Accuracy of Emergency Department Clinical Findings for Diagnosis of Coronavirus Disease 2019.

STUDY OBJECTIVE: We seek to describe the medical history and clinical findings of patients attending the emergency department (ED) with suspected coronavirus disease 2019 (COVID-19) and estimate the diagnostic accuracy of patients' characteristics for predicting COVID-19. METHODS: We prospectively enrolled all patients tested for severe acute respiratory syndrome coronavirus 2 by reverse-transcriptase polymerase chain reaction in our ED from March 9, 2020, to April 4, 2020. We abstracted medical history, physical examination findings, and the clinical probability of COVID-19 (low, moderate, and high) rated by emergency physicians, depending on their clinical judgment. We assessed diagnostic accuracy of these characteristics for COVID-19 by calculating positive and negative likelihood ratios. RESULTS: We included 391 patients, of whom 225 had positive test results for severe acute respiratory syndrome coronavirus 2. Reverse-transcriptase polymerase chain reaction result was more likely to be negative when the emergency physician thought that clinical probability was low, and more likely to be positive when he or she thought that it was high. Patient-reported anosmia and the presence of bilateral B lines on lung ultrasonography had the highest positive likelihood ratio for the diagnosis of COVID-19 (7.58, 95% confidence interval [CI] 2.36 to 24.36; and 7.09, 95% CI 2.77 to 18.12, respectively). The absence of a high clinical probability determined by the emergency physician and the absence of bilateral B lines on lung ultrasonography had the lowest negative likelihood ratio for the diagnosis of COVID-19 (0.33, 95% CI 0.25 to 0.43; and 0.26, 95% CI 0.15 to 0.45, respectively). CONCLUSION: Anosmia, emergency physician estimate of high clinical probability, and bilateral B lines on lung ultrasonography increased the likelihood of identifying COVID-19 in patients presenting to the ED.

Fulminant diabetes due to immune checkpoint inhibitors in the emergency department.

Immune checkpoint inhibitors (ICIs) are of growing importance in new cancer therapies, exposing patients to various and potentially severe immune-related adverse events and placing emergency physicians on the front line when they occur. If endocrine toxicity is a well-known complication of ICIs, fulminant diabetes with diabetic ketoacidosis is exceptional. We present a case of fulminant diabetes after only two cycles of pembrolizumab in a 53-year-old man with a history of metastatic lung cancer who presented to our emergency department with coma and acidosis revealing diabetic ketoacidosis. The patient was rehydrated and treated with insulin and recovered quickly. Lung toxicity was also suspected on CT-scan findings. This rare and life-threatening complication that developed unusually early during the treatment course may be challenging in a cancer patient. Therefore, emergency physicians should investigate symptoms in patients treated with checkpoint inhibitors and consider toxicity when they present to the ED with complaints compatible with an immune-related adverse event.

Immune checkpoint blockade toxicity among patients with cancer presenting to the emergency department.

OBJECTIVES: We sought to estimate the prevalence of patients with cancer presenting to the emergency department (ED) who are undergoing treatment with immune checkpoint blockade (ICB) therapy; report their chief complaints; describe and estimate the prevalence of immune-related adverse events (IRAEs). METHODS: Four abstractors reviewed the medical records of patients with cancer treated with ICB who presented to an ED in Paris, France between January 2012 and June 2017. Chief complaints, underlying malignancy and ICB characteristics, and the final diagnoses according to the emergency physician were recorded. Abstractors noted if an emergency physician identified that a patient was receiving an ICB and if the emergency physician considered the possibility of an IRAE. The gold standard as to whether an IRAE was the cause was the patients' referring oncologist's opinion that the ED symptoms were attributed to ICB and IRAE according to post-ED medical records. Descriptive statistics were reported. RESULTS: Among the 409 patients treated with ICB at our institution, 139 presented to the ED. Chief complaints were fatigue (25.2%), fever (23%), vomiting (13.7%), diarrhoea (13.7%), dyspnoea (12.2%), abdominal pain (11.5%), confusion (8.6%) and headache (7.9%). Symptoms were due to IRAEs in 20 (14.4%) cases. The most frequent IRAEs were colitis (40%), endocrine toxicity (30%), hepatitis (25%) and pulmonary toxicity (5%). Patients with IRAEs compared with those without them more frequently had melanoma; had received more distinct courses of ICB treatment, an increased number of ICB medications and ICB cycles; and had a shorter time course since the last infusion of ICB. Emergency physicians considered the possibility of an IRAE in 24 (17.3%) of cases and diagnosed IRAE in 10 (50%) of those with later confirmed IRAE. IRAE was more likely to be missed when the referring oncologist was not contacted or when the patient had respiratory symptoms, fatigue or fever. CONCLUSIONS: ICB exposes patients to potentially severe IRAEs. Emergency physicians must identify patients treated with ICB and consider their toxicity when patients present to the ED with symptoms compatible with IRAEs.

[Predictors of online medical appointments with general practitioners]. / Facteurs associés à la prise de rendez-vous en ligne pour une consultation de médecine générale.

CONTEXT: Appointments with general practitioners constitute the first point of contact with broader healthcare services for most patients. This study assessed sociodemographic factors associated with online appointments with general practitioners in Paris. METHOD: A multicentre cross-sectional epidemiological study was conducted from January to April 2017 in 61 pharmacies in the east of Paris, marked by a high social gradient. Pharmacists invited patients who had consulted a general practitioner to fill in a questionnaire. The questionnaire helped define the sociodemographic characteristics of the patients as well as how they made their appointments. RESULTS: A total of 423 patients were included in the study. Multivariate analysis indicated that the age category over 40 years (age 40-59 years: ORajusted = 0.46, 95% CI = [0.236; 0.879], p = 0.02 and age over 60 years: ORadjusted = 0.023, 95% CI = [0.109; 0.49], p = 0.0001), non-use of Internet (ORadjusted = 10.55 [3.62; 45.04], p = 0.0001), and residents from priority areas of the city of Paris (ORadjusted =0.227, 95% CI = [0.23; 0.76], p = 0.004]) were far less likely to make online appointments with their general practitioners. CONCLUSION: To provide equal access to care for all, traditional appointment methods (open-door consultations and telephone bookings) must be provided alongside new Internet appointment services.

Misdiagnosis of thrombotic microangiopathy in the emergency department: a multicenter retrospective study.

To estimate the rate of inappropriate diagnosis in patients who visited the ED with thrombotic microangiopathy (TMA) and to assess the factors and outcomes associated with emergency department (ED) misdiagnosis. Retrospective multicenter study of adult patients admitted to the intensive care unit (ICU) for TMA from 2012 to 2021 who had previously attended the ED for a reason related to TMA. Patient characteristics and outcomes were compared in a univariate analysis based on whether a TMA diagnosis was mentioned in the ED or not. Forty patients were included. The diagnosis of TMA was not mentioned in the ED in 16 patients (40%). Patients for whom the diagnosis was mentioned in the ED had more frequently a request for schistocytes research, and therefore had more often objectified schistocytes. They also had more frequently a troponin dosage in the ED (even if the difference was not significant), an ECG performed or interpreted, and were admitted more quickly in the ICU (0 [0-0] vs 2 [0-2] days; P = 0.002). Hemoglobin levels decreased significantly in both groups, and creatinine levels increased significantly in the misdiagnosis group between ED arrival and ICU admission. In patients with a final diagnosis of TTP, the time to platelets durable recovery was shorter for those in whom the diagnosis was mentioned in the ED without reaching statistical significance (7 [5-11] vs 14 [5-21] days; P = 0.3).

Effect of a delayed admission to the intensive care unit on survival after emergency department visit in patients with cancer: a retrospective observational study.

BACKGROUND AND IMPORTANCE: Delayed admission to the ICU is reported to be associated with worse outcomes in cancer patients. OBJECTIVE: The main objective of this study was to compare the 180-day survival of cancer patients whether they were directly admitted to the ICU from the emergency department (ED) or secondarily from the wards after the ED visit. DESIGN, SETTINGS AND PARTICIPANTS: This was a retrospective observational study including all adult cancer patients that visited the ED in 2018 and that were admitted to the ICU at some point within 7 days from the ED visit. EXPOSURE: Delayed ICU admission. OUTCOME MEASURE AND ANALYSIS: Survival at day 180 was plotted using Kaplan-Meier curves, and hazard ratio (HR) from Cox proportional-hazard models was used to quantify the association between admission modality (directly from the ED or later from wards) and survival at day 180, after adjustment to baseline characteristics. RESULTS: During the study period, 4560 patients were admitted to the hospital following an ED visit, among whom 136 (3%) patients had cancer and were admitted to the ICU, either directly from the ED in 101 (74%) cases or secondarily from the wards in 35 (26%) cases. Patients admitted to the ICU from the ED had a better 180-day survival than those admitted secondarily from wards (log-rank P = 0.006). After adjustment to disease status (remission or uncontrolled malignancy), survival at day 180 was significantly improved in the case of admission to the ICU directly from the ED with an adjusted HR of 0.50 (95% confidence interval, 0.26-0.95), P = 0.03. CONCLUSION: In ED patients with cancer, a direct admission to the ICU was associated with better 180-day survival compared with patients with a delayed ICU admission secondary from the wards. However, several confounders were not taken into account, which limits the validity of this result.

Impact of Fast SARS-CoV-2 Molecular Point-Of-Care Testing on Patients' Length of Stay in an Emergency Department.

The ID NOW COVID-19 system (IDNOW) is a point-of-care test (POCT) providing results within 15 min. We evaluated the impact of IDNOW use on patient length of stay (LOS) in an emergency department (ED). In the ED of Saint-Louis Hospital, Paris, France, adult patients requiring a rapid diagnosis of SARS-CoV-2 were tested with Cepheid Xpert Xpress SARS-CoV-2 or FilmArray respiratory panel RP2 in the virology laboratory between 18 October and 3 November 2020 (period 1) and with IDNOW between 4 November and 30 November 2020 (period 2). A total of 676 patients participated in the study, 337 during period 1 and 339 during period 2. The median LOS in ED was significantly higher in period 1 than in period 2 (276 versus 208 min, P < 0.0001). More patients spent less than 4 h in the ED in period 2 (61.3%) than in period 1 (38.3%) (P < 0.0001). By univariate analysis, factors associated with ED LOS were hypertension, anosmia/ageusia, number of patients per day, and ID NOW implementation in period 2. By multivariate analysis, the period of testing remained significantly associated with ED LOS. Rapid molecular SARS-CoV-2 POCT was associated with a reduced LOS for patients admitted to an ED. IMPORTANCE During COVID-19 pandemic upsurges, emergency departments had to deal with a massive flow of incoming patients. The need for COVID-19 infection status determination before medical ward admission worsened ED overcrowding. The development of molecular point-of-care testing gave new opportunities for getting faster results of SARS-CoV-2 genome detection 24 h a day. In our study, we show, with a multivariate analysis, that the use of the POCT COVID-19 IDNOW reduced the ED length of stay by 1 h. The rate of patients who waited less than 4 h in the ED increased significantly. Our study highlights the benefit of COVID-19 molecular POCT for preventing ED overcrowding and facilitating bed allocation and SARS-CoV-2-infected patient isolation.

Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction.

Mitochondrial diseases due to mutations in mitochondrial DNA can no longer be ignored in most medical areas. With prevalence certainly higher than one in 6000, they probably represent the most common form of metabolic disorders. Despite progress in identification of their molecular mechanisms, little has been done with regard to therapy. We have recently optimized the allotopic expression for the mitochondrial genes ATP6, ND1, and ND4 and obtained a complete and long-lasting rescue of mitochondrial dysfunction in the human fibroblasts in which these genes were mutated. However, biosafety and benefit to mitochondrial function must be validated in animal models prior to clinical applications. To create an animal model of Leber Hereditary Optic Neuropathy (LHON), we introduced the human ND4 gene harboring the G11778A mutation, responsible of 60% of LHON cases, to rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells (RGCs), which were 40% less abundant in treated eyes than in control eyes. This deleterious effect was also confirmed in primary cell culture, in which both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wild-type ND4 prevented both RGC loss and the impairment of visual function. Hence, these data provide the proof-of-principle that optimized allotopic expression can be an effective treatment for LHON, and they open the way to clinical studies on other devastating mitochondrial disorders.

Antibiotic prescribing and outcomes in cancer patients with febrile neutropenia in the emergency department.

INTRODUCTION: The benefit of reducing the time of antibiotic initiation in the emergency department (ED) for neutropenic patients is controversial and the research on the impact of antibiotic adherence to international guidelines in the ED is scarce. We aimed to investigate the effect of antibiotic timing and appropriateness on outcomes in patients with febrile neutropenia (FN) and to assess the performance of the MASCC risk-index to risk-stratify such patients in the ED. METHODS: We prospectively identified patients with FN who presented to our ED and assessed their Multinational Association of Supportive Care in Cancer (MASCC) risk-index. The time to parenteral antibiotic initiation and the appropriateness of the antibiotic regimen according to international guidelines were retrospectively abstracted. The performance of the MASCC risk-index in predicting the absence of complication was assessed with sensitivity, specificity and the area under the receiver operating characteristics curve (AUC). We investigated the effect of the time to antibiotic initiation and the appropriateness of the antibiotic regimen on the outcome (ICU admission or death) by logistic regression analyses. RESULTS: We included 249 patients. Median age was 60 years and 67.9% had hematological malignancies, 26 (10.4%) were admitted to the ICU and 23 (9.8%) died during hospital stay. Among the 173 patients at low risk according to the MASCC risk-index, 56 (32.4%) presented at least one complication including 11 deaths. The MASCC risk-index had a sensitivity and a specificity of 0.78% and 0.43%, respectively, in predicting the absence of complication and the AUC was 0.67. The time to antibiotic initiation in the ED was not associated with the outcome after adjusting for performance status and shock-index. Conversely, an inadequate ED antibiotic regimen was associated with higher ICU admission or death during hospital stay (OR = 3.50; 95% CI = 1.49 to 8.28). CONCLUSION: An inadequate ED antibiotic regimen in patients with FN was significantly associated with higher ICU admission or death during hospital stay.

Surfaces and equipment contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the emergency department at a university hospital.

OBJECTIVES: Environmental contamination by patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through respiratory droplets suggests that surfaces and equipment could be a medium of transmission. We aimed to assess the surface and equipment contamination by SARS-COV-2 of an emergency department (ED) during the coronavirus infectious disease-2019 (COVID-19) outbreak. METHODS: We performed multiple samples from different sites in ED patients care and non-patient care areas with sterile premoistened swabs and used real-time reverse transcriptase polymerase chain reaction (RT-PCR) to detect the presence of SARS-CoV-2 ribonucleic acid (RNA). We also sampled the personal protective equipment (PPE) from health care workers (HCWs). RESULTS: Among the 192 total samples, 10 (5.2%) were positive. In patient care areas, 5/46 (10.9%) of the surfaces directly in contact with COVID-19 patients revealed the presence of SARS-CoV-2 RNA, and 4/56 (7.1%) of the surfaces that were not directly in contact with COVID-19 patients were positive. SARS-CoV-2 RNA was present only in the patients' examination and monitoring rooms. Before decontamination SARS-CoV-2 RNA was present on the saturation clip, the scuff for blood pressure measurement, the stretcher, the plastic screens between patients and the floor. After decontamination, SARS-CoV-2 RNA remained on the scuff, the stretcher and the trolleys. All samples from non-patient care areas or staff working rooms were negative. Only one sample from the PPE of the HCWs was positive. CONCLUSIONS: Our findings suggest that surfaces and equipment contamination by SARS-CoV-2 RNA in an ED during the COVID-19 outbreak is low and concerns exclusively patients' examination and monitoring rooms, preserving non-patient care areas.

Association Between Pulmonary Embolism and COVID-19 in Emergency Department Patients Undergoing Computed Tomography Pulmonary Angiogram: The PEPCOV International Retrospective Study.

BACKGROUND: There have been reports of procoagulant activity in patients with COVID-19. Whether there is an association between pulmonary embolism (PE) and COVID-19 in the emergency department (ED) is unknown. The aim of this study was to assess whether COVID-19 is associated with PE in ED patients who underwent a computed tomographic pulmonary angiogram (CTPA). METHODS: A retrospective study in 26 EDs from six countries. ED patients in whom a CTPA was performed for suspected PE during a 2-month period covering the pandemic peak. The primary endpoint was the occurrence of a PE on CTPA. COVID-19 was diagnosed in the ED either on CT or reverse transcriptase-polymerase chain reaction. A multivariable binary logistic regression was built to adjust with other variables known to be associated with PE. A sensitivity analysis was performed in patients included during the pandemic period. RESULTS: A total of 3,358 patients were included, of whom 105 were excluded because COVID-19 status was unknown, leaving 3,253 for analysis. Among them, 974 (30%) were diagnosed with COVID-19. Mean (±SD) age was 61 (±19) years and 52% were women. A PE was diagnosed on CTPA in 500 patients (15%). The risk of PE was similar between COVID-19 patients and others (15% in both groups). In the multivariable binary logistic regression model, COVID-19 was not associated with higher risk of PE (adjusted odds ratio = 0.98, 95% confidence interval = 0.76 to 1.26). There was no association when limited to patients in the pandemic period. CONCLUSION: In ED patients who underwent CTPA for suspected PE, COVID-19 was not associated with an increased probability of PE diagnosis. These results were also valid when limited to the pandemic period. However, these results may not apply to patients with suspected COVID-19 in general.

High-throughput single-cell activity-based screening and sequencing of antibodies using droplet microfluidics.

Mining the antibody repertoire of plasma cells and plasmablasts could enable the discovery of useful antibodies for therapeutic or research purposes1. We present a method for high-throughput, single-cell screening of IgG-secreting primary cells to characterize antibody binding to soluble and membrane-bound antigens. CelliGO is a droplet microfluidics system that combines high-throughput screening for IgG activity, using fluorescence-based in-droplet single-cell bioassays2, with sequencing of paired antibody V genes, using in-droplet single-cell barcoded reverse transcription. We analyzed IgG repertoire diversity, clonal expansion and somatic hypermutation in cells from mice immunized with a vaccine target, a multifunctional enzyme or a membrane-bound cancer target. Immunization with these antigens yielded 100-1,000 IgG sequences per mouse. We generated 77 recombinant antibodies from the identified sequences and found that 93% recognized the soluble antigen and 14% the membrane antigen. The platform also allowed recovery of ~450-900 IgG sequences from ~2,200 IgG-secreting activated human memory B cells, activated ex vivo, demonstrating its versatility.

Author Correction: High-throughput single-cell activity-based screening and sequencing of antibodies using droplet microfluidics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes.

Leber's Hereditary Optic Neuropathy (LHON) was the first maternally inherited mitochondrial disease identified and is now considered the most prevalent mitochondrial disorder. LHON patients harbor mutations in mitochondrial DNA (mtDNA). In about 90% of cases, the genes involved encode proteins of the respiratory chain complex I. Even though the molecular bases are known since 20 years almost all remains to be done regarding physiopathology and therapy. In this study, we report a severe decrease of complex I activity in cultured skin fibroblasts isolated from two LHON patients harboring mutations in ND4 or ND1 genes. Most importantly, we were able to restore sustainably (a) the ability to grow on galactose, (b) the ATP synthesis rate and (c) the complex I activity, initially impaired in these cells. Our strategy consisted of forcing mRNAs from nuclearly-encoded ND1 and ND4 genes to localize to the mitochondrial surface. The rescue of the respiratory chain defect observed was possible by discreet amounts of hybrid mRNAs and fusion proteins demonstrating the efficiency of their mitochondrial import. Hence, we confirmed here for two mitochondrial genes located in the organelle that the optimized allotopic expression approach represents a powerful tool that could ultimately be applied in human therapy for LHON.

Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits.

The possibility of synthesizing mitochondrial DNA (mtDNA)-coded proteins in the cytosolic compartment, called allotopic expression, provides an attractive option for genetic treatment of human diseases caused by mutations of the corresponding genes. However, it is now appreciated that the high hydrophobicity of proteins encoded by the mitochondrial genome represents a strong limitation on their mitochondrial import when translated in the cytosol. Recently, we optimized the allotopic expression of a recoded ATP6 gene in human cells, by forcing its mRNA to localize to the mitochondrial surface. In this study, we show that this approach leads to a long-lasting and complete rescue of mitochondrial dysfunction of fibroblasts harboring the neurogenic muscle weakness, ataxia and retinitis Pigmentosa T8993G ATP6 mutation or the Leber hereditary optic neuropathy G11778A ND4 mutation. The recoded ATP6 gene was associated with the cis-acting elements of SOD2, while the ND4 gene was associated with the cis-acting elements of COX10. Both ATP6 and ND4 gene products were efficiently translocated into the mitochondria and functional within their respective respiratory chain complexes. Indeed, the abilities to grow in galactose and to produce adenosine triphosphate (ATP) in vitro were both completely restored in fibroblasts allotopically expressing either ATP6 or ND4. Notably, in fibroblasts harboring the ATP6 mutation, allotopic expression of ATP6 led to the recovery of complex V enzymatic activity. Therefore, mRNA sorting to the mitochondrial surface represents a powerful strategy that could ultimately be applied in human therapy and become available for an array of devastating disorders caused by mtDNA mutations.

Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss.

Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in ~70% of all cases, a point mutation in the mitochondrial NADH dehydrogenase subunit 4, ND4, gene leads to central vision loss. We optimized allotopic expression (nuclear transcription of a gene that is normally transcribed inside the mitochondria) aimed at designing a gene therapy for ND4; its coding sequence was associated with the cis-acting elements of the human COX10 mRNA to allow the efficient mitochondrial delivery of the protein. After ocular administration to adult rats of a recombinant adeno-associated viral vector containing the human ND4 gene, we demonstrated that: (i) the sustained expression of human ND4 did not lead to harmful effects, instead the human protein is efficiently imported inside the mitochondria and assembled in respiratory chain complex I; (ii) the presence of the human protein in the experimental model of Leber hereditary optic neuropathy significantly prevents retinal ganglion cell degeneration and preserves both complex I function in optic nerves and visual function. Hence, the use of optimized allotopic expression is relevant for treating mitochondrial disorders due to mutations in the organelle genome.

Gene therapy for mitochondrial diseases: Leber Hereditary Optic Neuropathy as the first candidate for a clinical trial.

Mitochondrial disorders cannot be ignored anymore in most medical disciplines; indeed their minimum estimated prevalence is superior to 1 in 5000 births. Despite the progress made in the last 25 years on the identification of gene mutations causing mitochondrial pathologies, only slow progress was made towards their effective treatments. Ocular involvement is a frequent feature in mitochondrial diseases and corresponds to severe and irreversible visual handicap due to retinal neuron loss and optic atrophy. Interestingly, three clinical trials for Leber Congenital Amaurosis due to RPE65 mutations are ongoing since 2007. Overall, the feasibility and safety of ocular Adeno-Associated Virus delivery in adult and younger patients and consistent visual function improvements have been demonstrated. The success of gene-replacement therapy for RPE65 opens the way for the development of similar approaches for a broad range of eye disorders, including those with mitochondrial etiology such as Leber Hereditary Optic Neuropathy (LHON).