Oral History Interview: Milton J. Ferguson

Mr. Ferguson was born in Wayne, West Virginia, on a farm at the Forks of Twelve Pole Creek. At the time of the interview he was still living in Wayne. Subjects discussed in this interview include: family background, early education and transportation. He also talks about his work as an attorney, Director of the Federal Land Bank, and as a U.S. District Attorney. Mr. Ferguson recollects the Scopes Trial and the Harding Scandals.https://mds.marshall.edu/oral_history/1075/thumbnail.jp

Territorial rights and colonial wrongs

What is wrong with colonialism? The standard—albeit often implicit—answer to this question has been that colonialism was wrong because it violated the territorial rights of indigenous peoples, where territorial rights were grounded on acquisition theories. Recently, the standard view has come under attack: according to critics, acquisition based accounts do not provide solid theoretical grounds to condemn colonial relations. Indeed, historically they were used to justify colonialism. Various alternative accounts of the wrong of colonialism have been developed. According to some, colonialism involved a violation of territorial rights grounded on legitimate state theory. Others reject all explanations of colonialism's wrongfulness based on territorial rights, and argue that colonial practices were wrong because they departed from ideals of economic, social, and political association. In this article, we articulate and defend the standard view against critics: colonialism involved a procedural wrong; this wrong is not the violation of standards of equality and reciprocity, but the violation of territorial rights; and the best foundation for such territorial rights is acquisition based, not legitimacy based. We argue that this issue is not just of historical interest, it has relevant implications for the normative evaluation of contemporary inequalities

Mycobacterium tuberculosis Glucosyl-3-Phosphoglycerate Synthase: Structure of a Key Enzyme in Methylglucose Lipopolysaccharide Biosynthesis

Tuberculosis constitutes today a serious threat to human health worldwide, aggravated by the increasing number of identified multi-resistant strains of Mycobacterium tuberculosis, its causative agent, as well as by the lack of development of novel mycobactericidal compounds for the last few decades. The increased resilience of this pathogen is due, to a great extent, to its complex, polysaccharide-rich, and unusually impermeable cell wall. The synthesis of this essential structure is still poorly understood despite the fact that enzymes involved in glycosidic bond synthesis represent more than 1% of all M. tuberculosis ORFs identified to date. One of them is GpgS, a retaining glycosyltransferase (GT) with low sequence homology to any other GTs of known structure, which has been identified in two species of mycobacteria and shown to be essential for the survival of M. tuberculosis. To further understand the biochemical properties of M. tuberculosis GpgS, we determined the three-dimensional structure of the apo enzyme, as well as of its ternary complex with UDP and 3-phosphoglycerate, by X-ray crystallography, to a resolution of 2.5 and 2.7 Å, respectively. GpgS, the first enzyme from the newly established GT-81 family to be structurally characterized, displays a dimeric architecture with an overall fold similar to that of other GT-A-type glycosyltransferases. These three-dimensional structures provide a molecular explanation for the enzyme's preference for UDP-containing donor substrates, as well as for its glucose versus mannose discrimination, and uncover the structural determinants for acceptor substrate selectivity. Glycosyltransferases constitute a growing family of enzymes for which structural and mechanistic data urges. The three-dimensional structures of M. tuberculosis GpgS now determined provide such data for a novel enzyme family, clearly establishing the molecular determinants for substrate recognition and catalysis, while providing an experimental scaffold for the structure-based rational design of specific inhibitors, which lay the foundation for the development of novel anti-tuberculosis therapies

State-level tracking of COVID-19 in the United States

As of 1st June 2020, the US Centers for Disease Control and Prevention reported 104,232 confirmed or probable COVID-19-related deaths in the US. This was more than twice the number of deaths reported in the next most severely impacted country. We jointly model the US epidemic at the state-level, using publicly available deathdata within a Bayesian hierarchical semi-mechanistic framework. For each state, we estimate the number of individuals that have been infected, the number of individuals that are currently infectious and the time-varying reproduction number (the average number of secondary infections caused by an infected person). We use changes in mobility to capture the impact that non-pharmaceutical interventions and other behaviour changes have on therate of transmission of SARS-CoV-2. We estimate thatRtwas only below one in 23 states on 1st June. We also estimate that 3.7% [3.4%-4.0%] of the total population of the US had been infected, with wide variation between states, and approximately 0.01% of the population was infectious. We demonstrate good 3 week model forecasts of deaths with low error and good coverage of our credible intervals

Long-Term Outcomes in Percutaneous Radiofrequency Ablation for Histologically Proven Colorectal Lung Metastasis

Introduction To evaluate the long-term outcome of image-guided radiofrequency ablation (RFA) when treating histologically confirmed colorectal lung metastasis in terms of overall survival (OS), progression-free survival (PFS) and local tumour control (LTC). Materials and Methods Retrospective single-centre study. Consecutive RFA treatments of histologically proven lung colorectal metastases between 01/01/2008 and 31/12/14. The primary outcome was patient survival (OS and PFS). Secondary outcomes were local tumour progression (LTP) and complications. Prognostic factors associated with OS/ PFS were determined by univariate and multivariate analyses. Results Sixty patients (39 males: 21 females; median age 69 years) and 125 colorectal lung metastases were treated. Eighty percent (n = 48) also underwent lung surgery for lung metastases. Mean metastasis size (cm) was 1.4 ± 0.6 (range 0.3–4.0). Median number of RFA sessions was 1 (1–4). During follow-up (median 45.5 months), 45 patients died (75%). The estimated OS and PFS survival rates at 1, 3, 5, 7, 9 years were 96.7%, 74.7%, 44.1%, 27.5%, 16.3% (median OS, 52 months) and 66.7%, 31.2%, 25.9%, 21.2% and 5.9% (median PFS, 19 months). The LTC rate was 90% with 6 patients developing LTP with 1-, 2-, 3- and 4-year LTP rates of 3.3%, 8.3%, 10.0% and 10.0%. Progression-free interval < 1 year (P = 0.002, HR = 0.375) and total number of pulmonary metastases (≥ 3) treated (P = 0.037, HR = 0.480) were independent negative prognostic factors. Thirty-day mortality rate was 0% with no intra-procedural deaths. Conclusion The long-term OS and PFS following RFA for the treatment of histologically confirmed colorectal lung metastases demonstrate comparable oncological durability to surgery

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

Geoffrey Wingfield Harris’ demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the G(q) signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention

An Isolated Stellar-Mass Black Hole Detected Through Astrometric Microlensing

We report the first unambiguous detection and mass measurement of an isolated stellar-mass black hole (BH). We used the Hubble Space Telescope (HST) to carry out precise astrometry of the source star of the long-duration (t_E ~ 270 days), high-magnification microlensing event MOA-2011-BLG-191/OGLE-2011-BLG-0462, in the direction of the Galactic bulge. HST imaging, conducted at eight epochs over an interval of six years, reveals a clear relativistic astrometric deflection of the background star's apparent position. Ground-based photometry shows a parallactic signature of the effect of the Earth's motion on the microlensing light curve. Combining the HST astrometry with the ground-based light curve and the derived parallax, we obtain a lens mass of 7.1 +/- 1.3 M_Sun and a distance of 1.58 +/- 0.18 kpc. We show that the lens emits no detectable light, which, along with having a mass higher than is possible for a white dwarf or neutron star, confirms its BH nature. Our analysis also provides an absolute proper motion for the BH. The proper motion is offset from the mean motion of Galactic-disk stars at similar distances by an amount corresponding to a transverse space velocity of ~45 km/s, suggesting that the BH received a modest natal 'kick' from its supernova explosion. Previous mass determinations for stellar-mass BHs have come from radial-velocity measurements of Galactic X-ray binaries, and from gravitational radiation emitted by merging BHs in binary systems in external galaxies. Our mass measurement is the first ever for an isolated stellar-mass BH using any technique

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure &lt;= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt