High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT

Supermanifolds, symplectic geometry and curvature

We present a survey of some results and questions related to the notion of scalar curvature in the setting of symplectic supermanifolds.Comment: Dedicated to Jaime Mu\~noz-Masqu\'e on occasion of his 65th birthda

Particle Collisions on Stringy Black Hole Background

The collision of two particles in the background of a Sen black hole is studied. With the equations of motion of the particles, the center-of-mass energy is investigated when the collision takes place at the horizon of a Sen black hole. For an extremal Sen black hole, we find that the center-of-mass energy will be arbitrarily high with two conditions: (1) spin $a\neq 0$ and (2) one of the colliding particles has the critical angular momentum $l_{\text{c}}=2$. For a nonextremal Sen black hole, we show that, in order to obtain an unlimited center-of-mass energy, one of the colliding particles should have the critical angular momentum $l'_{\text{c}}=2 r_{+}/a$ ($r_{+}$ is the radius of the outer horizon for a nonextremal black hole). However, a particle with the angular momentum $l=l'_{\text{c}}$ could not approach the black hole from outside of the horizon through free fall, which implies that the collision with arbitrarily high center-of-mass energy could not take place. Thus, there is an upper bound of the center-of-mass energy for the nonextremal black hole. We also obtain the maximal center-of-mass energy for a near-extremal black hole and the result implies that the Planck-scale energy is hard to be approached. Furthermore, we also consider the back-reaction effects. The result shows that, neglecting the gravitational radiation, it has a weak effect on the center-of-mass energy. However, we argue that the maximum allowed center-of-mass energy will be greatly reduced to below the Planck-scale when the gravitational radiation is included.Comment: 17 pages, 4 figures, published versio

Staphylococcus aureus in the oral cavity: a three-year retrospective analysis of clinical laboratory data

OBJECTIVE: A retrospective analysis of laboratory data to investigate the isolation of Staphylococcus aureus from the oral cavity and facial area in specimens submitted to a regional diagnostic oral microbiology laboratory. METHODS: A hand search of laboratory records for a three-year period (1998-2000) was performed for specimens submitted to the regional diagnostic oral microbiology laboratory based at Glasgow Dental Hospital and School. Data were collected from forms where S. aureus was isolated. These data included demographics, referral source, specimen type, methicillin susceptibility and clinical details. RESULTS: For the period 1998-2000, there were 5,005 specimens submitted to the laboratory. S. aureus was isolated from 1,017 specimens, of which 967 (95%) were sensitive to methicillin (MSSA) and 50 (5%) were resistant to methicillin (MRSA). The 1,017 specimens were provided from 615 patients. MRSA was isolated from 37 (6%) of patients. There was an increasing incidence of S. aureus with age, particularly in the greater than 70 years age group. The most common specimen from which MSSA was isolated was an oral rinse (38%) whilst for MRSA isolates this was a tongue swab (28%). The clinical condition most commonly reported for MSSA isolates was angular cheilitis (22%). Erythema, swelling, pain or burning of the oral mucosa was the clinical condition most commonly reported for MRSA isolates (16%). Patients from whom the MSSA isolates were recovered were most commonly (55%) seen in the oral medicine clinic at the dental hospital, whilst patients with MRSA were more commonly seen in primary care settings such as nursing homes, hospices and general dental practice (51%). CONCLUSION: In line with more recent surveys, this retrospective study suggests that S. aureus may be a more frequent isolate from the oral cavity than hitherto suspected. A small proportion of the S. aureus isolates were MRSA. There were insufficient data available to determine whether the S. aureus isolates were colonising or infecting the oral cavity. However, the role of S. aureus in several diseases of the oral mucosa merits further investigation

Lifting defects for nonstable K_0-theory of exchange rings and C*-algebras

The assignment (nonstable K_0-theory), that to a ring R associates the monoid V(R) of Murray-von Neumann equivalence classes of idempotent infinite matrices with only finitely nonzero entries over R, extends naturally to a functor. We prove the following lifting properties of that functor: (1) There is no functor F, from simplicial monoids with order-unit with normalized positive homomorphisms to exchange rings, such that VF is equivalent to the identity. (2) There is no functor F, from simplicial monoids with order-unit with normalized positive embeddings to C*-algebras of real rank 0 (resp., von Neumann regular rings), such that VF is equivalent to the identity. (3) There is a {0,1}^3-indexed commutative diagram D of simplicial monoids that can be lifted, with respect to the functor V, by exchange rings and by C*-algebras of real rank 1, but not by semiprimitive exchange rings, thus neither by regular rings nor by C*-algebras of real rank 0. By using categorical tools from an earlier paper (larders, lifters, CLL), we deduce that there exists a unital exchange ring of cardinality aleph three (resp., an aleph three-separable unital C*-algebra of real rank 1) R, with stable rank 1 and index of nilpotence 2, such that V(R) is the positive cone of a dimension group and V(R) is not isomorphic to V(B) for any ring B which is either a C*-algebra of real rank 0 or a regular ring.Comment: 34 pages. Algebras and Representation Theory, to appea

Get screened: a pragmatic randomized controlled trial to increase mammography and colorectal cancer screening in a large, safety net practice

Abstract Background Most randomized controlled trials of interventions designed to promote cancer screening, particularly those targeting poor and minority patients, enroll selected patients. Relatively little is known about the benefits of these interventions among unselected patients. Methods/Design "Get Screened" is an American Cancer Society-sponsored randomized controlled trial designed to promote mammography and colorectal cancer screening in a primary care practice serving low-income patients. Eligible patients who are past due for mammography or colorectal cancer screening are entered into a tracking registry and randomly assigned to early or delayed intervention. This 6-month intervention is multimodal, involving patient prompts, clinician prompts, and outreach. At the time of the patient visit, eligible patients receive a low-literacy patient education tool. At the same time, clinicians receive a prompt to remind them to order the test and, when appropriate, a tool designed to simplify colorectal cancer screening decision-making. Patient outreach consists of personalized letters, automated telephone reminders, assistance with scheduling, and linkage of uninsured patients to the local National Breast and Cervical Cancer Early Detection program. Interventions are repeated for patients who fail to respond to early interventions. We will compare rates of screening between randomized groups, as well as planned secondary analyses of minority patients and uninsured patients. Data from the pilot phase show that this multimodal intervention triples rates of cancer screening (adjusted odds ratio 3.63; 95% CI 2.35 - 5.61). Discussion This study protocol is designed to assess a multimodal approach to promotion of breast and colorectal cancer screening among underserved patients. We hypothesize that a multimodal approach will significantly improve cancer screening rates. The trial was registered at Clinical Trials.gov NCT00818857http://deepblue.lib.umich.edu/bitstream/2027.42/78264/1/1472-6963-10-280.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78264/2/1472-6963-10-280.pdfPeer Reviewe

Photoswitchable diacylglycerols enable optical control of protein kinase C.

Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling

Supersymmetric Aether

It has been suggested by Groot Nibbelink and Pospelov that Lorentz invariance can be an emergent symmetry of low-energy physics provided the theory enjoys a non-relativistic version of supersymmetry. We construct a model that realizes the latter symmetry dynamically: it breaks Lorentz invariance but leaves the supersymmetry generators intact. The model is a supersymmetric extension of the dynamical aether theory of Jacobson and Mattingly. It shows rich dynamics and possesses a family of inequivalent vacua realizing different symmetry breaking patterns. In particular, we find stable vacua that break spontaneously spatial isotropy. Supersymmetry breaking terms give masses to fermionic and bosonic partners of the aether field. We comment on the coupling of the model to supergravity and on the implications for Horava gravity.Comment: 21 pages, no figure

Translational Retinal Research and Therapies

The following review summarizes the state of the art in representative aspects of gene therapy/translational medicine and evolves from a symposium held at the School of Veterinary Medicine, University of Pennsylvania on November 16, 2017 honoring Dr. Gustavo Aguirre, recipient of ARVO's 2017 Proctor Medal. Focusing on the retina, speakers highlighted current work on moving therapies for inherited retinal degenerative diseases from the laboratory bench to the clinic

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression