Real-time detection of neonatal seizures improves with on demand EEG interpretation.

OBJECTIVE: Under- and overtreatment of seizures may result in adverse outcomes; thus, early, reliable seizure identification is crucial. Continuous conventional ElectroEncephaloGram (cEEG) is the gold standard, but amplitude integrated EEG (aEEG) is most widely-used in the Neonatal Intensive Care Unit (NICU). We aimed to determine whether a novel pathway combining cEEG and aEEG for seizure detection would improve real-time seizure identification. METHODS: A single-center, prospective quality improvement project cohort. Patients at-risk of seizures were monitored by cEEG and aEEG concurrently, with the option for the neonatologist to contact a neurologist for real-time cEEG interpretation. The primary outcome was correct identification of seizures by the new combined pathway compared to aEEG alone. RESULTS: Seizure detection using aEEG had a sensitivity of 46.2%; specificity of 93.3%; PPV of 66.7%; and NPV of 85.7%. Utilizing the new on-demand, real-time cEEG interpretation by a neurologist, correct seizure identification increased by 27% (95%CI: 10-56%). Over-diagnosis of seizures was avoided in 33.3% (95% CI: 12.1-64.6%) and misuse of anti-seizure medication was prevented. CONCLUSIONS: Combining aEEG with on-demand cEEG interpretation improved accurate seizure detection in a high-risk NICU population, with the potential to avoid over-treatment. SIGNIFICANCE: We describe a novel combined EEG monitoring pathway to improve seizure detection, and prevent unnecessary treatment.

Targeting Epilepsy Through the Foremen Ovale: How Many Helical Needles are Needed?

Laser ablation of the hippocampus offers medically refractory epilepsy patients an alternative to invasive surgeries. Emerging commercial solutions deliver the ablator through a burr hole in the back of the head. We recently introduced a new access path through the foremen ovale, using a helical needle, which minimizes the amount of healthy brain tissue the needle must pass through on its way to the hippocampus, and also enables the needle to follow the medial axis of the hippocampus more closely. In this paper, we investigate whether helical needles should be designed and fabricated on a patient-specific basis as we had previously proposed, or whether a small collection of pre-defined needle shapes can apply across many patients. We propose a new optimization strategy to determine this needle set using patient data, and investigate the accuracy with which these needles can reach the the medial axis of the hippocampus. We find that three basic tube shapes (mirrored as necessary for left vs. right hippocampi) are all that is required, across 20 patient datasets (obtained from 10 patient CT scans), to reduce worst-case maximum error below 2 mm.

The (Under)Use of Eye-Tracking in Evolutionary Ecology.

To survive and pass on their genes, animals must perform many tasks that affect their fitness, such as mate-choice, foraging, and predator avoidance. The ability to make rapid decisions is dependent on the information that needs to be sampled from the environment and how it is processed. We highlight the need to consider visual attention within sensory ecology and advocate the use of eye-tracking methods to better understand how animals prioritise the sampling of information from their environments prior to making a goal-directed decision. We consider ways in which eye-tracking can be used to determine how animals work within attentional constraints and how environmental pressures may exploit these limitations.

Discovering human germ cell mutagens with whole genome sequencing: Insights from power calculations reveal the importance of controlling for between-family variability.

Mutations in germ cells pose potential genetic risks to offspring. However, de novo mutations are rare events that are spread across the genome and are difficult to detect. Thus, studies in this area have generally been under-powered, and no human germ cell mutagen has been identified. Whole Genome Sequencing (WGS) of human pedigrees has been proposed as an approach to overcome these technical and statistical challenges. WGS enables analysis of a much wider breadth of the genome than traditional approaches. Here, we performed power analyses to determine the feasibility of using WGS in human families to identify germ cell mutagens. Different statistical models were compared in the power analyses (ANOVA and multiple regression for one-child families, and mixed effect model sampling between two to four siblings per family). Assumptions were made based on parameters from the existing literature, such as the mutation-by-paternal age effect. We explored two scenarios: a constant effect due to an exposure that occurred in the past, and an accumulating effect where the exposure is continuing. Our analysis revealed the importance of modeling inter-family variability of the mutation-by-paternal age effect. Statistical power was improved by models accounting for the family-to-family variability. Our power analyses suggest that sufficient statistical power can be attained with 4-28 four-sibling families per treatment group, when the increase in mutations ranges from 40 to 10% respectively. Modeling family variability using mixed effect models provided a reduction in sample size compared to a multiple regression approach. Much larger sample sizes were required to detect an interaction effect between environmental exposures and paternal age. These findings inform study design and statistical modeling approaches to improve power and reduce sequencing costs for future studies in this area.

Hemlock Woolly Adelgid (Hemiptera: Adelgidae) Abundance and Hemlock Canopy Health Numerous Years After Imidacloprid Basal Drench Treatments: Implications for Management Programs.

Hemlock woolly adelgid (Adelges tsugae [Annand]), an invasive insect in the eastern United States, has caused widespread decline of eastern hemlock, Tsuga canadensis (L.) Carriére. Imidacloprid basal drench treatments were assessed 4-7 yr after a single treatment to determine hemlock woolly adelgid population suppression and effects on hemlock canopy health. The effects of sampling site, years post-treatment, and hemlock diameter at breast height (DBH) size classes were evaluated relative to imidacloprid treatment on hemlock woolly adelgid populations and hemlock canopy health characteristics. The influence of hemlock woolly adelgid populations on canopy health characteristics was also assessed. Imidacloprid treatments resulted in low-level hemlock woolly adelgid populations 7 yr post-treatment. Hemlock woolly adelgid was present on more hemlocks 7 yr compared with 4-6 yr post-treatment. Smaller hemlocks, dosed with 0.7 g active ingredient (AI)/2.5 cm DBH, had higher populations of hemlock woolly adelgid than the largest size class, which were treated at twice that dosage. Concentrations of imidacloprid and its olefin metabolite below the LC50 were sufficient for suppression of hemlock woolly adelgid populations, which suggests an additive effect of imidacloprid and olefin that compounds hemlock woolly adelgid mortality over many generations. Hemlock woolly adelgid populations observed in this study were too low to have an observable effect on hemlock canopy health, indicating that application intervals of up to 7 yr may be adequate to protect hemlocks.

Initial Experiments with the Leap Motion as a User Interface in Robotic Endonasal Surgery.

The Leap Motion controller is a low-cost, optically-based hand tracking system that has recently been introduced on the consumer market. Prior studies have investigated its precision and accuracy, toward evaluating its usefulness as a surgical robot master interface. Yet due to the diversity of potential slave robots and surgical procedures, as well as the dynamic nature of surgery, it is challenging to make general conclusions from published accuracy and precision data. Thus, our goal in this paper is to explore the use of the Leap in the specific scenario of endonasal pituitary surgery. We use it to control a concentric tube continuum robot in a phantom study, and compare user performance using the Leap to previously published results using the Phantom Omni. We find that the users were able to achieve nearly identical average resection percentage and overall surgical duration with the Leap.

Assessment of Imidacloprid and Its Metabolites in Foliage of Eastern Hemlock Multiple Years Following Treatment for Hemlock Woolly Adelgid, Adelges tsugae (Hemiptera: Adelgidae), in Forested Conditions.

Widespread decline and mortality of eastern hemlock, Tsuga canadensis (L.) Carrière, have been caused by hemlock woolly adelgid, Adelges tsugae (Annand) (HWA) (Hemiptera: Adelgidae). The current study is a retrospective analysis conducted in collaboration with Great Smoky Mountains National Park (GRSM) to determine longevity of imidacloprid and its insecticidal metabolites (imidacloprid olefin, 5-hydroxy, and dihydroxy) in GRSM's HWA integrated pest management (IPM) program. Foliage samples were collected from three canopy strata of hemlocks that were given imidacloprid basal drench treatments 4-7 yr prior to sampling. Foliage was analyzed to assess concentrations in parts per billion (ppb) of imidacloprid and its metabolites. Imidacloprid and its olefin metabolite were present in most, 95 and 65%, respectively, branchlets 4-7 yr post-treatment, but the 5-hydroxy and dihydroxy metabolites were present in only 1.3 and 11.7%, respectively, of the branchlets. Imidacloprid and olefin concentrations significantly decreased between 4 and 7 yr post-treatment. Concentrations of both imidacloprid and olefin were below the LC50 for HWA 5-7 yr post-treatment. Knowledge of the longevity of imidacloprid treatments and its metabolite olefin can help maximize the use of imidacloprid in HWA IPM programs.

The aggregation of early-onset melanoma in young Western Australian families.

BACKGROUND: Few studies have examined the familial aggregation of melanoma or its co-aggregation with other cancers using whole-population based designs. This study aimed to investigate aggregation patterns in young Western Australian families, using population-based linked health data to identify individuals born in Western Australia between 1974 and 2007, their known relatives, and all incident cancer diagnoses within the resulting 1,506,961 individuals. METHODS: Cox proportional hazards regression models were used to compare the risk of melanoma for first-degree relatives of melanoma cases to that for first-degree relatives of controls, with bootstrapping used to account for correlations within families. The risk of (i) developing melanoma based on the number of first-degree relatives with other cancers, and (ii) developing non-melanoma cancers based on the number of first-degree relatives diagnosed with melanoma was also investigated. RESULTS: First-degree relatives of melanoma cases had a significantly greater incidence of melanoma than first-degree relatives of individuals not affected with melanoma (Hazard Ratio (HR)=3.58, 95% bootstrap confidence interval (CI): 2.43-5.43). Sensitivity analyses produced a higher hazard ratio estimate when restricted to melanoma cases diagnosed before 40 years of age (HR=3.77, bootstrap 95% CI: 2.49-6.39) and a lower estimate when only later-onset cases (>40 years) were considered (HR=2.45, bootstrap 95% CI: 1.23-4.82). No significant evidence was found for co-aggregation between melanoma and any other cancers. CONCLUSIONS: Results indicated a strong familial basis of melanoma, with the higher than expected hazard ratio observed likely to reflect early-age at onset cases in this young cohort, supported by the results of the sensitivity analyses. Exploratory analyses suggested that the determinants of melanoma causing the observed aggregation within families may be independent of other malignancies, although these analyses were limited by the young age of the sample. Determining familial aggregation patterns will provide valuable knowledge regarding improved clinical risk prediction and the underlying biological mechanisms of melanoma and other cancers.

A study on the theoretical and practical accuracy of conoscopic holography-based surface measurements: toward image registration in minimally invasive surgery.

BACKGROUND: Registered medical images can assist with surgical navigation and enable image-guided therapy delivery. In soft tissues, surface-based registration is often used and can be facilitated by laser surface scanning. Tracked conoscopic holography (which provides distance measurements) has been recently proposed as a minimally invasive way to obtain surface scans. Moving this technique from concept to clinical use requires a rigorous accuracy evaluation, which is the purpose of our paper. METHODS: We adapt recent non-homogeneous and anisotropic point-based registration results to provide a theoretical framework for predicting the accuracy of tracked distance measurement systems. Experiments are conducted a complex objects of defined geometry, an anthropomorphic kidney phantom and a human cadaver kidney. RESULTS: Experiments agree with model predictions, producing point RMS errors consistently < 1 mm, surface-based registration with mean closest point error < 1 mm in the phantom and a RMS target registration error of 0.8 mm in the human cadaver kidney. CONCLUSIONS: Tracked conoscopic holography is clinically viable; it enables minimally invasive surface scan accuracy comparable to current clinical methods that require open surgery.

Percutaneous inner-ear access via an image-guided industrial robot system.

Image-guided robots have been widely used for bone shaping and percutaneous access to interventional sites. However, due to high-accuracy requirements and proximity to sensitive nerves and brain tissues, the adoption of robots in inner-ear surgery has been slower. In this paper the authors present their recent work towards developing two image-guided industrial robot systems for accessing challenging inner-ear targets. Features of the systems include optical tracking of the robot base and tool relative to the patient and Kalman filter-based data fusion of redundant sensory information (from encoders and optical tracking systems) for enhanced patient safety. The approach enables control of differential robot positions rather than absolute positions, permitting simplified calibration procedures and reducing the reliance of the system on robot calibration in order to ensure overall accuracy. Lastly, the authors present the results of two phantom validation experiments simulating the use of image-guided robots in inner-ear surgeries such as cochlear implantation and petrous apex access.

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits.

AIMS/HYPOTHESIS: Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels. METHODS: The individuals analysed were participants in the Busselton Health Survey (n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models. RESULTS: The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p = 0.0004) and raised HDL-C levels (p = 0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p = 0.0007). CONCLUSIONS/INTERPRETATION: The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.

Sphingosine effects on the contractile behavior of skinned cardiac myocytes.

Sphingosine modulates myocyte beating behavior by acting on the sarcoplasmic reticulum calcium release channel, the ryanodine receptor. Chemically skinned myocytes isolated from adult rabbit ventricles exhibited spontaneous asynchonous contractions in response to micromolar levels of calcium. These cells do not have a functional sarcolemma but exhibit spontaneous contraction-relaxation cycles which are controlled by the sarcoplasmic reticulum. The intracellular second messenger, sphingosine, significantly reduced myocyte beat frequency in a biphasic manner with an IC50 of c. 0.5 microM. A computerized video-enhancement micrography system was used to determine the effect of sphingosine on sarcomere contractile parameters and to determine the potential source of the altered beating behavior produced by sphingosine. Contraction parameters related to sarcomere shortening were unaffected by sphingosine in the submicromolar range, suggesting that sphingosine had no effect on the contractile machinery itself. However, submicromolar sphingosine had a significant inhibitory effect on the spread of activation from sarcomere to sarcomere in these cells. Activation waves were propagated with an average velocity of 331 and 199 microns/s in control and sphingosine (0.58 microM) treated cells, respectively. Permeabilized myocyte calcium uptake was markedly increased by treatment with sphingosine, consistent with an inhibitory effect of sphingosine on sarcoplasmic reticulum calcium release. Sphingosine blocked calcium-induced calcium release from isolated cardiac sarcoplasmic reticulum membranes containing the ryanodine receptor. The results suggest that the site of sphingosine action on calcium signaling and beating behavior in the cardiac cell is the sarcoplasmic reticulum ryanodine receptor. By inhibiting channel opening sphingosine may increase the calcium threshold necessary to trigger calcium-induced calcium release, thus modulating cardiac excitation-contraction coupling.

Relationship between inducible H-2 expression and the immunogenicity of murine skin neoplasms. I. Evidence that the immunogenicity of ultraviolet radiation-chemically induced tumors is associated with their susceptibility to gamma-interferon-mediated enhancement of H-2Kk expression.

Our objective was to determine the relationship between major histocompatibility complex class I molecule expression and the tumorigenic properties of cutaneous neoplasms induced by ultraviolet radiation or chemical carcinogens. All tumors tested were found to express low constitutive levels of MHC class I molecules in vitro as determined by indirect immunofluorescence and flow cytometry. Those tumors capable of growth in UVR-exposed but not in normal recipients (regressors) were found to express enhanced levels of H-2Kk following incubation in the presence of gamma-IFN. In contrast, only one of the tumors that were capable of growth in normal recipients (progressors) exhibited more than moderate enhancement of H-2Kk expression in response to gamma-IFN. Analysis of tumor variants obtained by conversion of a UVR-induced regressor tumor to the progressor phenotype by passage through sublethally gamma-irradiated hosts, or the generation of regressor tumors by mutagen exposure of a benz [A] pyrene (BAP) induced progressor tumor, further supported the direct relationship between tumor immunogenicity in vivo and the capacity to elevate H-2Kk expression in response to gamma-IFN. No correlation existed between H-2Dk expression by the tumors and their transplantation phenotype. Furthermore, we failed to observe MHC class II expression by any of the tumors tested. Finally, the growth rate of a regressor tumor implanted into UVR-exposed hosts was significantly reduced if the tumor was pretreated with gamma-IFN in vitro prior to inoculation. This result suggests that UVR-exposed animals may be deficient in their ability to enhance the expression of MHC class I molecules on developing tumors. This alteration may, in part, account for the state of tumor susceptibility caused by UVR exposure.