A study of validity and usability evidence for non-technical skills assessment tools in simulated adult resuscitation scenarios.

BACKGROUND: Non-technical skills (NTS) assessment tools are widely used to provide formative and summative assessment for healthcare professionals and there are now many of them. This study has examined three different tools designed for similar settings and gathered evidence to test their validity and usability. METHODS: Three NTS assessment tools designed for use in the UK were used by three experienced faculty to review standardized videos of simulated cardiac arrest scenarios: ANTS (Anesthetists' Non-Technical Skills), Oxford NOTECHS (Oxford NOn-TECHnical Skills) and OSCAR (Observational Skill based Clinical Assessment tool for Resuscitation). Internal consistency, interrater reliability and quantitative and qualitative analysis of usability were analyzed for each tool. RESULTS: Internal consistency and interrater reliability (IRR) varied considerably for the three tools across NTS categories and elements. Intraclass correlation scores of three expert raters ranged from poor (task management in ANTS [0.26] and situation awareness (SA) in Oxford NOTECHS [0.34]) to very good (problem solving in Oxford NOTECHS [0.81] and cooperation [0.84] and SA [0.87] in OSCAR). Furthermore, different statistical tests of IRR produced different results for each tool. Quantitative and qualitative examination of usability also revealed challenges in using each tool. CONCLUSIONS: The lack of standardization of NTS assessment tools and training in their use is unhelpful for healthcare educators and students. Educators require ongoing support in the use of NTS assessment tools for the evaluation of individual healthcare professionals or healthcare teams. Summative or high-stakes examinations using NTS assessment tools should be undertaken with at least two assessors to provide consensus scoring. In light of the renewed focus on simulation as an educational tool to support and enhance training recovery in the aftermath of COVID-19, it is even more important that assessment of these vital skills is standardized, simplified and supported with adequate training.

Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial.

Importance: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. ß-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. Objectives: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. Design, Setting, and Participants: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 µg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Intervention: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. Main Outcomes and Measures: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. Results: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, -0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, -4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, -1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. Conclusion and Relevance: Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919.

The Use of Primary Care Big Data in Understanding the Pharmacoepidemiology of COVID-19: A Consensus Statement From the COVID-19 Primary Care Database Consortium.

The use of big data containing millions of primary care medical records provides an opportunity for rapid research to help inform patient care and policy decisions during the first and subsequent waves of the coronavirus disease 2019 (COVID-19) pandemic. Routinely collected primary care data have previously been used for national pandemic surveillance, quantifying associations between exposures and outcomes, identifying high risk populations, and examining the effects of interventions at scale, but there is no consensus on how to effectively conduct or report these data for COVID-19 research. A COVID-19 primary care database consortium was established in April 2020 and its researchers have ongoing COVID-19 projects in overlapping data sets with over 40 million primary care records in the United Kingdom that are variously linked to public health, secondary care, and vital status records. This consensus agreement is aimed at facilitating transparency and rigor in methodological approaches, and consistency in defining and reporting cases, exposures, confounders, stratification variables, and outcomes in relation to the pharmacoepidemiology of COVID-19. This will facilitate comparison, validation, and meta-analyses of research during and after the pandemic.

Day-to-day progression of vital-sign circadian rhythms in the intensive care unit.

BACKGROUND: Disrupted vital-sign circadian rhythms in the intensive care unit (ICU) are associated with complications such as immune system disruption, delirium and increased patient mortality. However, the prevalence and extent of this disruption is not well understood. Tools for its detection are currently limited. METHODS: This paper evaluated and compared vital-sign circadian rhythms in systolic blood pressure, heart rate, respiratory rate and temperature. Comparisons were made between the cohort of patients who recovered from the ICU and those who did not, across three large, publicly available clinical databases. This comparison included a qualitative assessment of rhythm profiles, as well as quantitative metrics such as peak-nadir excursions and correlation to a demographically matched 'recovered' profile. RESULTS: Circadian rhythms were present at the cohort level in all vital signs throughout an ICU stay. Peak-nadir excursions and correlation to a 'recovered' profile were typically greater throughout an ICU stay in the cohort of patients who recovered, compared to the cohort of patients who did not. CONCLUSIONS: These results suggest that vital-sign circadian rhythms are typically present at the cohort level throughout an ICU stay and that quantitative assessment of these rhythms may provide information of prognostic use in the ICU.

Treatment strategies for new onset atrial fibrillation in patients treated on an intensive care unit: a systematic scoping review.

BACKGROUND: New-onset atrial fibrillation (NOAF) in patients treated on an intensive care unit (ICU) is common and associated with significant morbidity and mortality. We undertook a systematic scoping review to summarise comparative evidence to inform NOAF management for patients admitted to ICU. METHODS: We searched MEDLINE, EMBASE, CINAHL, Web of Science, OpenGrey, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, ISRCTN, ClinicalTrials.gov, EU Clinical Trials register, additional WHO ICTRP trial databases, and NIHR Clinical Trials Gateway in March 2019. We included studies evaluating treatment or prevention strategies for NOAF or acute anticoagulation in general medical, surgical or mixed adult ICUs. We extracted study details, population characteristics, intervention and comparator(s), methods addressing confounding, results, and recommendations for future research onto study-specific forms. RESULTS: Of 3,651 citations, 42 articles were eligible: 25 primary studies, 12 review articles and 5 surveys/opinion papers. Definitions of NOAF varied between NOAF lasting 30 s to NOAF lasting > 24 h. Only one comparative study investigated effects of anticoagulation. Evidence from small RCTs suggests calcium channel blockers (CCBs) result in slower rhythm control than beta blockers (1 study), and more cardiovascular instability than amiodarone (1 study). Evidence from 4 non-randomised studies suggests beta blocker and amiodarone therapy may be equivalent in respect to rhythm control. Beta blockers may be associated with improved survival compared to amiodarone, CCBs, and digoxin, though supporting evidence is subject to confounding. Currently, the limited evidence does not support therapeutic anticoagulation during ICU admission. CONCLUSIONS: From the limited evidence available beta blockers or amiodarone may be superior to CCBs as first line therapy in undifferentiated patients in ICU. The little evidence available does not support therapeutic anticoagulation for NOAF whilst patients are critically ill. Consensus definitions for NOAF, rate and rhythm control are needed.

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial.

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.

Anxiety, depression and post-traumatic stress disorder management after critical illness: a UK multi-centre prospective cohort study.

BACKGROUND: Survivors of critical illness have significant psychopathological comorbidity. The treatments offered by primary health care professionals to affected patients are unstudied. AIM: To report the psychological interventions after GPs received notification of patients who showed severe symptoms of anxiety, depression or Post-Traumatic Stress Disorder. METHODS: Design: Multi-centre prospective cohort sub-study of the ICON study. SETTING: NHS primary care in the United Kingdom. PARTICIPANTS: Adult patients, November 2006-October 2010 who had received at least 24 h of intensive care, where the general practitioner recorded notification that the patient had reported severe symptoms or caseness using the Hospital Anxiety and Depression Scale (HADS) or the Post-Traumatic Stress Disorder Check List-Civilian (PCL-C). INTERVENTIONS: We notified general practitioners (GPs) by post if a patient reported severe symptoms or caseness and sent a postal questionnaire to determine interventions after notification. MAIN OUTCOME MEASURE: Primary or secondary healthcare interventions instigated by general practitioners following notification of a patient's caseness. RESULTS: Of the 11,726 patients, sent questionnaire packs containing HADS and PCL-C, 4361 (37%) responded. A notification of severe symptoms was sent to their GP in 25% (1112) of cases. Of notified GPs, 65% (725) responded to our postal questionnaire. Of these 37% (266) had no record of receipt of the original notification. Of the 459 patients where GPs had record of notification (the study group for this analysis), 21% (98) had pre-existing psychopathology. Of those without a pre-existing diagnosis 45% (162) received further psychological assessment or treatment. GP screening or follow-up alone occurred in 18% (64) whilst 27% (98) were referred to mental health services or received drug therapy following notification. CONCLUSIONS: Postal questionnaire identifies a burden of psychopathology in survivors of critical illness that have otherwise gone undiagnosed following discharge from an intensive care unit (ICU). After being alerted to the presence of psychological symptoms, GPs instigate treatment in 27% and augmented surveillance in 18% of cases. TRIAL REGISTRATION: ISRCTN69112866 (assigned 02/05/2006).

Using Bayesian adaptive designs to improve phase III trials: a respiratory care example.

BACKGROUND: Bayesian adaptive designs can improve the efficiency of trials, and lead to trials that can produce high quality evidence more quickly, with fewer patients and lower costs than traditional methods. The aim of this work was to determine how Bayesian adaptive designs can be constructed for phase III clinical trials in critical care, and to assess the influence that Bayesian designs would have on trial efficiency and study results. METHODS: We re-designed the High Frequency OSCillation in Acute Respiratory distress syndrome (OSCAR) trial using Bayesian adaptive design methods, to allow for the possibility of early stopping for success or futility. We constructed several alternative designs and studied their operating characteristics via simulation. We then performed virtual re-executions by applying the Bayesian adaptive designs using the OSCAR data to demonstrate the practical applicability of the designs. RESULTS: We constructed five alternative Bayesian adaptive designs and identified a preferred design based on the simulated operating characteristics, which had similar power to the original design but recruited fewer patients on average. The virtual re-executions showed the Bayesian sequential approach and original OSCAR trial yielded similar trial conclusions. However, using a Bayesian sequential design could have led to a reduced sample size and earlier completion of the trial. CONCLUSIONS: Using the OSCAR trial as an example, this case study found that Bayesian adaptive designs can be constructed for phase III critical care trials. If the OSCAR trial had been run using one of the proposed Bayesian adaptive designs, it would have terminated at a smaller sample size with fewer deaths in the trial, whilst reaching the same conclusions. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials. TRIAL REGISTRATION: OSCAR Trial registration ISRCTN, ISRCTN10416500 . Retrospectively registered 13 June 2007.

Anxiety, Depression and Post Traumatic Stress Disorder after critical illness: a UK-wide prospective cohort study.

BACKGROUND: Survivors of intensive care are known to be at increased risk of developing longer-term psychopathology issues. We present a large UK multicentre study assessing the anxiety, depression and post-traumatic stress disorder (PTSD) caseness in the first year following discharge from an intensive care unit (ICU). METHODS: Design: prospective multicentre follow-up study of survivors of ICU in the UK. SETTING: patients from 26 ICUs in the UK. INCLUSION CRITERIA: patients who had received at least 24 h of level 3 ICU care and were 16 years of age or older. INTERVENTIONS: postal follow up: Hospital Anxiety and Depression Score (HADS) and the Post-Traumatic Stress Disorder (PTSD) Check List-Civilian (PCL-C) at 3 and 12 months following discharge from ICU. MAIN OUTCOME MEASURE: caseness of anxiety, depression and PTSD, 2-year survival. RESULTS: In total, 21,633 patients admitted to ICU were included in the study. Postal questionnaires were sent to 13,155 survivors; of these 38% (4943/13155) responded and 55% (2731/4943) of respondents passed thresholds for one or more condition at 3 or 12 months following discharge. Caseness prevalence was 46%, 40% and 22% for anxiety, depression and PTSD respectively; 18% (870/4943 patients) met the caseness threshold for all three psychological conditions. Patients with symptoms of depression were 47% more likely to die during the first 2 years after discharge from ICU than those without (HR 1.47, CI 1.19-1.80). CONCLUSIONS: Over half of those who respond to postal questionnaire following treatment on ICU in the UK reported significant symptoms of anxiety, depression or PTSD. When symptoms of one psychological disorder are present, there is a 65% chance they will co-occur with symptoms of one of the other two disorders. Depression following critical illness is associated with an increased mortality risk in the first 2 years following discharge from ICU. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN69112866 . Registered on 2 May 2006.

Severity of Hypoxemia and Effect of High-Frequency Oscillatory Ventilation in Acute Respiratory Distress Syndrome.

RATIONALE: High-frequency oscillatory ventilation (HFOV) is theoretically beneficial for lung protection, but the results of clinical trials are inconsistent, with study-level meta-analyses suggesting no significant effect on mortality. OBJECTIVES: The aim of this individual patient data meta-analysis was to identify acute respiratory distress syndrome (ARDS) patient subgroups with differential outcomes from HFOV. METHODS: After a comprehensive search for trials, two reviewers independently identified randomized trials comparing HFOV with conventional ventilation for adults with ARDS. Prespecified effect modifiers were tested using multivariable hierarchical logistic regression models, adjusting for important prognostic factors and clustering effects. MEASUREMENTS AND MAIN RESULTS: Data from 1,552 patients in four trials were analyzed, applying uniform definitions for study variables and outcomes. Patients had a mean baseline PaO2/FiO2 of 114 ± 39 mm Hg; 40% had severe ARDS (PaO2/FiO2 <100 mm Hg). Mortality at 30 days was 321 of 785 (40.9%) for HFOV patients versus 288 of 767 (37.6%) for control subjects (adjusted odds ratio, 1.17; 95% confidence interval, 0.94-1.46; P = 0.16). This treatment effect varied, however, depending on baseline severity of hypoxemia (P = 0.0003), with harm increasing with PaO2/FiO2 among patients with mild-moderate ARDS, and the possibility of decreased mortality in patients with very severe ARDS. Compliance and body mass index did not modify the treatment effect. HFOV increased barotrauma risk compared with conventional ventilation (adjusted odds ratio, 1.75; 95% confidence interval, 1.04-2.96; P = 0.04). CONCLUSIONS: HFOV increases mortality for most patients with ARDS but may improve survival among patients with severe hypoxemia on conventional mechanical ventilation.

Australian employee perceptions of an organizational-level intervention to reduce sitting.

Stand Up Lendlease-a cluster-randomized trial targeting reductions in sitting time in Australian office workers (n = 153, 18 manager-led teams, 1 organization)-effectively reduced sitting time during work hours and across the day after 12 months. The trial included two arms: organizational-support strategies (e.g. manager support, emails) with or without an activity tracker. The current study aimed to examine participant perceptions of the intervention, and perceived barriers and facilitators for reducing sitting time. Telephone interviews (n = 50 participants; conducted at 6-10 months) and three focus groups (n = 21 participants; conducted at 16 months) evaluated the intervention with qualitative data analysed thematically. Several consistent themes emerged across both short and long-term time points and intervention groups. Support and role modelling of desired behaviours from important organization personnel and receiving feedback on sitting levels were key drivers of change. Improvements in awareness about sitting, and workplace culture changes supporting active work practices were positive impacts of the intervention, but some participants also reported that initial cultural effects had dissipated and the intervention needed 'reinvigoration'. Participants desired additional 'tools' to maintain sitting less and being active, such as sit-stand desks, standing meeting tables and activity trackers. In summary, the intervention raised awareness and initiated cultural changes towards active work practices, however, additional support may be required to maintain changes in organizational culture long term. Practical tools to support sitting changes, organizational and management support and role modelling, as well as ongoing 'reinvigoration' are key strategies for short and long-term intervention success in office workplaces.

Effect of Protocolized Weaning With Early Extubation to Noninvasive Ventilation vs Invasive Weaning on Time to Liberation From Mechanical Ventilation Among Patients With Respiratory Failure: The Breathe Randomized Clinical Trial.

Importance: In adults in whom weaning from invasive mechanical ventilation is difficult, noninvasive ventilation may facilitate early liberation, but there is uncertainty about its effectiveness in a general intensive care patient population. Objective: To investigate among patients with difficulty weaning the effects of protocolized weaning with early extubation to noninvasive ventilation on time to liberation from ventilation compared with protocolized invasive weaning. Design, Setting, and Participants: Randomized, allocation-concealed, open-label, multicenter clinical trial enrolling patients between March 2013 and October 2016 from 41 intensive care units in the UK National Health Service. Follow-up continued until April 2017. Adults who received invasive mechanical ventilation for more than 48 hours and in whom a spontaneous breathing trial failed were enrolled. Interventions: Patients were randomized to receive either protocolized weaning via early extubation to noninvasive ventilation (n = 182) or protocolized standard weaning (continued invasive ventilation until successful spontaneous breathing trial, followed by extubation) (n = 182). Main Outcomes and Measures: Primary outcome was time from randomization to successful liberation from all forms of mechanical ventilation among survivors, measured in days, with the minimal clinically important difference defined as 1 day. Secondary outcomes were duration of invasive and total ventilation (days), reintubation or tracheostomy rates, and survival. Results: Among 364 randomized patients (mean age, 63.1 [SD, 14.8] years; 50.5% male), 319 were evaluable for the primary effectiveness outcome (41 died before liberation, 2 withdrew, and 2 were discharged with ongoing ventilation). The median time to liberation was 4.3 days in the noninvasive group vs 4.5 days in the invasive group (adjusted hazard ratio, 1.1; 95% CI, 0.89-1.40). Competing risk analysis accounting for deaths had a similar result (adjusted hazard ratio, 1.1; 95% CI, 0.86-1.34). The noninvasive group received less invasive ventilation (median, 1 day vs 4 days; incidence rate ratio, 0.6; 95% CI, 0.47-0.87) and fewer total ventilator days (median, 3 days vs 4 days; incidence rate ratio, 0.8; 95% CI, 0.62-1.0). There was no significant difference in reintubation, tracheostomy rates, or survival. Adverse events occurred in 45 patients (24.7%) in the noninvasive group compared with 47 (25.8%) in the invasive group. Conclusions and Relevance: Among patients requiring mechanical ventilation in whom a spontaneous breathing trial had failed, early extubation to noninvasive ventilation did not shorten time to liberation from any ventilation. Trial Registration: ISRCTN Identifier: ISRCTN15635197.

The effect of postal questionnaire burden on response rate and answer patterns following admission to intensive care: a randomised controlled trial.

BACKGROUND: The effects of postal questionnaire burden on return rates and answers given are unclear following treatment on an intensive care unit (ICU). We aimed to establish the effects of different postal questionnaire burdens on return rates and answers given. METHODS: Design: A parallel group randomised controlled trial. We assigned patients by computer-based randomisation to one of two questionnaire packs (Group A and Group B). SETTING: Patients from 26 ICUs in the United Kingdom. INCLUSION CRITERIA: Patients who had received at least 24 h of level 3 care and were 16 years of age or older. Patients did not know that there were different questionnaire burdens. The study included 18,490 patients. 12,170 were eligible to be sent a questionnaire pack at 3 months. We sent 12,105 questionnaires (6112 to group A and 5993 to group B). INTERVENTIONS: The Group A pack contained demographic and EuroQol group 5 Dimensions 3 level (EQ-5D-3 L) questionnaires, making four questionnaire pages. The Group B pack also contained the Hospital Anxiety and Depression Score (HADS) and the Post-Traumatic Stress Disorder Check List-Civilian (PCL-C) questionnaires, making eight questionnaire pages in total. MAIN OUTCOME MEASURE: Questionnaire return rate 3 months after ICU discharge by group. RESULTS: In group A, 2466/6112 (40.3%) participants responded at 3 months. In group B 2315/ 5993 (38.6%) participants responded (difference 1.7% CI for difference 0-3.5% p = 0.053). Group A reported better functionality than group B in the EQ-5D-3 L mobility (41% versus 37% reporting no problems p = 0.003) and anxiety/depression (59% versus 55% reporting no problems p = 0.017) domains. CONCLUSIONS: In survivors of intensive care, questionnaire burden had no effect on return rates. However, questionnaire burden affected answers to the same questionnaire (EQ-5D-3 L). TRIAL REGISTRATION: ISRCTN69112866 (assigned 02/05/2006).

A dynamic early East Antarctic Ice Sheet suggested by ice-covered fjord landscapes.

The first Cenozoic ice sheets initiated in Antarctica from the Gamburtsev Subglacial Mountains and other highlands as a result of rapid global cooling ∼34 million years ago. In the subsequent 20 million years, at a time of declining atmospheric carbon dioxide concentrations and an evolving Antarctic circumpolar current, sedimentary sequence interpretation and numerical modelling suggest that cyclical periods of ice-sheet expansion to the continental margin, followed by retreat to the subglacial highlands, occurred up to thirty times. These fluctuations were paced by orbital changes and were a major influence on global sea levels. Ice-sheet models show that the nature of such oscillations is critically dependent on the pattern and extent of Antarctic topographic lowlands. Here we show that the basal topography of the Aurora Subglacial Basin of East Antarctica, at present overlain by 2-4.5 km of ice, is characterized by a series of well-defined topographic channels within a mountain block landscape. The identification of this fjord landscape, based on new data from ice-penetrating radar, provides an improved understanding of the topography of the Aurora Subglacial Basin and its surroundings, and reveals a complex surface sculpted by a succession of ice-sheet configurations substantially different from today's. At different stages during its fluctuations, the edge of the East Antarctic Ice Sheet lay pinned along the margins of the Aurora Subglacial Basin, the upland boundaries of which are currently above sea level and the deepest parts of which are more than 1 km below sea level. Although the timing of the channel incision remains uncertain, our results suggest that the fjord landscape was carved by at least two iceflow regimes of different scales and directions, each of which would have over-deepened existing topographic depressions, reversing valley floor slopes.

Evidence for elevated and spatially variable geothermal flux beneath the West Antarctic Ice Sheet.

Heterogeneous hydrologic, lithologic, and geologic basal boundary conditions can exert strong control on the evolution, stability, and sea level contribution of marine ice sheets. Geothermal flux is one of the most dynamically critical ice sheet boundary conditions but is extremely difficult to constrain at the scale required to understand and predict the behavior of rapidly changing glaciers. This lack of observational constraint on geothermal flux is particularly problematic for the glacier catchments of the West Antarctic Ice Sheet within the low topography of the West Antarctic Rift System where geothermal fluxes are expected to be high, heterogeneous, and possibly transient. We use airborne radar sounding data with a subglacial water routing model to estimate the distribution of basal melting and geothermal flux beneath Thwaites Glacier, West Antarctica. We show that the Thwaites Glacier catchment has a minimum average geothermal flux of ∼ 114 ± 10 mW/m(2) with areas of high flux exceeding 200 mW/m(2) consistent with hypothesized rift-associated magmatic migration and volcanism. These areas of highest geothermal flux include the westernmost tributary of Thwaites Glacier adjacent to the subaerial Mount Takahe volcano and the upper reaches of the central tributary near the West Antarctic Ice Sheet Divide ice core drilling site.

Two-pore Channels (TPC2s) and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) at Lysosomal-Sarcoplasmic Reticular Junctions Contribute to Acute and Chronic ß-Adrenoceptor Signaling in the Heart.

Ca(2+)-permeable type 2 two-pore channels (TPC2) are lysosomal proteins required for nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca(2+) release in many diverse cell types. Here, we investigate the importance of TPC2 proteins for the physiology and pathophysiology of the heart. NAADP-AM failed to enhance Ca(2+) responses in cardiac myocytes from Tpcn2(-/-) mice, unlike myocytes from wild-type (WT) mice. Ca(2+)/calmodulin-dependent protein kinase II inhibitors suppressed actions of NAADP in myocytes. Ca(2+) transients and contractions accompanying action potentials were increased by isoproterenol in myocytes from WT mice, but these effects of ß-adrenoreceptor stimulation were reduced in myocytes from Tpcn2(-/-) mice. Increases in amplitude of L-type Ca(2+) currents evoked by isoproterenol remained unchanged in myocytes from Tpcn2(-/-) mice showing no loss of ß-adrenoceptors or coupling mechanisms. Whole hearts from Tpcn2(-/-) mice also showed reduced inotropic effects of isoproterenol and a reduced tendency for arrhythmias following acute ß-adrenoreceptor stimulation. Hearts from Tpcn2(-/-) mice chronically exposed to isoproterenol showed less cardiac hypertrophy and increased threshold for arrhythmogenesis compared with WT controls. Electron microscopy showed that lysosomes form close contacts with the sarcoplasmic reticulum (separation ∼ 25 nm). We propose that Ca(2+)-signaling nanodomains between lysosomes and sarcoplasmic reticulum dependent on NAADP and TPC2 comprise an important element in ß-adrenoreceptor signal transduction in cardiac myocytes. In summary, our observations define a role for NAADP and TPC2 at lysosomal/sarcoplasmic reticulum junctions as unexpected but major contributors in the acute actions of ß-adrenergic signaling in the heart and also in stress pathways linking chronic stimulation of ß-adrenoceptors to hypertrophy and associated arrhythmias.

High-frequency oscillation for acute respiratory distress syndrome.

BACKGROUND: Patients with the acute respiratory distress syndrome (ARDS) require mechanical ventilation to maintain arterial oxygenation, but this treatment may produce secondary lung injury. High-frequency oscillatory ventilation (HFOV) may reduce this secondary damage. METHODS: In a multicenter study, we randomly assigned adults requiring mechanical ventilation for ARDS to undergo either HFOV with a Novalung R100 ventilator (Metran) or usual ventilatory care. All the patients had a ratio of the partial pressure of arterial oxygen (PaO) to the fraction of inspired oxygen (FiO) of 200 mm Hg (26.7 kPa) or less and an expected duration of ventilation of at least 2 days. The primary outcome was all-cause mortality 30 days after randomization. RESULTS: There was no significant between-group difference in the primary outcome, which occurred in 166 of 398 patients (41.7%) in the HFOV group and 163 of 397 patients (41.1%) in the conventional-ventilation group (P=0.85 by the chi-square test). After adjustment for study center, sex, score on the Acute Physiology and Chronic Health Evaluation (APACHE) II, and the initial PaO:FiO ratio, the odds ratio for survival in the conventional-ventilation group was 1.03 (95% confidence interval, 0.75 to 1.40; P=0.87 by logistic regression). CONCLUSIONS: The use of HFOV had no significant effect on 30-day mortality in patients undergoing mechanical ventilation for ARDS. (Funded by the National Institute for Health Research Health Technology Assessment Programme; OSCAR Current Controlled Trials number, ISRCTN10416500.).

Evidence for a water system transition beneath Thwaites Glacier, West Antarctica.

Thwaites Glacier is one of the largest, most rapidly changing glaciers on Earth, and its landward-sloping bed reaches the interior of the marine West Antarctic Ice Sheet, which impounds enough ice to yield meters of sea-level rise. Marine ice sheets with landward-sloping beds have a potentially unstable configuration in which acceleration can initiate or modulate grounding-line retreat and ice loss. Subglacial water has been observed and theorized to accelerate the flow of overlying ice dependent on whether it is hydrologically distributed or concentrated. However, the subglacial water systems of Thwaites Glacier and their control on ice flow have not been characterized by geophysical analysis. The only practical means of observing these water systems is airborne ice-penetrating radar, but existing radar analysis approaches cannot discriminate between their dynamically critical states. We use the angular distribution of energy in radar bed echoes to characterize both the extent and hydrologic state of subglacial water systems across Thwaites Glacier. We validate this approach with radar imaging, showing that substantial water volumes are ponding in a system of distributed canals upstream of a bedrock ridge that is breached and bordered by a system of concentrated channels. The transition between these systems occurs with increasing surface slope, melt-water flux, and basal shear stress. This indicates a feedback between the subglacial water system and overlying ice dynamics, which raises the possibility that subglacial water could trigger or facilitate a grounding-line retreat in Thwaites Glacier capable of spreading into the interior of the West Antarctic Ice Sheet.