Mark E. Mikkelsen

To study the association between time to antibiotic administration and survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department.Single-center cohort study.The emergency department of an academic tertiary care center from 2005 through 2006.Two hundred sixty-one patients undergoing early goal-directed therapy.None.Effects of different time cutoffs from triage to antibiotic administration, qualification for early goal-directed therapy to antibiotic administration, triage to appropriate antibiotic administration, and qualification for early goal-directed therapy to appropriate antibiotic administration on in-hospital mortality were examined. The mean age of the 261 patients was 59 +/- 16 yrs; 41% were female. In-hospital mortality was 31%. Median time from triage to antibiotics was 119 mins (interquartile range, 76-192 mins) and from qualification to antibiotics was 42 mins (interquartile range, 0-93 mins). There was no significant association between time from triage or time from qualification for early goal-directed therapy to antibiotics and mortality when assessed at different hourly cutoffs. When analyzed for time from triage to appropriate antibiotics, there was a significant association at the <1 hr (mortality 19.5 vs. 33.2%; odds ratio, 0.30 [95% confidence interval, 0.11-0.83]; p = .02) time cutoff; similarly, for time from qualification for early goal-directed therapy to appropriate antibiotics, a significant association was seen at the < or =1 hr (mortality 25.0 vs. 38.5%; odds ratio, 0.50 [95% confidence interval, 0.27-0.92]; p = .03) time cutoff.Elapsed times from triage and qualification for early goal-directed therapy to administration of appropriate antimicrobials are primary determinants of mortality in patients with severe sepsis and septic shock treated with early goal-directed therapy.

Serum lactate is a potentially useful biomarker to risk-stratify patients with severe sepsis; however, it is plausible that elevated serum lactate is simply a manifestation of clinically apparent organ dysfunction and/or shock (i.e., refractory hypotension).To test whether the association between initial serum lactate level and mortality in patients presenting to the emergency department (ED) with severe sepsis is independent of organ dysfunction and shock.Single-center cohort study. The primary outcome was 28-day mortality and the risk factor variable was initial venous lactate (mmol/L), categorized as low (< 2), intermediate (2-3.9), or high (> or = 4). Potential covariates included age, sex, race, acute and chronic organ dysfunction, severity of illness, and initiation of early goal-directed therapy. Multivariable logistic regression analyses were stratified on the presence or absence of shock.The ED of an academic tertiary care center from 2005 to 2007.Eight hundred thirty adults admitted with severe sepsis in the ED.None.Mortality at 28 days was 22.9% and median serum lactate was 2.9 mmol/L. Intermediate (odds ratio [OR] = 2.05, p = 0.024) and high serum lactate levels (OR = 4.87, p < 0.001) were associated with mortality in the nonshock subgroup. In the shock subgroup, intermediate (OR = 3.27, p = 0.022) and high serum lactate levels (OR = 4.87, p = 0.001) were also associated with mortality. After adjusting for potential confounders, intermediate and high serum lactate levels remained significantly associated with mortality within shock and nonshock strata.Initial serum lactate was associated with mortality independent of clinically apparent organ dysfunction and shock in patients admitted to the ED with severe sepsis. Both intermediate and high serum lactate levels were independently associated with mortality.

Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies.To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS).In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions.Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7).ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772).

Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking.To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment.As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post-hospital discharge.Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02).Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation.

The coronavirus disease 2019 (COVID-19) pandemic challenges hospital leaders to make time-sensitive, critical decisions about clinical operations and resource allocations.To estimate the timing of surges in clinical demand and the best- and worst-case scenarios of local COVID-19-induced strain on hospital capacity, and thus inform clinical operations and staffing demands and identify when hospital capacity would be saturated.Monte Carlo simulation instantiation of a susceptible, infected, removed (SIR) model with a 1-day cycle.3 hospitals in an academic health system.All people living in the greater Philadelphia region.The COVID-19 Hospital Impact Model (CHIME) (http://penn-chime.phl.io) SIR model was used to estimate the time from 23 March 2020 until hospital capacity would probably be exceeded, and the intensity of the surge, including for intensive care unit (ICU) beds and ventilators.Using patients with COVID-19 alone, CHIME estimated that it would be 31 to 53 days before demand exceeds existing hospital capacity. In best- and worst-case scenarios of surges in the number of patients with COVID-19, the needed total capacity for hospital beds would reach 3131 to 12 650 across the 3 hospitals, including 338 to 1608 ICU beds and 118 to 599 ventilators.Model parameters were taken directly or derived from published data across heterogeneous populations and practice environments and from the health system's historical data. CHIME does not incorporate more transition states to model infection severity, social networks to model transmission dynamics, or geographic information to account for spatial patterns of human interaction.Publicly available and designed for hospital operations leaders, this modeling tool can inform preparations for capacity strain during the early days of a pandemic.University of Pennsylvania Health System and the Palliative and Advanced Illness Research Center.

Background: After critical illness, new or worsening impairments in physical, cognitive, and/or mental health function are common among patients who have survived. Who should be screened for long-term impairments, what tools to use, and when remain unclear. Objectives: Provide pragmatic recommendations to clinicians caring for adult survivors of critical illness related to screening for postdischarge impairments. Participants: Thirty-one international experts in risk-stratification and assessment of survivors of critical illness, including practitioners involved in the Society of Critical Care Medicine’s Thrive Post-ICU Collaboratives, survivors of critical illness, and clinical researchers. Design: Society of Critical Care Medicine consensus conference on post-intensive care syndrome prediction and assessment, held in Dallas, in May 2019. A systematic search of PubMed and the Cochrane Library was conducted in 2018 and updated in 2019 to complete an original systematic review and to identify pre-existing systematic reviews. Meeting Outcomes: We concluded that existing tools are insufficient to reliably predict post-intensive care syndrome. We identified factors before (e.g., frailty, preexisting functional impairments), during (e.g., duration of delirium, sepsis, acute respiratory distress syndrome), and after (e.g., early symptoms of anxiety, depression, or post-traumatic stress disorder) critical illness that can be used to identify patients at high-risk for cognitive, mental health, and physical impairments after critical illness in whom screening is recommended. We recommend serial assessments, beginning within 2–4 weeks of hospital discharge, using the following screening tools: Montreal Cognitive Assessment test; Hospital Anxiety and Depression Scale; Impact of Event Scale-Revised (post-traumatic stress disorder); 6-minute walk; and/or the EuroQol-5D-5L, a health-related quality of life measure (physical function). Conclusions: Beginning with an assessment of a patient’s pre-ICU functional abilities at ICU admission, clinicians have a care coordination strategy to identify and manage impairments across the continuum. As hospital discharge approaches, clinicians should use brief, standardized assessments and compare these results to patient’s pre-ICU functional abilities (“functional reconciliation”). We recommend serial assessments for post-intensive care syndrome-related problems continue within 2–4 weeks of hospital discharge, be prioritized among high-risk patients, using the identified screening tools to prompt referrals for services and/or more detailed assessments.

Increasing numbers of intensive care units (ICUs) are adopting the practice of nighttime intensivist staffing despite the lack of experimental evidence of its effectiveness.We conducted a 1-year randomized trial in an academic medical ICU of the effects of nighttime staffing with in-hospital intensivists (intervention) as compared with nighttime coverage by daytime intensivists who were available for consultation by telephone (control). We randomly assigned blocks of 7 consecutive nights to the intervention or the control strategy. The primary outcome was patients' length of stay in the ICU. Secondary outcomes were patients' length of stay in the hospital, ICU and in-hospital mortality, discharge disposition, and rates of readmission to the ICU. For length-of-stay outcomes, we performed time-to-event analyses, with data censored at the time of a patient's death or transfer to another ICU.A total of 1598 patients were included in the analyses. The median Acute Physiology and Chronic Health Evaluation (APACHE) III score (in which scores range from 0 to 299, with higher scores indicating more severe illness) was 67 (interquartile range, 47 to 91), the median length of stay in the ICU was 52.7 hours (interquartile range, 29.0 to 113.4), and mortality in the ICU was 18%. Patients who were admitted on intervention days were exposed to nighttime intensivists on more nights than were patients admitted on control days (median, 100% of nights [interquartile range, 67 to 100] vs. median, 0% [interquartile range, 0 to 33]; P<0.001). Nonetheless, intensivist staffing on the night of admission did not have a significant effect on the length of stay in the ICU (rate ratio for the time to ICU discharge, 0.98; 95% confidence interval [CI], 0.88 to 1.09; P=0.72), ICU mortality (relative risk, 1.07; 95% CI, 0.90 to 1.28), or any other end point. Analyses restricted to patients who were admitted at night showed similar results, as did sensitivity analyses that used different definitions of exposure and outcome.In an academic medical ICU in the United States, nighttime in-hospital intensivist staffing did not improve patient outcomes. (Funded by University of Pennsylvania Health System and others; ClinicalTrials.gov number, NCT01434823.).

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

Processing and quantitative analysis of magnetic resonance spectroscopy (MRS) data are far from standardized and require interfacing with third-party software. Here, we present Osprey, a fully integrated open-source data analysis pipeline for MRS data, with seamless integration of pre-processing, linear-combination modelling, quantification, and data visualization. Osprey loads multiple common MRS data formats, performs phased-array coil combination, frequency-and phase-correction of individual transients, signal averaging and Fourier transformation. Linear combination modelling of the processed spectrum is carried out using simulated basis sets and a spline baseline. The MRS voxel is coregistered to an anatomical image, which is segmented for tissue correction and quantification is performed based upon modelling parameters and tissue segmentation. The results of each analysis step are visualized in the Osprey GUI. The analysis pipeline is demonstrated in 12 PRESS, 11 MEGA-PRESS, and 8 HERMES datasets acquired in healthy subjects. Osprey successfully loads, processes, models, and quantifies MRS data acquired with a variety of conventional and spectral editing techniques. Osprey is the first MRS software to combine uniform pre-processing, linear-combination modelling, tissue correction and quantification into a coherent ecosystem. Compared to existing compiled, often closed-source modelling software, Osprey’s open-source code philosophy allows researchers to integrate state-of-the-art data processing and modelling routines, and potentially converge towards standardization of analysis. Osprey combines robust, peer-reviewed data processing methods into a modular workflow that is easily augmented by community developers, allowing the rapid implementation of new methods.

The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally.To describe the epidemiology of COVID-19-related critical illness, including trends in outcomes and care delivery.Single-health system, multihospital retrospective cohort study.5 hospitals within the University of Pennsylvania Health System.Adults with COVID-19-related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic.The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions.Among 468 patients with COVID-19-related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change.Single-health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications.Among patients with COVID-19-related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms.Agency for Healthcare Research and Quality.

Background: Little is known about recovery from coronavirus disease 2019 (COVID-19) after hospital discharge. Objective: To describe the home health recovery of patients with COVID-19 and risk factors associated with rehospitalization or death. Design: Retrospective observational cohort. Setting: New York City. Participants: 1409 patients with COVID-19 admitted to home health care (HHC) between 1 April and 15 June 2020 after hospitalization. Measurements: Covariates and outcomes were obtained from the mandated OASIS (Outcome and Assessment Information Set). Cox proportional hazards models were used to estimate the hazard ratio (HR) of risk factors associated with rehospitalization or death. Results: After an average of 32 days in HHC, 94% of patients were discharged and most achieved statistically significant improvements in symptoms and function. Activity-of-daily-living dependencies decreased from an average of 6 (95% CI, 5.9 to 6.1) to 1.2 (CI, 1.1 to 1.3). Risk for rehospitalization or death was higher for male patients (HR, 1.45 [CI, 1.04 to 2.03]); White patients (HR, 1.74 [CI, 1.22 to 2.47]); and patients with heart failure (HR, 2.12 [CI, 1.41 to 3.19]), diabetes with complications (HR, 1.71 [CI, 1.17 to 2.52]), 2 or more emergency department visits in the past 6 months (HR, 1.78 [CI, 1.21 to 2.62]), pain daily or all the time (HR, 1.46 [CI, 1.05 to 2.05]), cognitive impairment (HR, 1.49 [CI, 1.04 to 2.13]), or functional dependencies (HR, 1.09 [CI, 1.00 to 1.20]). Eleven patients (1%) died, 137 (10%) were rehospitalized, and 23 (2%) remain on service. Limitations: Care was provided by 1 home health agency. Information on rehospitalization and death after HHC discharge is not available. Conclusion: Symptom burden and functional dependence were common at the time of HHC admission but improved for most patients. Comorbid conditions of heart failure and diabetes, as well as characteristics present at admission, identified patients at greatest risk for an adverse event. Primary Funding Source: No direct funding.

To determine the frequency of use of low-tidal-volume ventilation in appropriate patients with acute lung injury (ALI) and the factors associated with the choice of tidal volume.Prospective observational cohort study of patients identified with ALI or acute respiratory distress syndrome from September 2000 to November 2002.Medical and surgical intensive care unit (ICU) at an academic tertiary-care hospital.Measurements included the proportion for whom the ventilation tidal volume (TV) was <or=7.5 mL/kg predicted body weight (PBW) on days 2, 4, and 7 of ALI and the proportion for whom the ventilation TV was <or=6.5 and <or=8.5 mL/kg/PBW (sensitivity analysis). Demographic and clinical characteristics of patients undergoing ventilation with low and high TV were compared. Of 88 total patients studied, 39% had ventilation with TV <or=7.5 mL/kg/PBW on day 2 of ALI, 49% on day 4, and 56% on day 7. In contrast, 49% of patients had ventilation with TV >8.5 mL/kg/PBW on day 2 of ALI, 30% on day 4, and 24% on day 7. The use of low TV was significantly associated with clinical parameters indicative of worse disease severity, including low values for Pao2 (p = .01), Pao2/Fio2 (p = .08), and static compliance of the respiratory system (p = .006).Ventilation with a low TV was used in a minority of patients with ALI, despite results published in 1998 and 2000 supporting this approach. This may be related to clinicians' underrecognition of less severe cases of ALI, their reserving of low-TV ventilation for more severe cases, or both.

Early recognition and timely intervention significantly reduce sepsis-related mortality.Describe the development, implementation, and impact of an early warning and response system (EWRS) for sepsis.After tool derivation and validation, a preimplementation/postimplementation study with multivariable adjustment measured impact.Urban academic healthcare system.Adult non-ICU patients admitted to acute inpatient units from October 1, 2011 to October 31, 2011 for tool derivation, June 6, 2012 to July 5, 2012 for tool validation, and June 6, 2012 to September 4, 2012 and June 6, 2013 to September 4, 2013 for the preimplementation/postimplementation analysis.An EWRS in our electronic health record monitored laboratory values and vital signs in real time. If a patient had ≥4 predefined abnormalities at any single time, the provider, nurse, and rapid response coordinator were notified and performed an immediate bedside patient evaluation.Screen positive rates, test characteristics, predictive values, and likelihood ratios; system utilization; and resulting changes in processes and outcomes.The tool's screen positive, sensitivity, specificity, and positive and negative predictive values and likelihood ratios for our composite of intensive care unit (ICU) transfer, rapid response team call, or death in the derivation cohort was 6%, 16%, 97%, 26%, 94%, 5.3, and 0.9, respectively. Validation values were similar. The EWRS resulted in a statistically significant increase in early sepsis care, ICU transfer, and sepsis documentation, and decreased sepsis mortality and increased discharge to home, although neither of these latter 2 findings reached statistical significance.An automated prediction tool identified at-risk patients and prompted a bedside evaluation resulting in more timely sepsis care, improved documentation, and a suggestion of reduced mortality.

Background: Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis, and sepsis-associated ARDS is associated with significant morbidity and mortality. To date, no study has directly examined the epidemiology of ARDS in severe sepsis from the earliest presentation to the health care system, the emergency department (ED). Methods: This was a single-center retrospective, observational cohort study of 778 adults with severe sepsis presenting to the ED. The primary outcome was the development of ARDS requiring mechanical ventilation during the first 5 hospital days. Acute respiratory distress syndrome was defined using the Berlin definition. We used multivariable logistic regression to identify risk factors associated independently with ARDS development. Results: The incidence of ARDS was 6.2% (48/778 patients) in the entire cohort. Acute respiratory distress syndrome development varied across the continuum of care: 0.9% of patients fulfilled criteria for ARDS in the ED, 1.4% admitted to the ward developed ARDS, and 8.9% admitted to the intensive care unit developed ARDS. Acute respiratory distress syndrome developed a median of 1 day after admission and was associated with a 4-fold higher risk of in-hospital mortality (14% vs. 60%, P < 0.001). Independent risk factors associated with increased risk of ARDS development included intermediate (2–3.9 mmol/L) (P = 0.04) and high (≥4) serum lactate levels (P = 0.008), Lung Injury Prediction score (P < 0.001), and microbiologically proven infection (P = 0.01). Conclusions: In patients presenting to the ED with severe sepsis, the rate of sepsis-associated ARDS development varied across the continuum of care. Acute respiratory distress syndrome developed rapidly and was associated with significant mortality. Elevated serum lactate levels in the ED and a recently validated clinical prediction score were independently associated with the development of ARDS in severe sepsis.

The epidemiology of severe sepsis is derived from administrative databases that rely on International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to select cases. We compared the sensitivity of two code abstraction methods in identifying severe sepsis cases using a severe sepsis registry.Single-center retrospective cohort study.Tertiary care, Academic, University Hospital.One thousand seven hundred thirty-five patients with severe sepsis or septic shock.None.Proportion identified as severe sepsis using two code abstraction methods: 1) the new specific ICD-9 codes for severe sepsis and septic shock, and 2) a validated method requiring two ICD-9 codes for infection and end-organ dysfunction. Multivariable logistic regression was performed to determine sociodemographics and clinical characteristics associated with documentation and coding accuracy.The strategy combining a code for infection and end-organ dysfunction was more sensitive in identifying cases than the method requiring specific ICD-9 codes for severe sepsis or septic shock (47% vs. 21%). Elevated serum lactate level (p<0.001), ICU admission (p<0.001), presence of shock (p<0.001), bacteremia as the source of sepsis (p=0.02), and increased Acute Physiology and Chronic Health Evaluation II score (p<0.001) were independently associated with being appropriately documented and coded. The 28-day mortality was significantly higher in those who were accurately documented/coded (41%, compared with 14% in those who were not, p<0.001), reflective of a more severe presentation on admission.Patients admitted with severe sepsis and septic shock were incompletely documented and under-coded, using either ICD-9 code abstracting method. Documentation of subsequent coding of severe sepsis was more common in more severely ill patients. These findings are important when evaluating current national estimates and when interpreting epidemiologic studies of severe sepsis as cohorts derived from claims-based strategies appear to be biased toward a more severely ill patient population.

Intensive care unit (ICU)-based randomized clinical trials (RCTs) among adult critically ill patients commonly fail to detect treatment benefits.Appraise the rates of success, outcomes used, statistical power, and design characteristics of published trials.One hundred forty-six ICU-based RCTs of diagnostic, therapeutic, or process/systems interventions published from January 2007 to May 2013 in 16 high-impact general or critical care journals were studied.Of 146 RCTs, 54 (37%) were positive (i.e., the a priori hypothesis was found to be statistically significant). The most common primary outcomes were mortality (n = 40 trials), infection-related outcomes (n = 33), and ventilation-related outcomes (n = 30), with positive results found in 10, 58, and 43%, respectively. Statistical power was discussed in 135 RCTs (92%); 92 cited a rationale for their power parameters. Twenty trials failed to achieve at least 95% of their reported target sample size, including 11 that were stopped early due to insufficient accrual/logistical issues. Of 34 superiority RCTs comparing mortality between treatment arms, 13 (38%) accrued a sample size large enough to find an absolute mortality reduction of 10% or less. In 22 of these trials the observed control-arm mortality rate differed from the predicted rate by at least 7.5%.ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects, particularly when using mortality as the primary outcome. Additional concerns include a lack of standardized methods for assessing common outcomes, unclear justifications for statistical power calculations, insufficient patient accrual, and incorrect predictions of baseline event rates.

Predictions of long-term survival and functional outcomes influence decision making for critically ill patients, yet little is known regarding their accuracy.To determine the discriminative accuracy of intensive care unit (ICU) physicians and nurses in predicting 6-month patient mortality and morbidity, including ambulation, toileting, and cognition.Prospective cohort study conducted in 5 ICUs in 3 hospitals in Philadelphia, Pennsylvania, and enrolling patients who spent at least 3 days in the ICU from October 2013 until May 2014 and required mechanical ventilation, vasopressors, or both. These patients' attending physicians and bedside nurses were also enrolled. Follow-up was completed in December 2014.ICU physicians' and nurses' binary predictions of in-hospital mortality and 6-month outcomes, including mortality, return to original residence, ability to toilet independently, ability to ambulate up 10 stairs independently, and ability to remember most things, think clearly, and solve day-to-day problems (ie, normal cognition). For each outcome, physicians and nurses provided a dichotomous prediction and rated their confidence in that prediction on a 5-point Likert scale. Outcomes were assessed via interviews with surviving patients or their surrogates at 6 months. Discriminative accuracy was measured using positive and negative likelihood ratios (LRs), C statistics, and other operating characteristics.Among 340 patients approached, 303 (89%) consented (median age, 62 years [interquartile range, 53-71]; 57% men; 32% African American); 6-month follow-up was completed for 299 (99%), of whom 169 (57%) were alive. Predictions were made by 47 physicians and 128 nurses. Physicians most accurately predicted 6-month mortality (positive LR, 5.91 [95% CI, 3.74-9.32]; negative LR, 0.41 [95% CI, 0.33-0.52]; C statistic, 0.76 [95% CI, 0.72-0.81]) and least accurately predicted cognition (positive LR, 2.36 [95% CI, 1.36-4.12]; negative LR, 0.75 [95% CI, 0.61-0.92]; C statistic, 0.61 [95% CI, 0.54-0.68]). Nurses most accurately predicted in-hospital mortality (positive LR, 4.71 [95% CI, 2.94-7.56]; negative LR, 0.61 [95% CI, 0.49-0.75]; C statistic, 0.68 [95% CI, 0.62-0.74]) and least accurately predicted cognition (positive LR, 1.50 [95% CI, 0.86-2.60]; negative LR, 0.88 [95% CI, 0.73-1.06]; C statistic, 0.55 [95% CI, 0.48-0.62]). Discriminative accuracy was higher when physicians and nurses were confident about their predictions (eg, for physicians' confident predictions of 6-month mortality: positive LR, 33.00 [95% CI, 8.34-130.63]; negative LR, 0.18 [95% CI, 0.09-0.35]; C statistic, 0.90 [95% CI, 0.84-0.96]). Compared with a predictive model including objective clinical variables, a model that also included physician and nurse predictions had significantly higher discriminative accuracy for in-hospital mortality, 6-month mortality, and return to original residence (P < .01 for all).ICU physicians' and nurses' discriminative accuracy in predicting 6-month outcomes of critically ill patients varied depending on the outcome being predicted and confidence of the predictors. Further research is needed to better understand how clinicians derive prognostic estimates of long-term outcomes.

In-hospital cardiac arrest (IHCA) is a major public health problem with significant mortality. A better understanding of where IHCA occurs in hospitals (intensive care unit [ICU] versus monitored ward [telemetry] versus unmonitored ward) could inform strategies for reducing preventable deaths.This is a retrospective study of adult IHCA events in the Get with the Guidelines-Resuscitation database from January 2003 to September 2010. Unadjusted analyses were used to characterize patient, arrest, and hospital-level characteristics by hospital location of arrest (ICU versus inpatient ward). IHCA event rates and outcomes were plotted over time by arrest location. Among 85 201 IHCA events at 445 hospitals, 59% (50 514) occurred in the ICU compared to 41% (34 687) on the inpatient wards. Compared to ward patients, ICU patients were younger (64±16 years versus 69±14; P<0.001) and more likely to have a presenting rhythm of ventricular tachycardia/ventricular fibrillation (21% versus 17%; P<0.001). In the ICU, mean event rate/1000 bed-days was 0.337 (±0.215) compared with 0.109 (±0.079) for telemetry wards and 0.134 (±0.098) for unmonitored wards. Of patients with an arrest in the ICU, the adjusted mean survival to discharge was 0.140 (0.037) compared with the unmonitored wards 0.106 (0.037) and telemetry wards 0.193 (0.074). More IHCA events occurred in the ICU compared to the inpatient wards and there was a slight increase in events/1000 patient bed-days in both locations.Survival rates vary based on location of IHCA. Optimizing patient assignment to unmonitored wards versus telemetry wards may contribute to improved survival after IHCA.

Rationale: Post-intensive care syndrome (PICS), defined as new or worsening impairment in cognition, mental health, or physical function after critical illness, is an important development in survivors.Although studies to date have focused on the frequency of these impairments, fundamental questions remain unanswered regarding the survivor experience and the impact of the critical illness event on survivor resilience and recovery.Objectives: To examine the association between resilience and neuropsychological and physical function and to contextualize these findings within the survivors' recovery experience.Methods: We conducted a mixed-methods pilot investigation of resilience among 43 survivors from two medical intensive care units (ICUs) within an academic health-care system.We interviewed survivors to identify barriers to and facilitators of recovery in the ICU, on the medical ward, and at home, using qualitative methods.We used a telephone battery of standardized tests to examine resilience, neuropsychological and physical function, and quality of life.We examined PICS in two ways.First, we identified how frequently survivors were impaired in one or more domains 6-12 months postdischarge.Second, we identified how frequently survivors reported that neuropsychological or physical function was worse. Measurements and Main Results:Resilience was low in 28% of survivors, normal in 63% of survivors, and high in 9% of survivors.Resilience was inversely correlated with self-reported executive dysfunction, symptoms of anxiety, depression, and post-traumatic stress disorder, difficulty with self-care, and pain (P , 0.05).PICS was present in 36 survivors (83.7%; 95% confidence interval, 69.3-93.2%),whereas 23 survivors (53.5%; 95% confidence interval, 37.6-68.8%)reported worsening of neuropsychological or physical function after critical illness.We identified challenges along the recovery path of ICU survivors, finding that physical limitations and functional dependence were the most frequent challenges experienced in the ICU, medical ward, and on return to home.Spiritual and family support facilitated recovery.Conclusions: Resilience was inversely correlated with neuropsychological impairment, pain, and difficulty with self-care.PICS was present in most survivors of critical illness, and 54% reported neuropsychological or physical function to be worse, yet resilience was normal or high in most survivors.Survivors experienced many challenges during recovery, while spiritual and family support facilitated recovery.

Sensory processing abnormalities are among the most common behavioral phenotypes seen in autism spectrum disorder (ASD), typically characterized by either over- or under-responsiveness to stimulation. In this review, we focus on tactile processing dysfunction in ASD. We firstly review clinical studies wherein sensitivity to tactile stimuli has traditionally been assessed by self-, parent- and experimenter-reports. We also discuss recent investigations using psychophysical paradigms that gauge individual tactile thresholds. These more experimentally rigorous studies allow for more objective assessments of tactile abnormalities in ASD. However, little is understood about the neurobiological mechanisms underlying these abnormalities, or the link between tactile abnormalities and ASD symptoms. Neurobiological research that has been conducted has pointed toward dysfunction in the excitation/inhibition balance of the central nervous system of those with ASD. This review covers recent efforts that have investigated tactile dysfunction in ASD from clinical and behavioral perspectives, and some of the efforts to link these to neurobiology. On the whole, findings are inconsistent, which can be ascribed to the subjectivity of clinical assessments, the heterogeneity of ASD cohorts, and the diversity of tactile sensitivity measures. Future endeavors into understanding tactile processing differences in ASD will greatly benefit from controlled experiments driven by neurobiological hypotheses.

Rationale:The epidemiology of post-acute care use and hospital readmission after sepsis remains largely unknown.Objectives: To examine the rate of post-acute care use and hospital readmission after sepsis and to examine risk factors and outcomes for hospital readmissions after sepsis. Methods:In an observational cohort study conducted in an academic health care system (2010-2012), we compared post-acute care use at discharge and hospital readmission after 3,620 sepsis hospitalizations with 108,958 nonsepsis hospitalizations.We used three validated, claims-based approaches to identify sepsis and severe sepsis.Measurements and Main Results: Post-acute care use at discharge was more likely after sepsis, driven by skilled care facility placement (35.4% after sepsis vs. 15.8%;P , 0.001), with the highest rate observed after severe sepsis.Readmission rates at 7, 30, and 90 days were higher postsepsis (P , 0.001).Compared with nonsepsis hospitalizations (15.6% readmitted within 30 d), the increased readmission risk was present regardless of sepsis severity (27.3% after sepsis and 26.0-26.2%after severe sepsis).After controlling for presepsis characteristics, the readmission risk was found to be 1.51 times greater (95% CI, 1.38-1.66)than nonsepsis hospitalizations.Readmissions after sepsis were more likely to result in death or transition to hospice care (6.1% vs. 13.3% after sepsis; P , 0.001).Independent risk factors associated with 30-day readmissions after sepsis hospitalizations included age, malignancy diagnosis, hospitalizations in the year prior to the index hospitalization, nonelective index admission type, one or more procedures during the index hospitalization, and low hemoglobin and high red cell distribution width at discharge. Conclusions:Post-acute care use and hospital readmissions were common after sepsis.The increased readmission risk after sepsis was observed regardless of sepsis severity and was associated with adverse readmission outcomes.

Objectives: Data are lacking regarding implementation of novel strategies such as follow-up clinics and peer support groups, to reduce the burden of postintensive care syndrome. We sought to discover enablers that helped hospital-based clinicians establish post-ICU clinics and peer support programs, and identify barriers that challenged them. Design: Qualitative inquiry. The Consolidated Framework for Implementation Research was used to organize and analyze data. Setting: Two learning collaboratives (ICU follow-up clinics and peer support groups), representing 21 sites, across three continents. Subjects: Clinicians from 21 sites. Measurement and Main Results: Ten enablers and nine barriers to implementation of “ICU follow-up clinics” were described. A key enabler to generate support for clinics was providing insight into the human experience of survivorship, to obtain interest from hospital administrators. Significant barriers included patient and family lack of access to clinics and clinic funding. Nine enablers and five barriers to the implementation of “peer support groups” were identified. Key enablers included developing infrastructure to support successful operationalization of this complex intervention, flexibility about when peer support should be offered, belonging to the international learning collaborative. Significant barriers related to limited attendance by patients and families due to challenges in creating awareness, and uncertainty about who might be appropriate to attend and target in advertising. Conclusions: Several enablers and barriers to implementing ICU follow-up clinics and peer support groups should be taken into account and leveraged to improve ICU recovery. Among the most important enablers are motivated clinician leaders who persist to find a path forward despite obstacles.

Critically ill patients require significant time and care coordination in the emergency department (ED). We hypothesized that ED crowding would delay time to intravenous fluids and antibiotics, decrease utilization of protocolized care, and increase mortality for patients with severe sepsis or septic shock.This was a retrospective cohort study of severe sepsis patients admitted to the hospital from the ED between January 2005 and February 2010. Associations between four validated measures of ED crowding (occupancy, waiting patients, admitted patients, and patient-hours) assigned at triage, and time of day, time to antibiotics and fluids, and mortality were tested by analyzing trends across crowding quartiles.During the study period, 2913 severe sepsis patients were admitted to the hospital and 1127 (38.7%) qualified for protocolized care. In-hospital mortality was 14.3% overall and 26% for patients qualifying for protocolized care. Time to IV fluids was delayed as ED occupancy rate increased and as patient hours increased. Time to antibiotics increased as occupancy rates, patient hours, and the number of boarding inpatients increased. Implementation rates of protocolized care decreased from 71.3% to 50.5% (p<0.0001, OR 0.39) as the number of ED inpatient boarders increased; initiation of protocolized care was significantly higher as occupancy increased (OR 1.52). Mortality was unaffected by crowding parameters in all analyses.With increased ED crowding, time to critical severe sepsis therapies significantly increased and protocolized care initiation decreased. As crowding increases, EDs must implement systems that optimize delivery of time-sensitive therapies to critically ill patients.

The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown.To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill.Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States.Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76).The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days.Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54).Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting.clinicaltrials.gov Identifier: NCT01335932.

Post–intensive care syndrome, a condition defined by new or worsening impairment in cognition, mental health, and physical function after critical illness, has emerged in the past decade as a common and life-altering consequence of critical illness. New strategies are urgently needed to mitigate the risk of neuropsychological and functional impairment common after critical illness and to prepare and support survivors on their road toward recovery. The present state of critical care survivorship is described, and postdischarge care delivery in the United States and the potential impact of the present-day fragmented model of care delivery are detailed. A novel strategy that uses peer support groups could more effectively meet the needs of survivors of critical illness and mitigate post–intensive care syndrome.

Objectives: Patients and caregivers can experience a range of physical, psychologic, and cognitive problems following critical care discharge. The use of peer support has been proposed as an innovative support mechanism. Design: We sought to identify technical, safety, and procedural aspects of existing operational models of peer support, among the Society of Critical Care Medicine Thrive Peer Support Collaborative. We also sought to categorize key distinctions between these models and elucidate barriers and facilitators to implementation. Subjects and Setting: Seventeen Thrive sites from the United States, United Kingdom, and Australia were represented by a range of healthcare professionals. Measurements and Main Results: Via an iterative process of in-person and email/conference calls, members of the Collaborative defined the key areas on which peer support models could be defined and compared, collected detailed self-reports from all sites, reviewed the information, and identified clusters of models. Barriers and challenges to implementation of peer support models were also documented. Within the Thrive Collaborative, six general models of peer support were identified: community based, psychologist-led outpatient, models-based within ICU follow-up clinics, online, groups based within ICU, and peer mentor models. The most common barriers to implementation were recruitment to groups, personnel input and training, sustainability and funding, risk management, and measuring success. Conclusions: A number of different models of peer support are currently being developed to help patients and families recover and grow in the postcritical care setting.

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

Objectives: A growing number of patients survive sepsis hospitalizations each year and are at high risk for readmission. However, little is known about temporal trends in hospital-based acute care (emergency department treat-and-release visits and hospital readmission) after sepsis. Our primary objective was to measure temporal trends in sepsis survivorship and hospital-based acute care use in sepsis survivors. In addition, because readmissions after pneumonia are subject to penalty under the national readmission reduction program, we examined whether readmission rates declined after sepsis hospitalizations related to pneumonia. Design and Setting: Retrospective, observational cohort study conducted within an academic healthcare system from 2010 to 2015. Patients: We used three validated, claims-based approaches to identify 17,256 sepsis or severe sepsis hospitalizations to examine trends in hospital-based acute care after sepsis. Interventions: None. Measurements and Main Results: From 2010 to 2015, sepsis as a proportion of medical and surgical admissions increased from 3.9% to 9.4%, whereas in-hospital mortality rate for sepsis hospitalizations declined from 24.1% to 14.8%. As a result, the proportion of medical and surgical discharges at-risk for hospital readmission after sepsis increased from 2.7% to 7.8%. Over 6 years, 30-day hospital readmission rates declined modestly, from 26.4% in 2010 to 23.1% in 2015, driven largely by a decline in readmission rates among survivors of nonsevere sepsis, and nonpneumonia sepsis specifically, as the readmission rate of severe sepsis survivors was stable. The modest decline in 30-day readmission rates was offset by an increase in emergency department treat-and-release visits, from 2.8% in 2010 to a peak of 5.4% in 2014. Conclusions: Owing to increasing incidence and declining mortality, the number of sepsis survivors at risk for hospital readmission rose significantly between 2010 and 2015. The 30-day hospital readmission rates for sepsis declined modestly but were offset by a rise in emergency department treat-and-release visits.

Background: Patients who survive critical illness have well-defined physical, cognitive, emotional, and familial problems. However, the impact of these problems on survivors' ability to return to work and other financial outcomes is less clear.Objectives: To determine the financial and employment consequences of an intensive care stay, we performed a systematic review and meta-analysis.Data Sources: We searched the MEDLINE, Embase, and CINAHL databases (1970-2018). All publication types except narrative reviews, case reports, case-control studies, and editorials were included. Included studies assessed financial outcomes in patients admitted to critical care and their caregivers.Data Extraction: Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcome reported was return to employment among those previously employed. We also examined financial stress and the impact financial outcomes had on quality of life and psychosocial health.Data Synthesis: Of 5,765 eligible abstracts, 51 studies were included, which provided data on 858 caregivers/family members and 7,267 patients. Forty-two papers reported patient outcomes, and 11 papers described caregivers/family members. Two papers included data from both patients and caregivers/family members. Return to employment was the most commonly reported financial outcome for critical care survivors. The pooled estimates for return to employment among those who were employed before critical illness were 33% (95% confidence interval [CI], 21-48%), 55% (95% CI, 45-64%), and 56% (95% CI, 45-66%) at 3, 6, and 12 months, respectively. Across the studies included in this review, there was a positive association with psychosocial health if patients returned to employment. This included improved health-related quality of life and fewer depressive symptoms. Regarding caregivers/family members, six studies reported changes in employment such as reduced hours and lost earnings.Conclusions: After critical illness, many patients who were previously employed do not return to work, even one year later. This new job loss is associated with worse health-related quality of life among survivors and worse psychological function among survivors and caregivers/family members. More interventional research is required to understand how best to support employability after critical illness.Registered with PROSPERO (CRD42018102360).

Edited MRS allows the detection of low-concentration metabolites, whose signals are not resolved in the MR spectrum. Tailored acquisitions can be designed to detect, for example, the inhibitory neurotransmitter γ-aminobutyric acid (GABA), or the reduction-oxidation (redox) compound glutathione (GSH), and single-voxel edited experiments are generally acquired at a rate of one metabolite-per-experiment. We demonstrate that simultaneous detection of the overlapping signals of GABA and GSH is possible using Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy (HERMES). HERMES applies orthogonal editing encoding (following a Hadamard scheme), such that GSH- and GABA-edited difference spectra can be reconstructed from a single multiplexed experiment. At a TE of 80 ms, 20-ms editing pulses are applied at 4.56 ppm (on GSH),1.9 ppm (on GABA), both offsets (using a dual-lobe cosine-modulated pulse) or neither. Hadamard combinations of the four sub-experiments yield GABA and GSH difference spectra. It is shown that HERMES gives excellent separation of the edited GABA and GSH signals in phantoms, and resulting edited lineshapes agree well with separate Mescher-Garwood Point-resolved Spectroscopy (MEGA-PRESS) acquisitions. In vivo, the quality and signal-to-noise ratio (SNR) of HERMES spectra are similar to those of sequentially acquired MEGA-PRESS spectra, with the benefit of saving half the acquisition time.

To identify the key mechanisms that clinicians perceive improve care in the intensive care unit (ICU), as a result of their involvement in post-ICU programs.Qualitative inquiry via focus groups and interviews with members of the Society of Critical Care Medicine's THRIVE collaborative sites (follow-up clinics and peer support). Framework analysis was used to synthesize and interpret the data.Five key mechanisms were identified as drivers of improvement back into the ICU: (1) identifying otherwise unseen targets for ICU quality improvement or education programs-new ideas for quality improvement were generated and greater attention paid to detail in clinical care. (2) Creating a new role for survivors in the ICU-former patients and family members adopted an advocacy or peer volunteer role. (3) Inviting critical care providers to the post-ICU program to educate, sensitize, and motivate them-clinician peers and trainees were invited to attend as a helpful learning strategy to gain insights into post-ICU care requirements. (4) Changing clinician's own understanding of patient experience-there appeared to be a direct individual benefit from working in post-ICU programs. (5) Improving morale and meaningfulness of ICU work-this was achieved by closing the feedback loop to ICU clinicians regarding patient and family outcomes.The follow-up of patients and families in post-ICU care settings is perceived to improve care within the ICU via five key mechanisms. Further research is required in this novel area.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

The levels of several brain metabolites were investigated in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) in 13 healthy controls (HC) and 13 patients with mild cognitive impairment (MCI) using single-voxel magnetic resonance spectroscopy at 7T. Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr). The effect of diagnosis on metabolite levels, and relationships between metabolite levels and memory and executive function, correcting for age, were investigated. MCI patients showed significantly decreased GABA/tCr (ACC, PCC), Glu/tCr (PCC), and NAA/tCr (PCC), and significantly increased mI/tCr (ACC). In the combined group, worse episodic verbal memory performance was correlated with lower Glu/tCr (PCC), lower NAA/tCr (PCC), and higher mI/tCr (ACC, PCC). Worse verbal fluency performance was correlated with lower GSH/tCr (PCC). In summary, MCI is associated with decreased GABA and Glu, most consistently in the PCC. Further studies in larger patient samples should be undertaken to determine the utility of 7T magnetic resonance spectroscopy in detecting MCI-related neurochemical changes.

To understand from the perspective of patients who did, and did not attend ICU recovery programs, what were the most important components of successful programs and how should they be organized.International, qualitative study.Fourteen hospitals in the United States, United Kingdom, and Australia.We conducted 66 semi-structured interviews with a diverse group of patients, 52 of whom had used an ICU recovery program and 14 whom had not.None.Using content analysis, prevalent themes were documented to understand what improved their outcomes. Contrasting quotes from patients who had not received certain aspects of care were used to identify perceived differential effectiveness. Successful ICU recovery programs had five key components: 1) Continuity of care; 2) Improving symptom status; 3) Normalization and expectation management; 4) Internal and external validation of progress; and 5) Reducing feelings of guilt and helplessness. The delivery of care which achieved these goals was facilitated by early involvement (even before hospital discharge), direct involvement of ICU staff, and a focus on integration across traditional disease, symptom, and social welfare needs.In this multicenter study, conducted across three continents, patients identified specific and reproducible modes of benefit derived from ICU recovery programs, which could be the target of future intervention refinement.

Edited MRS sequences are widely used for studying γ-aminobutyric acid (GABA) in the human brain. Several algorithms are available for modelling these data, deriving metabolite concentration estimates through peak fitting or a linear combination of basis spectra. The present study compares seven such algorithms, using data obtained in a large multisite study. GABA-edited (GABA+, TE = 68 ms MEGA-PRESS) data from 222 subjects at 20 sites were processed via a standardised pipeline, before modelling with FSL-MRS, Gannet, AMARES, QUEST, LCModel, Osprey and Tarquin, using standardised vendor-specific basis sets (for GE, Philips and Siemens) where appropriate. After referencing metabolite estimates (to water or creatine), systematic differences in scale were observed between datasets acquired on different vendors' hardware, presenting across algorithms. Scale differences across algorithms were also observed. Using the correlation between metabolite estimates and voxel tissue fraction as a benchmark, most algorithms were found to be similarly effective in detecting differences in GABA+. An interclass correlation across all algorithms showed single-rater consistency for GABA+ estimates of around 0.38, indicating moderate agreement. Upon inclusion of a basis set component explicitly modelling the macromolecule signal underlying the observed 3.0 ppm GABA peaks, single-rater consistency improved to 0.44. Correlation between discrete pairs of algorithms varied, and was concerningly weak in some cases. Our findings highlight the need for consensus on appropriate modelling parameters across different algorithms, and for detailed reporting of the parameters adopted in individual studies to ensure reproducibility and meaningful comparison of outcomes between different studies.

The aim of this guideline is to provide a series of evidence-based recommendations that allow those new to using MEGA-PRESS to produce high-quality data for the measurement of GABA levels using edited magnetic resonance spectroscopy with the MEGA-PRESS sequence at 3T. GABA is the main inhibitory neurotransmitter of the central nervous system and has been increasingly studied due to its relevance in many clinical disorders of the central nervous system. MEGA-PRESS is the most widely used method for quantification of GABA at 3T, but is technically challenging and operates at a low signal-to-noise ratio. Therefore, the acquisition of high-quality MRS data relies on avoiding numerous pitfalls and observing important caveats. The guideline was developed by a working party that consisted of experts in MRS and experts in guideline development and implementation, together with key stakeholders. Strictly following a translational framework, we first identified evidence using a systematically conducted scoping literature review, then synthesized and graded the quality of evidence that formed recommendations. These recommendations were then sent to a panel of 21 world leaders in MRS for feedback and approval using a modified-Delphi process across two rounds. The final guideline consists of 23 recommendations across six domains essential for GABA MRS acquisition (Parameters, Practicalities, Data acquisition, Confounders, Quality/reporting, Post-processing). Overall, 78% of recommendations were formed from high-quality evidence, and 91% received agreement from over 80% of the expert panel. These 23 expert-reviewed recommendations and accompanying extended documentation form a readily useable guideline to allow those new to using MEGA-PRESS to design appropriate MEGA-PRESS study protocols and generate high-quality data.

Abstract The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS

Serum lactate values in the emergency department (ED) have been associated with mortality in diverse populations of critically ill patients. This study investigates whether serum lactate values measured in the ED are associated with mortality in older patients admitted to the hospital, both with and without infections.This is a retrospective cohort study performed at two urban teaching hospitals. The study population includes 1,655 older ED patients (age>or=65 years) over a 3-year period (2004-2006) who had serum lactate measured prior to admission. The presence or absence of infection was determined by review of International Classification of Diseases Ninth Revision (ICD-9) admission diagnosis codes. Mortality during hospitalization was determined by review of inpatient records. Mortality at 30 and at 60 days was determined using a state death registry.In patients with infections, increasing serum lactate values of >or=2.0 mmol/L were linearly associated with relative risk (RR) of mortality during hospitalization (RR=1.9 to 3.6 with increasing lactate), at 30 days (RR=1.7 to 2.6), and at 60 days (RR=1.4 to 2.3) when compared to patients with serum lactate levels of <2.0 mmol/L. In patients without infections, a similar association was observed (RR=1.1 to 3.9 during hospitalization, RR=1.2 to 2.6 at 30 days, RR=1.1 to 2.4 at 60 days). In both groups of patients, serum lactate had a greater magnitude of association with mortality than either of two other commonly ordered laboratory tests, leukocyte count and serum creatinine.Higher ED lactate values are associated with greater mortality in a broad cohort of admitted patients over age 65 years, regardless of the presence or absence of infection.

Our objective was to describe the outcomes for extracorporeal life support (ECLS) use in adult respiratory failure because of status asthmaticus and to determine whether ECLS use in status asthmaticus is associated with greater survival than other indications for ECLS. This retrospective cohort study used the multicenter, International ECLS Organization Registry. The study population included 1,257 adults with respiratory failure requiring ECLS. Status asthmaticus was the primary indication for ECLS in 24 patients. A total of 83.3% of asthmatics survived to hospital discharge compared with 50.8% of nonasthmatics (n = 1,233) [odds ratio (OR) favoring survival for asthmatics = 4.86, 95% confidence interval (CI) 1.65–14.31, p = 0.004]. The survival advantage for asthmatics remained significant after adjustment for potential confounders. Complications were noted in 19 of 24 asthmatics (79.2%). In conclusion, we found that status asthmaticus, as an indication for ECLS in adult respiratory failure, seemed to be associated with greater survival than other indications for ECLS. However, complications are common and whether ECLS confers a survival advantage compared with other salvage treatment options remains unknown. More detailed information and complete reporting of ECLS use for status asthmaticus are needed to determine whether and when the potentially life-saving intervention of ECLS should be initiated in the asthmatic failing conventional therapy.

Background Protocol-driven early goal-directed therapy (EGDT) has been shown to reduce mortality in patients with severe sepsis and septic shock in the ED. EGDT appears to be underused, even in centers with formalized protocols. The aim of our study was to identify factors associated with not initiating EGDT in the ED. Methods This was a cohort study of 340 EGDT-eligible patients presenting to a single center ED from 2005 to 2007. EGDT eligibility was defined as a serum lactate ≥ 4 mmol/L or systolic BP< 90 mm Hg after volume resuscitation. EGDT initiation was defined as the measurement of central venous oxygen saturation via central venous catheter. Multivariable logistic regression was used to adjust for potential confounding. Results EGDT was not initiated in 142 eligible patients (42%). EGDT was not completed in 43% of patients in whom EGDT was initiated. Compliance with the protocol varied significantly at the physician level, ranging from 0% to 100%. Four risk factors were found to be associated independently with decreased odds of initiating EGDT: female sex of the patient (P = .001), female sex of the clinician (P = .041), serum lactate (rather than hemodynamic) criterion for EGDT (P = .018), and nonconsultation to the Severe Sepsis Service (P < .001). Conclusions Despite a formalized protocol, we found that EGDT was underused. We identified potential barriers to the effective implementation of EGDT at the patient, clinician, and organizational level. The use of a consultation service to facilitate the implementation of EGDT may be an effective strategy to improve protocol adherence. Protocol-driven early goal-directed therapy (EGDT) has been shown to reduce mortality in patients with severe sepsis and septic shock in the ED. EGDT appears to be underused, even in centers with formalized protocols. The aim of our study was to identify factors associated with not initiating EGDT in the ED. This was a cohort study of 340 EGDT-eligible patients presenting to a single center ED from 2005 to 2007. EGDT eligibility was defined as a serum lactate ≥ 4 mmol/L or systolic BP< 90 mm Hg after volume resuscitation. EGDT initiation was defined as the measurement of central venous oxygen saturation via central venous catheter. Multivariable logistic regression was used to adjust for potential confounding. EGDT was not initiated in 142 eligible patients (42%). EGDT was not completed in 43% of patients in whom EGDT was initiated. Compliance with the protocol varied significantly at the physician level, ranging from 0% to 100%. Four risk factors were found to be associated independently with decreased odds of initiating EGDT: female sex of the patient (P = .001), female sex of the clinician (P = .041), serum lactate (rather than hemodynamic) criterion for EGDT (P = .018), and nonconsultation to the Severe Sepsis Service (P < .001). Despite a formalized protocol, we found that EGDT was underused. We identified potential barriers to the effective implementation of EGDT at the patient, clinician, and organizational level. The use of a consultation service to facilitate the implementation of EGDT may be an effective strategy to improve protocol adherence.

Rationale: Severe sepsis is increasing in incidence and has a high rate of inpatient mortality. Hospitals that treat a larger number of patients with severe sepsis may offer a survival advantage.Objectives: We sought to assess the effect of severe sepsis case volume on mortality, hypothesizing that higher volume centers would have lower rates of inpatient death.Methods: We performed a retrospective cohort study over a 7-year period (2004–2010), using a nationally representative sample of hospital admissions, examining the relation between volume, urban location, organ dysfunction, and survival.Measurements and Main Results: To identify potential differences in outcomes, hospitals were divided into five categories (<50, 50–99, 100–249, 250–499, and 500+ annual cases) and adjusted mortality was compared by volume. A total of 914,200 patients with severe sepsis were identified over a 7-year period (2004–2010). Overall in-hospital mortality was 28.1%. In a fully adjusted model, there was an inverse relationship between severe sepsis case volume and inpatient mortality. Hospitals in the highest volume category had substantially improved survival compared with hospitals with the lowest case volume (adjusted odds ratio, 0.64; 95% confidence interval, 0.60–0.69). In cases of severe sepsis with one reported organ dysfunction, a mortality of 18.9% was found in hospitals with fewer than 50 annual cases compared with 10.4% in hospitals treating 500+ cases (adjusted odds ratio, 0.54; 95% confidence interval, 0.49–0.59). Similar differences were found in patients with up to three total organ dysfunctions.Conclusions: Patients with severe sepsis treated in hospitals with higher case volumes had improved adjusted outcomes.

The relationship between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness remains unclear. We examined the association between neuromuscular blocking agents and ICU-acquired weakness, critical illness polyneuropathy, and critical illness myopathy.PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and bibliographies of included studies were searched from database inception until September 24, 2015.Randomized controlled trials and prospective observational studies examining the association between neuromuscular blocking agents and ICU-acquired weakness, critical illness polyneuropathy, or critical illness myopathy.One author screened titles/abstracts. Two authors independently reviewed full text and extracted data from included studies. Meta-analysis was performed using the DerSimonian-Laird random effects model (OpenMetaAnalyst 10.10 for OS.X). We assessed reporting bias with funnel plots and heterogeneity with the I statistic.Of 2,170 titles/abstracts screened, 99 full texts were selected for review, yielding one randomized controlled trial and 18 prospective observational studies, for a total of 2,254 patients. The randomized controlled trial did not show an association between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness (odds ratio, 1.21; 95% CI, 0.67-2.19), but pooled data from all included studies suggested a modest association (odds ratio, 1.25; 95% CI, 1.06-1.48; I = 16%). Funnel plots suggested reporting bias, and sensitivity analyses showed a disproportionate contribution from critical illness polyneuropathy/critical illness myopathy and severe sepsis/septic shock studies.This meta-analysis suggests a modest association between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness; limitations include studies with a high risk of bias and a disproportionate contribution from studies examining patients for critical illness polyneuropathy/critical illness myopathy and those with severe sepsis/septic shock.

Objectives: Septic shock is associated with increased long-term morbidity and mortality. However, little is known about the use of hospital-based acute care in survivors after hospital discharge. The objectives of the study were to examine the frequency, timing, causes, and risk factors associated with emergency department visits and hospital readmissions within 30 days of discharge. Design: Retrospective cohort study. Setting: Tertiary, academic hospital in the United States. Patients: Patients admitted with septic shock (serum lactate ≥ 4 mmol/L or refractory hypotension) and discharged alive to a nonhospice setting between 2007 and 2010. Interventions: None. Measurements and Main Results: The coprimary outcomes were all-cause hospital readmission and emergency department visits (treat-and-release encounters) within 30 days to any of the three health system hospitals. Of 269 at-risk survivors, 63 (23.4%; 95% CI, 18.2–28.5) were readmitted within 30 days of discharge and another 12 (4.5%; 95% CI, 2.3–7.7) returned to the emergency department for a treat-and-release visit. Readmissions occurred within 15 days of discharge in 75% of cases and were more likely in oncology patients (p = 0.001) and patients with a longer hospital length of stay (p = 0.04). Readmissions were frequently due to another life-threatening condition and resulted in death or discharge to hospice in 16% of cases. The reasons for readmission were deemed potentially related to the index septic shock hospitalization in 78% (49 of 63) of cases. The most common cause was infection related, accounting for 46% of all 30-day readmissions, followed by cardiovascular or thromboembolic events (18%). Conclusions: The use of hospital-based acute care appeared to be common in septic shock survivors. Encounters often led to readmission within 15 days of discharge, were frequently due to another acute condition, and appeared to result in substantial morbidity and mortality. Given the potential public health implications of these findings, validation studies are needed.

Hospital readmission is common after sepsis, yet the relationship between the index admission and readmission remains poorly understood. We sought to examine the relationship between infection during the index acute care hospitalization and readmission and to identify potentially modifiable factors during the index sepsis hospitalization associated with readmission.In a retrospective cohort study, we evaluated 444 sepsis survivors at risk of an unplanned hospital readmission in 2012. The primary outcome was 30-day unplanned hospital readmission.Three hospitals within an academic healthcare system.Four hundred forty-four sepsis survivors.Of 444 sepsis survivors, 23.4% (95% CI, 19.6-27.6%) experienced an unplanned 30-day readmission compared with 10.1% (95% CI, 9.6-10.7%) among 11,364 nonsepsis survivors over the same time period. The most common cause for readmission after sepsis was infection (69.2%, 72 of 104). Among infection-related readmissions, 51.4% were categorized as recurrent/unresolved. Patients with sepsis present on their index admission who also developed a hospital-acquired infection ("second hit") were nearly twice as likely to have an unplanned 30-day readmission compared with those who presented with sepsis at admission and did not develop a hospital-acquired infection or those who presented without infection and then developed hospital-acquired sepsis (38.6% vs 22.2% vs 20.0%, p = 0.04). Infection-related hospital readmissions, specifically, were more likely in patients with a "second hit" and patients receiving a longer duration of antibiotics. The use of total parenteral nutrition (p = 0.03), longer duration of antibiotics (p = 0.047), prior hospitalizations, and lower discharge hemoglobin (p = 0.04) were independently associated with hospital readmission.We confirmed that the majority of unplanned hospital readmissions after sepsis are due to an infection. We found that patients with sepsis at admission who developed a hospital-acquired infection, and those who received a longer duration of antibiotics, appear to be high-risk groups for unplanned, all-cause 30-day readmissions and infection-related 30-day readmissions.

Neuron-specific enolase (NSE) concentrations are prognostic following traumatic and anoxic brain injury and may provide a method to quantify neuronal injury in other populations. We determined the association of admission plasma NSE concentrations with mortality and delirium in critically ill septic patients.We performed a retrospective analysis of 124 patients from a larger sepsis cohort. Plasma NSE was measured in the earliest blood draw at intensive care unit admission. Primary outcomes were 30-day mortality and intensive care unit delirium determined by chart review.Sixty-one patients (49.2%) died within 30 days, and delirium developed in 34 (31.5%) of the 108 patients who survived at least 24 hours and were not persistently comatose. Each doubling of the NSE concentration was associated with a 7.3% (95% confidence interval [CI] 2.5-12.0, P= .003) increased risk of 30-day mortality and a 5.2% (95% CI 3.2-7.2, P< .001) increased risk of delirium. An NSE concentration >12.5 μg/L was independently associated with a 23.3% (95% CI 6.7-39.9, P= .006) increased risk of 30-day mortality and a 29.3% (95% CI 8.8-49.8, P= .005) increased risk of delirium.Higher plasma NSE concentrations were associated with mortality and delirium in critically ill septic patients, suggesting that NSE may have utility as a marker of neuronal injury in sepsis.

Rationale: Cognitive and psychiatric impairments are threats to functional independence, general health, and quality of life.Evidence regarding these outcomes after lung transplantation is limited.Objectives: Determine the frequency of cognitive and psychiatric impairment after lung transplantation and identify potential factors associated with cognitive impairment after lung transplantation.Methods: In a retrospective cohort study, we assessed cognitive function, mental health, and health-related quality of life using a validated battery of standardized tests in 42 subjects posttransplantation.The battery assessed cognition, depression, anxiety, resilience, and post-traumatic stress disorder (PTSD).Cognitive function was assessed using the Montreal Cognitive Assessment, a validated screening test with a range of 0 to 30.We hypothesized that cognitive function post-transplantation would be associated with type of transplant, cardiopulmonary bypass, primary graft dysfunction, allograft ischemic time, and physical therapy posttransplantation.We used multivariable linear regression to examine the relationship between candidate risk factors and cognitive function post-transplantation.Measurements and Main Results: Mild cognitive impairment (score, 18-25) was observed in 67% of post-transplant subjects (95% confidence interval [CI]: 50-80%) and moderate cognitive impairment (score, 10-17) was observed in 5% (95% CI, 1-16%) of post-transplant subjects.Symptoms of moderate to severe anxiety and depression were observed in 21 and 3% of post-transplant subjects, respectively.No transplant recipients reported symptoms of PTSD.Higher resilience correlated with less psychological distress in the domains of depression (P , 0.001) and PTSD (P = 0.02).Prolonged graft ischemic time was independently associated with worse cognitive performance after lung transplantation (P = 0.001).The functional gain in 6-minute-walk distance achieved at the end of post-transplant physical rehabilitation (P = 0.04) was independently associated with improved cognitive performance post-transplantation.Conclusions: Mild cognitive impairment was present in the majority of patients after lung transplantation.Prolonged allograft ischemic time may be associated with cognitive impairment.Poor physical performance and cognitive impairment are linked, and physical rehabilitation post-transplant and psychological resilience may be protective against the development of long-term impairment.Further study is warranted to confirm these potential associations and to examine the trajectory of cognitive function after lung transplantation.

An algorithm for retrospective correction of frequency and phase offsets in MRS data is presented. The algorithm, termed robust spectral registration (rSR), contains a set of subroutines designed to robustly align individual transients in a given dataset even in cases of significant frequency and phase offsets or unstable lipid contamination and residual water signals. Data acquired by complex multiplexed editing approaches with distinct subspectral profiles are also accurately aligned. Automated removal of unstable lipid contamination and residual water signals is applied first, when needed. Frequency and phase offsets are corrected in the time domain by aligning each transient to a weighted average reference in a statistically optimal order using nonlinear least-squares optimization. The alignment of subspectra in edited datasets is performed using an approach that specifically targets subtraction artifacts in the frequency domain. Weighted averaging is then used for signal averaging to down-weight poorer-quality transients. Algorithm performance was assessed on one simulated and 67 in vivo pediatric GABA-/GSH-edited HERMES datasets and compared with the performance of a multistep correction method previously developed for aligning HERMES data. The performance of the novel approach was quantitatively assessed by comparing the estimated frequency/phase offsets against the known values for the simulated dataset or by examining the presence of subtraction artifacts in the in vivo data. Spectral quality was improved following robust alignment, especially in cases of significant spectral distortion. rSR reduced more subtraction artifacts than the multistep method in 64% of the GABA difference spectra and 75% of the GSH difference spectra. rSR overcomes the major challenges of frequency and phase correction.

Letters20 October 2020Locally Informed Simulation to Predict Hospital Capacity Needs During the COVID-19 PandemicFREEGary E. Weissman, MD, MSHP, Andrew Crane-Droesch, PhD, Corey Chivers, PhD, Mark E. Mikkelsen, MD, MSCE, and Scott D. Halpern, MD, PhDGary E. Weissman, MD, MSHPUniversity of Pennsylvania, Philadelphia, Pennsylvania (G.E.W., M.E.M., S.D.H.)Search for more papers by this author, Andrew Crane-Droesch, PhDUniversity of Pennsylvania and Penn Medicine Predictive Healthcare, Philadelphia, Pennsylvania (A.C.)Search for more papers by this author, Corey Chivers, PhDPenn Medicine Predictive Healthcare, Philadelphia, Pennsylvania (C.C.)Search for more papers by this author, Mark E. Mikkelsen, MD, MSCEUniversity of Pennsylvania, Philadelphia, Pennsylvania (G.E.W., M.E.M., S.D.H.)Search for more papers by this author, and Scott D. Halpern, MD, PhDUniversity of Pennsylvania, Philadelphia, Pennsylvania (G.E.W., M.E.M., S.D.H.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1062 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Dr. Stern highlights 2 important limitations of the SIR model that underlie the CHIME planning tool. We agree that the cohort structure—defined by differences in demographic characteristics, disease response, and contact patterns, among others—influences the course and severity of the pandemic. Using an agent-based model with a first-in, first-out process as Dr. Stern suggests would permit the representation of some of these cohort characteristics. However, this approach would come at the cost of increased complexity, with accompanying difficulty in identifying reliable parameter estimates based on limited published data early in the pandemic.The SIR assumption of a constant doubling time does not reflect the effects of rapidly changing physical distancing behaviors and other policies that might alter viral transmission. Thus, we have advised that the CHIME tool be used only for reliable short-term forecasts. We advocate that users of CHIME and any other COVID-19–related pandemic model iteratively review all parameters based on empirical observations of the pandemic course.As our model has been iteratively revised since publication, the subsequent CHIME estimates have also indicated an earlier but not higher peak, as suggested by Dr. Stern's calculations. However, we disagree that the direction of SIR model bias is yet definitely known in the case of COVID-19. The cited article suggests that the SIR model underestimates model peak and timing compared with 1 matrix model (1). At the same time, other work has suggested that SIR models may overestimate total epidemic size compared with contact models that account for social network structure (2). Further work is needed to validate all COVID-19–related pandemic models against both each other and empirically observed counts of infected cases and their subsequent care utilization patterns. As such, our original manuscript included a plan to undertake such an empirical validation.At this time, we again acknowledge the limitations of SIR models and have since extended CHIME to account for more complex dynamics as more data have become available (https://penn-chime.phl.io). The performance of CHIME has improved with updating since publication, and CHIME has so far proved useful to guide planning efforts in our health system. However, we will continue to revise and assess the model in order to apply these lessons to more efficiently and effectively model future epidemics.References1. Grant A. Dynamics of COVID-19 epidemics: SEIR models underestimate peak infection rates and overestimate epidemic duration. medRxiv. Preprint posted online 12 April 2020. doi:10.1101/2020.04.02.20050674 Google Scholar2. Hébert-Dufresne L, Althouse BM, Scarpino SV, et al. Beyond R0 : the importance of contact tracing when predicting epidemics. arXiv. Preprint posted online 10 February 2020. Accessed at http://arxiv.org/abs/2002.04004 on 10 April 2020. Google Scholar Comments 0 Comments Sign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Gary E. Weissman, MD, MSHP; Andrew Crane-Droesch, PhD; Corey Chivers, PhD; Mark E. Mikkelsen, MD, MSCE; Scott D. Halpern, MD, PhDAffiliations: University of Pennsylvania, Philadelphia, Pennsylvania (G.E.W., M.E.M., S.D.H.)University of Pennsylvania and Penn Medicine Predictive Healthcare, Philadelphia, Pennsylvania (A.C.)Penn Medicine Predictive Healthcare, Philadelphia, Pennsylvania (C.C.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-1260. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoLocally Informed Simulation to Predict Hospital Capacity Needs During the COVID-19 Pandemic Gary E. Weissman , Andrew Crane-Droesch , Corey Chivers , ThaiBinh Luong , Asaf Hanish , Michael Z. Levy , Jason Lubken , Michael Becker , Michael E. Draugelis , George L. Anesi , Patrick J. Brennan , Jason D. Christie , C. William Hanson III , Mark E. Mikkelsen , and Scott D. Halpern Locally Informed Simulation to Predict Hospital Capacity Needs During the COVID-19 Pandemic Ralph H. 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Halpern, MD, PhD and Franklin G. Miller, PhDCOVID-19 Nonessential Surgery Restrictions and Spine SurgeryAn interactive online dashboard for tracking COVID-19 in U.S. counties, cities, and states in real timeCOVID-19 e saúde mental: a emergência do cuidado 20 October 2020Volume 173, Issue 8 Page: 680-681 Keywords Behavior COVID-19 Disclosure Forecasting ePublished: 20 October 2020 Issue Published: 20 October 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

Spectral editing allows direct measurement of low-concentration metabolites, such as GABA, glutathione (GSH) and lactate (Lac), relevant for understanding brain (patho)physiology. The most widely used spectral editing technique is MEGA-PRESS, which has been diversely implemented across research sites and vendors, resulting in variations in the final resolved edited signal. In this paper, we describe an effort to develop a new universal MEGA-PRESS sequence with HERMES functionality for the major MR vendor platforms with standardized RF pulse shapes, durations, amplitudes and timings. New RF pulses were generated for the universal sequence. Phantom experiments were conducted on Philips, Siemens, GE and Canon 3 T MRI scanners using 32-channel head coils. In vivo experiments were performed on the same six subjects on Philips and Siemens scanners, and on two additional subjects, one on GE and one on Canon scanners. On each platform, edited MRS experiments were conducted with the vendor-native and universal MEGA-PRESS sequences for GABA (TE = 68 ms) and Lac editing (TE = 140 ms). Additionally, HERMES for GABA and GSH was performed using the universal sequence at TE = 80 ms. The universal sequence improves inter-vendor similarity of GABA-edited and Lac-edited MEGA-PRESS spectra. The universal HERMES sequence yields both GABA- and GSH-edited spectra with negligible levels of crosstalk on all four platforms, and with strong agreement among vendors for both edited spectra. In vivo GABA+/Cr, Lac/Cr and GSH/Cr ratios showed relatively low variation between scanners using the universal sequence. In conclusion, phantom and in vivo experiments demonstrate successful implementation of the universal sequence across all four major vendors, allowing editing of several metabolites across a range of TEs.

Improved ability to predict impairments after critical illness could guide clinical decision-making, inform trial enrollment, and facilitate comprehensive patient recovery. A systematic review of the literature was conducted to investigate whether physical, cognitive, and mental health impairments could be predicted in adult survivors of critical illness.A systematic search of PubMed and the Cochrane Library (Prospective Register of Systematic Reviews ID: CRD42018117255) was undertaken on December 8, 2018, and the final searches updated on January 20, 2019.Four independent reviewers assessed titles and abstracts against study eligibility criteria. Studies were eligible if a prediction model was developed, validated, or updated for impairments after critical illness in adult patients. Discrepancies were resolved by consensus or an independent adjudicator.Data on study characteristics, timing of outcome measurement, candidate predictors, and analytic strategies used were extracted. Risk of bias was assessed using the Prediction model Risk Of Bias Assessment Tool.Of 8,549 screened studies, three studies met inclusion. All three studies focused on the development of a prediction model to predict (1) a mental health composite outcome at 3 months post discharge, (2) return-to-pre-ICU functioning and residence at 6 months post discharge, and (3) physical function 2 months post discharge. Only one model had been externally validated. All studies had a high risk of bias, primarily due to the sample size, and statistical methods used to develop and select the predictors for the prediction published model.We only found three studies that developed a prediction model of any post-ICU impairment. There are several opportunities for improvement for future prediction model development, including the use of standardized outcomes and time horizons, and improved study design and statistical methodology.

Models of healthy brain function and psychiatric conditions assume that excitatory and inhibitory activity are balanced in the human brain at multiple spatial and temporal scales. In human neuroimaging, concentrations of the major excitatory (glutamate) and inhibitory (γ-aminobutyric acid, GABA) neurotransmitters are measured in vivo using magnetic resonance spectroscopy (MRS). However, despite the central importance of E/I balance to theories of brain function, a relationship between regional glutamate and GABA levels in the human brain has not been shown. We addressed this question in a large corpus of edited MRS data collected at 19 different sites (n ​= ​220). Consistent with the notion of E/I balance, we found that levels of glutamate+glutamine (Glx) and GABA+ were highly correlated (R ​= ​0.52, p ​= ​2.86 x 10−14). This relationship held when controlling for site, scanner vendor, and demographics. Controlling for neurochemicals associated with neuronal density and metabolism (i.e. N-acetylaspartate and creatine) significantly reduced the correlation between GABA+ and Glx, suggesting that the levels of GABA+ and Glx may be critically linked to regional metabolism. These results are consistent with the notion that excitation and inhibition are balanced in the human brain.

Anticoagulation may be a challenge in coronavirus disease 2019 (COVID-19) extracorporeal membrane oxygenation due to endothelial injury and dysregulation of coagulation, which may increase the risk of thrombotic and bleeding complications. This report was created to describe the authors' single institutional experience, with emphasis on the high rate of intracranial hemorrhage for the first 10 patients with COVID-19 placed on venovenous extracorporeal membrane oxygenation (VV ECMO).Case series, retrospective analysis.Single institution.Ten patients.None.Patient characteristics, mortality, stroke rate, and length of stay data were collected in all patients. In addition, laboratory values of D-dimer and C-reactive protein and standard measurements of prothrombin and activated partial thromboplastin time were collected on all patients. Ten patients, each confirmed with COVID-19 via reverse transcription-polymerase chain reaction, were supported on VV ECMO for acute respiratory distress syndrome (ARDS) for a mean duration of 9.4 ± 7 days. Four of 10 patients had hemorrhagic strokes, 3 of which resulted in death. At 30 days after initiation of VV ECMO, a total of 7 survivors included 6 patients discharged from the hospital and 1 patient who remained in the intensive care unit.In this small study of 10 patients, intracranial hemorrhage was a common complication, resulting in a high rate of death. The authors urge caution in the anticoagulation management of VV ECMO for patients with severe ARDS and COVID-19 patients. Close monitoring of all hematologic parameters is recommended during ECMO support while awaiting larger, multicenter studies to examine the best practice.

Investigate the challenges experienced by survivors of critical illness and their caregivers across the transitions of care from intensive care to community, and the potential problem-solving strategies used to navigate these challenges.Qualitative design-data generation via interviews and data analysis via the framework analysis method.Patients and caregivers from three continents, identified through the Society of Critical Care Medicine's THRIVE international collaborative sites (follow-up clinics and peer support groups).Patients and caregivers following critical illness.Nil.From 86 interviews (66 patients, 20 caregivers), we identified the following major themes: 1) Challenges for patients-interacting with the health system and gaps in care; managing others' expectations of illness and recovery. 2) Challenges for caregivers-health system shortfalls and inadequate communication; lack of support for caregivers. 3) Patient and caregiver-driven problem solving across the transitions of care-personal attributes, resources, and initiative; receiving support and helping others; and acceptance.Survivors and caregivers experienced a range of challenges across the transitions of care. There were distinct and contrasting themes related to the caregiver experience. Survivors and caregivers used comparable problem-solving strategies to navigate the challenges encountered across the transitions of care.

Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites.A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC).Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI.This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Individuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

<h3>BACKGROUND:</h3> Pulse oximetry is the mainstay of patient oxygen monitoring. Measurement error from pulse oximetry is more common for those with darker skin pigmentation, yet this topic remains understudied, and evidence-based clinical mitigation strategies do not currently exist. Our objectives were to measure the rate of occult hypoxemia, defined as arterial oxygen saturation (S_aO₂) &lt; 88% when pulse oximeter oxygen saturation was between 92–96%, in a racially diverse critically ill population; to analyze degree, direction, and consistency of measurement error; and to develop a mitigation strategy that minimizes occult hypoxemia in advance of technological advancements. <h3>METHODS:</h3> We performed a multi-center retrospective cohort study of critically ill subjects. <h3>RESULTS:</h3> Among 105,467 paired observations from 7,693 subjects, we found occult hypoxemia was more common among minority subjects. The frequency of occult hypoxemia was 7.9% versus 2.9% between Black and white subjects, respectively, (<i>P</i> &lt; .001). Pulse oximeter measurement errors were inconsistent throughout a patient encounter, with 67% of encounters having a range of intra-subject measurement errors &gt; 4 percentage points. In 75% of encounters, the intra-subject errors were bidirectional. S_aO₂ &lt; 88% was less common at higher pulse oximeter oxygenation ranges (4.1% and 1.8% of observations among Black and white subjects at a pulse oximeter threshold of 94–98%). Although occult hypoxemia was further reduced at oxygenation saturation range 95–100%, the frequency of hyperoxemia (partial pressure of arterial oxygen &gt; 110 mm Hg) became more common, occurring in 42.3% of Black and 46.0% of white observations. <h3>CONCLUSIONS:</h3> Measurement error in pulse oximetry is common for all racial groups, but occult hypoxemia occurred most commonly in Black subjects. The highly variable magnitude and direction of measurement error preclude an individualized mitigation approach. In advance of technological advancements, we recommend targeting a pulse oximetry saturation goal of 94–98% for all patients.

Multiple data formats in the MRS community currently hinder data sharing and integration. NIfTI-MRS is proposed as a standard spectroscopy data format, implemented as an extension to the Neuroimaging informatics technology initiative (NIfTI) format. This standardized format can facilitate data sharing and algorithm development as well as ease integration of MRS analysis alongside other imaging modalities.A file format using the NIfTI header extension framework incorporates essential spectroscopic metadata and additional encoding dimensions. A detailed description of the specification is provided. An open-source command-line conversion program is implemented to convert single-voxel and spectroscopic imaging data to NIfTI-MRS. Visualization of data in NIfTI-MRS is provided by development of a dedicated plugin for FSLeyes, the FMRIB Software Library (FSL) image viewer.Online documentation and 10 example datasets in the proposed format are provided. Code examples of NIfTI-MRS readers are implemented in common programming languages. Conversion software, spec2nii, currently converts 14 formats where data is stored in image-space to NIfTI-MRS, including Digital Imaging and Communications in Medicine (DICOM) and vendor proprietary formats.NIfTI-MRS aims to solve issues arising from multiple data formats being used in the MRS community. Through a single conversion point, processing and analysis of MRS data are simplified, thereby lowering the barrier to use of MRS. Furthermore, it can serve as the basis for open data sharing, collaboration, and interoperability of analysis programs. Greater standardization and harmonization become possible. By aligning with the dominant format in neuroimaging, NIfTI-MRS enables the use of mature tools present in the imaging community, demonstrated in this work by using a dedicated imaging tool, FSLeyes, for visualization.

Background Gamma‐Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. Clozapine, the only approved drug for treatment‐resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, as measured by proton magnetic resonance spectroscopy ( 1 H‐MRS), and clozapine response in patients with TRS. Methods This study enrolled patients with TRS who did not respond to clozapine (ultra‐resistant schizophrenia: URS) and who responded to clozapine (non‐URS), patients with schizophrenia who responded to first‐line antipsychotics (first‐line responders: FLR), and healthy controls (HCs). We measured GABA levels in the midcingulate cortex (MCC) using 3T 1 H‐MRS and compared these levels among the groups. The associations between GABA levels and symptom severity were also explored within the patient groups. Results A total of 98 participants (URS: n = 22; non‐URS: n = 25; FLR: n = 16; HCs: n = 35) completed the study. We found overall group differences in MCC GABA levels ( F (3,86) = 3.25, P = 0.04). Specifically, patients with URS showed higher GABA levels compared to those with non‐URS ( F (1,52) = 8.40, P = 0.03, Cohen's d = 0.84). MCC GABA levels showed no associations with any of the symptom severity scores within each group or the entire patient group. Conclusion Our study is the first to report elevated GABA levels in the MCC in patients with schizophrenia resistant to clozapine treatment compared with those responsive to clozapine. Longitudinal studies are required to evaluate if GABA levels are a suitable biomarker to predict clozapine resistance.

Background Asthma exacerbations with respiratory failure (AERF) are associated with hospital mortality of 7% to 15%. Extracorporeal membrane oxygenation (ECMO) has been used as a salvage therapy for refractory AERF, but controlled studies showing its association with mortality have not been performed. Research Question Is treatment with ECMO associated with lower mortality in refractory AERF compared with standard care? Study Design and Methods This is a retrospective, epidemiologic, observational cohort study using a national, administrative data set from 2010 to 2020 that includes 25% of US hospitalizations. People were included if they were admitted to an ECMO-capable hospital with an asthma exacerbation, and were treated with short-acting bronchodilators, systemic corticosteroids, and invasive ventilation. People were excluded for age < 18 years, no ICU stay, nonasthma chronic lung disease, COVID-19, or multiple admissions. The main exposure was ECMO vs No ECMO. The primary outcome was hospital mortality. Key secondary outcomes were ICU length of stay (LOS), hospital LOS, time receiving invasive ventilation, and total hospital costs. Results The study analyzed 13,714 patients with AERF, including 127 with ECMO and 13,587 with No ECMO. ECMO was associated with reduced mortality in the covariate-adjusted (OR, 0.33; 95% CI, 0.17-0.64; P = .001), propensity score-adjusted (OR, 0.36; 95% CI, 0.16-0.81; P = .01), and propensity score-matched models (OR, 0.48; 95% CI, 0.24-0.98; P = .04) vs No ECMO. Sensitivity analyses showed that mortality reduction related to ECMO ranged from OR 0.34 to 0.61. ECMO was also associated with increased hospital costs in all three models (P < .0001 for all) vs No ECMO, but not with decreased ICU LOS, hospital LOS, or time receiving invasive ventilation. Interpretation ECMO was associated with lower mortality and higher hospital costs, suggesting that it may be an important salvage therapy for refractory AERF following confirmatory clinical trials. Asthma exacerbations with respiratory failure (AERF) are associated with hospital mortality of 7% to 15%. Extracorporeal membrane oxygenation (ECMO) has been used as a salvage therapy for refractory AERF, but controlled studies showing its association with mortality have not been performed. Is treatment with ECMO associated with lower mortality in refractory AERF compared with standard care? This is a retrospective, epidemiologic, observational cohort study using a national, administrative data set from 2010 to 2020 that includes 25% of US hospitalizations. People were included if they were admitted to an ECMO-capable hospital with an asthma exacerbation, and were treated with short-acting bronchodilators, systemic corticosteroids, and invasive ventilation. People were excluded for age < 18 years, no ICU stay, nonasthma chronic lung disease, COVID-19, or multiple admissions. The main exposure was ECMO vs No ECMO. The primary outcome was hospital mortality. Key secondary outcomes were ICU length of stay (LOS), hospital LOS, time receiving invasive ventilation, and total hospital costs. The study analyzed 13,714 patients with AERF, including 127 with ECMO and 13,587 with No ECMO. ECMO was associated with reduced mortality in the covariate-adjusted (OR, 0.33; 95% CI, 0.17-0.64; P = .001), propensity score-adjusted (OR, 0.36; 95% CI, 0.16-0.81; P = .01), and propensity score-matched models (OR, 0.48; 95% CI, 0.24-0.98; P = .04) vs No ECMO. Sensitivity analyses showed that mortality reduction related to ECMO ranged from OR 0.34 to 0.61. ECMO was also associated with increased hospital costs in all three models (P < .0001 for all) vs No ECMO, but not with decreased ICU LOS, hospital LOS, or time receiving invasive ventilation. ECMO was associated with lower mortality and higher hospital costs, suggesting that it may be an important salvage therapy for refractory AERF following confirmatory clinical trials. Is Extracorporeal Membrane Oxygenation More Than Just Salvage Therapy in Acute Life-Threatening Asthma?CHESTVol. 163Issue 1PreviewIn recent years, the incidence of life-threatening asthma has declined because of significant advances in its pharmacologic therapy, which allows for better control of symptoms and reduction of the risk of exacerbation.1 However, very little advancement has occurred in management of patients presenting with acute life-threatening asthma and who develop acute respiratory failure. The care of such patients, who often are admitted to the ICU, can be very complex, especially when they require intubation and mechanical ventilation, which can be complicated by barotrauma and volutrauma. Full-Text PDF

Fourteen male Göttingen minipigs were used in this study. Nine were administered N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dosage of 1 mg/kg/day, SC, for 6 days, the last five pigs received saline injections for 6 days. All MPTP-treated animals developed Parkinson symptoms, i.e., muscle rigidity, hypokinesia, and impaired coordination within 5 days. The brain levels of dopamine (DA), and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in caudatum and putamen 2, 14, and 93 days (n = 3/time point) after the last drug administration. In eight of the MPTP-treated animals, striatal DA, DOPAC, and HVA concentrations were reduced from 50 to 95% compared to control animals at all time intervals. Animals with the lowest striatal DA concentrations showed the most severe signs of Parkinsonism. The number of cells in substantia nigra (SN) showed a decline only 3 months after MPTP treatment. The minipigs represent a nonprimate model of MPTP-induced parkinsonism syndromes lasting at least months.

ABSTRACT Background and objective: There is increasing evidence that survivors of ARDS may have impairments in cognitive function, mood and quality of life. This study investigated associations between cognitive impairment, mood disorders and quality of life in a select group of ARDS survivors. Methods: A cross‐sectional study was conducted to describe the specific impairments in cognitive function, mood and quality of life in a group of 79 self‐selected ARDS survivors who contacted an Internet‐based support site. A battery of cognitive tests was administered by telephone interview. Standardized scores on cognitive tests were compared with normative values and tested for associations with indices of anxiety, depression and quality of life. Results: Cognitive impairment was found in 56% of subjects. Compared with population norms, 24% of subjects had deficiencies in short‐term memory ( P = 0.04) and 29% in executive functioning ( P = 0.001). Moderate or severe anxiety was present in 48% of the study population, and 34% had moderate or severe depression. Moderate or severe anxiety was present in 61% of subjects with evidence of cognitive impairment as compared with 31% of subjects without. Subjects with cognitive impairment scored worse than subjects without cognitive impairment on most subscales of the SF‐36 and the Sickness Impact Profile questionnaire. Conclusions: Significant cognitive abnormalities may be present in long‐term ARDS survivors, particularly in memory and executive function. Impairments in cognition appear to be associated with significantly increased anxiety and worse quality of life.

Early recognition and treatment in severe sepsis improve outcomes. However, out-of-hospital patient characteristics and emergency medical services (EMS) care in severe sepsis is understudied. Our goals were to describe out-of-hospital characteristics and EMS care in patients with severe sepsis and to evaluate associations between out-of-hospital characteristics and severity of organ dysfunction in the emergency department (ED).We performed a secondary data analysis of existing data from patients with severe sepsis transported by EMS to an academic medical center. We constructed multivariable linear regression models to determine if out-of-hospital factors are associated with serum lactate and sequential organ failure assessment (SOFA) in the ED.Two hundred sixteen patients with severe sepsis arrived by EMS. Median serum lactate in the ED was 3.0 mmol/L (interquartile range, 2.0-5.0) and median SOFA score was 4 (interquartile range, 2-6). Sixty-three percent (135) of patients were transported by advanced life support providers and 30% (62) received intravenous fluid. Lower out-of-hospital Glasgow Coma Scale score was independently associated with elevated serum lactate (P < .01). Out-of-hospital hypotension, greater respiratory rate, and lower Glasgow Coma Scale score were associated with greater SOFA (P < .01).Out-of-hospital fluid resuscitation occurred in less than one third of patients with severe sepsis, and routinely measured out-of-hospital variables were associated with greater serum lactate and SOFA in the ED.

Formal guidelines recommend that therapeutic hypothermia be considered after in-hospital cardiac arrest. The rate of therapeutic hypothermia use after in-hospital cardiac arrest and details about its implementation are unknown. We aimed to determine the use of therapeutic hypothermia for adult in-hospital cardiac arrest, whether use has increased over time, and to identify factors associated with its use.Multicenter, prospective cohort study.A total of 538 hospitals participating in the Get With the Guidelines-Resuscitation database (2003-2009).A total of 67,498 patients who had return of spontaneous circulation after in-hospital cardiac arrest.None.The primary outcome was the initiation of therapeutic hypothermia. We measured the proportion of therapeutic hypothermia patients who achieved target temperature (32-34 °C) and were overcooled. Of 67,498 patients, therapeutic hypothermia was initiated in 1,367 patients (2.0%). The target temperature (32-34 °C) was not achieved in 44.3% of therapeutic hypothermia patients within 24 hours and 17.6% were overcooled. The use of therapeutic hypothermia increased from 0.7% in 2003 to 3.3% in 2009 (p < 0.001). We found that younger age (p < 0.001) and occurrence in a non-ICU location (p < 0.001), on a weekday (p = 0.005), and in a teaching hospital (p = 0.001) were associated with an increased likelihood of therapeutic hypothermia being initiated.After in-hospital cardiac arrest, therapeutic hypothermia was used rarely. Once initiated, the target temperature was commonly not achieved. The frequency of use increased over time but remained low. Factors associated with therapeutic hypothermia use included patient age, time and location of occurrence, and type of hospital.

To systematically evaluate the effect of extracorporeal membrane oxygenation on survival in adults with acute respiratory failure and to help inform institutional decisions about implementing an extracorporeal membrane oxygenation program or transferring patients to experienced extracorporeal membrane oxygenation centers during the H1N1 influenza pandemic.National Guideline Clearinghouse, MEDLINE, EMBASE, Agency for Healthcare Research and Quality Evidence-based Practice reports, National Institute for Health and Clinical Excellence, Cochrane Library, International Network of Agencies for Health Technology Assessment, and citation review.Studies of extracorporeal membrane oxygenation in adult acute respiratory failure, reporting mortality rates for at least 10 patients in extracorporeal membrane oxygenation and nonextracorporeal membrane oxygenation groups.Mortality rates were abstracted for all patients and for patients with influenza. Risk ratios were meta-analyzed using random-effects methods and assessed for heterogeneity.There are no evidence-based clinical guidelines on the use of extracorporeal membrane oxygenation in patients with influenza. Three randomized controlled trials and three cohort studies evaluated extracorporeal membrane oxygenation in patients with acute respiratory failure; none reported specifically on patients with influenza. Meta-analysis of the randomized controlled trials revealed significant heterogeneity in risk of mortality. The summary risk ratio found by the meta-analysis was 0.93 (95% confidence interval, 0.71 to 1.22). The most recent trial found a reduction in mortality and severe disability at 6 months among patients in whom extracorporeal membrane oxygenation was considered. Observational studies suggest that extracorporeal membrane oxygenation for acute respiratory failure resulting from viral pneumonia is associated with improved mortality compared with other etiologies of acute respiratory failure.The best evidence to guide decisions regarding the use of extracorporeal membrane oxygenation for patients with influenza stems from trials of extracorporeal membrane oxygenation for acute respiratory failure of all etiologies, among which significant heterogeneity exists, and from case series describing outcomes of extracorporeal membrane oxygenation in patients with influenza. Thus, there is insufficient evidence to provide a recommendation for extracorporeal membrane oxygenation use among patients with respiratory failure resulting from influenza. However, clinicians should consider extracorporeal membrane oxygenation within the context of other salvage therapies for acute respiratory failure.

Background. Early identification and treatment of patients with severe sepsis improves outcome, yet the role of out-of-hospital intravenous (IV) fluid is unknown. Objective. To determine if the delivery of out-of-hospital fluid in patients with severe sepsis is associated with reduced time to achievement of goal-oriented resuscitation in the emergency department (ED). Methods. We performed a secondary data analysis of a retrospective cohort study in a metropolitan, tertiary care, university-based medical center supported by a two-tiered system of out-of-hospital emergency medical services (EMS) providers. We studied the association between delivery of out-of-hospital fluid by advanced life support (ALS) providers and the achievement of resuscitation endpoints (central venous pressure [CVP] ≥8 mmHg, mean arterial pressure [MAP] ≥65 mmHg, and central venous oxygen saturation [ScvO2] ≥70%%) within six hours after triage during early goal-directed therapy (EGDT) in the ED. Results. Twenty five (48%%) of 52 patients transported by ALS with severe sepsis received out-of-hospital fluid. Data for age, gender, source of sepsis, and presence of comorbidities were similar between patients who did and did not receive out-of-hospital fluid. Patients receiving out-of-hospital fluid had lower out-of-hospital mean (± standard deviation) systolic blood pressure (95 ± 40 mmHg vs. 117 ± 29 mmHg; p == 0.03) and higher median (interquartile range) Sequential Organ Failure Assessment (SOFA) scores in the ED (7 [5–8] vs. 4 [4–6]; p == 0.01) than patients not receiving out-of-hospital fluid. Despite greater severity of illness, patients receiving out-of-hospital fluid approached but did not attain a statistically significant increase in the likelihood of achieving MAP ≥65 mmHg within six hours after ED triage (70%% vs. 44%%, p == 0.09). On average, patients receiving out-of-hospital fluid received twice the fluid volume within one hour after ED triage (1.1 L [1.0–2.0 L] vs. 0.6 L [0.3–1.0 L]; p == 0.01). No difference in achievement of goal CVP (72%% vs. 60%%; p == 0.6) or goal ScvO2 (54%% vs. 36%%; p == 0.25) was observed between groups. Conclusions. Less than half of patients with severe sepsis transported by ALS received out-of-hospital fluid. Patients receiving out-of-hospital IV access and fluids approached but did not attain a statistically significant increase in the likelihood of achieving goal MAP during EGDT. These preliminary findings require additional investigation to evaluate the optimal role of out-of-hospital resuscitation in treating patients with severe sepsis.

Endocan is a proteoglycan expressed by endothelial cells in the lung that may inhibit leukocyte recruitment and thus prevent the development of acute lung injury (ALI). We tested the association of serum endocan levels with subsequent development of ALI after major trauma.This was a single-center nested case-control study within a prospective cohort study of major trauma patients. Using an enzyme-linked immunosorbent assay test, we measured endocan levels from admission serum in 24 controls (no ALI) and 24 cases (ALI within 5 days of trauma). Multivariable logistic regression was used to test the association of admission serum endocan levels with subsequent ALI.Patients who developed ALI had lower levels of endocan on admission (mean, 3.5 ± 1.4 ng/mL vs 4.9 ± 2.6 ng/mL in controls; P = .02). For each 1-unit increase in serum endocan level, the odds ratio for ALI development decreased (0.69; 95% confidence interval, 0.49-0.97; P = .03). Lower endocan levels remained associated with a higher incidence of ALI after adjustment for age and illness severity.Lower levels of serum endocan on admission are associated with subsequent development of ALI in trauma patients. These observations may be explained by endocan-mediated blockade of leukocyte recruitment in the lung.

Immunocompromised patients who develop sepsis while neutropenic are at high risk for morbidity and mortality; however, it is unknown if neutropenic sepsis is associated with distinct clinical and biological characteristics.We conducted a prospective cohort study of patients admitted to the medical intensive care unit of an academic medical center with severe sepsis. Patients were followed for the development of acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality. Plasma proteins, representing the host inflammatory response, anti-inflammatory response, and endothelial leak were measured in 30 % of subjects. Clinical characteristics and plasma protein concentrations of patients with neutropenia at enrollment were compared to patients without neutropenia.Of 797 subjects enrolled, 103 (13 %) were neutropenic at ICU admission. The neutropenic subjects were more often in shock, admitted from the hospital ward, had higher APACHE III scores, and more likely bacteremic. Neutropenia was an independent risk factor for AKI (RR 1.28; 95 % CI 1.04, 1.57; p = 0.03), but not ARDS (RR 0.90; 95 % CI 0.70, 1.17; p = 0.42) or 30-day mortality (RR 1.05; 95 % CI 0.85, 1.31; p = 0.65). Neutropenic subjects had higher plasma interleukin (IL)-6 (457 vs. 249 pg/ml; p = 0.03), IL-8 (581 vs. 94 pg/ml; p <0.001), and granulocyte colony-stimulating factor (G-CSF) (3624 vs. 99 pg/ml; p <0.001). Angiopoietin-2 and IL-1 receptor antagonist concentrations did not differ between groups.Neutropenic sepsis is associated with a higher AKI risk and concentrations of inflammatory mediators IL-6, IL-8, and G-CSF relative to non-neutropenic patients. These differences may have implications for future therapies targeting neutropenic sepsis.

A number of observational studies have evaluated the association between arterial oxygen tensions and outcome after cardiac arrest with variable results. The objective of this study is to determine the association between arterial oxygen tension and neurological outcome after cardiac arrest. A retrospective cohort analysis was performed using the Penn Alliance for Therapeutic Hypothermia registry. Adult patients who experienced return of spontaneous circulation after in-hospital or out-of-hospital cardiac arrest (OHCA) and had a partial pressure of arterial oxygen (PaO2) recorded within 48 hours were included. Our primary exposure of interest was PaO2. Hyperoxemia was defined as PaO2 > 300 mmHg, hypoxemia as PaO2 < 60 mmHg, and optimal oxygenation as PaO2 60-300 mmHg. The primary outcome was neurological function at hospital discharge among survivors, as described by the cerebral performance category (CPC) score, dichotomized into "favorable" (CPCs 1-2) and "unfavorable" (CPCs 3-5). Secondary outcomes included in-hospital mortality. A total of 544 patients from 13 institutions were included. Average age was 61 years, 56% were male, and 51% were white. A total of 64% experienced OHCA, 81% of arrests were witnessed, and pulseless electrical activity was the most common initial rhythm (40%). More than 72% of the patients had cardiac etiology for their arrests, and 55% underwent targeted temperature management. A total of 38% of patients survived to hospital discharge. There was no significant association between PaO2 at any time interval and neurological outcome at hospital discharge. Hyperoxemia at 12 hours after cardiac arrest was associated with decreased odds of survival (OR 0.17 [0.03-0.89], p = 0.032). There was no significant association between arterial oxygen tension measured within the first 48 hours after cardiac arrest and neurological outcome.

The relationships between scan duration, signal-to-noise ratio (SNR) and sample size must be considered and understood to design optimal GABA-edited magnetic resonance spectroscopy (MRS) studies. Simulations investigated the effects of signal averaging on SNR, measurement error and group-level variance against a known ground truth. Relative root mean square errors (measurement error) and coefficients of variation (group-level variance) were calculated. GABA-edited data from 18 participants acquired from five voxels were used to examine the relationships between scan duration, SNR and quantitative outcomes in vivo. These relationships were then used to determine the sample sizes required to observe different effect sizes. In both simulated and in vivo data, SNR increased with the square root of the number of averages. Both measurement error and group-level variance were shown to follow an inverse-square-root function, indicating no significant impact of cumulative artifacts. Comparisons between the first two-thirds of the data and the full dataset showed no statistical difference in group-level variance. There was, however, some variability across the five voxels depending on SNR, which impacted the sample sizes needed to detect group differences in specific brain regions. Typical scan durations can be reduced if taking into account a statistically acceptable amount of variance and the magnitudes of predicted effects. While scan duration in GABA-edited MRS has typically been considered in terms of SNR, it is more appropriate to think in terms of the amount of measurement error and group-level variance that provides sufficient statistical power.

Establishing the associations between magnetic resonance spectroscopy (MRS)-assessed gamma-aminobutyric acid (GABA) levels and transcranial magnetic stimulation (TMS)-derived 'task-related' modulations in GABAA receptor-mediated inhibition and how these associations change with advancing age is a topic of interest in the field of human neuroscience. In this study, we identified the relationship between GABA levels and task-related modulations in GABAA receptor-mediated inhibition in the dominant (left) and non-dominant (right) sensorimotor (SM) cortices. GABA levels were measured using edited MRS and task-related GABAA receptor-mediated inhibition was measured using a short-interval intracortical inhibition (SICI) TMS protocol during the preparation and premotor period of a choice reaction time (CRT) task in 25 young (aged 18-33 years) and 25 older (aged 60-74 years) adults. Our results demonstrated that GABA levels in both SM voxels were lower in older adults as compared to younger adults; and higher SM GABA levels in the dominant as compared to the non-dominant SM voxel pointed to a lateralization effect, irrespective of age group. Furthermore, older adults showed decreased GABAA receptor-mediated inhibition in the preparation phase of the CRT task within the dominant primary motor cortex (M1), as compared to young adults. Finally, results from an exploratory correlation analysis pointed towards positive relationships between MRS-assessed GABA levels and TMS-derived task-related SICI measures. However, after correction for multiple comparisons none of the correlations remained significant.

Background: There is little evidence to guide the care of over a million sepsis survivors following hospital discharge despite high rates of hospital readmission. Objective: We examined whether early home health nursing (first visit within 2 days of hospital discharge and at least 1 additional visit in the first posthospital week) and early physician follow-up (an outpatient visit in the first posthospital week) reduce 30-day readmissions among Medicare sepsis survivors. Design: A pragmatic, comparative effectiveness analysis of Medicare data from 2013 to 2014 using nonlinear instrumental variable analysis. Subjects: Medicare beneficiaries in the 50 states and District of Columbia discharged alive after a sepsis hospitalization and received home health care. Measures: The outcomes, protocol parameters, and control variables were from Medicare administrative and claim files and the home health Outcome and Assessment Information Set (OASIS). The primary outcome was 30-day all-cause hospital readmission. Results: Our sample consisted of 170,571 mostly non-Hispanic white (82.3%), female (57.5%), older adults (mean age, 76 y) with severe sepsis (86.9%) and a multitude of comorbid conditions and functional limitations. Among them, 44.7% received only the nursing protocol, 11.0% only the medical doctor protocol, 28.1% both protocols, and 16.2% neither. Although neither protocol by itself had a statistically significant effect on readmission, both together reduced the probability of 30-day all-cause readmission by 7 percentage points ( P =0.006; 95% confidence interval=2, 12). Conclusions: Our findings suggest that, together, early postdischarge care by home health and medical providers can reduce hospital readmissions for sepsis survivors.

Examine well-being, measured as burnout and professional fulfillment, across critical care healthcare professionals, ICUs, and hospitals within a health system; examine the impact of the coronavirus disease 2019 pandemic.To complement a longitudinal survey administered to medical critical care physicians at the end of an ICU rotation, which began in May 2018, we conducted a cross-sectional survey among critical care professionals across four hospitals in December 2018 to January 2019. We report the results of the cross-sectional survey and, to examine the impact of the coronavirus disease 2019 pandemic, the longitudinal survey results from July 2019 to May 2020.Academic medical center.Four-hundred eighty-one critical care professionals, including 353 critical care nurses, 58 advanced practice providers, 57 physicians, and 13 pharmacists, participated in the cross-sectional survey; 15 medical critical care physicians participated in the longitudinal survey through the coronavirus disease 2019 pandemic.None.Burnout was present in 50% of ICU clinicians, ranging from 42% for critical care physicians to 55% for advanced practice providers. Professional fulfillment was less common at 37%, with significant variability across provider (p = 0.04), with a low of 23% among critical care pharmacists and a high of 53% among physicians. Well-being varied significantly at the hospital and ICU level. Workload and job demand were identified as drivers of burnout and meaning in work, culture and values of work community, control and flexibility, and social support and community at work were each identified as drivers of well-being. Between July 2019 and March 2020, burnout and professional fulfillment were present in 35% (15/43) and 58% (25/43) of medical critical care physician responses, respectively. In comparison, during the coronavirus disease 2019 pandemic, burnout and professional fulfillment were present in 57% (12/21) and 38% (8/21), respectively.Burnout was common across roles, yet differed across ICUs and hospitals. Professional fulfillment varied by provider role. We identified potentially modifiable factors related to clinician well-being that can inform organizational strategies at the ICU and hospital level. Longitudinal studies, designed to assess the long-term impact of the coronavirus disease 2019 pandemic on the well-being of the critical care workforce, are urgently needed.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Brain markers of oxidative damage increase with advancing age. In response, brain antioxidant levels may also increase with age, although this has not been well investigated. Here, we used edited magnetic resonance spectroscopy to quantify endogenous levels of glutathione (GSH, one of the most abundant brain antioxidants) in 37 young [mean: 21.8 (2.5) years; 19 female] and 23 older adults [mean: 72.8 (8.9) years; 19 female]. Accounting for age-related atrophy, we identified higher frontal and sensorimotor GSH levels for the older compared with the younger adults. For the older adults only, higher sensorimotor (but not frontal) GSH was correlated with poorer balance and gait. This suggests a regionally specific relationship between higher brain oxidative stress levels and motor performance declines with age. We suggest these findings reflect an upregulation of GSH in response to increasing brain oxidative stress with normal aging. Together, these results provide insight into age differences in brain antioxidant levels and implications for motor function.

To understand the unmet needs of caregivers of ICU survivors, how they accessed support post ICU, and the key components of beneficial ICU recovery support systems as identified from a caregiver perspective.International, qualitative study.We conducted 20 semistructured interviews with a diverse group of caregivers in the United States, the United Kingdom, and Australia, 11 of whom had interacted with an ICU recovery program.Seven hospitals in the United States, United Kingdom, and Australia.None.Content analysis was used to explore prevalent themes related to unmet needs, as well as perceived strategies to improve ICU outcomes. Post-ICU care was perceived to be generally inadequate. Desired caregiver support fell into two main categories: practical support and emotional support. Successful care delivery initiatives included structured programs, such as post discharge telephone calls, home health programs, post-ICU clinics, and peer support groups, and standing information resources, such as written educational materials and online resources.This qualitative, multicenter, international study of caregivers of critical illness survivors identified consistently unmet needs, means by which caregivers accessed support post ICU, and several care mechanisms identified by caregivers as supporting optimal ICU recovery.

After critical illness, patients are often left with impairments in physical, social, emotional, and cognitive functioning. Peer support interventions have been implemented internationally to ameliorate these issues.To explore what patients believed to be the key mechanisms of effectiveness of peer support programs implemented during critical care recovery.In a secondary analysis of an international qualitative data set, 66 telephone interviews with patients were undertaken across 14 sites in Australia, the United Kingdom, and the United States to understand the effect of peer support during recovery from critical illness. Prevalent themes were documented with framework analysis.Most patients who had been involved in peer support programs reported benefit. Patients described 3 primary mechanisms: (1) sharing experiences, (2) care debriefing, and (3) altruism.Peer support is a relatively simple intervention that could be implemented to support patients during recovery from critical illness. However, more research is required into how these programs can be implemented in a safe and sustainable way in clinical practice.

Abstract Alterations of tactile processing have long been identified in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the extent to which these alterations are disorder-specific, rather than disorder-general, and how they relate to the core symptoms of each disorder, remains unclear. We measured and compared tactile detection, discrimination, and order judgment thresholds between a large sample of children with ASD, ADHD, ASD + ADHD combined and typically developing controls. The pattern of results suggested that while difficulties with tactile detection and order judgement were more common in children with ADHD, difficulties with tactile discrimination were more common in children with ASD. Interestingly, in our subsequent correlation analyses between tactile perception and disorder-specific clinical symptoms, tactile detection and order judgment correlated exclusively with the core symptoms of ADHD, while tactile discrimination correlated exclusively with the symptoms of ASD. When taken together, these results suggest that disorder-specific alterations of lower-level sensory processes exist and are specifically related to higher-level clinical symptoms of each disorder.

Estimates from the coronavirus disease 2019 (COVID-19) pandemic suggest that about 20% of adults with COVID-19 are hospitalized, and in approximately 20% of those, severe acute respiratory failure develops that requires life-support treatments such as invasive mechanical ventilation.1,2 Results of research from before the COVID-19 pandemic suggest that most of these adults with critical illness will survive to hospital discharge.3,4 Survival, for many, will come with a legacy of new or worsening deficits in physical,5 mental,6,7 or cognitive health in the months to years after hospital discharge.8,9Post–intensive care syndrome has become the agreed-upon term for these new or worsening health problems that can persist beyond an acute hospitalization for serious illness.8The psychosocial outcomes in survivors of critical illness include high rates of clinically significant anxiety,10 depression,11 and posttraumatic stress symptoms.12 Related, many survivors are unable to return to work13 and thereby suffer financial consequences that further the distress of survivors and their loved ones14; income loss by both the survivor and family members who curtail work to serve as caregivers may contribute further to their collective psychological distress.The multiple challenges of providing recovery-focused care in the intensive care unit (ICU) during the pandemic, along with the stigma and social isolation unique to COVID-19 survivors, may contribute to a high level of psychological distress in COVID-19 survivors.15 Urgent innovation is needed to mitigate psychosocial distress among COVID-19 survivors. In this review, we leverage the growing expertise within the Critical and Acute Illness Recovery Organization (CAIRO), an international multi-disciplinary organization committed to improving the quality of life of patients and families after critical illness, to (1) define peer support and provide a vision for its potential role in COVID-19 recovery and (2) summarize key strategies for developing and sustaining a peer support program during the pandemic.Peer support is a system of giving and receiving help in relationship with others who share similar experiences. Table 1 summarizes key principles of peer support, which include acceptance, respect with dignity,16 reciprocity,17–19 mutual responsibility, and trust/integrity. Within the health care context, peer support or peer-based support programs are complex interventions studied as an approach to (1) improve patient outcomes after transitional stressors (eg, pregnancy, postpartum depression, bereavement), (2) improve patients' and families' adjustment to chronic diseases (eg, cancer , drug addiction, diabetes), and (3) promote healthful living or disease prevention (eg, use of peers to prevent sexually transmitted diseases or to promote cancer-screening behaviors).20Since we suggested peer support as a novel strategy to mitigate psychological distress after critical illness,21 many health systems have started to integrate various models of peer support22 into their ICU recovery treatment as a way to promote resilience, provide social and emotional support, and ensure informational exchange between critical illness survivors. The 6 models of peer support that have been described include community based, psychologist-led outpatient, within ICU, within ICU follow-up clinics, online, and peer mentor models.22Before the COVID-19 pandemic, few of the health systems that had started peer support programs for ICU survivors had transitioned to a true peer-led model. As health systems respond to the moral call to develop robust infrastructure to improve the recovery and social integration of adult COVID-19 survivors, the pandemic may catalyze the transition and growth of peer-led models for 2 reasons. First, a unifying, singular diagnosis may serve to overcome a barrier to the peer-led model, which is the heterogeneity of experiences that lead to critical illness. Although survivors who required invasive mechanical ventilation have much in common, the stories of patients who arrived in that state may differ dramatically. For example, a car accident, a pneumonia, and a progressive chronic condition can each lead to the common pathway of requiring life support. Although similarities abound, including the frequency of long-term impairments and recovery challenges, an anchoring diagnosis is often lacking. Second, the high number of health care workers affected by COVID-19 may motivate a quicker transition to a peer-led model of support.Despite the limited evidence of the effectiveness of peer support interventions in ICU survivors,23 recent qualitative analyses elucidate 3 potential mechanisms by which peer support programs could be beneficial to COVID-19 survivors. First, by providing a forum for survivors to share their experiences, peer support may improve psychological morbidity, increase motivation for rehabilitation therapy, and reduce social isolation. Second, by providing a means for patients to better understand their acute illness experience, peer support may provide survivors with internal and external validation of recovery progress, may help provide tools to improve patients' understanding of the relevant parts of the health care system, and may help manage expectations for recovery. Third, by providing the structure for survivors to give benefits to another person as they receive benefit (reciprocity), peer support may facilitate resilience, trust, and a sense of purpose.24Using qualitative analysis, researchers from our group have identified barriers and enablers to starting peer support programs.25 In Table 2, we summarize 6 key strategies for developing and sustaining a peer support program during the pandemic. The preparation steps include setting goals and objectives for the peer support program, assembling a multi-disciplinary team of innovators, and deciding which online platform to use for the meeting. Although ideally the innovation team would include a survivor of COVID-19 or another critical illness, most of the peer support programs currently being sustained for ICU survivors are facilitated by behavioral health experts, and it may take several years to identify a suitable peer leader. Each platform for online meetings has advantages and disadvantages; teams should be aware of their local institutional policies regarding best practices for meeting online via these platforms. Although phone conferences are an option, we believe video platforms are the best choice to enhance the social connection of the group.26 Other online communities allow survivors to interact with one another asynchronously, meaning that participants can interact on their own timeline, thereby allowing group members from across multiple time zones to connect with one another. One pervasive challenge remains for peer support online programs during COVID-19: how to be more intentional about including participants across all racial/ethnic backgrounds and all physical and cognitive abilities.Despite the high volume of COVID-19 survivors, the recruitment of suitable participants for a peer support program requires intention and care. Starting the recruitment during the hospitalization period is feasible by providing information about critical illness recovery to patients, caregivers, and health care providers. Where active, ICU follow-up clinics can also serve to identify patients and family members who may benefit from engaging in peer support.Choosing facilitators who are skilled and motivated to work with COVID-19 survivors will be instrumental for the success of the peer support program. Effective facilitators engage the group members; prioritize safety, respect, and privacy; and keep the conversation focused and fluid. Facilitators foster the development of empathic, respectful, and collaborative relationships between the participants. On a video platform, it may be crucial that facilitators be visible at all times during the meeting in order to maintain a strong collaborative relationship during these group interactions.26 Cofacilitation may help improve the effectiveness and safety of the peer support by addressing the challenge of effectively responding to intense emotions through online platforms.Given the high prevalence of traumatic experiences in ICU survivors and their families, facilitators should use a trauma-informed approach to facilitation, which acknowledges that all types of trauma may adversely affect how survivors interact and cope.27 (See Table 3 for key principles of trauma-informed peer support.) Whether peer support programs can be useful in facilitating posttraumatic growth, defined as a positive psychological change that can come from processing a trauma, is a question that could be investigated in future research studies.28 For facilitators of an asynchronous online community, ensuring that group members feel heard and acknowledged may take extra effort. Unlike in-person and video groups, where feedback and comments are in real time, groups whose members connect asynchronously run the risk of having members feel alone or unheard if responses to their participation are not timely.29Negotiating ground rules at the beginning of the online meeting is particularly important. These rules ensure that everyone participating adheres to shared general concepts that preserve the privacy and safety of all participants. Particularly when using online platforms, participants must be able to ensure that their privacy is upheld, that no one who was not specifically invited to the group can overhear or observe the group's activity.After each meeting, cofacilitators should debrief and reflect on key aspects of the group encounter. As peer support is a still in an early phase of innovation, an important role for any peer support program is to serve as a bridge between the world of the COVID-19 survivor and the acute care setting of the hospital: certain themes that emerge from survivors can facilitate intra-ICU and in-hospital care improvements for future COVID-19 patients.30 Peer support programs can create new roles for COVID-19 survivors in the hospital setting and help improve the morale of the acute care staff.30 Program leaders should also have a plan to systematically collect quantitative or qualitative feedback from the participants and be willing to disseminate information about both their successes and their failures.31,32The COVID-19 pandemic will require health systems to test interventions to improve the recovery and social integration of adult survivors of COVID-19. Peer support is a complex intervention that allows COVID-19 survivors to give and receive practical and emotional support in relationship with other survivors of acute illness. The growing expertise within CAIRO can be leveraged by stakeholders interested in starting and sustaining a peer support program for COVID-19 survivors.Aluko A. Hope and Andrea Johnson served as cochairs of the CAIRO Peer Support Collaborative, served as co–first authors, and contributed equally to the work. We would like to acknowledge the administrative support of Max Monahan and the help in facilitating the preparation of this work from CAIRO administrative support staff.

To determine the prevalence and extent of impairments impacting health-related quality of life among survivors of COVID-19 who required mechanical ventilation, 6 months after hospital discharge.Multicenter, prospective cohort study, enrolling adults 18 years old or older with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection who received mechanical ventilation for 48 hours or more and survived to hospital discharge. Eligible patients were contacted 6 months after discharge for telephone-based interviews from March 2020 to December 2020. Assessments included: Montreal Cognitive Assessment-Blind, Hospital Anxiety and Depression Scale, Impact of Event Scale-6, EuroQOL 5 domain quality-of-life questionnaire, and components of the Multidimensional Dyspnea Profile.Two tertiary academic health systems.Of 173 eligible survivors, a random sample of 63 were contacted and 60 consented and completed interviews.None.Mean age was 57 + 13 years and mean duration of invasive mechanical ventilation was 14 + 8.2 days. Six months post-discharge, 48 patients (80%; 95% CI, 68-88%) met criteria for post-intensive care syndrome (PICS), with one or more domains impaired. Among patients with PICS, 28 (47%; 95% CI, 35-59%) were impaired in at least 2 domains, and 12 (20%; 95% CI, 12-32%) impaired in all three domains. Significant symptoms of post-traumatic stress were present in 20 patients (33%; 95% CI, 23-46%), anxiety in 23 (38%; 95% CI, 27-51%), and depression in 25 (42%; 95% CI, 30-54%). Thirty-three patients (55%; 95% CI, 42-67%) had impairments in physical activity; 25 patients (42%; 95% CI, 30-54%) demonstrated cognitive impairment.Eighty percent of COVID-19 survivors who required mechanical ventilation demonstrated PICS 6 months after hospital discharge. Patients were commonly impaired in multiple PICS domains as well as coexisting mental health domains.

Historically, extensively drug-resistant tuberculosis has been notoriously difficult to treat with devasting outcomes. As we are coming to the end of an era where the 2006 extensively drug-resistant tuberculosis definitions and old treatment regimens are being replaced, we aimed to estimate the proportion of extensively drug-resistant tuberculosis patients globally who achieved successful treatment outcomes.We conducted a systematic review of PubMed/MEDLINE, Scopus, Web of Science, and Embase from January 1, 2005, through April 3, 2023. Included studies reported WHO treatment outcomes, or adaptions hereof, for pre-extensively and/or extensively drug-resistant tuberculosis patients according to the 2006 WHO definition. Eligible studies included cohorts of at least 10 adults (aged>18 years) that were not pregnant. Using a random-effects model, we calculated pooled proportions of treatment outcomes and performed sensitivity and subgroup analyses. PROSPERO registration number: CRD42022340961.Among 5056 studies reviewed, we identified 94 studies from 26 countries, involving 10,223 extensively drug-resistant tuberculosis patients. The pooled proportion of successful treatment outcomes was 44.2% (95%CI: 38.3-50.3). Sensitivity analyses consistently produced similar estimates. A slight improvement in treatment outcomes was observed after 2013. Furthermore, 25 studies reported outcomes for 3564 individuals with pre-extensively drug-resistant tuberculosis, of which 63.3% achieved successful treatment (95%CI: 43.1-72.5).Globally, the success rate of extensively drug-resistant tuberculosis treatment is 44.2%, far below the WHO's target rate of 75%. These results may serve as a reference for future studies assessing extensively drug-resistant tuberculosis treatment outcomes under the 2021 definition treated with better treatment regimens available. Comprehensive surveillance data of extensively drug-resistant tuberculosis outcomes from the whole world are desirable to monitor treatment progress.

Sepsis hospitalizations are frequently followed by hospital readmissions, often for recurrent sepsis. However, it is unclear how often sepsis readmissions are for relapsed/recrudescent versus new infections. The aim of this study was to assess the extent to which 90-day readmissions for recurrent sepsis are due to infection of the same site and same pathogen as the initial episode.Retrospective cohort study.University of Michigan Health System.All hospitalizations (May 15, 2013 to May 14, 2015) with a principal International Classification of Diseases, Ninth revision, Clinical Modification diagnosis of septicemia (038.x), severe sepsis (995.92), or septic shock (785.52), as well as all subsequent hospitalizations and sepsis readmissions within 90 days. We determined organism and site of sepsis through manual chart abstraction.None.We identified 472 readmissions within 90 days of sepsis, of which 137 (29.1%) were for sepsis. In sepsis readmissions, the site and organisms were most commonly urinary (29.2%), gastrointestinal (20.4%), Gram negative (29.9%), Gram positive (16.8%), and culture negative (30.7%). Ninety-four readmissions (68.6%) were for infection at the same site as initial sepsis hospitalization. Nineteen percent of readmissions were confirmed to be same site and same organism. However, accounting for the uncertainty from culture-negative sepsis, as many as 53.2% of readmissions could plausibly due to infections with both the same organism and same site.Of the patients readmitted with sepsis within 90 days, two thirds had infection at the same site as their initial admission. Just 19% had infection confirmed to be from the same site and organism as the initial sepsis hospitalization. Half of readmissions were definitively for new infections, whereas an additional 34% were unclear since cultures were negative in one of the hospitalizations.

The purpose of this study was to detail the trajectory and outcomes of patients with severe sepsis admitted from the emergency department to a non-intensive care unit (ICU) setting and identify risk factors associated with adverse outcomes.This was a single-center retrospective cohort study conducted at a tertiary, academic hospital in the United States between 2005 and 2009. The primary outcome was a composite outcome of ICU transfer within 48 hours of admission and/or 28-day mortality.Of 1853 patients admitted with severe sepsis, 841 (45%) were admitted to a non-ICU setting, the rate increased over time (P < .001), and 12.5% of these patients were transferred to the ICU within 48 hours and/or died within 28 days. In multivariable models, age (P < .001), an oncology diagnosis (P < .001), and illness severity as measured by Acute Physiologic and Chronic Health Evaluation II (P = .04) and high (≥4 mmol/L) initial serum lactate levels (P = .005) were associated with the primary outcome.Patients presenting to the emergency department with severe sepsis were frequently admitted to a non-ICU setting, and the rate increased over time. Of 8 patients admitted to the hospital ward, one was transferred to the ICU within 48 hours and/or died within 28 days of admission. Factors present at admission were identified that were associated with adverse outcomes.

Rationale: Understanding long-term outcomes of critically ill patients may inform shared decision-making in the intensive care unit (ICU).Objectives: To quantify 6-month functional outcomes of general ICU patients, and develop a multivariable model comprising factors present during the first ICU day to predict which patients will return to their baseline function 6 months later.Methods: We conducted a prospective cohort study in three medical ICUs and two surgical ICUs in three hospitals. We enrolled patients who spent at least 3 days in the ICU and received mechanical ventilation for more than 48 hours and/or vasoactive infusions for more than 24 hours.Results: We measured 6-month outcomes including survival, return to original place of residence, and physical and cognitive function. Of 303 enrolled patients, 299 (98.7%) had complete follow-up at 6 months. Among the 169 patients (56.5%) who survived to 6 months, 82.8% returned home, 81.9% were able to toilet, 71.3% were able to ambulate 10 stairs, and 62.4% reported normal cognition. Overall, 31.1% of patients returned to their baseline status on these measures. Factors associated with not returning to baseline included higher APACHE III score, being a medical patient, older age, nonwhite race, recent hospitalization, prior transplantation, and a history of cancer or of neurologic or liver disease. A model including only these Day 1 factors had good discrimination (area under receiver operating characteristic curve, 0.778; 95% confidence interval, 0.724–0.832) and calibration (difference between observed and expected P value, 0.36).Conclusions: Among patients spending at least 3 days in an ICU and requiring even brief periods of life-sustaining therapy, nearly one-half will be dead and less than one-third will have returned to their baseline status at 6 months. Of those who survive, the majority of patients will be back at home at 6 months. Future research is needed to validate this multivariable model, including readily available patient characteristics available on the first ICU day, that seems to identify patients who will return to baseline at 6 months.

We implemented an electronic early warning and response system (EWRS) to improve detection of and response to severe sepsis. Sustainability of such a system requires stakeholder acceptance. We hypothesized that clinicians receiving such alerts perceive them to be useful and effective.To survey clinicians after EWRS notification about perceptions of the system.For a 6-week study period 1 month after EWRS implementation in a large tertiary referral medical center, bedside clinicians, including providers (physicians, advanced practice providers) and registered nurses (RNs), were surveyed confidentially within 2 hours of an alert.For the 247 alerts that triggered, 127 providers (51%) and 105 RNs (43%) completed the survey. Clinicians perceived most patients as stable before and after the alert. Approximately half (39% providers, 48% RNs) felt the alert provided new information, and about half (44% providers, 56% RNs) reported changes in management as a result of the alert, including closer monitoring and additional interventions. Over half (54% providers, 65% RNs) felt the alert was appropriately timed. Approximately one-third found the alert helpful (33% providers, 40% RNs) and fewer felt it improved patient care (24% providers, 35% RNs).A minority of responders perceived the EWRS to be useful, likely related to the perception that most patients identified were stable. However, management was altered half the time after an alert. These results suggest further improvements to the system are needed to enhance clinician perception of the system's utility.

Sepsis is a major risk factor for acute respiratory distress syndrome (ARDS). However, there remains a paucity of literature examining risk factors for ARDS in septic patients early in their course. This study examined the role of early fluid administration and identified other risk factors within the first 6 h of hospital presentation associated with developing ARDS in septic patients.This was a secondary analysis of septic adult patients presenting to the Emergency Department or being admitted for high-risk elective surgery from the multicenter observational cohort study, US Critical Injury and Illness trial Group-Lung Injury Prevention Study 1 (USCIITG-LIPS 1, NCT00889772). Multivariable logistic regression was performed to identify potential early risk factors for ARDS. Stratified analysis by shock status was performed to examine the association between early fluid administration and ARDS.Of the 5584 patients in the original study cohort, 2534 (45.4%) met our criteria for sepsis. One hundred and fifty-six (6.2%) of these patients developed ARDS during the hospital stay. In multivariable analyses, Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR 1.10, 95% CI 1.07-1.13), age (OR 0.97, 95% CI 0.96-0.98), total fluid infused in the first 6 h (in liters) (OR 1.15, 95% CI 1.03-1.29), shock (OR 2.57, 95% CI 1.62-4.08), pneumonia as a site of infection (OR 2.31, 95% CI 1.59-3.36), pancreatitis (OR 3.86, 95% CI 1.33-11.24), and acute abdomen (OR 3.77, 95% CI 1.37-10.41) were associated with developing ARDS. In the stratified analysis, total fluid infused in the first 6 h (in liters) (OR 1.05, 95% CI 0.87-1.28) was not associated with the development of ARDS in the shock group, while there was an association in the non-shock group (OR 1.21, 95% CI 1.05-1.38).In septic patients, the following risk factors identified within the first 6 h of hospital presentation were associated with ARDS: APACHE II score, presence of shock, pulmonary source of infection, pancreatitis, and presence of an acute abdomen. In septic patients without shock, the amount of fluid infused during the first 6 h of hospital presentation was associated with developing ARDS.

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) can be measured in vivo using edited magnetic resonance spectroscopy (MRS), but quantification suffers from contamination by macromolecules (MM). It is possible to suppress this contamination using symmetric editing, but this procedure potentially compromises reliability of the GABA measurement. The aim of this study was to compare the repeatability of GABA-edited MRS with and without MM suppression.GABA' (non-MM contaminated) and GABA'+MM (MM-contaminated) concentration was measured in the occipital lobe (OCC) and anterior cingulate (AC) using symmetric and standard editing (n = 15). Each method was performed twice in each region.Within-participant coefficients of variation for each technique were 4.0% (GABA'+MM) and 8.6% (GABA') in the OCC and 14.8% (GABA'+MM) and 12.6% (GABA') in the AC. Intraclass correlation coefficients were better for the suppression method than standard editing in both the OCC (0.72 versus 0.67) and AC (0.41 versus 0.16). These findings were replicated in the OCC of a second cohort (n = 15).Symmetric suppression is shown to be comparable in repeatability to standard GABA-editing. Measuring a purer quantification of GABA becomes increasingly important as more research is conducted on links between GABA concentration, pathology and healthy behavior.

Motivated by an observational study of the effect of hospital ward versus intensive care unit admission on severe sepsis mortality, we develop methods to address two common problems in observational studies: (1) when there is a lack of covariate overlap between the treated and control groups, how to define an interpretable study population wherein inference can be conducted without extrapolating with respect to important variables; and (2) how to use randomization inference to form confidence intervals for the average treatment effect with binary outcomes. Our solution to problem (1) incorporates existing suggestions in the literature while yielding a study population that is easily understood in terms of the covariates themselves, and can be solved using an efficient branch-and-bound algorithm. We address problem (2) by solving a linear integer program to use the worst-case variance of the average treatment effect among values for unobserved potential outcomes that are compatible with the null hypothesis. Our analysis finds no evidence for a difference between the 60-day mortality rates if all individuals were admitted to the ICU and if all patients were admitted to the hospital ward among less severely ill patients and among patients with cryptic septic shock. We implement our methodology in R, providing scripts in the supplementary material.

To demonstrate the framework of a novel Hadamard-encoded spectral editing approach for simultaneously detecting multiple low-concentration brain metabolites in vivo at 3T. HERCULES (Hadamard Editing Resolves Chemicals Using Linear-combination Estimation of Spectra) is a four-step Hadamard-encoded editing scheme. 20-ms editing pulses are applied at: (A) 4.58 and 1.9 ppm; (B) 4.18 and 1.9 ppm; (C) 4.58 ppm; and (D) 4.18 ppm. Edited signals from γ-aminobutyric acid (GABA), glutathione (GSH), ascorbate (Asc), N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), aspartate (Asp), lactate (Lac), and likely 2-hydroxyglutarate (2-HG) are separated with reduced signal overlap into distinct Hadamard combinations: (A+B+C+D); (A+B–C–D); and (A–B+C–D). HERCULES uses a novel multiplexed linear-combination modeling approach, fitting all three Hadamard combinations at the same time, maximizing the amount of information used for model parameter estimation, in order to quantify the levels of these compounds. Fitting also allows estimation of the levels of total choline (tCho), myo-inositol (Ins), glutamate (Glu), and glutamine (Gln). Quantitative HERCULES results were compared between two grey- and white-matter-rich brain regions (11 min acquisition time each) in 10 healthy volunteers. Coefficients of variation (CV) of quantified measurements from the HERCULES fitting approach were compared against those from a single-spectrum fitting approach, and against estimates from short-TE PRESS data. HERCULES successfully segregates overlapping resonances into separate Hadamard combinations, allowing for the estimation of levels of seven coupled metabolites that would usually require a single 11-min editing experiment each. Metabolite levels and CVs agree well with published values. CVs of quantified measurements from the multiplexed HERCULES fitting approach outperform single-spectrum fitting and short-TE PRESS for most of the edited metabolites, performing only slightly to moderately worse than the fitting method that gives the lowest CVs for tCho, NAA, NAAG, and Asp. HERCULES is a new experimental approach with the potential for simultaneous editing and multiplexed fitting of up to seven coupled low-concentration and six high-concentration metabolites within a single 11-min acquisition at 3T.

To investigate whether a deep learning-based (DL) approach can be used for frequency-and-phase correction (FPC) of MEGA-edited MRS data.Two neural networks (1 for frequency, 1 for phase) consisting of fully connected layers were trained and validated using simulated MEGA-edited MRS data. This DL-FPC was subsequently tested and compared to a conventional approach (spectral registration [SR]) and to a model-based SR implementation (mSR) using in vivo MEGA-edited MRS datasets. Additional artificial offsets were added to these datasets to further investigate performance.The validation showed that DL-based FPC was capable of correcting within 0.03 Hz of frequency and 0.4°of phase offset for unseen simulated data. DL-based FPC performed similarly to SR for the unmanipulated in vivo test datasets. When additional offsets were added to these datasets, the networks still performed well. However, although SR accurately corrected for smaller offsets, it often failed for larger offsets. The mSR algorithm performed well for larger offsets, which was because the model was generated from the in vivo datasets. In addition, the computation times were much shorter using DL-based FPC or mSR compared to SR for heavily distorted spectra.These results represent a proof of principle for the use of DL for preprocessing MRS data.

Recent advances in J-difference-edited proton magnetic resonance spectroscopy (1H MRS) data acquisition and processing have led to the development of Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) techniques, which enable the simultaneous measurement of ɣ-aminobutyric acid (GABA), the primary inhibitory amino acid neurotransmitter in the central nervous system, and of glutathione (GSH), the most abundant antioxidant in living tissue, at the commonly available magnetic field strength of 3 T. However, the reproducibility of brain levels of GABA and GSH measured across multiple scans in human subjects using HERMES remains to be established. In the present study, twelve healthy volunteers completed two consecutive HERMES scans of the dorsal anterior cingulate cortex (dACC) to assess the test-retest reproducibility of the technique for GABA and GSH measurements at TE = 80 ms. Eleven of the twelve participants additionally completed two consecutive MEGA-PRESS scans at TE = 120 ms, with editing pulses configured for GSH acquisition, to compare the reliability of GSH in the same voxel measured using the standard MEGA-PRESS at TE = 120 ms. The primary findings of study were that, 1) the coefficient of variation (CV) of measuring GABA with HERMES was 16.7%, which is in agreement with the reliability we previously reported for measuring GABA using MEGA-PRESS; and 2) the reliability of measuring GSH with MEGA-PRESS at TE = 120 ms was more than twice as high as that for measuring the antioxidant with HERMES at TE = 80 ms (CV = 7.3% vs. 19.0% respectively). These findings suggest that HERMES and MEGA-PRESS offer similar reliabilities for measuring GABA, while MEGA-PRESS at TE = 120 ms is more reliable for measuring GSH relative to HERMES at TE = 80 ms.

<h3>Importance</h3> Despite a growing recognition of the increased mortality risk among sepsis survivors, little is known about the patterns of end-of-life care among this population. <h3>Objective</h3> To describe patterns of end-of-life care among a national sample of sepsis survivors and identify factors associated with long-term mortality risk and hospice use. <h3>Design, Setting, and Participants</h3> This cohort study assessed sepsis survivors who were Medicare fee-for-service beneficiaries discharged to home health care using national Medicare administrative, claims, and home health assessment data from 2013 to 2014. The initial and final primary analyses were conducted in July 2017 and from July to August 2019, respectively. <h3>Exposures</h3> Sepsis hospital discharge and 1 or more home health assessments within 1 week. <h3>Main Outcomes and Measures</h3> Outcomes were 1-year mortality among all sepsis survivors and hospitalization in the last 30 days of life, death in an acute care hospital, and hospice use among decedents. Multivariate logistic regression was used to identify factors associated with 1-year mortality and hospice use. <h3>Results</h3> Among 87 581 sepsis survivors who were Medicare fee-for-service beneficiaries discharged to home health care, 49 323 (56.3%) were aged 75 years or older, 69 499 (79.4%) were non-Hispanic white, and 48 472 (55.3%) were female. Among the total survivors, 24 423 (27.9%) people died within 1 year of discharge, with a median (interquartile range) survival time of 119 (51-220) days. Among these decedents, 16 684 (68.2%) were hospitalized in the last 30 days of life, 6560 (26.8%) died in an acute care hospital, and 12 573 (51.4%) were enrolled in hospice, with 5729 (45.6%) using hospice for 7 or fewer days. Several factors were associated with 1-year mortality, including a cancer diagnosis (odds ratio [OR], 3.66; 95% CI, 3.50-3.83;<i>P</i> &lt; .001), multiple dependencies of activities of daily living or instrumental activities of daily living (OR, 2.80; 95% CI, 2.57-3.05;<i>P</i> &lt; .001), and an overall poor health status (OR, 2.21; 95% CI, 2.01-2.44;<i>P</i> &lt; .001) documented on home health assessment. Among the decedents, cancer was associated with hospice use (OR, 2.25; 95% CI, 2.11-2.41;<i>P</i> &lt; .001), patients aged 85 years or older (OR, 1.49; 95% CI, 1.37-1.61;<i>P</i> &lt; .001), and living in an assisted living setting (OR, 1.93; 95% CI, 1.69-2.19;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> The findings of this study suggest that death within 1 year after sepsis discharge may be common among Medicare beneficiaries discharged to home health care. Although 1 in 2 decedents used hospice, aggressive care near the end of life and late hospice referral were common. Readily identifiable risk factors suggest opportunities to target efforts to improve palliative and end-of-life care among high-risk sepsis survivors.

Summary Survivors of critical illness frequently require increased healthcare resources after hospital discharge. We undertook a systematic review and meta‐analysis to assess hospital re‐admission rates following critical care admission and to explore potential re‐admission risk factors. We searched the MEDLINE, Embase and CINAHL databases on 05 March 2020. Our search strategy incorporated controlled vocabulary and text words for hospital re‐admission and critical illness, limited to the English language. Two reviewers independently applied eligibility criteria and assessed quality using the Newcastle Ottawa Score checklist and extracted data. The primary outcome was acute hospital re‐admission in the year after critical care discharge. Of the 8851 studies screened, 87 met inclusion criteria and 41 were used within the meta‐analysis. The analysis incorporated data from 3,897,597 patients and 741,664 re‐admission episodes. Pooled estimates for hospital re‐admission after critical illness were 16.9% (95%CI: 13.3–21.2%) at 30 days; 31.0% (95%CI: 24.3–38.6%) at 90 days; 29.6% (95%CI: 24.5–35.2%) at six months; and 53.3% (95%CI: 44.4–62.0%) at 12 months. Significant heterogeneity was observed across included studies. Three risk factors were associated with excess acute care rehospitalisation one year after discharge: the presence of comorbidities; events during initial hospitalisation (e.g. the presence of delirium and duration of mechanical ventilation); and subsequent infection after hospital discharge. Hospital re‐admission is common in survivors of critical illness. Careful attention to the management of pre‐existing comorbidities during transitions of care may help reduce healthcare utilisation after critical care discharge. Future research should determine if targeted interventions for at‐risk critical care survivors can reduce the risk of subsequent rehospitalisation.

Healthy aging is associated with mechanistic changes in gamma-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter in the human brain. While previous work mainly focused on magnetic resonance spectroscopy (MRS)-based GABA+ levels and transcranial magnetic stimulation (TMS)-based GABAA receptor (GABAAR) activity in the primary sensorimotor (SM1) cortex, the aim of the current study was to identify age-related differences in positron emission tomography (PET)-based GABAAR availability and its relationship with GABA+ levels (i.e. GABA with the contribution of macromolecules) and GABAAR activity. For this purpose, fifteen young (aged 20-28 years) and fifteen older (aged 65-80 years) participants were recruited. PET and MRS images were acquired using simultaneous time-of-flight PET/MR to evaluate age-related differences in GABAAR availability (distribution volume ratio with pons as reference region) and GABA+ levels. TMS was applied to identify age-related differences in GABAAR activity by measuring short-interval intracortical inhibition (SICI). Whereas GABAAR availability was significantly higher in the SM cortex of older as compared to young adults (18.5%), there were neither age-related differences in GABA+ levels nor SICI. A correlation analysis revealed no significant associations between GABAAR availability, GABAAR activity and GABA+ levels. Although the exact mechanisms need to be further elucidated, it is possible that a higher GABAAR availability in older adults is a compensatory mechanism to ensure optimal inhibitory functionality during the aging process.

Abstract Purpose To acquire the mobile macromolecule (MM) spectrum from healthy participants, and to investigate changes in the signals with age and sex. Methods 102 volunteers (49 M/53 F) between 20 and 69 years were recruited for in vivo data acquisition in the centrum semiovale (CSO) and posterior cingulate cortex (PCC). Spectral data were acquired at 3T using PRESS localization with a voxel size of 30 × 26 × 26 mm 3 , pre‐inversion (TR/TI 2000/600 ms) and CHESS water suppression. Metabolite‐nulled spectra were modeled to eliminate residual metabolite signals, which were then subtracted out to yield a “clean” MM spectrum using the Osprey software. Pearson’s correlation coefficient was calculated between integrals and age for the 14 MM signals. One‐way ANOVA was performed to determine differences between age groups. An independent t ‐test was carried out to determine differences between sexes. Results MM spectra were successfully acquired in 99 (CSO) and 96 (PCC) of 102 subjects. No significant correlations were seen between age and MM signals. One‐way ANOVA also suggested no age‐group differences for any MM peak (all p &gt; .004). No differences were observed between sex groups. WM and GM voxel fractions showed a significant ( p &lt; .05) negative linear association with age in the WM‐predominant CSO ( R = –0.29) and GM‐predominant PCC regions ( R = –0.57) respectively while CSF increased significantly with age in both regions. Conclusion Our findings suggest that a pre‐defined MM basis function can be used for linear combination modeling of metabolite data from different age and sex groups.

<h3>Background</h3> Prior studies suggest that mortality differs by sex and race in patients who develop acute lung injury (ALI). Whether differences in presentation account for these disparities remains unclear. We sought to determine whether sexual and racial differences exist in the rate of ALI development and ALI-related mortality after accounting for differences in clinical presentations. <h3>Methods</h3> This was a multicenter, observational cohort study of 5,201 patients at risk for ALI. Multivariable logistic regression with adjustment for center-level effects was used to adjust for potential covariates. <h3>Results</h3> The incidence of ALI development was 5.9%; in-hospital mortality was 5.0% for the entire cohort, and 24.4% for those patients who developed ALI. Men were more likely to develop ALI compared to women (6.9% vs 4.7%, <i>P</i> < .001) and had a nonsignificant increase in mortality when ALI developed (27.6% vs 18.5%, <i>P</i> = .08). However, after adjustment for baseline imbalances between sexes these differences were no longer significant. Black patients, compared to white patients, presented more frequently with pneumonia, sepsis, or shock and had higher severity of illness. Black patients were less likely to develop ALI than whites (4.5% vs. 6.5%, <i>P</i> = .014), and this association remained statistically significant after adjusting for differences in presentation (OR, 0.66; 95 % CI, 0.45-0.96). <h3>Conclusions</h3> Sex and race differences exist in the clinical presentation of patients at risk of developing ALI. After accounting for differences in presentation, there was no sex difference in ALI development and outcome. Black patients were less likely to develop ALI despite increased severity of illness on presentation.

The purpose was to identify risk factors associated with in-hospital mortality among emergency department (ED) patients with severe sepsis and septic shock managed with early protocolized resuscitation.This was a retrospective, observational cohort study in an academic, tertiary care ED. We enrolled 411 adult patients with severe sepsis and lactate ≥4.0 mmol/L (n = 203) or septic shock (n = 208) who received protocolized resuscitation from 2005 to 2009. Emergency department variables, microbial cultures, and in-hospital outcomes were obtained from the medical record. Multivariable regression was used to identify factors independently associated with in-hospital mortality.Mean age was 59.5 ± 16.3 years; 57% were male. Mean lactate was 4.8 mmol/L (3.5-6.7), 54% had positive cultures, and 27% received vasopressors in the ED. One hundred and five (26%) patients died in-hospital. Age, active cancer, do-not-resuscitate status on ED arrival, lack of fever, hypoglycemia, and intubation were independently associated with increased in-hospital mortality. Lactate clearance and diabetes were associated with a decreased risk of in-hospital death.We identified a number of factors that were associated with in-hospital mortality among ED patients with severe sepsis or septic shock despite treatment with early protocolized resuscitation. These findings provide insights into aspects of early sepsis care that can be targets for future intervention.

Sepsis is an acute, life-threatening condition that afflicts millions of patients annually. Advances in care and heightened awareness have led to substantial declines in short-term mortality. An expanding body of literature describes the long-term impact of sepsis, revealing long-term cognitive and functional impairments, sustained inflammation and immune dysfunction, increased healthcare resource use, reduced health-related quality of life, and increased mortality. The evidence challenges the notion that sepsis is an acute, transient illness, revealing rather that sepsis is an acute illness with lingering consequences. This article provides a state-of-the-art review of the emerging literature of the long-term consequences of sepsis.

Attention-deficit hyperactivity disorder (ADHD) is characterized by an inability to concentrate, heightened activity, and hypermotoric behavior, but sensory (e.g., tactile) problems are common. The literature on tactile impairments in ADHD is limited, with most work employing clinical observations or questionnaires. We studied tactile processing in children with ADHD and hypothesized that children with ADHD would show reduced performance in tasks closely linked to inhibition. Sixty-seven children with ADHD and 62 typically developing children (TDC) performed a battery of tasks grouped in domains: simple and choice reaction time; static and dynamic detection threshold (probing feedforward inhibition); amplitude discrimination without adaptation and with dual and single-site adaptation (probing lateral inhibition and adaptation); sequential and simultaneous frequency discrimination (previously linked to GABA); and temporal order judgment with and without a synchronous carrier stimulus. Children with ADHD could discriminate different amplitudes without adaptation, suggesting lateral inhibition is intact, but were negatively affected in all adaptation conditions, whereas TDC were only affected during single-site adaptation. Children with ADHD also showed normal frequency discrimination. Children with ADHD showed slower reaction times and higher detection threshold, likely driven by IQ and inattention, because reaction time and detection thresholds correlated with IQ and subtle motor signs. Children with ADHD showed a pattern of altered tactile processing on specific tasks, suggesting that higher cognitive function and cortical mechanisms related to adaptation are affected in ADHD, but no clear conclusion can be drawn toward impaired inhibition.NEW & NOTEWORTHY This manuscript presents the first tactile psychophysical study testing different aspects of tactile processing in attention-deficit hyperactivity disorder (ADHD), using large cohort sizes of 67 children with ADHD and 65 Typically Developing Children. This study demonstrates impaired tactile processing in children with ADHD, on some, but not all tasks (showing this is not just due to attention), related to impaired cortical mechanisms. Furthermore, both IQ and soft motor skill abnormalities (common in ADHD) are correlated with tactile abnormalities.

Purpose Detection of endogenous metabolites using multiplexed editing substantially improves the efficiency of edited magnetic resonance spectroscopy. Multiplexed editing (i.e., performing more than one edited experiment in a single acquisition) requires a tailored, robust approach for correction of frequency and phase offsets. Here, a novel method for frequency and phase correction (FPC) based on spectral registration is presented and compared against previously presented approaches. Methods One simulated dataset and 40 γ‐aminobutyric acid‐/glutathione‐edited HERMES datasets acquired in vivo at three imaging centers were used to test four FPC approaches: no correction; spectral registration; spectral registration with post hoc choline‐creatine alignment; and multistep FPC. The performance of each routine for the simulated dataset was assessed by comparing the estimated frequency/phase offsets against the known values, whereas the performance for the in vivo data was assessed quantitatively by calculation of an alignment quality metric based on choline subtraction artifacts. Results The multistep FPC approach returned corrections that were closest to the true values for the simulated dataset. Alignment quality scores were on average worst for no correction, and best for multistep FPC in both the γ‐aminobutyric acid‐ and glutathione‐edited spectra in the in vivo data. Conclusions Multistep FPC results in improved correction of frequency/phase errors in multiplexed γ‐aminobutyric acid‐/glutathione‐edited magnetic resonance spectroscopy experiments. The optimal FPC strategy is experiment‐specific, and may even be dataset‐specific. Magn Reson Med 80:21–28, 2018. © 2017 International Society for Magnetic Resonance in Medicine.