Inter-rater reliability and prognostic value of baseline Radiographic Assessment of Lung Edema (RALE) scores in observational cohort studies of inpatients with COVID-19.

OBJECTIVES: To reliably quantify the radiographic severity of COVID-19 pneumonia with the Radiographic Assessment of Lung Edema (RALE) score on clinical chest X-rays among inpatients and examine the prognostic value of baseline RALE scores on COVID-19 clinical outcomes. SETTING: Hospitalised patients with COVID-19 in dedicated wards and intensive care units from two different hospital systems. PARTICIPANTS: 425 patients with COVID-19 in a discovery data set and 415 patients in a validation data set. PRIMARY AND SECONDARY OUTCOMES: We measured inter-rater reliability for RALE score annotations by different reviewers and examined for associations of consensus RALE scores with the level of respiratory support, demographics, physiologic variables, applied therapies, plasma host-response biomarkers, SARS-CoV-2 RNA load and clinical outcomes. RESULTS: Inter-rater agreement for RALE scores improved from fair to excellent following reviewer training and feedback (intraclass correlation coefficient of 0.85 vs 0.93, respectively). In the discovery cohort, the required level of respiratory support at the time of CXR acquisition (supplemental oxygen or non-invasive ventilation (n=178); invasive-mechanical ventilation (n=234), extracorporeal membrane oxygenation (n=13)) was significantly associated with RALE scores (median (IQR): 20.0 (14.1-26.7), 26.0 (20.5-34.0) and 44.5 (34.5-48.0), respectively, p<0.0001). Among invasively ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, soluble receptor of advanced glycation end-products and soluble tumour necrosis factor receptor 1 (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted HR 1.04 (1.02-1.07), p=0.002). We replicated the significant associations of RALE scores with baseline disease severity and mortality in the independent validation data set. CONCLUSIONS: With a reproducible method to measure radiographic severity in COVID-19, we found significant associations with clinical and physiologic severity, host inflammation and clinical outcomes. The incorporation of radiographic severity assessments in clinical decision-making may provide important guidance for prognostication and treatment allocation in COVID-19.

Radiographic Assessment of Lung Edema (RALE) Scores are Highly Reproducible and Prognostic of Clinical Outcomes for Inpatients with COVID-19.

INTRODUCTION: Chest imaging is necessary for diagnosis of COVID-19 pneumonia, but current risk stratification tools do not consider radiographic severity. We quantified radiographic heterogeneity among inpatients with COVID-19 with the Radiographic Assessment of Lung Edema (RALE) score on Chest X-rays (CXRs). METHODS: We performed independent RALE scoring by ≥2 reviewers on baseline CXRs from 425 inpatients with COVID-19 (discovery dataset), we recorded clinical variables and outcomes, and measured plasma host-response biomarkers and SARS-CoV-2 RNA load from subjects with available biospecimens. RESULTS: We found excellent inter-rater agreement for RALE scores (intraclass correlation co-efficient=0.93). The required level of respiratory support at the time of baseline CXRs (supplemental oxygen or non-invasive ventilation [n=178]; invasive-mechanical ventilation [n=234], extracorporeal membrane oxygenation [n=13]) was significantly associated with RALE scores (median [interquartile range]: 20.0[14.1-26.7], 26.0[20.5-34.0] and 44.5[34.5-48.0], respectively, p<0.0001). Among invasively-ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, sRAGE and TNFR1 levels (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted hazard ratio 1.04[1.02-1.07], p=0.002). We validated significant associations of RALE scores with baseline severity and mortality in an independent dataset of 415 COVID-19 inpatients. CONCLUSION: Reproducible assessment of radiographic severity revealed significant associations with clinical and physiologic severity, host-response biomarkers and clinical outcome in COVID-19 pneumonia. Incorporation of radiographic severity assessments may provide prognostic and treatment allocation guidance in patients hospitalized with COVID-19.

Primary Central Nervous System Lymphoma: A Case of Solitary Brain Lesion.

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin's lymphoma (NHL) that involves the brain, leptomeninges, eyes, or spinal cord without evidence of systemic disease. This article presents a case of a 63-year-old Caucasian female with high-grade B-cell lymphoma who was found to have a solitary brain lesion and no distant metastasis upon diagnosis. The patient had left-sided weakness and difficulty standing on presentation and was found to have a right frontal lobe mass with surrounding mild vasogenic edema and a small focal area of hemorrhage concerning for high-grade glioma versus lymphoma on MRI. However, pathology results revealed high-grade B-cell lymphoma. The case reinforces the importance of working up any lesion suspicious for lymphoma/glioma. Diagnosis of high-grade B-cell lymphoma can be difficult based on morphological and cytological appearance due to varying gene expression and presentation at diagnosis. It can closely mimic diffuse B-cell lymphoma. Extensive workup including HIV serology, MRI imaging, evaluation for spinal cord involvement, and lumbar puncture (LP), to rule out cerebrospinal fluid (CSF) involvement, prior to initiating treatment needs to be done. The case also addresses high-grade methotrexate (MTX)-based chemotherapy as a treatment that improves mortality in patients with primary central nervous system (CNS) lymphoma.

Nasopharyngeal Swab for COVID-19 Test Necessitating Mechanical Ventilation and Tracheostomy.

We present the first-ever reported case of massive epistaxis following nasopharyngeal (NP) swabbing requiring intubation and tracheostomy. A 67-year-old male with a mechanical aortic valve on warfarin presented from a nursing home to the emergency department with hypoxia. NP swab for coronavirus disease 2019 (COVID-19) was obtained, immediately followed by significant epistaxis. Patient desaturated to low 80s requiring intubation for airway protection and hypoxemic respiratory failure. Anterior nasal packing was performed. The COVID-19 test resulted negative. Extubation was unsuccessful on days four and nine. The patient subsequently underwent tracheostomy and percutaneous endoscopic gastrostomy (PEG) tube placement. The patient was transferred to sub-acute rehabilitation with a tracheostomy tube on minimal ventilator support. The World Health Organization (WHO) has recommended obtaining an NP swab in COVID-19 suspects to test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using reverse transcriptase polymerase chain reaction (PCR).A study found that NP swabbing was associated with epistaxis in approximately 5-10% of the cases. Nursing home populations are at higher risk for COVID-19 and also reported to have increased use of oral anticoagulation for chronic atrial fibrillation with other co-morbidities (high CHADVASc score) which may increase bleeding risk with NP swabbing. Less invasive methods such as salivary and mid-turbinate sampling, nasal swab or saliva can be a better alternative sample for detecting SARS-CoV-2 as recommended by the Centers for Disease Control and Prevention (CDC) and suggested by FDA. Positive PCR testing beyond nine days of illness is likely due to persistent dead virus particles and thus repeat testing is not suggested. Obtaining a history of bleeding diathesis, use of oral anticoagulants and consideration of NP anatomy is advised before swabbing. This case report raises the concern against inadvertent NP swabbing in cases with a low pretest probability of COVID-19 infection with higher bleeding risk.

A 45-Year-Old Man with Scleroderma Renal Crisis Associated with a History of Systemic Sclerosis Sine Scleroderma.

BACKGROUND The diagnosis of systemic sclerosis sine scleroderma (ssSSc) with renal crisis is difficult because of its unusual presentation and rarity. CASE REPORT A 45-year-old man presented to the Emergency Department with worsening nausea, vomiting, and exertional dyspnea for 3 weeks. Initial examination showed blood pressure 182/108 mmHg without skin thickening or other skin manifestations. Laboratory investigations showed serum creatinine level 21.73 mg/dL and diffuse airspace opacities on chest radiography. He was admitted to the intensive care unit and started on emergent hemodialysis. He was anemic and became gradually hypoxic, requiring supplemental oxygen. Computed tomography of the chest showed bilateral infiltrates. Antinuclear antibodies (ANA) were positive for centromere pattern with titer of 320. Antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were negative. He was started on therapeutic plasmapheresis (TP) and captopril, which resulted in significant improvement of respiratory symptoms. The kidney biopsy revealed thrombotic microangiopathy. Anticentromere, anti-Scl-70, and antiribonucleic acid polymerase III antibodies, drawn after 4 sessions of TP, were not detected. CONCLUSIONS Here we report a rare case of ssSSc with renal crisis in a patient who presented with acute renal failure requiring hemodialysis and suspected pulmonary hemorrhage. Clinical improvement was achieved by TP and angiotensin-converting enzyme inhibitor. The diagnosis of ssSSc was difficult and required an ANA pattern and kidney biopsy.

Metformin Associated Lactic Acidosis in the Intensive Care Unit: A Rare Condition Mimicking Sepsis.

Metformin-associated lactic acidosis (MALA) is a rare but serious complication of metformin use, associated with high mortality. MALA can occur any time a patient on metformin suffers disruption in renal function resulting in the accumulation of metformin. A 63-year-old man with a history of non-insulin-dependent type 2 diabetes mellitus, alcohol abuse, and hypothyroidism was brought to the emergency department with altered mental status, nausea, vomiting, and abdominal pain. He was found to be in respiratory distress, was hypotensive and hypoglycemic (48 mg/dL), and required emergent intubation. Blood work was significant for pH<6.69, undetectable bicarbonate, anion gap 37.2 mEq/L, lactate >12 mmol/L, creatinine 15.95 mg/dL, blood urea nitrogen (BUN) 112 mg/dL, glomerular filtration rate (GFR), 3 ml/min/1.73sqm, and potassium 7 mmol/L. He suffered cardiac arrest, underwent cardiopulmonary resuscitation (CPR), and was admitted to the intensive care unit (ICU) where he required multiple vasopressors, bicarbonate infusion, and bicarbonate pushes. He was started on continuous renal replacement therapy with a high flux membrane. A high dose of pre- and post- filter fluids was used to improve conductive clearance. His pH corrected to normal in less than 24 hours, and hemodialysis was initiated the following day for a total of four days. Head/chest/abdomen/pelvis CT, urine, and blood cultures did not reveal any pathology that would explain lactic acidosis. The patient's dose of metformin was 1 gr twice daily and sitagliptin, 100 mg daily. Blood metformin that had been tested on admission was 29 mcg/ml (therapeutic range, 1-2 mcg/ml). Methanol, ethanol, ethylene glycol, propylene glycol, and isopropanol levels were negative. He had been started on lisinopril 5 mg and amitriptyline 25 mg four weeks prior to admission and had normal creatinine at that time. He was discharged to an acute rehabilitation facility on day seven of hospitalization. MALA generally presents with nausea, vomiting, and fatigue-often mimicking sepsis. It is possible that our patient progressively developed alcoholic ketoacidosis and acute renal failure from dehydration and excessive drinking in the setting of newly started Angiotensin-converting-enzyme (ACE) inhibitor. Recommendations for the optimal treatment of MALA mostly depend on expert opinion and case reports. Treatment is restricted to supportive measures, although hemodialysis may offer a protective effect. Our case demonstrates that even in extreme cases of MALA, prompt and adequate supportive measures can produce a favorable outcome.

Design and implementation of structural bioinformatics projects for biological sciences undergraduate students.

Contemporary biology is currently undergoing a revolution, driven by the availability of high-throughput technologies and a wide variety of bioinformatics tools. However, bioinformatics education and practice is still in its infancy in most of the African continent. Consequently, concerted efforts have been made in recent years to incorporate bioinformatics modules into biological sciences curriculum of African Universities. Despite this, one aspect of bioinformatics that is yet to be incorporated is structural bioinformatics. In this article, we report on a structural bioinformatics project carried out by final year project students in a Nigerian university. The target protein was the thermoacidophilic Sulfolobus islandicus rod-shaped virus 1 (SIRV1) Rep protein, which was further characterized using various free, user-friendly and online sequence-based and structure-based bioinformatics tools. This exercise gave students the opportunity to generate new data, interpret the data, and acquire collaborative research skills. In this report, emphasis is placed on analysis of the data generated to further encourage analytical skills. By sharing this experience, it is anticipated that other similar institutions would adopt parallel strategies to expose undergraduate students to structural biology, and increase awareness of freely available bioinformatics tools for tackling pertinent biological questions. © 2018 International Union of Biochemistry and Molecular Biology, 46(5):547-554, 2018.