Transbronchial lung cryobiopsy performed in acute COVID-19 pneumonia: first report

A COVID-19 diagnosis is usually based on PCR detection of viral RNA in airway specimens in a patient with typical clinical fea-tures. Histological features of the COVID-19 lung disease are reported from autopsies. Transbronchial cryobiopsy (TBCB) is an evolving technique usually performed in the diagnosis of interstitial lung disease.We report a TBCB in a 76-year-old female patient who had repeatedly tested negative for SARS-CoV-2 infection. The pathological examination revealed the presence of interstitial pneumonia with lymphocytic infiltration. The qRT-PCR against SARS-CoV-2 from a pharyngeal swab was positive after performing the TBCB

Opportunities for mobilizing private climate finance through Article 6

Together with Climate Focus and Frankfurt School of Finance & Management, Perspectives has analyzed how Article 6 market mechanisms can be designed to incentivize mobilization of private financing and to reorient global finance flows towards low-carbon development and climate resilience in line with Article 2.1c of the Paris Agreement. On the international level, private and public sector trust in Article 6 mechanisms must be enhanced through keeping transaction low while robustly safeguarding integrity. On the national level, mitigation policy instruments should incentivize demand for emission reduction units, while higher-cost private sector mitigation should be mobilized through effective blending of ITMO revenues with public climate finance

Opportunities for mobilizing private climate finance through Article 6

The ambitious long-term target of the Paris Agreement (PA) can only be achieved if private sector action on climate change is scaled up and global finance flows are reoriented towards low-carbon development and climate resilience. Governments will need to trigger climate-compatible investments through targeted national policy instruments. International market mechanisms introduced by the PA in Article 6 are expected to play a critical role in creating the right incentives for mitigation activities financed and managed by the private sector. The upcoming Conference of the Parties (COP) in Chile is to deliver a final rulebook for Article 6, which will define the framework within which the private sector can operate and will define how generated mitigation results can be brought to market. While the price level achieved for internationally transferred mitigation outcomes (ITMO) or Article 6.4 Emission Reductions (A6.4ERs) will be the key driver for private sector engagement in market mechanisms, several other parameters will be relevant: the level of transaction costs, the degree of government interference, the scope of eligible activities, and the stringency of additionality determination and baseline setting. Balancing the delicate trade-off between private sector costs and assurance of environmental integrity is vital if new market mechanisms are to trigger private sector participation in climate change mitigation and adaptation activities at scale. This study seeks to answer the overarching question: How can Article 6 market mechanisms be designed to incentivize mobilization of private financing and contribute to support Article 2.1c in the Paris Agreement? While a wide definition of climate finance would cover finance triggered by market mechanisms; a narrow definition consistent with Article 9 PA would not cover market mechanism financing that aims to generate market mechanism units (ITMOs/A6.4ERs) for compliance with NDC targets. It should however be noted that no consensus on definitions has been achieved internationally so far

Opportunities for mobilizing private climate finance through Article 6

The ambitious long-term target of the Paris Agreement (PA) can only be achieved if private sector action on climate change is scaled up and global finance flows are reoriented towards low-carbon development and climate resilience. Governments will need to trigger climate-compatible investments through targeted national policy instruments. International market mechanisms introduced by the PA in Article 6 are expected to play a critical role in creating the right incentives for mitigation activities financed and managed by the private sector. The upcoming Conference of the Parties (COP) in Chile is to deliver a final rulebook for Article 6, which will define the framework within which the private sector can operate and will define how generated mitigation results can be brought to market. While the price level achieved for internationally transferred mitigation outcomes (ITMO) or Article 6.4 Emission Reductions (A6.4ERs) will be the key driver for private sector engagement in market mechanisms, several other parameters will be relevant: the level of transaction costs, the degree of government interference, the scope of eligible activities, and the stringency of additionality determination and baseline setting. Balancing the delicate trade-off between private sector costs and assurance of environmental integrity is vital if new market mechanisms are to trigger private sector participation in climate change mitigation and adaptation activities at scale. This study seeks to answer the overarching question: How can Article 6 market mechanisms be designed to incentivize mobilization of private financing and contribute to support Article 2.1c in the Paris Agreement? While a wide definition of climate finance would cover finance triggered by market mechanisms; a narrow definition consistent with Article 9 PA would not cover market mechanism financing that aims to generate market mechanism units (ITMOs/A6.4ERs) for compliance with NDC targets. It should however be noted that no consensus on definitions has been achieved internationally so far

GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN)

Background: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy. Methods: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400 mg/ivacaftor 250 mg for >= 12 weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics. Results: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75 mg; n = 14) or placebo (n = 8) capsules twice daily for 28 days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference - 19.6 mmol/L [95% confidence interval (CI) -36.0, -3.2], p = .0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1 s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected. Conclusions: GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination. (C) 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society

Risk factors for long-term invasive mechanical ventilation: a longitudinal study using German health claims data

Abstract Background Long-term invasive mechanical ventilation (IMV) is a major burden for those affected and causes high costs for the health care system. Early risk assessment is a prerequisite for the best possible support of high-risk patients during the weaning process. We aimed to identify risk factors for long-term IMV within 96 h (h) after the onset of IMV. Methods The analysis was based on data from one of Germany's largest statutory health insurance funds; patients who received IMV ≥ 96 h and were admitted in January 2015 at the earliest and discharged in December 2017 at the latest were analysed. OPS and ICD codes of IMV patients were considered, including the 365 days before intubation and 30 days after discharge. Long-term IMV was defined as evidence of invasive home mechanical ventilation (HMV), IMV ≥ 500 h, or readmission with (re)prolonged ventilation. Results In the analysis of 7758 hospitalisations, criteria for long-term IMV were met in 38.3% of cases, of which 13.9% had evidence of HMV, 73.1% received IMV ≥ 500 h and/or 40.3% were re-hospitalised with IMV. Several independent risk factors were identified (p < 0.005 each), including pre-diagnoses such as pneumothorax (OR 2.10), acute pancreatitis (OR 2.64), eating disorders (OR 1.99) or rheumatic mitral valve disease (OR 1.89). Among ICU admissions, previous dependence on an aspirator or respirator (OR 5.13), and previous tracheostomy (OR 2.17) were particularly important, while neurosurgery (OR 2.61), early tracheostomy (OR 3.97) and treatment for severe respiratory failure such as positioning treatment (OR 2.31) and extracorporeal lung support (OR 1.80) were relevant procedures in the first 96 h after intubation. Conclusion This comprehensive analysis of health claims has identified several risk factors for the risk of long-term ventilation. In addition to the known clinical risks, the information obtained may help to identify patients at risk at an early stage. Trial registration The PRiVENT study was retrospectively registered at ClinicalTrials.gov (NCT05260853). Registered at March 2, 2022

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia : a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

Altres ajuts: Professional medical writing assistance was provided by Fiona Boswell, PhD, and editorial assistance was provided by Katie Lay, MSc, at Caudex (Oxford, UK), funded by Biotest AG. Accovion GmbH, Eschborn, Germany (now Clinipace Worldwide, Morrisville, North Carolina, USA) provided study management services. We would like to thank all centers and staff involved in this study, and the patients and their families. Bernd H. Belohradsky, V. Marco Ranieri (Chair), Richard Strauss, and Gerhard W. Sybrecht monitored patient safety and data integrity as members of the DSMB.The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [ n = 81]) and placebo (mean 9.6; median 8 [ n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58-78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation. Trial registration: NCT01420744. The online version of this article (10.1007/s00134-018-5143-7) contains supplementary material, which is available to authorized users

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

PURPOSE: The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). METHODS: In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). RESULTS: Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58-78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. CONCLUSIONS: No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation