Point of care coagulometry in prehospital emergency care: an observational study

Background: Haemostatic impairment can have a crucial impact on the outcome of emergency patients, especially in cases of concomitant antithrombotic drug treatment. In this prospective observational study we used a point of care (POC) coagulometer in a prehospital physician-based emergency medical system in order to test its validity and potential value in the treatment of emergency patients. Methods: During a study period of 12 months, patients could be included if venous access was mandatory for further treatment. The POC device CoaguChek® was used to assess international normalized ratio (INR) after ambulance arrival at the scene. Results were compared with in-hospital central laboratory assessment of INR. The gain of time was analysed as well as the potential value of POC testing through a questionnaire completed by the responsible prehospital emergency physician. Results: A total of 103 patients were included in this study. POC INR results were highly correlated with results of conventional assessment of INR (Bland-Altman-bias: 0.014). Using a cutoff value of INR >1.3, the device’s sensitivity to detect coagulopathy was 100 % with a specificity of 98.7 %. The median gain of time was 69 min. Treating emergency physicians considered the value of prehospital POC INR testing ‘high’ in 9 % and ‘medium’ in 21 % of all patients. In patients with tracer diagnosis ‘neurology’, the value of prehospital INR assessment was considered ‘high’ or ‘medium’ (63 %) significantly more often than in patients with non-neurological tracer diagnoses (24 %). Conclusions: Assessment of INR through a POC coagulometer is feasible in prehospital emergency care and provides valuable information on haemostatic parameters in patients. Questionnaire results suggest that POC INR testing may present a valuable technique in selected patients. Whether this information translates into an improved management of respective patients has to be evaluated in further studies

EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations

To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation. Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity. Thirteen out of 27 CA-medication exposure signals, based on 389 exposed cases, passed data validation. There was some prior evidence in the literature to support six signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining six signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists. Signals which strengthened prior evidence should be prioritized for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible

Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells

Proton pump inhibitors (PPI) target tumour acidic pH and have an antineoplastic effect in melanoma. The PPI esomeprazole (ESOM) kills melanoma cells through a caspase-dependent pathway involving cytosolic acidification and alkalinization of tumour pH. In this paper, we further investigated the mechanisms of ESOM-induced cell death in melanoma. ESOM rapidly induced accumulation of reactive oxygen species (ROS) through mitochondrial dysfunctions and involvement of NADPH oxidase. The ROS scavenger N-acetyl--cysteine (NAC) and inhibition of NADPH oxidase significantly reduced ESOM-induced cell death, consistent with inhibition of cytosolic acidification. Autophagy, a cellular catabolic pathway leading to lysosomal degradation and recycling of proteins and organelles, represents a defence mechanism in cancer cells under metabolic stress. ESOM induced the early accumulation of autophagosomes, at the same time reducing the autophagic flux, as observed by WB analysis of LC3-II accumulation and by fluorescence microscopy. Moreover, ESOM treatment decreased mammalian target of rapamycin signalling, as reduced phosphorylation of p70-S6K and 4-EBP1 was observed. Inhibition of autophagy by knockdown of Atg5 and Beclin-1 expression significantly increased ESOM cytotoxicity, suggesting a protective role for autophagy in ESOM-treated cells. The data presented suggest that autophagy represents an adaptive survival mechanism to overcome drug-induced cellular stress and cytotoxicity, including alteration of pH homeostasis mediated by proton pump inhibition

Health-Related Quality of Life is Linked to the Gut Microbiome in Kidney Transplant Recipients

Kidney transplant recipients (KTR) have impaired health-related quality of life (HRQoL) and suffer from intestinal dysbiosis. Increasing evidence shows that gut health and HRQoL are tightly related in the general population. We investigated the association between the gut microbiome and HRQoL in KTR, using metagenomic sequencing data from fecal samples collected from 507 KTR. Multiple bacterial species were associated with lower HRQoL, many of which have previously been associated with adverse health conditions. Gut microbiome dissimilarity to the general population was highest among KTR with an impaired physical HRQoL (R=-0.20, P=2.3x10-5) and mental HRQoL (R=-0.14, P=1.3x10-3). Physical and mental HRQoL explained a significant part of the variance in the gut microbiome (R2=0.63%, FDR=5.40x10-4 and R2=0.37%, FDR=1.40x10-3, respectively). Additionally, multiple metabolic and neuroactive pathways (gut brain modules) were associated with lower HRQoL. These results put forward the microbiome as a potential target to improve HRQoL in KTR

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

Adaptation, spread and transmission of SARS-CoV-2 in farmed minks and associated humans in the Netherlands

In the first wave of the COVID-19 pandemic (April 2020), SARS-CoV-2 was detected in farmed minks and genomic sequencing was performed on mink farms and farm personnel. Here, we describe the outbreak and use sequence data with Bayesian phylodynamic methods to explore SARS-CoV-2 transmission in minks and humans on farms. High number of farm infections (68/126) in minks and farm workers (>50% of farms) were detected, with limited community spread. Three of five initial introductions of SARS-CoV-2 led to subsequent spread between mink farms until November 2020. Viruses belonging to the largest cluster acquired an amino acid substitution in the receptor binding domain of the Spike protein (position 486), evolved faster and spread longer and more widely. Movement of people and distance between farms were statistically significant predictors of virus dispersal between farms. Our study provides novel insights into SARS-CoV-2 transmission between mink farms and highlights the importance of combining genetic information with epidemiological information when investigating outbreaks at the animal-human interface

The Arabidopsis thaliana Homeobox Gene ATHB12 Is Involved in Symptom Development Caused by Geminivirus Infection

BACKGROUND: Geminiviruses are single-stranded DNA viruses that infect a number of monocotyledonous and dicotyledonous plants. Arabidopsis is susceptible to infection with the Curtovirus, Beet severe curly top virus (BSCTV). Infection of Arabidopsis with BSCTV causes severe symptoms characterized by stunting, leaf curling, and the development of abnormal inflorescence and root structures. BSCTV-induced symptom development requires the virus-encoded C4 protein which is thought to interact with specific plant-host proteins and disrupt signaling pathways important for controlling cell division and development. Very little is known about the specific plant regulatory factors that participate in BSCTV-induced symptom development. This study was conducted to identify specific transcription factors that are induced by BSCTV infection. METHODOLOGY/PRINCIPAL FINDINGS: Arabidopsis plants were inoculated with BSCTV and the induction of specific transcription factors was monitored using quantitative real-time polymerase chain reaction assays. We found that the ATHB12 and ATHB7 genes, members of the homeodomain-leucine zipper family of transcription factors previously shown to be induced by abscisic acid and water stress, are induced in symptomatic tissues of Arabidopsis inoculated with BSCTV. ATHB12 expression is correlated with an array of morphological abnormalities including leaf curling, stunting, and callus-like structures in infected Arabidopsis. Inoculation of plants with a BSCTV mutant with a defective c4 gene failed to induce ATHB12. Transgenic plants expressing the BSCTV C4 gene exhibited increased ATHB12 expression whereas BSCTV-infected ATHB12 knock-down plants developed milder symptoms and had lower ATHB12 expression compared to the wild-type plants. Reporter gene studies demonstrated that the ATHB12 promoter was responsive to BSCTV infection and the highest expression levels were observed in symptomatic tissues where cell cycle genes also were induced. CONCLUSIONS/SIGNIFICANCE: These results suggest that ATHB7 and ATHB12 may play an important role in the activation of the abnormal cell division associated with symptom development during geminivirus infection