BACKGROUNDThe appropriate oxygenation target for mechanical ventilation in comatose survivors of out-of-hospital cardiac arrest is unknown. METHODSIn this randomized trial with a 2-by-2 factorial design, we randomly assigned comatose adults with out-of-hospital cardiac arrest in a 1:1 ratio to either a restrictive oxygen target of a partial pressure of arterial oxygen (Pao 2 ) of 9 to 10 kPa (68 to 75 mm Hg) or a liberal oxygen target of a Pao 2 of 13 to 14 kPa (98 to 105 mm Hg); patients were also assigned to one of two blood-pressure targets (reported separately). The primary outcome was a composite of death from any cause or hospital discharge with severe disability or coma (Cerebral Performance Category [CPC] of 3 or 4; categories range from 1 to 5, with higher values indicating more severe disability), whichever occurred first within 90 days after randomization. Secondary outcomes were neuron-specific enolase levels at 48 hours, death from any cause, the score on the Montreal Cognitive Assessment (ranging from 0 to 30, with higher scores indicating better cognitive ability), the score on the modified Rankin scale (ranging from 0 to 6, with higher scores indicating greater disability), and the CPC at 90 days. RESULTSA total of 789 patients underwent randomization. A primary-outcome event occurred in 126 of 394 patients (32.0%) in the restrictive-target group and in 134 of 395 patients (33.9%) in the liberal-target group (hazard ratio, 0.95; 95% confidence interval, 0.75 to 1.21; P = 0.69). At 90 days, death had occurred in 113 patients (28.7%) in the restrictive-target group and in 123 (31.1%) in the liberal-target group. On the CPC, the median category was 1 in the two groups; on the modified Rankin scale, the median score was 2 in the restrictive-target group and 1 in the liberaltarget group; and on the Montreal Cognitive Assessment, the median score was 27 in the two groups. At 48 hours, the median neuron-specific enolase level was 17 μg per liter in the restrictive-target group and 18 μg per liter in the liberaltarget group. The incidence of adverse events was similar in the two groups. CONCLUSIONSTargeting of a restrictive or liberal oxygenation strategy in comatose patients after resuscitation for cardiac arrest resulted in a similar incidence of death or severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials .gov number, NCT03141099.

51 biopsies from healthy and diseased epithelium from human urinary bladders were examined by scanning electron microscopy. The luminal surface of the cover cells was marked by microvilli and microplicae. The replacement of the cover cells takes place by simple desquamination. This exposes cover cells having numerous microvilli, and these later develop characteristic microplicae. The ability to form cover cells is lost by the transitional epithelium following tumour formation. No tumour-specific surface morphology was observed.

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Background and objectives:Electroencephalography (EEG) is widely used for prediction of neurological outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explore the association between EEG and neurofilament light (NFL) as a marker of neuroaxonal injury. We evaluate whether highly malignant EEG patterns are reflected by high NFL levels. Additionally, we explore the association of EEG backgrounds and EEG discharges with NFL.Methods:Post-hoc analysis of the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours post-arrest. Patients who awoke or died prior to 36 hours post-arrest were excluded. EEG-experts blinded to clinical information classified EEG background, amount of discharges and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NFL after trial completion. The highest available concentration at 48 or 72-hours post-arrest was used.Results:262/939 patients with EEG and NFL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NFL levels than patients with malignant patterns and NFL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI: 1.4-6.1 and 6.5-26.2 respectively, effect size 0.47, p<0.001). Both background and the amount of discharges were independently strongly associated with NFL levels (p<0.001). The EEG background had a stronger association with NFL levels than EEG discharges (R2=0.30 and R2=0.10, respectively). NFL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression and suppression, respectively: 2.26-18.06, 3.91-41.71 and 5.74-41.74, effect size 0.30 and p<0.001 for all). NFL levels did not differ between suppression and burst-suppression. Superimposed discharges were only associated with higher NFL levels if the EEG background was continuous.Discussion:Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NFL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NFL may be useful to better identify patients misclassified by single methods.Clinical Trials Registration Number:clinicaltrials.gov, NCT01020916

The ultrastructure of the dermo-epidermal junctional area in biopsy material from 5 patients suffering from lichen planus has been studied during treatment with steroids. Tannic acid was used on the tissue blocks in order to provide high and diversified contrast for electron microscopy. The changes observed in the basal cells consisted mainly of degeneration of the mitochondria and disorganization of the tonofilaments. No ultrastructural changes were seen in the basal lamina, apart from occasional gaps, whose significance for pigment incontinence in old lichen planus lesions is discussed. Cellular infiltration was seen in the dermis, while the ultrastructure of the collagen fibrils of the papillary layer was normal. It is suggested that degeneration of mitochondria with subsequent disturbance of the organization and fixation of tonofilaments are events in the pathogenesis of the condition.

Background Quantitative pupillometry is part of multimodal neuroprognostication of comatose patients after out-of-hospital cardiac arrest (OHCA). However, the reproducibility, repeatability, and reliability of quantitative pupillometry in this setting have not been investigated. Methods In a prospective blinded validation study, we compared manual and quantitative measurements of pupil size. Observer and device variability for all available parameters are expressed as mean difference (bias), limits of agreement (LoA), and reliability expressed as intraclass correlation coefficients (ICC) with a 95% confidence interval. Results Fifty-six unique quadrupled sets of measurement derived from 14 sedated and comatose patients (mean age 70±12 years) were included. For manually measured pupil size, inter-observer bias was -0.14±0.44 mm, LoA of -1.00 to 0.71 mm, and ICC at 0.92 (0.86–0.95). For quantitative pupillometry, we found bias at 0.03±0.17 mm, LoA of -0.31 to 0.36 mm and ICCs at 0.99. Quantitative pupillometry also yielded lower bias and LoA and higher ICC for intra-observer and inter-device measurements. Correlation between manual and automated pupillometry was better in larger pupils, and quantitative pupillometry had less variability and higher ICC, when assessing small pupils. Further, observers failed to detect 26% of the quantitatively estimated abnormal reactivity with manual assessment. We found ICC >0.91 for all quantitative pupillary response parameters (except for latency with ICC 0.81–0.91). Conclusion Automated quantitative pupillometry has excellent reliability and twice the reproducibility and repeatability than manual pupillometry. This study further presents novel estimates of variability for all quantitative pupillary response parameters with excellent reliability.

In a systematic study of bladders from consecutively cystectomized patients, 40 primary urinary bladder carcinomas were examined with regard to the type of differentiation. Metaplastic areas were found in 24 of the tumours. A positive reaction of keratin to Kreybergs stain was required for the definition squamous metaplasia. Squamous areas were found in 16 of the tumours. In 4 tumours there was, in addition to squamos metaplasia, glandular metaplasia which was defined as definite glandular tissue with dysplasia of the epithelium. In 4 tumours, glandular metaplasia was also present in addition to the urothelial carcinoma. In 18 cases, metaplastic changes were present in the luminal portion of the tumour from which the biopsy material and desqaminated material originated. The occurrence of metaplasia was related to the degree of differentiation of the urothelial part of the tumour. Metaplastic changes were most frequent in the poorly differentiated tumours. The biopsies obtained pre‐operatively permitted of the diagnosis metaplasia being made in 15 cases, while the cytological material suggested metaplastic changes in 4 cases only. The biological function of metaplasia is unknown. The possibility that these areas will react differently to radiation and chemotherapy is present and the frequency of such changes would suggest that their importance should be studied by their registration as mixed forms as stated by WHO.

Background Cardiac arrest (CA) represents the third leading cause of death worldwide. Among patients resuscitated and admitted to hospital, death and severe neurological sequelae are frequent but difficult to predict. Blood biomarkers offer clinicians the potential to improve prognostication. Previous studies suggest that circulating non-coding RNAs constitute a reservoir of novel biomarkers. Therefore, this study aims to identify circulating circular RNAs (circRNAs) associated with clinical outcome after CA. Results Whole blood samples obtained 48 h after return of spontaneous circulation in 588 survivors from CA enrolled in the Target Temperature Management trial (TTM) were used in this study. Whole transcriptome RNA sequencing in 2 groups of 23 sex-matched patients identified 28 circRNAs associated with neurological outcome and survival. The circRNA circNFAT5 was selected for further analysis using quantitative PCR. In the TTM-trial (n = 542), circNFAT5 was upregulated in patients with poor outcome as compared to patients with good neurological outcome (p < 0.001). This increase was independent of TTM regimen and sex. The adjusted odds ratio of circNFAT5 to predict neurological outcome was 1.39 [1.07–1.83] (OR [95% confidence interval]). CircNFAT5 predicted 6-month survival with an adjusted hazard ratio of 1.31 [1.13–1.52]. Conclusion We identified circulating circRNAs associated with clinical outcome after CA, among which circNFAT5 may have potential to aid in predicting neurological outcome and survival when used in combination with established biomarkers of CA.