Travel Burden as a Measure of Healthcare Access and the Impact of Telehealth within the Veterans Health Administration.

BACKGROUND: Travel is a major barrier to healthcare access for Veteran Affairs (VA) patients, and disproportionately affects rural Veterans (approximately one quarter of Veterans). The CHOICE/MISSION acts' intent is to increase timeliness of care and decrease travel, although not clearly demonstrated. The impact on outcomes remains unclear. Increased community care increases VA costs and increases care fragmentation. Retaining Veterans within the VA is a high priority, and reduction of travel burdens will help achieve this goal. Sleep medicine is presented as a use case to quantify travel related barriers. OBJECTIVE: The Observed and Excess Travel Distances are proposed as two measures of healthcare access, allowing for quantification of healthcare delivery related to travel burden. A telehealth initiative that reduced travel burden is presented. DESIGN: Retrospective, observational, utilizing administrative data. SUBJECTS: VA patients with sleep related care between 2017 and 2021. In-person encounters: Office visits and polysomnograms; telehealth encounters: virtual visits and home sleep apnea tests (HSAT). MAIN MEASURES: Observed distance: distance between Veteran's home and treating VA facility. Excess distance: difference between where Veteran received care and nearest VA facility offering the service of interest. Avoided distance: distance between Veteran's home and nearest VA facility offering in-person equivalent of telehealth service. KEY RESULTS: In-person encounters peaked between 2018 and 2019, and have down trended since, while telehealth encounters have increased. During the 5-year period, Veterans traveled an excess 14.1 million miles, while 10.9 million miles of travel were avoided due to telehealth encounters, and 48.4 million miles were avoided due to HSAT devices. CONCLUSIONS: Veterans often experience a substantial travel burden when seeking medical care. Observed and excess travel distances are valuable measures to quantify this major healthcare access barrier. These measures allow for assessment of novel healthcare approaches to improve Veteran healthcare access and identify specific regions that may benefit from additional resources.

Evaluation of Severe Acute Respiratory Syndrome Coronavirus 2 Transmission Mitigation Strategies on a University Campus Using an Agent-Based Network Model.

Universities are faced with decisions on how to resume campus activities while mitigating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) risk. To provide guidance for these decisions, we developed an agent-based network model of SARS-CoV-2 transmission to assess the potential impact of strategies to reduce outbreaks. The model incorporates important features related to risk at the University of California San Diego. We found that structural interventions for housing (singles only) and instructional changes (from in-person to hybrid with class size caps) can substantially reduce the basic reproduction number, but masking and social distancing are required to reduce this to at or below 1. Within a risk mitigation scenario, increased frequency of asymptomatic testing from monthly to twice weekly has minimal impact on average outbreak size (1.1-1.9), but substantially reduces the maximum outbreak size and cumulative number of cases. We conclude that an interdependent approach incorporating risk mitigation, viral detection, and public health intervention is required to mitigate risk.

Burden and Cost of Caring for US Veterans With CKD: Initial Findings From the VA Renal Information System (VA-REINS).

Kidney disease is a common, complex, costly, and life-limiting condition. Most kidney disease registries or information systems have been limited to single institutions or regions. A national US Department of Veterans Affairs (VA) Renal Information System (VA-REINS) was recently developed. We describe its creation and present key initial findings related to chronic kidney disease (CKD) without kidney replacement therapy (KRT). Data from the VA's Corporate Data Warehouse were processed and linked with national Medicare data for patients with CKD receiving KRT. Operational definitions for VA user, CKD, acute kidney injury, and kidney failure were developed. Among 7 million VA users in fiscal year 2014, CKD was identified using either a strict or liberal operational definition in 1.1 million (16.4%) and 2.5 million (36.3%) veterans, respectively. Most were identified using an estimated glomerular filtration rate laboratory phenotype, some through proteinuria assessment, and very few through International Classification of Diseases, Ninth Revision coding. The VA spent ∼$18 billion for the care of patients with CKD without KRT, most of which was for CKD stage 3, with higher per-patient costs by CKD stage. VA-REINS can be leveraged for disease surveillance, population health management, and improving the quality and value of care, thereby enhancing VA's capacity as a patient-centered learning health system for US veterans.

Appointment utilization as a trigger for palliative care introduction: A retrospective cohort study.

BACKGROUND: Chronic kidney disease palliative care guidelines would benefit from more diverse and objectively defined health status measures. AIM: The aim is to identify high-risk patients from administrative data and facilitate timely and uniform palliative care involvement. DESIGN: It is a retrospective cohort study. SETTING/PARTICIPANTS: In total, 45,368 Veterans, with chronic kidney disease Stage 3, 4, or 5, were monitored for up to 6 years and categorized into three groups, based on whether they died, started dialysis, or avoided both outcomes. RESULTS: Patient's appointment utilization was a significant predictor for both outcomes. It separated individuals into low, medium, and high appointment utilizers. Among the low appointment utilizers, the risk of death did not change significantly, while the risk of dialysis increased. Medium appointment utilizers had a stable risk of death and a decreasing risk of dialysis. Significant appointment utilization (above 31 visits during the baseline year) helped high-risk patients avoid both outcomes of interest-death and dialysis. CONCLUSION: Our model could justify the creation of a novel palliative care introduction trigger, as patients with medium demand for care may benefit from additional palliative care evaluation. The trigger could facilitate the uniformization of conservative treatment preparations. It could prompt messages to a managing physician when a patient crosses the threshold between low and medium appointment utilization. It may also aid in system-level policy development. Furthermore, our results highlight the benefit of significant appointment utilization among high-risk patients.

Intermediate addition multifocals provide safe stair ambulation with adequate 'short-term' reading.

PURPOSE: A recent randomised controlled trial indicated that providing long-term multifocal wearers with a pair of distance single-vision spectacles for use outside the home reduced falls risk in active older people. However, it also found that participants disliked continually switching between using two pairs of glasses and adherence to the intervention was poor. In this study we determined whether intermediate addition multifocals (which could be worn most of the time inside and outside the home and thus avoid continual switching) could provide similar gait safety on stairs to distance single vision spectacles whilst also providing adequate 'short-term' reading and near vision. METHODS: Fourteen healthy long-term multifocal wearers completed stair ascent and descent trials over a 3-step staircase wearing intermediate and full addition bifocals and progression-addition lenses (PALs) and single-vision distance spectacles. Gait safety/caution was assessed using foot clearance measurements (toe on ascent, heel on descent) over the step edges and ascent and descent duration. Binocular near visual acuity, critical print size and reading speed were measured using Bailey-Lovie near charts and MNRead charts at 40 cm. RESULTS: Gait safety/caution measures were worse with full addition bifocals and PALs compared to intermediate bifocals and PALs. The intermediate PALs provided similar gait ascent/descent measures to those with distance single-vision spectacles. The intermediate addition PALs also provided good reading ability: Near word acuity and MNRead critical print size were better with the intermediate addition PALs than with the single-vision lenses (p < 0.0001), with a mean near visual acuity of 0.24 ± 0.13 logMAR (~N5.5) which is satisfactory for most near vision tasks when performed for a short period of time. CONCLUSIONS: The better ability to 'spot read' with the intermediate addition PALs compared to single-vision spectacles suggests that elderly individuals might better comply with the use of intermediate addition PALs outside the home. A lack of difference in gait parameters for the intermediate addition PALs compared to distance single-vision spectacles suggests they could be usefully used to help prevent falls in older well-adapted full addition PAL wearers. A randomised controlled trial to investigate the usefulness of intermediate multifocals in preventing falls seems warranted.

The health equity implications of the Health Resources and Services Administration's Ryan White HIV/AIDS Program.

OBJECTIVE: Investigate the role of the Ryan White HIV/AIDS Program (RWHAP) - which funds services for vulnerable and historically disadvantaged populations with HIV - in reducing health inequities among people with HIV over a 10-year horizon. DESIGN: We use an agent-based microsimulation model to incorporate the complexity of the program and long-time horizon. METHODS: We use a composite measure (the Theil index) to evaluate the health equity implications of the RWHAP for each of four subgroups (based on race and ethnicity, age, gender, and HIV transmission category) and two outcomes (probability of being in care and treatment and probability of being virally suppressed). We compare results with the RWHAP fully funded versus a counterfactual scenario, in which the medical and support services funded by the RWHAP are not available. RESULTS: The model indicates the RWHAP will improve health equity across all demographic subgroups and outcomes over a 10-year horizon. In Year 10, the Theil index for race and ethnicity is 99% lower for both outcomes under the RWHAP compared to the non-RWHAP scenario; 71-93% lower across HIV transmission categories; 31-44% lower for age; and 73-75% lower for gender. CONCLUSION: Given the large number of people served by the RWHAP and our findings on its impact on equity, the RWHAP represents an important vehicle for achieving the health equity goals of the National HIV/AIDS Strategy (2022-2025) and the Ending the HIV Epidemic Initiative goal of reducing new infections by 90% by 2030.

Medical practices display power law behaviors similar to spoken languages.

BACKGROUND: Medical care commonly involves the apprehension of complex patterns of patient derangements to which the practitioner responds with patterns of interventions, as opposed to single therapeutic maneuvers. This complexity renders the objective assessment of practice patterns using conventional statistical approaches difficult. METHODS: Combinatorial approaches drawn from symbolic dynamics are used to encode the observed patterns of patient derangement and associated practitioner response patterns as sequences of symbols. Concatenating each patient derangement symbol with the contemporaneous practitioner response symbol creates "words" encoding the simultaneous patient derangement and provider response patterns and yields an observed vocabulary with quantifiable statistical characteristics. RESULTS: A fundamental observation in many natural languages is the existence of a power law relationship between the rank order of word usage and the absolute frequency with which particular words are uttered. We show that population level patterns of patient derangement: practitioner intervention word usage in two entirely unrelated domains of medical care display power law relationships similar to those of natural languages, and that-in one of these domains-power law behavior at the population level reflects power law behavior at the level of individual practitioners. CONCLUSIONS: Our results suggest that patterns of medical care can be approached using quantitative linguistic techniques, a finding that has implications for the assessment of expertise, machine learning identification of optimal practices, and construction of bedside decision support tools.

A neural hierarchy for illusions of time: duration adaptation precedes multisensory integration.

Perceived time is inherently malleable. For example, adaptation to relatively long or short sensory events leads to a repulsive aftereffect such that subsequent events appear to be contracted or expanded (duration adaptation). Perceived visual duration can also be distorted via concurrent presentation of discrepant auditory durations (multisensory integration). The neural loci of both distortions remain unknown. In the current study we use a psychophysical approach to establish their relative positioning within the sensory processing hierarchy. We show that audiovisual integration induces marked distortions of perceived visual duration. We proceed to use these distorted durations as visual adapting stimuli yet find subsequent visual duration aftereffects to be consistent with physical rather than perceived visual duration. Conversely, the concurrent presentation of adapted auditory durations with nonadapted visual durations results in multisensory integration patterns consistent with perceived, rather than physical, auditory duration. These results demonstrate that recent sensory history modifies human duration perception prior to the combination of temporal information across sensory modalities and provides support for adaptation mechanisms mediated by duration selective neurons situated in early areas of the visual and auditory nervous system (Aubie, Sayegh, & Faure, 2012; Duysens, Schaafsma, & Orban, 1996; Leary, Edwards, & Rose, 2008).

Duration channels mediate human time perception.

The task of deciding how long sensory events seem to last is one that the human nervous system appears to perform rapidly and, for sub-second intervals, seemingly without conscious effort. That these estimates can be performed within and between multiple sensory and motor domains suggest time perception forms one of the core, fundamental processes of our perception of the world around us. Given this significance, the current paucity in our understanding of how this process operates is surprising. One candidate mechanism for duration perception posits that duration may be mediated via a system of duration-selective 'channels', which are differentially activated depending on the match between afferent duration information and the channels' 'preferred' duration. However, this model awaits experimental validation. In the current study, we use the technique of sensory adaptation, and we present data that are well described by banks of duration channels that are limited in their bandwidth, sensory-specific, and appear to operate at a relatively early stage of visual and auditory sensory processing. Our results suggest that many of the computational principles the nervous system applies to coding visual spatial and auditory spectral information are common to its processing of temporal extent.

Care of the critically ill patient with advanced chronic kidney disease or end-stage renal disease.

PURPOSE OF REVIEW: The number of individuals with chronic kidney disease (CKD) and end-stage renal disease (ESRD) is rising, and these individuals often require intensive care. RECENT FINDINGS: Patients with CKD and ESRD require critical care more frequently than those without these conditions and have similar reasons for requiring critical care as the general population. However, the burden of comorbidities, overall severity of illness as assessed by standard scoring systems, and mortality are higher in patients with ESRD than in the non-ESRD critically ill. After adjustment for demographics, comorbidities, and physiologic variables, the increased mortality risk in patients with ESRD is attenuated. In comparison to patients with dialysis-requiring acute kidney injury (AKI), critically ill patients with ESRD have a more favorable prognosis. Severity of illness scoring systems such as Acute Physiology and Chronic Health Evaluation and Simplified Acute Physiology Score tend to overestimate the risk of death in critically ill ESRD patients. ICU admission does not appear to dramatically affect long-term mortality in those with ESRD who survive their initial acute illness as compared ESRD patients without critical illness. SUMMARY: Despite the manifest physiologic derangements attending CKD/ESRD, a higher burden of comorbid conditions and a greater severity of illness on presentation account for much of the increased mortality. There is no justification for therapeutic nihilism in this population.

A Monte Carlo analysis of peritoneal antimicrobial pharmacokinetics.

Peritoneal dialysis-associated peritonitis (PDAP) can be treated using very different regimens of antimicrobial administration, regimens that result in different pharmacokinetic outcomes and systemic exposure levels. Currently, there is no population-level pharmacokinetic framework germane to the treatment of PDAP. We coupled a differential-equation-based model of antimicrobial kinetics to a Monte Carlo simulation framework, and conducted "in silico" clinical trials to explore the anticipated effects of different antimicrobial dosing regimens on relevant pharmacokinetic parameters (AUC/MIC and time greater than 5 ×MIC) and the level of systemic exposure.

Cost-Effectiveness of HRSA's Ryan White HIV/AIDS Program?

BACKGROUND: With an annual budget of more than $2 billion, the Health Resources and Services Administration's Ryan White HIV/AIDS Program (RWHAP) is the third largest source of public funding for HIV care and treatment in the United States, yet little analysis has been done to quantify the long-term public health and economic impacts of the federal program. METHODS: Using an agent-based, stochastic model, we estimated health care costs and outcomes over a 50-year period in the presence of the RWHAP relative to those expected to prevail if the comprehensive and integrated system of medical and support services funded by the RWHAP were not available. We made a conservative assumption that, in the absence of the RWHAP, only uninsured clients would lose access to these medical and support services. RESULTS: The model predicts that the proportion of people with HIV who are virally suppressed would be 25.2 percentage points higher in the presence of the RWHAP (82.6 percent versus 57.4 percent without the RWHAP). The number of new HIV infections would be 18 percent (190,197) lower, the number of deaths among people with HIV would be 31 percent (267,886) lower, the number of quality-adjusted life years would be 2.7 percent (5.6 million) higher, and the cumulative health care costs would be 25 percent ($165 billion) higher in the presence of the RWHAP relative to the counterfactual. Based on these results, the RWHAP has an incremental cost-effectiveness ratio of $29,573 per quality-adjusted life year gained compared with the non-RWHAP scenario. Sensitivity analysis indicates that the probability of transmitting HIV via male-to-male sexual contact and the cost of antiretroviral medications have the largest effect on the cost-effectiveness of the program. CONCLUSIONS: The RWHAP would be considered very cost-effective when using standard guidelines of less than the per capita gross domestic product of the United States. The results suggest that the RWHAP plays a critical and cost-effective role in the United States' public health response to the HIV epidemic.

Development of a Mathematical Model to Estimate the Cost-Effectiveness of HRSA's Ryan White HIV/AIDS Program.

BACKGROUND: The Health Resources and Services Administration's Ryan White HIV/AIDS Program provides services to more than half of all people diagnosed with HIV in the United States. We present and validate a mathematical model that can be used to estimate the long-term public health and cost impact of the federal program. METHODS: We developed a stochastic, agent-based model that reflects the current HIV epidemic in the United States. The model simulates everyone's progression along the HIV care continuum, using 2 network-based mechanisms for HIV transmission: injection drug use and sexual contact. To test the validity of the model, we calculated HIV incidence, mortality, life expectancy, and lifetime care costs and compared the results with external benchmarks. RESULTS: The estimated HIV incidence rate for men who have sex with men (502 per 100,000 person years), mortality rate of all people diagnosed with HIV (1663 per 100,000 person years), average life expectancy for individuals with low CD4 counts not on antiretroviral therapy (1.52-3.78 years), and lifetime costs ($362,385) all met our validity criterion of within 15% of external benchmarks. CONCLUSIONS: The model represents a complex HIV care delivery system rather than a single intervention, which required developing solutions to several challenges, such as calculating need for and receipt of multiple services and estimating their impact on care retention and viral suppression. Our strategies to address these methodological challenges produced a valid model for assessing the cost-effectiveness of the Ryan White HIV/AIDS Program.

Abnormal nocturnal heart rate variability response among chronic kidney disease and dialysis patients during wakefulness and sleep.

BACKGROUND: Dialysis patients and patients with chronic kidney disease (CKD) experience a substantial risk for abnormal autonomic function and abnormal heart rate variability (HRV). It remains unknown whether HRV changes across sleep stages in patients with different severity of CKD or dialysis dependency. We hypothesized that high-frequency (HF) HRV (vagal tone) will be attenuated from wakefulness to non-rapid eye movement (NREM) and then to rapid eye movement (REM) sleep in dialysis patients as compared to patients with CKD. METHODS: In-home polysomnography was performed in 95 patients with stages 4-5 CKD or end-stage renal disease (ESRD) on haemodialysis (HD) or peritoneal dialysis (PD). HRV was measured using fast Fourier transform of interbeat intervals during wakefulness and sleep. Low-frequency (LF) and HF intervals were generated. Natural logarithm HF (LNHF) and the logarithm LF/HF ratio (sympathovagal tone) were analysed by multivariable quantile regression and generalized estimating equations. RESULTS: Of the 95 patients, 63.2% (n = 60) was male, 35.8% (n = 34) was African American and 20.4% (n = 19) was diabetic. Average age was 51.6 ± 15.1 (range 19-82). HRV variables were significantly associated with diabetic status, higher periodic limb movement indices and lower bicarbonate levels. Patients with advanced CKD did not differ from dialysis patients in their inability to increase vagal tone during sleep. During wakefulness, female gender (P = 0.05) was associated with the increases in the vagal tone. CONCLUSIONS: Patients with CKD/ESRD exhibit dysregulation of the autonomic nervous system tone manifesting as a failure to increase HRV during wakefulness and sleep. Different patient characteristics are associated with changes in HRV at different sleep stages.

Effects of vascular flow and PEEP in a multiple hit model of lung injury in isolated perfused rabbit lungs.

BACKGROUND: High vascular flow aggravates lung damage in animal models of ventilator-induced lung injury. Positive end-expiratory pressure (PEEP) can attenuate ventilator-induced lung injury, but its continued effectiveness in the setting of antecedent lung injury is unclear. The objective of the present study was to evaluate whether the application of PEEP diminishes lung injury induced by concurrent high vascular flow and high alveolar pressures in normal lungs and in a preinjury lung model. METHODS: Two series of experiments were performed. Fifteen sets of isolated rabbit lungs were randomized into three groups (n = 5): low vascular flow/low PEEP; high vascular flow/low PEEP, and high vascular flow/high PEEP. Subsequently, the same protocol was applied in an additional 15 sets of isolated rabbit lungs in which oleic acid was added to the vascular perfusate to produce mild to moderate lung injury. All lungs were ventilated with peak airway pressure of 30 cm H2O for 30 minutes. Outcome measures included frequency of gross structural failure, pulmonary hemorrhage, edema formation, changes in static compliance, pulmonary vascular resistance, and pulmonary ultrafiltration coefficient. RESULTS: In the context of high vascular flow, application of a moderate level of PEEP reduced pulmonary rupture, edema formation, and lung hemorrhage. The protective effects of PEEP were not observed in lungs concurrently injured with oleic acid. CONCLUSIONS: Under these experimental conditions, PEEP attenuates lung injury in the setting of high vascular flow. The protective effect of PEEP is lost in a two-hit model of lung injury.

Evidence-based modeling of critical illness: an initial consensus from the Society for Complexity in Acute Illness.

INTRODUCTION: Given the complexity of biological systems, understanding their dynamic behaviors, such as the Acute Inflammatory Response (AIR), requires a formal synthetic process. Dynamic Mathematical Modeling (DMM) represents a suite of methods intended for inclusion within the required synthetic framework. The DMM, however, is a relatively novel approach in the practice of biomedical research. The Society for Complexity in Acute Illness (SCAI) was formed in 2004 from the leading research groups using DMM in the study of acute inflammation. This society believes that it is important to offer guidelines for the design, development, and use of DMM in the setting of AIR research to avoid the "garbage in, garbage out" problem. Accordingly, SCAI identified a need for and carried out a critical appraisal of DMM as currently used in the setting of acute illness. METHODS: The SCAI annual meeting in 2005, the Fourth International Conference on Complexity in Acute Illness (Cologne, Germany), was structured with the intent of developing a consensus statement on the methods and execution of DMM in AIR research. The conference was organized to include a series of interactive breakout sessions that included thought leaders from both the DMM and acute illness fields, the results of which were then presented in summary form to the entire group for discussion and consensus. The information in this article represents the concatenation of those presentations. RESULTS: The output from the Fourth International Conference on Complexity in Acute Illness involved consensus statements for the following topics: (1) the need for DMM; (2) a suggested approach for the process of establishing a modeling project; (3) the type of "wet" laboratory experiments and data needed to establish a modeling project; (4) general quality measures for data to be input to a modeling project; and (5) a descriptive list of several types of DMM to provide guidance in selection of a method for a project. CONCLUSION: We believe that the complexity of biological systems requires that DMM needs to be among the methods used to improve understanding and make progress with attempts to characterize and manipulate the AIR. We believe that this consensus statement will help guide the integration, rational implementation, and standardization of DMM into general biomedical research.

Inhibition of 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) activity of human lung microsomes by genistein, daidzein, coumestrol and C(18)-, C(19)- and C(21)-hydroxysteroids and ketosteroids.

Epidemiologic data suggest a relationship between dietary intake of phytochemicals and a lower incidence of some cancers. Modulation of steroid hormone metabolism has been proposed as a basis for this effect. It has been shown that aromatase, 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) are inhibited by the isoflavones, genistein and daidzein, and by coumestrol. In general, the extent of inhibition has been expressed in terms of IC50-values, which do not give information as to the pattern of inhibition, i.e., competitive, non-competitive, or mixed. Less is known of the effects of these compounds on 3alpha-HSD. The human lung is known to have a high level of 17beta-HSD and 3alpha-HSD activity. During the course of studies to characterize both activities in normal and inflamed lung and lung tumors we noted that 3alpha-HSD activity with 5alpha-DHT of microsomes from normal, adult lung was particularly susceptible to inhibition by coumestrol. To clarify the pattern of inhibition, the inhibition constants Ki and K'i were evaluated from plots of 1/v versus [I] and [S]/v versus [I]. Genistein, daidzein and coumestrol gave mixed inhibition patterns versus both 5alpha-DHT and NADH. In contrast, 5alpha-androstane-3,17-dione and 5alpha-pregnane-3,20-dione were competitive with 5alpha-DHT. NAD inhibited competitively with NADH. Our findings demonstrate that phytochemicals have the potential to inhibit 5alpha-DHT metabolism and thereby affect the androgen status of the human lung. The observation of a mixed inhibition pattern suggests these compounds bind to more than one form of the enzyme within the catalytic pathway.

Applications of machine learning and high-dimensional visualization in cancer detection, diagnosis, and management.

Recent technical advances in combinatorial chemistry, genomics, and proteomics have made available large databases of biological and chemical information that have the potential to dramatically improve our understanding of cancer biology at the molecular level. Such an understanding of cancer biology could have a substantial impact on how we detect, diagnose, and manage cancer cases in the clinical setting. One of the biggest challenges facing clinical oncologists is how to extract clinically useful knowledge from the overwhelming amount of raw molecular data that are currently available. In this paper, we discuss how the exploratory data analysis techniques of machine learning and high-dimensional visualization can be applied to extract clinically useful knowledge from a heterogeneous assortment of molecular data. After an introductory overview of machine learning and visualization techniques, we describe two proprietary algorithms (PURS and RadViz) that we have found to be useful in the exploratory analysis of large biological data sets. We next illustrate, by way of three examples, the applicability of these techniques to cancer detection, diagnosis, and management using three very different types of molecular data. We first discuss the use of our exploratory analysis techniques on proteomic mass spectroscopy data for the detection of ovarian cancer. Next, we discuss the diagnostic use of these techniques on gene expression data to differentiate between squamous and adenocarcinoma of the lung. Finally, we illustrate the use of such techniques in selecting from a database of chemical compounds those most effective in managing patients with melanoma versus leukemia.

Tracheal gas insufflation during late exhalation efficiently reduces PaCO(2) in experimental acute lung injury.

OBJECTIVE: Tracheal gas insufflation (TGI) reduces PaCO(2) by flushing the tracheal and mechanical deadspace, and may have its maximum benefit when TGI gas is unopposed by significant expiratory gas flow. Thus, limiting TGI to the late expiratory period may diminish tracheal exposure to TGI gas while preserving the efficacy of TGI. This study examined the gas exchange consequences of such late-expiratory TGI. DESIGN AND SETTING: Randomized controlled trial, animal study. MATERIALS: Eleven pigs. INTERVENTIONS: After stable lung injury was established using oleic acid 11 pigs were ventilated using a standardized lung protective strategy. Phasic expiratory TGI was applied for 30 min stages during the last 20%, 40%, 60%, and 100% of expiration in random sequence. PaCO(2) was continuously measured via an indwelling blood gas analysis system. MEASUREMENTS AND RESULTS: PaCO(2) at baseline was 86.1+/-4.7 mmHg, and decreased progressively with increasing TGI duration of 20%, 40%, and 60%, but not 100%, of expiration (PaCO(2)=75.7+/-5.2, 68.8+/-3.6, 65.1+/-5.3 and 65.2+/-5.2 mmHg, respectively). For all stages the reduction in PaCO(2) relative to baseline was significant. Trends of increasing PaO(2) and airway pressure with increasing TGI duration were noted and most likely associated with a TGI-induced increase in lung volume. CONCLUSIONS: Under these conditions confining TGI to the final 60% of expiration achieved effective PaCO(2) reduction, not significantly different from panexpiratory TGI, while limiting exposure of the trachea to TGI gas, and reducing the potential for TGI-induced hyperinflation. These findings suggest that TGI is most effectively applied in a phasic manner in late expiration, with its duration titrated to effect.

Distal projection of insufflated gas during tracheal gas insufflation.

Tracheal gas insufflation (TGI) flushes expired gas from the ventilator circuitry and central airways, augmenting CO2 clearance. Whereas a significant portion of this washout effect may occur distal to the injection orifice, the penetration and mixing behavior of TGI gas has not been studied experimentally. We examined the behavior of 100% oxygen TGI injected at set flow rates of 1-20 l/min into a simulated trachea consisting of a smooth-walled, 14-mm-diameter tube. Models incorporating a separate coaxial TGI injector, a rough-walled trachea, and a bifurcated trachea were also studied. One-hundred percent nitrogen, representing expiratory flow, passed in the direction opposite to TGI at set flow rates of 1-25 l/min. Oxygen concentration within the "trachea" was mapped as a function of axial and radial position. Three consistent findings were observed: 1) mixing of expiratory and TGI gases occurred close to the TGI orifice; 2) the oxygenated domain extended several centimeters beyond the endotracheal tube, even at high-expiratory flows, but had a defined distal limit; and 3) more distally from the site of gas injection, the TGI gas tended to propagate along the tracheal wall, rather than as a central projection. We conclude that forward-directed TGI penetrates a substantial distance into the central airways, extending the compartment susceptible to CO2 washout.