Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

Predicting performance using background characteristics of international medical graduates in an inner-city university-affiliated Internal Medicine residency training program

<p>Abstract</p> <p>Background</p> <p>IMGs constitute about a third of the United States (US) internal medicine graduates. US residency training programs face challenges in selection of IMGs with varied background features. However data on this topic is limited. We analyzed whether any pre-selection characteristics of IMG residents in our internal medicine program are associated with selected outcomes, namely competency based evaluation, examination performance and success in acquiring fellowship positions after graduation.</p> <p>Methods</p> <p>We conducted a retrospective study of 51 IMGs at our ACGME accredited teaching institution between 2004 and 2007. Background resident features namely age, gender, self-reported ethnicity, time between medical school graduation to residency (pre-hire time), USMLE step I & II clinical skills scores, pre-GME clinical experience, US externship and interest in pursuing fellowship after graduation expressed in their personal statements were noted. Data on competency-based evaluations, in-service exam scores, research presentation and publications, fellowship pursuance were collected. There were no fellowships offered in our hospital in this study period. Background features were compared between resident groups according to following outcomes: (a) annual aggregate graduate PGY-level specific competency-based evaluation (CBE) score above versus below the median score within our program (scoring scale of 1 – 10), (b) US graduate PGY-level specific resident in-training exam (ITE) score higher versus lower than the median score, and (c) those who succeeded to secure a fellowship within the study period. Using appropriate statistical tests & adjusted regression analysis, odds ratio with 95% confidence intervals were calculated.</p> <p>Results</p> <p>94% of the study sample were IMGs; median age was 35 years (Inter-Quartile range 25th – 75th percentile (IQR): 33–37 years); 43% women and 59% were Asian physicians. The median pre-hire time was 5 years (IQR: 4–7 years) and USMLE step I & step II clinical skills scores were 85 (IQR: 80–88) & 82 (IQR: 79–87) respectively. The median aggregate CBE scores during training were: PG1 5.8 (IQR: 5.6–6.3); PG2 6.3 (IQR 6–6.8) & PG3 6.7 (IQR: 6.7 – 7.1). 25% of our residents scored consistently above US national median ITE scores in all 3 years of training and 16% pursued a fellowship.</p> <p>Younger residents had higher aggregate annual CBE score than the program median (p < 0.05). Higher USMLE scores were associated with higher than US median ITE scores, reflecting exam-taking skills. Success in acquiring a fellowship was associated with consistent fellowship interest (p < 0.05) and research publications or presentations (p <0.05). None of the other characteristics including visa status were associated with the outcomes.</p> <p>Conclusion</p> <p>Background IMG features namely, age and USMLE scores predict performance evaluation and in-training examination scores during residency training. In addition enhanced research activities during residency training could facilitate fellowship goals among interested IMGs.</p

An Early Cambrian Rift to Post-Rift Transition in the Cordillera of Western North America

The upper Proterozoic and lower Palaeozoic wedge of miogeoclinal strata in the North American Cordillera is widely regarded as evidence for a proto-Pacific passive margin. The rifting history of this margin appears to have been protracted, possibly spanning more than 200 Myr in a tectonic setting that is not well understood. Quantitative subsidence analyses of lower Palaeozoic strata between British Columbia and Utah, however, provide indirect evidence that the transition from rifting to post-rift cooling occurred within a relatively short interval of time, although probably not synchronously, between 600 and 555 Myr. This age is significantly younger than that implied in previous studies. We describe here new field data, which, together with published geological data, provide direct evidence of a latest Proterozoic or early Cambrian age for the rift to post-rift transition. The data support recent arguments for widespread initiation of passive margins around the edge of the North American craton close to the Cambrian-Precambrian boundary

Selective expansion of viral variants following experimental transmission of a reconstituted feline immunodeficiency virus quasispecies

Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development

Nonthermal Emission from Star-Forming Galaxies

The detections of high-energy gamma-ray emission from the nearby starburst galaxies M82 & NGC253, and other local group galaxies, broaden our knowledge of star-driven nonthermal processes and phenomena in non-AGN star-forming galaxies. We review basic aspects of the related processes and their modeling in starburst galaxies. Since these processes involve both energetic electrons and protons accelerated by SN shocks, their respective radiative yields can be used to explore the SN-particle-radiation connection. Specifically, the relation between SN activity, energetic particles, and their radiative yields, is assessed through respective measures of the particle energy density in several star-forming galaxies. The deduced energy densities range from O(0.1) eV/cm^3 in very quiet environments to O(100) eV/cm^3 in regions with very high star-formation rates.Comment: 17 pages, 5 figures, to be published in Astrophysics and Space Science Proceeding

Testing the isotropy of the Dark Energy Survey's extreme trans-Neptunian objects

We test whether the population of "extreme" trans-Neptunian objects (eTNOs) detected in the Y4 Dark Energy Survey (DES) data exhibit azimuthal asymmetries which might be evidence of gravitational perturbations from an unseen super-Earth in a distant orbit. By rotating the orbits of the detected eTNOs, we construct a synthetic population which, when subject to the DES selection function, reproduces the detected distribution of eTNOs in the orbital elements $a,e,$ and $i$ as well as absolute magnitude $H$, but has uniform distributions in mean anomaly $M$, longitude of ascending node $\Omega,$ and argument of perihelion $\omega.$ We then compare the detected distributions in each of $\Omega, \omega,$ and $\varpi\equiv\Omega+\omega$ to those expected from the isotropic population, using Kuiper's variant of the Kolmogorov-Smirnov test. The three angles are tested for each of 4 definitions of the eTNO population, choosing among $a>(150,250)$ AU and perihelion $q>(30,37)$ AU. These choices yield 3--7 eTNOs in the DES Y4 sample. Among the twelve total tests, two have the likelihood of drawing the observed angles from the isotropic population at $p250, q>37$ AU, and the 4 detections at $a>250, q>30$ AU, have $\Omega$ distribution with $p=0.03$ of coming from the isotropic construction, but this is not strong evidence of anisotropy given the 12 different tests. The DES data taken on their own are thus consistent with azimuthal isotropy and do not require a "Planet 9" hypothesis. The limited sky coverage and object count mean, however, that the DES data by no means falsify this hypothesis.Comment: Accepted on PS

Testing the isotropy of the dark energy Survey's extreme trans-neptunian objects

We test whether the population of "extreme"trans-Neptunian objects (eTNOs) detected in the first four years of the Dark Energy Survey (DES Y4) data exhibit azimuthal asymmetries that might be evidence of gravitational perturbations from an unseen super-Earth in a distant orbit. By rotating the orbits of the detected eTNOs, we construct a synthetic population that, when subject to the DES selection function, reproduces the detected distribution of eTNOs in the orbital elements a, e, and i as well as absolute magnitude H, but has uniform distributions in mean anomaly M, longitude of ascending node Ω, and argument of perihelion ω. We then compare the detected distributions in each of Ω, ω, and the longitude of perihelion {equation presented} to those expected from the isotropic population, using Kuiper's variant of the Kolmogorov-Smirnov test. The three angles are tested for each of four definitions of the eTNO population, choosing among a > (150, 250) au and perihelion q > (30, 37) au. These choices yield 3-7 eTNOs in the DES Y4 sample. Among the 12 total tests, two have the likelihood of drawing the observed angles from the isotropic population at p 250 and q > 37 au and the four detections at a > 250 and q > 30 au have a Ω distribution with p ≈ 0.03 coming from the isotropic construction, but this is not strong evidence of anisotropy given the 12 different tests. The DES data taken on their own are thus consistent with azimuthal isotropy and do not require a "Planet 9"hypothesis. The limited sky coverage and object count mean, however, that the DES data by no means falsify this hypothesis

Phenotypic redshifts with self-organizing maps: A novel method to characterize redshift distributions of source galaxies for weak lensing

Wide-field imaging surveys such as the Dark Energy Survey (DES) rely on coarse measurements of spectral energy distributions in a few filters to estimate the redshift distribution of source galaxies. In this regime, sample variance, shot noise, and selection effects limit the attainable accuracy of redshift calibration and thus of cosmological constraints. We present a new method to combine wide-field, few-filter measurements with catalogs from deep fields with additional filters and sufficiently low photometric noise to break degeneracies in photometric redshifts. The multi-band deep field is used as an intermediary between wide-field observations and accurate redshifts, greatly reducing sample variance, shot noise, and selection effects. Our implementation of the method uses self-organizing maps to group galaxies into phenotypes based on their observed fluxes, and is tested using a mock DES catalog created from N-body simulations. It yields a typical uncertainty on the mean redshift in each of five tomographic bins for an idealized simulation of the DES Year 3 weak-lensing tomographic analysis of $\sigma_{\Delta z} = 0.007$, which is a 60% improvement compared to the Year 1 analysis. Although the implementation of the method is tailored to DES, its formalism can be applied to other large photometric surveys with a similar observing strategy.Comment: 24 pages, 11 figures; matches version accepted to MNRA

Systematic reviews of complementary therapies - an annotated bibliography. Part 1: Acupuncture

Background Complementary therapies are widespread but controversial. We aim to provide a comprehensive collection and a summary of systematic reviews of clinical trials in three major complementary therapies (acupuncture, herbal medicine, homeopathy). This article is dealing with acupuncture. Potentially relevant reviews were searched through the register of the Cochrane Complementary Medicine Field, the Cochrane Library, Medline, and bibliographies of articles and books. To be included articles had to review prospective clinical trials of acupuncture; had to describe review methods explicitly; had to be published; and had to focus on treatment effects. Information on conditions, interventions, methods, results and conclusions was extracted using a pretested form and summarized descriptively. Results From a total of 48 potentially relevant reviews preselected in a screeening process 39 met the inclusion criteria. 22 were on various pain syndromes or rheumatic diseases. Other topics addressed by more than one review were addiction, nausea, asthma and tinnitus. Almost unanimously the reviews state that acupuncture trials include too few patients. Often included trials are heterogeneous regarding patients, interventions and outcome measures, are considered to have insufficient quality and contradictory results. Convincing evidence is available only for postoperative nausea, for which acupuncture appears to be of benefit, and smoking cessation, where acupuncture is no more effective than sham acupuncture. Conclusions A large number of systematic reviews on acupuncture exists. What is most obvious from these reviews is the need for (the funding of) well-designed, larger clinical trials