Our Toil Respite Only: Woolf, Diamond and the Difficulty of Reality

In this essay, I read Woolf’s To the Lighthouse together with philosopher Cora Diamond’s writing on literature and moral life, writing marked by her inheritance from Wittgenstein. I first attend to Woolf’s commitment (one she shares with Wittgenstein) to grappling with what I take to be signature issues of modernism: question, quest, and a longing for vision or revised understanding as a way of confronting the difficulty of reality. I then probe Woolf’s engagement with these issues by reading her novel in light of Diamond’s essay “The Difficulty of Philosophy and the Difficulty of Reality.” Diamond’s insights about literature’s capacity for ethical instruction, and her discussion in that essay of the experience of an ordinary sublime so painful or astonishing that it resists our understanding and categories of thought, illuminate a new philosophical context in which to understand more clearly and profoundly the stakes and aims of Woolf’s novel. Reading Woolf alongside Diamond also prompts us to recognize important ways in which matters that lie at the heart of To the Lighthouseintersect with the Wittgensteinian preoccupations that inform Diamond’s own thinking—concerns about the ethics of difficulty; skepticism about what other people think and feel; the search for communicative and existential clarity; the capacity of literature and fairy tale to convey a sense of beauty or of the “terrible” in the world; the status of expressions of our ethical experience as necessarily nonsensical; a longing for the sense of wholeness, transformative understanding, wonder, safety, and peace to stave off illusion or despair. One important subsidiary effect of looking at Woolf and Diamond together is that doing so also allows us to make significant oblique connections between Woolf’s thinking and Wittgenstein’s, connections that continue to bring into focus the philosophical sympathies that attest to the mutual relevance of their peculiar brands of modernism

Seasonal Variation of \u3ci\u3eE. coli\u3c/i\u3e Abundance and Antibiotic Resistance Patterns in Water and Sediment Samples From Two Creeks With Different Potential Fecal Contamination Sources.

Escherichia coli has served as the primary indicator for fecal contamination for the past 30 years, but more recent studies suggest that this bacteria may survive the cold weather in the soil making it difficult to tell whether it is new contamination or old contamination. Studies have found that exposure to various contaminants such as heavy metals, water treatment chemicals, agricultural runoff, fecal contamination, and antibiotics, creates an increase in the resistance of the microbes exposed to it. Wastewater treatment facilities, animal hospitals and wastewater sites increase the bacterial load and the prevalence of antibiotic resistance of bacteria residing bacteria in these watersheds. This research analyzed the prevalence, the antibiotic resistance, and the seasonal distribution of E. coli found in liquid and sediment samples from Thorn Creek and Deer Creek. It was hypothesized that where the highest potential for fecal contamination and nutrient loading exist would show increases in E. coli and changes to and increases in resistance to a variety of antibiotics. Thorn Creek and Deer Creek water and sediment were sampled and tested accordingly in late summer and mid-autumn. Both E. coli and coliform bacteria were enumerated. E. coli was then isolated and tested for antibiotic resistance patterns. The results found that there were spikes in E. coli counts at various intervals along the stream, with both expected results and some that did not support the original hypothesis. Differences in antibiotic resistance patterns among isolated E. coli were not significant, although some changes were apparent. The seasonal distribution of the E. coli was higher the liquid samples from those collected in summer having significantly more than those in autumn and spikes occurred at sites predicted to be higher based on potential fecal contamination. The sediment samples were still found to be contaminated with E. coli even after freezing. The data analysis revealed that resistance patterns were not heavily influenced by the potential fecal contamination as predicted. However, this research does suggest that E. coli may not be the most accurate indicator of fecal contamination as it is retained in the sediment well after it likely entered the ecosystem and if the resident E. coli are disturbed could falsely indicate novel fecal point source contamination

Rezidivrate bei rezidivierender Erosio corneae nach phototherapeutischer Keratektomie und Abhängigkeit der Rezidivrate von der Ablationstiefe und Erosiogenese

Der Erfolg der phototherapeutischen Keratektomie wurde bei 112 Patienten mit rezidivierender Erosio corneae über einen Nachbeobachtungszeitraum von 4,99 Jahren untersucht. Die Rezidivfreiheit bei rezidivierender Erosio traumatischer Genese (n=60) und subepithelialer Photoablation lag bei 73,5% (p=0,033) und bei transepithelialer PTK bei 66,6%, bei Map-Dot-Fingerprint Dystrophie (n=11) und subepithelialer PTK bei 71,4% und bei transepithelialer Photoablation bei 66,6%. Unter Einbeziehung der Pathogenese empfiehlt sich bei rezidivierender Erosio bei Map-Dot-Fingerprint Dystrophie eine Basalmembran nahe Ablationstiefe, um den immunohistochemischen Effekt am Ort des Stoffwechseldefekts zu induzieren. Bei der rez. Erosio traumatischer Genese ist eine subepitheliale oberflächliche Photoablation mit einer Ablationstiefe von ungefähr 2,5 bis 3,0µm ausreichend, da die PTK bedingte biochemische Kaskade eine gute Rezidivfreiheit (73,5%) mit einem Minimum an unerwünschten Wirkungen garantiert

Vasoaktive und immunologische Faktoren und ihre Veränderung nach koronarer Diagnostik und Intervention

Die Entwicklung der Restenose nach erfolgreicher koronarer Intervention ist immer noch eine problematische Komplikation. Einige neurohumerale, inflammatorische und antiinflammatorische Faktoren wurden in einer eigenen Studie untersucht. In dieser kontrollierten klinischen Studie an 96 Pat., die zur routinemässigen Durchführung einer Coronarangiographie, PTCA oder Stentimplantation stationär aufgenommen wurden, erfolgten zu definierten Zeitpunkten Bestimmungen der Plasmakonzentrationen von Adrenalin, Noradrenalin, Endothelin, CRP, IL-6, IL-10 und MCP-1. Infolge der koronaren Intervention kam es nicht nur zu einem Anstieg der neurohumeralen, sondern auch zu einem vermehrten Anstieg an inflammatorischen Faktoren, die untereinander eine Interaktion erkennen lassen. Auch ein erhöhter IL-10 Spiegel in der Stent-Gruppe läßt eine mögliche Reduktion der intimalen Hyperplasie vermuten. Ferner konnte anhand des MCP-1 für die routinemäßig gegebenen Medikamente antagonistische Wirkungen auf die nachgewiesene inflammatorische Reaktion nach Intervention aufgezeigt werden

Intraoperative Defibrillation Testing of Subcutaneous Implantable Cardioverter‐Defibrillator Systems—A Simple Issue?

Background: The results of the recently published randomized SIMPLE trial question the role of routine intraoperative defibrillation testing. However, testing is still recommended during implantation of the entirely subcutaneous implantable cardioverter‐defibrillator (S‐ICD) system. To address the question of whether defibrillation testing in S‐ICD systems is still necessary, we analyzed the data of a large, standard‐of‐care prospective single‐center S‐ICD registry. // Methods and Results: In the present study, 102 consecutive patients received an S‐ICD for primary (n=50) or secondary prevention (n=52). Defibrillation testing was performed in all except 4 patients. In 74 (75%; 95% CI 0.66–0.83) of 98 patients, ventricular fibrillation was effectively terminated by the first programmed internal shock. In 24 (25%; 95% CI 0.22–0.44) of 98 patients, the first internal shock was ineffective and further internal or external shock deliveries were required. In these patients, programming to reversed shock polarity (n=14) or repositioning of the sensing lead (n=1) or the pulse generator (n=5) led to successful defibrillation. In 4 patients, a safety margin of <10 J was not attained. Nevertheless, in these 4 patients, ventricular arrhythmias were effectively terminated with an internal 80‐J shock. // Conclusions: Although it has been shown that defibrillation testing is not necessary in transvenous ICD systems, it seems particular important for S‐ICD systems, because in nearly 25% of the cases the primary intraoperative test was not successful. In most cases, a successful defibrillation could be achieved by changing shock polarity or by optimizing the shock vector caused by the pulse generator or lead repositioning.<br

Tpeak-Tend, Tpeak-Tend/QT ratio and Tpeak-Tend dispersion for risk stratification in Brugada Syndrome:A systematic review and meta-analysis

Background: Brugada syndrome is an ion channelopathy that predisposes affected subjects to ventricular tachycardia/fibrillation (VT/VF), potentially leading to sudden cardiac death (SCD). Tpeak-Tend intervals, (Tpeak-Tend)/QT ratio and Tpeak-Tend dispersion have been proposed for risk stratification, but their predictive values in Brugada syndrome have been challenged recently. Methods: A systematic review and meta-analysis was conducted to examine their values in predicting arrhythmic and mortality outcomes in Brugada Syndrome. PubMed and Embase databases were searched until 1 May 2018, identifying 29 and 57 studies. Results: Nine studies involving 1740 subjects (mean age 45 years old, 80% male, mean follow-up duration was 68 ± 27 months) were included. The mean Tpeak-Tend interval was 98.9 ms (95% CI: 90.5-107.2 ms) for patients with adverse events (ventricular arrhythmias or SCD) compared to 87.7 ms (95% CI: 80.5-94.9 ms) for those without such events, with a mean difference of 11.9 ms (95% CI: 3.6-20.2 ms, P = 0.005; I2 = 86%). Higher (Tpeak-Tend)/QT ratios (mean difference = 0.019, 95% CI: 0.003-0.036, P = 0.024; I2 = 74%) and Tpeak-Tend dispersion (mean difference = 7.8 ms, 95% CI: 2.1-13.4 ms, P = 0.007; I2 = 80%) were observed for the event-positive group. Conclusion: Tpeak-Tend interval, (Tpeak-Tend)/QT ratio and Tpeak-Tend dispersion were higher in high-risk than low-risk Brugada subjects, and thus offer incremental value for risk stratification

Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome.

BACKGROUND: The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial. OBJECTIVES: This study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation. METHODS: Six whole hearts from male post-mortem cases of unexplained sudden death (mean age 23.2 years) with negative specialist cardiac autopsy and familial BrS were used and matched to 6 homograft control hearts by sex and age (within 3 years) by random risk set sampling. Cardiac autopsy sections from cases and control hearts were stained with picrosirius red for collagen. The RVOT was evaluated in detail, including immunofluorescent stain for connexin-43 (Cx43). Collagen and Cx43 were quantified digitally and compared. An in vivo study was undertaken on 6 consecutive BrS patients (mean age 39.8 years, all men) during epicardial RVOT ablation for arrhythmia via thoracotomy. Abnormal late and fractionated potentials indicative of slowed conduction were identified, and biopsies were taken before ablation. RESULTS: Collagen was increased in BrS autopsy cases compared with control hearts (odds ratio [OR]: 1.42; p = 0.026). Fibrosis was greatest in the RVOT (OR: 1.98; p = 0.003) and the epicardium (OR: 2.00; p = 0.001). The Cx43 signal was reduced in BrS RVOT (OR: 0.59; p = 0.001). Autopsy and in vivo RVOT samples identified epicardial and interstitial fibrosis. This was collocated with abnormal potentials in vivo that, when ablated, abolished the type 1 Brugada electrocardiogram without ventricular arrhythmia over 24.6 ± 9.7 months. CONCLUSIONS: BrS is associated with epicardial surface and interstitial fibrosis and reduced gap junction expression in the RVOT. This collocates to abnormal potentials, and their ablation abolishes the BrS phenotype and life-threatening arrhythmias. BrS is also associated with increased collagen throughout the heart. Abnormal myocardial structure and conduction are therefore responsible for BrS

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P&lt;5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P&lt;10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P&lt;10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P&lt;0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.</p

Genome Wide Analysis of Drug-Induced Torsades de Pointes: Lack of Common Variants with Large Effect Sizes

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing