We evaluated the safety and efficacy of partial liquid ventilation (PLV) with perflubron in adult patients with acute lung injury and the acute respiratory distress syndrome (ARDS) in a multicenter, ...prospective, controlled, randomized exploratory clinical trial. Ninety adult patients with PaO2/FIO2 ratios > 60 and < 300 with ARDS for no more than 24 hours were randomized to receive PLV (n = 65) with administration of perflubron through an endotracheal tube sideport or conventional mechanical ventilation (CMV, n = 25) for a maximum of five days. Although a significant reduction in progression to ARDS was noted among patients with PLV, no significant differences in the number of days free from the ventilator at 28 days (CMV = 6.7 +/- 1.8, PLV = 6.3 +/- 1.0 days, p = 0.85), the incidence of mortality (CMV = 36%, PLV = 42%, p = 0.63), or any pulmonary-related parameter were observed. During a post hoc subgroup analysis, significantly more rapid discontinuation of mechanical ventilation (p = 0.045) and a trend toward an increase in the number of days free from the ventilator at 28 days (CMV = 3.2 +/- 1.9, PLV = 8.0 +/- 2.2 days, p = 0.06) were observed during PLV among those patients under 55 years of age with acute lung injury or ARDS. Episodes of hypoxia, respiratory acidosis, and bradycardia occurred more frequently in the PLV group, but these were transient and self-limited. Further evaluation of PLV is warranted to further define beneficial effects in well-defined groups of patients and also to gain additional information regarding safety.
Prostate cancer (PCa) becomes lethal when cancer cells develop into castration-resistant PCa (CRPC). Androgen receptor (AR) gene mutation, altered AR regulation, or overexpression of AR often found ...in CRPC is believed to become one of the key factors to the lethal phenotype. Here we identify Slug, a member of the Snail family of zinc-finger transcription factors associated with cancer metastasis, as a unique androgen-responsive gene in PCa cells. In addition, the presence of constitutively active AR can induce Slug expression in a ligand-independent manner. Slug overexpression will increase AR protein expression and form a complex with AR. In addition, Slug appears to be a novel coactivator to enhance AR transcriptional activities and AR-mediated cell growth with or without androgen. In vivo, elevated Slug expression provides a growth advantage for PCa cells in androgen-deprived conditions. Most importantly, these observations were validated by several data sets from tissue microarrays. Overall, there is a reciprocal regulation between Slug and AR not only in transcriptional regulation but also in protein bioactivity, and Slug-AR complex plays an important role in accelerating the androgen-independent outgrowth of CRPC.
Hemoglobin mass (tHb) is considered to be a main factor for sea-level performance after "live high-train low" (LHTL) altitude training, but little research has focused on the persistence of tHb ...following cessation of altitude exposure. The aim of the case study was to investigate short-term effects of various hematological measures including tHb upon completion of a simulated altitude camp. Five female cyclists spent 26 nights at simulated altitude (LHTL, 16.6 ± 0.4 h/d, 3000 m in an altitude house) where tHb was measured at baseline, at cessation of the camp, and 9 d thereafter. Venous blood measures (hemoglobin concentration, hematocrit, %reticulocytes, serum erythropoietin, ferritin, lactate dehydrogenase, and haptoglobin) were determined at baseline; on day 21 during LHTL; and at days 2, 5, and 9 after LHTL. Hemoglobin mass increased by 5.5% (90% confidence limits CL 2.5 to 8.5%, very likely) after the LHTL training camp. At day 9 after simulated LHTL, tHb decreased by 3.0% (90%CL -5.1 to -1.0%, likely). There was a substantial decrease in serum EPO (-34%, 90%CL -50 to -12%) at 2 d after return to sea level and a rise in ferritin (23%, 90%CL 3 to 46%) coupled with a decrease in %reticulocytes (-23%, 90%CL -34 to -9%) between day 5 and 9 after LHTL. Our findings show that following a hypoxic intervention with a beneficial tHb outcome, there may be a high probability of a rapid tHb decrease upon return to normoxic conditions. This highlights a rapid component in red-cell control and may have implications for the appropriate timing of altitude training in relation to competition.
Concerns have been raised about the morality of using simulated altitude facilities in an attempt to improve athletic performance. One assumption that has been influential in this debate is the ...belief that altitude houses simply mimic the physiological effects of illegal recombinant human erythropoietin (r-HuEpo) doping. To test the validity of this assumption, the haematological and physiological responses of 23 well-trained athletes exposed to a simulated altitude of 2650-3000 m for 11-23 nights were contrasted with those of healthy volunteers receiving a low dose (150 IU·kg
-1
per week) of r-HuEpo for 25 days. Serial blood samples were analysed for serum erythropoietin and percent reticulocytes; maximal oxygen uptake (VdotO
2max
) was assessed before and after r-HuEpo administration or simulated altitude exposure. The group mean increase in serum erythropoietin (422% for r-HuEpo vs 59% for simulated altitude), percent reticulocytes (89% vs 30%) and VdotO
2max
(6.6% vs -2.0%) indicated that simulated altitude did not induce the changes obtained with r-HuEpo administration. Based on the disparity of these responses, we conclude that simulated altitude facilities should not be considered unethical based solely on the tenet that they provide an alternative means of obtaining the benefits sought by illegal r-HuEpo doping.
The question of whether altitude training can enhance subsequent sea-level performance has been well investigated over many decades. However, research on this topic has focused on athletes from ...individual or endurance sports, with scant number of studies on team-sport athletes. Questions that need to be answered include whether this type of training may enhance team-sport athlete performance, when success in team-sport is often more based on technical and tactical ability rather than physical capacity per se. This review will contrast and compare athletes from two sports representative of endurance (cycling) and team-sports (soccer). Specifically, we draw on the respective competition schedules, physiological capacities, activity profiles and energetics of each sport to compare the similarities between athletes from these sports and discuss the relative merits of altitude training for these athletes. The application of conventional live-high, train-high; live-high, train-low; and intermittent hypoxic training for team-sport athletes in the context of the above will be presented. When the above points are considered, we will conclude that dependent on resources and training objectives, altitude training can be seen as an attractive proposition to enhance the physical performance of team-sport athletes without the need for an obvious increase in training load.
Direct-acting antivirals are successful in curing hepatitis C virus infection in more than 95% of patients treated for 12 weeks, but they are expensive. Shortened treatment durations, which may have ...lower cure rates, have been proposed to reduce costs.
To evaluate the lifetime cost-effectiveness of different shortened treatment durations for genotype 1 noncirrhotic treatment-naive patients.
Assuming a UK National Health Service perspective, we used a probabilistic decision tree and Markov model to compare 3 unstratified shortened treatment durations (8, 6, and 4 weeks) against a standard 12-week treatment duration. Patients failing shortened first-line treatment were re-treated with a 12-week treatment regimen. Parameter inputs were taken from published studies.
The 8-week treatment duration had an expected incremental net monetary benefit of £7737 (95% confidence interval £3242-£11 819) versus the standard 12-week treatment, per 1000 patients. The 6-week treatment had a positive incremental net monetary benefit, although some uncertainty was observed. The probability that the 8- and 6-week treatments were the most cost-effective was 56% and 25%, respectively, whereas that for the 4-week treatment was 17%. Results were generally robust to sensitivity analyses, including a threshold analysis that showed that the 8-week treatment was the most cost-effective at all drug prices lower than £40 000 per 12-week course.
Shortening treatments licensed for 12 weeks to 8 weeks is cost-effective in genotype 1 noncirrhotic treatment-naive patients. There was considerable uncertainty in the estimates for 6- and 4-week treatments, with some indication that the 6-week treatment may be cost-effective.
•The cost effectiveness of direct-acting antiviral treatment for chronic hepatitis C virus has been well documented, although the cost of treatment is considerable. Shortened treatment durations have been proposed to reduce costs, albeit at the expense of potentially curing fewer patients.•Shortening treatment duration from 12 to 8 weeks using direct-acting antiviral therapy is cost-effective for treatment of mild chronic hepatitis C virus in genotype 1 noncirrhotic treatment-naive patients, provided a re-treatment strategy is adopted for patients who fail first-line treatment.•There was considerable uncertainty in the cost-effectiveness estimates for the 6- and 4-week shortened treatments, with some indication that the 6-week treatment may be cost-effective, but the 4-week treatment may not. More robust evidence on the efficacy of the 6- and 4-week shortened treatment durations is needed.
Faced with the COVID-19 pandemic, the US system for developing and testing technologies was challenged in unparalleled ways. This article describes the multi-institutional, transdisciplinary team of ...the "RADx SM Tech Test Verification Core" and its role in expediting evaluations of COVID-19 testing devices. Expertise related to aspects of diagnostic testing was coordinated to evaluate testing devices with the goal of significantly expanding the ability to mass screen Americans to preserve lives and facilitate the safe return to work and school. Focal points included: laboratory and clinical device evaluation of the limit of viral detection, sensitivity, and specificity of devices in controlled and community settings; regulatory expertise to provide focused attention to barriers to device approval and distribution; usability testing from the perspective of patients and those using the tests to identify and overcome device limitations, and engineering assessment to evaluate robustness of design including human factors, manufacturability, and scalability.
1 Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas and University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; 2 Institut Nacional d'Educació ...Física de Catalunya, Universitat de Barcelona, Spain; 3 New South Wales Institute of Sport, Sydney, Australia; 4 Faculty of Human Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; 5 Australian Institute of Sport, Canberra; and 6 Exercise Physiology Laboratory, School of Education, Flinders University, Adelaide, Australia
Submitted 21 November 2006
; accepted in final form 19 November 2007
To evaluate the effect of intermittent hypobaric hypoxia combined with sea level training on exercise economy, 23 well-trained athletes (13 swimmers, 10 runners) were assigned to either hypobaric hypoxia (simulated altitude of 4,000–5,500 m) or normobaric normoxia (0–500 m) in a randomized, double-blind design. Both groups rested in a hypobaric chamber 3 h/day, 5 days/wk for 4 wk. Submaximal economy was measured twice before (Pre) and after (Post) the treatment period using sport-specific protocols. Economy was estimated both from the relationship between oxygen uptake ( O 2 ) and speed, and from the absolute O 2 at each speed using sport-specific protocols. O 2 was measured during the last 60 s of each (3–4 min) stage using Douglas bags. Ventilation ( E ), heart rate (HR), and capillary lactate concentration (La – ) were measured during each stage. Velocity at maximal O 2 (velocity at O 2 max) was used as a functional indicator of changes in economy. The average O 2 for a given speed of the Pre values was used for Post test comparison using a two-way, repeated-measures ANOVA. Typical error of measurement of O 2 was 4.7% (95% confidence limits 3.6–7.1), 3.6% (2.8–5.4), and 4.2% (3.2–6.9) for speeds 1 , 2 , and 3 , respectively. There was no change in economy within or between groups (ANOVA interaction P = 0.28, P = 0.23, and P = 0.93 for speeds 1, 2 , and 3 ). No differences in submaximal HR, La – , E , or velocity at O 2 max were found between groups. It is concluded that 4 wk of intermittent hypobaric hypoxia did not improve submaximal economy in this group of well-trained athletes.
altitude; running; swimming
Address for reprint requests and other correspondence: B. D. Levine, Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, 7232 Greenville Ave., Dallas, TX 75231 (e-mail: benjaminlevine{at}texashealth.org )
We describe here the 3-year process underpinning a multinational collaboration to investigate soccer played at high altitude--La Paz, Bolivia (3600 m). There were two main aims: first, to quantify ...the extent to which running performance would be altered at 3600 m compared with near sea level; and second, to characterise the time course of acclimatisation of running performance and underlying physiology to training and playing at 3600 m. In addition, this project was able to measure the physiological changes and the effect on running performance of altitude-adapted soccer players from 3600 m playing at low altitude.
A U20 Bolivian team ('The Strongest' from La Paz, n=19) played a series of five games against a U17 team from sea level in Australia (The Joeys, n=20). 2 games were played near sea level (Santa Cruz 430 m) over 5 days and then three games were played in La Paz over the next 12 days. Measures were (1) game and training running performance--including global positioning system (GPS) data on distance travelled and velocity of movement; (2) blood--including haemoglobin mass, blood volume, blood gases and acid-base status; (3) acclimatisation--including resting heart rate variability, perceived altitude sickness, as well as heart rate and perceived exertion responses to a submaximal running test; and (4) sleep patterns.
Pivotal to the success of the project were the strong professional networks of the collaborators, with most exceeding 10 years, the links of several of the researchers to soccer federations, as well as the interest and support of the two head coaches.
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