The Five Faces of Freedom in American Political and Constitutional Thought

In the deepest sense, this Article seeks to bridge the gap between philosophy, political theory, and constitutional law. It examines how our constitutional tradition conceives of freedom, perhaps the most important value in the American legal order. It discusses five distinct though intertwined traditions, each drawn from a different philosophical theory of freedom. These five faces of freedom are (1) the positive ideal—freedom as the right to vote and to take part in government, (2) the negative ideal—freedom from constraint or government interference, (3) the progressive ideal, (4) self-individuating liberalism— freedom as the right to discover, develop, and express one\u27s core identity, and (5) the homeostatic-communitarian ideal—freedom as inhering in a network of communal social relations located within a broader pluralistic society. Each Part. provides an overview of the philosophical foundation of one of the faces of freedom and then traces its constitutional development. The Article concludes by discussing how the contours of freedom have changed over the course of our history

3D printed ultrasound phantoms for clinical training

Ultrasound is a ubiquitous, portable structural imaging technique which is used to provide visual feedback for a range of diagnostic and surgical techniques. Training for these techniques demands a range of teaching models tailored for each application. Existing anatomical models are often overly simple or prohibitively expensive, causing difficulties in obtaining patient or procedure specific models. In this study we present ultrasonic rib phantoms for clinical teaching and training purposes, fabricated by three-dimensional (3D) printing technologies. Models were produced using freely available software and data, and their effectiveness as teaching phantoms evaluated using clinical ultrasound scans of the phantoms

Factors associated with variability in the assessment of UK doctors' professionalism: analysis of survey results.

OBJECTIVES: To investigate potential sources of systematic bias arising in the assessment of doctors' professionalism. DESIGN: Linear regression modelling of cross sectional questionnaire survey data. SETTING: 11 clinical practices in England and Wales. PARTICIPANTS: 1065 non-training grade doctors from various clinical specialties and settings, 17,031 of their colleagues, and 30,333 of their patients. MAIN OUTCOME MEASURES: Two measures of a doctor's professional performance using patient and colleague questionnaires from the United Kingdom's General Medical Council (GMC). We selected potential predictor variables from the characteristics of the doctors and of their patient and colleague assessors. RESULTS: After we adjusted for characteristics of the doctor as well as characteristics of the patient sample, less favourable scores from patient feedback were independently predicted by doctors having obtained their primary medical degree from any non-European country; doctors practising as a psychiatrist; lower proportions of white patients providing feedback; lower proportions of patients rating their consultation as being very important; and lower proportions of patients reporting that they were seeing their usual doctor. Lower scores from colleague feedback were independently predicted by doctors having obtained their primary medical degree from countries outside the UK and South Asia; currently employed in a locum capacity; working as a general practitioner or psychiatrist; being employed in a staff grade, associate specialist, or other equivalent role; and with a lower proportion of colleagues reporting they had daily or weekly professional contact with the doctor. In fully adjusted models, the doctor's age, sex, and ethnic group were not independent predictors of patient or colleague feedback. Neither the age or sex profiles of the patient or colleague samples were independent predictors of doctors' feedback scores, and nor was the ethnic group of colleague samples. CONCLUSIONS: Caution is necessary when considering patient and colleague feedback regarding doctors' professionalism. Multisource feedback undertaken for revalidation using the GMC patient and colleague questionnaires should, at least initially, be principally formative in nature

A critical evaluation of the Oscillayers methods and datasets

Here we evaluate Oscillayers, a new method that aims to estimate palaeoclimates for the past 5.4 Myr, and discuss the associated theoretical and methodological issues. We show that the theoretical foundation of Oscillayers is inherently limited, because the method cannot incorporate spatio‐temporal variation and different forcing mechanisms into climate reconstructions. In addition, several methodological weaknesses are clarified that entrench the palaeoclimatic reconstruction of Oscillayers to patterns of climate change observed between the Last Glacial Maximum and current climates. We test the utility of the Oscillayers method to produce palaeoclimatic reconstructions that are similar to general circulation model (GCM)‐based estimates. On average, only 55.6% of values in the mean annual temperature datasets across the Pliocene and Pleistocene were within ±3°C when compared with corresponding GCM‐based datasets. Furthermore, on average only 75.3% of values in the mean annual precipitation datasets across the Pliocene and Pleistocene were within ±200 mm of rainfall of the GCM‐based estimates. Our results demonstrate that the Oscillayers approach does not provide a robust approximation of palaeoclimatic conditions throughout the Plio‐Pleistocene. Thus, when these datasets are used for scientific analyses, the results should be interpreted with a full appreciation of their limitations, particularly for periods outside the last glacial cycle

Unraveling the B. pseudomallei Heptokinase WcbL: from structure to drug discovery

Journal ArticleOpen Access funded by Biotechnology and Biological Sciences Research Council under a Creative Commons Attribution 4.0 International Public LicenseGram-negative bacteria utilize heptoses as part of their repertoire of extracellular polysaccharide virulence determinants. Disruption of heptose biosynthesis offers an attractive target for novel antimicrobials. A critical step in the synthesis of heptoses is their 1-O phosphorylation, mediated by kinases such as HldE or WcbL. Here, we present the structure of WcbL from Burkholderia pseudomallei. We report that WcbL operates through a sequential ordered Bi-Bi mechanism, loading the heptose first and then ATP. We show that dimeric WcbL binds ATP anti-cooperatively in the absence of heptose, and cooperatively in its presence. Modeling of WcbL suggests that heptose binding causes an elegant switch in the hydrogen-bonding network, facilitating the binding of a second ATP molecule. Finally, we screened a library of drug-like fragments, identifying hits that potently inhibit WcbL. Our results provide a novel mechanism for control of substrate binding and emphasize WcbL as an attractive anti-microbial target for Gram-negative bacteria.Biotechnology and Biological Sciences Research Counci

Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism

<p>Abstract</p> <p>Background</p> <p>Arginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (<it>AVPR1A</it>) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at <it>AVPR1A </it>has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5'-flanking region of <it>AVPR1A </it>in variable gene expression and social behaviour.</p> <p>Methods</p> <p>We examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the <it>AVPR1A </it>gene for association in an autism cohort from Ireland. Two 5'-flanking region polymorphisms in the human <it>AVPR1A</it>, RS3 and RS1, were also tested for their effect on relative promoter activity.</p> <p>Results</p> <p>The short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (<it>P </it>= 0.036 and <it>P </it>= 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y.</p> <p>Conclusions</p> <p>These aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased <it>AVPR1A </it>transcription, which may proffer increased susceptibility to the autism phenotype.</p

Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials

Objectives. To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination. Design. There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naı¨ve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime–MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG. Results. MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination. Conclusions. The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here. Trial Registration. ClinicalTrials.Oxford University was the sponsor for all the clinical trials reported here

The Mechanical Behavior of a 25Cr Super Duplex Stainless Steel at Elevated Temperature

Peer reviewedPostprin