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BackgroundTest-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls.MethodsAdults hospitalized at 21 medical centers in 18 states March 11-August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group.Results5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18-64years, VE was 93% (95% CI: 90-94) using syndrome-negative controls and 91% (95% CI: 88-93) using test-negative controls.ConclusionsDespite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

Purpose To measure the rate of recall of study participation and study attrition in survivors of acute respiratory distress syndrome(ARDS). Materials/Methods In this ancillary study of the Re-evaluation of Systemic Early neuromuscular blockade(ROSE) trial, we measured the rate of study participation recall 3 months following discharge and subsequent study attrition at 6 months. We compared patient and hospital characteristics, and long-term outcomes by recall. As surrogate decision-makers provided initial consent, we measured the rate of patient reconsent and its association with study recall. Results Of 487 patients evaluated, recall status was determined in 386(82.7%). Among these, 287(74.4%) patients recalled participation in the ROSE trial, while 99(25.6%) did not. There was no significant difference in 6-month attrition among patients who recalled study participation (9.1%) and those who did not (12.1%) (p = 0.38). Patient characteristics were similar between groups, except SOFA scores, ventilator-free days, and length of stay. 330(68%) were reconsented. Compared to those not reconsented, significantly more patients who were reconsented recalled study participation(78% vs. 66%;p = 0.01). Conclusions One in 4 ARDS survivors do not recall their participation in a clinical trial during hospitalization 3 months following hospital discharge, which did not influence 6-month attrition. However, more patients recall study participation if reconsent is obtained.

Background: Equitable protocols to triage scarce life-saving resources must be specified prior to disasters in order to promote transparency, trust and consistency. The degree to which proposed utilitarian protocols may maximize lives saved is unknown. Methods: We constructed a simulation model based on New York State 2015 guidelines for ventilator triage (NYS) compared to a first-come-first-served (FCFS) method for ventilator allocation under various hypothetical ventilator shortages. We included patients with laboratory confirmed SARs-CoV-2 infection admitted with respiratory failure requiring mechanical ventilation to three acute care hospitals in New York from 3/01/2020 and 5/27/2020. We estimated (1) survival rates, (2) number of excess deaths, (3) number of patients extubated early due to capacity constraints, (4) survival rates among patients not allocated a ventilator at triage or extubated early due to capacity constraints. Findings: 807 patients were included in the study. Survival rates were similar between the NYS and FCFS policies at all the survival probabilities estimated for those triaged to removal of the ventilator. At the lowest ventilator capacity, the NYS policy has an estimated survival of 28.5% (CI: 28.4-28.6), compared to 28.1% (CI: 27.7-28.5) for the FCFS policy. The two policies had similar estimated excess deaths above historical observed deaths. Interpretation: This simulation of a SOFA-based triage protocol for distributing ventilators during the COVID-19 pandemic revealed limitations in achieving the utilitarian goals these protocols are designed to fulfill. Quantifying these outcomes can inform a better balance competing moral aims. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Albert Einstein College of Medicine/Montefiore Medical Center IRB (IRB # 2020-12128) and the Columbia University IRB (IRB # AAAT4062).

Background An update of evidence-based guidelines concerning liberation from mechanical ventilation is needed as new evidence has become available. The American College of Chest Physicians (CHEST) and the American Thoracic Society (ATS) have collaborated to provide recommendations to clinicians concerning liberation from the ventilator. Methods Comprehensive evidence syntheses, including meta-analyses, were performed to summarize all available evidence relevant to the guideline panel's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, and the results were summarized in evidence profiles. The evidence syntheses were discussed and recommendations developed and approved by a multidisciplinary committee of experts in mechanical ventilation. Results Recommendations for three population, intervention, comparator, outcome (PICO) questions concerning ventilator liberation are presented in this document. The guideline panel considered the balance of desirable (benefits) and undesirable (burdens, adverse effects, costs) consequences, quality of evidence, feasibility, and acceptability of various interventions with respect to the selected questions. Conditional (weak) recommendations were made to use inspiratory pressure augmentation in the initial spontaneous breathing trial (SBT) and to use protocols to minimize sedation for patients ventilated for more than 24 h. A strong recommendation was made to use preventive noninvasive ventilation (NIV) for high-risk patients ventilated for more than 24 h immediately after extubation to improve selected outcomes. The recommendations were limited by the quality of the available evidence. Conclusions The guideline panel provided recommendations for inspiratory pressure augmentation during an initial SBT, protocols minimizing sedation, and preventative NIV, in relation to ventilator liberation.

Background This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society (ATS) and the American College of Chest Physicians (CHEST). Methods A multidisciplinary panel posed six clinical questions in a population, intervention, comparator, outcomes (PICO) format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, confidence in the evidence, certainty about how much the public values the main outcomes, magnitude and balance of desirable and undesirable outcomes, resources and costs associated with the intervention, impact on health disparities, and acceptability and feasibility of the intervention. Results Evidence-based recommendations were formulated and graded initially by subcommittees and then modified following full panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation. Conclusions The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and CHEST.

Background Infection with some types of parasites can significantly prolong allograft survival in mice. It is unknown whether the soluble tachyzoite antigen (STAg) from Toxoplasma gondii has the same effect and by what mechanism it acts. Methods A mouse model of cardiac and skin allograft transplantation was established between BALB/c (H-2 d ) and C57BL/6(H-2 b ) mice. T gondii STAg was prepared, and 5 μg was administered subcutaneously to recipient mice 4 days before transplantation. The graft status was checked daily, and histologic and immunohistochemical assays were used to evaluate rejection. The serum cytokine levels from the recipient mice were analyzed by Luminex. Result The administration of 5 μg STAg 4 days before transplantation significantly prolonged the survival time of the heart and skin allografts to 85.17 ± 14.06 and 24.17 ± 2.32 days, respectively. Immunohistochemical staining showed that the CD4 + and CD8 + T lymphocytes were markedly reduced in the allografts at day 7 posttransplantation. Notably, interleukin (IL)-12, IL-2, and IL-17 levels were significantly reduced in the serum of mice treated with STAg compared with untreated mice 7 days after transplantation. In contrast, the levels of the antiinflammatory cytokine IL-10 were elevated. Conclusion A single administration of STAg before transplantation can significantly prolong the allograft survival time, which is accompanied by impaired lymphocyte infiltration and a reduced Th1 response.

This paper presents a leak-before-break (LBB) analysis for a dissimilar metal welded joint (DMWJ) connected the safe end to pipe-nozzle of a reactor pressure vessel of which is relevant to safety of nuclear power plant. Three-dimensional finite element analysis models were built for the DMWJ structure, and the initial inner circumferential surface cracks were postulated at the interface between A508 steel and buttering Alloy82. Based on the elastic–plastic fracture mechanics theory of J-integral, the crack growth stability was analyzed, and the pipe-nozzle geometry effect and inhomogeneous material properties of the DMWJ have been incorporated. Base on the analysis results, the LBB curves and LBB assessment diagrams were constructed for the DMWJ, and effects of applied bending moment loads and J-resistance curves of materials on LBB behavior were analyzed. The results show that the LBB behavior of a defect in the DMWJ under an upmost severe load can be assessed and predicted by plotting the defect size and its propagation path in the LBB assessment diagrams. With decreasing the maximum bending moment load and increasing the crack growth resistance of materials, the ligament instability lines shift upward and the critical crack length lines move to the right in the LBB assessment diagrams, which leads to enlargement of the feasibility region in the LBB behavior.

Background Pre-B-cell colony-enhancing factor (PBEF) is a potential biomarker for acute lung injury (ALI) in sepsis. We aimed to determine the clinical correlates for elevated plasma PBEF upon ICU admission for severe sepsis and the usefulness of PBEF to predict ALI development and sepsis mortality. Methods This is a prospective cohort of patients admitted to the medical ICU with severe sepsis. Patients without available blood samples or who were not enrolled within 24 h of admission were excluded. Plasma collected within 24 h of ICU admission was measured for PBEF concentrations by enzyme-linked immunosorbent assay. Patients were followed for ALI development as defined by the American-European Consensus Conference and for all-cause hospital mortality. Results Between September 30, 2008, and March 10, 2009, 113 patients were enrolled, and 50 (44%) developed ALI. Elevated PBEF levels significantly correlated with higher APACHE (Acute Physiology and Chronic Health Evaluation) III scores ( R 2 = 0.08, P = .003) and failure to reach early sepsis goals within 6 h of severe sepsis ( P = .003). PBEF did not differ by ALI status ( P = .58). The mortality rate was 46%. Nonsurvivors had higher PBEF levels than survivors (2.53 ng/mL; interquartile range [IQR], 1.07-8.16 vs 1.44 ng/mL; IQR, 0.84-2.81; P = .02). After adjusting for severity of illness, PBEF levels were no longer significantly associated with mortality (OR, 1.44 per 10-fold increase; 95% CI, 0.69-3.03, P = .34). Conclusions In this study, elevated PBEF did not correlate with lung injury in sepsis. However, it was associated with sepsis mortality mainly due to its association with greater severity of illness on ICU admission.

The genetic susceptibility to the development of and variable outcomes in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has become a topic of great interest in the pulmonary and critical care community. Published studies of variable genetic susceptibility to ALI/ARDS already have identified some important candidate genes and potential gene-environment interactions. This article reviews these recent studies, features of the current approach, and implications for future prevention and treatment in ALI. The challenges and potential contributions of genetic epidemiology to the future prevention and treatment in ALI are discussed.

Zooplankton abundance and euphausiid community composition were sampled seasonally (spring, summer, fall) within Monterey Bay, California, between 1997 and 1999. Measurements of sea surface temperature (SST), mixed layer depth, and upwelling indices provided concurrent data on physical oceanographic parameters. Both total zooplankton and krill abundance dramatically declined in the summer of 1997 coincident with a rapid increase in SST and mixed layer depth. Changes in euphausiid community composition occurred in concert with the decline in overall abundance. The relative abundance of the southern neritic Nyctiphanes simplex increased from August to November in 1997, the abundance of cold temperate Euphausia pacifica decreased significantly, and that of the northern neritic Thysanoessa spinifera declined dramatically. The sudden appearance of an adult cohort of N. simplex in July 1997 suggests that rapid poleward flow characteristic of coastally trapped Kelvin waves occurred between June and July of 1997. The persistent presence of warm temperate and subtropical taxa in samples collected between August 1997 and October 1998 indicates that this poleward flow continued in 1998. Zooplankton abundance, euphausiid community composition, and physical oceanographic parameters gradually returned to a more typical upwelling-dominated state in the spring and summer of 1998. E. pacifica and T. spinifera abundances gradually increased during the summer and fall of 1998, while N. simplex abundance abruptly declined in the spring of 1998. However, this recovery was confined to a narrow coastal band as a result of the onshore movement of the oceanic waters of the California Current. This was reflected by higher than normal numbers of the oceanic Nematoscelis difficilis within samples collected during the spring and summer of 1998. By the spring and summer of 1999, both zooplankton and euphausiid abundance had increased to the highest levels recorded during the 3-year study. Both E. pacifica and T. spinifera abundance increased relative to 1998 while N. simplex was completely absent in all samples. These changes reflected the cooler, highly productive environmental conditions associated with the 1998/1999 La Nina.

Chronic rejection is a major cause of transplant loss that is effected by the extracellular signal-regulated kinases (ERK) pathway. This study investigated the effects of antisense ERK1/2 oligodeoxynucleotide(ODN) gene therapy on chronic rejection.Lewis (RT1(1)) rats served as recipients of Brown-Norway (BN, RT1n) grafts. The BN rat abdominal aortas were harvested and orthotopically grafted into Lewis rats. The recipients were divided into three groups: (1) control group (n = 9), (2) random ODN transfer group (n = 10), and (3) antisense ODN transfer group (n = 10). At day 60 after transplantation, the recipients were sacrificed; the grafted aortas were evaluated histologically and immunohistochemically. ERK1/2 protein expression in the grafts was determined using Western Blot assays. Serum levels of slCAM-1 were detected by ELISA.In the control group and random ODN transfer group, we observed a remarkable degree of intimal hyperplasia and inflammatory cell infiltration, including macrophages and T cells. Compared with the control group, antisense ERK1/2 ODN gene therapy resulted in a significant reduction in neointimal proliferation (P.01), inhibition of ERK1/2 protein expression (P.01), decreased graft infiltration with CD4+ T lymphocytes (P.01), CD8+ T lymphocytes(P.05), and ED-1 macrophages (P.01) with decreased serum levels of sICAM-1 (P.05). We obtained a negative correlation between ERK1/2 expression and immune cell infiltration or ICAM-1 level.Antisense ERK1/2 gene therapy can attenuate graft arteriosclerosis so as to protect aortic allografts. The protection seemed to correlate with inhibition of inflammatory infiltration, implying that the ERK1/2 signal transduction pathway plays an important role in the process of chronic vascular rejection.