Towers of Gravitational Theories

In this essay we introduce a theoretical framework designed to describe black hole dynamics. The difficulties in understanding such dynamics stems from the proliferation of scales involved when one attempts to simultaneously describe all of the relevant dynamical degrees of freedom. These range from the modes that describe the black hole horizon, which are responsible for dissipative effects, to the long wavelength gravitational radiation that drains mechanical energy from macroscopic black hole bound states. We approach the problem from a Wilsonian point of view, by building a tower of theories of gravity each of which is valid at different scales. The methodology leads to multiple new results in diverse topics including phase transitions of Kaluza-Klein black holes and the interactions of spinning black hole in non-relativistic orbits. Moreover, our methods tie together speculative ideas regarding dualities for black hole horizons to real physical measurements in gravitational wave detectors.Comment: Awarded second prize for 2006 Gravity Research Foundation essay contes

Relationship among surgical volume, repair quality, and perioperative outcomes for repair of mitral insufficiency in a mitral valve reference center

ObjectiveAlthough it has been demonstrated that the repair rates and quality of the repair of mitral insufficiency are superior in mitral valve reference centers, it has not been studied whether an advantage exists for perioperative morbidity and mortality. We report 1 surgeon's evolution over 7 years, specifically considering the changes in perioperative morbidity and mortality.MethodsWe performed a retrospective review of 1054 patients who had undergone elective, day-of-surgery-admission mitral valve repair by a single surgeon (D.H.A.) at our institution from April 2005 to June 2012. The outcome variables studied were operative mortality (30-day or in-hospital mortality, if longer), length of stay, low cardiac output state after cardiopulmonary bypass, and major morbidity.ResultsThe overall operative mortality was 0.58%. Of the 1054 patients, 31% developed a low cardiac output state postoperatively and 6.52% experienced at least 1 of the composite morbidity events. Increased aortic crossclamp times were significantly and independently associated with a low cardiac output state, length of stay, and morbidity. When divided by service year, a statistically and clinically significant decrease was found in the aortic crossclamp time, despite an increase in the complexity of cases. The morbidity decreased concurrently with the decreases in crossclamp times.ConclusionsAs the number of mitral valve repairs performed each year by a single surgeon at a single institution increased, morbidity, including postoperative heart function and length of stay, decreased. This was demonstrated to occur in large part from a reduction in the aortic crossclamp times, despite an increase in the complexity of the procedures. This further demonstrates the value of reference centers for mitral valve surgery

Bayesian Analysis of the Polarization of Distant Radio Sources: Limits on Cosmological Birefringence

A recent study of the rotation of the plane of polarization of light from 160 cosmological sources claims to find significant evidence for cosmological anisotropy. We point out methodological weaknesses of that study, and reanalyze the same data using Bayesian methods that overcome these problems. We find that the data always favor isotropic models for the distribution of observed polarizations over counterparts that have a cosmological anisotropy of the type advocated in the earlier study. Although anisotropic models are not completely ruled out, the data put strong lower limits on the length scale $\lambda$ (in units of the Hubble length) associated with the anisotropy; the lower limits of 95% credible regions for $\lambda$ lie between 0.43 and 0.62 in all anisotropic models we studied, values several times larger than the best-fit value of $\lambda \approx 0.1$ found in the earlier study. The length scale is not constrained from above. The vast majority of sources in the data are at distances closer than 0.4 Hubble lengths (corresponding to a redshift of $\approx$0.8); the results are thus consistent with there being no significant anisotropy on the length scale probed by these data.Comment: 8 pages, 3 figures; submitted to Phys. Rev.

Spectroscopic investigations of intermediates in the reaction of cytochrome P450BM3–F87G with surrogate oxygen atom donors

Rapid mixing of substrate-free ferric cytochrome P450BM3–F87G with m-chloroperoxybenzoic acid (mCPBA) resulted in the sequential formation of two high-valent intermediates. The first was spectrally similar to compound I species reported previously for P450CAM and CYP 119 using mCPBA as an oxidant, and it featured a low intensity Soret absorption band characterized by shoulder at 370 nm. This is the first direct observation of a P450 compound I intermediate in a type II P450 enzyme. The second intermediate, which was much more stable at pH values below 7.0, was characterized by an intense Soret absorption peak at 406 nm, similar to that seen with P450CAM [T. Spolitak, J.H. Dawson, D.P. Ballou, J. Biol. Chem. 280 (2005) 20300–20309]. Double mixing experiments in which NADPH was added to the transient 406 nm-absorbing intermediate resulted in rapid regeneration of the resting ferric state, with the flavins of the flavoprotein domain in their reduced state. EPR results were consistent with this stable intermediate species being a cytochrome c peroxidase compound ES-like species containing a protein-based radical, likely localized on a nearby Trp or Tyr residue in the active site. Iodosobenzene, peracetic acid, and sodium m-periodate also generated the intermediate at 406 nm, but not the 370 nm intermediate, indicating a probable kinetic barrier to accumulating compound I in reactions with these oxidants. The P450 ES intermediate has not been previously reported using iodosobenzene or m-periodate as the oxygen donor

An exploration of the role of religion/spirituality in the promotion of physicians\u27 wellbeing in Emergency Medicine

BACKGROUND: Burnout is highly prevalent among Emergency Medicine (EM) physicians and has significant impact on quality of care and workforce retention. The objective of this study was to determine whether higher religion/spirituality (R/S) is associated with a lower prevalence of burnout among EM physicians (primary outcome). A history of malpractice lawsuits and maladaptive behaviors were the secondary outcomes. METHODS: This was a cross-sectional, survey-based study conducted among a random sample of physicians from the Massachusetts College of Emergency Physicians mailing list. Burnout was measured using a validated 2-item version of the Maslach Burnout Inventory. Maladaptive behaviors (smoking, drinking, and substance use) and medical malpractice were self-reported. R/S measures included organized religiosity, religious affiliation, private R/S practice, self-rated spirituality, religious rest, and religious commitment. Logistic regression was used to model study outcomes as a function of R/S predictors. RESULTS: Of 422 EM physicians who received the invitation to participate, 138 completed the survey (32.7%). The prevalence of burnout was 27%. No significant associations were observed between burnout and R/S indicators. Maladaptive behaviors (adjusted OR = 0.42, CI: 0.19 to 0.96; p = 0.039) and history of medical malpractice (adjusted OR = 0.32; CI: 0.11 to 0.93; p = 0.037) were less likely among physicians reporting to be more involved in organized religious activity and to observe a day of rest for religious reasons, respectively. CONCLUSION: This study provides preliminary evidence for a possible protective association of certain dimensions of R/S on maladaptive behaviors and medical malpractice among EM physicians

Magnetour: Surfing Planetary Systems on Electromagnetic and Multi-Body Gravity Fields

In this NIAC Phase One study, we propose a new mission concept, named Magnetour, to facilitate the exploration of outer planet systems and address both power and propulsion challenges. Our approach would enable a single spacecraft to orbit and travel between multiple moons of an outer planet, with no propellant required. Our approach would enable a single spacecraft to orbit and travel between multiple moons of an outer planet, with no propellant nor onboard power source required. To achieve this free-lunch _Grand Tour', we exploit the unexplored combination of magnetic and multi-body gravitational fields of planetary systems, with a unique focus on using a bare tether for power and propulsion. The main objective of the study is to develop this conceptually novel mission architecture, explore its design space, and investigate its feasibility and applicability to enhance the exploration of planetary systems within a 10-year timeframe. Propellantless propulsion technology offers enormous potential to transform the way NASA conducts outer planet missions. We hope to demonstrate that our free-lunch tour concept can replace heavy, costly, traditional chemical-based missions and can open up a new variety of trajectories around outer planets. Leveraging the powerful magnetic and multi-body gravity fields of planetary systems to travel freely among planetary moons would allow for long-term missions and provide unique scientific capabilities and flagship-class science for a fraction of the mass and cost of traditional concepts. New mission design techniques are needed to fully exploit the potential of this new concept.This final report contains the results and findings of the Phase One study, and is organized as follows. First, an overview of the Magnetour mission concept is presented. Then, the research methodology adopted for this Phase One study is described, followed by a brief outline of the main findings and their correspondence with the original Phase One task plan. Next, an overview of the environment of outer planets is provided, including magnetosphere, radiation belt and planetary moons. Then performance of electrodynamic tethers is assessed, as well as other electromagnetic systems. A method to exploit multi-body dynamics is given next. These analyses allow us to carry out a Jovian mission design to gain insight in the benefits of Magnetour. In addition, a spacecraft configuration is presented that fully incorporates the tether in the design. Finally technology roadmap considerations are discussed

Resolution of hepatic fibrosis after ZFN-mediated gene editing in the PiZ mouse model of human α1-antitrypsin deficiency

BACKGROUND: α1-antitrypsin deficiency is most commonly caused by a mutation in exon-7 of SERPINA1 (SA1-ATZ), resulting in hepatocellular accumulation of a misfolded variant (ATZ). Human SA1-ATZ-transgenic (PiZ) mice exhibit hepatocellular ATZ accumulation and liver fibrosis. We hypothesized that disrupting the SA1-ATZ transgene in PiZ mice by in vivo genome editing would confer a proliferative advantage to the genome-edited hepatocytes, enabling them to repopulate the liver. METHODS: To create a targeted DNA break in exon-7 of the SA1-ATZ transgene, we generated 2 recombinant adeno-associated viruses (rAAV) expressing a zinc-finger nuclease pair (rAAV-ZFN), and another rAAV for gene correction by targeted insertion (rAAV-TI). PiZ mice were injected i.v. with rAAV-TI alone or the rAAV-ZFNs at a low (7.5×1010vg/mouse, LD) or a high dose (1.5×1011vg/mouse, HD), with or without rAAV-TI. Two weeks and 6 months after treatment, livers were harvested for molecular, histological, and biochemical analyses. RESULTS: Two weeks after treatment, deep sequencing of the hepatic SA1-ATZ transgene pool showed 6%±3% or 15%±4% nonhomologous end joining in mice receiving LD or HD rAAV-ZFN, respectively, which increased to 36%±12% and 36%±12%, respectively, 6 months after treatment. Two weeks postinjection of rAAV-TI with LD or HD of rAAV-ZFN, repair by targeted insertion occurred in 0.10%±0.09% and 0.25%±0.14% of SA1-ATZ transgenes, respectively, which increased to 5.2%±5.0% and 33%±13%, respectively, 6 months after treatment. Six months after rAAV-ZFN administration, there was a marked clearance of ATZ globules from hepatocytes, and resolution of liver fibrosis, along with reduction of hepatic TAZ/WWTR1, hedgehog ligands, Gli2, a TIMP, and collagen content. CONCLUSIONS: ZFN-mediated SA1-ATZ transgene disruption provides a proliferative advantage to ATZ-depleted hepatocytes, enabling them to repopulate the liver and reverse hepatic fibrosis

NS5A Resistance-Associated Substitutions in Patients with Genotype 1 Hepatitis C Virus:Prevalence and Effect on Treatment Outcome

Background & Aims The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. Methods NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. Results Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naïve patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. Conclusions Pretreatment ledipasvir-specific RASs that were present in 8–16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. Lay summary The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical trials where patients with genotype 1 HCV infection received treatments that included ledipasvir-sofosbuvir to determine how prevalent NS5A RASs are in patients at baseline, and found that ledipasvir-specific RASs were present in 8–16% of patients prior to treatment and had a negative impact on treatment outcome in subset of patient groups, particularly treatment-experienced patients with genotype 1a HCV