Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The Pneumonectomy Model of Compensatory Lung Growth: insights into lung regeneration

Pneumonectomy (PNX) in experimental animals leads to a species- and age-dependent compensatory growth of the remaining lung lobes. PNX mimics the loss of functional gas exchange units observed in a number of chronic destructive lung diseases. However, unlike in disease models, this tissue loss is well defined, reproducible and lacks accompanying inflammation. Furthermore, compensatory responses to the tissue loss can be easily quantified. This makes PNX a potentially useful model for the study of the cellular and molecular events which occur during realveolarisation. It may therefore help to get a better understanding of how manipulate these pathways, in order to promote the generation of new alveolar tissue as therapies for destructive lung diseases. This review will explore the important insights that experimental PNX has provided into the physiological factors which promote compensatory lung growth as well as the importance of age and species in the rate and extent of compensation. In addition, more recent studies which are beginning to uncover the key cellular and molecular pathways involved in realveolarisation will be highlighted. The potential relevance of experimental pneumonectomy to novel therapeutic strategies which aim to promote lung regeneration will also be discussed

Regulation of airway mucosal hydration

Ion channels control the hydration status of the airway epithelium through apical anion secretion and cation absorption, which is accompanied by osmotically obligated water. The key channels in this process are the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), which is principally responsible for Cl- secretion by airway epithelial cells, and the epithelial Na+ channel (ENaC), which is responsible for the absorption of Na ions. In CF, defective CFTR-mediated Cl- secretion and an accompanying upregulation in ENaC-mediated Na absorption results in a reduction in airway surface liquid volume, leading to poorly hydrated mucus and impaired mucociliary clearance. Restoration of normal airway hydration by modulation of ion channel activity represents an important therapeutic strategy for CF. CFTR corrector and potentiator compounds are being developed with the aim of recovering normal Cl- secretion. Ca2+-activated Cl- channels (CaCCs) are expressed by the respiratory epithelia and are reported to be functionally upregulated in CF and offer a 'surrogate pathway for Cl- secretion. TMEM16A has recently been described as a CaCC in the airway epithelium and, as such, represents an alternative target for restoring Cl- secretion in CF. An alternative therapeutic strategy for CF is to inhibit ENaC, thereby blocking excessive Na absorption. This can be achieved by direct blockade of ENaC or inhibition of the channel-activating proteases (CAPs), whose activity regulates ENaC function. This review will describe the regulation of airway mucosal hydration by ion channels and the efforts currently underway to restore normal mucosal hydration in disease patients by modulating the function of these channels. © 2010 Expert Reviews Ltd

Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines

We report the synthesis and biological evaluation of a series of novel α-branched pyrazinoyl quaternary amines for their ability to block ion transport via the epithelial sodium channel (ENaC) in human bronchial epithelial cells (HBECs). Compound 12g has an IC50 of 37 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 1 μgkg-1 at 1 h. In addition the SAR results demonstrate for the first time the chiral nature of the binding site of human ENaC. As such, pyrazinoyl quaternary amines represent a promising new class of ENaC blockers for the treatment of cystic fibrosis that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride

Dimeric modulators of ENaC for the treatment of cystic fibrosis

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Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: Quaternary amines

We report the identification of a novel series of human epithelial sodium channel (ENaC) blockers that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. Following a rational design hypothesis a series of quaternary amines were prepared and evaluated for their ability to block ion transport via ENaC in human bronchial epithelial cells (HBECs). Compound 11 has an IC50 of 200 nM and is efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 44 μg kg−1 at 1 h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers

Male Infertility and DNA Damage in Doppel Knockout and Prion Protein/Doppel Double-Knockout Mice

The prion protein (PrP) and Doppel (Dpl) have many structural and biochemical properties in common, leading to the suggestion that the lack of an obvious phenotype in PrP-deficient mice maybe because of compensation by Dpl. To test this hypothesis and also investigate the function of Dpl we have generated Prnd(−/−) and Prnp(−/−)/Prnd(−/−) mouse lines. Both develop normally and display an identical male sterility phenotype that differs from that reported for another Prnd(−/−) mouse line. Sperm from both our mutant lines were present at normal concentrations, had normal motility, and no morphological abnormalities. Despite only rarely fertilizing oocytes in vivo, because of an inability to perform the acrosome reaction, mutant sperm were capable of fertilization in vitro, albeit at reduced rates compared to wild type. Elevated levels of oxidative DNA damage were found in both types of mutant sperm and resulting embryos failed at an early stage. Therefore we found no evidence that Dpl compensates for the loss of PrP function in mutant mouse lines, but it does have an important anti-oxidant function necessary for sperm integrity and male fertility