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Aims Data on safety outcomes of left atrial appendage occlusion (LAAO) in elderly patients are limited. This study aimed to compare the outcomes of LAAO between octogenarians (age 80–89) and nonagenarians (age ≥90) vs. younger patients (age ≤79). Methods and results We conducted a retrospective cohort study using the National Inpatient Sample database to identify patients hospitalized for LAAO from 2016 to 2020 and to compare in-hospital safety outcomes in octogenarians and nonagenarians vs. younger patients. The primary outcome was a composite of in-hospital all-cause mortality or stroke. Secondary outcomes included procedural complications, length of stay (LOS), and total costs. Outcomes were determined using logistic regression models. Among 84 140 patients hospitalized for LAAO, 32.9% were octogenarians, 2.8% were nonagenarians, and 64.3% were ≤79 years of age. Over the study period, the volume of LAAO increased in all age groups (all P trend < 0.01). After adjustment for clinical and demographic factors, octogenarians and nonagenarians had similar odds of in-hospital all-cause mortality or stroke [adjusted odds ratio (aOR) 1.41, 95% confidence interval (CI) 0.93–2.13 for octogenarians; aOR 1.69, 95% CI 0.67–3.92 for nonagenarians], cardiac tamponade, acute kidney injury, major bleeding, and blood transfusion, in addition to similar LOS and total costs compared with younger patients (all P > 0.05). However, octogenarians and nonagenarians had higher odds of vascular complications compared with younger patients (aOR 1.47, 95% CI 1.08–1.99 for octogenarians; aOR 1.60, 95% CI 1.18–2.97 for nonagenarians). Conclusion Octogenarians and nonagenarians undergoing LAAO have a similar safety profile compared with clinically similar younger patients except for higher odds of vascular complications. [ABSTRACT FROM AUTHOR]

Aims No prior study has been adequately powered to evaluate real-world safety outcomes in those receiving adjunctive ablation lesions beyond pulmonary vein isolation (PVI). We sought to evaluate characteristics and in-hospital complications among patients undergoing PVI with and without adjunctive lesions. Methods and results Patients in the National Cardiovascular Data Registry AFib Ablation Registry undergoing first-time atrial fibrillation (AF) ablation between 2016 and 2020 were identified and stratified into paroxysmal (PAF) and persistent AF, and separated into PVI only, PVI + cavotricuspid isthmus (CTI) ablation, and PVI + adjunctive (superior vena cava isolation, coronary sinus, vein of Marshall, atypical atrial flutter lines, other). Adjusted odds of adverse events were calculated using multivariable logistic regression. A total of 50 937 patients [PAF: 30 551 (60%), persistent AF: 20 386 (40%)] were included. Among those with PAF, there were no differences in the adjusted odds of complications between PVI + CTI or PVI + adjunctive when compared with PVI only. Among persistent AF, PVI + adjunctive was associated with a higher risk of any complication [3.0 vs. 4.5%, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.07–1.58] and major complication (0.8 vs. 1.4%, OR 1.56, 95% CI 1.10–2.21), while no differences were observed in PVI + CTI compared with PVI only. Overall, there was high heterogeneity in adjunctive lesion type, and those receiving adjunctive lesions had a higher comorbidity burden. Conclusion Additional CTI ablation was common without an increased risk of complications. Adjunctive lesions other than CTI are commonly performed in those with more comorbidities and were associated with an increased risk of complications in persistent AF, although the current analysis is limited by high heterogeneity in adjunctive lesion set type. [ABSTRACT FROM AUTHOR]

The article explores the fragment of a late medieval English folding almanac, analysed by historian Hilary Carey and academic J. P. Gumbert. Topics discussed include the acknowledgment of its textual contents in the 1963 book "A Catalogue of Incipits of Mediaeval Scientific Writings in Latin," the presence of schematic diagrams of the Vein Man and Zodiac Man on the parchment, and the accessibility of the fragment through the medieval manuscript collection of Cambridge University Library.

Objectives: Sofosbuvir and daclatasvir are direct-acting antivirals highly effective against hepatitis C virus. There is some in silico and in vitro evidence that suggests these agents may also be effective against SARS-CoV-2. This trial evaluated the effectiveness of sofosbuvir in combination with daclatasvir in treating patients with COVID-19.Methods: Patients with a positive nasopharyngeal swab for SARS-CoV-2 on RT-PCR or bilateral multi-lobar ground-glass opacity on their chest CT and signs of severe COVID-19 were included. Subjects were divided into two arms with one arm receiving ribavirin and the other receiving sofosbuvir/daclatasvir. All participants also received the recommended national standard treatment which, at that time, was lopinavir/ritonavir and single-dose hydroxychloroquine. The primary endpoint was time from starting the medication until discharge from hospital with secondary endpoints of duration of ICU stay and mortality.Results: Sixty-two subjects met the inclusion criteria, with 35 enrolled in the sofosbuvir/daclatasvir arm and 27 in the ribavirin arm. The median duration of stay was 5 days for the sofosbuvir/daclatasvir group and 9 days for the ribavirin group. The mortality in the sofosbuvir/daclatasvir group was 2/35 (6%) and 9/27 (33%) for the ribavirin group. The relative risk of death for patients treated with sofosbuvir/daclatasvir was 0.17 (95% CI 0.04-0.73, P = 0.02) and the number needed to treat for benefit was 3.6 (95% CI 2.1-12.1, P < 0.01).Conclusions: Given these encouraging initial results, and the current lack of treatments proven to decrease mortality in COVID-19, further investigation in larger-scale trials seems warranted. [ABSTRACT FROM AUTHOR]

Background: PD‐1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD‐L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD‐1 inhibitor pembrolizumab. Methods: Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6–12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD‐L1. Results: CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD‐L1+ CTCs (14/25, 64%) had significantly longer progression‐free survival (PFS) compared with patients with PD‐L1− CTCs (26.6 months vs. 5.5 months; p =.018). The 12‐month PFS rates were 76% versus 22% in the PD‐L1+ versus PD‐L1− CTCs groups (p =.012), respectively. A multivariate linear regression analysis confirmed that PD‐L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052–1.012; p =.026). Conclusion: Our results reveal the potential of CTCs as a noninvasive real‐time biopsy to evaluate PD‐L1 expression in patients with melanoma. PD‐L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. Implications for Practice: The present data suggest that PD‐L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings. The objective of this study was to determine whether PD‐L1 expression on circulating tumor cells can serve as a predictive biomarker of clinical benefit and response to treatment with the PD‐1 inhibitor pembrolizumab. [ABSTRACT FROM AUTHOR]

It is often assumed that 'Hayekian' or 'neoliberal' influences lay behind Conservative attacks on socialism in 1945 and subsequent calls to 'set the people free' in 1950 and 1951. This assumption has had consequences for our understanding of late-1940s Conservatism and for wider interpretations of post-war politics. Heeding recent calls to reconnect the inter-war and post-war parties and to pay closer attention to how opponents and contexts generate arguments, this article revisits senior Conservatives' rhetoric between 1945 and 1951 to break the link between neoliberal influence and freedom rhetoric. First, it argues that the rhetoric of 1945 was derived from a distinctly Conservative lineage of interwar argument and reflected strategies developed before the publication of F. A. Hayek's 'The Road to Serfdom'. Second, it demonstrates that senior Conservatives' emancipatory rhetoric in opposition after 1945 was neither a simple continuation of these themes nor primarily a response to the public's growing antipathy towards rationing and controls. Rather, such rhetoric was a complex response to Britain's immediate economic difficulties and the political challenges presented by austerity. Finally, the article sheds new light on the strategy that governed the party's campaigns in 1950 and 1951. Churchill and others' calls to 'set the people free' stemmed from a belief that the rhetorical opportunity lay in reconciling liberty with security. In that sense, the leadership had moved beyond begrudging compromises with the 'Attleean settlement' and was instead attempting to define a new identity within the parameters of the welfare state. [ABSTRACT FROM AUTHOR]

The Evidence-based Toxicology Collaboration hosted a workshop on "The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology," on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers fromagencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews inmedicine and healthcare, and stakeholders in industry, government, academia, and nongovernmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic reviewmethods in toxicology, historical antecedents in bothmedicine and toxicology, challenges to the translation of systematic review frommedicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic reviewmethods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic reviewmethods are applied in toxicology. [ABSTRACT FROM AUTHOR]

A list of full manuscripts, fragment manuscripts and excerpts from Ranulf Higden's "Polychronicon," discovered as of December 2016, is presented.

Interdisciplinary (ID) teams were created by the US Forest Service in response to environmental legislation. In 2008, we surveyed ID team leaders for National Environmental Policy Act (NEPA) analysis of 106 recreation-related projects conducted between 2005 and 2008. Results were compared with current workforce data and previous studies of ID team leadership and composition for NEPA assessments. ID teams were large in size and diverse in composition, with representatives of a broad range of disciplines and functional areas. The composition of ID teams may be changing from traditional natural resource management to more discipline-specific expertise. The role of social scientists and other human dimension specialists remains modest, despite the importance of social science questions inherent in recreation projects. Results reflect changes in agency hiring practices in the last 20 years and raise questions about the interdisciplinary nature of US Forest Service ID teams. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbon (PAH) quinone reductase (PQR) and catechol-O-methyltransferase (COMT), from the PAH-degradingMycobacteriumvanbaaleniiPYR-1, were demonstrated to be constitutive enzymes located in the soluble fraction of cell extracts. PQR activities for the reduction of 9,10-phenanthrenequinone and 4,5-pyrene- quinone were 1.40±0.13 and 0.12±0.01 µmol min-1 mg-protein-1, respectively. The exogenous catechols alizarin, anthrarobin, 2,3-dihydroxynaphthalene and esculetin inhibited PQR activity. Anthrarobin (100 µM) and esculetin (100 µM) inhibited 4,5-pyrenequinone reduction by 64-92%. COMT was involved in theO-methylation of 1,2-dihydroxyphenanthrene to form 1-methoxy-2-hydroxyphenanthrene and 1,2-dimethoxyphenanthrene. Both pyrene and 1-hydroxypyrene were metabolized byM. vanbaaleniiPYR-1 to form 1-methoxypyrene, 1-methoxy-2-hydroxypyrene, 1-hydroxy-2-methoxypyrene and 1,2-dimethoxypyrene. Among the catechols tested, anthrarobin showed the highest COMT activity (1.06±0.04 nmol/30 min-1 mg-protein-1). These results suggest that the PQR and COMT activities ofM. vanbaaleniiPYR-1 may play an important role in the detoxification of PAH catechols. [ABSTRACT FROM AUTHOR]

The ability of the fungus Beauveria bassiana ATCC 7159 to transform the antibacterial agent cinoxacin was investigated. Cultures in sucrose–peptone broth were dosed with cinoxacin, grown for 20 days, and then extracted with ethyl acetate. Two metabolites were detected and purified by high-performance liquid chromatography. The major metabolite was identified by mass and proton nuclear magnetic resonance spectra as 1-ethyl-1,4-dihydro-3-(hydroxymethyl)[1,3]dioxolo[4,5-g]cinnolin-4-one and the minor metabolite was identified as 1-ethyl-1,4-dihydro-6,7-dihydroxy-3-(hydroxymethyl)cinnolin-4-one. B. bassiana also reduced quinoline-3-carboxylic acid to 3-(hydroxymethyl)quinoline. [Copyright &y& Elsevier]

Petroleum middle distillates (PMDs), a class of hydrocarbons which boil between 350-700°F, are tumor promoters in mouse skin. The promotional activity is produced under conditions that also result in local changes, including chronic irritation and epidermal hyperplasia. The present study was conducted by comparing equal weekly doses of irritating and minimally or nonirritating test materials, to assess whether tumor promotion was a secondary response to these effects. Four PMDs, C10-C14 normal paraffins (NP), lightly refined paraffinic oil (LRPO), Jet Fuel A (JF), and steam-cracked gas oil (SCGO), were evaluated. Test materials were applied undiluted (2x/week) or as 28.6% (7x/week) or 50% (4x/week) concentrations in mineral oil for 52 weeks following initiation with dimethylbenzanthracene (DMBA). When applied undiluted, all materials produced moderate irritation and significant increases in tumor incidence. When NP, LRPO, or JF were applied in mineral oil diluent, skin irritation was generally ameliorated and few, if any, tumors were produced. SCGO was irritating and produced a significant increase in tumor frequency when administered in mineral-oil diluent. These data indicate that the promotional activity of straight-run PMDs is likely related to chronic irritation at the application site and not to dose. Thus, when used appropriately in the absence of prolonged irritation, these materials should not present a tumorigenic hazard to humans. [ABSTRACT FROM PUBLISHER]

Topical application of certain petroleum middle distillates (PMD) to mice produces skin tumors after long latency, and initiation/promotion protocols indicate that effect is associated with their tumor promoting activity. Since induction of sustained, potentiated epidermal hyperplasia is predictive of promoting activity, five compositionally distinct PMD [hydrodesulfurized kerosene (API 81-70); hydrodesulfurized PMD (API 81-10); odorless light petroleum hydrocarbons; severely hydrotreated light vacuum distillate (LVD); and lightly refined paraffinic oil (LRPO)] were assessed for their effects on epidermal hyperplasia PMD were administered (2 ×/week for 2 weeks) to skin of CD-1 mice Four quantitative biomarkers of epidermal hyperplasia were evaluated: epidermal thickness, number of nucleated epidermal cells per unit length of basement membrane, labeling (BrdUrd) index of epidermal cells, and induction of epidermal ornithine decarboxylase (ODC) activity. As positive controls, 12-O-tetradecanoylphorbol-13-acetate (TPA) and n-dodecane were utilized. PMD-induced skin irritation was evaluated visually and/or histopathologically. All five PMD produced dose-dependent, skin irritation and epidermal hyperplasia. On a weight basis the magnitude of the maximal PMD-induced effects was similar to that produced by n-dodecane, but >1000-fold less than that produced by TPA. Epidermal hyperplasia and subacute skin irritancy produced by the five PMD were similar. Of the four short-term markers of tumor promotion assessed, labeling index and epidermal ODC activity were predictive of the relative promoting activities of those PMD for which tumorigenicity bioassay data are available, i.e, API 81-07 > API 81-10 > LRPO. An apparent discrepancy to the predictability of epidermal ODC activity occurred with LRPO:toluene [1:1(v/v)]. This mixture is nontumorigenic, yet significantly induced epidermal ODC activity. This mixture, however, produced severe epidermal toxicity that precluded any meaningful analysis of short-term biomarkers in relationship to biological activity. [ABSTRACT FROM PUBLISHER]

The Metabolism of Acetonitrile to Cyanide by Isolated Rat Hepatocytes. FREEMAN, J. J., and HAYES, E. P. (1987). . , 263–271. The metabolism of saturated nitriles, including acetonitrile, has been assumed to occur by a cytochrome -450-dependent oxidation at the α-carbon, yielding a cyanohydrin intermediate which may spontaneously degrade to hydrogen cyanide and an aldehyde. However, results of studies in our laboratory suggest that formaldehyde is not a metabolite of acetonitrile. Since acetonitrile is structurally similar to iodomethane, a substrate for glutathione (GSH) -transferases, we hypothesized that the metabolism of acetonitrile to cyanide might also occur by a nucleophilic substitution reaction involving GSH. The present studies were conducted to investigate these hypotheses and to further our study of the effects of acetone on acetonitrile metabolism. Female Sprague–Dawley rats were pretreated with buthionine sulfoximine BSO (4 mmol/kg ip, at −4 and −2 hr), cobalt heme (90 μmol/kg sc, at −48 hr), acetone (1960 mg/kg po, at −24 hr), or vehicle, and hepatocytes were isolated after collagenase perfusion of the liver. BSO reduced the cellular GSH content by >80%, but did not appear to affect the metabolism of acetonitrile: the liberation of cyanide correlated with cytochrome -450, and not GSH, concentrations. Cobalt heme depleted hepatocellular cytochrome -450 (−45%) content, decreased cell yield and viability, and resulted in a marked reduction in the metabolism of acetonitrile to cyanide. Cobalt heme did not affect the recovery of sodium cyanide from hepatocyte suspensions. Pretreatment of rats with acetone resulted in a twofold increase in the metabolism of acetonitrile to cyanide. Addition of acetone inhibited acetonitrile metabolism, with an IC50 of 319 μM. These results suggest that the metabolism of acetonitrile to cyanide occurs by a cytochrome -40-dependent pathway, and not by a nucleophilic substitution reaction with GSH. [ABSTRACT FROM PUBLISHER]