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Studies of administrative politics focus primarily on political control and ignore organizational capacity. We argue that political and organizational factors, as well as the interaction between the two, are necessary for explaining executive policymaking. To test this theory, we consider the Office of Information and Regulatory Affairs (OIRA), an agency often perceived to be the president's political instrument. Using a new dataset of over 22,000 regulations reviewed by OIRA, we demonstrate that political factors influence review lengths, but organizational factors also exhibit a significant role. We find that reviews are longer when OIRA is understaffed and over-worked. Significantly, we demonstrate that low organizational capacity inhibits the president's ability to expedite priority rules. Overall, this study highlights the organizational limits of political control.

\"The Cambridge Companion to Twentieth Century Literature and Politics For a long time, people had been schooled to think of modern literature's relationship to politics as indirect or obscure, and often to find the politics of literature deep within its unconsciously ideological structures and forms. But twentieth-century writers were directly involved in political parties and causes, and many viewed their writing as part of their activism. This Companion tell a story of the rich and diverse ways in which literature and politics over the twentieth century coincided, overlapped - and also clashed. Covering some of the century's most influential political ideas, moments, and movements, nineteen academic experts uncover new ways of thinking about the relationship between literature and politics\"-- Provided by publisher.

The innate immune response is the first line of defense against viral pathogens, and in turn, many viruses have evolved strategies to evade detection by the host’s innate immune surveillance machinery. Investigation of the interplay between viruses and the innate immune response provides valuable insight into potential therapeutic targets against viral infectious diseases. JC polyomavirus (JCV), a DNA virus that leads to persistent infection in humans, is the causative agent of progressive multifocal leukoencephalopathy, a lethal brain disease that affects immunocompromised individuals. Almost nothing is currently known about how JCV infection is controlled by the innate immune response and, further, whether JCV has evolved mechanisms to antagonize antiviral immunity. Here, we show that the innate immune sensors retinoic acid-inducible gene I (RIG-I) and cGMP-AMP synthase (cGAS) control JCV replication in human astrocytes. We further identify that the small t antigen (tAg) of JCV functions as an interferon (IFN) antagonist by suppressing RIG-I-mediated signal transduction. JCV tAg interacts with the E3 ubiquitin ligase TRIM25, thereby preventing its ability to bind RNA and to induce the K63-linked ubiquitination of RIG-I, which is known to facilitate RIG-I-mediated cytokine responses. Antagonism of RIG-I K63-linked ubiquitination and antiviral signaling is also conserved in the tAg of the related polyomavirus BK virus (BKV). These findings highlight how JCV and BKV manipulate a key innate surveillance pathway, which may stimulate research into designing novel therapies. IMPORTANCE The innate immune response is the first line of defense against viral pathogens, and in turn, many viruses have evolved strategies to evade detection by the host’s innate immune surveillance machinery. Investigation of the interplay between viruses and the innate immune response provides valuable insight into potential therapeutic targets against viral infectious diseases. JC polyomavirus (JCV) is associated with a lifelong, persistent infection that can cause a rare neurodegenerative disease, called progressive multifocal leukoencephalopathy, in individuals that are immunosuppressed. The molecular mechanisms of JCV infection and persistence are not well understood, and very little is currently known about the relevance of innate immunity for the control of JCV replication. Here, we define the intracellular innate immune sensors responsible for controlling JCV infection and also demonstrate a novel mechanism by which a JCV-encoded protein acts as an antagonist of the type I interferon-mediated innate immune response.

Background Most adults with migraine never consult their family doctor or receive a formal diagnosis. It is often these people that turn to the internet for healthcare information. Here we describe the development and testing of an on-line version of a previously validated telephone migraine classification interview. Methods We co-produced and tested the tool with people with migraine, clinicians, a web-design company and the National Migraine Centre, a UK based charity. We started with an online stakeholder meeting to understand what resources people wanted and any potential obstacles and facilitators to successful implementation. At a consensus meeting we used nominal group technique to gain consensus on the key questions to include. We used a ‘Think Aloud technique’ with people with migraine to explore the performance and acceptability of the questions in the new tool. To validate it, we asked people with headache disorders, including migraine, to complete the online tool before a doctor specialising in headache diagnosed their headache type. Level of agreement was measured between the outcome of the new migraine tool and the diagnosis by the doctor for 100 participants. Results At the consensus meeting it was agreed that the questions for the new tool should be clear and easy to understand and distinguish between migraine, tension type headache, other primary headache disorders and medication overuse headache. For our initial validation exercise the level of agreement between the migraine quiz and the doctor diagnosis for 100 participants was 78% agreement. We made some adjustments to the wording and logic of the tool and repeated the validation exercise with 130 participants; the level of agreement was 80%. Conclusions Despite a careful development process our on-line tool did not perform to an adequate standard. There is a risk that misclassification could lead to people receiving inappropriate treatment. Any on-line classification tool for multiple headache disorders should be adequately validated before widespread use to avoid risk of iatrogenic harm. Clinical trial number Not applicable.

Low-back pain is a common and costly problem. We estimated the effectiveness of a group cognitive behavioural intervention in addition to best practice advice in people with low-back pain in primary care. In this pragmatic, multicentre, randomised controlled trial with parallel cost-effectiveness analysis undertaken in England, 701 adults with troublesome subacute or chronic low-back pain were recruited from 56 general practices and received an active management advisory consultation. Participants were randomly assigned by computer-generated block randomisation to receive an additional assessment and up to six sessions of a group cognitive behavioural intervention (n=468) or no further intervention (control; n=233). Primary outcomes were the change from baseline in Roland Morris disability questionnaire and modified Von Korff scores at 12 months. Assessment of outcomes was blinded and followed the intention-to-treat principle, including all randomised participants who provided follow-up data. This study is registered, number ISRCTN54717854. 399 (85%) participants in the cognitive behavioural intervention group and 199 (85%) participants in the control group were included in the primary analysis at 12 months. The most frequent reason for participant withdrawal was unwillingness to complete questionnaires. At 12 months, mean change from baseline in the Roland Morris questionnaire score was 1·1 points (95% CI 0·39–1·72) in the control group and 2·4 points (1·89–2·84) in the cognitive behavioural intervention group (difference between groups 1·3 points, 0·56–2·06; p=0·0008). The modified Von Korff disability score changed by 5·4% (1·99–8·90) and 13·8% (11·39–16·28), respectively (difference between groups 8·4%, 4·47–12·32; p<0·0001). The modified Von Korff pain score changed by 6·4% (3·14–9·66) and 13·4% (10·77–15·96), respectively (difference between groups 7·0%, 3·12–10·81; p<0·0001). The additional quality-adjusted life-year (QALY) gained from cognitive behavioural intervention was 0·099; the incremental cost per QALY was £1786, and the probability of cost-effectiveness was greater than 90% at a threshold of £3000 per QALY. There were no serious adverse events attributable to either treatment. Over 1 year, the cognitive behavioural intervention had a sustained effect on troublesome subacute and chronic low-back pain at a low cost to the health-care provider. National Institute for Health Research Health Technology Assessment Programme.

•Vaccine exemption cluster areas can help identify communities at high risk for disease outbreaks.•Heterogeneity of vaccine exemptions clusters exists in Michigan.•Vaccine exemption clusters can be delineated by exemption type (medical, religious and philosophical) in Michigan.•Michigan’s administrative rule change for vaccine exemptions impacted exemption clusters.•Vaccine exemption cluster type specific interventions may make best use of limited resources. This study explored vaccine exemption clustering in Michigan and examined whether vaccine exemptions clustered by exemption type (medical, religious, and philosophical). Furthermore, the study investigated whether Michigan’s nonmedical vaccine exemption policy change had an impact on type-specific vaccine exemption clusters following its implementation. The study used the ArcGIS optimized hot spot analysis tool to visually examine vaccine exemption clustering by type in Michigan. The study analyzed secondary kindergarten vaccine exemption data from 2301 elementary school buildings in Michigan for years spanning 2008 to 2015 and 2016 to 2017 post policy change. Clustering of vaccine exemptions by type was present both before and after implementation of the policy with fewer statistically significant features and differences regarding the distribution of hot spot clusters following the policy change. Considering the heterogeneity in vaccine exemption hot spot clustering by type can help to inform public health officials to areas/communities at high risk for vaccine preventable disease outbreaks. Such analysis can allow for the implementation of vaccine exemption interventions that are exemption type specific and tailored for a given area, thus maximizing impact and making best use of limited public health resources. This analysis was also able to showcase the impact of Michigan’s nonmedical vaccine exemption policy on vaccine exemption hot spot clusters.

In white wines, early detection of oxidation would alert winemakers to monitor potentially troubled wine more closely and take preventative measures to mitigate undesirable browning, flavors, and odors in their products. Current early oxidation detection methods include assessment by browning index, trained sensory panels, and quantification of byproducts such as quinones. The objective of this study was to assess the capability of the e‐tongue, a fairly new instrument that has previously been used to detect wine faults caused by spoilage organisms, in detecting early oxidative changes in Chardonnay wine. Clear bottles of Chardonnay were stored partially opened (treatment) in the dark at 2.2°C for 24 weeks. Wines were assessed at seven time intervals (0, 1, 2, 4, 8, 16, and 24 weeks) using the e‐tongue and a semi‐trained sensory panel with rate‐all‐that‐apply descriptors. Beginning at week 8 of storage, the e‐tongue discrimination indices (DI) between control and treated wine (sealed wine stored alongside partially opened wine bottles) were high (DI > 80%) and remained high throughout the study, indicating that the e‐tongue distinguished between control and treated samples. However, sensory panelists detected an increase in the intensity of vinegar/nail polish remover aroma attributes, attributes associated with wine oxidation, after 16 weeks of storage. These results suggest that the e‐tongue is a useful tool in the early detection of oxidized wine samples as compared to a sensory panel that perceived differences between control and treated wines 8 weeks after differences were detected by the e‐tongue. Beginning at week 8 of storage, the e‐tongue discrimination indices (DI) between control and treated wine (sealed wine stored alongside partially opened wine bottles) were high (DI > 80%) and remained high throughout the study, indicating that the e‐tongue distinguished between control and treated samples. However, sensory panelists detected an increase in the intensity of vinegar/nail polish remover aroma attributes, attributes associated with wine oxidation, after 16 weeks of storage. Alongside sensory testing, the e‐tongue shows promise for detecting early signs of oxidation.

ObjectiveTypically, migraine prevention trials focus on reducing migraine days. This narrow focus may not capture all that is important to people with migraine. Inconsistency in outcome selection across trials limits the potential for data pooling and evidence synthesis. In response, we describe the development of core outcome set for migraine (COSMIG).DesignA two-stage approach sought to achieve international, multistakeholder consensus on both the core domain set and core measurement set. Following construction of a comprehensive list of outcomes, expert panellists (patients, healthcare professionals and researchers) completed a three-round electronic-Delphi study to support a reduction and prioritisation of core domains and outcomes. Participants in a consensus meeting finalised the core domains and methods of assessment. All stages were overseen by an international core team, including patient research partners.ResultsThere was a good representation of patients (episodic migraine (n=34) and chronic migraine (n=42)) and healthcare professionals (n=33) with high response and retention rates. The initial list of domains and outcomes was reduced from >50 to 7 core domains for consideration in the consensus meeting, during which a 2-domain core outcome set was agreed.ConclusionInternational and multistakeholder consensus emerged to describe a two-domain core outcome set for reporting research on preventive interventions for chronic and episodic migraine: migraine-specific pain and migraine-specific quality of life. Intensity of migraine pain assessed with an 11-point Numerical Rating Scale and the frequency as the number of headache/migraine days over a specified time period. Migraine-specific quality of life assessed using the Migraine Functional Impact Questionnaire.

The endotoxin lipopolysaccharide (LPS) from Gram-negative bacteria exerts a direct and rapid effect on tissues. While most attention is given to the downstream actions of the immune system in response to LPS, this study focuses on the direct actions of LPS on skeletal muscle in Drosophila melanogaster. It was noted in earlier studies that the membrane potential rapidly hyperpolarizes in a dose-dependent manner with exposure to LPS from Pseudomonas aeruginosa and Serratia marcescens. The response is transitory while exposed to LPS, and the effect does not appear to be due to calcium-activated potassium channels, activated nitric oxide synthase (NOS), or the opening of Cl− channels. The purpose of this study was to further investigate the mechanism of the hyperpolarization of the larval Drosophila muscle due to exposure of LPS using several different experimental paradigms. It appears this response is unlikely related to activation of the Na-K pump or Ca2+ influx. The unknown activation of a K+ efflux could be responsible. This will be an important factor to consider in treatments of bacterial septicemia and cellular energy demands.