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Observations of CO2 were made in the upper troposphere and lower stratosphere in the deep tropics in order to determine the patterns of large-scale vertical transport and age of air in the Tropical Tropopause Layer (TTL). Flights aboard the NASA WB-57F aircraft over Central America and adjacent ocean areas took place in January and February, 2004 (Pre-AURA Validation Experiment, Pre-AVE) and 2006 (Costa Rice AVE, CR-AVE), and for the same flight dates of 2006, aboard the Proteus aircraft from the surface to 15 km over Darwin, Australia (Tropical Warm Pool International Cloud Experiment, TWP-ICE). The data demonstrate that the TTL is composed of two layers with distinctive features: (1) the lower TTL, 350-360K (potential temperature(θ); approximately 12-14 km), is subject to inputs of convective outflows, as indicated by layers of variable CO2 concentrations, with air parcels of zero age distributed throughout the layer; (2) the upper TTL, from θ=~360K to ~390K (14-18 km), ascends slowly and ages uniformly, as shown by a linear decline in CO2 mixing ratio tightly correlated with altitude, associated with increasing age. This division is confirmed by ensemble trajectory analysis. The CO2 concentration at the level of 360K was 380.0(±0.2) ppmv, indistinguishable from surface site values in the Intertropical Convergence Zone (ITCZ) for the flight dates. Values declined with altitude to 379.2(±0.2) ppmv at 390 K, implying that air in the upper TTL monotonically ages while ascending. In combination with the winter slope of the CO2 seasonal cycle (+10.8±0.4 ppmv/yr), the vertical gradient of -0.78 (±0.09) ppmv gives a mean age of 26(±3) days for the air at 390K and a mean ascent rate of 1.5(±0.3) mms-1. The TTL near 360K in the Southern Hemisphere over Australia is very close in CO2 composition to the TTL in the Northern Hemisphere over Costa Rica, with strong contrasts emerging at lower altitudes (<360 K). Both Pre-AVE and CR-AVE CO2 observed unexpected input from deep convection over Amazônia deep into the TTL. The CO2 data confirm the operation of a highly accurate tracer clock in the TTL that provides a direct measure of the ascent rate of the TTL and of the age of air entering the stratosphere. [ABSTRACT FROM AUTHOR]

Background: Global trends in mitral valve surgery (MVSx) suggest increasing repair compared with replacement, especially in the United States and European countries. The relative use, and outcomes of, MV repair and replacement in Australia are unknown., Methods: New South Wales residents who underwent isolated MVSx between 2001 and 2017 were identified from the Admitted-Patient-Data-Collection database. Mortality outcomes were tracked to 31 Dec 2018 and adjusted based on age, sex, urgency of operation, and comorbidity status., Results: The study cohort comprised 5,693 patients: 2020 (35%) underwent repair (MVr), 1,656 (29%) underwent mechanical replacement (mech.MVR), and 2017 (35%) underwent bioprosthetic replacement (bio.MVR). Respective median ages [interquartile range] were 67 yo [59-75 yo], 64 yo [55-71 yo], and 75 yo [68-80 yo] (p<0.001 across groups). Between 2001 and 2017, total MVSx increased steadily with population growth. Whereas the relative use of MVr remained static (34% to 38%), that for bio.MVR (22% to 50%) and mech.MVR (45% to 13%) changed significantly. MVr had the best outcome with 1.2% in-hospital, 2.5% 1-year, and 21.6% total cumulative mortality during a median follow-up of 6.5 years. Compared to MVr, the adjusted hazard ratio (aHR) for mech.MVR and bio.MVR for long-term mortality were 1.41 (95% confidence interval [CI]=1.24-1.61) and 1.73 (95% CI=1.53-1.95), respectively. Heart failure and sepsis were the main cardiovascular and noncardiovascular causes of death in all groups., Conclusion: In this statewide Australian cohort examined over 17 years, MVr is potentially underutilised despite having superior outcomes to MVR. Access to quality dataset which provides the indication for MVSx and quantitative clinical factors is critical to further improve MVr coverage and outcome MVSx., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

ABP 654 is a proposed biosimilar to ustekinumab reference product (RP) which works through antagonism of interleukin-12 and interleukin-23. Ustekinumab RP is used for the treatment of chronic inflammatory conditions, including some forms of plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. A randomized, double-blinded, single-dose, 3-arm, parallel-group study was conducted to assess the pharmacokinetic (PK) similarity of ABP 654 with ustekinumab RP sourced from the United States (US) and the European Union (EU); the PK similarity of ustekinumab US versus ustekinumab EU; and the comparative safety, tolerability, and immunogenicity of all 3 products. A total of 238 healthy subjects were randomized 1:1:1 and stratified by gender and ethnicity (Japanese versus non-Japanese) to receive a single 90 mg subcutaneous injection of ABP 654 or ustekinumab US or ustekinumab EU. PK similarity was established based on 90% confidence intervals (CIs) for the primary endpoints of area under the concentration-time curve from time 0 extrapolated to infinity (AUC inf ) and maximum observed serum concentration (C max ) being contained within the prespecified margin of 0.8-1.25. No clinically meaningful differences in immunogenicity were found among the 3 products. Adverse events were similar between treatment groups and consistent with the safety profile of ustekinumab RP. Results indicate that ABP 654, ustekinumab US and ustekinumab EU share similar PK and safety profiles., (© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

This was a randomized, single-blind, single-dose, 3-arm parallel-group study. Healthy subjects were randomized to receive ABP 710 (n = 50) or infliximab reference product (RP) sourced from the United States (infliximab US; n = 50) or the European Union (infliximab EU; n = 50) 5 mg/kg intravenously over 2 hours. The primary endpoint was area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC inf ) for the comparison of ABP 710 to infliximab US and infliximab EU. Secondary endpoints included safety, tolerability, and immunogenicity. AUC inf was similar across the 3 groups, showing similarity of ABP 710 to infliximab RP as well as similarity of infliximab US with infliximab EU. Geometric mean ratio of AUC inf was 0.89 between ABP 710 and infliximab US, 1.00 between ABP 710 and infliximab EU, and 1.11 between infliximab US and infliximab EU. All 90% confidence intervals of the geometric mean ratios were fully contained within the prespecified standard pharmacokinetic equivalence criteria range of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and reported for 83.7%, 86.0%, and 83.7% of subjects in the ABP 710, infliximab US, and infliximab EU treatment groups, respectively; incidence of antidrug antibody rates observed across the 3 groups were similar. Results of this study demonstrated pharmacokinetic similarity of ABP 710 with infliximab RP following a single 5-mg/kg intravenous injection. The safety and tolerability of ABP 710 and infliximab RP were comparable. These results add to the totality of evidence providing further support that the proposed biosimilar ABP 710 is similar to infliximab RP. (Trial ID: ACTRN12614000903684.)., (© 2019 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

ABP 501 [United States: AMJEVITA™ (adalimumab-atto); European Union: AMGEVITA ® (adalimumab)] is the first approved biosimilar to adalimumab [reference product (RP)], a monoclonal antibody (mAb) targeting tumor necrosis factor-alfa (TNF-α). ABP 501 has received approval for use in indications that adalimumab RP is approved for, except those protected by regulatory exclusivity. A systematic step-wise totality of evidence (TOE) approach formed the basis of approval of ABP 501; this involved methodical accumulation of scientifically robust comparative data supporting similarity in analytical, preclinical, and clinical [pharmacokinetics (PK)], efficacy, safety and immunogenicity) evaluations. As a foundational first step, comprehensive analytical assessments demonstrated that ABP 501 is structurally and functionally similar to adalimumab RP in critical quality attributes. Preclinical assessments confirmed similar activity in assessing mechanisms of action and toxicology. Clinical evaluation included a phase 1 PK equivalence study in healthy subjects and two comparative phase 3 studies that evaluated ABP 501 and adalimumab RP in two sensitive patient populations, plaque psoriasis (PsO) and rheumatoid arthritis (RA). The PK profiles of ABP 501 and adalimumab RP were similar in healthy subjects as well as patients with PsO and RA. The pivotal phase 3 study in patients with PsO demonstrated that ABP 501 was clinically similar to adalimumab RP in terms of efficacy, safety and immunogenicity in both the primary and transition phases. The pivotal phase 3 study in patients with RA also established clinical similarity between ABP 501 and adalimumab RP; an open-label extension of this study demonstrated sustained efficacy over an additional 72 weeks, with no new safety or immunogenicity concerns with ABP 501 treatment. Overall, the TOE supported the conclusion that ABP 501 is highly similar to adalimumab RP and provided scientific justification for extrapolation to all the approved indications of adalimumab RP not protected by exclusivities.Funding: Amgen Inc.

Background: Clergy are often important sources of guidance for patients and family members making medical decisions at the end-of-life (EOL). Previous research revealed spiritual support by religious communities led to more aggressive care at the EOL, particularly among minority patients. Understanding this phenomenon is important to help address disparities in EOL care., Objective: The study objective was to explore and describe clergy perspectives regarding "good" versus "poor" death within the participant's spiritual tradition., Methods: This was a qualitative, descriptive study. Community clergy from various spiritual backgrounds, geographical locations within the United States, and races/ethnicities were recruited. Participants included 35 clergy who participated in one-on-one interviews (N = 14) and two focus groups (N = 21). Semistructured interviews explored clergy viewpoints on factors related to a "good death." Principles of grounded theory were used to identify a final set of themes and subthemes., Results: A good death was characterized by wholeness and certainty and emphasized being in relationship with God. Conversely, a "poor death" was characterized by separation, doubt, and isolation. Clergy identified four primary determinants of good versus poor death: dignity, preparedness, physical suffering, and community. Participants expressed appreciation for contextual factors that affect the death experience; some described a "middle death," or one that integrates both positive and negative elements. Location of death was not viewed as a significant contributing factor., Conclusions: Understanding clergy perspectives regarding quality of death can provide important insights to help improve EOL care, particularly for patients highly engaged with faith communities. These findings can inform initiatives to foster productive relationships between clergy, clinicians, and congregants and reduce health disparities.

Background: Little data exist regarding the association of presence of an invasive airway before cardiac arrest or early placement of an invasive airway after cardiac arrest with outcomes in children who experience in-hospital cardiac arrest., Methods: We conducted a retrospective review of patients aged 1 day to 18 years who received cardiopulmonary resuscitation (CPR) for ≥ 1 min in any of the three intensive care units (ICUs) at a tertiary care, academic children's hospital between 2002 and 2010. Specific outcomes evaluated included survival to hospital discharge, return of spontaneous circulation (ROSC), 24-h survival, and good neurological status at hospital discharge. We fitted multivariable logistic regression models to evaluate the association between the presence of an invasive airway prior to cardiac arrest and timing of placement of an invasive airway with these outcomes., Results: Three hundred and ninety-one patients were included. Of these, 197 (51%) patients were already tracheally intubated before the occurrence of cardiac arrest. Median time to intubation was 6 min [interquartile range (IQR): 2, 12] among the 194 patients tracheally intubated following cardiac arrest. We found lower survival to hospital discharge among patients intubated prior to cardiac arrest (intubated vs. non-intubated group, 43% vs. 61%, p < 0.001). After adjusting for patient and event characteristics, presence of an invasive airway prior to cardiac arrest was not associated with a significant improvement in survival to hospital discharge [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.42-1.16, p = 0.17], or good neurological outcomes (OR: 0.60, 95% CI: 0.34-1.05, p = 0.07). Similarly, early placement of an invasive airway after cardiac arrest was also not associated with an improvement in survival to hospital discharge (OR: 1.05, 95% CI: 0.78-1.42, p = 0.73), or good neurological outcomes (OR: 1.08, 95% CI: 0.77-1.53, p = 0.65)., Conclusions: Our study demonstrates that presence of an invasive airway prior to cardiac arrest or early placement of an invasive airway after cardiac arrest is not associated with an improvement in survival to hospital discharge or good neurological outcomes. Further study of the relationship between invasive airway management and survival following cardiac arrest is warranted., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)