Previous investigations have combined transcriptional and genetic analyses in human cell lines1-3, but few have applied these techniques to human neural tissue4-8. To gain a global molecular perspective on the role of the human genome in cortical development, function and ageing, we explore the temporal dynamics and genetic control of transcription in human prefrontal cortex in an extensive series of post-mortem brains from fetal development through ageing. We discover a wave of gene expression changes occurring during fetal development which are reversed in early postnatal life. One half-century later in life, this pattern of reversals is mirrored in ageing and in neurodegeneration. Although we identify thousands of robust associations of individual genetic polymorphisms with gene expression, we also demonstrate that there is no association between the total extent of genetic differences between subjects and the global similarity of their transcriptional profiles. Hence, the human genome produces a consistent molecular architecture in the prefrontal cortex, despite millions of genetic differences across individuals and races. To enable further discovery, this entire data set is freely available (from Gene Expression Omnibus: accession GSE30272; and dbGaP: accession phs000417.v1.p1) and can also be interrogated via a biologist-friendly stand-alone application (http://www.libd.org/braincloud).

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Objective To determine if a quality improvement (QI) intervention improves sleep and delirium/cognition. Design Observational, pre-post design. Setting A tertiary academic hospital in the US. Patients 300 medical ICU (MICU) patients. Interventions This MICU-wide project involved a “usual care” baseline stage, followed by a QI stage incorporating multi-faceted sleep-promoting interventions implemented with the aid of daily reminder checklists for ICU staff. Measurements and Main Results Primary ICU outcomes were perceived sleep quality and noise ratings (measured on a 0-100 scale using the valid and reliable Richards-Campbell Sleep Questionnaire [RCSQ]) and delirium/coma-free days. Secondary outcomes included ICU and hospital length of stay and mortality. Post-ICU measures of cognition and perceived sleep quality were evaluated in an ICU patient subset. During the baseline and sleep QI stages there were 122 and 178 patients, respectively, with >1 night in the ICU, accounting for 634 and 826 patient-days. Within the groups, 78 (63.9%) and 83 (46.6%) patients received mechanical ventilation. Over the 826 patient-day QI period, checklist item completion rates ranged from 86-94%. In multivariable regression analysis of the QI vs. baseline stages, improvements in overall RCSQ sleep quality ratings did not reach statistical significance, but there were significant improvements in daily noise ratings (mean ± standard deviation: 65.9 ± 26.6 vs. 60.5 ± 26.3, P=0.001), incidence of delirium/coma (odds ratio: 0.46; 95% confidence interval, 0.23-0.89; P=0.02), and daily delirium/coma-free status (odds ratio: 1.64; 95% confidence interval, 1.04-2.58; P=0.03). Improvements in secondary ICU outcomes and post-ICU outcomes did not reach statistical significance. Conclusions An ICU-wide QI intervention to improve sleep and delirium is feasible and associated with significant improvements in perceived nighttime noise, incidence of delirium/coma, and daily delirium/coma-free status. Improvement in perceived sleep quality did not reach statistical significance.

Objective To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury.Design Prospective cohort study.Setting 13 intensive care units at four hospitals in Baltimore, Maryland, USA.Participants 485 consecutive mechanically ventilated patients with acute lung injury.Main outcome measure Two year survival after onset of acute lung injury.Results 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011).Conclusions Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury.Trial registration Clinicaltrials.gov NCT00300248. IntroductionSurvivors of severe critical illness, such as acute lung injury, and its more severe subset, acute respiratory distress syndrome (ARDS), commonly experience increased mortality and morbidity in the months and years after hospital discharge. [1][2][3] Compared with age matched and sex matched controls, patients discharged from intensive care are two to five times more likely to die during three to 15 years' follow-up. 3 Few interventions have been evaluated for improving this increased long term mortality. 4 Randomised trials and meta-analyses have shown that use of volume limited and pressure limited mechanical ventilation (lung protective ventilation) in patients with acute lung injury substantially decreases short term mortality. [5][6][7][8][9] A randomised trial of lung protective ventilation carried out by the ARDS Network 8 found an 8.8% absolute reduction in short term mortality. This trial evaluated a ventilator tidal volume of 6 mL/kg predicted body weight (calculated on the basis of a patient's sex and height 8 ) and a plateau pressure (airway pressure measured after a 0.5 second end inspiratory pause) of ≤30 cm of water compared with a tidal volume of 12 mL/kg predicted body weight and a plateau pressure of ≤50 cm of water. Understanding the effect of lung protective ventilation on long term survival is important, 4 5 especially since critical care interventions with a mortality benefit at hospital dischar...

Obesity is not associated with increased risk for ICU mortality, but may be associated with lower hospital mortality. There is a critical lack of research on how obesity may affect complications of critical illness and patient long-term outcomes.

Rationale: Reducing tidal volume decreases mortality in acute respiratory distress syndrome (ARDS). However, the effect of the timing of low tidal volume ventilation is not well understood.Objectives: To evaluate the association of intensive care unit (ICU) mortality with initial tidal volume and with tidal volume change over time.Methods: Multivariable, time-varying Cox regression analysis of a multisite, prospective study of 482 patients with ARDS with 11,558 twice-daily tidal volume assessments (evaluated in milliliter per kilogram of predicted body weight [PBW]) and daily assessment of other mortality predictors.Measurements and Main Results: An increase of 1 ml/kg PBW in initial tidal volume was associated with a 23% increase in ICU mortality risk (adjusted hazard ratio, 1.23; 95% confidence interval [CI], 1.06-1.44; P = 0.008). Moreover, a 1 ml/kg PBW increase in subsequent tidal volumes compared with the initial tidal volume was associated with a 15% increase in mortality risk (adjusted hazard ratio, 1.15; 95% CI, 1.02-1.29; P = 0.019). Compared with a prototypical patient receiving 8 days with a tidal volume of 6 ml/kg PBW, the absolute increase in ICU mortality (95% CI) of receiving 10 and 8 ml/kg PBW, respectively, across all 8 days was 7.2% (3.0-13.0%) and 2.7% (1.2-4.6%). In scenarios with variation in tidal volume over the 8-day period, mortality was higher when a larger volume was used earlier.Conclusions: Higher tidal volumes shortly after ARDS onset were associated with a greater risk of ICU mortality compared with subsequent tidal volumes. Timely recognition of ARDS and adherence to low tidal volume ventilation is important for reducing mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00300248).

OBJECTIVE:To determine whether a multidisciplinary mobility promotion quality-improvement (QI) project would increase patient mobility and reduce hospital length of stay (LOS). PATIENTS AND METHODS:Implemented using a structured QI model, the project took place between March 1, 2013 and March 1, 2014 on 2 general medicine units in a large academic medical center. There were 3352 patients admitted during the QI project period. The Johns Hopkins Highest Level of Mobility (JH-HLM) scale, an 8-point ordinal scale ranging from bed rest (score 5 1) to ambulating 250 feet (score 5 8), was used to quantify mobility. Changes in JH-HLM scores were compared for the first 4 months of the project (ramp-up phase) versus 4 months after project completion (post-QI phase) using generalized estimating equations. We compared the relative change in median LOS for the project months versus 12 months prior among the QI units, using multivariable linear regression analysis adjusting for 7 demographic and clinically relevant variables. RESULTS:Comparing the ramp-up versus post-QI phases, patients reaching JH-HLM's ambulation status increased from 43% to 70% (P < 0.001), and patients with improved JH-HLM mobility scores between admission and discharge increased from 32% to 45% (P < 0.001). For all patients, the QI project was associated with an adjusted median LOS reduction of 0.40 (95% confidence interval [CI]: 20.57 to 20.21, P < 0.001) days compared to 12 months prior. A subgroup of patients expected to have a longer LOS (expected LOS >7 days), were associated with a significantly greater adjusted median reduction in LOS of 1.11 (95% CI: 21.53 to 20.65, P < 0.001) days. Increased mobility was not associated with an increase in injurious falls compared to 12 months prior on the QI units (P 5 0.73).

Our data suggest that as many as 40,500 adult patients in an ICU in USA may die with an ICU misdiagnoses annually. Despite this, diagnostic errors receive relatively little attention and research funding. Future studies should seek to prospectively measure the prevalence and impact of diagnostic errors and potential strategies to reduce them.