Utilization of care among drug resistant epilepsy patients with symptoms of anxiety and depression

AbstractPurposeEpilepsy patients have a significantly higher rate of anxiety and depression than the general population, and psychiatric disease is particularly prevalent among drug resistant epilepsy patients. Symptoms of anxiety and depression might serve as a barrier to appropriate epilepsy care.The aim of this study was to determine if drug resistant epilepsy patients with symptoms of anxiety and/or depression receive different epilepsy management than controls.MethodWe identified 83 patients with drug resistant focal epilepsy seen at the Penn Epilepsy Center. Upon enrollment, all patients completed 3 self-report scales and a neuropsychiatric inventory and were grouped into those with symptoms of anxiety and/or depression and controls. Each patient's medical records were retrospectively reviewed for 1–2 years, and objective measures of outpatient and inpatient epilepsy management were assessed.ResultsAt baseline, 53% (n=43) of patients screened positive for symptoms of anxiety and/or depression. The remaining 47% (n=38) served as controls. Patients with anxiety and/or depression symptoms had more missed outpatient visits per year compared to controls (median 0.84 vs. 0.48, p=0.02). Patients with symptoms of both anxiety and depression were more likely to undergo an inpatient admission or procedure (56% vs. 24%, p=0.02).ConclusionFor most measures of epilepsy management, symptoms of anxiety and/or depression do not alter epilepsy care; however, drug resistant epilepsy patients with anxiety and/or depression symptoms may be more likely to miss outpatient appointments, and those with the highest burden of psychiatric symptoms may be admitted more frequently for inpatient services compared to controls

Descriptive oceanography during the Frontal Air‐Sea Interaction Experiment: Medium‐ to large‐scale variability

Medium‐ and large‐scale oceanographic variability in the Sargasso Sea is examined during the Frontal Air‐Sea Interaction Experiment (FASINEX), focusing primarily on processes that influence the formation of subtropical fronts. From Fall to Spring the mean meridional gradient of meridional Ekman transport in the Subtropical Convergence Zone (STCZ) enhances the meridional sea surface temperature (Ts) gradients between 26° and 32°N. In the presence of this enhanced mean gradient, baroclinic eddies with zonal wavelengths of ≈800 km and periods of ≈200 days exert the dominant influence on the formation of subtropical fronts at medium and large scales. These eddies generate westward propagating Ts anomaly features with the same dominant wavelengths and periods. They are confined between 26° and 32°N and have amplitudes that occasionally exceed ±1°C. Ts fronts tend to be found within bands ≈200 km wide that roughly follow the periphery of these anomaly features. Deformation in the horizontal eddy current field is primarily responsible for the existence of these frontal bands. The migration of the strong front originally bracketed by the FASINEX moored array was related to the westward propagation of the larger‐scale eddy/anomaly/frontal‐band pattern. The moored array was located within a warm‐anomaly feature during most of the experiment, which produced exceptionally warm conditions in the upper ocean. These anomalies are confined between 26° and 32°N, not only because the relatively large seasonal mean Tsy there allows horizontal eddy currents to force strong anomalies, but also because the baroclinic eddies with wavelengths of ≈800 km and periods of ≈200 days are confined to the STCZ. Large meridional variability exists in many properties of the eddy field, much of which can be traced to the influence of the Sargasso Sea mean current field on eddy variability

An Exactly Conservative Integrator for the n-Body Problem

The two-dimensional n-body problem of classical mechanics is a non-integrable Hamiltonian system for n > 2. Traditional numerical integration algorithms, which are polynomials in the time step, typically lead to systematic drifts in the computed value of the total energy and angular momentum. Even symplectic integration schemes exactly conserve only an approximate Hamiltonian. We present an algorithm that conserves the true Hamiltonian and the total angular momentum to machine precision. It is derived by applying conventional discretizations in a new space obtained by transformation of the dependent variables. We develop the method first for the restricted circular three-body problem, then for the general two-dimensional three-body problem, and finally for the planar n-body problem. Jacobi coordinates are used to reduce the two-dimensional n-body problem to an (n-1)-body problem that incorporates the constant linear momentum and center of mass constraints. For a four-body choreography, we find that a larger time step can be used with our conservative algorithm than with symplectic and conventional integrators.Comment: 17 pages, 3 figures; to appear in J. Phys. A.: Math. Ge

Substitution Patterns Are GC-Biased in Divergent Sequences across the Metazoans

The fastest-evolving regions in the human and chimpanzee genomes show a remarkable excess of weak (A,T) to strong (G,C) nucleotide substitutions since divergence from their common ancestor. We investigated the phylogenetic extent and possible causes of this weak to strong (W→S) bias in divergent sequences (BDS) using recently sequenced genomes and recombination maps from eight trios of eukaryotic species. To quantify evidence for BDS, we inferred substitution histories using an efficient maximum likelihood approach with a context-dependent evolutionary model. We then annotated all lineage-specific substitutions in terms of W→S bias and density on the chromosomes. Finally, we used the inferred substitutions to calculate a BDS score—a log odds ratio between substitution type and density—and assessed its statistical significance with Fisher's exact test. Applying this approach, we found significant BDS in the coding and noncoding sequence of human, mouse, dog, stickleback, fruit fly, and worm. We also observed a significant lack of W→S BDS in chicken and yeast. The BDS score varies between species and across the chromosomes within each species. It is most strongly correlated with different genomic features in different species, but a strong correlation with recombination rates is found in several species. Our results demonstrate that a W→S substitution bias in fast-evolving sequences is a widespread phenomenon. The patterns of BDS observed suggest that a recombination-associated process, such as GC-biased gene conversion, is involved in the production of the bias in many species, but the strength of the BDS likely depends on many factors, including genome stability, variability in recombination rate over time and across the genome, the frequency of meiosis, and the amount of outcrossing in each species

Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition

ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure. Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs. Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine

Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour

The mechanism of eukaryotic chemotaxis remains unclear despite intensive study. The most frequently described mechanism acts through attractants causing actin polymerization, in turn leading to pseudopod formation and cell movement. We recently proposed an alternative mechanism, supported by several lines of data, in which pseudopods are made by a self-generated cycle. If chemoattractants are present, they modulate the cycle rather than directly causing actin polymerization. The aim of this work is to test the explanatory and predictive powers of such pseudopod-based models to predict the complex behaviour of cells in chemotaxis. We have now tested the effectiveness of this mechanism using a computational model of cell movement and chemotaxis based on pseudopod autocatalysis. The model reproduces a surprisingly wide range of existing data about cell movement and chemotaxis. It simulates cell polarization and persistence without stimuli and selection of accurate pseudopods when chemoattractant gradients are present. It predicts both bias of pseudopod position in low chemoattractant gradients and-unexpectedly-lateral pseudopod initiation in high gradients. To test the predictive ability of the model, we looked for untested and novel predictions. One prediction from the model is that the angle between successive pseudopods at the front of the cell will increase in proportion to the difference between the cell's direction and the direction of the gradient. We measured the angles between pseudopods in chemotaxing Dictyostelium cells under different conditions and found the results agreed with the model extremely well. Our model and data together suggest that in rapidly moving cells like Dictyostelium and neutrophils an intrinsic pseudopod cycle lies at the heart of cell motility. This implies that the mechanism behind chemotaxis relies on modification of intrinsic pseudopod behaviour, more than generation of new pseudopods or actin polymerization by chemoattractant

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies