The effect of an acute aspirin challenge on intestinal permeability in healthy adults with and without prophylactic probiotic consumption: a double-blind, placebo-controlled, randomized trial.

BACKGROUND: Healthy individuals may experience increases in intestinal permeability after chronic or acute use of non-steroidal anti-inflammatory drugs, which may be attenuated by probiotics. This study investigates the effects of an acute aspirin challenge on gastroduodenal barrier function with or without prophylactic probiotic consumption. METHODS: Twenty-nine generally healthy participants (26 ± 6 years) completed a 14-week randomized, double-blind, crossover trial. A probiotic containing 2 Lactobacilli strains or placebo was administered for 3 weeks, with a 4-week washout period between crossover phases. Daily and weekly questionnaires assessing gastrointestinal function were completed for 2 weeks before until 2 weeks after each intervention to assess gastrointestinal function. Gastroduodenal permeability was assessed by urinary excretion of orally administered sucrose after 1, 2, and 3 weeks of each intervention with a 1950 mg-aspirin challenge after 2 weeks of supplementation. Stool samples were collected weekly during supplementation for detection of species of interest. RESULTS: Gastroduodenal permeability increased with aspirin challenge (Week 1: 3.4 ± 0.6 µmol vs Week 2: 9.9 ± 1.0 µmol urinary sucrose; p < 0.05). There were no differences in the change in permeability after the aspirin challenge or gastrointestinal function between interventions. CONCLUSION: The acute aspirin challenge significantly increased intestinal permeability similarly in both groups, and prophylactic probiotic consumption was unable to prevent the loss in this particular model.

Forming a new perspective: Post-structural approaches to determination of donor compatibility and post-transplant assessment of allograft health.

The purpose of this review is to encourage a new perspective on the question of donor-recipient compatibility and post-transplant assessment of graft health based on functional measures. The premise is that we should be better sighted on what (and how) the immune system responds toward rather than what is merely there. Continuance of the pursuit of further and better definition of antigens and antibodies is not however discouraged but seen as necessary to improved understanding of the structural correlates of functional immunity. There currently exists, in the opinion of the authors, an opportunity for histocompatibility and immunogenetics laboratories to develop and widen their scope of involvement into these new areas of laboratory activity in support and to the benefit of the transplant programmes they serve.

Fanconi Syndrome in Patients With Human Immunodeficiency Virus Treated With Tenofovir-Based Antiretroviral Therapy: A Systematic Literature Review.

OBJECTIVE: Several cases of Fanconi syndrome (FS), a severe form of nephrotoxicity, have been reported in patients with HIV on tenofovir-containing antiretroviral therapy. A systematic review of the published literature on tenofovir-related FS in patients with HIV was conducted. DATA SOURCES: PubMed and Embase were queried to identify articles in English published between January 2005 and June 2023, reporting tenofovir-related FS in adults with HIV. Preclinical studies, conference/poster abstracts, commentaries and responses, and review papers were excluded. STUDY SELECTION AND DATA EXTRACTION: Of the 256 articles screened, 57 met the inclusion criteria. These comprised 37 case reports, 11 case series, 1 cross-sectional study, 1 case-control study, 4 cohort studies, 1 single-arm open-label clinical trial, 1 sub-analysis of clinical trials, and 1 pooled analysis of clinical trials. DATA SYNTHESIS: Among 56 cases on which information was abstracted, median age at FS diagnosis was 50 years, 51.8% were men, and duration of tenofovir use ranged from 6 weeks to 11 years. Ritonavir was co-prescribed in almost half the cases. In observational and interventional studies, incidence of FS was low. Many studies reported resolution of FS symptoms after tenofovir discontinuation. All FS occurrences were identified in those on tenofovir disoproxil fumarate (TDF), except for one patient on tenofovir alafenamide (TAF). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Continuous monitoring of signs and symptoms of renal and bone toxicity is essential for patients with HIV on tenofovir-containing therapy. CONCLUSIONS: Occurrence of FS is low in patients with HIV treated with tenofovir-based regimens. Concomitant use of ritonavir may increase risk of FS. TAF may be a safer alternative than TDF in terms of nephrotoxicity.

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.

Safety of same-day discharge after uncomplicated, minimalist transcatheter aortic valve replacement in the COVID-19 era.

OBJECTIVES: We sought to evaluate the safety, efficacy and feasibility of same-day discharge after uncomplicated, minimalist TAVR. BACKGROUND: At the start of the COVID-19 pandemic, we created a same-day discharge (SDD) pathway after conscious sedation, transfemoral (minimalist) TAVR to help minimize risk of viral transmission and conserve hospital resources. Studies support that next-day discharge (NDD) for carefully selected patients following minimalist TAVR is safe and feasible. There is a paucity of data regarding the safety of SDD after TAVR. METHODS: In-hospital and 30 day outcomes of consecutive patients meeting pre-specified criteria for SDD after minimalist TAVR at our institution between March and July of 2020 were reviewed. Outcomes were compared to a NDD cohort from July 2018 through July 2020 that would have met SDD criteria. Primary endpoints were mortality, delayed pacemaker placement, stroke and cardiovascular readmission at 30 days. RESULTS: Twenty nine patients were discharged via the SDD pathway after TAVR. 128 prior NDD patients were identified who met all criteria for SDD. The STS scores were similar between the two groups (SDD 2.6% ±1.5 vs. NDD 2.3% ± 1.2). There were no deaths at 30 days in either group. There was no significant difference in delayed pacemaker placement (SDD 0% vs. NDD 0.8%, p > .99) or cardiovascular readmission (SDD 0% vs. NDD 5.5%, p = .35) at 30 days. CONCLUSIONS: Same day discharge following uncomplicated, minimalist TAVR in selected patients appears to be safe, achieving similar 30 day outcomes as a cohort of next day discharge patients.

SARS-CoV-2: An immunogenetics call to arms.

Susceptibility to viral infection, development of immunity, response to treatment and patient clinical outcomes are all under the control of heritable factors in the host. In the context of the current SARS-Cov-2 pandemic, this review considers existing immunogenetic knowledge of virus-immune system interactions. A major focus is to highlight areas in which work is required in order to improve understanding of antiviral immune responses and to move towards improved patient management.

The histocompatibility and immunogenetics of hand transplantation.

This short review will be concerned with the literature that has developed connected with the immunogenetic and tissue compatibility aspects of hand transplantation and will also draw on connected work in the more general area of vascularized composite allotransplantation (VCA) which includes face, abdominal wall uterus and larynx.

The Leeds hand transplant programme: Review of the laboratory management of the first six cases.

The UK hand transplantation programme is hosted by the Department of Plastic and Reconstructive Surgery at Leeds Teaching Hospitals under the leadership of Professor Simon Kay. Since programme launch in 2013, ten procedures in six individuals have been performed involving unilateral or bilateral transplants. The multi-disciplinary team that delivers the programme includes the transplant immunology service. The laboratory experience in programme support is reported here.

A role for human leucocyte antigens in the susceptibility to SARS-Cov-2 infection observed in transplant patients.

We analysed data from 80 patients who tested positive for SARS-CoV-2 RNA who had previously been HLA typed to support transplantation. Data were combined from two adjacent centres in Manchester and Leeds to achieve a sufficient number for early analysis. HLA frequencies observed were compared against two control populations: first, against published frequencies in a UK deceased donor population (n = 10,000) representing the target population of the virus, and second, using a cohort of individuals from the combined transplant waiting lists of both centres (n = 308), representing a comparator group of unaffected individuals of the same demographic. We report a significant HLA association with HLA- DQB1*06 (53% vs. 36%; p < .012; OR 1.96; 95% CI 1.94-3.22) and infection. A bias towards an increased representation of HLA-A*26, HLA-DRB1*15, HLA-DRB1*10 and DRB1*11 was also noted but these were either only significant using the UK donor controls, or did not remain significant after correction for multiple tests. Likewise, HLA-A*02, HLA-B*44 and HLA-C*05 may exert a protective effect, but these associations did not remain significant after correction for multiple tests. This is relevant information for the clinical management of patients in the setting of the current SARS-CoV-2 pandemic and potentially in risk-assessing staff interactions with infected patients.

Patterns of utilization and effects of hospital-specific factors on physical, occupational, and speech therapy for critically ill patients with acute respiratory failure in the USA: results of a 5-year sample.

BACKGROUND: Timely initiation of physical, occupational, and speech therapy in critically ill patients is crucial to reduce morbidity and improve outcomes. Over a 5-year time interval, we sought to determine the utilization of these rehabilitation therapies in the USA. METHODS: We performed a retrospective cohort study utilizing a large, national administrative database including ICU patients from 591 hospitals. Patients over 18 years of age with acute respiratory failure requiring invasive mechanical ventilation within the first 2 days of hospitalization and for a duration of at least 48 h were included. RESULTS: A total of 264,137 patients received invasive mechanical ventilation for a median of 4.0 [2.0-8.0] days. Overall, patients spent a median of 5.0 [3.0-10.0] days in the ICU and 10.0 [7.0-16.0] days in the hospital. During their hospitalization, 66.5%, 41.0%, and 33.2% (95% CI = 66.3-66.7%, 40.8-41.2%, 33.0-33.4%, respectively) received physical, occupational, and speech therapy. While on mechanical ventilation, 36.2%, 29.7%, and 29.9% (95% CI = 36.0-36.4%, 29.5-29.9%, 29.7-30.1%) received physical, occupational, and speech therapy. In patients receiving therapy, their first physical therapy session occurred on hospital day 5 [3.0-8.0] and hospital day 6 [4.0-10.0] for occupational and speech therapy. Of all patients, 28.6% (95% CI = 28.4-28.8%) did not receive physical, occupational, or speech therapy during their hospitalization. In a multivariate analysis, patients cared for in the Midwest and at teaching hospitals were more likely to receive physical, occupational, and speech therapy (all P < 0.05). Of patients with identical covariates receiving therapy, there was a median of 61%, 187%, and 70% greater odds of receiving physical, occupational, and speech therapy, respectively, at one randomly selected hospital compared with another (median odds ratio 1.61, 2.87, 1.70, respectively). CONCLUSIONS: Physical, occupational, and speech therapy are not routinely delivered to critically ill patients, particularly while on mechanical ventilation in the USA. The utilization of these therapies varies according to insurance coverage, geography, and hospital teaching status, and at a hospital level.

Half-Dose Versus Full-Dose Alteplase for Treatment of Pulmonary Embolism.

OBJECTIVES: Recent evidence suggests that half-dose thrombolysis for pulmonary embolism may provide similar efficacy with reduced bleeding risk compared with full-dose therapy, but comparative studies are lacking. We aimed to evaluate the effectiveness and safety of half-dose versus full-dose alteplase for treatment of pulmonary embolism. DESIGN: A retrospective cohort study comparing outcomes in patients receiving half-dose (50 mg) versus full-dose (100 mg) alteplase for pulmonary embolism. We used propensity score matching and sensitivity analyses to address confounding and hospital-level clustering. SETTING: Data from 420 hospitals obtained from the Premier Healthcare Database between January 2010 and December 2014. SUBJECTS: Adult critically ill patients with acute pulmonary embolism treated with IV alteplase therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study included 3,768 patients: 699 (18.6%) in the half-dose and 3,069 (81.4%) in the full-dose group. At baseline, patients receiving half-dose alteplase required vasopressor therapy (23.3% vs 39.4%; p < 0.01) and invasive ventilation (14.3% vs 28.5%; p < 0.01) less often, compared with full dose. After propensity matching (n = 548 per group), half-dose alteplase was associated with increased treatment escalation (53.8% vs 41.4%; p < 0.01), driven mostly by secondary thrombolysis (25.9% vs 7.3%; p < 0.01) and catheter thrombus fragmentation (14.2% vs 3.8%; p < 0.01). Hospital mortality was similar (13% vs 15%; p = 0.3). There was no difference in cerebral hemorrhage (0.5% vs 0.4%; p = 0.67), gastrointestinal bleeding (1.6% vs 1.6%; p = 0.99), acute blood loss anemia (6.9% vs 4.6%; p = 0.11), use of blood products (p > 0.05 for all), or documented fibrinolytic adverse events (2.6% vs 2.8%; p = 0.82). CONCLUSIONS: Compared with full-dose alteplase, half-dose was associated with similar mortality and rates of major bleeding. Treatment escalation occurred more often in half-dose-treated patients. These results question whether half-dose alteplase provides similar efficacy with improved safety, and highlights the need for further study before use of half-dose alteplase therapy can be routinely recommended in patients with pulmonary embolism.

Reduced human transitional B cell T1/T2 ratio is associated with subsequent deterioration in renal allograft function.

Human transitional B cells express relatively high IL-10 and low TNF-α levels, which correlate with B regulatory activity in vitro. Herein, we aim to further define B regulatory phenotype and determine whether B regulatory activity can serve as a prognostic marker for renal allograft dysfunction (graft loss or 2-fold fall in estimated glomerular filtration rate). Transitional B cells can be divided into T1 and T2 subsets based on surface phenotype. T1 cells express a significantly higher ratio of IL-10 to TNF-α than T2 cells or other B subsets. When analyzed in 45 kidney transplant recipients at the time of late for-cause biopsy, the T1/T2 ratio was independently associated with allograft dysfunction over the next 5 years. Next, the T1/T2 ratio was examined in an independent set of 97 clinically stable kidney transplant recipients 2 years after transplant. Again, the T1/T2 ratio was strongly and independently associated with allograft dysfunction over the ensuing 5 years. In these clinically quiescent patients, a low T1/T2 ratio identified a 41-patient subgroup in which 35% developed allograft dysfunction, with 25% losing their allografts. However, none of the 56 patients with a high ratio developed graft dysfunction. In both the initial study and validation groups, the T1/T2 ratio was a much stronger predictor of graft dysfunction than donor-specific antibodies or the estimated glomerular filtration rate. Thus, the T1/T2 ratio, a relative measure of expressing an anti-inflammatory cytokine profile, is a novel prognostic marker that might inform individualized immunosuppression.

Outcomes of ICU Patients With a Discharge Diagnosis of Critical Illness Polyneuromyopathy: A Propensity-Matched Analysis.

OBJECTIVES: To assess the impact of a discharge diagnosis of critical illness polyneuromyopathy on health-related outcomes in a large cohort of patients requiring ICU admission. DESIGN: Retrospective cohort with propensity score-matched analysis. SETTING: Analysis of a large multihospital database. PATIENTS: Adult ICU patients without preexisting neuromuscular abnormalities and a discharge diagnosis of critical illness polyneuropathy and/or myopathy along with adult ICU propensity-matched control patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 3,567 ICU patients with a discharge diagnosis of critical illness polyneuropathy and/or myopathy, we matched 3,436 of these patients to 3,436 ICU patients who did not have a discharge diagnosis of critical illness polyneuropathy and/or myopathy. After propensity matching and adjusting for unbalanced covariates, we used conditional logistic regression and a repeated measures model to compare patient outcomes. Compared to patients without a discharge diagnosis of critical illness polyneuropathy and/or myopathy, patients with a discharge diagnosis of critical illness polyneuropathy and/or myopathy had fewer 28-day hospital-free days (6 [0.1] vs 7.4 [0.1] d; p < 0.0001), had fewer 28-day ventilator-free days (15.7 [0.2] vs 17.5 [0.2] d; p < 0.0001), had higher hospitalization charges (313,508 [4,853] vs 256,288 [4,470] dollars; p < 0.0001), and were less likely to be discharged home (15.3% vs 32.8%; p < 0.0001) but had lower in-hospital mortality (13.7% vs 18.3%; p < 0.0001). CONCLUSIONS: In a propensity-matched analysis of a large national database, a discharge diagnosis of critical illness polyneuropathy and/or myopathy is strongly associated with deleterious outcomes including fewer hospital-free days, fewer ventilator-free days, higher hospital charges, and reduced discharge home but also an unexpectedly lower in-hospital mortality. This study demonstrates the clinical importance of a discharge diagnosis of critical illness polyneuropathy and/or myopathy and the need for effective preventive interventions.

Cut-Point Levels of Phosphatidylethanol to Identify Alcohol Misuse in a Mixed Cohort Including Critically Ill Patients.

BACKGROUND: Although alcohol misuse is associated with deleterious outcomes in critically ill patients, its detection by either self-report or examination of biomarkers is difficult to obtain consistently. Phosphatidylethanol (PEth) is a direct alcohol biomarker that can characterize alcohol consumption patterns; however, its diagnostic accuracy in identifying misuse in critically ill patients is unknown. METHODS: PEth values were obtained in a mixed cohort comprising 122 individuals from medical and burn intensive care units (n = 33), alcohol detoxification unit (n = 51), and healthy volunteers (n = 38). Any alcohol misuse and severe misuse were referenced by Alcohol Use Disorders Identification Test (AUDIT) and AUDIT-C scores separately. Mixed-effects logistic regression analysis was performed, and the discrimination of PEth was evaluated using the area under the receiver-operating characteristic (ROC) curve. RESULTS: The area under the ROC curve for PEth was 0.927 (95% CI: 0.877, 0.977) for any misuse and 0.906 (95% CI: 0.850, 0.962) for severe misuse defined by AUDIT. By AUDIT-C, the area under the ROC curves was 0.948 (95% CI: 0.910, 0.956) for any misuse and 0.913 (95% CI: 0.856, 0.971) for severe misuse. The PEth cut-points of ≥250 and ≥400 ng/ml provided optimal discrimination for any misuse and severe misuse, respectively. The positive predictive value for ≥250 ng/ml was 88.7% (95% CI: 77.5, 95.0), and the negative predictive value was 86.7% (95% CI: 74.9, 93.7). PEth ≥ 400 ng/ml achieved similar values, and similar results were shown for AUDIT-C. In a subgroup analysis of critically ill patients only, test characteristics were similar to the mixed cohort. CONCLUSIONS: PEth is a strong predictor and has good discrimination for any and severe alcohol misuse in a mixed cohort that includes critically ill patients. Cut-points at 250 ng/ml for any, and 400 ng/ml for severe, are favorable. External validation will be required to establish these cut-points in critically ill patients.

Prolonged acute care and post-acute care admission and recovery of physical function in survivors of acute respiratory failure: a secondary analysis of a randomized controlled trial.

BACKGROUND: The proportion of survivors of acute respiratory failure is growing; yet, many do not regain full function and require prolonged admission in an acute or post-acute care facility. Little is known about their trajectory of functional recovery. We sought to determine whether prolonged admission influenced the trajectory of physical function recovery and whether patient age modified the recuperation rate. METHODS: We performed a secondary analysis of a randomized clinical trial of intensive physical therapy for patients with acute respiratory failure requiring mechanical ventilation for ≥4 days. The primary outcome was Continuous Scale Physical Functional Performance, short form (CS-PFP-10), score. Predictor variables included prolonged admission in an acute or post-acute care facility at 1 month, time, and patient age. To determine whether the association between admission and functional outcome varied over time, a multivariable mixed effects linear regression model was fit using an interaction between prolonged admission and time with a primary outcome of total CS-PFP-10 score. RESULTS: Of the 89 patients included, 56% (50 of 89) required prolonged admission. At 1 month, patients who remained admitted had CS-PFP-10 scores that were 20.1 (CI 10.4-29.8) points lower (p < 0.0001) than patients who were discharged to home. However, there was no difference in the rate at which physical function improved from 3 to 6 months for patients who required prolonged admission compared with those who returned home (p = 0.24 for interaction between prolonged admission and time). Adjusted for age, Acute Physiology and Chronic Health Evaluation II score, and sex, both groups had CS-PFP-10 scores that were 8.2 (CI 4.5-12.0) points higher at 6 months than at 3 months (p < 0.0001). For each additional year in patient age, CS-PFP-10 recovered 0.36 points slower (95% CI 0.12-0.61; p = 0.004). CONCLUSIONS: Patients who require prolonged admission after acute respiratory failure have significantly lower physical functional performance than patients who return home. However, the rates of physical functional recovery between the two groups do not differ. The majority of survivors do not recover sufficiently to achieve functional independence by 6 months. Older age negatively influences the trajectory of functional recovery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01058421 . Registered on 26 January 2010.

Alcohol screening scores and the risk of intensive care unit admission and hospital readmission.

BACKGROUND: The association between alcohol misuse and the need for intensive care unit admission as well as hospital readmission among those discharged from the hospital following a critical illness is unclear. This study sought to determine whether alcohol misuse was associated with (1) admission to an intensive care unit (ICU) among a cohort of patients receiving outpatient care and (2) hospital readmission among those discharged from the hospital following critical illness. METHODS: This was a retrospective cohort study conducted with data from 24 Veterans Affairs (VA) health care facilities between 2004 and 2007. Scores on the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire were used to identify patients with past-year abstinence, lower-risk alcohol use, moderate alcohol misuse, or severe alcohol misuse. The primary outcome was admission to a VA intensive care unit within the year following administration of the AUDIT-C. In an analysis focused on patients discharged from the ICU, the 2 main outcomes were hospital readmission within 1 year and within 30 days. RESULTS: Among 486,115 veterans receiving outpatient care, the adjusted probability of ICU admission within 1 year was 2.0% (95% confidence interval [CI]: 1.7%-2.3%) for abstinent patients, 1.6% (95% CI: 1.3%-1.8%) for patients with lower-risk alcohol use, 1.8% (1.4%-2.3%) for patients with moderate alcohol misuse, and 2.5% (2.0%-2.9%) for patients with severe alcohol misuse. Among the 9,030 patients discharged from an ICU, the adjusted probability of hospital readmission within 1 year was 48% (46%-49%) in abstinent patients, 44% (42%-45%) in patients with lower-risk alcohol use, 42% (39%-45%) in patients with moderate alcohol misuse, and 55% (49%-60%) in patients with severe alcohol misuse. CONCLUSIONS: Alcohol misuse may represent a modifiable risk factor for a cycle of ICU admission and subsequent hospital readmission.

Brief Versus Full Alcohol Use Disorders Identification Test in National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network Clinical Trials.

OBJECTIVES: Alcohol use disorders are common among patients admitted to an ICU, yet systematic screening is rarely performed. We sought to confirm the construct validity of the full Alcohol Use Disorders Identification Test and to evaluate the performance of the brief three-item Alcohol Use Disorders Identification Test-C using the full Alcohol Use Disorders Identification Test as a proxy gold standard in a population of patients with a medical critical illness. DESIGN: Secondary analysis. SETTING: The acute respiratory distress syndrome network, a consortium of 12 university centers (44 hospitals) dedicated to conducting multicenter clinical trials in patients with acute respiratory distress syndrome. SUBJECTS: Patients meeting consensus criteria for acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,133 patients enrolled in one of three acute respiratory distress syndrome network studies, 1,037 (92%) had full Alcohol Use Disorders Identification Test data available. Of the included patients, 236 (23%) scored above the screening threshold for an alcohol use disorder on the full Alcohol Use Disorders Identification Test. Construct validity analysis of the full Alcohol Use Disorders Identification Test supported a three-factor model. Compared with the full Alcohol Use Disorders Identification Test, the Alcohol Use Disorders Identification Test -C had an area under the receiver operating characteristic curve of 0.99 for men and 0.98 for women. The optimal cutoff was 4 for both genders. At this cutoff, the Alcohol Use Disorders Identification Test -C had a sensitivity of 95% (95% CI, 92-98%) and specificity of 94% (95% CI, 92-96%) for men and sensitivity of 89% (95% CI, 82-96%) and specificity of 99% (95% CI, 98-100%) for women. CONCLUSIONS: Although a three-factor structure for the Alcohol Use Disorders Identification Test was confirmed in ICU patients with acute respiratory distress syndrome, the first three questions focusing on alcohol consumption provide information that is comparable with the full 10-item Alcohol Use Disorders Identification Test screening questionnaire. This study is limited by the lack of a true gold standard, and the performance of the Alcohol Use Disorders Identification Test -C is likely overestimated due to this limitation.

Impact of the new fast track kidney allocation scheme for declined kidneys in the United Kingdom.

INTRODUCTION: A "new" fast track kidney allocation scheme (FTKAS) was implemented in the UK in 2012 for offering of previously declined kidneys. We evaluated the impact of the FTKAS in utilization of declined kidneys and outcome. METHODS: Adult renal transplant centers were surveyed. Overall utilization was evaluated using National Health Service Blood and Transplant (NHSBT) data. Outcome of FTKAS kidneys in our center was analyzed. RESULTS: Centers cited graft, patient outcome concerns, and inadequate logistical support for their non-FTKAS participation. In the first year of the scheme, 266 kidneys were offered through the FTKAS, 158 were transplanted in 10 centers (59%). In comparison, 166 kidneys were offered through previous system over five yr (2006-2011), and 65 were utilized in 59 transplants (39%). In our center, 42 kidneys were transplanted in 39 recipients. One-yr graft and patient survival were both 95%. Results were comparable to a matched group of kidney transplants during the same periods allocated via the standard scheme. CONCLUSIONS: The FTKAS has led to effective utilization of the declined kidneys with outcome comparable to kidneys allocated through the standard scheme. Non-participation based on outcome concerns is mostly subjective while logistical issues need to be addressed.

Immunologic human renal allograft injury associates with an altered IL-10/TNF-α expression ratio in regulatory B cells.

Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-α increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-α expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.