Managing the Next Wave of Influenza and/or SARS-CoV-2 in the ICU—Practical Recommendations from an Expert Group for CAPA/IAPA Patients

COVID-19; Critical patients; Intensive care unitCOVID-19; Pacientes críticos; Unidad de cuidados intensivosCOVID-19; Pacients crítics; Unitat de cures intensivesThe aim of this study was to establish practical recommendations for the diagnosis and treatment of influenza-associated invasive aspergillosis (IAPA) based on the available evidence and experience acquired in the management of patients with COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA/IAPA expert group defined 14 areas in which recommendations would be made. To search for evidence, the PICO strategy was used for both CAPA and IAPA in PubMed, using MeSH terms in combination with free text. Based on the results, each expert developed recommendations for two to three areas that they presented to the rest of the group in various meetings in order to reach consensus. As results, the practical recommendations for the management of CAPA/IAPA patients have been grouped into 12 sections. These recommendations are presented for both entities in the following situations: when to suspect fungal infection; what diagnostic methods are useful to diagnose these two entities; what treatment is recommended; what to do in case of resistance; drug interactions or determination of antifungal levels; how to monitor treatment effectiveness; what action to take in the event of treatment failure; the implications of concomitant corticosteroid administration; indications for the combined use of antifungals; when to withdraw treatment; what to do in case of positive cultures for Aspergillus spp. in a patient with severe viral pneumonia or Aspergillus colonization; and how to position antifungal prophylaxis in these patients. Available evidence to support the practical management of CAPA/IAPA patients is very scarce. Accumulated experience acquired in the management of CAPA patients can be very useful for the management of IAPA patients. The expert group presents eminently practical recommendations for the management of CAPA/IAPA patients

Complete inhibition of extranodal dissemination of lymphoma by edelfosine-loaded lipid nanoparticles

Lipid nanoparticles (LN) made of synthetic lipids Compritol® 888 ATO and Precirol® ATO 5 were developed, presenting an average size of 110.4 ± 2.1 nm and 103.1 ± 2.9 nm, for Compritol® and Precirol®, respectively, and encapsulation efficiency above 85 % for both type of lipids. These LN decrease the hemolytic toxicity of the drug by 90 %. Pharmacokinetic and biodistribution profiles of the drug were studied after intravenous and oral administration of edelfosine-containing LN, providing an increase in relative oral bioavailability of 1500 % after a single oral administration of drug-loaded LN, maintaining edelfosine plasma levels over 7 days in contrast to a single oral administration of edelfosine solution, which presents a relative oral bioavailability of 10 %. Moreover, edelfosine-loaded LN showed a high accumulation of the drug in lymph nodes and resulted in slower tumor growth than the free drug in a murine lymphoma xenograft model, as well as potent extranodal dissemination inhibition

Mortality comparison between the first and second/third waves among 3,795 critical COVID-19 patients with pneumonia admitted to the ICU : A multicentre retrospective cohort study

It is unclear whether the changes in critical care throughout the pandemic have improved the outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care units (ICUs). We conducted a retrospective cohort study in adults with COVID-19 pneumonia admitted to 73 ICUs from Spain, Andorra and Ireland between February 2020 and March 2021. The first wave corresponded with the period from February 2020 to June 2020, whereas the second/third waves occurred from July 2020 to March 2021. The primary outcome was ICU mortality between study periods. Mortality predictors and differences in mortality between COVID-19 waves were identified using logistic regression. As of March 2021, the participating ICUs had included 3795 COVID-19 pneumonia patients, 2479 (65·3%) and 1316 (34·7%) belonging to the first and second/third waves, respectively. Illness severity scores predicting mortality were lower in the second/third waves compared with the first wave according with the Acute Physiology and Chronic Health Evaluation system (median APACHE II score 12 [IQR 9-16] vs 14 [IQR 10-19]) and the organ failure assessment score (median SOFA 4 [3-6] vs 5 [3-7], p <0·001). The need of invasive mechanical ventilation was high (76·1%) during the whole study period. However, a significant increase in the use of high flow nasal cannula (48·7% vs 18·2%, p <0·001) was found in the second/third waves compared with the first surge. Significant changes on treatments prescribed were also observed, highlighting the remarkable increase on the use of corticosteroids to up to 95.9% in the second/third waves. A significant reduction on the use of tocilizumab was found during the study (first wave 28·9% vs second/third waves 6·2%, p <0·001), and a negligible administration of lopinavir/ritonavir, hydroxychloroquine, and interferon during the second/third waves compared with the first wave. Overall ICU mortality was 30·7% (n = 1166), without significant differences between study periods (first wave 31·7% vs second/third waves 28·8%, p = 0·06). No significant differences were found in ICU mortality between waves according to age subsets except for the subgroup of 61-75 years of age, in whom a reduced unadjusted ICU mortality was observed in the second/third waves (first 38·7% vs second/third 34·0%, p = 0·048). Non-survivors were older, with higher severity of the disease, had more comorbidities, and developed more complications. After adjusting for confounding factors through a multivariable analysis, no significant association was found between the COVID-19 waves and mortality (OR 0·81, 95% CI 0·64-1·03; p = 0·09). Ventilator-associated pneumonia rate increased significantly during the second/third waves and it was independently associated with ICU mortality (OR 1·48, 95% CI 1·19-1·85, p <0·001). Nevertheless, a significant reduction both in the ICU and hospital length of stay in survivors was observed during the second/third waves. Despite substantial changes on supportive care and management, we did not find significant improvement on case-fatality rates among critical COVID-19 pneumonia patients. Ricardo Barri Casanovas Foundation (RBCF2020) and SEMICYU

Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies

The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.We particularly acknowledge the Biobank of the University of Navarra for its collaboration. We thank Dr Edorta Martínez de Marigorta and Dr Francisco Palacios from Departamento de Química Orgánica I, Facultad de Farmacia, Universidad del Pais Vasco for 13C NMR determination and Angel Irigoyen Barrio and Dr Ana Romo Hualde, from University of Navarra, for HRMS determination. Dr. Irene de Miguel Turrullols from Small Molecule Discovery Platform, CIMA, University of Navarra is acknowledged for NMR data interpretation. This work was funded by grants from Instituto de Salud Carlos III (ISCIII) PI10/01691, PI13/01469, PI14/01867, PI10/2983, TRASCAN (EPICA), CIBERONC, cofinanciacion FEDER, RTICC RD12/0036/0068, Fundació La Marató de TV3 (20132130-31-32) and ‘Fundación Fuentes Dutor’. B.P. is supported by a Sara Borrell fellowship CD13/00340 and X.A. is a Marie Curie researcher under contract ‘LincMHeM-330598’.S

Impact of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients: A nationwide study in Spain

Objective To assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain. Settings The initial flood of COVID-19 patients overwhelmed an unprepared healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied. Participants This was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020. Interventions An exploratory factorial analysis was performed to select the most relevant variables of the sample. Primary and secondary outcome measures Univariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection. Results Sixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/10 5 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade =3 (OR 2.5) and preoperative GCS 3-8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/10 5 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated. Conclusions Perioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/10 5 people/week) was a statistically independent predictor of mortality. Trial registration number CEIM 20/217

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Abstract 1120: The Histone Deacetylase 9 Gene Is Regulated by Multiple Promoters and Expresses Lymphoid-Specific Isoforms.

Histone deacetylases (HDACs) perform key functions in transcriptional regulation by modifying the core histones of the nucleosome as well as non-histone targets. We have previously cloned and characterized HDAC9, a member of the Class IIa HDAC family, which also contains HDACs 4,5 and 7. These are characterized by the presence of a common N-terminal region, which mediates direct interactions with transcription factors such as BCL-6 or MEF2. The HDAC9 gene encodes multiple protein isoforms some of which display distinct cellular localization patterns and biological activities. The transcribed region of HDAC9 is very large, spanning more than 900 kilobases, with approximately 50% of these sequences being non-coding. Consistent with its size as well as the multiplicity and structural complexity of expressed HDAC9 isoforms, we report that HDAC9 expression is under the control of three independent promoter regions, one of which possesses a CpG island. This is in contrast to other HDAC genes thus far identified, each of which appears to possess a single CpG island-containing promoter. Transcripts initiating from the individual HDAC9 promoters are differentially expressed and encode specific HDAC9 isoforms. A comparison of the human and mouse HDAC9 genes reveals some important differences in both regulatory regions and coding sequences. Specifically, the human HDAC9 gene can express from its second promoter, which is not present in the mouse gene, hematopoietic-specific transcripts (i.e. only found in the lymph node, spleen and lymphocytes in normal tissue) that encode isoforms containing previously unidentified N-terminal sequences. In normal B cells, HDAC9 mRNA transcripts are initiated from the second and proximal promoters and stimulation of these cells with IL2, α-CD40 MoAb, Staphylococcus aureus Cowan strain 1, or arsenic trioxide had no appreciable affect on HDAC9 expression. However, due to a potentially abnormal differential promoter usage and alternative splicing, chronic lymphocytic leukemia (CLL) patient B-cells displayed HDAC9 isoform expression pattern that was dramatically distinct from that observed in normal B-cells. Specifically, there was significant expression from the distal (CpG island containing) promoter, which is not utilised in normal B cells, and overexpression from the second and proximal promoters. With regard to alternative splicing, the CLL patient cells lacked exon7, which contains a nuclear localization signal and exon12, which contains a site of sumoylation - a modification linked to deacetylase activity. Moreover, these changes were specific for full-length HDAC9, and not the MITR isoform that lacks catalytic domain. Stimulation of CLL patient B-cells with SAC/IL-2 caused a switch in promoter usage leading to the change in isoform specific expression to a pattern that is identical to that of normal B-cells. These results suggest that deregulation of HDAC9 expression may play a role in B-cell development and the pathogenesis of B-cell neoplasms. Given the need for development of better therapies for indolent B-cell malignancies such as CLL, the finding that HDAC9 expression in cancer cells is modulated by SAC/IL-2 points to a possible combinatorial therapy with HDAC inhibitors, which have been shown to induce apoptosis in CLL cells

Decision-Making on Withholding or Withdrawing Life Support in the ICU: A Worldwide Perspective

Background Many critically ill patients who die will do so after a decision has been made to withhold/withdraw life-sustaining therapy. The objective of this study was to document the characteristics of ICU patients with a decision to withhold/withdraw life-sustaining treatment, including the types of supportive treatments used, patterns of organ dysfunction, and international differences, including gross national income (GNI). Methods In this observational cohort study conducted in 730 ICUs in 84 countries, all adult patients admitted between May 8, 2012, and May 18, 2012 (except admissions for routine postoperative surveillance), were included. Results The analysis included 9,524 patients, with a hospital mortality of 24%. A decision to withhold/withdraw life-sustaining treatment was reported during the ICU stay in 1,259 patients (13%), including 820 (40%) nonsurvivors and 439 (5%) survivors. Hospital mortality in patients with a decision to withhold/withdraw life-sustaining treatment was 69%. The proportion of deaths in patients with a decision to withhold/withdraw life-sustaining treatment ranged from 10% in South Asia to 67% in Oceania. Decisions to withhold/withdraw life-sustaining treatment were less frequent in low/lower-middle GNI countries than in high GNI countries (6% vs 14%; P <.001). Greater disease severity, presence of ≥ 2 organ failures, severe comorbidities, medical and trauma admissions, and admission from the ED or hospital floor were independent predictors of a decision to withhold/withdraw life-sustaining treatment. Conclusions There is considerable worldwide variability in decisions to withhold/withdraw life-sustaining treatments. Interestingly, almost one-third of patients with a decision to withhold/withdraw life-sustaining treatment left the hospital alive.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Complete inhibition of extranodal dissemination of lymphoma by edelfosine-loaded lipid nanoparticles

[Background]: Lipid nanoparticles (LNs) made of synthetic lipids Compritol® 888 ATO and Precirol® ATO 5 were developed with an average size of 110.4 ± 2.1 and 103.1 ± 2.9 nm, and an encapsulation efficiency above 85% for both type of lipids. These LNs decrease the hemolytic toxicity of the drug by 90%. [Materials & methods]: Pharmacokinetic and biodistribution profiles of the drug were studied after intravenous and oral administration of edelfosine-containing LNs. [Results]: This provided an increase in relative oral bioavailability of 1500% after a single oral administration of drug-loaded LNs, maintaining edelfosine plasma levels over 7 days in contrast to a single oral administration of edelfosine solution, which presented a relative oral bioavailability of 10%. Moreover, edelfosine-loaded LNs showed a high accumulation of the drug in lymph nodes and resulted in slower tumor growth than the free drug in a murine lymphoma xenograft model, as well as potent extranodal dissemination inhibition. Original submitted 5 April 2011; Revised submitted 5 July 201. © 2012 Future Medicine Ltd.Peer Reviewe