Center variability in the prognostic value of a cumulative acute cellular rejection "A-score" for long-term lung transplant outcomes.

The acute rejection score (A-score) in lung transplant recipients, calculated as the average of acute cellular rejection A-grades across transbronchial biopsies, summarizes the cumulative burden of rejection over time. We assessed the association between A-score and transplant outcomes in 2 geographically distinct cohorts. The primary cohort included 772 double lung transplant recipients. The analysis was repeated in 300 patients from an independent comparison cohort. Time-dependent multivariable Cox models were constructed to evaluate the association between A-score and chronic lung allograft dysfunction or graft failure. Landmark analyses were performed with A-score calculated at 6 and 12 months posttransplant. In the primary cohort, no association was found between A-score and graft outcome. However, in the comparison cohort, time-dependent A-score was associated with chronic lung allograft dysfunction both as a time-dependent variable (hazard ratio, 1.51; P < .01) and when calculated at 6 months posttransplant (hazard ratio, 1.355; P = .031). The A-score can be a useful predictor of lung transplant outcomes in some settings but is not generalizable across all centers; its utility as a prognostication tool is therefore limited.

Canadian Multicentric Pan-TRK (CANTRK) Immunohistochemistry Harmonization Study.

Tumor-agnostic testing for NTRK1-3 gene rearrangements is required to identify patients who may benefit from TRK inhibitor therapies. The overarching objective of this study was to establish a high-quality pan-TRK immunohistochemistry (IHC) screening assay among 18 large regional pathology laboratories across Canada using pan-TRK monoclonal antibody clone EPR17341 in a ring study design. TRK-fusion positive and negative tumor samples were collected from participating sites, with fusion status confirmed by panel next-generation sequencing assays. Each laboratory received: (1) unstained sections from 30 cases of TRK-fusion-positive or -negative tumors, (2) 2 types of reference standards: TRK calibrator slides and IHC critical assay performance controls (iCAPCs), (3) EPR17341 antibody, and (4) suggestions for developing IHC protocols. Participants were asked to optimize the IHC protocol for their instruments and detection systems by using iCAPCs, to stain the 30 study cases, and to report the percentage scores for membranous, cytoplasmic, and nuclear staining. TRK calibrators were used to assess the analytical sensitivity of IHC protocols developed by using the 2 reference standards. Fifteen of 18 laboratories achieved diagnostic sensitivity of 100% against next-generation sequencing. The diagnostic specificity ranged from 40% to 90%. The results did not differ significantly between positive scores based on the presence of any type of staining vs the presence of overall staining in ≥1% of cells. The median limit of detection measured by TRK calibrators was 76,000 molecules/cell (range 38,000 to >200,000 molecules/cell). Three different patterns of staining were observed in 19 TRK-positive cases, cytoplasmic-only in 7 samples, nuclear and cytoplasmic in 9 samples, and cytoplasmic and membranous in 3 samples. The Canadian multicentric pan-TRK study illustrates a successful strategy to accelerate the multicenter harmonization and implementation of pan-TRK immunohistochemical screening that achieves high diagnostic sensitivity by using laboratory-developed tests where laboratories used centrally developed reference materials. The measurement of analytical sensitivity by using TRK calibrators provided additional insights into IHC protocol performance.

Utility of molecular markers in predicting local control specific to lung cancer spine metastases treated with stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: We report outcomes following spine stereotactic body radiotherapy (SBRT) in metastatic non-small cell lung cancer (NSCLC) and the significance of programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR) mutation and timing of immune check point inhibitors (ICI) on local failure (LF). MATERIALS AND METHODS: 165 patients and 389 spinal segments were retrospectively reviewed from 2009 to 2021. Baseline patient characteristics, treatment and outcomes were abstracted. Primary endpoint was LF and secondary, overall survival (OS) and vertebral compression fracture (VCF). Multivariable analysis (MVA) evaluated factors predictive of LF and VCF. RESULTS: The median follow-up and OS were: 13.0 months (range, 0.5-95.3 months) and 18.4 months (95% CI 11.4-24.6). 52.1% were male and 76.4% had adenocarcinoma. Of the 389 segments, 30.3% harboured an EGFR mutation and 17.0% were PD-L1 ≥ 50%. The 24 months LF rate in PD-L1 ≥ 50% vs PD-L1 < 50% was 10.7% vs. 38.0%, and in EGFR-positive vs. negative was 18.1% vs. 30.0%. On MVA, PD-L1 status of ≥ 50% (HR 0.32, 95% CI 0.15-0.69, p = 0.004) significantly predicted for lower LF compared to PD-L1 < 50%. Lower LF trend was seen with ICI administration peri and post SBRT (HR 0.41, 95% CI 0.16-1.05, p = 0.062). On MVA, polymetastatic disease (HR 3.28, 95% CI 1.84-5.85, p < 0.0001) and ECOG ≥ 2 (HR 1.87, 95% CI 1.16-3.02, p = 0.011) significantly predicted for worse OS and absence of baseline VCF predicted for lower VCF rate (HR 0.20, 95% CI 0.10-0.39, p < 0.0001). CONCLUSION: We report a significant association of PD-L1 ≥ 50% status on improved LC rates from spine SBRT in NSCLC patients.

Predictive modeling of antibiotic eradication therapy success for new-onset Pseudomonas aeruginosa pulmonary infections in children with cystic fibrosis.

Chronic Pseudomonas aeruginosa (Pa) lung infections are the leading cause of mortality among cystic fibrosis (CF) patients; therefore, the eradication of new-onset Pa lung infections is an important therapeutic goal that can have long-term health benefits. The use of early antibiotic eradication therapy (AET) has been shown to clear the majority of new-onset Pa infections, and it is hoped that identifying the underlying basis for AET failure will further improve treatment outcomes. Here we generated machine learning models to predict AET outcomes based on pathogen genomic data. We used a nested cross validation design, population structure control, and recursive feature selection to improve model performance and showed that incorporating population structure control was crucial for improving model interpretation and generalizability. Our best model, controlling for population structure and using only 30 recursively selected features, had an area under the curve of 0.87 for a holdout test dataset. The top-ranked features were generally associated with motility, adhesion, and biofilm formation.

Thematic Analysis of Psychosocial Stressors and Adaptive Coping Strategies Among Informal Caregivers of Patients Surviving ICU Admission for Coma.

BACKGROUND: Family caregivers of patients with severe acute brain injury (SABI) admitted to intensive care units (ICUs) with coma experience heightened emotional distress stemming from simultaneous stressors. Stress and coping frameworks can inform psychosocial intervention development by elucidating common challenges and ways of navigating such experiences but have yet to be employed with this population. The present study therefore sought to use a stress and coping framework to characterize the stressors and coping behaviors of family caregivers of patients with SABI hospitalized in ICUs and recovering after coma. METHODS: Our qualitative study recruited a convenience sample from 14 US neuroscience ICUs. Participants were family caregivers of patients who were admitted with ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, or hypoxic-ischemic encephalopathy; had experienced a comatose state for > 24 h; and completed or were scheduled for tracheostomy and/or gastrostomy tube placement. Participants were recruited < 7 days after transfer out of the neuroscience ICU. We conducted live online video interviews from May 2021 to January 2022. One semistructured interview per participant was recorded and subsequently transcribed. Recruitment was stopped when thematic saturation was reached. We deductively derived two domains using a stress and coping framework to guide thematic analysis. Within each domain, we inductively derived themes to comprehensively characterize caregivers' experiences. RESULTS: We interviewed 30 caregivers. We identified 18 themes within the two theory-driven domains, including ten themes describing practical, social, and emotional stressors experienced by caregivers and eight themes describing the psychological and behavioral coping strategies that caregivers attempted to enact. Nearly all caregivers described using avoidance or distraction as an initial coping strategy to manage overwhelming emotions. Caregivers also expressed awareness of more adaptive strategies (e.g., cultivation of positive emotions, acceptance, self-education, and soliciting social and medical support) but had challenges employing them because of their heightened emotional distress. CONCLUSIONS: In response to substantial stressors, family caregivers of patients with SABI attempted to enact various psychological and behavioral coping strategies. They described avoidance and distraction as less helpful than other coping strategies but had difficulty engaging in alternative strategies because of their emotional distress. These findings can directly inform the development of additional resources to mitigate the long-term impact of acute psychological distress among this caregiver population.

Guidelines for Neuroprognostication in Critically Ill Adults with Intracerebral Hemorrhage.

BACKGROUND: The objective of this document is to provide recommendations on the formal reliability of major clinical predictors often associated with intracerebral hemorrhage (ICH) neuroprognostication. METHODS: A narrative systematic review was completed using the Grading of Recommendations Assessment, Development, and Evaluation methodology and the Population, Intervention, Comparator, Outcome, Timing, Setting questions. Predictors, which included both individual clinical variables and prediction models, were selected based on clinical relevance and attention in the literature. Following construction of the evidence profile and summary of findings, recommendations were based on Grading of Recommendations Assessment, Development, and Evaluation criteria. Good practice statements addressed essential principles of neuroprognostication that could not be framed in the Population, Intervention, Comparator, Outcome, Timing, Setting format. RESULTS: Six candidate clinical variables and two clinical grading scales (the original ICH score and maximally treated ICH score) were selected for recommendation creation. A total of 347 articles out of 10,751 articles screened met our eligibility criteria. Consensus statements of good practice included deferring neuroprognostication-aside from the most clinically devastated patients-for at least the first 48-72 h of intensive care unit admission; understanding what outcomes would have been most valued by the patient; and counseling of patients and surrogates whose ultimate neurological recovery may occur over a variable period of time. Although many clinical variables and grading scales are associated with ICH poor outcome, no clinical variable alone or sole clinical grading scale was suggested by the panel as currently being reliable by itself for use in counseling patients with ICH and their surrogates, regarding functional outcome at 3 months and beyond or 30-day mortality. CONCLUSIONS: These guidelines provide recommendations on the formal reliability of predictors of poor outcome in the context of counseling patients with ICH and surrogates and suggest broad principles of neuroprognostication. Clinicians formulating their judgments of prognosis for patients with ICH should avoid anchoring bias based solely on any one clinical variable or published clinical grading scale.

Guidelines for neuroprognostication in adults with traumatic spinal cord injury.

BACKGROUND: Traumatic spinal cord injury (tSCI) impacts patients and their families acutely and often for the long term. The ability of clinicians to share prognostic information about mortality and functional outcomes allows patients and their surrogates to engage in decision-making and plan for the future. These guidelines provide recommendations on the reliability of acute-phase clinical predictors to inform neuroprognostication and guide clinicians in counseling adult patients with tSCI or their surrogates. METHODS: A narrative systematic review was completed using Grading of Recommendations Assessment, Development, and Evaluation methodology. Candidate predictors, including clinical variables and prediction models, were selected based on clinical relevance and presence of an appropriate body of evidence. The Population/Intervention/Comparator/Outcome/Timing/Setting question was framed as "When counseling patients or surrogates of critically ill patients with traumatic spinal cord injury, should < predictor, with time of assessment if appropriate > be considered a reliable predictor of < outcome, with time frame of assessment >?" Additional full-text screening criteria were used to exclude small and lower quality studies. Following construction of an evidence profile and summary of findings, recommendations were based on four Grading of Recommendations Assessment, Development, and Evaluation criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. Good practice recommendations addressed essential principles of neuroprognostication that could not be framed in the Population/Intervention/Comparator/Outcome/Timing/Setting format. Throughout the guideline development process, an individual living with tSCI provided perspective on patient-centered priorities. RESULTS: Six candidate clinical variables and one prediction model were selected. Out of 11,132 articles screened, 369 met inclusion criteria for full-text review and 35 articles met eligibility criteria to guide recommendations. We recommend pathologic findings on magnetic resonance imaging, neurological level of injury, and severity of injury as moderately reliable predictors of American Spinal Cord Injury Impairment Scale improvement and the Dutch Clinical Prediction Rule as a moderately reliable prediction model of independent ambulation at 1 year after injury. No other reliable or moderately reliable predictors of mortality or functional outcome were identified. Good practice recommendations include considering the complete clinical condition as opposed to a single variable and communicating the challenges of likely functional deficits as well as potential for improvement and for long-term quality of life with SCI-related deficits to patients and surrogates. CONCLUSIONS: These guidelines provide recommendations about the reliability of acute-phase predictors of mortality, functional outcome, American Spinal Injury Association Impairment Scale grade conversion, and recovery of independent ambulation for consideration when counseling patients with tSCI or their surrogates and suggest broad principles of neuroprognostication in this context.

Guidelines for Neuroprognostication in Critically Ill Adults with Moderate-Severe Traumatic Brain Injury.

BACKGROUND: Moderate-severe traumatic brain injury (msTBI) carries high morbidity and mortality worldwide. Accurate neuroprognostication is essential in guiding clinical decisions, including patient triage and transition to comfort measures. Here we provide recommendations regarding the reliability of major clinical predictors and prediction models commonly used in msTBI neuroprognostication, guiding clinicians in counseling surrogate decision-makers. METHODS: Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, we conducted a systematic narrative review of the most clinically relevant predictors and prediction models cited in the literature. The review involved framing specific population/intervention/comparator/outcome/timing/setting (PICOTS) questions and employing stringent full-text screening criteria to examine the literature, focusing on four GRADE criteria: quality of evidence, desirability of outcomes, values and preferences, and resource use. Moreover, good practice recommendations addressing the key principles of neuroprognostication were drafted. RESULTS: After screening 8125 articles, 41 met our eligibility criteria. Ten clinical variables and nine grading scales were selected. Many articles varied in defining "poor" functional outcomes. For consistency, we treated "poor" as "unfavorable". Although many clinical variables are associated with poor outcome in msTBI, only the presence of bilateral pupillary nonreactivity on admission, conditional on accurate assessment without confounding from medications or injuries, was deemed moderately reliable for counseling surrogates regarding 6-month functional outcomes or in-hospital mortality. In terms of prediction models, the Corticosteroid Randomization After Significant Head Injury (CRASH)-basic, CRASH-CT (CRASH-basic extended by computed tomography features), International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)-core, IMPACT-extended, and IMPACT-lab models were recommended as moderately reliable in predicting 14-day to 6-month mortality and functional outcomes at 6 months and beyond. When using "moderately reliable" predictors or prediction models, the clinician must acknowledge "substantial" uncertainty in the prognosis. CONCLUSIONS: These guidelines provide recommendations to clinicians on the formal reliability of individual predictors and prediction models of poor outcome when counseling surrogates of patients with msTBI and suggest broad principles of neuroprognostication.

National Cost Estimates of Invasive Mechanical Ventilation and Tracheostomy in Acute Stroke, 2008-2017.

BACKGROUND: Patients with stroke receiving invasive mechanical ventilation (IMV) and tracheostomy incur intense treatment and long hospitalizations. We aimed to evaluate US hospitalization costs for patients with stroke requiring IMV, tracheostomy, or no ventilation. METHODS: We performed a retrospective observational study of US hospitalizations for acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage receiving IMV, tracheostomy, or none using the National Inpatient Sample, 2008 to 2017. We calculated hospitalization costs using cost-to-charge ratios adjusted to 2017 US dollars for inpatients with stroke by ventilation status (no IMV, IMV alone, tracheostomy). RESULTS: Of an estimated 5.2 million (95% CI, 5.1-5.3) acute stroke hospitalizations, 2008 to 2017; 9.4% received IMV alone and 1.4% received tracheostomy. Length of stay for patients without IMV was shorter (median, 4 days; interquartile range [IQR], 2-6) compared with IMV alone (median, 6 days; [IQR, 2-13]), and tracheostomy (median, 25 days; [IQR, 18-36]; P<0.001). Mortality for patients without IMV was 3.2% compared with 51.2% for IMV alone and 9.8% for tracheostomy (P<0.001). Median hospitalization costs for patients without IMV was $9503 (IQR, $6544-$14 963), compared with $23 774 (IQR, $10 900-$47 735) for IMV alone and $95 380 (IQR, $63 921-$144 019) for tracheostomy. Tracheostomy placement in ≤7 days had lower costs compared with placement in >7 days (median, $71 470 [IQR, $47 863-$108 250] versus $102 979 [IQR, $69 563-$152 543]; P<0.001). Each day awaiting tracheostomy was associated with a 2.9% cost increase (95% CI, 2.6%-3.1%). US hospitalization costs for patients with acute stroke were $8.7 billion/y (95% CI, $8.5-$8.9 billion). For IMV alone, costs were $1.8 billion/y (95% CI, $1.7-$1.9 billion) and for tracheostomy $824 million/y (95% CI, $789.7-$858.3 million). CONCLUSIONS: Patients with acute stroke who undergo tracheostomy account for 1.4% of stroke admissions and 9.5% of US stroke hospitalization costs. Future research should focus on the added value to society and patients of IMV and tracheostomy, in particular after 7 days for the latter procedure given the increased costs incurred and poor outcomes in stroke.

Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity.

In acute lung injury, the lung endothelial barrier is compromised. Loss of endothelial barrier integrity occurs in association with decreased levels of the tight junction protein claudin-5. Restoration of their levels by gene transfection may improve the vascular barrier, but how to limit transfection solely to regions of the lung that are injured is unknown. We hypothesized that thoracic ultrasound in combination with intravenous microbubbles (USMBs) could be used to achieve regional gene transfection in injured lung regions and improve endothelial barrier function. Since air blocks ultrasound energy, insonation of the lung is only achieved in areas of lung injury (edema and atelectasis); healthy lung is spared. Cavitation of the microbubbles achieves local tissue transfection. Here we demonstrate successful USMB-mediated gene transfection in the injured lungs of mice. After thoracic insonation, transfection was confined to the lung and only occurred in the setting of injured (but not healthy) lung. In a mouse model of acute lung injury, we observed downregulation of endogenous claudin-5 and an acute improvement in lung vascular leakage and in oxygenation after claudin-5 overexpression by transfection. The improvement occurred without any impairment of the immune response as measured by pathogen clearance, alveolar cytokines, and lung histology. In conclusion, USMB-mediated transfection targets injured lung regions and is a novel approach to the treatment of lung injury.NEW & NOTEWORTHY Acute respiratory distress syndrome is characterized by spatial heterogeneity, with severely injured lung regions adjacent to relatively normal areas. This makes targeting treatment to the injured regions difficult. Here we use thoracic ultrasound and intravenous microbubbles (USMBs) to direct gene transfection specifically to injured lung regions. Transfection of the tight junction protein claudin-5 improved oxygenation and decreased vascular leakage without impairing innate immunity. These findings suggest that USMB is a novel treatment for ARDS.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Goals-of-Care and Family/Surrogate Decision-Maker Data.

BACKGROUND: To facilitate comparative research, it is essential for the fields of neurocritical care and rehabilitation to establish common data elements (CDEs) for disorders of consciousness (DoC). Our objective was to identify CDEs related to goals-of-care decisions and family/surrogate decision-making for patients with DoC. METHODS: To achieve this, we formed nine CDE working groups as part of the Neurocritical Care Society's Curing Coma Campaign. Our working group focused on goals-of-care decisions and family/surrogate decision-makers created five subgroups: (1) clinical variables of surrogates, (2) psychological distress of surrogates, (3) decision-making quality, (4) quality of communication, and (5) quality of end-of-life care. Each subgroup searched for existing relevant CDEs in the National Institutes of Health/CDE catalog and conducted an extensive literature search for additional relevant study instruments to be recommended. We classified each CDE according to the standard definitions of "core", "basic", "exploratory", or "supplemental", as well as their use for studying the acute or chronic phase of DoC, or both. RESULTS: We identified 32 relevant preexisting National Institutes of Health CDEs across all subgroups. A total of 34 new instruments were added across all subgroups. Only one CDE was recommended as disease core, the "mode of death" of the patient from the clinical variables subgroup. CONCLUSIONS: Our findings provide valuable CDEs specific to goals-of-care decisions and family/surrogate decision-making for patients with DoC that can be used to standardize studies to generate high-quality and reproducible research in this area.

Guidelines for Neuroprognostication in Comatose Adult Survivors of Cardiac Arrest.

BACKGROUND: Among cardiac arrest survivors, about half remain comatose 72 h following return of spontaneous circulation (ROSC). Prognostication of poor neurological outcome in this population may result in withdrawal of life-sustaining therapy and death. The objective of this article is to provide recommendations on the reliability of select clinical predictors that serve as the basis of neuroprognostication and provide guidance to clinicians counseling surrogates of comatose cardiac arrest survivors. METHODS: A narrative systematic review was completed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Candidate predictors, which included clinical variables and prediction models, were selected based on clinical relevance and the presence of an appropriate body of evidence. The Population, Intervention, Comparator, Outcome, Timing, Setting (PICOTS) question was framed as follows: "When counseling surrogates of comatose adult survivors of cardiac arrest, should [predictor, with time of assessment if appropriate] be considered a reliable predictor of poor functional outcome assessed at 3 months or later?" Additional full-text screening criteria were used to exclude small and lower-quality studies. Following construction of the evidence profile and summary of findings, recommendations were based on four GRADE criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. In addition, good practice recommendations addressed essential principles of neuroprognostication that could not be framed in PICOTS format. RESULTS: Eleven candidate clinical variables and three prediction models were selected based on clinical relevance and the presence of an appropriate body of literature. A total of 72 articles met our eligibility criteria to guide recommendations. Good practice recommendations include waiting 72 h following ROSC/rewarming prior to neuroprognostication, avoiding sedation or other confounders, the use of multimodal assessment, and an extended period of observation for awakening in patients with an indeterminate prognosis, if consistent with goals of care. The bilateral absence of pupillary light response > 72 h from ROSC and the bilateral absence of N20 response on somatosensory evoked potential testing were identified as reliable predictors. Computed tomography or magnetic resonance imaging of the brain > 48 h from ROSC and electroencephalography > 72 h from ROSC were identified as moderately reliable predictors. CONCLUSIONS: These guidelines provide recommendations on the reliability of predictors of poor outcome in the context of counseling surrogates of comatose survivors of cardiac arrest and suggest broad principles of neuroprognostication. Few predictors were considered reliable or moderately reliable based on the available body of evidence.

Guidelines for Neuroprognostication in Adults with Guillain-Barré Syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) often carries a favorable prognosis. Of adult patients with GBS, 10-30% require mechanical ventilation during the acute phase of the disease. After the acute phase, the focus shifts to restoration of motor strength, ambulation, and neurological function, with variable speed and degree of recovery. The objective of these guidelines is to provide recommendations on the reliability of select clinical predictors that serve as the basis of neuroprognostication and provide guidance to clinicians counseling adult patients with GBS and/or their surrogates. METHODS: A narrative systematic review was completed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Candidate predictors, including clinical variables and prediction models, were selected based on clinical relevance and presence of appropriate body of evidence. The Population/Intervention/Comparator/Outcome/Time frame/Setting (PICOTS) question was framed as follows: "When counseling patients or surrogates of critically ill patients with Guillain-Barré syndrome, should [predictor, with time of assessment if appropriate] be considered a reliable predictor of [outcome, with time frame of assessment]?" Additional full-text screening criteria were used to exclude small and lower quality studies. Following construction of an evidence profile and summary of findings, recommendations were based on four GRADE criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. In addition, good practice recommendations addressed essential principles of neuroprognostication that could not be framed in PICOTS format. RESULTS: Eight candidate clinical variables and six prediction models were selected. A total of 45 articles met our eligibility criteria to guide recommendations. We recommend bulbar weakness (the degree of motor weakness at disease nadir) and the Erasmus GBS Respiratory Insufficiency Score as moderately reliable for prediction of the need for mechanical ventilation. The Erasmus GBS Outcome Score (EGOS) and modified EGOS were identified as moderately reliable predictors of independent ambulation at 3 months and beyond. Good practice recommendations include consideration of both acute and recovery phases of the disease during prognostication, discussion of the possible need for mechanical ventilation and enteral nutrition during counseling, and consideration of the complete clinical condition as opposed to a single variable during prognostication. CONCLUSIONS: These guidelines provide recommendations on the reliability of predictors of the need for mechanical ventilation, poor functional outcome, and independent ambulation following GBS in the context of counseling patients and/or surrogates and suggest broad principles of neuroprognostication. Few predictors were considered moderately reliable based on the available body of evidence, and higher quality data are needed.

Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: Data from a multicenter prospective cohort study.

We determined prognostic implications of acute lung injury (ALI) and organizing pneumonia (OP), including timing relative to transplantation, in a multicenter lung recipient cohort. We sought to understand clinical risks that contribute to development of ALI/OP. We analyzed prospective, histologic diagnoses of ALI and OP in 4786 lung biopsies from 803 adult lung recipients. Univariable Cox regression was used to evaluate the impact of early (≤90 days) or late (>90 days) posttransplant ALI or OP on risk for chronic lung allograft dysfunction (CLAD) or death/retransplantation. These analyses demonstrated late ALI/OP conferred a two- to threefold increase in the hazards of CLAD or death/retransplantation; there was no association between early ALI/OP and these outcomes. To determine risk factors for late ALI/OP, we used univariable Cox models considering donor/recipient characteristics and posttransplant events as candidate risks. Grade 3 primary graft dysfunction, higher degree of donor/recipient human leukocyte antigen mismatch, bacterial or viral respiratory infection, and an early ALI/OP event were significantly associated with increased late ALI/OP risk. These data from a contemporary, multicenter cohort underscore the prognostic implications of ALI/OP on lung recipient outcomes, clarify the importance of the timing of these events, and identify clinical risks to target for ALI/OP prevention.

Ex vivo delivery of regulatory T-cells for control of alloimmune priming in the donor lung.

BACKGROUND: Survival after lung transplantation (LTx) is hampered by uncontrolled inflammation and alloimmunity. Regulatory T-cells (Tregs) are being studied as a cellular therapy in solid organ transplantation. Whether these systemically administered Tregs can function at the appropriate location and time is an important concern. We hypothesised that in vitro-expanded recipient-derived Tregs can be delivered to donor lungs prior to LTx via ex vivo lung perfusion (EVLP), maintaining their immunomodulatory ability. METHODS: In a rat model, Wistar Kyoto (WKy) CD4+CD25high Tregs were expanded in vitro prior to EVLP. Expanded Tregs were administered to Fisher 344 (F344) donor lungs during EVLP; left lungs were transplanted into WKy recipients. Treg localisation and function post-transplant were assessed. In a proof-of-concept experiment, cryopreserved expanded human CD4+CD25+CD127low Tregs were thawed and injected into discarded human lungs during EVLP. RESULTS: Rat Tregs entered the lung parenchyma and retained suppressive function. Expanded Tregs had no adverse effect on donor lung physiology during EVLP; lung water as measured by wet-to-dry weight ratio was reduced by Treg therapy. The administered cells remained in the graft at 3 days post-transplant where they reduced activation of intra-graft effector CD4+ T-cells; these effects were diminished by day 7. Human Tregs entered the lung parenchyma during EVLP where they expressed key immunoregulatory molecules (CTLA4+, 4-1BB+, CD39+ and CD15s+). CONCLUSIONS: Pre-transplant Treg administration can inhibit alloimmunity within the lung allograft at early time points post-transplant. Our organ-directed approach has potential for clinical translation.

Effect of Early vs Standard Approach to Tracheostomy on Functional Outcome at 6 Months Among Patients With Severe Stroke Receiving Mechanical Ventilation: The SETPOINT2 Randomized Clinical Trial.

Importance: Many patients with severe stroke have impaired airway protective reflexes, resulting in prolonged invasive mechanical ventilation. Objective: To test whether early vs standard tracheostomy improved functional outcome among patients with stroke receiving mechanical ventilation. Design, Setting, and Participants: In this randomized clinical trial, 382 patients with severe acute ischemic or hemorrhagic stroke receiving invasive ventilation were randomly assigned (1:1) to early tracheostomy (≤5 days of intubation) or ongoing ventilator weaning with standard tracheostomy if needed from day 10. Patients were randomized between July 28, 2015, and January 24, 2020, at 26 US and German neurocritical care centers. The final date of follow-up was August 9, 2020. Interventions: Patients were assigned to an early tracheostomy strategy (n = 188) or to a standard tracheostomy (control group) strategy (n = 194). Main Outcomes and Measures: The primary outcome was functional outcome at 6 months, based on the modified Rankin Scale score (range, 0 [best] to 6 [worst]) dichotomized to a score of 0 (no disability) to 4 (moderately severe disability) vs 5 (severe disability) or 6 (death). Results: Among 382 patients randomized (median age, 59 years; 49.8% women), 366 (95.8%) completed the trial with available follow-up data on the primary outcome (177 patients [94.1%] in the early group; 189 patients [97.4%] in the standard group). A tracheostomy (predominantly percutaneously) was performed in 95.2% of the early tracheostomy group in a median of 4 days after intubation (IQR, 3-4 days) and in 67% of the control group in a median of 11 days after intubation (IQR, 10-12 days). The proportion without severe disability (modified Rankin Scale score, 0-4) at 6 months was not significantly different in the early tracheostomy vs the control group (43.5% vs 47.1%; difference, -3.6% [95% CI, -14.3% to 7.2%]; adjusted odds ratio, 0.93 [95% CI, 0.60-1.42]; P = .73). Of the serious adverse events, 5.0% (6 of 121 reported events) in the early tracheostomy group vs 3.4% (4 of 118 reported events) were related to tracheostomy. Conclusions and Relevance: Among patients with severe stroke receiving mechanical ventilation, a strategy of early tracheostomy, compared with a standard approach to tracheostomy, did not significantly improve the rate of survival without severe disability at 6 months. However, the wide confidence intervals around the effect estimate may include a clinically important difference, so a clinically relevant benefit or harm from a strategy of early tracheostomy cannot be excluded. Trial Registration: ClinicalTrials.gov Identifier: NCT02377167.

Viscous liquid-liquid wetting and dewetting of textured surfaces.

We experimentally investigate the spreading and receding behavior of small water droplets immersed in viscous oils on grid-patterned surfaces using synchronized bottom and profile views. In particular, the evolution of apparent advancing and receding contact angles of droplets fed at constant flow rate is studied as a function of grid surface coverage and height for a wide range of external phase viscosity. Detailed examination of droplet aspect ratio during inflation process provides an averaging method for characterization of quasi-static advancing angles on heterogeneous surfaces. Droplets spreading in partial Cassie state on planar microfluidic grids are also shown to capture oil patches that further evolve into trapped oil droplets depending on grid aspect ratio. The natural retraction velocity of thin water films is examined based on external phase velocity and regime maps of trapped droplets are delineated based on control parameters.

Eosinophils in transbronchial biopsies: a predictor of chronic lung allograft dysfunction and reduced survival after lung transplantation - a retrospective single-center cohort study.

Long-term outcomes after lung transplantation remain inferior to those of other solid organ groups. The significance of eosinophils detected on transbronchial biopsies (TBBx) after lung transplantation and their relationship to long-term outcomes remain unknown. A retrospective single-center cohort study was performed of patients transplanted between January 01, 2001, and July 31, 2018, who had at least 1 TBBx with evaluable parenchymal tissue. Multivariable Cox proportional hazard models were used to assess the associations between eosinophil detection and: all-cause mortality and Chronic Lung Allograft Dysfunction (CLAD). 8887 TBBx reports from 1440 patients were reviewed for the mention of eosinophils in the pathology report. 112 (7.8%) patients were identified with eosinophils on at least one TBBx. The median (95% CI) survival time for all patients was 8.28 (7.32-9.31) years. Multivariable analysis, adjusted for clinical variables known to affect post-transplant outcomes, showed that the detection of eosinophils was independently associated with an increased risk of death (HR 1.51, 95% CI 1.24-1.85, p < 0.01) and CLAD (HR 1.35, 95% CI 1.07-1.70, P = 0.01). Eosinophils detected in TBBx are associated with an increased risk of CLAD and death. There may be benefit in specifically reporting the presence of eosinophils in TBBx reports and incorporating their presence in clinical decision-making.

Predicting Coma Trajectories: The Impact of Bias and Noise on Shared Decisions.

Coma trajectories are characterized by quick awakening or protracted awakening. Outcome is bookended by restored functionality or permanent cognitively and physically debilitated states. Given the stakes, prognostication cannot be easily questioned as a judgment call, and a scientific underpinning is elemental. Conventional wisdom in determining coma-outcome trajectories posits that (1) predictive models are better than personal experiences, (2) self-fulfilling prophesy is unchecked and driven by nihilism, with little regard for prior probability outcomes, and (3) recovery is impacted by patients' prior wishes and preexisting medical conditions-but also by what families are told about the patient's state and anticipated clinical course. Moreover, a predicted good outcome can be offset by a major subsequent complication, or a predicted poor outcome can be offset by aggressive care. This article examines some of these concepts, including how we decide on aggressiveness of care, how we judge quality of life, and the impact on outcome. Most patients who awaken quickly do well and can resume their pretrauma injury lives. In worse off, slow-to-awaken patients, outcomes are a mixed bag of limited innate resilience, depleted cognitive and physical reserves, and adjusted quality of life. Bias and noise are factors not easily measured in outcome prediction, but their influence on recovery trajectories raises some troubling issues.

Predictors of Family Dissatisfaction with Support During Neurocritical Care Shared Decision-Making.

BACKGROUND: There is a critical need to improve support for families making difficult shared decisions about patient care with clinicians in the neuroscience ICU (neuro-ICU). The aim of this study is to identify patient- and family-related factors associated with dissatisfaction with shared decision-making support among families of neuro-critically ill patients. METHODS: We conducted a retrospective observational cohort study using survey data that had been collected from a consecutive sample of family members of patients in the neuro-ICU (one family member per patient) at two US academic centers. Satisfaction with shared decision-making support on ICU discharge had been measured among family members using one specific Likert scale item on the Family Satisfaction in the ICU 24 survey, a validated survey instrument for families of patients in the ICU. We dichotomized top-box responses for this particular item as an outcome variable and identified available patient- and family-related covariates associated with dissatisfaction (i.e., less than complete satisfaction) via univariate and multivariate analyses. RESULTS: Among 355 surveys, 180 (49.5%) of the surveys indicated dissatisfaction with support during decision-making. In a multivariate model, no preexisting characteristics of families or patients ascertainable on ICU admission were predictive of dissatisfaction. However, among family factors determined during the ICU course, experiencing three or fewer formal family meetings (odds ratio 1.93 [confidence interval 1.13-3.31]; p = 0.01) was significantly predictive of dissatisfaction with decisional support in this cohort with an average patient length of stay of 8.6 days (SD 8.4). There was also a trend toward a family's decision to keep a patient as full code, without treatment limitations, being predictive of dissatisfaction (odds ratio 1.80 [confidence interval 0.93-3.51]; p = 0.08). CONCLUSIONS: Family dissatisfaction with neuro-ICU shared decision-making support is not necessarily predicted by any preexisting family or patient variables but appears to correlate with participating in fewer formal family meetings during ICU admission. Future studies to improve family satisfaction with neurocritical care decision-making support should have broad inclusion criteria for participants and should consider promoting frequency of family meetings as a core strategy.