Exposure to cis- and trans-regioisomers of S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-glutathione result in quantitatively and qualitatively different cellular effects in RPTEC/TERT1 cells.

Bioactivation of trichloroethylene (TCE) via glutathione conjugation is associated with several adverse effects in the kidney and other extrahepatic tissues. Of the three regioisomeric conjugates formed, S-(1,2-trans-dichlorovinyl)-glutathione (1,2-trans-DCVG), S-(1,2-cis-dichlorovinyl)-glutathione and S-(2,2-dichlorovinyl)-glutathione, only 1,2-trans-DCVG and its corresponding cysteine-conjugate, 1,2-trans-DCVC, have been subject to extensive mechanistic studies. In the present study, the metabolism and cellular effects of 1,2-cis-DCVG, the major regioisomer formed by rat liver fractions, and 1,2-cis-DCVC were investigated for the first time using RPTEC/TERT1-cells as in vitro renal model. In contrast to 1,2-trans-DCVG/C, the cis-regioisomers showed minimal effects on cell viability and mitochondrial respiration. Transcriptomics analysis showed that both 1,2-cis-DCVC and 1,2-trans-DCVC caused Nrf2-mediated antioxidant responses, with 3 µM as lowest effective concentration. An ATF4-mediated integrated stress response and p53-mediated responses were observed starting from 30 µM for 1,2-trans-DCVC and 125 µM for 1,2-cis-DCVC. Comparison of the metabolism of the DCVG regioisomers by LC/MS showed comparable rates of processing to their corresponding DCVC. No detectable N-acetylation was observed in RPTEC/TERT1 cells. Instead, N-glutamylation of DCVC to form N-γ-glutamyl-S-(dichlorovinyl)-L-cysteine was identified as a novel route of metabolism. The results suggest that 1,2-cis-DCVC may be of less toxicological concern for humans than 1,2-trans-DCVC, considering its lower intrinsic toxicity and lower rate of formation by human liver fractions.

Transcriptional landscape of mitochondrial electron transport chain inhibition in renal cells.

Analysis of the transcriptomic alterations upon chemical challenge, provides in depth mechanistic information on the compound's toxic mode of action, by revealing specific pathway activation and other transcriptional modulations. Mapping changes in cellular behaviour to chemical insult, facilitates the characterisation of chemical hazard. In this study, we assessed the transcriptional landscape of mitochondrial impairment through the inhibition of the electron transport chain (ETC) in a human renal proximal tubular cell line (RPTEC/TERT1). We identified the unfolded protein response pathway (UPR), particularly the PERK/ATF4 branch as a common cellular response across ETC I, II and III inhibitions. This finding and the specific genes elaborated may aid the identification of mitochondrial liabilities of chemicals in both legacy data and prospective transcriptomic studies.

Transcriptomic-based evaluation of trichloroethylene glutathione and cysteine conjugates demonstrate phenotype-dependent stress responses in a panel of human in vitro models.

Environmental or occupational exposure of humans to trichloroethylene (TCE) has been associated with different extrahepatic toxic effects, including nephrotoxicity and neurotoxicity. Bioactivation of TCE via the glutathione (GSH) conjugation pathway has been proposed as underlying mechanism, although only few mechanistic studies have used cell models of human origin. In this study, six human derived cell models were evaluated as in vitro models representing potential target tissues of TCE-conjugates: RPTEC/TERT1 (kidney), HepaRG (liver), HUVEC/TERT2 (vascular endothelial), LUHMES (neuronal, dopaminergic), human induced pluripotent stem cells (hiPSC) derived peripheral neurons (UKN5) and hiPSC-derived differentiated brain cortical cultures containing all subtypes of neurons and astrocytes (BCC42). A high throughput transcriptomic screening, utilizing mRNA templated oligo-sequencing (TempO-Seq), was used to study transcriptomic effects after exposure to TCE-conjugates. Cells were exposed to a wide range of concentrations of S-(1,2-trans-dichlorovinyl)glutathione (1,2-DCVG), S-(1,2-trans-dichlorovinyl)-L-cysteine (1,2-DCVC), S-(2,2-dichlorovinyl)glutathione (2,2-DCVG), and S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCVC). 1,2-DCVC caused stress responses belonging to the Nrf2 pathway and Unfolded protein response in all the tested models but to different extents. The renal model was the most sensitive model to both 1,2-DCVC and 1,2-DCVG, with an early Nrf2-response at 3 µM and hundreds of differentially expressed genes at higher concentrations. Exposure to 2,2-DCVG and 2,2-DCVC also resulted in the upregulation of Nrf2 pathway genes in RPTEC/TERT1 although at higher concentrations. Of the three neuronal models, both the LUHMES and BCC42 showed significant Nrf2-responses and at higher concentration UPR-responses, supporting recent hypotheses that 1,2-DCVC may be involved in neurotoxic effects of TCE. The cell models with the highest expression of γ-glutamyltransferase (GGT) enzymes, showed cellular responses to both 1,2-DCVG and 1,2-DCVC. Little to no effects were found in the neuronal models from 1,2-DCVG exposure due to their low GGT-expression. This study expands our knowledge on tissue specificity of TCE S-conjugates and emphasizes the value of human cell models together with transcriptomics for such mechanistic studies.

An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat.

Most OECD guidelines for chemical risk assessment include tests performed on animals, raising financial, ethical and scientific concerns. Thus, the development of human-based models for toxicity testing is highly encouraged. Here, we propose an in vitro multi-organ strategy to assess the toxicity of chemicals. Human induced pluripotent stem cells (hiPSCs)-derived models of the brain, blood-brain barrier, kidney, liver and vasculature were generated and exposed to paraquat (PQ), a widely employed herbicide with known toxic effects in kidneys and brain. The models showed differential cytotoxic sensitivity to PQ after acute exposure. TempO-Seq analysis with a set of 3565 probes revealed the deregulation of oxidative stress, unfolded protein response and estrogen receptor-mediated signaling pathways, in line with the existing knowledge on PQ mechanisms of action. The main advantages of this strategy are to assess chemical toxicity on multiple tissues/organs in parallel, exclusively in human cells, eliminating the interspecies bias, allowing a better evaluation of the differential sensitivity of the models representing the diverse organs, and increasing the chance to identify toxic compounds. Furthermore, although we focused on the mechanisms of action of PQ shared by the different models, this strategy would also allow for organ-specific toxicity testing, by including more cell type-specific probes for TempO-Seq analyses. In conclusion, we believe this strategy will participate in the further improvement of chemical risk assessment for human health.

Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation.

Mitochondrial perturbation is a key event in chemical-induced organ toxicities that is incompletely understood. Here, we studied how electron transport chain (ETC) complex I, II, or III (CI, CII and CIII) inhibitors affect mitochondrial functionality, stress response activation, and cell viability using a combination of high-content imaging and TempO-Seq in HepG2 hepatocyte cells. CI and CIII inhibitors perturbed mitochondrial membrane potential (MMP) and mitochondrial and cellular ATP levels in a concentration- and time-dependent fashion and, under conditions preventing a switch to glycolysis attenuated cell viability, whereas CII inhibitors had no effect. TempO-Seq analysis of changes in mRNA expression pointed to a shared cellular response to CI and CIII inhibition. First, to define specific ETC inhibition responses, a gene set responsive toward ETC inhibition (and not to genotoxic, oxidative, or endoplasmic reticulum stress) was identified using targeted TempO-Seq in HepG2. Silencing of one of these genes, NOS3, exacerbated the impact of CI and CIII inhibitors on cell viability, indicating its functional implication in cellular responses to mitochondrial stress. Then by monitoring dynamic responses to ETC inhibition using a HepG2 GFP reporter panel for different classes of stress response pathways and applying pathway and gene network analysis to TempO-Seq data, we looked for downstream cellular events of ETC inhibition and identified the amino acid response (AAR) as being triggered in HepG2 by ETC inhibition. Through in silico approaches we provide evidence indicating that a similar AAR is associated with exposure to mitochondrial toxicants in primary human hepatocytes. Altogether, we (i) unravel quantitative, time- and concentration-resolved cellular responses to mitochondrial perturbation, (ii) identify a gene set associated with adaptation to exposure to active ETC inhibitors, and (iii) show that ER stress and an AAR accompany ETC inhibition in HepG2 and primary hepatocytes.

Temporal transcriptomic alterations of cadmium exposed human iPSC-derived renal proximal tubule-like cells.

Cadmium is a well-studied environmental pollutant where the kidney and particularly the proximal tubule cells are especially sensitive as they are exposed to higher concentrations of cadmium than other tissues. Here we investigated the temporal transcriptomic alterations (TempO-Seq) of human induced pluripotent stem cell (iPSC)-derived renal proximal tubule-like (PTL) cells exposed to 5 µM cadmium chloride for 1, 2, 4, 8, 12, 16, 20, 24, 72 and 168 h. There was an early activation (within 4 h) of the metal and oxidative stress responses (metal-responsive transcription factor-1 (MTF1) and nuclear factor erythroid-2-related factor 2 (Nrf2) genes). The Nrf2 response returned to baseline within 24 h. The Activator Protein 1 (AP-1) regulated genes HSPA6 and FOSL-1 followed the Nrf2 time course. While the MTF1 genes also spiked at 4 h, they remained strongly elevated over the entire exposure period. The data and cell culture model utilised will be useful in further research aimed at the refinement of safe human exposure limits for cadmium, other metals and their mixtures.

Bioactivation of trichloroethylene to three regioisomeric glutathione conjugates by liver fractions and recombinant human glutathione transferases: Species differences and implications for human risk assessment.

Enzymatic conjugation of glutathione (GSH) to trichloroethylene (TCE) followed by catabolism to the corresponding cysteine-conjugate, S-(dichlorovinyl)-L-cysteine (DCVC), and subsequent bioactivation by renal cysteine conjugate beta-lyases is considered to play an important role in the nephrotoxic effects observed in TCE-exposed rat and human. In this study, it is shown for the first time that three regioisomers of GSH-conjugates of TCE are formed by rat and human liver fractions, namely S-(1,2-trans-dichlorovinyl)-glutathione (1,2-trans-DCVG), S-(1,2-cis-dichlorovinyl)-glutathione (1,2-cis-DCVG) and S-(2,2-dichlorovinyl)-glutathione (2,2-DCVG). In incubations of TCE with rat liver fractions their amounts decreased in order of 1,2-cis-DCVG > 1,2-trans-DCVG > 2,2-DCVG. Human liver cytosol showed a more than 10-fold lower activity of GSH-conjugation, with amounts of regioisomers decreasing in order 2,2-DCVG > 1,2-trans-DCVG > 1,2-cis-DCVG. Incubations with recombinant human GSTs suggest that GSTA1-1 and GSTA2-2 play the most important role in human liver cytosol. GSTP1-1, which produces regioisomers in order 1,2-trans-DCVG > 2,2-cis-DCVG > 1,2-cis-DCVG, is likely to contribute to extrahepatic GSH-conjugation of TCE. Analysis of the products formed by a beta-lyase mimetic model showed that both 1,2-trans-DCVC and 1,2-cis-DCVC are converted to reactive products that form cross-links between the model nucleophile 4-(4-nitrobenzyl)-pyridine (NBP) and thiol-species. No NBP-alkylation was observed with 2,2-DCVC corresponding to its low cytotoxicity and mutagenicity. The lower activity of GSH-conjugation of TCE by human liver fractions, in combination with the lower fraction of potential nephrotoxic and mutagenic 1,2-DCVG-isomers, suggest that humans are at much lower risk for TCE-associated nephrotoxic effects than rats.

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors.

Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10-260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at > 1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency.

Rapid Administration of Methoxyflurane to Patients in the Emergency Department (RAMPED) Study: A Randomized Controlled Trial of Methoxyflurane Versus Standard Care.

OBJECTIVE: The objective was to evaluate the effectiveness of methoxyflurane versus standard care for the initial management of severe pain among adult emergency department (ED) patients. METHODS: This randomized parallel-group open-label phase IV trial of methoxyflurane was conducted in a tertiary hospital ED setting in Australia. Inclusion criteria required adult patients to have an initial pain score ≥ 8 on the 11-point Numerical Rating Scale (NRS). Patients were randomized 1:1 to receive either inhaled methoxyflurane (3 mL) or standard analgesic treatment at ED triage. The primary outcome was the proportion of patients achieving clinically substantial pain reduction, defined as a ≥50% drop in the pain score at 30 minutes. Secondary outcomes included the pain score at multiple time points (15, 30, 60, 90 minutes) and the difference in the proportion of patients achieving a >2-point reduction on the NRS. RESULTS: There were 120 patients randomized and analyzed between September 4, 2019, and January 16, 2020. The primary outcome was achieved in six (10%) patients in the methoxyflurane arm and three (5%) in the standard care arm (p = 0.49). A higher proportion of patients in the methoxyflurane arm reported a >2-point drop on the NRS at all time points (17% vs. 5% at 15 minutes, 25% vs. 9% at 30 minutes, 30% vs. 10% at 60 minutes, and 33% vs. 13% at 90 minutes). Methoxyflurane use was also associated with lower median pain scores at all time points. CONCLUSION: Initial management with inhaled methoxyflurane in the ED did not achieve the prespecified substantial reduction in pain, but was associated with clinically significant lower pain scores compared to standard therapy.

Cutaneous Cholangiocarcinoma: An Interesting Presentation.

This is a case of a 64-year-old white man with a history of CCA, originally diagnosed in May 2018 and returning in November 2019 with growing cutaneous nodules. These were removed for cosmetic and functional purposes. Pathologic findings of the lesions showed likely metastatic disease from his original CCA. This represents a relatively rare presentation of metastatic disease in the setting of CCA. In cases of CCA with metastatic spread, treatment is not curative and should be focused on measures to improve the patient's quality of life. This includes acceptable cosmesis, as well as factors aiding in completing activities of daily living.

Multiparametric assessment of mitochondrial respiratory inhibition in HepG2 and RPTEC/TERT1 cells using a panel of mitochondrial targeting agrochemicals.

Evidence is mounting for the central role of mitochondrial dysfunction in several pathologies including metabolic diseases, accelerated ageing, neurodegenerative diseases and in certain xenobiotic-induced organ toxicity. Assessing mitochondrial perturbations is not trivial and the outcomes of such investigations are dependent on the cell types used and assays employed. Here we systematically investigated the effect of electron transport chain (ETC) inhibitors on multiple mitochondrial-related parameters in two human cell types, HepG2 and RPTEC/TERT1. Cells were exposed to a broad range of concentrations of 20 ETC-inhibiting agrochemicals and capsaicin, consisting of inhibitors of NADH dehydrogenase (Complex I, CI), succinate dehydrogenase (Complex II, CII) and cytochrome bc1 complex (Complex III, CIII). A battery of tests was utilised, including viability assays, lactate production, mitochondrial membrane potential (MMP) and the Seahorse bioanalyser, which simultaneously measures extracellular acidification rate [ECAR] and oxygen consumption rate [OCR]. CI inhibitors caused a potent decrease in OCR, decreased mitochondrial membrane potential, increased ECAR and increased lactate production in both cell types. Twenty-fourhour exposure to CI inhibitors decreased viability of RPTEC/TERT1 cells and 3D spheroid-cultured HepG2 cells in the presence of glucose. CI inhibitors decreased 2D HepG2 viability only in the absence of glucose. CII inhibitors had no notable effects in intact cells up to 10 µM. CIII inhibitors had similar effects to the CI inhibitors. Antimycin A was the most potent CIII inhibitor, with activity in the nanomolar range. The proposed CIII inhibitor cyazofamid demonstrated a mitochondrial uncoupling signal in both cell types. The study presents a comprehensive example of a mitochondrial assessment workflow and establishes measurable key events of ETC inhibition.

Fibrosing Mediastinitis Requiring Multimodality Treatment to Maintain Pulmonary Vein Patency.

Fibrosing mediastinitis is a rare condition with limited epidemiologic data. We detail a case of a 43-year-old female with no past medical history, who presented with chest pain and dyspnea on exertion. Chest computed tomography revealed a large mediastinal mass that was invading into the anterior chest as well as encasing the pulmonary hilum. Surgical pathology returned as dense hyaline fibrosis tissue with focal histiocytic aggregates and giant cells consistent with fibrosing mediastinitis. Treatment with rituximab and steroids showed a reduction in the size of her mass.

A twelve-year study of the prevalence, risk factors and characteristics of interval colorectal cancers after negative colonoscopy.

INTRODUCTION: The objective of our study was to describe and analyse the Post-Colonoscopy Colorectal Cancers (PCCRCs) and endoscopist performance-related risk factors in the Isère regional screening programme. METHOD: This was a population-based retrospective cohort study between 2002-2013, where Post-Colonoscopy Colorectal Cancers (PCCRCs) were defined as colorectal adenocarcinoma diagnosed between six and sixty months post-colonoscopy following a positive gFOBT. We analysed the endoscopist performance-related risk factors of the 62 gastroenterologists who had carried out at least 30 colonoscopies during this period. RESULTS: During the period reviewed, there were 10,557 negative colonoscopies performed. Fifteen post-colonoscopy colorectal cancers were diagnosed from 2002-2013 with an average patient age of 67.1 years. Men comprised 73% of the cases and 53% of all the cases were found in the distal colon. These 15 cases comprised 1.1% of all Colorectal Cancers (CRCs) diagnosed in the screening programme, with an incidence rate of 0.42 (0.21-0.77) per 1,000 person-years. The aetiological breakdown was as follows: 47% related to missed cancers, 27% were new cancers, 20% were failed biopsy detection, and 6% related to incomplete removal. The Adenoma Detection Rate (ADR) among gastroenterologists was an average of 30%, but large heterogeneity was present within this number, ranging from 11% to 49%. CONCLUSION: The post-colonoscopy colorectal cancer prevalence and incident rate were low relative to the literature. However, significant heterogeneity was present in the adenoma detection rate. Decreasing this heterogeneity by establishing a national benchmark, regular performance feedback and training modules should homogenise adenoma detection rates and decrease the number of interval cancers in the region.

Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases.

Toxicological responses to chemical insult are largely regulated by transcriptionally activated pathways that may be independent, correlated and partially or fully overlapping. Investigating the dynamics of the interactions between stress responsive transcription factors from toxicogenomic data and defining the signature of each of them is an additional step toward a system level understanding of perturbation driven mechanisms. To this end, we investigated the segregation of the genes belonging to the three following transcriptionally regulated pathways: the AhR pathway, the Nrf2 pathway and the ATF4 pathway. Toxicogenomic datasets from three projects (carcinoGENOMICS, Predict-IV and TG-GATEs) obtained in various experimental conditions (in human and rat in vitro liver and kidney models and rat in vivo, with bolus administration and with repeated doses) were combined and consolidated where overlaps between datasets existed. A bioinformatic analysis was performed to refine pathways' signatures and to create chemical activation capacity scores to classify chemicals by their potency and selectivity of activation of each pathway. With some refinement such an approach may improve chemical safety classification and allow biological read across on a pathway level.

Adverse outcome pathways: opportunities, limitations and open questions.

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

Moving forward in carcinogenicity assessment: Report of an EURL ECVAM/ESTIV workshop.

There is an increased need to develop novel alternative approaches to the two-year rodent bioassay for the carcinogenicity assessment of substances where the rodent bioassay is still a basic requirement, as well as for those substances where animal use is banned or limited or where information gaps are identified within legislation. The current progress in this area was addressed in a EURL ECVAM- ESTIV workshop held in October 2016, in Juan les Pins. A number of initiatives were presented and discussed, including data-driven, technology-driven and pathway-driven approaches. Despite a seemingly diverse range of strategic developments, commonalities are emerging. For example, providing insight into carcinogenicity mechanisms is becoming an increasingly appreciated aspect of hazard assessment and is suggested to be the best strategy to drive new developments. Thus, now more than ever, there is a need to combine and focus efforts towards the integration of available information between sectors. Such cross-sectorial harmonisation will aid in building confidence in new approach methods leading to increased implementation and thus a decreased necessity for the two-year rodent bioassay.

Transportation Safety of Lithium Iron Phosphate Batteries - A Feasibility Study of Storing at Very Low States of Charge.

In freight classification, lithium-ion batteries are classed as dangerous goods and are therefore subject to stringent regulations and guidelines for certification for safe transport. One such guideline is the requirement for batteries to be at a state of charge of 30%. Under such conditions, a significant amount of the battery's energy is stored; in the event of mismanagement, or indeed an airside incident, this energy can lead to ignition and a fire. In this work, we investigate the effect on the battery of removing 99.1% of the total stored energy. The performance of 8Ah C6/LiFePO4 pouch cells were measured following periods of calendar ageing at low voltages, at and well below the manufacturer's recommended value. Battery degradation was monitored using impedance spectroscopy and capacity tests; the results show that the cells stored at 2.3 V exhibited no change in cell capacity after 90 days; resistance rise was negligible. Energy-dispersive X-ray spectroscopy results indicate that there was no significant copper dissolution. To test the safety of the batteries at low voltages, external short-circuit tests were performed on the cells. While the cells discharged to 2.3 V only exhibited a surface temperature rise of 6 °C, cells at higher voltages exhibited sparks, fumes and fire.

Survival in Out-of-hospital Rapid Sequence Intubation of Non-Traumatic Brain Pathologies.

INTRODUCTION: Rapid sequence intubation (RSI) is not only used in traumatic brain injuries in the out-of-hospital setting, but also for non-traumatic brain pathologies (NTBP) such as brain tumors, meningitis, encephalitis, hypoxic/anoxic brain injury, stroke, arteriovenous malformations, tumors, aneurysms, brain hemorrhage, as well as brain injury due to diabetes, seizures and toxicity, metabolic conditions, and alcohol and drug overdose. Previous research suggests that RSI is common in non-traumatic coma, but with an unknown prevalence of NTBP in those that receive RSI. If NTBP is common and if brain trauma RSI evidence is not valid for NTBP then a sizable proportion of NTBP receive this treatment without evidence of benefit. This study calculated the out-of-hospital NTBP prevalence in patients that had received RSI and explored factors that predicted survival. METHODS: A retrospective cohort study based on data collected from an ambulance service and seven hospitals based in Melbourne, Australia. Non-traumatic brain pathologies were defined using ICD10-AM codes for the calculation of NTBP prevalence. Logistic regression modelled out-of-hospital predictors of survival to hospital discharge after adjustment for comorbidities. RESULTS: The seven participating hospitals treated 2,277 patients that received paramedic RSI for all illnesses and indications from January 1, 2008 to December 31, 2015, with survival data available for 1,940 (85%). Of the 1,940, 1,125 (58%) patients had at least one hospital-diagnosed NTBP. Sixty-nine percent all of NTBP survived to hospital discharge, compared to 65% for traumatic intracranial injury. Strokes were the most common and had poor survival to discharge (37%) compared to the second most common NTBP toxicity/toxic encephalopathy that had very high survival (98%). No out-of-hospital clinical intervention or prehospital time interval predicted survival. Factors that did predict survival include Glasgow Coma Scale (GCS), duration of mechanical ventilation, age, ICU length of stay, and comorbidities. CONCLUSIONS: Non-traumatic brain pathologies are seven times more prevalent than traumatic brain injuries in patients that underwent out-of-hospital RSI in Victoria, Australia. Since the mechanisms through which RSI impacts mortality might differ between traumatic brain injuries and NTBP, and given that NTBP is very prevalent, it follows that the use of RSI in NTBP could be unsupported.

An interesting finding of multiple calcified pulmonary nodules in a patient with rheumatoid arthritis.

Calcified pulmonary (lung parenchymal) densities can occur in a number of conditions. A patient with rheumatoid arthritis presented with new right lung base nodules and left long base soft-tissue densities on his chest X-ray. These findings did not exist on his chest X-ray performed 2 years earlier. A subsequent thoracic CT scan showed multiple pleural-based irregular nodules of soft-tissue density that were partially calcified. There was also mediastinal and hilar lymphadenopathy. Following a discussion at the respiratory multidisciplinary team meeting, a CT-guided nodal biopsy was performed that showed necrotic lung tissue with palisaded histiocytes and fibrosis with chronic inflammation. No vasculitis or granulomata were seen and no there was evidence of malignancy. Appearances were consistent with a rheumatoid nodule. No mycobacteria or fungi were seen on Ziehl-Neelsen, Wade-Fite or periodic acid-Schiff stains. We concluded that this patient had unusual calcified rheumatoid lung nodules. Previously, calcified pulmonary nodules have been reported in the setting of Caplan's syndrome in miners.