IMPORTANCE: Results of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium. OBJECTIVE: To determine whether ...prophylactic use of haloperidol improves survival among critically ill adults at high risk of delirium, which was defined as an anticipated intensive care unit (ICU) stay of at least 2 days. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled investigator-driven study involving 1789 critically ill adults treated at 21 ICUs, at which nonpharmacological interventions for delirium prevention are routinely used in the Netherlands. Patients without delirium whose expected ICU stay was at least a day were included. Recruitment was from July 2013 to December 2016 and follow-up was conducted at 90 days with the final follow-up on March 1, 2017. INTERVENTIONS: Patients received prophylactic treatment 3 times daily intravenously either 1 mg (n = 350) or 2 mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride. MAIN OUTCOME AND MEASURES: The primary outcome was the number of days that patients survived in 28 days. There were 15 secondary outcomes, including delirium incidence, 28-day delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay. RESULTS: All 1789 randomized patients (mean, age 66.6 years SD, 12.6; 1099 men 61.4%) completed the study. The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0-0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78-1.30, P=.82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, −3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0-0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0-0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 0.3% for the 2-mg haloperidol group vs 1 0.1% for the placebo group). CONCLUSIONS AND RELEVANCE: Among critically ill adults at high risk of delirium, the use of prophylactic haloperidol compared with placebo did not improve survival at 28 days. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically ill adults. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01785290
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission ...through the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2, as demonstrated by confocal and electron microscopy. Enterocytes produced infectious viral particles, whereas messenger RNA expression analysis of hSIOs revealed induction of a generic viral response program. Therefore, the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology.
Colour agnosia is a disorder that impairs colour knowledge (naming, recognition) despite intact colour perception. Previously, we have identified the first and only-known family with hereditary ...developmental colour agnosia. The aim of the current study was to explore genomic regions and candidate genes that potentially cause this trait in this family. For three family members with developmental colour agnosia and three unaffected family members CGH-array analysis and exome sequencing was performed, and linkage analysis was carried out using DominantMapper, resulting in the identification of 19 cosegregating chromosomal regions. Whole exome sequencing resulted in 11 rare coding variants present in all affected family members with developmental colour agnosia and absent in unaffected members. These variants affected genes that have been implicated in neural processes and functions (CACNA2D4, DDX25, GRINA, MYO15A) or that have an indirect link to brain function, development or disease (MAML2, STAU1, TMED3, RABEPK), and a remaining group lacking brain expression or involved in non-neural traits (DEPDC7, OR1J1, OR8D4). Although this is an explorative study, the small set of candidate genes that could serve as a starting point for unravelling mechanisms of higher level cognitive functions and cortical specialization, and disorders therein such as developmental colour agnosia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The use of microfluidics on synchrotron X-ray beamlines represents an advanced sample preparation and delivery platform for state-of-the-art X-ray characterization of micro-samples. The recent ...developments of 3D printing technologies have opened possibilities for rapid fabrication of complex microfluidic devices. One of the major challenges in 3D printing of microfluidic devices using a digital light processing (DLP) desktop printer is that the static liquid resin trapped in the channels, once the "ceiling" is printed, still receives small doses of light through the subsequently printed layers. This easily triggers partial polymerisation of the resin which impedes its flushing out of the channels after completion of the printing session. We show here that it is possible to gain better control over the resin polymerisation and improve the quality of the microfluidic devices by efficiently reducing the penetration depth of the UV LED light through wavelength selection combined with a careful choice of absorber and photo-initiator materials. We produced and tested several structures using a slightly modified desktop printer at 385 nm wavelength with 37 × 37 μm
2
pixel resolution at a printed layer thickness of 25 μm. The structures include particle filters, mixers, droplet generators and droplet storage traps with features below 100 μm. We demonstrate crystallisation of model inorganic and organic compounds in trapped droplets and assess the feasibility of in-device X-ray diffraction experiments. This research opens the path for the use of 3D printed microfluidic devices on X-ray beamlines.
Addition of a filter for wavelength selection enables accurate and rapid 3D printing of microfluidic devices on a DLP printer.
Purpose In a time of worldwide physician shortages, the advanced practice providers (APPs) might be a good alternative for physicians as the leaders of a rapid response team. This retrospective ...analysis aimed to establish whether the performance of APP-led rapid response teams is comparable to the performance of rapid response teams led by a medical resident of the ICU. Material and methods In a retrospective single-center cohort study, the electronic medical record of a tertiary hospital was queried during a 12-months period to identify patients who had been visited by our rapid response team. Patient- and process-related outcomes of interventions of rapid response teams led by an APP were compared with those of teams led by a medical resident using various parameters, including the MAELOR tool, which measures the performance of a rapid response team. Results In total, 179 responses of the APP-led teams were analyzed, versus 275 responses of the teams led by a resident. Per APP, twice as many calls were handled than per resident. Interventions of teams led by APPs, and residents did not differ in number of admissions (p = 0.87), mortality (p = 0.8), early warning scores (p = 0.2) or MAELOR tool triggering (p = 0.19). Both groups scored equally on time to admission (p = 0.67) or time until any performed intervention. Conclusion This retrospective analysis showed that the quality of APP-led rapid response teams was similar to the quality of teams led by a resident. These findings need to be confirmed by prospective studies with balanced outcome parameters.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transcatheter aortic valve implantation (TAVI) is invariably associated with the risk of clinically manifest transient or irreversible neurologic impairment. We sought to investigate the incidence ...and causes of clinically manifest stroke during TAVI. A total of 214 consecutive patients underwent TAVI with the Medtronic-CoreValve System from November 2005 to September 2011 at our institution. Stroke was defined according to the Valve Academic Research Consortium recommendations. Its cause was established by analyzing the point of onset of symptoms, correlating the symptoms with the computed tomography-detected defects in the brain, and analyzing the presence of potential coexisting causes of stroke, in addition to a multivariate analysis to determine the independent predictors. Stroke occurred in 19 patients (9%) and was major in 10 (5%), minor in 3 (1%), and transient (transient ischemic attack) in 6 (3%). The onset of symptoms was early (≤24 hours) in 8 patients (42%) and delayed (>24 hours) in 11 (58%). Brain computed tomography showed a cortical infarct in 8 patients (42%), a lacunar infarct in 5 (26%), hemorrhage in 1 (5%), and no abnormalities in 5 (26%). Independent determinants of stroke were new-onset atrial fibrillation after TAVI (odds ratio 4.4, 95% confidence interval 1.2 to 15.6), and baseline aortic regurgitation grade III or greater (odds ratio 3.2, 95% confidence interval 1.1 to 9.3). In conclusion, the incidence of stroke was 9%, of which >1/2 occurred >24 hours after the procedure. New-onset atrial fibrillation was associated with a 4.4-fold increased risk of stroke. In conclusion, these findings indicate that improvements in postoperative care after TAVI are equally, if not more, important for the reduction of periprocedural stroke than preventive measures during the procedure.
Abstract
Background
The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death ...in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury.
Methods
This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (
n
= 6) and bacterial sepsis (
n
= 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (
n
= 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3–4 days for bacterial sepsis patients.
Results
We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42,
p
= 0.0002) and bacterial sepsis patients (fold change 0.24,
p
< 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3,
p
= 0.0006, PV-1 fold change 1.5,
p
= 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27,
p
< 0.0001) and bacterial sepsis patients (fold change 0.67,
p
< 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33,
p
= 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09,
p
< 0.0001) suggest decreased microvascular flow in COVID-19.
Conclusions
In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.
The long-term ecological effects on the emergence of antimicrobial resistance at the ICU level during selective decontamination of the digestive tract (SDD) are unknown. We determined the incidence ...of newly acquired antimicrobial resistance of aerobic gram-negative potentially pathogenic bacteria (AGNB) during SDD.
In a single-centre observational cohort study over a 21-year period, all consecutive patients, treated with or without SDD, admitted to the ICU were included. The antibiotic regime was unchanged over the study period. Incidence rates for ICU-acquired AGNB's resistance for third-generation cephalosporins, colistin/polymyxin B, tobramycin/gentamicin or ciprofloxacin were calculated per year. Changes over time were tested by negative binomial regression in a generalized linear model.
Eighty-six percent of 14,015 patients were treated with SDD. Most cultures were taken from the digestive tract (41.9%) and sputum (21.1%). A total of 20,593 isolates of AGNB were identified. The two most often found bacteria were Escherichia coli (N = 6409) and Pseudomonas (N = 5269). The incidence rate per 1000 patient-day for ICU-acquired resistance to cephalosporins was 2.03, for polymyxin B/colistin 0.51, for tobramycin 2.59 and for ciprofloxacin 2.2. The incidence rates for ICU-acquired resistant microbes per year ranged from 0 to 4.94 per 1000 patient-days, and no significant time-trend in incidence rates were found for any of the antimicrobials. The background prevalence rates of resistant strains measured on admission for cephalosporins, polymyxin B/colistin and ciprofloxacin rose over time with 7.9%, 3.5% and 8.0% respectively.
During more than 21-year SDD, the incidence rates of resistant microbes at the ICU level did not significantly increase over time but the background resistance rates increased. An overall ecological effect of prolonged application of SDD by counting resistant microorganisms in the ICU was not shown in a country with relatively low rates of resistant microorganisms.
The aim of this study was to investigate whether in-hospital mortality was associated with the administered fraction of oxygen in inspired air (FiO2) and achieved arterial partial pressure of oxygen ...(PaO2).
This was a retrospective, observational study on data from the first 24 h after admission from 36,307 consecutive patients admitted to 50 Dutch intensive care units (ICUs) and treated with mechanical ventilation. Oxygenation data from all admission days were analysed in a subset of 3,322 patients in 5 ICUs.
Mean PaO2 and FiO2 in the first 24 h after ICU admission were 13.2 kPa (standard deviation (SD) 6.5) and 50% (SD 20%) respectively. Mean PaO2 and FiO2 from all admission days were 12.4 kPa (SD 5.5) and 53% (SD 18). Focusing on oxygenation in the first 24 h of admission, in-hospital mortality was shown to be linearly related to FiO2 value and had a U-shaped relationship with PaO2 (both lower and higher PaO2 values were associated with a higher mortality), independent of each other and of Simplified Acute Physiology Score (SAPS) II, age, admission type, reduced Glasgow Coma Scale (GCS) score, and individual ICU. Focusing on the entire ICU stay, in-hospital mortality was independently associated with mean FiO2 during ICU stay and with the lower two quintiles of mean PaO2 value during ICU stay.
Actually achieved PaO2 values in ICU patients in The Netherlands are higher than generally recommended in the literature. High FiO2, and both low PaO2 and high PaO2 in the first 24 h after admission are independently associated with in-hospital mortality in ICU patients. Future research should study whether this association is causal or merely a reflection of differences in severity of illness insufficiently corrected for in the multivariate analysis.
In patients with ESRD, the effects of online hemodiafiltration on all-cause mortality and cardiovascular events are unclear. In this prospective study, we randomly assigned 714 chronic hemodialysis ...patients to online postdilution hemodiafiltration (n=358) or to continue low-flux hemodialysis (n=356). The primary outcome measure was all-cause mortality. The main secondary endpoint was a composite of major cardiovascular events, including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, therapeutic coronary intervention, therapeutic carotid intervention, vascular intervention, or amputation. After a mean 3.0 years of follow-up (range, 0.4-6.6 years), we did not detect a significant difference between treatment groups with regard to all-cause mortality (121 versus 127 deaths per 1000 person-years in the online hemodiafiltration and low-flux hemodialysis groups, respectively; hazard ratio, 0.95; 95% confidence interval, 0.75-1.20). The incidences of cardiovascular events were 127 and 116 per 1000 person-years, respectively (hazard ratio, 1.07; 95% confidence interval, 0.83-1.39). Receiving high-volume hemodiafiltration during the trial associated with lower all-cause mortality, a finding that persisted after adjusting for potential confounders and dialysis facility. In conclusion, this trial did not detect a beneficial effect of hemodiafiltration on all-cause mortality and cardiovascular events compared with low-flux hemodialysis. On-treatment analysis suggests the possibility of a survival benefit among patients who receive high-volume hemodiafiltration, although this subgroup finding requires confirmation.
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