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Despite the numerous recent advancements in therapy, heart failure (HF) remains a principle cause of both morbidity and mortality. HF with preserved ejection fraction (HFpEF), a condition that shares the prevalence and adverse outcomes of HF with reduced ejection fraction, remains poorly recognised in its initial manifestations. Cardiopulmonary exercise testing (CPET), defined as a progressive work exercise test that includes non-invasive continuous measurement of cardiovascular and respiratory parameters, provides a reliable mode to evaluate for early features and for the assessment of prognostic features of both forms of HF. While CPET measurements are standard of care for advanced HF and transplant programmes, they merit a broader clinical application in the early diagnosis and assessment of patients with HFpEF. In this review, we provide an overview of the pathophysiology of exercise intolerance in HF and discuss key findings in CPETs used to evaluate both severity of impairment and the prognostic implications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Summary: Optimal timing and procedure selection that define staged treatment strategies can affect outcomes dramatically and remain an area of major debate in the treatment of multiply injured orthopaedic trauma patients. Decisions regarding timing and choice of orthopaedic procedure(s) are currently based on the physiologic condition of the patient, resource availability, and the expected magnitude of the intervention. Surgical decision-making algorithms rarely rely on precision-type data that account for demographics, magnitude of injury, and the physiologic/immunologic response to injury on a patient-specific basis. This study is a multicenter prospective investigation that will work toward developing a precision medicine approach to managing multiply injured patients by incorporating patient-specific indices that quantify (1) mechanical tissue damage volume; (2) cumulative hypoperfusion; (3) immunologic response; and (4) demographics. These indices will formulate a precision injury signature, unique to each patient, which will be explored for correspondence to outcomes and response to surgical interventions. The impact of the timing and magnitude of initial and staged surgical interventions on patient-specific physiologic and immunologic responses will be evaluated and described. The primary goal of the study will be the development of data-driven models that will inform clinical decision-making tools that can be used to predict outcomes and guide intervention decisions., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Penetrating cervical carotid artery injury is an uncommon but high-stake scenario associated with stroke and death. The objective of this study was to characterize and compare penetrating carotid injury in the military and civilian setting, as well as provide considerations for management., Methods: Cohorts with penetrating cervical carotid artery injury from the Department of Defense Trauma Registry (2002-2015) and the American Association for the Surgery of Trauma Prospective Observation Vascular Injury Treatment Registry (2012-2018) were analyzed. A least absolute shrinkage and selection operator multivariate analysis using random forest-based imputation was performed to identify risk factors affecting stroke and mortality., Results: There were a total of 157 patients included in the study, of which 56 (35.7%) were military and 101 (64.3%) were civilian. The military cohort was more likely to have been managed with open surgery (87.5% vs. 44.6%, p < 0.001) and to have had any procedure to restore or maintain flow to the brain (71.4% vs. 35.6%, p < 0.001), while the civilian cohort was more likely to undergo nonoperative management (45.5% vs. 12.5%, p < 0.001). Stroke rate was higher within the military cohort (41.1% vs. 13.9%, p < 0.001); however, mortality did not differ between the groups (12.5% vs. 17.8%, p = 0.52). On multivariate analysis, predictors for stroke were presence of a battle injury (log odds, 2.1; p < 0.001) and internal or common carotid artery ligation (log odds 1.5, p = 0.009). For mortality outcome, protective factors included a high Glasgow Coma Scale on admission (log odds, -0.21 per point; p < 0.001). Increased admission Injury Severity Score was a predictor of mortality (log odds, 0.05 per point; p = 0.005)., Conclusion: The stroke rate was higher in the military cohort, possibly reflecting complexity of injury; however, there was no difference in mortality between military and civilian patients. For significant injuries, concerted efforts should be made at carotid reconstruction to reduce the occurrence of stroke., Level of Evidence: Retrospective cohort analysis, level III., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial., Methods: Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions., Results: A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI., Conclusions: These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle., Competing Interests: Stealth BioTherapeutics provided funding for this work. Baback Roshanravan, Kevin Conley, and David Marcinek served as paid consultants for Stealth BioTherapeutics from 2014-2016. The authors worked with Stealth BioTherapeutics on the design of this study. Otherwise, the funders played no role in data collection and analysis nor the decision to publish this manuscript. These competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Enhanced recovery after surgery (ERAS) protocols have been shown to decrease length of stay (LOS) and improve patient outcomes in a wide variety of surgical fields; however, barriers exist preventing the implementation of all elements. We hypothesize that a subset of ERAS elements are most influential on LOS and readmission following colorectal surgery., Study Design: A retrospective review of 840 patients was performed and their compliance with 24 ERAS components evaluated. Two independent machine-learning statistical algorithms were employed to determine which subset of ERAS elements was most impactful on LOS <3 days and hospital readmission., Results: Increasing compliance with ERAS elements had an inverse linear relationship with LOS. Open (vs minimally invasive) surgery was associated with increased LOS. Early mobilization and multimodal pain management are the elements most protective against increased LOS. Readmissions increase with the number of morphine milligram equivalents (MME)/day. The subset of patients who underwent minimally invasive procedures, had multimodal pain control, and less than 16 MME per day were least likely (23%) to have >3-day LOS. Those patients who underwent an open procedure with less than 15 ERAS elements completed were most likely (84%) to have >3-day LOS., Conclusion: While increasing compliance with ERAS protocols and minimally invasive procedures decrease LOS and readmission overall, a subset of components-multimodal pain control, limited opioid use, and early mobilization-was most associated with decreased LOS and readmission. This study provides guidance on which ERAS elements should be emphasized.

Introduction: Botulinum toxin A (BTA) injection into the glabellar region is currently being studied as a treatment for major depressive disorder (MDD). Here we explore efficacy data of this novel approach in a pooled analysis., Methods: A literature search revealed 3 RCTs on this topic. Individual patient data and clinical end points shared by these 3 trials were pooled and analyzed as one study (n=134) using multiple regression models with random effects., Results: In the pooled sample, the BTA (n=59) and the placebo group (n=75) did not differ in the baseline variables. Efficacy outcomes revealed BTA superiority over placebo: Improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale 6 weeks after baseline was 45.7% for BTA vs. 14.6% for placebo (p<0.0001), corresponding to a BTA response rate of 54.2% (vs. 10.7%) and a BTA remission rate of 30.5% (vs. 6.7%)., Discussion: Equalling the status of a meta-analysis, this study increases evidence that a single treatment of BTA into the glabellar region can reduce symptoms of MDD. Further studies are needed to better understand how BTA exerts its mood-lifting effect., (© Georg Thieme Verlag KG Stuttgart · New York.)

An elevated physiological dead space, calculated from measurements of arterial CO2 and mixed expired CO2, has proven to be a useful clinical marker of prognosis both for patients with acute respiratory distress syndrome and for patients with severe heart failure. Although a frequently cited explanation for an elevated dead space measurement has been the development of alveolar regions receiving no perfusion, evidence for this mechanism is lacking in both of these disease settings. For the range of physiological abnormalities associated with an increased physiological dead space measurement, increased alveolar ventilation/perfusion ratio (V'A/Q') heterogeneity has been the most important pathophysiological mechanism. Depending on the disease condition, additional mechanisms that can contribute to an elevated physiological dead space measurement include shunt, a substantial increase in overall V'A/Q' ratio, diffusion impairment, and ventilation delivered to unperfused alveolar spaces., (Copyright ©ERS 2015.)

Objective: To determine whether a single treatment of botulinum toxin A in the forehead (glabellar) region can improve symptoms of depression in patients with major depressive disorder (MDD), as defined by DSM-IV criteria., Method: Thirty participants were randomly assigned to receive either placebo or botulinum toxin A (BTA; onabotulinumtoxinA) injections in the forehead. Female participants received 29 units; male participants received 39 units. At week 12, the groups were crossed over. Participants were evaluated at weeks 0, 3, 6, 12, 15, 18, and 24 for improvement in MDD symptoms using the Patient Health Care Questionnaire-9, Beck Depression Inventory (BDI), and 21-Item Hamilton Depression Rating Scale (HDRS-21) objective measurement scales. The primary outcome was the rate of HDRS-21 response, defined as ≥ 50% score reduction from baseline. The study occurred from July 2011 to November 2012., Results: Patients who received BTA at week 0 (BTA-first group) and at week 12 (BTA-second group) had a statistically significant reduction in MDD symptoms as compared to placebo. Improvement in MDD continued over 24 weeks in the group that received BTA first even though the cosmetic effects of BTA wore off at 12 to 16 weeks. HDRS-21 response rates were 55% (6/11) in the BTA-first group, 24% (4/17) in the BTA-second group, and 0% (0/19) in the placebo group (P < .0001). HDRS-21 remission rates (score ≤ 7) were 18% (2/11), 18% (3/17), and 0% (0/19), respectively (P = .057). HDRS-21 scores dropped -46% and -35% in the BTA-first and -second groups versus -2% in the placebo group (P < .0001). The BDI response rate (≥ 50% reduction from baseline) was 45% (5/11) in the BTA-first group, 33% (6/18) in the BTA-second group, and 5% (1/19) in the placebo group (P = .0067). BDI remission rates (score ≤ 9) were 27% (3/11), 33% (6/18), and 5% (1/19), respectively (P = .09). BDI scores dropped -42% and -35% in the BTA-first and -second groups versus -15% in the placebo group (P < .0001)., Conclusions: Botulinum toxin A injection in the glabellar region was associated with significant improvement in depressive symptoms and may be a safe and sustainable intervention in the treatment of MDD., Trial Registration: ClinicalTrials.gov identifier: NCT01392963., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Setting realistic weight loss goals may play a role in weight loss. We abstracted data from randomized controlled trials and observational studies conducted between 1998 and 2012 concerning the association of weight loss goals with weight loss. Studies included those that (i) were conducted in humans; (ii) delivered a weight loss intervention; (iii) lasted ≥6 weeks; (iv) assessed baseline weight loss goals; (vi) assessed pre- and post-weight either in the form of body mass index or some other measure that could be converted to weight loss based on information included in the original study or later provided by the author(s); and (vii) assessed the correlation between weight loss goals and final weight loss or provided data to calculate the correlation. Studies that included interventions to modify weight loss goals were excluded. Eleven studies met inclusion criteria. The overall correlation between goal weight and weight at intervention completion was small and statistically insignificant (ρ=0.0 5 ; P = 0.20). The current evidence does not demonstrate that setting realistic goals leads to more favourable weight loss outcomes. Thus, our field may wish to reconsider the value of setting realistic goals in successful weight loss., (© 2013 The Authors. obesity reviews © 2013 International Association for the Study of Obesity.)

Objective: We demonstrate the utility of parametric survival analysis. The analysis of longevity as a function of risk factors such as body mass index (BMI; kg/m(2) ), activity levels, and dietary factors is a mainstay of obesity research. Modeling survival through hazard functions, relative risks, or odds of dying with methods such as Cox proportional hazards or logistic regression are the most common approaches and have many advantages. However, they also have disadvantages in terms of the ease of interpretability, especially for non-statisticians; the need for additional data to convert parameter estimates to estimates of years of life lost (YLL); debates about the appropriate time scale in the model; and an inability to estimate median survival time when the censoring rate is too high., Design and Methods: We will conduct parametric survival analyses with multiple distributions, including distributions that are known to be poor fits (Gaussian), as well as a newly discovered "Compressed Gaussian"'' distribution., Results: Parametric survival analysis models were able to accurately estimate median survival times in a population-based data set of 15,703 individuals, even for distributions that were not good fits and the censoring rate was high, due to the central limit theorem., Conclusions: Parametric survival models are able to provide more direct answers, and in our analysis of an obesity-related data set, gave consistent YLL estimates regardless of the distribution used. We recommend increased consideration of parametric survival models in chronic disease and risk factor epidemiology., (Copyright © 2012 The Obesity Society.)

The role of imaging as a tool for investigating lung physiology is growing at an accelerating pace. Looking forward, we wished to identify unresolved issues in lung physiology that might realistically be addressed by imaging methods in development or imaging approaches that could be considered. The role of imaging is framed in terms of the importance of good spatial and temporal resolution and the types of questions that could be addressed as these technical capabilities improve. Recognizing that physiology is fundamentally a quantitative science, a recurring emphasis is on the need for imaging methods that provide reliable measurements of specific physiological parameters. The topics included necessarily reflect our perspective on what are interesting questions and are not meant to be a comprehensive review. Nevertheless, we hope that this essay will be a spur to physiologists to think about how imaging could usefully be applied in their research and to physical scientists developing new imaging methods to attack challenging questions imaging could potentially answer.

It has been suggested that poor immunogenicity may explain the lack of vaccine efficacy in preventing or controlling HIV infection in the Step trial. To investigate this issue we vaccinated eight Indian rhesus macaques with a trivalent replication-incompetent adenovirus serotype 5 vaccine expressing SIV Gag, Pol, and Nef using a regimen similar to that employed in the Step trial. We detected broad vaccine-induced CD8(+) (2-7 pool-specific responses) and CD4(+) (5-19 pool-specific responses) T-cell responses in IFN-γ ELISPOT assays at one week post-boost using fresh PBMC. However, using cryopreserved cells at one and four weeks post-boost we observed a reduction in both the number and magnitude of most vaccine-induced responses. This demonstrates that the time points and conditions chosen to perform immune assays may influence the observed breadth and frequency of vaccine-induced T-cell responses. To evaluate protective efficacy, we challenged the immunized macaques, along with naïve controls, with repeated, limiting doses of the heterologous swarm isolate SIVsmE660. Vaccination did not significantly affect acquisition or control of virus replication in vaccinees compared to naïve controls. Post-infection we observed an average of only two anamnestic CD8(+) T-cell responses per animal, which may not have been sufficiently broad to control heterologous virus replication. While the trivalent vaccine regimen induced relatively broad T-cell responses in rhesus macaques, it failed to protect against infection or control viral replication. Our results are consistent with those observed in the Step trial and indicate that SIV immunization and challenge studies in macaque models of HIV infection can be informative in assessing pre-clinical HIV vaccines., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Negatively skewed data arise occasionally in statistical practice; perhaps the most familiar example is the distribution of human longevity. Although other generalizations of the normal distribution exist, we demonstrate a new alternative that apparently fits human longevity data better. We propose an alternative approach of a normal distribution whose scale parameter is conditioned on attained age. This approach is consistent with previous findings that longevity conditioned on survival to the modal age behaves like a normal distribution. We derive such a distribution and demonstrate its accuracy in modeling human longevity data from life tables. The new distribution is characterized by 1. An intuitively straightforward genesis; 2. Closed forms for the pdf, cdf, mode, quantile, and hazard functions; and 3. Accessibility to non-statisticians, based on its close relationship to the normal distribution.

It has recently been shown that polymorphism at the rhesus macaque TRIM5 locus can affect simian immunodeficiency virus (SIV) replication. Here we show that TRIM5 alleles can also affect acquisition of SIVsmE660. Animals coexpressing the TRIM5(TFP) and TRIM5(CypA) alleles took significantly longer to become infected with SIVsmE660, but not SIVmac239, after repeated limiting-dose intrarectal challenge than did animals expressing other TRIM5 allele combinations. Our results indicate that the TRIM5 alleles can be a barrier to productive infection and that this should be taken into account when designing acquisition studies using SIVsmE660 or related viruses.

Objective: The health and longevity effects of body weight reduction resulting from exercise and caloric restriction in rodents are well known, but less is known about whether similar effects occur with weight reduction from the use of a pharmaceutical agent such as sibutramine, a serotonin-norepinephrine reuptake inhibitor., Results and Conclusion: Using data from a 2-year toxicology study of sibutramine in Sprague-Dawley CD rats and CD-1 mice, despite a dose-dependent reduction in food intake and body weight in rats compared with controls, and a body weight reduction in mice at the highest dose, there was no compelling evidence for reductions in mortality rate.

This review explores the pathophysiology of gas exchange abnormalities arising consequent to either acute or chronic elevation of pulmonary venous pressures. The initial experimental studies of acute pulmonary edema outlined the sequence of events from lymphatic congestion with edema fluid to frank alveolar flooding and its resultant hypoxemia. Clinical studies of acute heart failure (HF) suggested that hypoxemia was associated only with the final stage of alveolar flooding. However, in patients with chronic heart failure and normal oxygenation, hypoxemia could be produced by the administration of potent pulmonary vasodilators, suggesting that hypoxic pulmonary vasoconstriction is an important reflex for these patients. Patients with chronic left HF commonly manifest a reduced diffusing capacity, an abnormality that appears to be a consequence of chronic elevation of left atrial pressure. That reduction in diffusing capacity does not appear to be primarily attributable to increases in lung water but is improved by any sustained treatment that improves overall cardiac function. Patients with heart failure may also manifest an abnormally elevated VE/VCO2 during exercise, and that exercise ventilation abnormality arises as a consequence of both alveolar hyperventilation and elevated physiologic dead space. That elevated exercise VE/VCO2 in an HF patient has proven to be a powerful predictor of an adverse outcome and hence it has received sustained attention in the HF literature. At least three of the classes of drugs used to treat HF will normalize the exercise VE/VCO2, suggesting that the excessive ventilation response may be linked to elevated sympathetic activity., (© 2011 American Physiological Society. Compr Physiol 1:621-634, 2011.)

Many rodent experiments have assessed effects of diets, drugs, genes, and other factors on life span. A challenge with such experiments is their long duration, typically over 3.5 years given rodent life spans, thus requiring significant time costs until answers are obtained. We collected longevity data from 15 rodent studies and artificially truncated them at 2 years to assess the extent to which one will obtain the same answer regarding mortality effects. When truncated, the point estimates were not significantly different in any study, implying that in most cases, truncated studies yield similar estimates. The median ratio of variances of coefficients for truncated to full-length studies was 3.4, implying that truncated studies with roughly 3.4 times as many rodents will often have equivalent or greater power. Cost calculations suggest that shorter studies will be more expensive but perhaps not so much to not be worth the reduced time.

The primary function of the pulmonary circulation is to deliver blood to the alveolar capillaries to exchange gases. Distributing blood over a vast surface area facilitates gas exchange, yet the pulmonary vascular tree must be constrained to fit within the thoracic cavity. In addition, pressures must remain low within the circulatory system to protect the thin alveolar capillary membranes that allow efficient gas exchange. The pulmonary circulation is engineered for these unique requirements and in turn these special attributes affect the spatial distribution of blood flow. As the largest organ in the body, the physical characteristics of the lung vary regionally, influencing the spatial distribution on large-, moderate-, and small-scale levels., (© 2011 American Physiological Society.)

With increasing spatial resolution of regional ventilation and perfusion, it has become more apparent that ventilation and blood flow are quite heterogeneous in the lung. A number of mechanisms contribute to this regional variability, including hydrostatic gradients, pleural pressure gradients, lung compressibility, and the geometry of the airway and vascular trees. Despite this marked heterogeneity in both ventilation and perfusion, efficient gas exchange is possible through the close regional matching of the two. Passive mechanisms, such as the shared effect of gravity and the matched branching of vascular and airway trees, create efficient gas exchange through the strong correlation between ventilation and perfusion. Active mechanisms that match local ventilation and perfusion play little if no role in the normal healthy lung but are important under pathologic conditions., (© 2011 American Physiological Society.)

Local driving pressures and resistances within the pulmonary vascular tree determine the distribution of perfusion in the lung. Unlike other organs, these local determinants are significantly influenced by regional hydrostatic and alveolar pressures. Those effects on blood flow distribution are further magnified by the large vertical height of the human lung and the relatively low intravascular pressures in the pulmonary circulation. While the distribution of perfusion is largely due to passive determinants such as vascular geometry and hydrostatic pressures, active mechanisms such as vasoconstriction induced by local hypoxia can also redistribute blood flow. This chapter reviews the determinants of regional lung perfusion with a focus on vascular tree geometry, vertical gradients induced by gravity, the interactions between vascular and surrounding alveolar pressures, and hypoxic pulmonary vasoconstriction. While each of these determinants of perfusion distribution can be examined in isolation, the distribution of blood flow is dynamically determined and each component interacts with the others so that a change in one region of the lung influences the distribution of blood flow in other lung regions., (© 2011 American Physiological Society.)

We attempt to elucidate whether there might be a causal connection between the socioeconomic status (SES) of the rearing environment and obesity in the offspring using data from two large-scale adoption studies: (1) The Copenhagen Adoption Study of Obesity (CASO), and (2) The Survey of Holt Adoptees and Their Families (HOLT). In CASO, the SES of both biological and adoptive parents was known, but all children were adopted. In HOLT, only the SES of the rearing parents was known, but the children could be either biological or adopted. After controlling for relevant covariates (e.g., adoptee age at measurement, adoptee age at transfer, adoptee sex) the raw (unstandardized) regression coefficients for adoptive and biological paternal SES on adoptee body mass index (BMI: kg/m(2)) in CASO were -.22 and -.23, respectively, both statistically significant (p = 0.01). Controlling for parental BMI (both adoptive and biological) reduced the coefficient for biological paternal SES by 44% (p = .034) and the coefficient for adoptive paternal SES by 1%. For HOLT, the regression coefficients for rearing parent SES were -.42 and -.25 for biological and adoptive children, respectively. Controlling for the average BMI of the rearing father and mother (i.e., mid-parental BMI) reduced the SES coefficient by 47% in their biological offspring (p≤.0001), and by 12% in their adoptive offspring (p = .09). Thus, despite the differing structures of the two adoption studies, both suggest that shared genetic diathesis and direct environmental transmission contribute about equally to the association between rearing SES and offspring BMI.

This study was designed to validate a high-resolution method to measure regional ventilation (VA) in small laboratory animals, and to compare regional Va and perfusion (Q) before and after methacholine-induced bronchoconstriction. A mixture of two different colors of 0.04-microm fluorescent microspheres (FMS) was aerosolized and administered to five anesthetized, mechanically ventilated rats. Those rats also received an intravenous injection of a mixture of two different colors of 15-microm FMS to measure regional blood flow (Q). Five additional rats were labeled with aerosol and intravenous FMS, injected with intravenous methacholine, and then relabeled with a second pair of aerosol and intravenous FMS colors. After death, the lungs were reinflated, frozen, and sequentially sliced in 16-microm intervals on an imaging cryomicrotome set to acquire signal for each of the FMS colors. The reconstructed lung images were sampled using randomly placed 3-mm radius spheres. Va within each sphere was estimated from the aerosol fluorescence signal, and Q was estimated from the number of 15-microm FMS within each sphere. Method error ranged from 6 to 8% for Q and 0.5 to 4.0% for Va. The mean coefficient of variation for Q was 17%, and for Va was 34%. The administration of methacholine altered the distribution of both VA and Q within lung regions, with a change in Va distribution nearly twice as large as that seen for Q. The methacholine-induced changes in Va were not associated with compensatory shifts in Q. Cryomicrotome images of FMS markers provide a high-resolution, anatomically specific means of measuring regional VA/Q responses in the rat.

Context: In randomized controlled trials (RCTs), some drugs, including CB1 antagonists for obesity treatment, have been shown to cause increased suicidal ideation. A key question is whether drugs that increase or are associated with increased suicidal ideations are also associated with suicidal behavior, or whether drug-induced suicidal ideations are unlinked epiphenomena that do not presage the more troubling and potentially irrevocable outcome of suicidal behavior. This is difficult to determine in RCTs because of the rarity of suicidal attempts and completions., Objective: To determine whether drugs associated with more suicidal ideations are also associated with more suicide attempts in large spontaneous adverse event (AE) report databases., Methodology: Generalized linear models with negative binomial distribution were fitted to Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (AERS) data from 2004 to 2008. A total of 1,404,470 AEs from 832 drugs were analyzed as a function of reports of suicidal ideations; other non-suicidal adverse reactions; drug class; proportion of reports from males; and average age of subject for which AE was filed. Drug was treated as the unit of analysis, thus the statistical models effectively had 832 observations., Main Outcome Measures: Reported suicide attempts and completed suicides per drug., Results: 832 drugs, ranging from abacavir to zopiclone, were evaluated. The 832 drugs, as primary suspect drugs in a given adverse event, accounted for over 99.9% of recorded AERS. Suicidal ideations had a significant positive association with suicide attempts (p<.0001) and had an approximately 131-fold stronger magnitude of association than non-suicidal AERs, after adjusting for drug class, gender, and age., Conclusions: In AE reports, drugs that are associated with increased suicidal ideations are also associated with increased suicidal attempts or completions. This association suggests that drug-induced suicidal ideations observed in RCTs plausibly represent harbingers that presage the more serious suicide attempts and completions and should be a cause for concern.

Repeated high-resolution measurements of both regional pulmonary ventilation and regional blood flow (r ) have revealed that approximately 6 to 10% of the summed spatial and temporal heterogeneity can be attributed to spontaneous temporal variability. To test the hypothesis that the spontaneous temporal shifts of r and r are coordinated, 12 anaesthetized juvenile pigs had pairs of colours of aerosol and intravenous fluorescent microspheres (FMS) administered simultaneously at 20 min intervals to mark r and r . The animals were killed, the lungs inflated, air-dried and cut into approximately 2 cm(3) cubes. The concentrations of FMS colours from each cube, representing r and r at every 20 min interval, were measured with a fluorescence spectrophotometer. The correlation between per-piece temporal shifts in r and r , calculated as the mean within-piece covariance, was positive (P < 0.001) for every temporally adjacent pair of measurements in every animal, although there were large differences in the magnitude of the mean temporal covariance among animals. The individual cubes with the most positive temporal covariance across all measurement periods usually demonstrated a large single-interval coordinated shift of r and r , with average temporal covariance observed at the other intervals. The largest between-interval shifts in r and r included equal proportions of coordinated increases and coordinated decreases. High-resolution measurements of r and r acquired over 20 min intervals reveal that the overall positive correlation between temporal changes in r and r is driven by relatively infrequent large-magnitude changes within small regions of the lung.

Systematically mapped samples cut from lungs previously labeled with intravascular and aerosol microspheres can be used to create high-resolution maps of regional perfusion and regional ventilation. With multiple radioactive or fluorescent microsphere labels available, this methodology can compare regional flow responses to different interventions without partial volume effects or registration errors that complicate interpretation of in vivo imaging measurements. Microsphere blood flow maps examined at different levels of spatial resolution have revealed that regional flow heterogeneity increases progressively down to an acinar level of scale. This pattern of scale-dependent heterogeneity is characteristic of a fractal distribution network, and it suggests that the anatomic configuration of the pulmonary vascular tree is the primary determinant of high-resolution regional flow heterogeneity. At approximately 2-cm(3) resolution, the large-scale gravitational gradients of blood flow per unit weight of alveolar tissue account for <5% of the overall flow heterogeneity. Furthermore, regional blood flow per gram of alveolar tissue remains relatively constant with different body positions, gravitational stresses, and exercise. Regional alveolar ventilation is accurately represented by the deposition of inhaled 1.0-microm fluorescent microsphere aerosols, at least down to the approximately 2-cm(3) level of scale. Analysis of these ventilation maps has revealed the same scale-dependent property of regional alveolar ventilation heterogeneity, with a strong correlation between ventilation and blood flow maintained at all levels of scale. The ventilation-perfusion (VA/Q) distributions obtained from microsphere flow maps of normal animals agree with simultaneously acquired multiple inert-gas elimination technique VA/Q distributions, but they underestimate gas-exchange impairment in diffuse lung injury.

Ultraendurance athletic events tax the limits of physiological homeostasis. Maintenance of sodium and water balance is a particularly difficult challenge in such events. We present the case of a 38-yr-old participant in the Bicycle Race Across America who developed severe pulmonary edema while cycling at an altitude of 2380 m on the fourth day of the race. With hospitalization and standard support for pulmonary edema, he made a quick, full recovery. A post-race work-up revealed no evidence of underlying cardiopulmonary disease or susceptibility to high-altitude pulmonary edema. His weight on the day of hospitalization was 2.7 kg greater than his pre-race weight. We hypothesize that his excessive daily sodium intake (23-25 g, or 1000-1100 mEq) during the course of the race likely led to an expanded extracellular volume, increased hydrostatic pressure, and decreased oncotic pressure. These factors, in combination with ambient hypoxia, elevated cardiac output, and reduced renal perfusion expected with sustained, high-level exercise, may have led to the development of acute pulmonary edema. This case highlights the pitfalls of overly aggressive sodium intake in endurance races, particularly when such races are conducted at high altitude, where the hypoxia-induced rise in pulmonary artery pressures may amplify the effects of changes in hydrostatic and oncotic pressure that occur with extracellular volume expansion.

Previous studies in anesthetized humans positioned in the left lateral decubitus (LLD) posture have shown that unilateral positive end-expiratory pressure (PEEP) to the dependent lung produce a more even ventilation distribution and improves gas exchange. Unilateral PEEP to the dependent lung may offer special advantages during LLD surgery by reducing the alveolar-to-arterial oxygen pressure difference {(A-a)PO2 or venous admixture} in patients with thoracic trauma or unilateral lung injury. We measured the effects of unilateral PEEP on regional distribution of blood flow (Q) and ventilation (V(A)) using fluorescent microspheres in pentobarbital anesthetized and air ventilation dogs in left lateral decubitus posture with synchronous lung inflation. Tidal volume to left and right lung is maintained constant to permit the effect on gas exchange to be examined. The addition of unilateral PEEP to the left lung increased its FRC with no change in left-right blood flow distribution or venous admixture. The overall lung V(A)/Q distribution remained relatively constant with increasing unilateral PEEP. Bilateral PEEP disproportionately increased FRC in the right lung but again produced no significant changes in venous admixture or V(A)/Q distribution. We conclude that the reduced dependent lung blood flow observed without PEEP occurs secondary to a reduction in lung volume. When tidal volume is maintained, unilateral PEEP increases dependent lung volume with little effect of perfusion distribution maintaining gas exchange.

The effect of left lung atelectasis on the regional distribution of blood flow (Q), ventilation (V(A)) and gas exchange on the right lung ventilated with 100% O2 was studied in anesthetized dogs in the lateral decubitus posture. Q and V(A) were measured in 1.7 ml lung volume pieces using injected and aerosolized fluorescent microspheres, respectively. Hypoxic pulmonary vasoconstriction (HPV) in the atelectatic lung shifted flow to the ventilated lung. The increased flow in the ventilated lung ensured adequate gas exchange, compensating for the hypoxemia due to shunt contributed by the atelectatic lung. Left lung atelectasis caused a compensatory increase in the ventilated lung FRC that was smaller in the right (RLD) than left (LLD) lateral posture, the effect of lung compression by the atelectatic lung and mediastinal contents in the RLD posture. The O2 deficit measured by (A-a)DO2 increased with left lung atelectasis and was exacerbated in the LLD posture by 10 cm H2O PEEP, a result of increased shunt caused by a shift in Q from the ventilated to the atelectatic lung. The PEEP-induced O2 deficit was eliminated with inversion to the RLD posture.

High-resolution estimates of ventilation distribution in normal animals utilizing deposition of fluorescent microsphere aerosol (FMS technique) demonstrate substantial ventilation heterogeneity, but this finding has not been confirmed by an independent method. Five supine anesthetized sheep were used to compare the spatial and temporal heterogeneity of regional ventilation measured by both the FMS technique and by a ventilation model utilizing the data from computed tomography images of xenon gas washin (CT/Xe technique). An aerosol containing 1 microm fluorescent microspheres (FMS) was administered via a mechanical ventilator delivering a 2-s end-inspiration hold during each breath. Following the aerosol administration, sequential CT images of a transverse lung slice were acquired during each end-inspiration hold during washin of a 65% Xenon/35% oxygen gas mixture (CT/Xe technique). Four paired FMS and CT/Xe measurements were done at 30 min intervals, after which the animals were sacrificed. The lungs were extracted, air-dried and sliced in 1cm transverse sections. The lung section corresponding to the CT image was cut into 1 cm3 cubes, with notation of spatial coordinates. The individual cubes were soaked in solvent and the four fluorescent signals were measured with a fluorescence spectrophotometer. The color signals were normalized by the mean signal for all pieces and taken as the FMS estimate of ventilation heterogeneity. The CT images were clustered into 1 cm3 voxels and the rate of increase in voxel density was used to calculate voxel ventilation utilizing the model of . The regional ventilation voxel measurements were normalized by the mean value to give a CT/Xe estimate of ventilation heterogeneity comparable to the normalized FMS measurements. The overall of heterogeneity of ventilation at the 1 cm3 level of resolution was comparable by both techniques, with substantial differences among animals (coefficient of variation ranging from 37% to 74%). The repeated within-animal measurements by both techniques gave consistent values. Both techniques showed comparable large-scale distribution of regional ventilation in the caudal lobes of the supine animals. There were appreciable differences in the temporal variability of ventilation among animals. This study provides an independent confirmation of the scale-dependent heterogeneity of ventilation described by previous FMS aerosol studies of ventilation heterogeneity.

Patients with chronic heart failure have an abnormal pattern of exercise ventilation (Ve), characterized by small tidal volumes (Vt), increased alveolar ventilation, and elevated physiological dead space (Vd/Vt). To investigate whether increased lung water in isolation could reproduce this pattern of exercise ventilation, 30 ml/kg of saline were rapidly infused into nine normal subjects, immediately before a symptom-limited incremental exercise test. Saline infusion significantly reduced forced vital capacity, 1-s forced expiratory volume, and alveolar volume (P < 0.01 for all). After saline, exercise ventilation assessed by the Ve/Vco(2) slope increased from 24.9 +/- 2.4 to 28.0 +/- 2.9 l/l, (P < 0.0002), associated with a small decrease in arterial Pco(2), but without changes in Vt, Vd/Vt, or alveolar-arterial O(2) difference. A reduction in maximal O(2) uptake of 175 +/- 184 ml/min (P < 0.02) was observed in the postsaline infusion exercise studies, associated with a consistent reduction in maximal exercise heart rate (8.1 +/- 5.9 beats/min, P < 0.01), but without a change in the O(2) pulse. Therefore, infusion of saline to normal subjects before exercise failed to reproduce either the increase in Vd/Vt or the smaller exercise Vt described in heart failure patients. The observed increase in Ve can be attributed to dilution acidosis from infusion of the bicarbonate-free fluid and/or to afferent signals from lung and exercising muscles. The reduction in maximal power output, maximal O(2) uptake, and heart rate after saline infusion may be linked to accumulation of edema fluid in exercising muscle, impairing the diffusion of O(2) to muscle mitochondria.

We have shown previously that inspired CO2 (3-5%) improves ventilation-perfusion (Va/Q) matching but with the consequence of mild arterial hypercapnia and respiratory acidosis. We hypothesized that adding CO2 only late in inspiration to limit its effects to the conducting airways would enhance Va/Q matching and improve oxygenation without arterial hypercapnia. CO2 was added in the latter half of inspiration in a volume aimed to reach a concentration of 5% in the conducting airways throughout the respiratory cycle. Ten mixed-breed dogs were anesthetized and, in a randomized order, ventilated with room air, 5% CO2 throughout inspiration, and CO2 added only to the latter half of inspiration. The multiple inert-gas elimination technique was used to assess Va/Q heterogeneity. Late-inspired CO2 produced only very small changes in arterial pH (7.38 vs. 7.40) and arterial CO2 (40.6 vs. 39.4 Torr). Compared with baseline, late-inspired CO2 significantly improved arterial oxygenation (97.5 vs. 94.2 Torr), decreased the alveolar-arterial Po2 difference (10.4 vs. 15.7 Torr) and decreased the multiple inert-gas elimination technique-derived arterial-alveolar inert gas area difference, a global measurement of Va/Q heterogeneity (0.36 vs. 0.22). These changes were equal to those with 5% CO2 throughout inspiration (arterial Po2, 102.5 Torr; alveolar-arterial Po2 difference, 10.1 Torr; and arterial-alveolar inert gas area difference, 0.21). In conclusion, we have established that the majority of the improvement in gas exchange efficiency with inspired CO2 can be achieved by limiting its application to the conducting airways and does not require systemic acidosis.

We aimed to assess the influence of lateral decubitus postures and positive end-expiratory pressure (PEEP) on the regional distribution of ventilation and perfusion. We measured regional ventilation (VA) and regional blood flow (Q) in six anesthetized, mechanically ventilated dogs in the left (LLD) and right lateral decubitus (RLD) postures with and without 10 cmH(2)O PEEP. Q was measured by use of intravenously injected 15-microm fluorescent microspheres, and VA was measured by aerosolized 1-microm fluorescent microspheres. Fluorescence was analyzed in lung pieces approximately 1.7 cm(3) in volume. Multiple linear regression analysis was used to evaluate three-dimensional spatial gradients of Q, VA, the ratio VA/Q, and regional PO(2) (Pr(O(2))) in both lungs. In the LLD posture, a gravity-dependent vertical gradient in Q was observed in both lungs in conjunction with a reduced blood flow and Pr(O(2)) to the dependent left lung. Change from the LLD to the RLD or 10 cmH(2)O PEEP increased local VA/Q and Pr(O(2)) in the left lung and minimized any role of hypoxia. The greatest reduction in individual lung volume occurred to the left lung in the LLD posture. We conclude that lung distortion caused by the weight of the heart and abdomen is greater in the LLD posture and influences both Q and VA, and ultimately gas exchange. In this respect, the smaller left lung was the most susceptible to impaired gas exchange in the LLD posture.

We propose a model to measure both regional ventilation (V) and perfusion (Q) in which the regional radiodensity (RD) in the lung during xenon (Xe) washin is a function of regional V (increasing RD) and Q (decreasing RD). We studied five anesthetized, paralyzed, mechanically ventilated, supine sheep. Four 2.5-mm-thick computed tomography (CT) images were simultaneously acquired immediately cephalad to the diaphragm at end inspiration for each breath during 3 min of Xe breathing. Observed changes in RD during Xe washin were used to determine regional V and Q. For 16 mm(3), Q displayed more variance than V: the coefficient of variance of Q (CV(Q)) = 1.58 +/- 0.23, the CV of V (CV(V)) = 0.46 +/- 0.07, and the ratio of CV(Q) to CV(V) = 3.5 +/- 1.1. CV(Q) (1.21 +/- 0.37) and the ratio of CV(Q) to CV(V) (2.4 +/- 1.2) were smaller at 1,000-mm(3) scale, but CV(V) (0.53 +/- 0.09) was not. V/Q distributions also displayed scale dependence: log SD of V and log SD of Q were 0.79 +/- 0.05 and 0.85 +/- 0.10 for 16-mm(3) and 0.69 +/- 0.20 and 0.67 +/- 0.10 for 1,000-mm(3) regions of lung, respectively. V and Q measurements made with CT and Xe also demonstrate vertically oriented and isogravitational heterogeneity, which are described using other methodologies. Sequential images acquired by CT during Xe breathing can be used to determine both regional V and Q noninvasively with high spatial resolution.