HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics.

Chromatin, which consists of DNA and associated proteins, contains genetic information and is a mechanical component of the nucleus. Heterochromatic histone methylation controls nucleus and chromosome stiffness, but the contribution of heterochromatin protein HP1α (CBX5) is unknown. We used a novel HP1α auxin-inducible degron human cell line to rapidly degrade HP1α. Degradation did not alter transcription, local chromatin compaction, or histone methylation, but did decrease chromatin stiffness. Single-nucleus micromanipulation reveals that HP1α is essential to chromatin-based mechanics and maintains nuclear morphology, separate from histone methylation. Further experiments with dimerization-deficient HP1αI165E indicate that chromatin crosslinking via HP1α dimerization is critical, while polymer simulations demonstrate the importance of chromatin-chromatin crosslinkers in mechanics. In mitotic chromosomes, HP1α similarly bolsters stiffness while aiding in mitotic alignment and faithful segregation. HP1α is therefore a critical chromatin-crosslinking protein that provides mechanical strength to chromosomes and the nucleus throughout the cell cycle and supports cellular functions.

Impact of Caffeine Ingestion on the Driving Performance of Anesthesiology Residents After 6 Consecutive Overnight Work Shifts.

BACKGROUND: Residency training in anesthesiology involves care of hospitalized patients and necessitates overnight work, resulting in altered sleep patterns and sleep deprivation. Caffeine consumption is commonly used to improve alertness when fatigued after overnight work, in preparation for the commute home. METHODS: We studied the impact of drinking a caffeinated energy drink (160 mg of caffeine) on driving performance in a high-fidelity, virtual reality driving simulator (Virginia Driving Safety Laboratory using the Driver Guidance System) in anesthesiology resident physicians immediately after 6 consecutive night-float shifts. Twenty-six residents participated and were randomized to either consume a caffeinated or noncaffeinated energy drink 60 minutes before the driving simulation session. After a subsequent week of night-float work, residents performed the same driving session (in a crossover fashion) with the opposite intervention. Psychomotor vigilance task (PVT) testing was used to evaluate reaction time and lapses in attention. RESULTS: After 6 consecutive night-float shifts, anesthesiology residents who consumed a caffeinated energy drink had increased variability in driving for throttle, steering, and speed during the first 10 minutes of open-road driving but proceeded to demonstrate improved driving performance with fewer obstacle collisions (epoch 2: 0.65 vs 0.87; epoch 3: 0.47 vs 0.95; P = .03) in the final 30 minutes of driving as compared to driving performance after consumption of a noncaffeinated energy drink. Improved driving performance was most apparent during the last 30 minutes of the simulated drive in the caffeinated condition. Mean reaction time between the caffeine and noncaffeine states differed significantly (278.9 ± 29.1 vs 294.0 ± 36.3 milliseconds; P = .021), while the number of major lapses (0.09 ± 0.43 vs 0.27 ± 0.55; P = .257) and minor lapses (1.05 ± 1.39 vs 2.05 ± 3.06; P = .197) was not significantly different. CONCLUSIONS: After consuming a caffeinated energy drink on conclusion of 6 shifts of night-float work, anesthesiology residents had improved control of driving performance variables in a high-fidelity driving simulator, including a significant reduction in collisions as well as slightly faster reaction times.

Feasibility of Spinal Anesthesia Placement Using Automated Interpretation of Lumbar Ultrasound Images: A Prospective Randomized Controlled Trial.

BACKGROUND: This study evaluated the efficacy of spinal anesthesia administration by resident physicians when using an ultrasound system with automated neuraxial landmark detection capabilities. METHODS: 150 patients were enrolled in this trial. Anesthesiology residents placed spinals in subjects undergoing scheduled cesarean delivery using one of three techniques to identify neuraxial landmarks: palpation, ultrasound, or combined palpation and ultrasound. Ultrasound was performed using a handheld system that automatically identified neuraxial landmarks (e.g. midline, intervertebral spaces). All residents watched a 10-minute video and received 20 minutes of hands-on training prior to participating in the study. First insertion success rate was the primary end point. RESULTS: Among all patients, use of ultrasound resulted in a 11% greater first-insertion success rate (RR: 1.11 [0.85-1.47], p=0.431), a 15% reduction in needle insertions (RR: 0.85, p=0.052), and a 26% decrease in needle passes (RR: 0.74, p=0.070). In obese patients of BMI ≥ 30 kg/m2, use of ultrasound resulted in 26% greater first-insertion success rates (RR: 1.26, p=0.187), a 21% decrease in needle insertions (RR: 0.79, p=0.025), a 38% decrease in needle passes (RR: 0.62, p=0.030), and a 75% decrease in patients reporting neutral or low patient satisfaction with anesthesia administration (RR: 0.25, p=0.004). DISCUSSION: Resident anesthesiologists competently utilized the ultrasound system after receiving minimal training. Technical endpoints and patient satisfaction trended towards improvement when ultrasound was used prior to spinal placement, with stronger trends observed in obese patients. Additional study is required to fully characterize the impact of the ultrasound system on clinical efficacy.

Haptoglobin 2-2 Phenotype Is Associated With Increased Acute Kidney Injury After Elective Cardiac Surgery in Patients With Diabetes Mellitus.

BACKGROUND: Recent studies reported an association between the 2-2 phenotype of haptoglobin (Hp 2-2) and increased cardiorenal morbidity in nonsurgical diabetic patients. Our goal was to determine whether the Hp 2-2 phenotype was associated with acute kidney injury (AKI) after elective cardiac surgery in patients with diabetes mellitus. METHODS AND RESULTS: We prospectively enrolled 99 diabetic patients requiring elective cardiac surgery with cardiopulmonary bypass. Haptoglobin phenotypes were determined by gel electrophoresis. Cell-free hemoglobin, haptoglobin, and total serum bilirubin were quantified as hemolysis markers. The primary outcome was postoperative AKI, as defined by the Acute Kidney Injury Network classification. The incidence of AKI was significantly higher in Hp 2-2 patients compared with patients without this phenotype (non-Hp-2-2; 55.6% versus 27%, P<0.01). The need for renal replacement therapy was also significantly higher in the Hp 2-2 group (5 patients versus 1 patient, P=0.02). Thirty-day mortality (3 versus 0 patients, P=0.04) and 1-year mortality (5 versus 0 patients, P<0.01) were also significantly higher in patients with the Hp 2-2 phenotype. In multivariable analysis, Hp 2-2 was an independent predictor of postoperative AKI (P=0.01; odds ratio: 4.17; 95% confidence interval, 1.35-12.48). CONCLUSIONS: Hp 2-2 phenotype is an independent predictor of postoperative AKI and is associated with decreased short and long-term survival after cardiac surgery in patients with diabetes mellitus.

Perioperative statin use is associated with decreased incidence of primary graft dysfunction after lung transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after lung transplantation. Statins reduce the risk of chronic rejection after lung transplantation, but their effects on PGD are unknown. We hypothesized that perioperative statin therapy decreases the risk for PGD after lung transplantation. METHODS: We retrospectively reviewed records of all patients undergoing lung transplantation between January 1999 and December 2014 at the University of Virginia Health System. The primary outcome was PGD (grades 1-3). Secondary outcomes included grade 3 PGD, length of intensive care unit and hospital stay, and mortality. RESULTS: Of 266 patients who met final inclusion criteria, 138 (52%) were diagnosed with PGD. In-hospital mortality among patients with PGD was 6.5%. There were no deaths in patients without PGD (p < 0.001). PGD was diagnosed in 24 patients taking statins (34.8%) and in 114 patients (57.9%) who did not take statins (p = 0.001). After propensity score adjustments, perioperative statin use was independently associated with a reduced risk for PGD (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.20-0.84, p = 0.015) and reduced risk to develop grade 3 PGD (OR 0.42, 95% CI 0.18-0.94, p = 0.036). Other risk factors associated with PGD included intraoperative use of cardiopulmonary bypass (OR 3.74, 95% CI 1.75-8.02, p = 0.001) and positive donor smoking status (OR 2.27, 95% CI 1.18-4.35, p = 0.014). CONCLUSIONS: The results demonstrate that perioperative use of statins is independently associated with reduced risk for PGD after lung transplantation.

Imaging Performance of a Handheld Ultrasound System With Real-Time Computer-Aided Detection of Lumbar Spine Anatomy: A Feasibility Study.

OBJECTIVES: The aim of this study was to evaluate the imaging performance of a handheld ultrasound system and the accuracy of an automated lumbar spine computer-aided detection (CAD) algorithm in the spines of human subjects. MATERIALS AND METHODS: This study was approved by the institutional review board of the University of Virginia. The authors designed a handheld ultrasound system with enhanced bone image quality and fully automated CAD of lumbar spine anatomy. The imaging performance was evaluated by imaging the lumbar spines of 68 volunteers with body mass index between 18.5 and 48 kg/m. The accuracy, sensitivity, and specificity of the lumbar spine CAD algorithm were assessed by comparing the algorithm's results to ground-truth segmentations of neuraxial anatomy provided by radiologists. RESULTS: The lumbar spine CAD algorithm detected the epidural space with a sensitivity of 94.2% (95% confidence interval [CI], 85.1%-98.1%) and a specificity of 85.5% (95% CI, 81.7%-88.6%) and measured its depth with an error of approximately ±0.5 cm compared with measurements obtained manually from the 2-dimensional ultrasound images. The spine midline was detected with a sensitivity of 93.9% (95% CI, 85.8%-97.7%) and specificity of 91.3% (95% CI, 83.6%-96.9%), and its lateral position within the ultrasound image was measured with an error of approximately ±0.3 cm. The bone enhancement imaging mode produced images with 5.1- to 10-fold enhanced bone contrast when compared with a comparable handheld ultrasound imaging system. CONCLUSIONS: The results of this study demonstrate the feasibility of CAD for assisting with real-time interpretation of ultrasound images of the lumbar spine at the bedside.

Driving Performance of Residents after Six Consecutive Overnight Work Shifts.

BACKGROUND: Residency training requires work in clinical settings for extended periods of time, resulting in altered sleep patterns, sleep deprivation, and potentially deleterious effects on safe performance of daily activities, including driving a motor vehicle. METHODS: Twenty-nine anesthesiology resident physicians in postgraduate year 2 to 4 drove for 55 min in the Virginia Driving Safety Laboratory using the Driver Guidance System (MBFARR, LLC, USA). Two driving simulator sessions were conducted, one experimental session immediately after the final shift of six consecutive night shifts and one control session at the beginning of a normal day shift (not after call). Both sessions were conducted at 8:00 AM. Psychomotor vigilance task testing was employed to evaluate reaction time and lapses in attention. RESULTS: After six consecutive night shifts, residents experienced significantly impaired control of all the driving variables including speed, lane position, throttle, and steering. They were also more likely to be involved in collisions. After six consecutive night shifts, residents had a significant increase in reaction times (281.1 vs. 298.5 ms; P = 0.001) and had a significant increase in the number of both minor (0.85 vs. 1.88; P = 0.01) and major lapses (0.00 vs. 0.31; P = 0.008) in attention. CONCLUSIONS: Resident physicians have greater difficulty controlling speed and driving performance in the driving simulator after six consecutive night shifts. Reaction times are also increased with emphasis on increases in minor and major lapses in attention after six consecutive night shifts.

Prelamin A processing, accumulation and distribution in normal cells and laminopathy disorders.

Lamin A is part of a complex structural meshwork located beneath the nuclear envelope and is involved in both structural support and the regulation of gene expression. Lamin A is initially expressed as prelamin A, which contains an extended carboxyl terminus that undergoes a series of post-translational modifications and subsequent cleavage by the endopeptidase ZMPSTE24 to generate lamin A. To facilitate investigations of the role of this cleavage in normal and disease states, we developed a monoclonal antibody (PL-1C7) that specifically recognizes prelamin A at the intact ZMPSTE24 cleavage site, ensuring prelamin A detection exclusively. Importantly, PL-1C7 can be used to determine prelamin A localization and accumulation in cells where lamin A is highly expressed without the use of exogenous fusion proteins. Our results show that unlike mature lamin A, prelamin A accumulates as discrete and localized foci at the nuclear periphery. Furthermore, whereas treatment with farnesylation inhibitors of cells overexpressing a GFP-prelamin A fusion protein results in the formation of large nucleoplasmic clumps, these aggregates are not observed upon similar treatment of cells expressing endogenous prelamin A or in cells lacking ZMPSTE24 expression and/or activity. Finally, we show that specific laminopathy-associated mutations exhibit both positive and negative effects on prelamin A accumulation, indicating that these mutations affect prelamin A processing efficiency in different manners.

The redundancy of the mammalian heterochromatic compartment.

Two chromatin compartments are present in most mammalian cells; the first contains primarily euchromatic, early replicating chromatin and the second, primarily late-replicating heterochromatin, which is the subject of this review. Heterochromatin is concentrated in three intranuclear regions: the nuclear periphery, the perinucleolar space and in pericentromeric bodies. We review recent evidence demonstrating that the heterochromatic compartment is critically involved in global nuclear organization and the maintenance of genome stability, and discuss models regarding how this compartment is formed and maintained. We also evaluate our understanding of how heterochromatic sequences (herein named heterochromatic associated regions (HADs)) might be tethered within these regions and review experiments that reveal the stochastic nature of individual HAD positioning within the compartment. These investigations suggest a substantial level of functional redundancy within the heterochromatic compartment.

Wash interacts with lamin and affects global nuclear organization.

The cytoplasmic functions of Wiskott-Aldrich syndrome family (WAS) proteins are well established and include roles in cytoskeleton reorganization and membrane-cytoskeletal interactions important for membrane/vesicle trafficking, morphogenesis, immune response, and signal transduction. Misregulation of these proteins is associated with immune deficiency and metastasis [1-4]. Cytoplasmic WAS proteins act as effectors of Rho family GTPases and polymerize branched actin through the Arp2/3 complex [1, 5]. Previously, we identified Drosophila washout (wash) as a new member of the WAS family with essential cytoplasmic roles in early development [6, 7]. Studies in mammalian cells and Dictyostelium suggest that WASH functions primarily in a multiprotein complex that regulates endosome shape and trafficking in an Arp2/3-dependent manner [8-11]. However, roles for classically cytoplasmic proteins in the nucleus are beginning to emerge, in particular, as participants in the regulation of gene expression [12, 13]. Here, we show that Drosophila Wash is present in the nucleus, where it plays a key role in global nuclear organization. wash mutant and knockdown nuclei disrupt subnuclear structures/organelles and exhibit the abnormal wrinkled morphology reminiscent of those observed in diverse laminopathies [14-16]. We find that nuclear Wash interacts with B-type Lamin (Lamin Dm0), and, like Lamin, Wash associates with constitutive heterochromatin. Wash knockdown increases chromatin accessibility of repressive compartments and results in a global redistribution of repressive histone modifications. Thus, our results reveal a novel role for Wash in modulating nucleus morphology and in the organization of both chromatin and non-chromatin nuclear sub-structures.

Ventricular assist devices and increased blood product utilization for cardiac transplantation.

BACKGROUND AND AIM OF STUDY: The purpose of this study was to examine whether blood product utilization, one-year cell-mediated rejection rates, and mid-term survival significantly differ for ventricular assist device (VAD patients compared to non-VAD (NVAD) patients following cardiac transplantation. METHODS: From July 2004 to August 2011, 79 patients underwent cardiac transplantation at a single institution. Following exclusion of patients bridged to transplantation with VADs other than the HeartMate II® LVAD (n = 10), patients were stratified by VAD presence at transplantation: VAD patients (n = 35, age: 54.0 [48.0-59.0] years) vs. NVAD patients (n = 34, age: 52.5 [42.8-59.3] years). The primary outcomes of interest were blood product transfusion requirements, one-year cell-mediated rejection rates, and mid-term survival post-transplantation. RESULTS: Preoperative patient characteristics were similar for VAD and NVAD patients. NVAD patients presented with higher median preoperative creatinine levels compared to VAD patients (1.3 [1.1-1.6] vs. 1.1 [0.9-1.4], p = 0.004). VAD patients accrued higher intraoperative transfusion of all blood products (all p ≤ 0.001) compared to NVAD patients. The incidence of clinically significant cell-mediated rejection within the first posttransplant year was higher in VAD compared to NVAD patients (66.7% vs. 33.3%, p = 0.02). During a median follow-up period of 3.2 (2.0, 6.3) years, VAD patients demonstrated an increased postoperative mortality that did not reach statistical significance (20.0% vs. 8.8%, p = 0.20). CONCLUSIONS: During the initial era as a bridge to transplantation, the HeartMate II® LVAD significantly increased blood product utilization and one-year cell-mediated rejection rates for cardiac transplantation. Further study is warranted to optimize anticoagulation strategies and to define causal relationships between these factors for the current era of cardiac transplantation.

Functional redundancy in the nuclear compartmentalization of the late-replicating genome.

The eukaryotic nucleus is structurally and functionally organized, as reflected in the distribution of its protein and DNA components. The genome itself is segregated into euchromatin and heterochromatin that replicate in a distinct spatio-temporal manner. We used a combination of fluorescence in situ hybridization (FISH) and DamID to investigate the localization of the early and late replicating components of the genome in a lymphoblastoid cell background. Our analyses revealed that the bulk of late replicating chromatin localizes to the nuclear peripheral heterochromatin (PH) in a chromosome size and gene density dependent manner. Late replicating DNA on small chromosomes exhibits a much lower tendency to localize to PH and tends to associate with alternate repressive subcompartments such as pericentromeric (PCH) and perinucleolar heterochromatin (PNH). Furthermore, multicolor FISH analysis revealed that late replicating loci, particularly on the smaller chromosomes, may associate with any of these 3 repressive subcompartments, including more than one at the same time. These results suggest a functional equivalence or redundancy among the 3 subcompartments. Consistent with this notion, disruption of nucleoli resulted in an increased association of late replicating loci with peripheral heterochromatin. Our analysis reveals that rather than considering the morphologically distinct PH, PCH and PNH as individual subcompartments, they should be considered in aggregate as a functional compartment for late replicating chromatin.

TRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends.

Telomeres protect the ends of linear genomes, and the gradual loss of telomeres is associated with cellular ageing. Telomere protection involves the insertion of the 3' overhang facilitated by telomere repeat-binding factor 2 (TRF2) into telomeric DNA, forming t-loops. We present evidence suggesting that t-loops can also form at interstitial telomeric sequences in a TRF2-dependent manner, forming an interstitial t-loop (ITL). We demonstrate that TRF2 association with interstitial telomeric sequences is stabilized by co-localization with A-type lamins (lamin A/C). We also find that lamin A/C interacts with TRF2 and that reduction in levels of lamin A/C or mutations in LMNA that cause an autosomal dominant premature ageing disorder--Hutchinson Gilford Progeria Syndrome (HGPS)-lead to reduced ITL formation and telomere loss. We propose that cellular and organismal ageing are intertwined through the effects of the interaction between TRF2 and lamin A/C on chromosome structure.

Something silent this way forms: the functional organization of the repressive nuclear compartment.

The repressive compartment of the nucleus is comprised primarily of telomeric and centromeric regions, the silent portion of ribosomal RNA genes, the majority of transposable element repeats, and facultatively repressed genes specific to different cell types. This compartment localizes into three main regions: the peripheral heterochromatin, perinucleolar heterochromatin, and pericentromeric heterochromatin. Both chromatin remodeling proteins and transcription of noncoding RNAs are involved in maintenance of repression in these compartments. Global reorganization of the repressive compartment occurs at each cell division, during early development, and during terminal differentiation. Differential action of chromatin remodeling complexes and boundary element looping activities are involved in mediating these organizational changes. We discuss the evidence that heterochromatin formation and compartmentalization may drive nuclear organization.

Use of the intrathoracic pressure regulator to lower intracranial pressure in patients with altered intracranial elastance: a pilot study.

OBJECT: The intrathoracic pressure regulator (ITPR) is a novel noninvasive device designed to increase circulation and blood pressure. By applying negative pressure during the expiratory phase of ventilation it decreases intrathoracic pressure and enhances venous return, which increases cardiac output. It is possible that the ITPR may both decrease intracranial pressure (ICP) and increase cerebral perfusion pressure (CPP) in brain-injured patients by decreasing cerebral venous blood volume and increasing cardiac output. The authors conducted an open-label, "first-in-humans" study of the ITPR in patients with an ICP monitor or external ventricular drain and altered intracranial elastance. METHODS: This prospective randomized trial commenced July 2009. Baseline hemodynamic variables and ICP were recorded prior to inserting one of the two ITPRs into the ventilator circuit based on a randomization scheme. Depending on the device selected, activation provided either -5 or -9 mm Hg endotracheal tube pressure. Hemodynamic and ICP data were recorded sequentially every 2 minutes for 10 minutes. The first device was turned off for 10 minutes, then it was removed and the second device was applied, and then the procedure was repeated for the second device. RESULTS: Ten patients with elevated ICP secondary to intracranial hemorrhage (n = 4), trauma (n = 2), obstructive hydrocephalus (n = 2), or diffuse cerebral processes (n = 2) were enrolled. Baseline ICP ranged from 12 to 38 mm Hg. With device application, a decrease in ICP was observed in 16 of 20 applications. During treatment with the -5 mm Hg device, there was a mean maximal decrease of 3.3 mm Hg in ICP (21.7 vs 18.4 mm Hg, p = 0.003), which was associated with an increase in CPP of 6.5 mm Hg (58.2 vs 64.7 mm Hg, p = 0.019). During treatment with the -9 mm Hg device, there was a mean maximal decrease of 2.4 mm Hg in ICP (21.1 vs 18.7 mm Hg, p = 0.044), which was associated with an increase in CPP of 6.5 mm Hg (59.2 vs 65.7 mm Hg, p = 0.001). CONCLUSIONS: This pilot study demonstrates that use of the ITPR in patients with altered intracranial elastance is feasible. Although this study was not powered to demonstrate efficacy, these data strongly suggest that the ITPR may be used to rapidly lower ICP and increase CPP without apparent adverse effects. Additional studies will be needed to assess longitudinal changes in ICP when the device is in use and to delineate treatment parameters.

Ultrasound-guided common peroneal nerve block at the level of the fibular head.

A common peroneal nerve block at the fibular head is uncommon in clinical practice. The case of a 41 year old, morbidly obese woman requiring right total ankle replacement is presented. Ultrasound-guided common peroneal nerve block was performed at the fibular head after an unsuccessful popliteal approach.

Intraoperative factors and the risk of respiratory complications after pneumonectomy.

BACKGROUND: The potential effect of intraoperative factors on respiratory complications after pneumonectomy is still unclear. METHODS: We conducted a retrospective cohort study; charts of 129 patients who underwent elective pneumonectomy at the University of Virginia were reviewed. Logistic regression was used to estimate the effect of anesthetic factors on the odds of at least one respiratory complication. Linear regression models were fit to assess the impact of these outcomes on length of stay (LOS). RESULTS: The incidence of respiratory complications in this cohort was 21%. In univariate analysis total nonblood fluids (p = 0.001), and the blood products packed red blood cells (p < 0.001), plasma (p < 0.001), and platelets (p = 0.044) were significantly associated with respiratory complications. In a multivariable logistic regression analysis, single unit transfusion of any blood product (packed red blood cells, plasma, or platelets) was identified as a major risk factor for respiratory complications after controlling for covariates (odds ratio = 1.47, 95% confidence interval 1.06 to 2.05). Respiratory failure and complications were closely related to LOS, increasing the LOS by a factor of 4.7 (95% confidence interval 3.51 to 6.18) and 3.5 (95% confidence interval 2.69 to 4.41), respectively. CONCLUSIONS: Blood product transfusion affects respiratory function and is an independent risk factor for respiratory complications after pneumonectomy.

Losing control: cancer's catastrophic transition.

Adaptability and "emergent" properties are the dominant characteristics of complex systems, whether naturally occurring or engineered. Structurally, a complex system might be made up of a large number of simpler components, or it might be formed from hierarchies of smaller numbers of interacting subsystems and work together to produce a defined function. The nucleus of a cell has all of these features, many of which may become disrupted in cancer and other disease states. The general view is that cancer progresses gradually over time; cells become premalignant, then increasingly abnormal before they become cancerous. However, recent work by Stephens et al. (2011) has revealed that cancer can emerge much more rapidly. Based on DNA sequences from multiple cancer samples of various types, they show that cancer can arise suddenly from a single catastrophic event that causes massive genomic rearrangement.

The effect of the intrathoracic pressure regulator on hemodynamics and cardiac output.

The intrathoracic pressure regulator (ITPR) (CirQLator; Advanced Circulatory Systems Inc, Roseville, Minn) is a novel, noninvasive device intended to increase cardiac output and blood pressure in hypovolemic or cardiogenic shock by generating a continuous low-level intrathoracic vacuum in between positive pressure ventilations. Although there are robust data supporting the benefit of the ITPR in multiple animal models of shock, the device has not been used in humans.The goals of this study were to evaluate both the safety and efficacy of the ITPR in humans. Twenty patients undergoing coronary artery bypass graft surgery were enrolled in this phase 1 study. Intraoperative use of both pulmonary artery pressure monitoring and transesophageal echocardiography (TEE) was required for study inclusion. Hemodynamic variables as well as TEE measurements of left ventricular performance were collected at baseline and after the ITPR device was activated, before surgical incision. Thermodilution cardiac output increased significantly with the application of the ITPR (4.9 vs. 5.5 L/min; P = 0.017). Similarly, cardiac output was measured by TEE (5.1 vs. 5.7 L/min; P = 0.001).There were significant increases in pulmonary artery systolic blood pressures (35 vs. 38 mmHg; P G 0.001) and mean pulmonary artery pressures (24 vs. 26 mmHg; P = 0.008). There were no significant differences in systemic blood pressures, left ventricular volumes, stroke volume, or ejection fraction as measured by TEE. Using two different measurement techniques, application of the ITPR increased cardiac output in normovolemic anesthetized patients who underwent coronary artery bypass graft before sternotomy. These data suggest that the ITPR has the potential to safely and effectively increase cardiac output in humans.

Speed, accuracy, and confidence in Google, Ovid, PubMed, and UpToDate: results of a randomised trial.

BACKGROUND: The explosion of biomedical information has led to an 'information paradox'-the volume of biomedical information available has made it increasingly difficult to find relevant information when needed. It is thus increasingly critical for physicians to acquire a working knowledge of biomedical informatics. AIM: To evaluate four search tools commonly used to answer clinical questions, in terms of accuracy, speed, and user confidence. METHODS: From December 2008 to June 2009, medical students, resident physicians, and attending physicians at the authors' institution were asked to answer a set of four anaesthesia and/or critical care based clinical questions, within 5 min, using Google, Ovid, PubMed, or UpToDate (only one search tool per question). At the end of each search, participants rated their results on a four point confidence scale. One to 3 weeks after answering the initial four questions, users were randomised to one of the four search tools, and asked to answer eight questions, four of which were repeated. The primary outcome was defined as a correct answer with the highest level of confidence. RESULTS: Google was the most popular search tool. Users of Google and UpToDate were more likely than users of PubMed to answer questions correctly. Subjects had the most confidence in UpToDate. Searches with Google and UpToDate were faster than searches with PubMed or Ovid. CONCLUSION: Non-Medline based search tools are not inferior to Medline based search tools for purposes of answering evidence based anaesthesia and critical care questions.