Reduction in Hospitalizations for Respiratory Diseases during the First COVID-19 Wave in Greece.

INTRODUCTION: During the first COVID-19 wave, a considerable decline in hospital admissions was observed worldwide. AIM: This retrospective cohort study aimed to assess if there were any changes in the number of patients hospitalized for respiratory diseases in Greece during the first CO-VID-19 wave. METHODS: In the present study, we evaluated respiratory disease hospitalization rates across 9 tertiary hospitals in Greece during the study period (March-April 2020) and the corresponding period of the 2 previous years (2018-2019) that served as the control periods. Demographic data and discharge diagnosis were documented for every patient. RESULTS: Of the 1,307 patients who were hospitalized during the study period, 444 (35.5%) were males with a mean (±SD) age of 66.1 ± 16.6 years. There was a 47 and 46% reduction in all-cause respiratory morbidity compared to the corresponding periods of 2018 and 2019, respectively. The mean incidence rate for respiratory diseases during the study period was 21.4 admissions per day, and this rate was significantly lower than the rate during the same period in 2018 (40.8 admissions per day; incidence rate ratio [IRR], 0.525; 95% confidence interval [CI], 0.491-0.562; p < 0.001) or the rate during 2019 (39.9 admissions per day; IRR, 0.537; 95% CI, 0.502-0.574; p < 0.001). The greatest reductions (%) in the number of daily admissions in 2020 were observed for sleep apnoea (87% vs. 2018 and 84% vs. 2019) followed by admissions for asthma (76% vs. 2018 and 79% vs. 2019) and chronic obstructive pulmonary disease (60% vs. 2018 and 51% vs. 2019), while the lowest reductions were detected in hospitalizations for pulmonary embolism (6% vs. 2018 and 23% vs. 2019) followed by tuberculosis (25% vs. both 2018 and 2019). DISCUSSION/CONCLUSION: The significant reduction in respiratory admissions in 2020 raises the reasonable question of whether some patients may have avoided seeking medical attention during the COVID-19 pandemic and suggests an urgent need for transformation of healthcare systems during the pandemic to offer appropriate management of respiratory diseases other than COVID-19.

The role of Src & ERK1/2 kinases in inspiratory resistive breathing induced acute lung injury and inflammation.

BACKGROUND: Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with large negative intrathoracic pressures, due to strenuous contractions of the inspiratory muscles. IRB is shown to induce lung injury in previously healthy animals. Src is a multifunctional kinase that is activated in the lung by mechanical stress. ERK1/2 kinase is a downstream target of Src. We hypothesized that Src is activated in the lung during IRB, mediates ERK1/2 activation and IRB-induced lung injury. METHODS: Anaesthetized, tracheostomized adult rats breathed spontaneously through a 2-way non-rebreathing valve. Resistance was added to the inspiratory port to provide a peak tidal inspiratory pressure of 50% of maximum (inspiratory resistive breathing). Activation of Src and ERK1/2 in the lung was estimated during IRB. Following 6 h of IRB, respiratory system mechanics were measured by the forced oscillation technique and bronchoalveolar lavage (BAL) was performed to measure total and differential cell count and total protein levels. IL-1b and MIP-2a protein levels were measured in lung tissue samples. Wet lung weight to total body weight was measured and Evans blue dye extravasation was estimated to measure lung permeability. Lung injury was evaluated by histology. The Src inhibitor, PP-2 or the inhibitor of ERK1/2 activation, PD98059 was administrated 30 min prior to IRB. RESULTS: Src kinase was activated 30 min after the initiation of IRB. Src inhibition ameliorated the increase in BAL cellularity after 6 h IRB, but not the increase of IL-1ß and MIP-2a in the lung. The increase in BAL total protein and lung injury score were not affected. The increase in tissue elasticity was partly inhibited. Src inhibition blocked ERK1/2 activation at 3 but not at 6 h of IRB. ERK1/2 inhibition ameliorated the increase in BAL cellularity after 6 h of IRB, blocked the increase of IL-1ß and returned Evans blue extravasation and wet lung weight to control values. BAL total protein and the increase in elasticity were partially affected. ERK1/2 inhibition did not significantly change total lung injury score compared to 6 h IRB. CONCLUSIONS: Src and ERK1/2 are activated in the lung following IRB and participate in IRB-induced lung injury.

Lynamicin D an antimicrobial natural product affects splicing by inducing the expression of SR protein kinase 1.

The first total synthesis of the antimicrobial natural product lynamicin D has been developed using a Suzuki coupling to construct the bisindole pyrrole skeleton. An evaluation of the biological activity of lynamicin D reveals that it has a minor effect on cell viability but it can modulate splicing of pre-mRNAs. We provide evidence that this effect is mainly due to the ability of lynamicin D to alter the levels of SRPK1, the key kinase involved in both constitutive and alternative splicing.

Expression of SRPK1 in gliomas and its role in glioma cell lines viability.

Among factors regulating the splicing of major importance is serine/arginine protein kinase 1 (SRPK1) that phosphorylates SR splicing factors. SRPK1 is expressed in the mammalian central nervous system in a region- and neuron-specific manner. Based on previous observations that glial cells are practically devoid of SRPK1 and reports showing aberrant expression of SRPK1 in numerous tumors, but with conflicting roles, this study aims to investigate the expression of SRPK1 in glioma and its influence on tumor cell biological features. As shown by immunohistochemical analysis, malignant glioma cells express SRPK1 in glioblastomas with significant association between SRPK1 expression and patients' survival. SRPK1 expression was also significantly upregulated at the messenger RNA (mRNA) and protein level in glioma cell lines. Small interfering RNA-mediated downregulation of SRPK1 had little effect on cell viability, while it slightly enhanced the sensitivity of cells to killing by cisplatin. These results support the idea that at least in vitro, the effect of SRPK1 knockdown on the viability of glioma cell lines is rather limited, while the in vivo effects could be attributed to the modulation of angiogenesis by SRPK1.

Inspiratory resistive breathing induces MMP-9 and MMP-12 expression in the lung.

Inspiratory resistive breathing (IRB) is characterized by large negative intrathoracic pressures and was shown to induce pulmonary inflammation in previously healthy rats. Matrix metalloproteinases (MMP)-9 and -12 are induced by inflammation and mechanical stress in the lung. We hypothesized that IRB induces MMP-9 and -12 in the lung. Anesthetized, tracheostomized rats breathed spontaneously through a two-way valve, connected to an inspiratory resistance, with the tidal inspiratory tracheal pressure set at 50% of the maximum. Quietly breathing animals served as controls. After 3 and 6 h of IRB, respiratory mechanics were measured, bronchoalveolar lavage (BAL) was performed, lung injury score was estimated, and lung MMP-9 was estimated by zymography and ELISA. MMP-9 and MMP-12 immunohistochemistry was performed. Isolated normal alveolar macrophages were incubated with BAL from rats that underwent IRB. After 18 h, MMP-9 and -12 levels were measured in supernatants, and immunocytochemistry was performed. Macrophages were treated with IL-1ß, IL-6, or TNF-α, and MMP-9 in supernatants was measured. After 6 h of IRB, leukocytes in BAL increased, and IL-1ß and IL-6 levels were elevated. Elasticity and injury score were increased after 3 and 6 h of IRB. Lung MMP-9 levels increased after 6 h of IRB. MMP-9 and MMP-12 were detected in alveolar macrophages and epithelial (bronchial/alveolar) cells after 3 and 6 h of IRB. MMP-9 and MMP-12 were found in supernatants after treatment with 6 h of IRB BAL. Cytosolic immunostaining was detected after treatment with 3 and 6 h of IRB BAL. All cytokines induced MMP-9 in culture supernatants. In conclusion, IRB induces MMP-9 and -12 in the lung of previously healthy rats.

Severe Traumatic Brain Injury and Pulmonary Embolism: Risks, Prevention, Diagnosis and Management.

Severe traumatic brain injury (sTBI) is a silent epidemic, causing approximately 300,000 intensive care unit (ICU) admissions annually, with a 30% mortality rate. Despite worldwide efforts to optimize the management of patients and improve outcomes, the level of evidence for the treatment of these patients remains low. The concomitant occurrence of thromboembolic events, particularly pulmonary embolism (PE), remains a challenge for intensivists due to the risks of anticoagulation to the injured brain. We performed a literature review on sTBI and concomitant PE to identify and report the most recent advances on this topic. We searched PubMed and Scopus for papers published in the last five years that included the terms "pulmonary embolism" and "traumatic brain injury" in their title or abstract. Exclusion criteria were papers referring to children, non-sTBI populations, and post-acute care. Our search revealed 75 papers, of which 38 are included in this review. The main topics covered include the prevalence of and risk factors for pulmonary embolism, the challenges of timely diagnosis in the ICU, the timing of pharmacological prophylaxis, and the treatment of diagnosed PE.

Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors.

Acridones present numerous pharmacological activities, including inhibition of microtubule affinity-regulating kinase 4 (MARK4) kinase activity. To investigate structure-activity relationships and develop potent MARK4 inhibitors, derivatives of 2-methylacridone were synthesized and tested for their activity against MARK4 kinase. Selective substitutions at the nitrogen atom were accomplished by treating 2-methylacridone with alkyl halides in the presence of K2CO3. In addition, amidation of acridone acetic acid 11 with piperazine or tryptophan methyl ester followed by derivatization with various amines gave a series of new acridone derivatives. Among the tested compounds, six were identified as possessing high inhibitory activity against MARK4. The molecular modeling studies showed that the derivatives bearing piperazine or tryptophan bind well to the ATP-binding site of MARK4. The antiproliferative activity of six active compounds was evaluated against HeLa and U87MG cancer cells. Tryptophan derivatives 23a, 23b, and 23c showed significant cytotoxicity against both cell lines with EC50 values ranging from 2.13 to 4.22 µM, while derivatives bearing piperazine were found to be not cytotoxic. Additionally, compound 23a decreased the proliferation of human MDA-MB-435 and U251 cancer cells in the low micromolar range; however, it also affects the non-cancerous HGF cells. Due to their high binding affinity against MARK4, the synthesized compounds could be potential agents to target MARK4 against cancer and tauopathies.

Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates.

Peptide-drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the ανß3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases.

Additive benefit of rehabilitation on physical status, symptoms and mental health after hospitalisation for severe COVID-19 pneumonia.

INTRODUCTION: The potential additive benefits of rehabilitation beyond spontaneous recovery post-COVID-19 currently remain unknown. METHODS: In this prospective, interventional, non-randomised parallel assignment two-arm study, we investigated the effects of an 8-week rehabilitation programme (Rehab, n=25) added to usual care (UC) versus UC (n=27) on respiratory symptoms, fatigue, functional capacity, mental health and health-related quality of life in patients with COVID-19 pneumonia, 6-8 weeks post-hospital discharge. The rehabilitation programme included exercise, education, dietary and psychological support. Patients with chronic obstructive pulmonary disease, respiratory and heart failure were excluded from the study. RESULTS: At baseline, groups were not different in mean age (56 years), gender (53% female), intensive care unit admission (61%), intubation (39%), days of hospitalisation (25), number of symptoms (9) and number of comorbidities (1.4). Baseline evaluation was conducted at median (IQR) 76 (27) days after symptoms onset. Groups were not different regarding baseline evaluation outcomes. At 8 weeks, Rehab showed significantly greater improvement in COPD Assessment Test by a mean±SEM (95% CI) 7.07±1.36 (4.29-9.84), p <0.001 and all three fatigue questionnaires: Chalder-Likert: 5.65±1.27 (3.04-8.25), p <0.001; bimodal: 3.04±0.86 (1.28-4.79), p=0.001; Functional Assessment of Chronic Illness Therapy: 6.37±2.09 (2.08-10.65), p=0.005 and Fatigue Severity Scale: 1.36±0.433 (0.47-2.25), p=0.004. At 8 weeks rehab also showed significantly greater improvment in Short Physical Performance Battery: 1.13±0.33 (0.46-1.79), p=0.002; Hospital Anxiety and Depression Scale (HADS) Anxiety: 2.93±1.01 (0.67-5.18), p=0.013; Beck Depression Inventory: 7.81±3.07 (1.52-14.09), p=0.017; Montreal Cognitive Assessment: 2.83±0.63 (1.5-4.14), p <0.001; EuroQol (EQ-5D-5L) Utility Index: 0.21±0.05 (0.1-0.32), p=0.001 and Visual Analogue Scale: 6.57±3.21 (0.2-13.16), p=0.043. Both groups significantly improved 6-min walking distance by approximately 60 m and pulmonary function measures, whereas post-traumatic stress disorder measurement IES-R (Impact of Event Scale, Revised) and HADS-Depression score were not different between groups at 8 weeks. A 16% attrition rate was observed in the rehabilitation group exhibiting a threefold increase in training workload. There were no adverse effects reported during exercise training. DISCUSSION: These findings highlight the added value of rehabilitation post-COVID-19 to amplify the natural course of physical and mental recovery that otherwise would remain incomplete with UC.

Good Cop, Bad Cop: The Different Roles of SRPKs.

SR Protein Kinases (SRPKs), discovered approximately 30 years ago, are widely known as splice factor kinases due to their decisive involvement in the regulation of various steps of mRNA splicing. However, they were also shown to regulate diverse cellular activities by phosphorylation of serine residues residing in serine-arginine/arginine-serine dipeptide motifs. Over the last decade, SRPK1 has been reported as both tumor suppressor and promoter, depending on the cellular context and has been implicated in both chemotherapy sensitivity and resistance. Moreover, SRPK2 has been reported to exhibit contradictory functions in different cell contexts promoting either apoptosis or tumor growth. The aim of the current review is to broaden and deepen our understanding of the SRPK function focusing on the subcellular localization of the kinases. There is ample evidence that the balance between cytoplasmic and nuclear SRPK levels is tightly regulated and determines cell response to external signals. Specific cell states coupled to kinase levels, spatial specific interactions with substrates but also changes in the extent of phosphorylation that allow SRPKs to exhibit a rheostat-like control on their substrates, could decide the proliferative or antiproliferative role of SRPKs.

Older adults with severe coronavirus disease 2019 admitted to intensive care unit: prevalence, characteristics and risk factors for mortality.

BACKGROUND: Although older adults are at high risk for severe coronavirus disease 2019 (COVID-19) requiring intensive care unit (ICU) admission, age is often used as a selection criterion in case of ICU beds scarcity. We sought to compare the proportion, clinical features and mortality between patients ≥70 years old and younger ICU patients with COVID-19. METHODS: All patients, consecutively admitted to our COVID ICU, where age was not used as an admission criterion, from March 2020 through April 2021, were included. Demographics, clinical and laboratory characteristics were recorded. Illness severity and Charlson comorbidity Index (CCI) were calculated. Patients≥70 years old were compared to youngers. RESULTS: Of 458 patients (68 [59-76] years, 70% males), 206 (45%) were ≥70 years old. Compared to younger, older patients had higher illness severity scores (APACHE II 18 [14-23] versus 12 [9-16], P<0.001, SOFA 8 [6-10] versus 6 [2-8], P<0.001, CCI 5 [4-6] versus 2 [1-3], P<0.001), increased need for mechanical ventilation (92% vs. 72%, P<0.001) and ICU mortality (74% versus. 29%, P<0.001). Age (HR: 1.045, CI: 1.02-1.07, P=0.001), CCI (HR: 1.135, CI: 1.037-1.243, P=0.006) and APACHE II (HR: 1.070, CI: 1.013-1.130, P=0.015) were independently associated with mortality. Among comorbidities, obesity, chronic pulmonary disease and chronic kidney disease were independent risk factors for death. CONCLUSIONS: When age is not used as criterion for admission to COVID ICU, patients ≥70 years old represent a considerable proportion and, compared to younger ones, they have higher mortality. Age, severity of illness and CCI, and certain comorbidities are independent risk factors for mortality.

MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress.

Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-κB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-α, IL-10, IL-2, IL-1ß) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-κB. Inhibition of NF-κB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-κB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-κB/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-κB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-κB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm.

Expression and functional significance of nicotinamide N-methyl transferase in skeletal muscles of patients with chronic obstructive pulmonary disease.

RATIONALE: Nicotinamide N-methyl transferase (NNMT) is highly expressed in quadriceps muscles of patients with chronic obstructive pulmonary disease (COPD). However, its expression in the diaphragm of these patients has not been assessed. The functional significance of NNMT induction in skeletal muscles of patients with COPD is also unknown. OBJECTIVES: (1) To compare NNMT expressions in the diaphragm and quadriceps muscles of patients with COPD. (2) To identify the influence of proinflammatory cytokines on NNMT expression. (3) To assess the influence of NNMT on indices of myogenesis (satellite cell migration and proliferation) and the defense against oxidative stress. METHODS: Costal diaphragm muscle biopsies were acquired from 13 patients with moderate and severe COPD and 8 control subjects. Quadriceps muscle biopsies were obtained from 12 patients with COPD and 14 control subjects. MEASUREMENTS AND MAIN RESULTS: NNMT expressions were significantly elevated in the diaphragm and quadriceps muscles of patients with COPD; however, the relative induction of NNMT expression was greater in the quadriceps muscle (10-fold) than it was in the diaphragm (2-fold). NNMT expressions correlated negatively with the severity of COPD and limb muscle wasting. In skeletal myoblasts, NNMT expression was significantly induced by IL-6, transforming growth factor beta, and tumor necrosis factor-alpha. Overexpression of NNMT in myoblasts triggered a significant increase in proliferation and migration, but had no influence on cell death. Carbonyl formation, induced by exposing myoblasts to H(2)O(2), was significantly attenuated when NNMT was overexpressed. CONCLUSIONS: Up-regulation of NNMT expression in the skeletal muscles of patients with COPD may represent an adaptive response designed to improve myogenesis and defend against oxidative stress.

Inspiratory resistive breathing induces acute lung injury.

RATIONALE: Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation. OBJECTIVES: To determine the effects of resistive breathing on the healthy lung. METHODS: Anesthetized rats breathed through a two-way nonrebreathing valve. The inspiratory line was connected to a resistance setting peak inspiratory tracheal pressure at 50% of maximum (inspiratory resistive breathing), while 100% oxygen was supplied to prevent hypoxemia. Quietly breathing animals (100% oxygen) served as controls. Lung injury was evaluated after 3 and 6 hours of resistive breathing. MEASUREMENTS AND MAIN RESULTS: After both 3 and 6 hours of resistive breathing, lung permeability was increased, as assessed by (99m)Tc-diethylenetriaminepentaacetic acid scintigraphy and Evans blue dye extravasation. Tissue elasticity, measured on the basis of static pressure-volume curves and by the low-frequency forced oscillation technique, was also increased. After both 3 and 6 hours of resistive breathing, gravimetric measurements revealed the presence of pulmonary edema and analysis of bronchoalveolar lavage showed increased total protein content, whereas the total cell count was elevated only after 6 hours of resistive breathing. Cytokine levels were assessed in bronchoalveolar lavage fluid and lung tissue by ELISA and were increased after 6 hours compared with controls. Western blot analysis showed early activation of Src kinase via phosphorylation (at 30 min), and Erk1/2 and IκBα (nuclear factor-κB inhibitor) were phosphorylated at 3 and 6 hours. Pathology revealed the presence of lung injury after resistive breathing. CONCLUSIONS: Resistive breathing induces acute lung injury and inflammation.

Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy.

RATIONALE: Controlled mechanical ventilation (CMV) results in atrophy of the human diaphragm. The autophagy-lysosome pathway (ALP) contributes to skeletal muscle proteolysis, but its contribution to diaphragmatic protein degradation in mechanically ventilated patients is unknown. OBJECTIVES: To evaluate the autophagy pathway responses to CMV in the diaphragm and limb muscles of humans and to identify the roles of FOXO transcription factors in these responses. METHODS: Muscle biopsies were obtained from nine control subjects and nine brain-dead organ donors. Subjects were mechanically ventilated for 2 to 4 hours and 15 to 276 hours, respectively. Activation of the ubiquitin-proteasome system was detected by measuring mRNA expressions of Atrogin-1, MURF1, and protein expressions of UBC2, UBC4, and the α subunits of the 20S proteasome (MCP231). Activation of the ALP was detected by electron microscopy and by measuring the expressions of several autophagy-related genes. Total carbonyl content and HNE-protein adduct formation were measured to assess oxidative stress. Total AKT, phosphorylated and total FOXO1, and FOXO3A protein levels were also measured. MEASUREMENTS AND MAIN RESULTS: Prolonged CMV triggered activation of the ALP as measured by the appearance of autophagosomes in the diaphragm and increased expressions of autophagy-related genes, as compared with controls. Induction of autophagy was associated with increased protein oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A gene. CMV also triggered the inhibition of both AKT expression and FOXO1 phosphorylation. CONCLUSIONS: We propose that prolonged CMV causes diaphragm disuse, which, in turn, leads to activation of the ALP through oxidative stress and the induction of the FOXO1 transcription factor.

The Role of Noninvasive Respiratory Management in Patients with Severe COVID-19 Pneumonia.

Acute hypoxemic respiratory failure is the principal cause of hospitalization, invasive mechanical ventilation and death in severe COVID-19 infection. Nearly half of intubated patients with COVID-19 eventually die. High-Flow Nasal Oxygen (HFNO) and Noninvasive Ventilation (NIV) constitute valuable tools to avert endotracheal intubation in patients with severe COVID-19 pneumonia who do not respond to conventional oxygen treatment. Sparing Intensive Care Unit beds and reducing intubation-related complications may save lives in the pandemic era. The main drawback of HFNO and/or NIV is intubation delay. Cautious selection of patients with severe hypoxemia due to COVID-19 disease, close monitoring and appropriate employment and titration of HFNO and/or NIV can increase the rate of success and eliminate the risk of intubation delay. At the same time, all precautions to protect the healthcare personnel from viral transmission should be taken. In this review, we summarize the evidence supporting the application of HFNO and NIV in severe COVID-19 hypoxemic respiratory failure, analyse the risks associated with their use and provide a path for their proper implementation.

Nuclear Translocation of SRPKs Is Associated with 5-FU and Cisplatin Sensitivity in HeLa and T24 Cells.

Serine/arginine protein kinases (SRPKs) phosphorylate Arg/Ser dipeptide-containing proteins that play crucial roles in a broad spectrum of basic cellular processes. The existence of a large internal spacer sequence that separates the bipartite kinase catalytic core and anchors the kinases in the cytoplasm is a unique structural feature of SRPKs. Here, we report that exposure of HeLa and T24 cells to DNA damage inducers triggers the nuclear translocation of SRPK1 and SRPK2. Furthermore, we show that nuclear SRPKs did not protect from, but on the contrary, mediated the cytotoxic effects of genotoxic agents, such as 5-fluorouracil (5-FU) and cisplatin. Confirming previous data showing that the kinase activity is essential for the entry of SRPKs into the nucleus, SRPIN340, a selective SRPK1/2 inhibitor, blocked the nuclear accumulation of the kinases, thus diminishing the cytotoxic effects of the drugs. ATR/ATM-dependent phosphorylation of threonine 326 and serine 408 in the spacer domain of SRPK1 was essential for the redistribution of the kinase to the nucleus. Substitution of either of these two residues to alanine or inhibition of ATR/ATM kinase activity abolished nuclear localization of SRPK1 and conferred tolerance to 5-FU treatment. These findings suggest that SRPKs may play an important role in linking cellular signaling to DNA damage in eukaryotic cells.

Effect of COVID-19-Related Lockdown οn Hospital Admissions for Asthma and COPD Exacerbations: Associations with Air Pollution and Patient Characteristics.

We conducted a retrospective observational study to assess the hospitalization rates for acute exacerbations of asthma and COPD (chronic obstructive pulmonary disease) during the first imposed lockdown in Athens, Greece. Patient characteristics and the concentration of eight air pollutants [namely, NO (nitrogen monoxide), NO2 (nitrogen dioxide), CO (carbon monoxide), PM2.5 (particulate matter 2.5), PM10 (particulate matter 10), O3 (ozone), SO2 (sulfur dioxide) and benzene] were considered. A total of 153 consecutive hospital admissions were studied. Reduced admissions occurred in the Lockdown period compared to the Pre-lockdown 2020 (p < 0.001) or the Control 2019 (p = 0.007) period. Furthermore, the concentration of 6/8 air pollutants positively correlated with weekly hospital admissions in 2020 and significantly decreased during the lockdown. Finally, admitted patients for asthma exacerbation during the lockdown were younger (p = 0.046) and less frequently presented respiratory failure (p = 0.038), whereas patients with COPD presented higher blood eosinophil percentage (p = 0.017) and count (p = 0.012). Overall, admissions for asthma and COPD exacerbations decreased during the lockdown. This might be partially explained by reduction of air pollution during this period while medical care avoidance behavior, especially among elderly patients cannot be excluded. Our findings aid in understanding the untold impact of the pandemic on diseases beyond COVID-19, focusing on patients with obstructive diseases.

Synthesis and Biological Evaluation of a c(RGDyK) Peptide Conjugate of SRPIN803.

In the present study, SRPIN803 and c(RGDyK)-SRPIN803 hybrid compounds were efficiently synthesized and evaluated for their stability in human plasma and buffers of pH 7.4 and 5.2. The hybrids were mainly cytostatic against a panel of tested cancer cells, whereas one c(RGDyK)-SRPIN803 hybrid, geo35, was the most active compound in this screen and was cytotoxic against cell lines MCF7 and MRC5 with IC50 values of 61 and 63 µM, respectively. SRPIN803 and geo35 exhibited antiangiogenic activity in zebrafish embryos, and this effect was dose-dependent. Although c(RGDyK)-SRPIN803 hybrid compounds were found less potent compared to SRPIN803, they have shown activities interesting enough to illustrate the potential of this approach for the development of a new class of antiangiogenic compounds.

Bacteriology, antibiotic resistance and risk stratification of patients with culture-positive, community-acquired pleural infection.

BACKGROUND: Community-acquired pleural infection (CAPI) is a growing health problem worldwide. Although most CAPI patients recover with antibiotics and pleural drainage, 20% require surgical intervention. The use of inappropriate antibiotics is a common cause of treatment failure. Awareness of the common causative bacteria along with their patterns of antibiotic resistance is critical in the selection of antibiotics in CAPI-patients. This study aimed to define CAPI bacteriology from the positive pleural fluid cultures, determine effective antibiotic regimens and investigate for associations between clinical features and risk for death or antibiotic-resistance, in order to advocate with more invasive techniques in the optimal timing. METHODS: We examined 158 patients with culture positive, CAPI collected both retrospectively (2012-2013) and prospectively (2014-2018). Culture-positive, CAPI patients hospitalized in six tertiary hospitals in Greece were prospectively recruited (N=113). Bacteriological data from retrospectively detected patients were also used (N=45). Logistic regression analysis was performed to identify clinical features related to mortality, presence of certain bacteria and antibiotic resistance. RESULTS: Streptococci, especially the non-pneumococcal ones, were the most common bacteria among the isolates, which were mostly sensitive to commonly used antibiotic combinations. RAPID score (i.e., clinical score for the stratification of mortality risk in patients with pleural infection; parameters: renal, age, purulence, infection source, and dietary factors), diabetes and CRP were independent predictors of mortality while several patient co-morbidities (e.g., diabetes, malignancy, chronic renal failure, etc.) were related to the presence of certain bacteria or antibiotic resistance. CONCLUSIONS: The dominance of streptococci among pleural fluid isolates from culture-positive, CAPI patients was demonstrated. Common antibiotic regimens were found highly effective in CAPI treatment. The predictive strength of RAPID score for CAPI mortality was confirmed while additional risk factors for mortality and antibiotic resistance were detected.