An Acute Evolving Flaccid Quadriparesis in an Elderly Woman

Andrew Larner and colleagues discuss the differential diagnosis, investigation, and management of a 72-year-old woman presenting with progressive lower limb weakness who develops an acute evolving flaccid quadriparesis

A 50-Year-Old Man with Deteriorating Cognitive Function and Impaired Movement

Andrew Larner discusses the diagnosis and management of a man referred to the Cognitive Function Clinic with a 12- to 18-month history of deteriorating memory

On the dependence of the critical success index (CSI) on prevalence

The critical success index (CSI) is an established metric used in meteorology to verify the accuracy of weather forecasts. It is defined as the ratio of hits to the sum of hits, false alarms, and misses. Translationally, CSI has gained popularity as a unitary outcome measure in various clinical situations where large numbers of true negatives may influence the interpretation of other, more traditional, outcome measures, such as specificity (Spec) and negative predictive value (NPV), or when unified interpretation of positive predictive value (PPV) and sensitivity (Sens) is needed. The derivation of CSI from measures including PPV has prompted questions as to whether and how CSI values may vary with disease prevalence (P), just as PPV estimates are dependent on P, and hence whether CSI values are generalizable between studies with differing prevalences. As no detailed study of the relation of CSI to prevalence has been undertaken hitherto, the dataset of a previously published test accuracy study of a cognitive screening instrument was interrogated to address this question. Three different methods were used to examine the change in CSI across a range of prevalences, using both the Bayes formula and equations directly relating CSI to Sens, PPV, P, and the test threshold (Q). These approaches showed that, as expected, CSI does vary with prevalence, but the dependence differs according to the method of calculation that is adopted. Bayesian rescaling of both Sens and PPV generates a concave curve, suggesting that CSI will be maximal at a particular prevalence, which may vary according to the particular dataset

Critical success index or F measure to validate the accuracy of administrative healthcare data identifying epilepsy in deceased adults in Scotland

Background: Methods to undertake diagnostic accuracy studies of administrative epilepsy data are challenged bylack of a way to reliably rank case-ascertainment algorithms in order of their accuracy. This is because it isdifficult to know how to prioritise positive predictive value (PPV) and sensitivity (Sens). Large numbers of truenegative (TN) instances frequently found in epilepsy studies make it difficult to discriminate algorithm accuracyon the basis of negative predictive value (NPV) and specificity (Spec) as these become inflated (usually >90%).This study demonstrates the complementary value of using weather forecasting or machine learning metricscritical success index (CSI) or F measure, respectively, as unitary metrics combining PPV and sensitivity. Wereanalyse data published in a diagnostic accuracy study of administrative epilepsy mortality data in Scotland.Method: CSI was calculated as 1/[(1/PPV) + (1/Sens) – 1]. F measure was calculated as 2.PPV.Sens/(PPV +Sens). CSI and F values range from 0 to 1, interpreted as 0 = inaccurate prediction and 1 = perfect accuracy. Thepublished algorithms were reanalysed using these and their accuracy re-ranked according to CSI in order to allowcomparison to the original rankings.Results: CSI scores were conservative (range 0.02–0.826), always less than or equal to the lower of the correspondingPPV (range 39–100%) and sensitivity (range 2–93%). F values were less conservative (range0.039–0.905), sometimes higher than either PPV or sensitivity, but were always higher than CSI. Low CSI and Fvalues occurred when there was a large difference between PPV and sensitivity, e.g. CSI was 0.02 and F was0.039 in an instance when PPV was 100% and sensitivity was 2%. Algorithms with both high PPV and sensitivityperformed best in terms of CSI and F measure, e.g. CSI was 0.826 and F was 0.905 in an instance when PPV was90% and sensitivity was 91%.Conclusion: CSI or F measure can combine PPV and sensitivity values into a convenient single metric that is easierto interpret and rank in terms of diagnostic accuracy than trying to rank diagnostic accuracy according to the twomeasures themselves. CSI or F prioritise instances where both PPV and sensitivity are high over instances wherethere are large differences between PPV and sensitivity (even if one of these is very high), allowing diagnosticaccuracy thresholds based on combined PPV and sensitivity to be determined. Therefore, CSI or F measures maybe helpful complementary metrics to report alongside PPV and sensitivity in diagnostic accuracy studies ofadministrative epilepsy data

Asterixis.

Adams and Foley described asterixis in the 1940s in patients with hepatic encephalopathy, but it has since been associated with a wide range of potential causes, both in neurology and general medicine. Here, we review the history, characteristics and clinical significance of this important clinical sign

MicroRNA Expression Profiling in Mild Asthmatic Human Airways and Effect of Corticosteroid Therapy

BACKGROUND: Asthma is a common disease characterised by reversible airflow obstruction, bronchial hyperresponsiveness and chronic inflammation, which is commonly treated using corticosteroids such as budesonide. MicroRNAs (miRNAs) are a recently identified family of non-protein encoding genes that regulate protein translation by a mechanism entitled RNA interference. Previous studies have shown lung-specific miRNA expression profiles, although their importance in regulating gene expression is unresolved. We determined whether miRNA expression was differentially expressed in mild asthma and the effect of corticosteroid treatment. METHODOLOGY/PRINCIPAL FINDINGS: We have examined changes in miRNA using a highly sensitive RT-PCR based approach to measure the expression of 227 miRNAs in airway biopsies obtained from normal and mild asthmatic patients. We have also determined whether the anti-inflammatory action of corticosteroids are mediated through miRNAs by determining the profile of miRNA expression in mild asthmatics, before and following 1 month twice daily treatment with inhaled budesonide. Furthermore, we have analysed the expression of miRNAs from individual cell populations from the airway and lung. We found no significant difference in the expression of 227 miRNAs in the airway biopsies obtained from normal and mild asthmatic patients. In addition, despite improved lung function, we found no significant difference in the miRNA expression following one month treatment with the corticosteroid, budesonide. However, analysis of bronchial and alveolar epithelial cells, airway smooth muscle cells, alveolar macrophages and lung fibroblasts demonstrate a miRNA expression profile that is specific to individual cell types and demonstrates the complex cellular heterogeneity within whole tissue samples. CONCLUSIONS: Changes in miRNA expression do not appear to be involved in the development of a mild asthmatic phenotype or in the anti-inflammatory action of the corticosteroid budesonid

Stat3 oxidation-dependent regulation of gene expression impacts on developmental processes and involves cooperation with Hif-1α

© 2020 Grillo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Reactive oxygen species are bona fide intracellular second messengers that influence cell metabolism and aging by mechanisms that are incompletely resolved. Mitochondria generate superoxide that is dis-mutated to hydrogen peroxide, which in turn oxidises cysteine-based enzymes such as phosphatases, peroxiredoxins and redox-sensitive transcription factors to modulate their activity. Signal Transducer and Activator of Transcription 3 (Stat3) has been shown to participate in an oxidative relay with peroxiredoxin II but the impact of Stat3 oxidation on target gene expression and its biological consequences remain to be established. Thus, we created murine embryonic fibroblasts (MEFs) that express either WTStat3 or a redox-insensitive mutant of Stat3 (Stat3-C3S). The Stat3-C3S cells differed from WT-Stat3 cells in morphology, proliferation and resistance to oxidative stress; in response to cytokine stimulation, they displayed elevated Stat3 tyrosine phosphorylation and Socs3 expression, implying that Stat3-C3S is insensitive to oxidative inhibition. Comparative analysis of global gene expression in WT-Stat3 and Stat3-C3S cells revealed differential expression (DE) of genes both under basal conditions and during oxidative stress. Using differential gene regulation pattern analysis, we identified 199 genes clustered into 10 distinct patterns that were selectively responsive to Stat3 oxidation. GO term analysis identified down-regulated genes to be enriched for tissue/organ development and morphogenesis and up-regulated genes to be enriched for cell-cell adhesion, immune responses and transport related processes. Although most DE gene promoters contain consensus Stat3 inducible elements (SIEs), our chromatin immunoprecipitation (ChIP) and ChIP-seq analyses did not detect Stat3 binding at these sites in control or oxidant-stimulated cells, suggesting that oxidised Stat3 regulates these genes indirectly. Our further computational analysis revealed enrichment of hypoxia response elements (HREs) within DE gene promoters, implying a role for Hif-1. Experimental validation revealed that efficient stabilisation of Hif-1α in response to oxidative stress or hypoxia required an oxidation-competent Stat3 and that depletion of Hif-1α suppressed the inducible expression of Kcnb1, a representative DE gene. Our data suggest that Stat3 and Hif-1α cooperate to regulate genes involved in immune functions and developmental processes in response to oxidative stress

The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes

The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1-/- mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1-/- mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1-/- mice expressed increased amounts of PGC1α, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1α promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1α. Since STAT1-/-mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1-/- mice did not lose lipid from WAT. β-adrenergic stimulation of glycerol release from isolated STAT1-/- WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1-/- adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1-/- mice