Studying Cardiac Neural Network Dynamics: Challenges and Opportunities for Scientific Computing.

Neural control of the heart involves continuous modulation of cardiac mechanical and electrical activity to meet the organism's demand for blood flow. The closed-loop control scheme consists of interconnected neural networks with central and peripheral components working cooperatively with each other. These components have evolved to cooperate control of various aspects of cardiac function, which produce measurable "functional" outputs such as heart rate and blood pressure. In this review, we will outline fundamental studies probing the cardiac neural control hierarchy. We will discuss how computational methods can guide improved experimental design and be used to probe how information is processed while closed-loop control is operational. These experimental designs generate large cardio-neural datasets that require sophisticated strategies for signal processing and time series analysis, while presenting the usual large-scale computational challenges surrounding data sharing and reproducibility. These challenges provide unique opportunities for the development and validation of novel techniques to enhance understanding of mechanisms of cardiac pathologies required for clinical implementation.

Evaluating the effect of spaceflight on the host-pathogen interaction between human intestinal epithelial cells and Salmonella Typhimurium.

Spaceflight uniquely alters the physiology of both human cells and microbial pathogens, stimulating cellular and molecular changes directly relevant to infectious disease. However, the influence of this environment on host-pathogen interactions remains poorly understood. Here we report our results from the STL-IMMUNE study flown aboard Space Shuttle mission STS-131, which investigated multi-omic responses (transcriptomic, proteomic) of human intestinal epithelial cells to infection with Salmonella Typhimurium when both host and pathogen were simultaneously exposed to spaceflight. To our knowledge, this was the first in-flight infection and dual RNA-seq analysis using human cells.

Natural Perspiration Sampling and in Situ Electrochemical Analysis with Hydrogel Micropatches for User-Identifiable and Wireless Chemo/Biosensing.

Recent advances in microelectronics, microfluidics, and electrochemical sensing platforms have enabled the development of an emerging class of fully integrated personal health monitoring devices that exploit sweat to noninvasively access biomarker information. Despite such advances, effective sweat sampling remains a significant challenge for reliable biomarker analysis, with many existing methods requiring active stimulation (e.g., iontophoresis, exercise, heat). Natural perspiration offers a suitable alternative as sweat can be collected with minimal effort on the part of the user. To leverage this phenomenon, we devised a thin hydrogel micropatch (THMP), which simultaneously serves as an interface for sweat sampling and a medium for electrochemical sensing. To characterize the performance of the THMP, caffeine and lactate were selected as two representative target molecules. We demonstrated the suitability of the sampling method to track metabolic patterns, as well as to render sample-to-answer biomarker data for personal monitoring (through coupling with an electrochemical sensing system). To inform its potential application, this biomarker sampling and sensing system is incorporated within a distributed terminal-based sensing network, which uniquely capitalizes on the fingertip as a site for simultaneous biomarker data sampling and user identification.

Multiple resections and survival of recurrent glioblastoma patients in the temozolomide era.

Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor in adults for which recurrence is inevitable and surgical resection is often recommended. We investigated the relationship between multiple tumor resections and overall survival (OS) in adult glioblastoma patients who received adjuvant radiotherapy and temozolomide following initial surgery. We retrospectively reviewed the records of all newly diagnosed adult GBM patients with tumor recurrence at our institution from March 2003 to October 2012. Kaplan-Meier survival estimates and multivariate analysis using Cox's proportional hazards model were utilized to evaluate the impact of multiple resections on OS. A total of 202 GBM patients were analyzed; 83 (41.1%), 94 (46.5%), and 25 (12.4%) patients underwent one, two, and three or more total resections, respectively. Patients who underwent multiple resections were significantly younger (p<0.0001) and had higher perioperative Karnofsky Performance Status scores (p<0.0001) than single resection patients. The median OS in months was 21.1, 25.5, and 29.0 for patients who had one, two, and three or more resections, respectively (Wilcoxon p=0.03). In a confounder-adjusted multivariate model, patients with multiple resections did not have significantly improved survival (p=0.55). Older age was strongly associated with poorer OS (hazard ratio 1.34, p<0.0001). Age at diagnosis was the only predictor of survival for recurrent GBM patients. After adjusting for age at diagnosis, multiple resections were not an independent predictor of OS in our glioblastoma cohort treated in the temozolomide era.

Association between in-hospital adverse events and mortality for patients with brain tumors.

OBJECT: The Agency for Healthcare Research and Quality patient safety indicators (PSIs) and the Centers for Medicare and Medicaid Services hospital-acquired conditions (HACs) are administrative data-based metrics. The use of these outcomes as standard performance measures has been discussed in previous studies. With the objective of determining the applicability of these events as performance metrics among patients undergoing brain tumor surgery, this study had 2 aims: 1) to evaluate the association between PSIs, HACs, and in-hospital mortality rates; and 2) to determine a correlation between hospital volume, PSIs, and HACs. METHODS: Patients with brain tumors treated between 1998 and 2009 were captured in the Nationwide Inpatient Sample database. Hospitals were categorized into groups according to surgical volume. Associations between PSIs, HACs, and in-hospital mortality rates were studied. Factors associated with a PSI, HAC, and mortality were evaluated in a multivariate setting. RESULTS: A total of 444,751 patients with brain tumors underwent surgery in 1311 hospitals nationwide. Of these, 7.4% of patients experienced a PSI, 0.4% an HAC, and 1.9% died during their hospitalization. The occurrence of a PSI was strongly associated with mortality. Patients were 7.6 times more likely to die (adjusted odds ratio [aOR] 7.6, CI 6.7-8.7) with the occurrence of a PSI in a multivariate analysis. Moderate to strong associations were found between HACs, PSIs, and hospital volume. Patients treated at the highest-volume hospitals compared with the lowest-volume ones had reduced odds of a PSI (aOR 0.9, CI 0.8-1.0) and HAC (aOR 0.5, CI 0.5-0.08). CONCLUSIONS: Patient safety-related adverse events were strongly associated with in-hospital mortality. Moderate to strong correlations were found between PSIs, HACs, and hospital procedural volume. Patients treated at the highest-volume hospitals had consistently lower rates of mortality, PSIs, and HACs compared with those treated at the lowest-volume facilities.

Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis.

INTRODUCTION: Biochemical efficacy of somatostatin receptor ligand (SRL) treatment in acromegaly is defined by metrics for GH and IGF-1 control. Since the earliest therapeutic trials, biochemical control criteria, medical formulations, and assay techniques have evolved. MATERIALS AND METHODS: We searched PubMed for English-language trials published from 1974 to 2012 evaluating 10 or more patients, with a duration of more than 3 months and biochemical control as a key objective. We used a random-effects model to compare biochemical outcomes for octreotide and lanreotide trials according to study design characteristics. RESULTS: A total of 4464 patients were enrolled in the analyzed trials; 4125 were treated, and 3787 completed study treatment. Overall achieved control rates were 56% for mean GH and 55% for IGF-1 normalization. Treatment duration was significantly related to both GH (P < .001) and IGF-1 control (P = .02). Prior SRL therapy (P = .01), and year of study publication (P = .03) were related to biochemical control for GH but not IGF-1. No statistically significant differences in GH or IGF-1 response rates were observed for multicenter vs single center, retrospective vs prospective, study drug, and preselection for SRL responsiveness. Dosing scheme, GH response criterion, or switch study design were also not statistically significant in determining GH or IGF-1 response rate. CONCLUSIONS: Clinical design characteristics anticipated to impart efficacy bias including switching, preselection for SRL responsiveness, and retrospective design had no statistically significant impact on efficacy determination. Later year of publication, study duration, and prior SRL use are significant efficacy determinants for acromegaly trial outcomes.

Quality of surgical care and readmission in elderly glioblastoma patients.

BACKGROUND: Thirty-day readmissions post medical or surgical discharge have been analyzed extensively. Studies have shown that complex interactions of multiple factors are responsible for these hospitalizations. METHODS: A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Medicare database of newly diagnosed elderly glioblastoma multiforme (GBM) patients who underwent surgical resection between 1991 and 2007. Hospitals were classified into high- or low-readmission rate cohorts using a risk-adjusted methodology. Bivariate comparisons of outcomes were conducted. Multivariate analysis evaluated differences in quality of care according to hospital readmission rates. RESULTS: A total of 1,273 patients underwent surgery in 338 hospitals; 523 patients were treated in 228 high-readmission hospitals and 750 in 110 low-readmission hospitals. Patient characteristics for high-versus low-readmission hospitals were compared. In a confounder-adjusted model, patients treated in high- versus low-readmission hospitals had similar outcomes. The hazard of mortality for patients treated at high- compared to low-readmission hospitals was 1.06 (95% CI, 0.095%-1.19%). While overall complications were comparable between high- and low-readmission hospitals (16.3% vs 14.3%; P = .33), more postoperative pulmonary embolism/deep vein thrombosis complications were documented in patients treated at high-readmission hospitals (7.5% vs 4.1%; P = .01). Adverse events and levels of resection achieved during surgery were comparable at high- and low-readmission hospitals. CONCLUSIONS: For patients undergoing GBM resection, quality of care provided by hospitals with the highest adjusted readmission rates was similar to the care delivered by hospitals with the lowest rates. These findings provide evidence against the preconceived notion that 30-day readmissions can be used as a metric for quality of surgical and postsurgical care.

Does 30-day readmission affect long-term outcome among glioblastoma patients?

BACKGROUND: Research on readmissions has focused mainly on the economic and resource burden it places on hospitals. OBJECTIVE: To evaluate the effect of 30-day readmission on overall survival among newly diagnosed glioblastoma multiforme (GBM) patients. METHODS: A nationwide cohort of GBM patients diagnosed between 1991 and 2007 was studied using the Surveillance, Epidemiology and End Results Medicare database. Multivariate models were used to determine factors associated with readmission and overall survival. Odds ratio, hazard ratio, 95% confidence interval, and P values were reported. Complete case and multiple imputation analyses were performed. RESULTS: Among the 2774 newly diagnosed GBM patients undergoing surgery at 442 hospitals nationwide, 437 (15.8%) were readmitted within 30 days of the index hospitalization. Although 63% of readmitted patients returned to the index hospital where surgery was performed, a significant portion (37%) were readmitted to nonindex hospitals. The median overall survival for readmitted patients (6.0 months) was significantly shorter than for nonreadmitted (7.6 months; P < .001). In a confounder-adjusted imputed model, 30-day readmission increased the hazard of mortality by 30% (hazard ratio, 1.3; P < .001). Neurological symptoms (30.2%), thromboembolic complications (19.7%), and infections (17.6%) were the leading reasons for readmission. CONCLUSION: Prior studies that have reported only the readmissions back to index hospitals are likely underestimating the true 30-day readmission rate. GBM patients who were readmitted within 30 days had significantly shorter survival than nonreadmitted patients. Future studies that attempt to decrease readmissions and evaluate the impact of reducing readmissions on patient outcomes are needed.

Short interfering RNA guide strand modifiers from computational screening.

Short interfering RNAs (siRNAs) are promising drug candidates for a wide range of targets including those previously considered "undruggable". However, properties associated with the native RNA structure limit drug development, and chemical modifications are necessary. Here we describe the structure-guided discovery of functional modifications for the guide strand 5'-end using computational screening with the high-resolution structure of human Ago2, the key nuclease on the RNA interference pathway. Our results indicate the guide strand 5'-end nucleotide need not engage in Watson-Crick (W/C) H-bonding but must fit the general shape of the 5'-end binding site in MID/PIWI domains of hAgo2 for efficient knockdown. 1,2,3-Triazol-4-yl bases formed from the CuAAC reaction of azides and 1-ethynylribose, which is readily incorporated into RNA via the phosphoramidite, perform well at the guide strand 5'-end. In contrast, purine derivatives with modified Hoogsteen faces or N2 substituents are poor choices for 5'-end modifications. Finally, we identified a 1,2,3-triazol-4-yl base incapable of W/C H-bonding that performs well at guide strand position 12, where base pairing to target was expected to be important. This work expands the repertoire of functional nucleotide analogues for siRNAs.

An international comparison of male and female breast cancer incidence rates.

Global international trends in female breast cancer incidence have been described previously but no comparable analysis of male breast cancer incidence rates has been conducted. We obtained male and female case and population data using Cancer Incidence in Five Continents (CI5). We calculated age-adjusted, sex-specific incidence rates and female-to-male incidence rate ratios (FMIRRs) and compared trends of such for the period 1988-2002. This analysis included 8,681 male breast cancer cases and 1.14 million female breast cancer cases. The highest male incidence rate was observed in Israel at 1.24 per 100,000 man-years, and the highest female incidence rate was observed in the United States at 90.7 per 100,000 woman-years. The lowest incidence rates for males (0.16) and females (18.0) were observed in Thailand. In general, male breast cancer incidence trends were variable; a minority of countries displayed evidence for an increase. In contrast, female incidence rates have been increasing in a majority of countries. The Pearson correlation coefficient (r) for male and female breast cancer incidence rates by country during 1988-2002 was 0.69. Male breast cancer rates were generally less than 1 per 100,000 man-years, in contrast to the much higher rates of female breast cancer, providing for an overall FMIRR of 122. The differences in both incidence rates and time trends between males and females may reflect sex differences in underlying risk factors, pathogenesis, and/or overdiagnosis. Conversely, the high correlation between male and female breast cancer incidences may indicate that both sexes share some common risk factors for breast cancer.

The O/OREOS mission: first science data from the Space Environment Survivability of Living Organisms (SESLO) payload.

We report the first telemetered spaceflight science results from the orbiting Space Environment Survivability of Living Organisms (SESLO) experiment, executed by one of the two 10 cm cube-format payloads aboard the 5.5 kg Organism/Organic Exposure to Orbital Stresses (O/OREOS) free-flying nanosatellite. The O/OREOS spacecraft was launched successfully to a 72° inclination, 650 km Earth orbit on 19 November 2010. This satellite provides access to the radiation environment of space in relatively weak regions of Earth's protective magnetosphere as it passes close to the north and south magnetic poles; the total dose rate is about 15 times that in the orbit of the International Space Station. The SESLO experiment measures the long-term survival, germination, and growth responses, including metabolic activity, of Bacillus subtilis spores exposed to the microgravity, ionizing radiation, and heavy-ion bombardment of its high-inclination orbit. Six microwells containing wild-type (168) and six more containing radiation-sensitive mutant (WN1087) strains of dried B. subtilis spores were rehydrated with nutrient medium after 14 days in space to allow the spores to germinate and grow. Similarly, the same distribution of organisms in a different set of microwells was rehydrated with nutrient medium after 97 days in space. The nutrient medium included the redox dye Alamar blue, which changes color in response to cellular metabolic activity. Three-color transmitted intensity measurements of all microwells were telemetered to Earth within days of each of the 48 h growth experiments. We report here on the evaluation and interpretation of these spaceflight data in comparison to delayed-synchronous laboratory ground control experiments.