Creating Clinically Useful \u3ci\u3eIn Silico\u3c/i\u3e Models of Intracranial Pressure Dynamics

To create clinically useful computer simulation models of intracranial pressure (ICP) dynamics by using prospective clinical data to estimate subject-specific physiologic parameters

A Computer Model of Intracranial Pressure Dynamics During Traumatic Brain Injury that Explicitly Models Fluid Flows and Volumes

This report documents a computer model of intracranial pressure (ICP) dynamics that is used to evaluate clinical treatment options for elevated ICP during traumatic brain injury (TBI). The model uses fluid volumes as primary state variables and explicitly models fluid flows as well as the resistance, compliance, and pressure associated with each of the compartments (arteries and arterioles, capillary bed, veins, venous sinus, ventricles, and brain parenchyma). The model has been tested to assure that it reproduces a correct physiologic response to intra-and extra-parenchymal hemorrhage and edema, and to therapies directed at reducing ICP such as cerebral spinal fluid drainage, mannitol administration, head elevation, and mild hyperventilation. The model is able to replicate observed clinical behavior in many cases, including elevated ICP associated with severe cerebral edema, subdural hematoma, and cerebrospinal fluid blockage. The model also successfully reproduces tne cerebrovascular regulatory mechanisms that are activated during TBI in response to various abnormalities such as high or low systemic blood pressure. We conclude that incorporating fluid volumes and flows into a model of lCP dynamics significantly improved its clinical utility. Additional improvements are anticipated (or wil1 accrue or will result) as the specific mechanisms that modify cerebral compliance and autoregulation during TBI and elevated ICP are further delineated

The economic costs of schizophrenia: implications for public policy

The direct and indirect costs associated with schizophrenia in Australia were calculated using the incidence approach and compared with similar costings of myocardial infarction in Australia and the United States. In Australia schizophrenia affects one-twelfth as many people as does myocardial infarction, yet costs half as much. This is because the stream of costs associated with each case of schizophrenia is six times the stream of costs associated with myocardial infarction. To illustrate the utility of this costing approach, the information was used to estimate the cost-benefit ratio likely to follow the introduction of social intervention strategies. The information also showed that Australian support for research in schizophrenia is inadequate when compared with that for myocardial infarction and quite out of proportion to the cost of schizophrenia to the community

Cancer prevention in primary care: Predictors of patient counseling across four risk behaviors over 24 months

Objective: Rates of preventive counseling remain below national guidelines. We explored physician and patient predictors of preventive counseling across multiple cancer risk behaviors in at-risk primary care patients. Methods: We surveyed 3557 patients, with at least one of four cancer risk behaviors: smoking, diet, sun exposure, and/or mammography screening, at baseline and 24 months. Patients reported receipt of 4A\u27s (Ask, Advise, Assist, Arrange follow-up); responses were weighted and combined to reflect more thorough counseling (Ask = 1, Advise = 2, Assist = 3, Arrange = 4, score range 0–10) for each target behavior. A series of linear-regression models, controlling for office clustering, examined patient, physician and other situational predictors at 24 months. Results: Risk behavior topics were brought up more often for mammography (90%) and smoking (79%) than diet (56%) and sun protection (30%). Assisting and Arranging follow-up were reported at low frequencies across all behaviors. More thorough counseling for all behaviors was associated with multiple visits and higher satisfaction with care. Prior counseling predicted further counseling on all behaviors except smoking, which was already at high levels. Other predictors varied by risk behavior. Conclusions: More thorough risk behavior counseling can be delivered opportunistically across multiple visits; doing so is associated with more satisfaction with care

Development of TRU waste mobile analysis methods for RCRA-regulated metals

This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). Glow-discharge mass spectrometry (GD-MS), laser-induced breakdown spectroscopy (LIBS), dc-arc atomic-emission spectroscopy (DC-ARC-AES), laser-ablation inductively-coupled-plasma mass spectrometry (LA-ICP-MS), and energy-dispersive x-ray fluorescence (EDXRF) were identified as potential solid-sample analytical techniques for mobile characterization of TRU waste. Each technology developers was provided with surrogate TRU waste samples in order to develop an analytical method. Following successful development of the analytical method, five performance evaluation samples were distributed to each of the researchers in a blind round-robin format. Results of the round robin were compared to known values and Transuranic Waste Characterization Program (TWCP) data quality objectives. Only two techniques, DC-ARC-AES and EDXRF, were able to complete the entire project. Methods development for GD-MS and LA-ICP-MS was halted due to the stand-down at the CMR facility. Results of the round-robin analysis are given for the EDXRF and DCARC-AES techniques. While DC-ARC-AES met several of the data quality objectives, the performance of the EDXRF technique by far surpassed the DC-ARC-AES technique. EDXRF is a simple, rugged, field portable instrument that appears to hold great promise for mobile characterization of TRU waste. The performance of this technique needs to be tested on real TRU samples in order to assess interferences from actinide constituents. In addition, mercury and beryllium analysis will require another analytical technique because the EDXRF method failed to meet the TWCP data quality objectives. Mercury analysis is easily accomplished on solid samples by cold vapor atomic fluorescence (CVAFS). Beryllium can be analyzed by any of a variety of emission techniques

Correlation between Cognition and Balance among Middle-Aged and Older Adults Observed through a Tai Chi Intervention program

Background: Age-associated decline in cognition and balance may cause severe ability loss for daily living activities among middle-aged and older adults. The relationship between cognition and balance in this aging population remains to be explored. Objective: The present study Is exploratory in nature and aimed to examine the relationship between balance (both static and dynamic components) and global cognitive function among middle-aged and older adults through Tai Chi (TC) practice as a research avenue. Methods: A short-term (12 weeks) intervention of TC was conducted among middle-aged and older adults in the community setting. Global cognitive function (using the Chinese version of the Montreal Cognitive Assessment score (MoCA) and balance (i.e., one leg standing test score; Timed Up and Go Test score, TUGT) of all participants were assessed before and after the intervention. Age, body mass index (BMI), sex, and physical fitness variables (Chair Stand Test, CST; the 6-Meter Walk Test, 6MWT) were also collected as confounding factors. Results: Significant moderator effects of baseline CST on the association between the dichotomized baseline MoCA score and the baseline left leg balance score (p = 0.0247), the baseline right leg balance score (p = 0.0140) and the baseline TUGT score (p = 0.0346) were found. Change score of left score balance (p = 0.0192) and change score of TUGT (p = 0.0162) were found to be significantly associated with change score of cognitive function. Conclusion: Cognitive function and balance are interrelated in middle-aged and older adults. The association between global cognitive function and balance Is moderated by strength of lower limbs. The change scores of cognitive function and balance introduced by TC training were found to be positively correlated. Future research Is warranted to further confirm the cause-effect relationship of cognitive function and balance and its influencing factors among middle-aged and older adults utilizing intervention studies with larger sample sizes

Investigation of altering single-nucleotide polymorphism density on the power to detect trait loci and frequency of false positive in nonparametric linkage analyses of qualitative traits

Genome-wide linkage analysis using microsatellite markers has been successful in the identification of numerous Mendelian and complex disease loci. The recent availability of high-density single-nucleotide polymorphism (SNP) maps provides a potentially more powerful option. Using the simulated and Collaborative Study on the Genetics of Alcoholism (COGA) datasets from the Genetics Analysis Workshop 14 (GAW14), we examined how altering the density of SNP marker sets impacted the overall information content, the power to detect trait loci, and the number of false positive results. For the simulated data we used SNP maps with density of 0.3 cM, 1 cM, 2 cM, and 3 cM. For the COGA data we combined the marker sets from Illumina and Affymetrix to create a map with average density of 0.25 cM and then, using a sub-sample of these markers, created maps with density of 0.3 cM, 0.6 cM, 1 cM, 2 cM, and 3 cM. For each marker set, multipoint linkage analysis using MERLIN was performed for both dominant and recessive traits derived from marker loci. Our results showed that information content increased with increased map density. For the homogeneous, completely penetrant traits we created, there was only a modest difference in ability to detect trait loci. Additionally, as map density increased there was only a slight increase in the number of false positive results when there was linkage disequilibrium (LD) between markers. The presence of LD between markers may have led to an increased number of false positive regions but no clear relationship between regions of high LD and locations of false positive linkage signals was observed

The evidence base for the evaluation and management of dizziness

Dizziness presentations pose many clinical challenges. The objective of this study is to broadly summarize the evidence base that supports clinical decisions in dizziness presentations.MEDLINE (1966 to September 2007), Web of Science and The Cochrane Library were searched for articles with clinical relevance on topics concerning dizziness. Additional sources were also searched for clinical practice guidelines. The following information was abstracted from each article: year of publication, journal type, type of article and the topics of the article.Of nearly 3000 articles identified, 1244 articles met the inclusion criteria. The most common article type was a case report or case series, followed by expert opinion or review articles, studies of medical tests and clinical trials. Meta-analyses and systematic reviews were found on benign paroxysmal positional vertigo and Meniere's disease, but only a few other topics. No clinical practice guidelines were found that focus specifically on dizziness.The evidence base for the evaluation and management of dizziness seems to be weak. Future work to establish or summarize evidence in clinically meaningful ways could contribute to efforts to optimize patient care and health care utilization for one of the most common presenting symptoms.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78604/1/j.1365-2753.2009.01133.x.pd

A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer

Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy.

Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention