Estimating Productivity Loss from Breast and Non-Small-Cell Lung Cancer among Working-Age Patients and Unpaid Caregivers: A Survey Study Using the Multiplier Method.

Background. Traditional approaches to capturing health-related productivity loss (e.g., the human capital method) focus only on the foregone wages of affected patients, overlooking the losses caregivers can incur. This study estimated the burden of productivity loss among breast cancer (BC) and non-small-cell lung cancer (NSCLC) patients and individuals caring for such patients using an augmented multiplier method. Design. A cross-sectional survey of BC and NSCLC patients and caregivers measured loss associated with time absent from work (absenteeism) and reduced effectiveness (presenteeism). Respondents reported pre- and postcancer diagnosis income, hours worked, and time to complete tasks. Exploratory multivariable analyses examined correlations between respondents' clinical/demographic characteristics-including industry of employment-and postdiagnosis productivity. Results. Of 204 patients (104 BC, 100 NSCLC) and 200 caregivers (100 BC, 100 NSCLC) who completed the survey, 319 participants (162 BC, 157 NSCLC) working ≥40 wk/y prediagnosis were included in the analysis. More than one-third of the NSCLC (33%) and BC (43%) patients left the workforce postdiagnosis, whereas only 15% of caregivers did. The traditional estimate for the burden of productivity loss was 66% lower on average than the augmented estimate (NSCLC patients: 60%, BC patients: 69%, NSCLC caregivers: 59%, and BC caregivers: 73%). Conclusions. Although patients typically experience greater absenteeism, productivity loss incurred by caregivers is also substantial. Failure to account for such impacts can result in substantial underestimation of productivity gains novel cancer treatments may confer by enabling patients and caregivers to remain in the workforce longer. Our results underscore the importance of holistic approaches to understanding this impact on both patients and their caregivers and accounting for such considerations when making decisions about treatment and treatment value. Highlights: Cancer can have a profound impact on productivity. This study demonstrates how the disease affects not only patients but also the informal or unpaid individuals who care for patients.An augmented approach to calculating health-related productivity loss suggests that productivity impacts are much larger than previously understood.A more comprehensive understanding of the economic burden of cancer for both patients and their caregivers suggests the need for more support in the workplace for these individuals and a holistic approach to accounting for these impacts in treatment decision making.

Patient preferences for treatment in relapsed/refractory diffuse large B-cell lymphoma: a discrete choice experiment.

Aim: We quantified patient preferences for second-line diffuse large B-cell lymphoma therapies, including attributes of chimeric antigen receptor (CAR) T-cell therapy. Materials & methods: Using a discrete choice experiment, we surveyed 224 diffuse large B-cell lymphoma patients from the USA and Europe. Patients chose between two treatment options defined by six attributes with predefined levels for overall survival, adverse events (severe cytokine-release syndrome, severe neurological toxicities, severe infection) and time to return to pre-treatment functioning. Results: Increasing the probability of 1-year survival was most important to patients, followed by avoiding risks of cytokine-release syndrome and neurological toxicities. Respondents required a 13-14 percentage point increased 1-year survival probability to accept risks of treatment-associated adverse events. Conclusion: Patients prioritize survival and will accept certain adverse event risks to gain survival improvements.

Chimeric antigen receptor (CAR) T-cell therapy is a new treatment for patients with diffuse large B-cell lymphoma. CAR T-cell therapies are made from a patient's own cells, modified in a laboratory and used to attack cancer cells. While CAR T-cell therapies may increase long-term survival, they can also cause temporary but serious side effects, including neurological issues (e.g., headache, confusion, brain swelling) and cytokine-release syndrome (CRS), an inflammatory condition that can cause fever, breathing difficulties and organ dysfunction. To understand how patients' perspectives of CAR T-cell therapy compared with their perspectives on other treatments for diffuse large B-cell lymphoma, we surveyed 224 patients in the USA and Europe. They were asked to choose between two treatments in a series of choice sets, each displaying varying levels of aspects of cancer therapies, including survival and risks of serious side effects. Their choices allowed us to measure which factors were most important to patients when making decisions about treatment. We found that increasing the probability of survival was most important, followed by avoiding risks of neurological complications and CRS. Patients were willing to accept increased risks of neurological toxicities and CRS if they could obtain a 13­14 percentage point increase in the probability of surviving for at least 1 year after treatment.

Simulating the Fiscal Impact of Anti-Obesity Medications as an Obesity Reduction Strategy.

While substantial public health investment in anti-smoking initiatives has had demonstrated benefits on health and fiscal outcomes, similar investment in reducing obesity has not been undertaken, despite the substantial burden obesity places on society. Anti-obesity medications (AOMs) are poorly prescribed despite evidence that weight loss is not sustained using other strategies alone.We used a simulation model to estimate the potential impact of 100% uptake of AOMs on Medicare and Medicaid spending, disability payments, and taxes collected relative to status quo with negligible AOM use. Relative to status quo, AOM use simulation would result in Medicare and Medicaid savings of $231.5 billion and $188.8 billion respectively over 75 years. Government tax revenues would increase by $452.8 billion. Overall, the net benefit would be $746.6 billion. Anti-smoking efforts have had substantial benefits for society. A similar investment in obesity reduction, including broad use of AOMs, should be considered.

CAR-T therapy and historical trends in effectiveness and cost-effectiveness of oncology treatments.

Aim: This study examines how chimeric antigen receptor T-cell (CAR-T) therapy's incremental effectiveness and cost-effectiveness profile fits into the recent history of anticancer treatments. Materials & methods: We conducted graphical and multivariable analyses using data from the Cost-Effectiveness Analysis Registry of the Tufts Medical Center and the Institute for Clinical and Economic Review's analysis of CAR-T therapies. We collected additional information including the US FDA approval years for pharmacologic innovations. Results: CAR-T provided 5.03 (95% CI: 3.88-6.18) more incremental quality-adjusted life-years than the average pharmaceutical intervention and 4.61 (95% CI: 1.67-7.56) more than the average nonpharmaceutical intervention, while retaining similar cost-effectiveness. There was evidence of worsening cost-effectiveness by approval year for pharmaceutical interventions. Limitations: Analysis is limited to anticancer treatments studied in cost-utility analyses, estimated to cover approximately 60% of FDA-approved antineoplastic agents. Conclusion: CAR-T therapy breaks a pattern of stagnant efficacy growth in pharmaceutical innovation and demonstrates significantly greater incremental effectiveness and similar cost-effectiveness to prior innovations.

Cost variation and savings opportunities in the Oncology Care Model.

OBJECTIVES: This study seeks to identify service categories that present the greatest opportunities to reduce spending in oncology care episodes, as defined by the CMS Oncology Care Model (OCM). Regional variation in spending for similar patients is often interpreted as evidence that resources can be saved, because higher-spending regions could achieve savings by behaving more like their lower-spending counterparts. STUDY DESIGN: We used Surveillance, Epidemiology, and End Results Medicare data from 2006-2013 for this retrospective observational cohort study. Analysis focused on patients with non-small cell lung cancer, advanced (stage III or IV) breast cancer, renal cell carcinoma, multiple myeloma, or chronic myeloid leukemia. METHODS: Episodes were identified for patients with the 5 included cancers, following the episode definition used in the OCM. We estimated standardized episode-level spending for a standard patient across subcategories of care for each hospital referral region (HRR) defined by the Dartmouth Atlas. The contribution of each subcategory to interregional variation in total spending reflects that subcategory's potential to yield savings. RESULTS: Chemotherapy and acute inpatient hospital care tended to be the highest contributors to interregional variation. Imaging, nonchemotherapy Part B drugs, physician evaluation and management services, and diagnostics were negligible contributors to interregional variation for all 5 cancers. CONCLUSIONS: Chemotherapy and inpatient hospital care offer the most potential to reduce spending within OCM-defined episodes. Other sources of savings differ by type of cancer. Assuming patient outcomes are not compromised, low-spending HRRs may be models for lowering cost in cancer care.

Share of Oncology Versus Nononcology Spending in Episodes Defined by the Centers for Medicare & Medicaid Services Oncology Care Model.

PURPOSE: Performance-based payments to oncology providers participating in the Centers for Medicare & Medicaid Services (CMS) Oncology Care Model (OCM) are based, in part, on overall spending in 6-month episodes of care, including spending unrelated to oncology care. The amount of spending likely to occur outside of oncologists' purview is unknown. METHODS: Following the OCM definition of an episode, we used SEER-Medicare data from 2006 to 2013 to identify episodes of cancer care for the following diagnoses: breast cancer (BC), non-small-cell lung cancer, renal cell carcinoma, multiple myeloma (MM), and chronic myeloid leukemia. Claims were categorized by service type and, separately, whether the content fell within the purview of oncology providers (classified as oncology, with all other claims nononcology). We calculated the shares of episode spending attributable to oncology versus nononcology services. RESULTS: The percentage of oncology spending within OCM episodes ranged from 62.4% in BC to 85.5% in MM. The largest source of oncology spending was antineoplastic drug therapy, ranging from 21.8% of total episode spending in BC to 67.6% in chronic myeloid leukemia. The largest source of nononcology spending was acute hospitalization and inpatient physician costs, ranging from 6.6% of overall spending for MM to 10.4% for non-small-cell lung cancer; inpatient oncology spending contributed roughly similar shares to overall spending. CONCLUSION: Most spending in OCM-defined episodes was attributable to services related to cancer care, especially antineoplastic drug therapy. Inability to control nononcology spending may present challenges for practices participating in the OCM, however.

Greater Spending Associated with Improved Survival for Some Cancers in OCM-Defined Episodes.

BACKGROUND: Previous research finds significant variation in spending and utilization across regions, with little evidence of differences in outcomes. While such findings have been interpreted as evidence that spending can be reduced without compromising patient outcomes, the link between spending variation and outcomes remains a critical question. OBJECTIVE: To use evidence from geographic variations in spending and an individual-level survival analysis to test whether spending within oncology care episodes is associated with survival, where episodes are defined as in the Center for Medicare and Medicaid Innovation's Oncology Care Model (OCM). METHODS: In this retrospective cohort analysis, patient data from the Surveillance, Epidemiology and End Results Medicare (SEER-Medicare) database for 2007-2013 were linked to hospital referral regions (HRRs) using ZIP codes. Patients in the SEER program are a part of selected population-based cancer registries throughout the United States whose records are linked to Medicare enrollment and claims data (93% of elderly registry patients were successfully linked to Medicare data). Episodes of cancer care were defined as in the OCM: 6 months following a triggering chemotherapy claim. We analyzed episodes of care for 5 tumor types: advanced breast cancer (BC), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), multiple myeloma (MM), and chronic myeloid leukemia (CML). We removed the effects of differentials in Medicare payment rates, which were mostly geographic. Regression analysis was then used to calculate standardized spending levels for each HRR, that is, spending adjusted for differences in patient and episode characteristics. To examine the effect of spending during OCM-defined episodes on individual-level survival, we used Cox regression with patient characteristics and standardized HRR spending per episode as covariates. To address concerns that may arise from multiple comparisons across the 5 tumor types, we used the Benjamini-Hochberg procedure to control the false discovery rate. RESULTS: Our analysis showed significant differences in standardized spending across HRRs. Compared with spending at the 20th percentile episode, spending at the 80th percentile ranged from 25% higher ($57,392 vs. $45,995 for MM) to 47% higher ($36,920 vs. $24,127 for RCC), indicating practice style variation across regions. The hazard of dying for patients with NSCLC and MM statistically significantly decreased by 7% (HR = 0.93, P = 0.006) and 13% (HR = 0.87, P = 0.019), respectively, for a $10,000 increase in standardized spending (in 2013 U.S. dollars). For the 3 other cancers, spending effects were not statistically significant. After using the Benjamini-Hochberg procedure with a 5% false discovery rate, the effects of increased spending on improved survival for NSCLC and MM remained statistically significant. CONCLUSIONS: The association we found between spending and survival suggests caution may be warranted for physicians, pharmacists, other health care professionals, and policymakers involved in efforts to reduce across-the-board spending within OCM-defined episodes for at least 2 of the 5 cancers studied. DISCLOSURES: Funding for this research was provided by Novartis Pharmaceuticals to Precision Health Economics in support of research design, analysis, and technical writing services. The funder provided input on study design and comments on the draft report. Baumgardner, Shahabi, and Linthicum are employees of Precision Health Economics (PHE), a health care consultancy to the insurance and life science industries, including firms that market oncology therapies. Vine was an employee of PHE at the time of this research. Zacker is an employee of and shareholder in Novartis Pharmaceuticals. Lakdawalla is a consultant to PHE and holds equity in its parent company, Precision Medicine Group.

Effect of Bronchoconstriction-induced Ventilation-Perfusion Mismatch on Uptake and Elimination of Isoflurane and Desflurane.

BACKGROUND: Increasing numbers of patients with obstructive lung diseases need anesthesia for surgery. These conditions are associated with pulmonary ventilation/perfusion (VA/Q) mismatch affecting kinetics of volatile anesthetics. Pure shunt might delay uptake of less soluble anesthetic agents but other forms of VA/Q scatter have not yet been examined. Volatile anesthetics with higher blood solubility would be less affected by VA/Q mismatch. We therefore compared uptake and elimination of higher soluble isoflurane and less soluble desflurane in a piglet model. METHODS: Juvenile piglets (26.7 ± 1.5 kg) received either isoflurane (n = 7) or desflurane (n = 7). Arterial and mixed venous blood samples were obtained during wash-in and wash-out of volatile anesthetics before and during bronchoconstriction by methacholine inhalation (100 µg/ml). Total uptake and elimination were calculated based on partial pressure measurements by micropore membrane inlet mass spectrometry and literature-derived partition coefficients and assumed end-expired to arterial gradients to be negligible. VA/Q distribution was assessed by the multiple inert gas elimination technique. RESULTS: Before methacholine inhalation, isoflurane arterial partial pressures reached 90% of final plateau within 16 min and decreased to 10% after 28 min. By methacholine nebulization, arterial uptake and elimination delayed to 35 and 44 min. Desflurane needed 4 min during wash-in and 6 min during wash-out, but with bronchoconstriction 90% of both uptake and elimination was reached within 15 min. CONCLUSIONS: Inhaled methacholine induced bronchoconstriction and inhomogeneous VA/Q distribution. Solubility of inhalational anesthetics significantly influenced pharmacokinetics: higher soluble isoflurane is less affected than fairly insoluble desflurane, indicating different uptake and elimination during bronchoconstriction.

Implementation of a Tele-urology Program for Outpatient Hematuria Referrals: Initial Results and Patient Satisfaction.

OBJECTIVE: To report on results from a new tele-urology pathway for managing hematuria consults, including a survey of patient attitudes and satisfaction with such a program. Recent guideline changes have relaxed the definition of microscopic hematuria and may have significantly increased the number of hematuria evaluations. MATERIALS AND METHODS: Patients referred to the Atlanta Veterans Administration Medical Center with hematuria were scheduled for a tele-urology clinic encounter utilizing a telephone call to obtain hematuria-related clinical information via a standardized algorithm. At subsequent cystoscopy, patients were evaluated with a 29-question survey regarding overall acceptance and satisfaction of the clinic (8 questions) and impact factors (21 questions). RESULTS: One hundred fifty veterans participated in the survey. Median time from consult request to appointment was 12 days and thereafter to cystoscopy was 16 days. Patients reported high acceptance and overall satisfaction with telephone evaluation; mean scores exceeded 9 out of 10 for overall satisfaction, efficiency, convenience, friendliness, care quality, understandability, privacy, and professionalism. When presented with a choice, nearly all patients (98%) preferred telephone-based encounters to face-to-face clinic visits. Underlying negative factors responsible for patients' preferences included transportation-related issues (97%) and logistical clinic issues (65%). Ninety-seven percent of patients reported high-quality evaluation. CONCLUSION: Patients report high acceptance and satisfaction with telephone clinics as a mechanism for expedited hematuria evaluation, primarily due to avoiding barriers related to transportation and clinical operations, as well as a perceived high quality of evaluation. Telephone appointments have potential to positively impact healthcare access and productivity.

Ventilation/perfusion distributions revisited.

PURPOSE OF REVIEW: A major cause of hypoxemia in anesthesia is ventilation-perfusion (VA/Q) mismatch. With more advanced surgery and an aging population, monitoring of VA/Q is of increasing importance. RECENT FINDINGS: The classic multiple inert gas elimination technique has been simplified with a new approach based on mass spectrometry. VA/Q distributions can also be measured, at the bedside, by varying inspired oxygen concentration. MRI, 3-dimensional single photon emission computed tomography, positron emission tomography, and electrical impedance tomography enable imaging of perfusion and ventilation, and in some of the techniques also the distribution of inflammation. One-lung ventilation with thoracoscopy and capnothorax require careful monitoring of VA/Q, made possible bedside by electrical impedance tomography. Carbon dioxide, but not air, for pneumoperitoneum enhances shift of perfusion to ventilated regions. Ventilatory support during cardiopulmonary resuscitation causes less VA/Q mismatch when inspired oxygen concentrations are lower. Mechanisms of redistribution of lung blood flow by inhaled nitric oxide include endothelin-mediated vasoconstriction in collapsed lung regions. SUMMARY: Methods are continuously developing to simplify measurement of VA/Q and also to relate VA/Q to inflammation. The recording of VA/Q has helped to explain important aspects of gas exchange in thoracic anesthesiology and in intensive care medicine.

Effects of methacholine infusion on desflurane pharmacokinetics in piglets.

The data of a corresponding animal experiment demonstrates that nebulized methacholine (MCh) induced severe bronchoconstriction and significant inhomogeneous ventilation and pulmonary perfusion (V̇A/Q̇) distribution in pigs, which is similar to findings in human asthma. The inhalation of MCh induced bronchoconstriction and delayed both uptake and elimination of desflurane (Kretzschmar et al., 2015) [1]. The objective of the present data is to determine V̇A/Q̇ matching by Multiple Inert Gas Elimination Technique (MIGET) in piglets before and during methacholine- (MCh-) induced bronchoconstriction, induced by MCh infusion, and to assess the blood concentration profiles for desflurane (DES) by Micropore Membrane Inlet Mass Spectrometry (MMIMS). Healthy piglets (n=4) under general anesthesia were instrumented with arterial, central venous, and pulmonary artery lines. The airway was secured via median tracheostomy with an endotracheal tube, and animals were mechanically ventilated with intermittent positive pressure ventilation (IPPV) with a FiO2 of 0.4, tidal volume (V T)=10 ml/kg and PEEP of 5cmH2O using an open system. The determination of V.A/Q. was done by MIGET: before desflurane application and at plateau in both healthy state and during MCh infusion. Arterial blood was sampled at 0, 1, 2, 5, 10, 20, and 30 min during wash-in and washout, respectively. Bronchoconstriction was established by MCH infusion aiming at doubling the peak airway pressure, after which wash-in and washout of the anesthetic gas was repeated. Anesthesia gas concentrations were measured by MMIMS. Data were analyzed by ANOVA, paired t-test, and by nonparametric Friedman׳s test and Wilcoxon׳s matched pairs test. We measured airway pressures, pulmonary resistance, and mean paO2 as well as hemodynamic variables in all pigs before desflurane application and at plateau in both healthy state and during methacholine administration by infusion. By MIGET, fractional alveolar ventilation and pulmonary perfusion in relation to the V.A/Q. compartments, data of logSDQ̇ and logSDV̇ (the second moments describing global dispersion, i.e. heterogeneity of distribution) were estimated prior to and after MCh infusion. The uptake and elimination of desflurane was determined by MMIMS.

Multiple inert gas elimination technique by micropore membrane inlet mass spectrometry--a comparison with reference gas chromatography.

The mismatching of alveolar ventilation and perfusion (VA/Q) is the major determinant of impaired gas exchange. The gold standard for measuring VA/Q distributions is based on measurements of the elimination and retention of infused inert gases. Conventional multiple inert gas elimination technique (MIGET) uses gas chromatography (GC) to measure the inert gas partial pressures, which requires tonometry of blood samples with a gas that can then be injected into the chromatograph. The method is laborious and requires meticulous care. A new technique based on micropore membrane inlet mass spectrometry (MMIMS) facilitates the handling of blood and gas samples and provides nearly real-time analysis. In this study we compared MIGET by GC and MMIMS in 10 piglets: 1) 3 with healthy lungs; 2) 4 with oleic acid injury; and 3) 3 with isolated left lower lobe ventilation. The different protocols ensured a large range of normal and abnormal VA/Q distributions. Eight inert gases (SF6, krypton, ethane, cyclopropane, desflurane, enflurane, diethyl ether, and acetone) were infused; six of these gases were measured with MMIMS, and six were measured with GC. We found close agreement of retention and excretion of the gases and the constructed VA/Q distributions between GC and MMIMS, and predicted PaO2 from both methods compared well with measured PaO2. VA/Q by GC produced more widely dispersed modes than MMIMS, explained in part by differences in the algorithms used to calculate VA/Q distributions. In conclusion, MMIMS enables faster measurement of VA/Q, is less demanding than GC, and produces comparable results.

Influence of respiratory rate and end-expiratory pressure variation on cyclic alveolar recruitment in an experimental lung injury model.

INTRODUCTION: Cyclic alveolar recruitment/derecruitment (R/D) is an important mechanism of ventilator-associated lung injury. In experimental models this process can be measured with high temporal resolution by detection of respiratory-dependent oscillations of the paO2 (ΔpaO2). A previous study showed that end-expiratory collapse can be prevented by an increased respiratory rate in saline-lavaged rabbits. The current study compares the effects of increased positive end-expiratory pressure (PEEP) versus an individually titrated respiratory rate (RRind) on intra-tidal amplitude of Δ paO2 and on average paO2 in saline-lavaged pigs. METHODS: Acute lung injury was induced by bronchoalveolar lavage in 16 anaesthetized pigs. R/D was induced and measured by a fast-responding intra-aortic probe measuring paO2. Ventilatory interventions (RRind (n=8) versus extrinsic PEEP (n=8)) were applied for 30 minutes to reduce Δ paO2. Haemodynamics, spirometry and Δ paO2 were monitored and the Ventilation/Perfusion distributions were assessed by multiple inert gas elimination. The main endpoints average and Δ paO2 following the interventions were analysed by Mann-Whitney-U-Test and Bonferroni's correction. The secondary parameters were tested in an explorative manner. RESULTS: Both interventions reduced Δ paO2. In the RRind group, ΔpaO2 was significantly smaller (P<0.001). The average paO2 continuously decreased following RRind and was significantly higher in the PEEP group (P<0.001). A sustained difference of the ventilation/perfusion distribution and shunt fractions confirms these findings. The RRind application required less vasopressor administration. CONCLUSIONS: Different recruitment kinetics were found compared to previous small animal models and these differences were primarily determined by kinetics of end-expiratory collapse. In this porcine model, respiratory rate and increased PEEP were both effective in reducing the amplitude of paO2 oscillations. In contrast to a recent study in a small animal model, however, increased respiratory rate did not maintain end-expiratory recruitment and ultimately resulted in reduced average paO2 and increased shunt fraction.

A comparison of micropore membrane inlet mass spectrometry-derived pulmonary shunt measurement with Riley shunt in a porcine model.

BACKGROUND: The multiple inert gas elimination technique was developed to measure shunt and the ratio of alveolar ventilation to simultaneous alveolar capillary blood flow in any part of the lung (V(A)'/Q') distributions. Micropore membrane inlet mass spectrometry (MMIMS), instead of gas chromatography, has been introduced for inert gas measurement and shunt determination in a rabbit lung model. However, agreement with a frequently used and accepted method for quantifying deficits in arterial oxygenation has not been established. We compared MMIMS-derived shunt (M-S) as a fraction of total cardiac output (CO) with Riley shunt (R-S) derived from the R-S formula in a porcine lung injury model. METHODS: To allow a broad variance of atelectasis and therefore shunt fraction, 8 sham animals did not receive lavage, and 8 animals were treated by lung lavages with 30 mL/kg warmed lactated Ringer's solution as follows: 2 animals were lavaged once, 5 animals twice, and 1 animal 3 times. Variables were recorded at baseline and twice after induction of lung injury (T1 and T2). Retention data of sulfur hexafluoride, krypton, desflurane, enflurane, diethyl ether, and acetone were analyzed by MMIMS, and M-S was derived using a known algorithm for the multiple inert gas elimination technique. Standard formulas were used for the calculation of R-S. RESULTS: Forty-four pairs of M-S and R-S were recorded. M-S ranged from 0.1% to 35.4% and R-S from 3.7% to 62.1%. M-S showed a correlation with R-S described by linear regression: M-S = -4.26 + 0.59 x R-S (r(2) = 0.83). M-S was on average lower than R-S (mean = -15.0% CO, sd = 6.5% CO, and median = -15.1), with lower and upper limits of agreement of -28.0% and -2.0%, respectively. The lower and upper limits of the 95% confidence intervals were -17.0 and -13.1 (P < 0.001, Student's t-test). CONCLUSIONS: Shunt derived from MMIMS inert gas retention data correlated well with R-S during breathing of oxygen. Shunt as derived by MMIMS was generally less than R-S.

Spatial and temporal heterogeneity of ventilator-associated lung injury after surfactant depletion.

Volutrauma and atelectrauma have been proposed as mechanisms of ventilator-associated lung injury, but few studies have compared their relative importance in mediating lung injury. The objective of our study was to compare the injury produced by stretch (volutrauma) vs. cyclical recruitment (atelectrauma) after surfactant depletion. In saline-lavaged rabbits, we used high tidal volume, low respiratory rate, and low positive end-expiratory pressure to produce stretch injury in nondependent lung regions and cyclical recruitment in dependent lung regions. Tidal changes in shunt fraction were assessed by measuring arterial Po(2) oscillations. After ventilating for times ranging from 0 to 6 h, lungs were excised, sectioned gravitationally, and assessed for regional injury by evaluation of edema formation, chemokine expression, upregulation of inflammatory enzyme activity, and alveolar neutrophil accumulation. Edema formation, lung tissue interleukin-8 expression, and alveolar neutrophil accumulation progressed more rapidly in dependent lung regions, whereas macrophage chemotactic protein-1 expression progressed more rapidly in nondependent lung regions. Temporal and regional heterogeneity of lung injury were substantial. In this surfactant depletion model of acute lung injury, cyclical recruitment produced more injury than stretch.

Physiological and hypoxic O2 tensions rapidly regulate NO production by stimulated macrophages.

Nitric oxide (NO) production by inducible NO synthase (iNOS) is dependent on O(2) availability. The duration and degree of hypoxia that limit NO production are poorly defined in cultured cells. To investigate short-term O(2)-mediated regulation of NO production, we used a novel forced convection cell culture system to rapidly (response time of 1.6 s) and accurately (+/-1 Torr) deliver specific O(2) tensions (from <1 to 157 Torr) directly to a monolayer of LPS- and IFNgamma-stimulated RAW 264.7 cells while simultaneously measuring NO production via an electrochemical probe. Decreased O(2) availability rapidly (36 Torr], but it did not predict NO production. NO consumption was minimal at high O(2) and NO tensions and negligible at low O(2) and NO tensions. These results are consistent with O(2) substrate limitation as a regulatory mechanism during brief hypoxic exposure. The rapid and reversible effects of physiological and pathophysiological O(2) tensions suggest that O(2) tension has the potential to regulate NO production in vivo.

Radio frequency analog electronics based on carbon nanotube transistors.

The potential to exploit single-walled carbon nanotubes (SWNTs) in advanced electronics represents a continuing, major source of interest in these materials. However, scalable integration of SWNTs into circuits is challenging because of difficulties in controlling the geometries, spatial positions, and electronic properties of individual tubes. We have implemented solutions to some of these challenges to yield radio frequency (RF) SWNT analog electronic devices, such as narrow band amplifiers operating in the VHF frequency band with power gains as high as 14 dB. As a demonstration, we fabricated nanotube transistor radios, in which SWNT devices provide all of the key functions, including resonant antennas, fixed RF amplifiers, RF mixers, and audio amplifiers. These results represent important first steps to practical implementation of SWNTs in high-speed analog circuits. Comparison studies indicate certain performance advantages over silicon and capabilities that complement those in existing compound semiconductor technologies.