUSION: Our findings therefore suggest that the phenotype of COVID-19 associated PE indeed differs from PE in patients without COVID-19, fuelling the discussion on its pathophysiology.

Increasing the activity of copper exchanged mordenite in the direct isothermal conversion of methane to methanol by Pt and Pd doping.

PtCu- and PdCu-mordenite allow for isothermal reaction at 200 °C for the stepwise methane to methanol conversion with comparably high yields. In contrast to traditional Cu-zeolites, these materials are more reactive under isothermal conditions than after high temperature activation.

[The development of a treatment program for violent forensic psychiatric patients with a cluster B personality disorder]. / De ontwikkeling van een behandelprogramma voor gewelddadige forensisch psychiatrische patiënten met een cluster B-persoonlijkheidsstoornis.

BACKGROUND: Very few articles have been published in professional journals concerning the design, content, and results of treatment programs for violent forensic psychiatric patients in the Netherlands. AIM: To describe the development of a treatment program for forensic psychiatric patients with a cluster B personality disorder. In this program a treatment for aggression was combined with a treatment for substance abuse. METHOD: Clinical findings obtained with both treatments are discussed, followed by a description of new modules that were added because of recent research results. results The combined treatment program targets the principal dynamic factors that cause individuals to display criminal behaviour. CONCLUSION: Empirical research is needed in order to find out whether the treatment as a whole produces better results than the two treatments administered separately.

Cognitive problems in patients in a cardiac rehabilitation program after an out-of-hospital cardiac arrest.

OBJECTIVE: Estimate prevalence of cognitive problems due to hypoxic brain injury in out-of-hospital cardiac arrest (OHCA) survivors referred for cardiac rehabilitation and association with quality of life as well as autonomy and participation. DESIGN: Prospective cohort study. METHOD/DESIGN: Consecutive OHCA patients. The Mini-Mental State Examination (MMSE), Cognitive Failures Questionnaire (CFQ) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were administered 4 weeks after the OHCA. Cognitive problems were defined if MMSE <28, CFQ >32 or IQCODE >3.6. The Impact on Participation and Autonomy Questionnaire (IPAQ) (participation/autonomy), the SF-36 Health Survey (SF-36) (quality of life) and the Hospital Anxiety Depression Scale (HADS) (anxiety/depression) were administered. Correlations between cognitive problems and participation/autonomy and quality of life were calculated. RESULTS: 63 of 77 patients were male (82%), median age 59 years (range 15-84). MMSE median 29 (interquartile range 28-30), CFQ mean 20.9 (SD 9.4) and IQCODE mean 3.1 (SD 0.2). Eighteen patients (23%) scored positive for cognitive problems. Significant correlations were found between MMSE and IPAQ: autonomy inside (r = -0.38), family role (r = -0.26), autonomy outside (r = -0.32), social relations (r = -0.38) and social functioning (r = 0.32). MMSE was related to SF-36: social functioning (r = 0.32). The CFQ was related to IPAQ: autonomy outdoors (r = 0.29) and SF-36: bodily pain (r = -0.37), vitality (r = -0.25), mental health (r = -0.35) and role emotional (r = -0.40). The IQCODE was related to IPAQ: autonomy indoors (r = 0.26) and to SF-36: vitality (r = -0.33) and social functioning (r = -0.41). CONCLUSION: Twenty-three percent of the patients referred for cardiac rehabilitation showed cognitive problems. Associations were found between cognitive problems and several aspects of participation/autonomy and perceived quality of life.

Angle-dependent backscatter from the arterial wall.

The anisotropic nature of intra-arterial echographic images is reported, and the source of this anisotropy is investigated using postmortem human iliac arteries. A 27 MHz transducer, mounted on an ultrasonic microscope, is used to quantify the angular dependence of the backscatter power versus the angle of incidence, and these results are correlated with histological findings. Besides the observed differences in the acoustic response of morphologically different tissues, significant variations in backscatter power are found in both media and internal elastic lamina due to variations in the angle of incidence. This angle dependence is caused by the dominant orientation of fibers in tissue layers and by the shape and size various scattering particles. The results indicate that long microscopic structures with one main orientation are responsible for the backscattered signal and that the angular-dependent response is related to the histologically determined orientation of these fibers. These results may have an impact on the assessment of intra-arterial echographic images.

Solid phase microextraction as a tool to predict internal concentrations of soil contaminants in terrestrial organisms after exposure to a laboratory standard soil.

Uptake and accumulation of three chlorobenzenes was studied in both biota (Enchytraeus crypticus) and 30 mum polydimethylsiloxane (PDMS) solid phase microextraction (SPME) fibers after exposure to spiked OECD soil. The OECD soil was spiked with three different concentrations of all contaminants. Uptake of all three chlorobenzenes in E. crypticus was fast and steady state levels were reached within 2-4 days. Also in the PDMS-SPME fibers uptake was very fast for all three compounds, with steady state levels reached after 1 day. Comparison of steady state levels in biota and in the PDMS-SPME fibers showed a relationship which was consistent over the range of concentrations of chlorobenzenes in soil and the difference in logKow. This shows that measuring the concentrations of hydrophobic chemicals in a hydrophobic phase such as PDMS can be used as a simple tool to estimate internal concentrations of these chemicals in biota exposed to complex matrices such as soil.

Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis.

Cytotoxic lymphocyte protease granzyme M (GrM) is a potent inducer of tumor cell death. The apoptotic phenotype and mechanism by which it induces cell death, however, remain poorly understood and controversial. Here, we show that GrM-induced cell death was largely caspase-dependent with various hallmarks of classical apoptosis, coinciding with caspase-independent G2/M cell cycle arrest. Using positional proteomics in human tumor cells, we identified the nuclear enzyme topoisomerase II alpha (topoIIα) as a physiological substrate of GrM. Cleavage of topoIIα by GrM at Leu(1280) separated topoIIα functional domains from the nuclear localization signals, leading to nuclear exit of topoIIα catalytic activity, thereby rendering it nonfunctional. Similar to the apoptotic phenotype of GrM, topoIIα depletion in tumor cells led to cell cycle arrest in G2/M, mitochondrial perturbations, caspase activation, and apoptosis. We conclude that cytotoxic lymphocyte protease GrM targets topoIIα to trigger cell cycle arrest and caspase-dependent apoptosis.

Controlled release of theophylline monohydrate from amylodextrin tablets: in vitro observations.

Amylodextrin is a linear dextrin and can be produced by enzymatic hydrolysis of the alpha-1,6 glycosidic bonds of amylopectin. Tablets compacted from pure amylodextrin showed good binding properties and did not disintegrate in aqueous media. Extended and decreasing drug release rates were found for tablets of 300 mg with a diameter of 9 mm containing 70% amylodextrin and 30% theophylline monohydrate, when compacted at 5 kN. Almost-constant drug release rates were obtained for these tablets when compacted at 10 or 15 kN. Nearly constant drug release rates were also shown for amylodextrin tablets with a drug load up to 75% compacted at 10 kN. Both release rate and release profile could be adjusted by selecting tablet thickness and incorporation of either lactose as a highly soluble excipient or talc as a hydrophobic excipient.

Backscatter directivity and integrated backscatter power of arterial tissue.

A 27 MHz transducer, mounted on an ultrasonic microscope, was used to quantify the dependence of backscatter power on the angle of incidence of arterial vessels. Due to variations in the angle of incidence significant variations in backscatter power were found in the intima, the muscular and elastic media, the adventitia and the external elastic lamina. The muscular and the elastic media show anisotropic behaviour in their angle dependence, i.e. the extent of the angle dependence depends on the direction of angle variation. This anisotropic nature is probably caused by the dominant orientation of smooth muscle cells or elastin fibers in these tissue layers. Measurements on 13 specimens of the iliac artery showed that each tissue type of the vessel has its own specific angle dependent behaviour. In the future this property might be used for quantitative tissue characterization.

Determination of polycyclic aromatic hydrocarbons (PAH) and their metabolites in blood, feces, and urine of rats orally exposed to PAH contaminated soils.

Polycyclic aromatic hydrocarbons (PAH) have become an ubiquitous upper soil component as a consequence of industrialization involving a multitude of combustion processes. Ingestion of PAH contaminated soil is considered to be a major exposure route, specifically for small children living on these soils. Health risk assessment is based on extrapolations from data obtained via studies performed with pure chemicals. Additionally it is assumed that after oral intake all PAH present in the soil will be absorbed by the human body. Interactions with the soil matrix, however, may modulate the bioavailability of PAH. In this study, we examined the absorption and excretion of PAH in rats orally exposed either to industrially contaminated soils or pure model compounds as anthracene, pyrene and benzo(a)pyrene (B[a]P). The model compounds and the metabolites, 1-hydroxypyrene (1-OH-pyrene) and 3-hydroxybenzo(a)pyrene (3-OH-B[a]P), were measured in blood, feces or urine by means of HPLC with fluorescence detection. Because of rapid biotransformation only minimal levels of unmetabolized anthracene, pyrene and B[a]P in blood could be detected. The pharmacokinetic parameters were nonlinear and suggestive of enterohepatic cycling. Only low levels of the compounds were excreted unchanged in feces whereas the levels of the metabolites were considerably higher in feces and urine. These results indicate that the dosed PAH are largely absorbed by the gastrointestinal tract, subsequently metabolized and excreted as metabolites via urine and feces. Significant differences between the soil-treated group and the pure mixture-treated group could be observed; the soil-treated group showed higher fecal excretion of unchanged pyrene (0.5 versus 0.2% of the original dose) and B[a]P (1 versus 0.3%), lower excretion of 1-OH-pyrene in feces (5.1 versus 17. 0%), and lower excretion of 1-OH-pyrene in urine (0.2 versus 3.4%). The fecal excretion of 3-OH-B[a]P between the two groups was similar (8.8 versus 8.8%). These results suggest that the soil matrix is capable of reducing the absorption of at least pyrene. Therefore, exposure risk assessment models assuming complete bioavailability of soilmatrix-bound PAH probably overestimate the endogenous dose.