Digital government West, Darrell M
2011., 20110815, 2011, 2005, 2005-01-01, 20050101
eBook
Few developments have had broader consequences for the public sector than the introduction of the Internet and digital technology. In this book, Darrell West discusses how new technology is altering ...governmental performance, the political process, and democracy itself by improving government responsiveness and increasing information available to citizens.
Using multiple methods--case studies, content analysis of over 17,000 government Web sites, public and bureaucrat opinion survey data, an e-mail responsiveness test, budget data, and aggregate analysis--the author presents the most comprehensive study of electronic government ever undertaken. Among other topics, he looks at how much change has taken place in the public sector, what determines the speed and breadth of e-government adoption, and what the consequences of digital technology are for the public sector.
Written in a clear and analytical manner, this book outlines the variety of factors that have restricted the ability of policy makers to make effective use of new technology. Although digital government offers the potential for revolutionary change, social, political, and economic forces constrain the scope of transformation and prevent government officials from realizing the full benefits of interactive technology.
The COVID‐2019 pandemic is the most severe acute public health threat of the twenty‐first century. To properly address this crisis with both robust testing and novel treatments, we require a deep ...understanding of the life cycle of the causative agent, the SARS‐CoV‐2 coronavirus. Here, we examine the architecture and self‐assembly properties of the SARS‐CoV‐2 nucleocapsid protein, which packages viral RNA into new virions. We determined a 1.4 Å resolution crystal structure of this protein's N2b domain, revealing a compact, intertwined dimer similar to that of related coronaviruses including SARS‐CoV. While the N2b domain forms a dimer in solution, addition of the C‐terminal spacer B/N3 domain mediates formation of a homotetramer. Using hydrogen‐deuterium exchange mass spectrometry, we find evidence that at least part of this putatively disordered domain is structured, potentially forming an α‐helix that self‐associates and cooperates with the N2b domain to mediate tetramer formation. Finally, we map the locations of amino acid substitutions in the N protein from over 38,000 SARS‐CoV‐2 genome sequences. We find that these substitutions are strongly clustered in the protein's N2a linker domain, and that substitutions within the N1b and N2b domains cluster away from their functional RNA binding and dimerization interfaces. Overall, this work reveals the architecture and self‐assembly properties of a key protein in the SARS‐CoV‐2 life cycle, with implications for both drug design and antibody‐based testing.
PDB Code(s): 6WZO and 6WZQ;
Neurological diseases are becoming increasingly prominent worldwide due to rapidly aging populations, which greatly contributes to increasing healthcare costs. The development of neuroprotective ...drugs has so far proven exceptionally difficult due to the blood-brain barrier. One novel approach to address this challenge is to administer drugs intranasally to noninvasively bypass the blood-brain barrier. The intranasal route can thus transport drugs directly to the brain from the nasal cavity along the olfactory and trigeminal nerves. The purpose of this review is to describe the details of this mechanism to better direct future research. The intranasal route is composed of two pathways, one being intracellular while the other being extracellular. The intracellular pathway begins with endocytosis by olfactory sensory cells, followed by axonal transport to their synaptic clefts in the olfactory bulb where the drug is exocytosed. This transynaptic process is repeated by olfactory neurons, thereby distributing the drug to other brain regions. In the extracellular mechanism, drugs are transported directly into the cerebral spinal fluid by first passing through the paracellular space across the nasal epithelium, then through the perineural space to the subarachnoid space of the brain. With a growing body of evidence and trials in both rodent and human models, this is an exciting area for research as therapeutics come to market.
The flow chart illustrates the key aspects of the extracellular mechanism for transportation to the CNS following intranasal administration. Display omitted
Patients requiring surgery for locally advanced rectal cancer often additionally undergo neoadjuvant chemoradiotherapy (NACRT), of which the effects on physical fitness are unknown. The aim of this ...feasibility and pilot study was to investigate the effects of NACRT and a 6 week structured responsive exercise training programme (SRETP) on oxygen uptake (V˙O2) at lactate threshold ( θˆL) in such patients.
We prospectively studied 39 consecutive subjects (27 males) with T3–4/N+ resection margin threatened rectal cancer who completed standardized NACRT. Subjects underwent cardiopulmonary exercise testing at baseline (pre-NACRT), at week 0 (post-NACRT), and week 6 (post-SRETP). Twenty-two subjects undertook a 6 week SRETP on a training bike (three sessions per week) between week 0 and week 6 (exercise group). These were compared with 17 contemporaneous non-randomized subjects (control group). Changes in V˙O2 at θˆL over time and between the groups were compared using a compound symmetry covariance linear mixed model.
Of 39 recruited subjects, 22 out of 22 (exercise) and 13 out of 17 (control) completed the study. There were differences between the exercise and control groups at baseline age, ASA score physical status, World Health Organisation performance status, and Colorectal Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity (CR-POSSUM) predicted mortality. In all subjects, V˙O2 at θˆL significantly reduced between baseline and week 0 −1.9 ml kg−1 min−1; 95% confidence interval (CI) −1.3, −2.6; P<0.0001. In the exercise group, V˙O2 at θˆL significantly improved between week 0 and week 6 (+2.1 ml kg−1 min−1; 95% CI +1.3, +2.9; P<0.0001), whereas the control group values were unchanged (−0.7 ml kg−1 min−1; 95% CI −1.66, +0.37; P=0.204).
NACRT before rectal cancer surgery reduces physical fitness. A structured exercise intervention is feasible post-NACRT and returns fitness to baseline levels within 6 weeks.
NCT: 01325909.
Atmospheric aerosols are complex mixtures of different chemical species, and individual particles exist in many different shapes and morphologies. Together, these characteristics contribute to the ...aerosol mixing state. This review provides an overview of measurement techniques to probe aerosol mixing state, discusses how aerosol mixing state is represented in atmospheric models at different scales, and synthesizes our knowledge of aerosol mixing state's impact on climate‐relevant properties, such as cloud condensation and ice nucleating particle concentrations, and aerosol optical properties. We present these findings within a framework that defines aerosol mixing state along with appropriate mixing state metrics to quantify it. Future research directions are identified, with a focus on the need for integrating mixing state measurements and modeling.
Key Points
We define aerosol mixing state and connect it to the physicochemical properties of aerosol particles
We discuss existing measurements and models to understand chemical and physicochemical mixing state
We explain the connection between aerosol mixing state and climate‐relevant aerosol properties
Owing to advances in radiotherapy, the physical properties of radiation can be optimized to enable individualized treatment; however, optimization is rarely based on biological properties and, ...therefore, treatments are generally planned with the assumption that all tumours respond similarly to radiation. Radiation affects multiple cellular pathways, including DNA damage, hypoxia, proliferation, stem cell phenotype and immune response. In this Review, we summarize the effect of these pathways on tumour responses to radiotherapy and the current state of research on genomic classifiers designed to exploit these variations to inform treatment decisions. We also discuss whether advances in genomics have generated evidence that could be practice changing and whether advances in genomics are now ready to be used to guide the delivery of radiotherapy alone or in combination.
We explore a Portalino-like model of dark matter and neutrino masses in which right-handed neutrino fields connect gauge neutral operators from the Standard Model and Hidden Sector. Neutrino masses ...are generated via a seesaw-like mechanism that can explain the light active neutrino masses. The model includes a “Portalino” state that connects the two sectors via the neutrino portal. Dark Matter in this model consists of a hidden sector Dirac fermion that dominantly freezes-out via resonant annihilations into other hidden sector states, which ultimately results in a population of Portalinos. Due to small mixing in the extended neutrino sector these Portalinos tend to be cosmologically long lived, decaying into Standard Model particles leading to constraints on the model from Big Bang Nucleosynthesis and measurements of the Cosmic Microwave Background radiation. Combining these limits with direct constraints on the size of the Portalino–neutrino mixing and the assumptions of the model the viable mass ranges for the Portalino states are found to be
0.02
eV
≲
m
n
≲
6.4
eV
or
489
MeV
≲
m
n
≲
TeV. Indirect dark matter signals in the form of highly boosted, mono-energetic Portalinos produced in Dark Matter annihilations provide a target for neutrino telescopes.
Abstract Background For acute myocardial infarction (AMI) without heart failure (HF), it is unclear if β-blockers are associated with reduced mortality. Objectives The goal of this study was to ...determine the association between β-blocker use and mortality in patients with AMI without HF or left ventricular systolic dysfunction (LVSD). Methods This cohort study used national English and Welsh registry data from the Myocardial Ischaemia National Audit Project. A total of 179,810 survivors of hospitalization with AMI without HF or LVSD, between January 1, 2007, and June 30, 2013 (final follow-up: December 31, 2013), were assessed. Survival-time inverse probability weighting propensity scores and instrumental variable analyses were used to investigate the association between the use of β-blockers and 1-year mortality. Results Of 91,895 patients with ST-segment elevation myocardial infarction and 87,915 patients with non–ST-segment elevation myocardial infarction, 88,542 (96.4%) and 81,933 (93.2%) received β-blockers, respectively. For the entire cohort, with >163,772 person-years of observation, there were 9,373 deaths (5.2%). Unadjusted 1-year mortality was lower for patients who received β-blockers compared with those who did not (4.9% vs. 11.2%; p < 0.001). However, after weighting and adjustment, there was no significant difference in mortality between those with and without β-blocker use (average treatment effect ATE coefficient: 0.07; 95% confidence interval CI: −0.60 to 0.75; p = 0.827). Findings were similar for ST-segment elevation myocardial infarction (ATE coefficient: 0.30; 95% CI: −0.98 to 1.58; p = 0.637) and non–ST-segment elevation myocardial infarction (ATE coefficient: −0.07; 95% CI: −0.68 to 0.54; p = 0.819). Conclusions Among survivors of hospitalization with AMI who did not have HF or LVSD as recorded in the hospital, the use of β-blockers was not associated with a lower risk of death at any time point up to 1 year. (β-Blocker Use and Mortality in Hospital Survivors of Acute Myocardial Infarction Without Heart Failure; NCT02786654 )
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