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This multicenter randomized trial compared strategies of early and delayed renal-replacement therapy in patients with severe acute kidney injury. There was no significant difference in mortality, the primary outcome, between the study groups. Acute kidney injury is a common condition among patients in the intensive care unit 1 – 4 and is associated with high morbidity and mortality. 2 , 5 – 8 Renal-replacement therapy is the cornerstone of the management of severe acute kidney injury. Many studies have focused on methods of renal-replacement therapy, 5 , 6 , 8 , 9 but the issue of when to initiate the therapy in the absence of a potentially life-threatening complication directly related to renal failure remains a subject of debate. Indirect evidence has suggested that early renal-replacement therapy could confer a survival benefit. 10 – 12 However, two observational studies reported high survival rates among . . .

Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1–17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity. Hydroxychloroquine and chloroquine are closely-related drugs used for the treatment of malaria and rheumatological conditions, such as lupus. Laboratory tests have indicated that these drugs could also be used against the virus that causes COVID-19. Given the urgent need, these drugs have been fast-tracked into large-scale clinical trials, bypassing the usual stages that would provide estimates for suitable dosage. The dosage is a critical factor in a clinical trial: too low and the drug will not have an effect, too high and the side effects may counteract any potential benefits. Laboratory tests suggest that higher doses of chloroquine or hydroxychloroquine are needed for treating COVID-19 compared to malaria or lupus. However, there are concerns about the high doses used in some trials, as the drugs can have lethal side effects. Indeed, chloroquine has been used extensively in suicide attempts, particularly in France. To address these concerns, Watson et al. set out to determine the highest dosage of chloroquine (and thus of hydroxychloroquine, approximately) that does not cause unacceptable side effects. First, data was analysed regarding the concentration of chloroquine in the blood of 302 patients who had intentionally overdosed on the drug, since this concentration is tightly correlated with their risk of death. Watson et al. used a statistical model to calculate the maximal chloroquine concentration in a person’s blood associated with a one per cent risk of death. This is taken to be the threshold above which any potential benefit of chloroquine treatment would be outweighed by the possibility of lethal toxicity. Watson et al. also estimated the relationship between chloroquine concentrations and changes in electrocardiogram patterns, which record the electrical activity of the heart. This makes it possible to determine whether a high dose of chloroquine has led to dangerous levels in the blood. Using a mathematical model of how chloroquine is metabolised, Watson et al. predicted that most of the trials that tested chloroquine as a treatment for COVID-19 did not reach the calculated threshold concentration. An exception was the CloroCovid-19 trial in Brazil, which was stopped early because people in the higher dosage group suffered more heart problems and died in greater numbers than those in the lower dosage group. Two large randomised trials, RECOVERY and SOLIDARITY, have shown no benefit of hydroxychloroquine or chloroquine in the treatment of COVID-19, changing clinical practice worldwide. Both of these trials used high doses resulting in higher hydroxychloroquine or chloroquine concentrations than normally observed in the treatment of malaria or rheumatological conditions. The results from Watson et al demonstrate that the lack of benefit seen in these two large clinical trials is not due to the drug dosage being too high.

Background Although targeted temperature management (TTM) is recommended in comatose survivors after cardiac arrest (CA), the optimal method to deliver TTM remains unknown. We performed a meta-analysis to evaluate the effects of different TTM methods on survival and neurological outcome after adult CA. Methods We searched on the MEDLINE/PubMed database until 22 February 2019 for comparative studies that evaluated at least two different TTM methods in CA patients. Data were extracted independently by two authors. We used the Newcastle-Ottawa Scale and a modified Cochrane ROB tools for assessing the risk of bias of each study. The primary outcome was the occurrence of unfavorable neurological outcome (UO); secondary outcomes included overall mortality. Results Our search identified 6886 studies; 22 studies ( n  = 8027 patients) were included in the final analysis. When compared to surface cooling, core methods showed a lower probability of UO (OR 0.85 [95% CIs 0.75–0.96]; p  = 0.008) but not mortality (OR 0.88 [95% CIs 0.62–1.25]; p  = 0.21). No significant heterogeneity was observed among studies. However, these effects were observed in the analyses of non-RCTs. A significant lower probability of both UO and mortality were observed when invasive TTM methods were compared to non-invasive TTM methods and when temperature feedback devices (TFD) were compared to non-TFD methods. These results were significant particularly in non-RCTs. Conclusions Although existing literature is mostly based on retrospective or prospective studies, specific TTM methods (i.e., core, invasive, and with TFD) were associated with a lower probability of poor neurological outcome when compared to other methods in adult CA survivors (CRD42019111021).

We report an unusual case of severe hepatopulmonary syndrome with previously unrecognized cirrhosis, presenting with acute on chronic dyspnoea, extreme hypoxemia, secondary polycythemia as well as direct identification of arteriovenous communications on computed tomography angiography. Hepatopulmonary syndrome, defined as the combination of hepatopathy, arterial deoxygenation and pulmonary vascular dilatation, is increasingly recognized as a life-threatening complication in advanced liver disease and transplant candidacy. It is usually diagnosed in chronic liver disease patients following pre-transplant evaluation or mild dyspnea investigation. Diagnosis relies on the indirect evidence of pulmonary arteriovenous communications suggested by echocardiography with a bubble study. Clinicians need to be aware of this rare but potential acute presentation at the emergency room.

In toxicology, screenings are routinely performed using chromatographic methods coupled to detection systems such as high-resolution mass spectrometry (HR/MS). The increase in specificity and sensitivity of HRMS is responsible for the development of methods for alternative samples such as Volumetric Adsorptive Micro-Sampling. Whole blood overloaded with 90 drugs was sampled with 20 µL MitraTM to optimize the pre-analytical step as well as to determine the identification limits of drugs. Elution of chemicals was carried out in a solvent mixture through agitation and sonication. After dissolution, 10 μL was injected into the chromatographic system coupled to the OrbitrapTM HR/MS. Compounds were confirmed against the laboratory library. The clinical feasibility was assessed in fifteen poisoned patients using the simultaneous sampling of plasma, whole blood and MitraTM. The optimized extraction procedure allowed us to confirm 87 compounds out of the 90 present in the spiked whole blood. Cannabis derivatives were not detected. For 82.2% of the investigated drugs, the identification limits were below 12.5 ng·mL−1, with the extraction yields ranging from 80.6 to 108.7%. Regarding the patients’ analysis, 98% of the compounds in plasma were detected in MitraTM compared to whole blood, with a satisfying concordance (R2 = 0.827). Our novel screening approach opens new insights into different toxicologic fields appropriate for pediatrics, forensics or to perform mass screening.

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.

Background This study aimed to compare clinical and laboratory characteristics of supra-therapeutic (RSTI) and acute acetaminophen exposures using a predictive decision tree (DT) algorithm. Methods We conducted a retrospective cohort study using the National Poison Data System (NPDS). All patients with RSTI acetaminophen exposure (n = 4,522) between January 2012 and December 2017 were included. Additionally, 4,522 randomly selected acute acetaminophen ingestion cases were included. After that, the DT machine learning algorithm was applied to differentiate acute acetaminophen exposure from supratherapeutic exposures. Results The DT model had accuracy, precision, recall, and F1-scores of 0.75, respectively. Age was the most relevant variable in predicting the type of acetaminophen exposure, whether RSTI or acute. Serum aminotransferase concentrations, abdominal pain, drowsiness/lethargy, and nausea/vomiting were the other most important factors distinguishing between RST and acute acetaminophen exposure. Conclusion DT models can potentially aid in distinguishing between acute and RSTI of acetaminophen. Further validation is needed to assess the clinical utility of this model.