The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP.

Mutations in the gene encoding NLRP3 cause a spectrum of autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS). NLRP3 is a key component of one of several distinct cytoplasmic multiprotein complexes (inflammasomes) that mediate the maturation of the proinflammatory cytokine interleukin-1ß (IL-1ß) by activating caspase-1. Although several models for inflammasome activation, such as K(+) efflux, generation of reactive oxygen species and lysosomal destabilization, have been proposed, the precise molecular mechanism of NLRP3 inflammasome activation, as well as the mechanism by which CAPS-associated mutations activate NLRP3, remain to be elucidated. Here we show that the murine calcium-sensing receptor (CASR) activates the NLRP3 inflammasome, mediated by increased intracellular Ca(2+) and decreased cellular cyclic AMP (cAMP). Ca(2+) or other CASR agonists activate the NLRP3 inflammasome in the absence of exogenous ATP, whereas knockdown of CASR reduces inflammasome activation in response to known NLRP3 activators. CASR activates the NLRP3 inflammasome through phospholipase C, which catalyses inositol-1,4,5-trisphosphate production and thereby induces release of Ca(2+) from endoplasmic reticulum stores. The increased cytoplasmic Ca(2+) promotes the assembly of inflammasome components, and intracellular Ca(2+) is required for spontaneous inflammasome activity in cells from patients with CAPS. CASR stimulation also results in reduced intracellular cAMP, which independently activates the NLRP3 inflammasome. cAMP binds to NLRP3 directly to inhibit inflammasome assembly, and downregulation of cAMP relieves this inhibition. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is substantially lower than for wild-type NLRP3, and the uncontrolled mature IL-1ß production from CAPS patients' peripheral blood mononuclear cells is attenuated by increasing cAMP. Taken together, these findings indicate that Ca(2+) and cAMP are two key molecular regulators of the NLRP3 inflammasome that have critical roles in the molecular pathogenesis of CAPS.

Abdominal imaging can misdiagnose submassive hepatic necrosis as cirrhosis in acute liver failure.

Patients with acute liver failure (ALF) can be listed status I for liver transplantation (LT) whereas patients with cirrhosis must follow the MELD scoring system. Liver imaging can mistakenly diagnose submassive hepatic necrosis in ALF as cirrhosis. The purpose of our study was to assess the accuracy of ultrasound (US) and computed tomography (CT) in distinguishing cirrhosis from ALF. All patients listed for ALF and transplanted during the study period were included. Controls were age- and gender-matched cirrhotic patients who underwent LT during the same period. Abdominal US or CT scans obtained on all patients were independently reviewed by three blinded abdominal radiologists. Explants from all patients were reviewed by two blinded pathologists, and histological diagnosis was correlated with radiological diagnosis. Forty-one patients with ALF and 42 patients with cirrhosis were analyzed. Univariate and multivariate analyses both revealed overall accuracy of 85% for ultrasound and 93% for CT. US and CT scans both provide high levels of accuracy in terms of discriminating ALF from cirrhosis but measures taken to determine whether a patient has ALF vs. cirrhosis needs to approach 100% accuracy. Thus, imaging studies alone should not definitively diagnosis one etiology of liver failure over the other.

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.

Systematic review of evidence on public health in the Democratic People's Republic of Korea.

BACKGROUND: Engaging in public health activities in the Democratic People's Republic of Korea (DPRK, also known as North Korea) offers a means to improve population health for its citizens and the wider region. Such an engagement requires an understanding of current and future needs. METHODS: We conducted a systematic search of five English and eight Korean language databases to identify available literature published between 1988 and 2017. A narrative review of evidence was conducted for five major categories (health systems, communicable diseases (CDs), non-communicable diseases (NCDs), injuries, and reproductive, maternal, newborn and child health (RMNCH) and nutrition). FINDINGS: We found 465 publications on the DPRK and public health. Of the 253 articles that addressed major disease categories, we found under-representation of publications relative to proportion of disease burden for the two most significant causes: NCDs (54.5% publications vs 72.6% disability adjusted life years (DALYs)) and injuries (0.4% publications vs 12.1% DALYs), in comparison to publications on the third and fourth largest disease burdens, RMNCH and nutrition (30.4% publications vs 8.6% DALYs) and CDs (14.6% publications vs 6.7% DALYs) which were over-represented. Although most disease category articles were on NCDs, the majority of NCD articles addressed mental health of refugees. Only 165 articles addressed populations within the DPRK and among these, we found publication gaps on social and environmental determinants of health, CDs, and NCDs. CONCLUSION: There are gaps in the public health literature on the DPRK. Future research should focus on under-studied, significant burdens of disease. Moreover, establishing more precise estimates of disease burden and their distribution, as well as analysis on health systems responses aimed at addressing them, can result in improvements in population health.

Long-term follow-up of blunt cerebrovascular injuries: Does time heal all wounds?

BACKGROUND: The short-term natural history of blunt cerebrovascular injuries (BCVIs) has been previously described in the literature, but the purpose of this study was to analyze long-term serial follow-up and lesion progression of BCVI. METHODS: This is a single institution's retrospective review of a prospectively collected database over four years (2009-2013). All patients with a diagnosis of BCVI by computed tomographic (CT) scan were identified, and injuries were graded based on modified Denver scale. Management followed institutional algorithm: initial whole-body contrast-enhanced CT scan, followed by CT angiography at 24 to 72 hours, 5 to 7 days, 4 to 6 weeks, and 3 months after injury. All follow-up imaging, medication management, and clinical outcomes through 6 months following injury were recorded. RESULTS: There were 379 patients with 509 injuries identified. Three hundred eighty-one injuries were diagnosed as BCVI on first CT (Grade 1 injuries, 126; Grade 2 injuries, 116; Grade 3 injuries, 69; and Grade 4 injuries, 70); 100 "indeterminate" on whole-body CT; 28 injuries were found in patients reimaged only for lesions detected in other vessels. Sixty percent were male, mean (SD) age was 46.5 (19.9) years, 65% were white, and 62% were victims of a motor vehicle crash. Most frequently, Grade 1 injuries were resolved at all subsequent time points. Up to 30% of Grade 2 injuries worsened, but nearly 50% improved or resolved. Forty-six percent of injuries originally not detected were subsequently diagnosed as Grade 3 injuries. Greater than 70% of all imaged Grade 3 and Grade 4 injuries remained unchanged at all subsequent time points. CONCLUSIONS: This study revealed that there are many changes in grade throughout the six-month time period, especially the lesions that start out undetectable or indeterminate, which become various grade injuries. Low-grade injuries (Grades 1 and 2) are likely to remain stable and eventually resolve. Higher-grade injuries (Grades 3 and 4) persist, many up to six months. Inpatient treatment with antiplatelet or anticoagulation did not affect BCVI progression. LEVEL OF EVIDENCE: Prognostic study, level III; therapeutic study, level IV.

Treatment of hepatitis C.

Hepatitis C virus is a leading cause of chronic liver disease, with over 170 million people infected worldwide. It is also the leading indication for liver transplantation. Complications from chronic hepatitis C infection include cirrhosis, hepatic decompensation, and hepatocellular carcinoma. As a result, treatment strategies to prevent such complications have been widely researched, although many questions remain unanswered. To date, the standard therapy for chronic hepatitis C infection is the combination of peginterferon and ribavirin. Treatment strategies differ based on factors such as genotype and liver biopsy results. Other strategies must be considered for special groups, such as patients with acute hepatitis C infection, hepatitis C/human immunodeficiency virus (HIV) coinfection, and prior nonresponse to interferon or relapse after its use. The goal of therapy is to achieve a sustained virologic response (ie, no detectable hepatitis C ribonucleic acid 6 months after completion of therapy). The substantial adverse effects associated with both interferon alfa and ribavirin often make it difficult for patients to continue with their therapies.