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Abstract Background Subcutaneous erenumab reduced monthly migraine days and increased the likelihood of achieving a ≥ 50% reduction at all monthly assessment points tested in 2 pivotal trials in episodic migraine (EM) and chronic migraine (CM). Early efficacy of migraine preventive medications is an important treatment characteristic to patients. Delays in achievement of efficacy can result in failed adherence. The objective of these post-hoc analyses were to evaluate efficacy in the first 4 weeks after initial subcutaneous administration of erenumab 70 mg, erenumab 140 mg, or placebo. Methods There is no generally accepted methodology to measure onset of action for migraine preventive medications. We used a comprehensive approach with data from both studies to evaluate change from baseline in weekly migraine days (WMD), achievement of ≥ 50% reduction in WMD, and proportion of patients experiencing migraine measured on a daily basis. The 7-day moving averages were overlaid with observed data. Results In both studies (EM: N = 955; CM: N = 667), there was evidence of onset of efficacy of erenumab vs. placebo during the first week of treatment, which in some cases reached nominal significance. For EM the changes in WMD were (least squares mean [LSM] [95% CI]): placebo, − 0.1 (− 0.3, 0.0); erenumab 70 mg, − 0.3 (− 0.5, − 0.2) p = 0.130; erenumab 140 mg, − 0.6 (− 0.7, − 0.4) p

RATIONALE: Compositional changes in surfactant and/or decreased surfactant content of the lungs are common features in patients with acute respiratory failure. Instillation of exogenous surfactant into the lungs of neonates with respiratory distress syndrome or pediatric patients with acute respiratory distress syndrome (ARDS) has resulted in improved survival. OBJECTIVES: We conducted this trial to determine whether the instillation of exogenous surfactant would improve the Day 28 outcome of adult patients with acute lung injury (ALI) or ARDS. METHODS: A total of 418 patients with ALI and ARDS were included in an international, multicenter, stratified, randomized, controlled, open, parallel-group study. We randomly assigned 418 patients to receive usual care either with or without instillation of exogenous natural porcine surfactant HL 10 as large boluses. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was death rate before or on Day 28. Secondary endpoints were adverse event and death rate on day 180. The 28-day death rate in the usual care group was 24.5% compared with 28.8% in the HL 10 group. The estimated odds ratio for death at Day 28 in the usual care group versus the HL 10 group was 0.75 (95% CI, 0.48-1.18; P = 0.22). The most common adverse events related to HL 10 administration were temporary hypoxemia defined as oxygen saturation less than 88% (51.9% in HL 10 group vs. 25.2% in usual care) and hypotension defined as mean arterial blood pressure less than 60 mm Hg (34.1% in HL 10 group vs. 17.1% in usual care). CONCLUSIONS: In this study, instillation of a large bolus of exogenous natural porcine surfactant HL 10 into patients with acute lung injury and ARDS did not improve outcome and showed a trend toward increased mortality and adverse effects. Clinical trial registered with www.clinicaltrials.gov (NCT 00742482). [ABSTRACT FROM AUTHOR]

RATIONALE: It is commonly stated that mortality from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is decreasing. OBJECTIVES: To systematically review the literature assessing ARDS mortality over time and to determine patient- and study-level factors independently associated with mortality. METHODS: We searched multiple databases (MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL) for prospective observational studies or randomized controlled trials (RCTs) published during the period 1984 to 2006 that enrolled 50 or more patients with ALI/ARDS and reported mortality. We pooled mortality estimates using random-effects meta-analysis and examined mortality trends before and after 1994 (when a consensus definition of ALI/ARDS was published) and factors associated with mortality using meta-regression models. MEASUREMENTS AND MAIN RESULTS: Of 4,966 studies, 89 met inclusion criteria (53 observational, 36 RCTs). There was a total of 18,900 patients (mean age 51.6 years; 39% female). Overall pooled weighted mortality was 44.3% (95% confidence interval [CI], 41.8-46.9). Mortality decreased with time in observational studies conducted before 1994; no temporal associations with mortality were demonstrated in RCTs (any time) or observational studies (after 1994). Pooled mortality from 1994 to 2006 was 44.0% (95% CI, 40.1-47.5) for observational studies, and 36.2% (95% CI, 32.1-40.5) for RCTs. Meta-regression identified study type (observational versus RCT, odds ratio, 1.36; 95% CI, 1.08-1.73) and patient age (odds ratio per additional 10 yr, 1.27; 95% CI, 1.07-1.50) as the only factors associated with mortality. CONCLUSIONS: A decrease in ARDS mortality was only seen in observational studies from 1984 to 1993. Mortality did not decrease between 1994 (when a consensus definition was published) and 2006, and is lower in RCTs than observational studies. [ABSTRACT FROM AUTHOR]

Rationale: There are conflicting data regarding the safety and efficacy of recruitment maneuvers (RMs) in patients with acute lung injury (ALI). Objectives: To summarize the physiologic effects and adverse events in adult patients with ALI receiving RMs. Methods: Systematic review of case series, observational studies, and randomized clinical trials with pooling of study-level data. Measurements and Main Results: Forty studies (1,185 patients) met inclusion criteria. Oxygenation (31 studies; 636 patients) was significantly increased after an RM (Pa(O(2)): 106 versus 193 mm Hg, P = 0.001; and Pa(O(2))/Fi(O(2)) ratio: 139 versus 251 mm Hg, P < 0.001). There were no persistent, clinically significant changes in hemodynamic parameters after an RM. Ventilatory parameters (32 studies; 548 patients) were not significantly altered by an RM, except for higher PEEP post-RM (11 versus 16 cm H(2)O; P = 0.02). Hypotension (12%) and desaturation (9%) were the most common adverse events (31 studies; 985 patients). Serious adverse events (e.g., barotrauma [1%] and arrhythmias [1%]) were infrequent. Only 10 (1%) patients had their RMs terminated prematurely due to adverse events. Conclusions: Adult patients with ALI receiving RMs experienced a significant increase in oxygenation, with few serious adverse events. Transient hypotension and desaturation during RMs is common but is self-limited without serious short-term sequelae. Given the uncertain benefit of transient oxygenation improvements in patients with ALI and the lack of information on their influence on clinical outcomes, the routine use of RMs cannot be recommended or discouraged at this time. RMs should be considered for use on an individualized basis in patients with ALI who have life-threatening hypoxemia. [ABSTRACT FROM AUTHOR]

We report a case of fatal necrotizing pneumonia and sepsis caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in an otherwise well, 48-year-old Canadian man with type 2 diabetes mellitus who had travelled to Texas. Despite therapy that included intravenous antibiotics, intravenous immune globulin and other supportive measures, the patient succumbed to his illness. Recently, CA-MRSA pneumonia has been reported in several countries. The virulence of this organism may in part be related to its ability to produce toxins, such as Panton-Valentine leukocidin. As rates of CA-MRSA increase worldwide, physicians should be aware of the potential for MRSA to cause life-threatening infections in patients presenting to Canadian emergency departments (EDs). Necrotizing pneumonia caused by MRSA must be considered in the differential diagnosis of acute, severe respiratory illness. Early recognition of this syndrome in the ED may help physicians initiate appropriate antibiotic therapy in a timely manner. [ABSTRACT FROM AUTHOR]

Rationale: Little is known about the long-term outcomes and costs of survivors of acute respiratory distress syndrome (ARDS).Objectives: To describe functional and quality of life outcomes, health care use, and costs of survivors of ARDS 2 yr after intensive care unit (ICU) discharge.Methods: We recruited a cohort of ARDS survivors from four academic tertiary care ICUs in Toronto, Canada, and prospectively monitored them from ICU admission to 2 yr after ICU discharge.Measurements: Clinical and functional outcomes, health care use, and direct medical costs.Results: Eighty-five percent of patients with ARDS discharged from the ICU survived to 2 yr; overall 2-yr mortality was 49%. At 2 yr, survivors continued to have exercise limitation although 65% had returned to work. There was no statistically significant improvement in health-related quality of life as measured by Short-Form General Health Survey between 1 and 2 yr, although there was a trend toward better physical role at 2 yr (p = 0.0586). Apart from emotional role and mental health, all other domains remained below that of the normal population. From ICU admission to 2 yr after ICU discharge, the largest portion of health care costs for a survivor of ARDS was the initial hospital stay, with ICU costs accounting for 76% of these costs. After the initial hospital stay, health care costs were related to hospital readmissions and inpatient rehabilitation.Conclusions: Survivors of ARDS continued to have functional impairment and compromised health-related quality of life 2 yr after discharge from the ICU. Health care use and costs after the initial hospitalization were driven by hospital readmissions and inpatient rehabilitation. [ABSTRACT FROM AUTHOR]

The National Heart, Lung, and Blood Institute, along with the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases, convened a panel to develop recommendations for treatment, prevention, and research for respiratory failure from severe acute respiratory syndrome (SARS) and other newly emerging infections. The clinical and pathological features of acute lung injury (ALI) from SARS appear indistinguishable from ALI from other causes. The mainstay of treatments for ALI remains supportive. Patients with ALI from SARS who require mechanical ventilation should receive a lung protective, low tidal volume strategy. Adjuvant treatments recommended include prevention of venous thromboembolism, stress ulcer prophylaxis, and semirecumbent positioning during ventilation. Based on previous experience in Canada, infection control resources and protocols were recommended. Leadership structure, communication, training, and morale are an essential aspect of SARS management. A multicenter, placebo-controlled trial of corticosteroids for late SARS is justified because of widespread clinical use and uncertainties about relative risks and benefits. Studies of combined pathophysiologic endpoints were recommended, with mortality as a secondary endpoint. The group recommended preparation for studies, including protocols, ethical considerations, Web-based registries, and data entry systems. [ABSTRACT FROM AUTHOR]

Nosocomial transmission of severe acute respiratory syndrome from critically ill patients to healthcare workers has been a prominent and worrisome feature of existing outbreaks. We have observed a greater risk of developing severe acute respiratory syndrome for physicians and nurses performing endotracheal intubation (relative risk [RR], 13.29; 95% confidence interval [CI], 2.99 to 59.04; p = 0.003). Nurses caring for patients receiving noninvasive positive-pressure ventilation may be at an increased risk (RR, 2.33; 95% CI, 0.25 to 21.76; p = 0.5), whereas nurses caring for patients receiving high-frequency oscillatory ventilation do not appear at an increased risk (RR, 0.74; 95% CI, 0.11 to 4.92; p = 0.6) compared with their respective reference cohorts. Specific infection control recommendations concerning the care of critically ill patients may help limit further nosocomial transmission. [ABSTRACT FROM AUTHOR]

Abstract The second most serious neurodegenerative disease is Parkinson’s disease (PD). Over the past several decades, a strong body of evidence suggests that PD can begin years before the hallmark clinical motor symptoms appear. Biomarkers for PD are urgently needed to differentiate between neurodegenerative disorders, screen novel therapeutics, and predict eventual clinical PD before the onset of symptoms. Some clinical evaluations and neuroimaging techniques have been developed in the last several years with some success in this area. Moreover, other strategies have been utilized to identify biochemical and genetic markers associated with PD leading to the examination of PD progression and pathogenesis in cerebrospinal fluid, blood, or saliva. Finally, interesting results are surfacing from preliminary studies using known PD-associated genetic mutations to assess potential premotor PD biomarkers. The current review highlights recent advances and underscores areas of potential advancement.

Background and Objectives: Allergic rhinitis may contribute to sleep disordered breathing (SDB) in children. Although adenotonsillectomy is commonly performed to treat SDB, some patients will return to their primary practitioners with residual sleep symptoms. The aim of this study was to assess the incidence of allergic rhinitis via radioallergosorbent testing (RAST) in children undergoing adenotonsillectomy who had residual snoring or sleep symptoms., Method: A retrospective analysis of 500 patients post-adenotonsillectomy was undertaken. The incidence of residual snoring, residual sleep symptoms and results of RAST, as well as total immunoglobulin E (IgE) after surgical intervention, were documented., Results: Children with positive RAST results or elevated total IgE had a significantly greater incidence of residual snoring post-adenotonsillectomy (P = 0.049) and residual sleep symptoms after surgery (P <0.0001)., Discussion: A positive RAST or elevated IgE in children with SDB was associated with incomplete resolution of snoring and residual sleep symptoms after adenotonsillectomy. Thus, there should be raised suspicion of allergic rhinitis in this population.

Sea-level rise (SLR) impacts on intertidal habitat depend on coastal topology, accretion, and constraints from surrounding development. Such habitat changes might affect species like Belding's savannah sparrows ( Passerculus sandwichensis beldingi ; BSSP), which live in high-elevation salt marsh in the Southern California Bight. To predict how BSSP habitat might change under various SLR scenarios, we first constructed a suitability model by matching bird observations with elevation. We then mapped current BSSP breeding and foraging habitat at six estuarine sites by applying the elevation-suitability model to digital elevation models. To estimate changes in digital elevation models under different SLR scenarios, we used a site-specific, one-dimensional elevation model (wetland accretion rate model of ecosystem resilience). We then applied our elevation-suitability model to the projected digital elevation models. The resulting maps suggest that suitable breeding and foraging habitat could decline as increased inundation converts middle- and high-elevation suitable habitat to mudflat and subtidal zones. As a result, the highest SLR scenario predicted that no suitable breeding or foraging habitat would remain at any site by 2100 and 2110. Removing development constraints to facilitate landward migration of high salt marsh, or redistributing dredge spoils to replace submerged habitat, might create future high salt marsh habitat, thereby reducing extirpation risk for BSSP in southern California.

Early-life adversity can have long-lasting effects on physiological, behavioural, cognitive, and somatic processes. Consequently, these effects may alter an organism's life-history strategy and reproductive tactics.In response to early-life immune activation, we quantified levels of the acute phase protein haptoglobin (Hp) during development in male zebra finches ( Taeniopygia guttata ). Then, we examined the long-term impacts of early-life immune activation on an important static sexual signal, song complexity, as well as effects of early-life immune activation on the relationship between song complexity and a dynamic sexual signal, beak colouration. Finally, we performed mate-choice trials to determine if male early-life experience impacted female preference.Challenge with keyhole limpet hemocyanin (KLH) resulted in increased song complexity compared to lipopolysaccharide (LPS) treatment or the control. Hp levels were inversely correlated with song complexity. Moreover, KLH-treatment resulted in negative associations between the two sexual signals (beak colouration and song complexity). Females demonstrated some preference for KLH-treated males over controls and for control males over LPS-treated males in mate choice trials.Developmental immune activation has variable effects on the expression of secondary sexual traits in adulthood, including enhancing the expression of some traits. Because developmental levels of Hp and adult song complexity were correlated, future studies should explore a potential role for exposure to inflammation during development on song learning.Early-life adversity may differentially impact static versus dynamic signals. The use of phenotypic correlations can be a powerful tool for examining the impact of early-life experience on the associations among different traits, including sexual signals.

Most species aggregate in local patches. High host density in patches increases contact rate between hosts and parasites, increasing parasite transmission success. At the same time, for environmentally transmitted parasites, high host density can decrease infection risk to individual hosts, because infective stages are divided among all hosts in a patch, leading to safety in numbers. We tested these predictions using the California horn snail, Cerithideopsis californica (=Cerithidea californica), which is the first intermediate host for at least 19 digenean trematode species in California estuaries. Snails become infected by ingesting trematode eggs or through penetration by free-swimming miracidia that hatch from trematode eggs deposited with final-host (bird or mammal) feces. This complex life cycle decouples infective-stage production from transmission, raising the possibility of an inverse relationship between host density and infection risk at local scales. In a field survey, higher snail density was associated with increased trematode (infected snail) density, but decreased trematode prevalence, consistent with either safety in numbers, parasitic castration, or both. To determine the extent to which safety in numbers drove the negative snail-density-trematode-prevalence association, we manipulated uninfected snail density in 83 cages at eight sites within Carpinteria Salt Marsh (California, USA). At each site, we quantified snail density and used data on final-host (bird and raccoon) distributions to control for between-site variation in infective-stage supply. After three months, overall trematode infections per cage increased with snail biomass density. For egg-transmitted trematodes, per-snail infection risk decreased with snail biomass density in the cage and surrounding area, whereas per-snail infection risk did not decrease for miracidium-transmitted trematodes. Furthermore, both trematode recruitment and infection risk increased with infective-stage input, but this was significant only for miracidium-transmitted species. A model parameterized with our experimental results and snail densities from 524 field transects estimated that safety in numbers, when combined with patchy host density, halved per capita infection risk in this snail population. We conclude that, depending on transmission mode, host density can enhance parasite recruitment and reduce per capita infection risk., (© 2017 by the Ecological Society of America.)

Objectives: A recent individual patient data (IPD) meta-analysis suggested that patients with moderate or severe acute respiratory distress syndrome (ARDS) benefit from higher positive end-expiratory pressure (PEEP) ventilation strategies. However, thresholds for continuous variables (eg, hypoxaemia) are often arbitrary and linearity assumptions in regression approaches may not hold; the multivariable fractional polynomial interaction (MFPI) approach can address both problems. The objective of this study was to apply the MFPI approach to investigate interactions between four continuous patient baseline variables and higher versus lower PEEP on clinical outcomes., Setting: Pooled data from three randomised trials in intensive care identified by a systematic review., Participants: 2299 patients with acute lung injury requiring mechanical ventilation., Interventions: Higher (N=1136) versus lower PEEP (N=1163) ventilation strategy., Outcome Measures: Prespecified outcomes included mortality, time to death and time-to-unassisted breathing. We examined the following continuous baseline characteristics as potential effect modifiers using MFPI: PaO2/FiO2 (arterial partial oxygen pressure/ fraction of inspired oxygen), oxygenation index, respiratory system compliance (tidal volume/(inspiratory plateau pressure-PEEP)) and body mass index (BMI)., Results: We found that for patients with PaO2/FiO2 below 150 mm Hg, but above 100 mm Hg or an oxygenation index above 12 (moderate ARDS), higher PEEP reduces hospital mortality, but the beneficial effect appears to level off for patients with very severe ARDS. Patients with mild ARDS (PaO2/FiO2 above 200 mm Hg or an oxygenation index below 10) do not seem to benefit from higher PEEP and might even be harmed. For patients with a respiratory system compliance above 40 mL/cm H2O or patients with a BMI above 35 kg/m(2), we found a trend towards reduced mortality with higher PEEP, but there is very weak statistical confidence in these findings., Conclusions: MFPI analyses suggest a nonlinear effect modification of higher PEEP ventilation by PaO2/FiO2 and oxygenation index with reduced mortality for some patients suffering from moderate ARDS., Study Registration Number: CRD42012003129., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Ankle instantaneous axis of rotation (IAR) measurements represent a more complete parameter for characterizing joint motion. However, few studies have implemented this measurement to study normal, injured, or pathological foot ankle biomechanics. A novel testing protocol was developed to simulate aspects of in vivo foot ankle mechanics during mid-stance gait in a human cadaveric specimen. A lower leg was mounted in a robotic testing platform with the tibia upright and foot flat on the baseplate. Axial tibia loads (ATLs) were controlled as a function of a vertical ground reaction force (vGRF) set at half body weight (356 N) and a 50% vGRF (178 N) Achilles tendon load. Two specimens were repetitively loaded over 10 degrees of dorsiflexion and 20 degrees of plantar flexion. Platform axes were controlled within 2 microns and 0.008 degrees resulting in ATL measurements within ±2 N of target conditions. Mean ATLs and IAR values were not significantly different between cycles of motion, but IAR values were significantly different between dorsiflexion and plantar flexion. A linear regression analysis showed no significant differences between slopes of plantar flexion paths. The customized robotic platform and advanced testing protocol produced repeatable and accurate measurements of the IAR, useful for assessing foot ankle biomechanics under different loading scenarios and foot conditions.

Background: Shorter resident duty periods are increasingly mandated to improve patient safety and physician well-being. However, increases in continuity-related errors may counteract the purported benefits of reducing fatigue. We evaluated the effects of 3 resident schedules in the intensive care unit (ICU) on patient safety, resident well-being and continuity of care., Methods: Residents in 2 university-affiliated ICUs were randomly assigned (in 2-month rotation-blocks from January to June 2009) to in-house overnight schedules of 24, 16 or 12 hours. The primary patient outcome was adverse events. The primary resident outcome was sleepiness, measured by the 7-point Stanford Sleepiness Scale. Secondary outcomes were patient deaths, preventable adverse events, and residents' physical symptoms and burnout. Continuity of care and perceptions of ICU staff were also assessed., Results: We evaluated 47 (96%) of 49 residents, all 971 admissions, 5894 patient-days and 452 staff surveys. We found no effect of schedule (24-, 16- or 12-h shifts) on adverse events (81.3, 76.3 and 78.2 events per 1000 patient-days, respectively; p = 0.7) or on residents' sleepiness in the daytime (mean rating 2.33, 2.61 and 2.30, respectively; p = 0.3) or at night (mean rating 3.06, 2.73 and 2.42, respectively; p = 0.2). Seven of 8 preventable adverse events occurred with the 12-hour schedule (p = 0.1). Mortality rates were similar for the 3 schedules. Residents' somatic symptoms were more severe and more frequent with the 24-hour schedule (p = 0.04); however, burnout was similar across the groups. ICU staff rated residents' knowledge and decision-making worst with the 16-hour schedule., Interpretation: Our findings do not support the purported advantages of shorter duty schedules. They also highlight the trade-offs between residents' symptoms and multiple secondary measures of patient safety. Further delineation of this emerging signal is required before widespread system change., Trial Registration: ClinicalTrials.gov, no. NCT00679809., (© 2015 Canadian Medical Association or its licensors.)

Background: The Lung Open Ventilation Study (LOV Study) compared a low tidal volume strategy with an experimental strategy combining low tidal volume, lung recruitment maneuvers, and higher plateau and positive end-expiratory pressures (PEEP) in adults with acute respiratory distress syndrome (ARDS). Herein, we compared sedative, opioid, and neuromuscular blocker (NMB) use among patients managed with the intervention and control strategies and clinicians' assessment of comfort in both groups., Methods: This was an observational substudy of the LOV Study, a randomized trial conducted in 30 intensive care units in Canada, Australia, and Saudi Arabia. In 16 centers, we recorded daily doses of sedatives, opioids, and NMBs and surveyed bedside clinicians about their own comfort with the assigned ventilator strategy and their perceptions of patient comfort. We compared characteristics and outcomes of patients who did and did not receive NMBs., Results: Study groups received similar sedative, opioid, and NMB dosing on days 1, 3, and 7. Patient comfort as assessed by clinicians was not different in the two groups: 93% perceived patients had no/minimal discomfort. In addition, 92% of clinicians were comfortable with the assigned ventilation strategy without significant differences between the two groups. When clinicians expressed discomfort, more expressed discomfort about PEEP levels in the intervention vs control group (2.9% vs 0.7%, P <0.0001), and more perceived patient discomfort among controls (6.0% vs 4.3%, P = 0.049). On multivariable analysis, the strongest associations with NMB use were higher plateau pressure (hazard ratio (HR) 1.15; 95% confidence interval (CI) 1.07 to 1.23; P = 0.0002) and higher daily sedative dose (HR 1.03; 95% CI 1.02 to 1.05; P <0.0001). Patients receiving NMBs had more barotrauma, longer durations of mechanical ventilation and hospital stay, and higher mortality., Conclusions: In the LOV Study, high PEEP, low tidal volume ventilation did not increase sedative, opioid, or NMB doses in adults with ARDS, compared with a lower PEEP strategy, and appeared at least as comfortable for patients. NMB use may reflect worse lung injury, as these patients had more barotrauma, longer durations of ventilation, and higher mortality., Trial Registration: ClinicalTrials.gov Identifier NCT00182195.

Rationale: Previous trials of higher positive end-expiratory pressure (PEEP) for acute respiratory distress syndrome (ARDS) failed to demonstrate mortality benefit, possibly because of differences in lung recruitability among patients with ARDS., Objectives: To determine whether the physiological response to increased PEEP is associated with mortality., Methods: In a secondary analysis of the Lung Open Ventilation Study (LOVS, n = 983), we examined the relationship between the initial response to changes in PEEP after randomization and mortality. We sought to corroborate our findings using data from a different trial of higher PEEP (ExPress, n = 749)., Measurements and Main Results: The oxygenation response (change in ratio of arterial partial pressure of oxygen to fraction of inspired oxygen: P/F) after the initial change in PEEP after randomization varied widely (median, 9.5 mm Hg; interquartile range, -16 to 47) and was only weakly related to baseline P/F or the magnitude of PEEP change. Among patients in whom PEEP was increased after randomization, an increase in P/F was associated with reduced mortality (multivariable logistic regression; adjusted odds ratio, 0.80 [95% confidence interval, 0.72-0.89] per 25-mm Hg increase in P/F), particularly in patients with severe disease (baseline P/F [less-than-or-equal-to] 150 mm Hg). Changes in compliance and dead space were not associated with mortality. These findings were confirmed by a similar analysis of data from the ExPress trial., Conclusions: Patients with ARDS who respond to increased PEEP by improved oxygenation have a lower risk of death. The oxygenation response to PEEP might be used to predict whether patients will benefit from higher versus lower PEEP.

Background: There are limited data on the safety and efficacy of recruitment maneuvers (RMs) in acute lung injury (ALI) patients., Objective: To evaluate the frequency, timing, and risk factors for complications from RMs in adult ALI patients., Methods: Secondary analysis of data from a randomized controlled trial of a lung open ventilation strategy that included sustained inflation RMs., Results: Respiratory (eg, desaturation) and cardiovascular (eg, hypotension) complications from recruitment maneuvers were common (22% of all patients receiving RMs), and the majority occurred within 7 days of enrollment. New air leak through an existing chest tube was uncommon (< 5%). As compared to patients receiving 1 or fewer RMs, the number of RMs received was associated with increased risk in both younger (age ≤ 56 y) and older patients (age > 56 y): 2 RMs odds ratio [OR] 6.92 (95% CI 1.70-28.2), ≥ 3 RMs OR 15.4 (95% CI 4.77-49.6), and 2 RMs OR 5.43 (95% CI 1.76-16.8), ≥ 3 RMs OR 4.93 (95% CI 1.78-13.7), respectively. Patients with extrapulmonary ALI had decreased odds of developing complications (OR 0.42, 95% CI 0.22-0.80)., Conclusions: Complications in adult ALI patients receiving RMs were common, but serious complications (eg, new air leak through an existing chest tube) were infrequent. There is a significant association between the number of RMs received and complications, even after controlling for illness severity and duration. Given their uncertain benefit in ALI patients, and the potential for complications with repeated application, the routine use of sustained inflation RMs is not justified.

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life threatening clinical conditions seen in critically ill patients with diverse underlying illnesses. Lung injury may be perpetuated by ventilation strategies that do not limit lung volumes and airway pressures. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing pressure and volume-limited (PVL) ventilation strategies with more traditional mechanical ventilation in adults with ALI and ARDS., Methods and Findings: We searched Medline, EMBASE, HEALTHSTAR and CENTRAL, related articles on PubMed™, conference proceedings and bibliographies of identified articles for randomized trials comparing PVL ventilation with traditional approaches to ventilation in critically ill adults with ALI and ARDS. Two reviewers independently selected trials, assessed trial quality, and abstracted data. We identified ten trials (n = 1,749) meeting study inclusion criteria. Tidal volumes achieved in control groups were at the lower end of the traditional range of 10-15 mL/kg. We found a clinically important but borderline statistically significant reduction in hospital mortality with PVL [relative risk (RR) 0.84; 95% CI 0.70, 1.00; p = 0.05]. This reduction in risk was attenuated (RR 0.90; 95% CI 0.74, 1.09, p = 0.27) in a sensitivity analysis which excluded 2 trials that combined PVL with open-lung strategies and stopped early for benefit. We found no effect of PVL on barotrauma; however, use of paralytic agents increased significantly with PVL (RR 1.37; 95% CI, 1.04, 1.82; p = 0.03)., Conclusions: This systematic review suggests that PVL strategies for mechanical ventilation in ALI and ARDS reduce mortality and are associated with increased use of paralytic agents.

*We studied the relationship between virulence (ability to kill nondormant Bromus tectorum seeds) and mycelial growth index in the necrotrophic seed pathogen Pyrenophora semeniperda. Seed pathosystems involving necrotrophs differ from those commonly treated in traditional evolution-of-virulence models in that host death increases pathogen fitness by preventing germination, thereby increasing available resources. Because fast-germinating, nondormant B. tectorum seeds commonly escape mortality, we expected virulence to be positively correlated with mycelial growth index. *We performed seed inoculations using conidia from 78 pathogen isolates and scored subsequent mortality. For a subset of 40 of these isolates, representing a range of virulence phenotypes, we measured mycelial growth index. *Virulence varied over a wide range (3-43% seed mortality) and was significantly negatively correlated with mycelial growth index (R(2) = 0.632). More virulent isolates grew more slowly than less virulent isolates. *We concluded that there is an apparent tradeoff between virulence and growth in this pathogen, probably because the production of toxins necessary for necrotrophic pathogenesis competes with metabolic processes associated with growth. Variation in both virulence and growth rate in this pathosystem may be maintained in part by seasonal variation in the relative abundance of rapidly germinating vs dormant host seeds available to the pathogen.

Pyrenophora seminiperda (Brittleb. & D.B. Adam) Shoemaker (anamorph Drechslera campanulata (Lév.) B. Sutton) is a generalist seed pathogen that can cause high mortality in the seed banks of annual and perennial grasses and a minor leaf spot disease. Its current reported distribution is mainly temperate grasslands, deserts, and winter cereal-growing regions in Argentina, Australia, Canada, Egypt, New Zealand, South Africa, and the United States (2). P. seminiperda was originally described in France in the mid-1800s, but there are no recent reports from eastern Europe or Asia (2). In May of 2008, we observed what appeared to be P. seminiperda on seeds from seed bank samples collected in Turkey. Evidence of disease was observed as macroscopic black stromata protruding from the seed. The characteristic club-shaped stromata were collected from a Taeniatherum caput-medusae seed near Pamukkale, Turkey and six Bromus tectorum seeds in Love Valley near Goreme, Turkey. An additional collection from a single undispersed B. tectorum seed was obtained from Perissa, Greece. Identity of the pathogen was tentatively established by evaluating morphological characteristics for nine isolates in V8 agar culture. After 4 days of incubation at 20°C with a 12-h photoperiod, the cultures produced white mycelium. Following wounding, the mycelium produced black, club-shaped stromata (2 to 8 × 0.4 to 0.9 mm) in a radial pattern. These produced branched conidiophores bearing crescent-shaped, multicellular conidia (79 to 125 μm long). These attributes are consistent with those of the anamorph of P. seminiperda as described by Shoemaker (4) and Campbell et al. (1). The teleomorph was not observed. The identity of the isolates as P. seminiperda was confirmed with ribosomal DNA internal transcribed spacer (ITS) genetic sequencing analysis. ITS sequences obtained were identical to sequences for North American haplotypes of this species. Four of the Love Valley isolates, (representative isolate: GQ168725, BPI 879142, NRRL 54032) matched the HTA haplotype (GQ168724), while the other four (representative isolate: GQ168736, BPI 879143, NRRL 54033) matched the HTJ haplotype (GQ168735). The isolate from Perissa, Greece (GQ168728, BPI 879144, NRRL 54034) matched the HTC haplotype (GQ168727). Pathogenicity of several Love Valley isolates was confirmed by producing conidia in culture, dusting nondormant B. tectorum seeds with 0.003 g of conidial inoculum per 50 seeds, and incubating for 14 days at 10/20°C with a 12-h photoperiod. Stromata developed on >90% of inoculated seeds and mortality as high as 34% was observed. Morphological similarities combined with ITS sequence data provide conclusive evidence that P. seminiperda occurs in Turkey and Greece. The discovery of this pathogen in these countries indicates that it may be widespread in Eurasia and that it could have arrived in North America on seeds of B. tectorum (3) rather than representing a novel pathogen for this important weed in its North American range. References: (1) M. A. Campbell et al. Plant Pathol. 52:448, 2003. (2) R. W. Medd et al. Australas. Plant Pathol. 32:539, 2003. (3) S. E. Meyer et al. Can J. Plant Pathol. 30:525, 2008. (4) R. A. Shoemaker. Can. J. Bot. 44:1451, 1966.

Healthcare workers (HCWs) found the 2003 outbreak of severe acute respiratory syndrome (SARS) to be stressful, but the long-term impact is not known. From 13 to 26 months after the SARS outbreak, 769 HCWs at 9 Toronto hospitals that treated SARS patients and 4 Hamilton hospitals that did not treat SARS patients completed a survey of several adverse outcomes. Toronto HCWs reported significantly higher levels of burnout (p = 0.019), psychological distress (p<0.001), and posttraumatic stress (p<0.001). Toronto workers were more likely to have reduced patient contact and work hours and to report behavioral consequences of stress. Variance in adverse outcomes was explained by a protective effect of the perceived adequacy of training and support and by a provocative effect of maladaptive coping style and other individual factors. The results reinforce the value of effective staff support and training in preparation for future outbreaks.

Introduction: We aimed to determine the adverse events and important prognostic factors associated with interfacility transport of intubated and mechanically ventilated adult patients., Methods: We performed a systematic review of MEDLINE, CENTRAL, EMBASE, CINAHL, HEALTHSTAR, and Web of Science (from inception until 10 January 2005) for all clinical studies describing the incidence and predictors of adverse events in intubated and mechanically ventilated adult patients undergoing interfacility transport. The bibliographies of selected articles were also examined., Results: Five studies (245 patients) met the inclusion criteria. All were case-series and two were prospective in design. Due to the paucity of studies and significant heterogeneity in study population, outcome events, and results, we synthesized data in a qualitative manner. Pre-transport severity of illness was reported in only one study. The most common indication for transport was a need for investigations and/or specialist care (three studies, 220 patients). Transport modalities included air (fixed or rotor wing; 66% of patients) and ground (31%) ambulance, and commercial aircraft (3%). Transport teams included a physician in three studies (220 patients). Death during transfer was rare (n = 1). No other adverse events or significant therapeutic interventions during transport were reported. One study reported a 19% (28/145) incidence of respiratory alkalosis on arrival and another study documented a 30% overall intensive care unit mortality, while no adverse events or outcomes were reported after arrival in the three other studies., Conclusion: Insufficient data exist to draw firm conclusions regarding the mortality, morbidity, or risk factors associated with the interfacility transport of intubated and mechanically ventilated adult patients. Further study is required to define the risks and benefits of interfacility transfer in this patient population. Such information is important for the planning and allocation of resources related to transporting critically ill adults.

Disaster management plans have traditionally been required to manage major traumatic events that create a large number of victims. Infectious diseases, whether they be natural (e.g. SARS [severe acute respiratory syndrome] and influenza) or the result of bioterrorism, have the potential to create a large influx of critically ill into our already strained hospital systems. With proper planning, hospitals, health care workers and our health care systems can be better prepared to deal with such an eventuality. This review explores the Toronto critical care experience of coping in the SARS outbreak disaster. Our health care system and, in particular, our critical care system were unprepared for this event, and as a result the impact that SARS had was worse than it could have been. Nonetheless, we were able to organize a response rapidly during the outbreak. By describing our successes and failures, we hope to help others to learn and avoid the problems we encountered as they develop their own disaster management plans in anticipation of similar future situations.

Respiratory failure from severe asthma is a potentially reversible, life-threatening condition. Poor outcome in this setting is frequently a result of the development of gas-trapping. This condition can arise in any mechanically ventilated patient, but those with severe airflow limitation have a predisposition. It is important that clinicians managing these types of patients understand that the use of mechanical ventilation can lead to or worsen gas-trapping. In this review we discuss the development of this complication during mechanical ventilation, techniques to measure it and strategies to limit its severity. We hope that by understanding such concepts clinicians will be able to reduce further the poor outcomes occasionally related to severe asthma.

Introduction: Critical care physicians may benefit from immediate access to medical reference material. We evaluated the feasibility and potential benefits of a handheld computer based knowledge access system linking a central academic intensive care unit (ICU) to multiple community-based ICUs., Methods: Four community hospital ICUs with 17 physicians participated in this prospective interventional study. Following training in the use of an internet-linked, updateable handheld computer knowledge access system, the physicians used the handheld devices in their clinical environment for a 12-month intervention period. Feasibility of the system was evaluated by tracking use of the handheld computer and by conducting surveys and focus group discussions. Before and after the intervention period, participants underwent simulated patient care scenarios designed to evaluate the information sources they accessed, as well as the speed and quality of their decision making. Participants generated admission orders during each scenario, which were scored by blinded evaluators., Results: Ten physicians (59%) used the system regularly, predominantly for nonmedical applications (median 32.8/month, interquartile range [IQR] 28.3-126.8), with medical software accessed less often (median 9/month, IQR 3.7-13.7). Eight out of 13 physicians (62%) who completed the final scenarios chose to use the handheld computer for information access. The median time to access information on the handheld handheld computer was 19 s (IQR 15-40 s). This group exhibited a significant improvement in admission order score as compared with those who used other resources (P = 0.018). Benefits and barriers to use of this technology were identified., Conclusion: An updateable handheld computer system is feasible as a means of point-of-care access to medical reference material and may improve clinical decision making. However, during the study, acceptance of the system was variable. Improved training and new technology may overcome some of the barriers we identified.

Introduction: We conducted this study to evaluate the feasibility of implementing an internet-linked handheld computer procedure logging system in a critical care training program., Methods: Subspecialty trainees in the Interdepartmental Division of Critical Care at the University of Toronto received and were trained in the use of Palm handheld computers loaded with a customized program for logging critical care procedures. The procedures were entered into the handheld device using checkboxes and drop-down lists, and data were uploaded to a central database via the internet. To evaluate the feasibility of this system, we tracked the utilization of this data collection system. Benefits and disadvantages were assessed through surveys., Results: All 11 trainees successfully uploaded data to the central database, but only six (55%) continued to upload data on a regular basis. The most common reason cited for not using the system pertained to initial technical problems with data uploading. From 1 July 2002 to 30 June 2003, a total of 914 procedures were logged. Significant variability was noted in the number of procedures logged by individual trainees (range 13-242). The database generated by regular users provided potentially useful information to the training program director regarding the scope and location of procedural training among the different rotations and hospitals., Conclusion: A handheld computer procedure logging system can be effectively used in a critical care training program. However, user acceptance was not uniform, and continued training and support are required to increase user acceptance. Such a procedure database may provide valuable information that may be used to optimize trainees' educational experience and to document clinical training experience for licensing and accreditation.

Intravascular fluid therapy is a common critical care intervention. However, the optimal type of resuscitation fluid, crystalloid or colloid, remains controversial. Despite the many theoretical benefits of human albumin administration in critically ill patients, there has been little evidence to support its widespread clinical use. Previous systematic reviews have led to conflicting results regarding the safety and efficacy of albumin. The recently reported Saline versus Albumin Evaluation study has provided conclusive evidence that 4% albumin is as safe as saline for resuscitation, although no overall benefit of albumin use was seen. Subgroup analysis of the albumin-treated group revealed a trend towards decreased mortality in patients with septic shock, and a trend towards increased mortality in trauma patients, especially those with traumatic brain injury. The results of these subgroups, as well as the use of higher albumin concentrations and other synthetic colloids (dextrans, starches), require rigorous evaluation in clinical trials. Finally, the Saline versus Albumin Evaluation trial represents a methodological milestone in critical care medicine, due to its size, its efficient trial design, and its logistical coordination. Future studies are still required, however, to establish a therapeutic niche for albumin and other colloids.

Background: West Nile virus (WNV) is a rapidly spreading infectious disease in North America. Critical care issues related to WNV are not well described., Objectives: Three cases of severe WNV meningoencephalitis with flaccid paralysis are reported and relevant critical care issues are highlighted., Methods: Case series and a review of the literature., Results: Three patients with WNV meningoencephalitis and flaccid paralysis were admitted to the authors' academic, tertiary-care intensive care unit (ICU) in the late summer of 2002. All three patients were middle-aged or elderly and presented with a febrile illness that preceded or coincided with their neurological symptoms. Confirmation of WNV infection was problematic because each patient had at least one initial negative serum serology test. Radiological testing yielded nonspecific results. Serial electroencephalograms were consistent with severe toxic metabolic encephalopathy in all cases. All patients had a severe, diffuse axonal polyneuropathy demonstrated by nerve conduction studies and electromyography. Prolonged mechanical ventilation resulted in ICU lengths of stay of 44 to 118 days. At one point, 21% of the ICU beds were dedicated for these patients. All three patients died in hospital - two following the withdrawal of life support. One patient demonstrated resolving encephalitis and was discharged from the ICU after a 118-day ICU stay, but later died in a step-down unit., Conclusions: The management of WNV-related critical illness creates challenges in making a timely and accurate diagnosis, and predicting patient morbidity and mortality. As a consequence, end-of-life discussions with families are especially difficult. The prolonged ICU length of stay and growing incidence of this disease may challenge limited critical care resources.

It has recently been shown that strategies aimed at preventing ventilator-induced lung injury, such as ventilating with low tidal volumes, can reduce mortality in patients with acute respiratory distress syndrome (ARDS). High-frequency oscillatory ventilation (HFOV) seems ideally suited as a lung-protective strategy for these patients. HFOV provides both active inspiration and expiration at frequencies generally between 3 and 10 Hz in adults. The amount of gas that enters and exits the lung with each oscillation is frequently below the anatomic dead space. Despite this, gas exchange occurs and potential adverse effects of conventional ventilation, such as overdistension and the repetitive opening and closing of collapsed lung units, are arguably mitigated. Although many investigators have studied the merits of HFOV in neonates and in pediatric populations, evidence for its use in adults with ARDS is limited. A recent multicenter, randomized, controlled trial has shown that HFOV, when used early in ARDS, is at least equivalent to conventional ventilation and may have beneficial effects on mortality. The present article reviews the principles and practical aspects of HFOV, and the current evidence for its application in adults with ARDS.

Handheld computers have become a valuable and popular tool in various fields of medicine. A systematic review of articles was undertaken to summarize the current literature regarding the use of handheld devices in medicine. A variety of articles were identified, and relevant information for various medical fields was summarized. The literature search covered general information about handheld devices, the use of these devices to access medical literature, electronic pharmacopoeias, patient tracking, medical education, research, business management, e-prescribing, patient confidentiality, and costs as well as specialty-specific uses for personal digital assistants (PDAs). The authors concluded that only a small number of articles provide evidence-based information about the use of PDAs in medicine. The majority of articles provide descriptive information, which is nevertheless of value. This article aims to increase the awareness among physicians about the potential roles for handheld computers in medicine and to encourage the further evaluation of their use.

Objective: To evaluate the feasibility of incorporating hand-held computing technology in a surgical residency program, by means of hand-held devices for surgical procedure logging linked through the Internet to a central database., Setting: Division of General Surgery, University of Toronto., Design: A survey of general surgery residents., Methods: The 69 residents in the general surgery training program received hand-held computers with preinstalled medical programs and a program designed for surgical procedure logging. Procedural data were uploaded via the Internet to a central database. Survey data were collected regarding previous computer use as well as previous procedure logging methods., Main Outcome Measure: Utilization of the procedure logging system., Results: After a 5-month pilot period, 38% of surgical residents were using the procedure-logging program successfully and on a regular basis. Program use was higher among more junior trainees. Analysis of the database provided valuable information on individual trainees, hospital programs and supervising surgeons, data that would assist in program development., Conclusions: Hand-held devices can be implemented in a large division of general surgery to provide a reference database and a procedure-logging platform. However, user acceptance is not uniform and continued training and support are necessary to increase acceptance. The procedure database provides important information for optimizing trainees' educational experience.

Observational studies of high-frequency oscillatory ventilation in adults with the acute respiratory distress syndrome have demonstrated improvements in oxygenation. We designed a multicenter, randomized, controlled trial comparing the safety and effectiveness of high-frequency oscillatory ventilation with conventional ventilation in adults with acute respiratory distress syndrome; 148 adults with acute respiratory distress syndrome (Pa(O2)/fraction of inspired oxygen

Background: Evidence from recent literature shows that protocol-directed extubation is a useful approach to liberate patients from mechanical ventilation (MV). However, research evidence does not necessarily provide guidance on how to implement changes in individual intensive care units (ICUs). We conducted the present study to determine whether such an evidence-based strategy can be implemented safely and effectively using a multidisciplinary team (MDT) approach., Method: We designed a MDT-driven extubation protocol. Multiple meetings were held to encourage constructive criticism of the design by attending physicians, nurses and respiratory care practitioners (RCPs), in order to define a protocol that was evidence based and acceptable to all clinical staff involved in the process of extubation. It was subsequently implemented and evaluated in our medical/ surgical ICU. Outcomes included response of the MDT to the initiative, duration of MV and stay in the ICU, as well as reintubation rate., Results: The MDT responded favourably to the design and implementation of this MDT-driven extubation protocol, because it provided greater autonomy to the staff. Outcomes reported in the literature and in the historical control group were compared with those in the protocol group, and indicated similar durations of MV and ICU stay, as well as reintubation rates. No adverse events were documented., Conclusion: An MDT approach to protocol-directed extubation can be implemented safely and effectively in a multidisciplinary ICU. Such an effort is viewed favourably by the entire team and is useful in enhancing team building.

Background: Computing technology has the potential to improve health care management but is often underutilized. Handheld computers are versatile and relatively inexpensive, bringing the benefits of computers to the bedside. We evaluated the role of this technology for managing patient data and accessing medical reference information, in an academic intensive-care unit (ICU)., Methods: Palm III series handheld devices were given to the ICU team, each installed with medical reference information, schedules, and contact numbers. Users underwent a 1-hour training session introducing the hardware and software. Various patient data management applications were assessed during the study period. Qualitative assessment of the benefits, drawbacks, and suggestions was performed by an independent company, using focus groups. An objective comparison between a paper and electronic handheld textbook was achieved using clinical scenario tests., Results: During the 6-month study period, the 20 physicians and 6 paramedical staff who used the handheld devices found them convenient and functional but suggested more comprehensive training and improved search facilities. Comparison of the handheld computer with the conventional paper text revealed equivalence. Access to computerized patient information improved communication, particularly with regard to long-stay patients, but changes to the software and the process were suggested., Conclusions: The introduction of this technology was well received despite differences in users' familiarity with the devices. Handheld computers have potential in the ICU, but systems need to be developed specifically for the critical-care environment.

To examine the agreement between two classifications of acute respiratory distress syndrome (ARDS) that are used interchangeably in clinical practice and clinical research, we classified 118 patients taking part in a randomized trial with respect to the presence of ARDS using the North American-European Consensus Committee (NAECC) and the Lung Injury Severity Score (LISS) criteria. The incidence of ARDS using NAECC criteria was 55.1% (95% confidence interval, 46.1% to 64.1%), and using the LISS criteria 61.9% (95% confidence interval, 53.1% to 70.6%). The p value on the difference between these proportions was 0.07. Raw agreement, chance-corrected agreement (kappa), and chance-independent agreement (phi) on the study occurrence of ARDS using the two classifications were, respectively, 0.73 (95% CI, 0.65 to 0.81), 0.46 (95% CI, 0.32 to 0.61), and 0.63 (95% CI, 0.41 to 0.79). No single component of either index contributed to disagreement to an appreciably greater extent than other components. Baseline characteristics and outcomes were similar among patients who developed ARDS according to either classification. We conclude that NAECC and LISS classifications resulted in similar estimates of the incidence of ARDS in this clinical trial, though patients were frequently classified as having ARDS with only one model. These discordant classifications had no prognostic importance.

To measure the reliability of chest radiographic diagnosis of acute respiratory distress syndrome (ARDS) we conducted an observer agreement study in which two of eight intensivists and a radiologist, blinded to one another's interpretation, reviewed 778 radiographs from 99 critically ill patients. One intensivist and a radiologist participated in pilot training. Raters made a global rating of the presence of ARDS on the basis of diffuse bilateral infiltrates. We assessed interobserver agreement in a pairwise fashion. For rater pairings in which one rater had not participated in the consensus process we found moderate levels of raw (0.68 to 0.80), chance-corrected (kappa 0.38 to 0.55), and chance-independent (Phi 0. 53 to 0.75) agreement. The pair of raters who participated in consensus training achieved excellent to almost perfect raw (0.88 to 0.94), chance-corrected (kappa 0.72 to 0.88), and chance-independent (Phi 0.74 to 0.89) agreement. We conclude that intensivists without formal consensus training can achieve moderate levels of agreement. Consensus training is necessary to achieve the substantial or almost perfect levels of agreement optimal for the conduct of clinical trials.

Acute respiratory distress syndrome is a common cause of morbidity and mortality in intensive care units. For the most part, the mortality of this syndrome has arguably not decreased since the syndrome was originally described. One of the major reasons for this lack of reduction in mortality may be related to adherence to more traditional ventilatory strategies that have the potential to cause ventilator-induced lung injury. Ventilator strategies that attempt to limit ventilator-induced lung injury and accept permissive hypercapnia have successfully demonstrated a marked reduction in mortality in uncontrolled settings. So encouraging are these reductions that there has been a subtle shift in philosophy of mechanical ventilation toward using lung-protective ventilatory strategies at all times. With broad acceptance of this shift in philosophy, and the use of recently standardized clinical definitions for controlled studies, we optimistically anticipate improved mortality rates for acute respiratory distress syndrome.

We have obtained Chinese hamster ovary cell mutants defective in the biosynthesis of glycosaminoglycans by screening replicate colonies immobilized on polyester cloth. Depending upon the strain, the mutants accumulated less 35S-labeled glycosaminoglycans per microgram of cell protein by a factor of 6-60 compared to the wild type. Some of the mutants incorporated [6-3H]glucosamine into glycosaminoglycans to the same extent as the wild type, suggesting that sulfate addition was specifically altered. In contrast, five strains failed to generate 3H-labeled glycosaminoglycans normally. In four of these, the initiation of glycosaminoglycan assembly was specifically altered, since the addition of p-nitrophenyl-beta-xyloside restored sulfation to normal. Enzymatic assay of the xylosyltransferase in extracts prepared from these mutants revealed that one of the strains, S745, contained less enzyme activity by a factor of 15 than the wild type. This mutant provides genetic evidence that the xylosyltransferase assayed in vitro is responsible for the initiation of chondroitin sulfate and heparan sulfate biosynthesis in vivo.