Anaesthesia and COVID-19: infection control.

The world is currently facing an unprecedented healthcare crisis caused by a pandemic novel beta coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pathogen is spread by human-to-human transmission via droplets exposure and contact transfer, causing mild symptoms in the majority of cases, but critical illness, bilateral viral pneumonia, and acute respiratory distress syndrome (ARDS) in a minority. Currently, controlling infection to prevent the spread of SARS-CoV-2 is the primary public healthcare intervention used. The pace of transmission and global scale of SARS-CoV-2 infections has implications for strategic oversight, resource management, and responsiveness in infection control. This article presents a summary of learning points in epidemiological infection control from the SARS epidemic, alongside a review of evidence connecting current understanding of the virologic and environmental contamination properties of SARS-CoV-2. We present suggestions for how personal protective equipment policies relate to the viral pandemic context and how the risk of transmission by and to anaesthetists, intensivists, and other healthcare workers can be minimised.

Magmatic Response to Subduction Initiation: Part 1. Fore-arc Basalts of the Izu-Bonin Arc From IODP Expedition 352.

The Izu-Bonin-Mariana (IBM) fore arc preserves igneous rock assemblages that formed during subduction initiation circa 52 Ma. International Ocean Discovery Program (IODP) Expedition 352 cored four sites in the fore arc near the Ogasawara Plateau in order to document the magmatic response to subduction initiation and the physical, petrologic, and chemical stratigraphy of a nascent subduction zone. Two of these sites (U1440 and U1441) are underlain by fore-arc basalt (FAB). FABs have mid-ocean ridge basalt (MORB)-like compositions, however, FAB are consistently lower in the high-field strength elements (TiO2, P2O5, Zr) and Ni compared to MORB, with Na2O at the low end of the MORB field and FeO* at the high end. Almost all FABs are light rare earth element depleted, with low total REE, and have low ratios of highly incompatible to less incompatible elements (Ti/V, Zr/Y, Ce/Yb, and Zr/Sm) relative to MORB. Chemostratigraphic trends in Hole U1440B are consistent with the uppermost lavas forming off axis, whereas the lower lavas formed beneath a spreading center axis. Axial magma of U1440B becomes more fractionated upsection; overlying off-axis magmas return to more primitive compositions. Melt models require a two-stage process, with early garnet field melts extracted prior to later spinel field melts, with up to 23% melting to form the most depleted compositions. Mantle equilibration temperatures are higher than normal MORB (1,400 °C-1,480 °C) at relatively low pressures (1-2 GPa), which may reflect an influence of the Manus plume during subduction initiation. Our data support previous models of FAB origin by decompression melting but imply a source more depleted than normal MORB source mantle.

Neuropeptide Y reduces acetylcholine release and vagal bradycardia via a Y2 receptor-mediated, protein kinase C-dependent pathway.

The co-transmitter neuropeptide Y (NPY), released during prolonged cardiac sympathetic nerve stimulation, can attenuate vagal-induced bradycardia. We tested the hypothesis that NPY reduces acetylcholine release, at similar concentrations to which it attenuates vagal bradycardia, via pre-synaptic Y2 receptors modulating a pathway that is dependent on protein kinase A (PKA) or protein kinase C (PKC). The Y2 receptor was immunofluorescently colocalized with choline acetyl-transferase containing neurons at the guinea pig sinoatrial node. The effect of NPY in the presence of various enzyme inhibitors was then tested on the heart rate response to vagal nerve stimulation in isolated guinea pig sinoatrial node/right vagal nerve preparations and also on (3)H-acetylcholine release from right atria during field stimulation. NPY reduced the heart rate response to vagal stimulation at 1, 3 and 5 Hz (significant at 100 nM and reaching a plateau at 250 nM NPY, p<0.05, n=6) but not to the stable analogue of acetylcholine, carbamylcholine (30, 60 or 90 nM, n=6) which produced similar degrees of bradycardia. The reduced vagal response was abolished by the Y2 receptor antagonist BIIE 0246 (1 microM, n=4). NPY also significantly attenuated the release of (3)H-acetylcholine during field stimulation (250 nM, n=6). The effect of NPY (250 nM) on vagal bradycardia was abolished by the PKC inhibitors calphostin C (0.1 microM, n=5) and chelerythrine chloride (25 microM, n=6) but not the PKA inhibitor H89 (0.5 microM, n=6). Conversely, the PKC activator Phorbol-12-myristate-13-acetate (0.5 microM, n=7) mimicked the effect of NPY and significantly reduced (3)H-acetylcholine release during field stimulation. These results show that NPY attenuates vagal bradycardia via a pre-synaptic decrease in acetylcholine release that appears to be mediated by a Y2 receptor pathway involving modulation of PKC.

Laryngeal tuberculosis: a rare cause of critical airway obstruction.

Laryngeal tuberculosis (TB) is a rare condition, occurring in less than 1% of patients infected with pulmonary TB. We present a case of a 57-year-old male patient, who presented in extremis with audible stridor, increased work of breathing and cyanosis. In addition, the patient had a complex medical history, including a recent diagnosis of congenital malformation of the epiglottis. Emergency intervention was required to secure the airway, and after initial attempts at intubation were unsuccessful, an emergency tracheostomy was performed. Four days after initial presentation, his sputum tested positive for acid-fast bacilli, and a subsequent CT chest revealed pulmonary as well as laryngeal TB, which was confirmed on biopsy of the larynx. The patient was commenced on a 24-week course of anti-tuberculous treatment and was successfully decannulated 6 months after the emergency airway was established.

Nivolumab-induced fulminant diabetic ketoacidosis followed by thyroiditis.

Five days following the 3rd cycle of nivolumab, a monoclonal antibody, which acts as immune checkpoint inhibitor against the programmed cell death protein-1, for metastatic lung adenocarcinoma, a 56-year-old woman presented at the hospital critically ill. On admission, she had severe diabetic ketoacidosis (DKA), as evidenced by venous glucose of 47 mmol/L, blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L. She has had no personal or family history of diabetes mellitus (DM), while random venous glucose, measured 1 week prior to hospitalisation, was 6.1 mmol/L. On admission, her HbA1c was 8.2% and anti-GAD antibodies were 12 kIU/L (0-5 kU/L), while islet cell antibodies and serum C-peptide were undetectable. Nivolumab was recommenced without the development of other immune-mediated phenomena until 6 months later, when she developed hypothyroidism with TSH 18 U/L and low free T4. She remains insulin dependent and has required levothyroxine replacement, while she has maintained good radiological and clinical response to immunotherapy. This case is notable for the rapidity of onset and profound nature of DKA at presentation, which occurred two months following commencement of immunotherapy. Despite the association of nivolumab with immune-mediated endocrinopathies, only a very small number of patients developing type 1 DM has been reported to date. Patients should be closely monitored for hyperglycaemia and thyroid dysfunction prior to and periodically during immunotherapy. LEARNING POINTS: Nivolumab can induce fulminant type 1 diabetes, resulting in DKA.Nivolumab is frequently associated with thyroid dysfunction, mostly hypothyroidism.Nivolumab-treated patients should be monitored regularly for hyperglycaemia and thyroid dysfunction.Clinicians should be aware and warn patients of potential signs and symptoms of severe hyperglycaemia.

Isoforms of apolipoprotein E can modulate tPA-induced clot lysis in vitro.

Apo E, and its respective isoforms, have been linked to outcome and survival in cerebral vascular and cardiovascular diseases. The effectiveness of intravenous tPA in patients with acute ischemic stroke appears to be enhanced in patients who have an Apo E2 phenotype. The ability of Apo E isoproteins (endogenous Apo E isoproteins or exogenous Apo E isoproteins) to modulate tPA-induced clot lysis in vitro was assessed using an in vitro clot assay system. Blood samples were obtained from 18-volunteers with three Apo E genotypes: E2, E3 and E4. tPA-induced clot lysis (0-4 microgram/ml tPA), was assessed in the presence or absence of supplemental Apo E2, E3 or E4 (9.8 microgram/ml). tPA-induced clot lysis was significantly (P equal or less than 0.0001) enhanced by supplementation with Apo E2 (EC50 0.20 0.06 microgram/ml) as compared to tPA alone (0.72 0.19). Apo E4 supplementation caused a significant (P < or = 0.05) inhibition of clot lysis (0.98 0.23), but there was no significant change caused by Apo E3. The genotype of the volunteer did not significantly affect the ability of the supplemental Apo E from modulating tPA-induced clot lysis. We conclude that the administration of Apo E isoproteins can modulate clot lysis in vitro. Our results suggest that the Apo E isoprotein may have an impact on clot dissolution and the effectiveness of thrombolytic therapy.

Gene transfer of neuronal nitric oxide synthase into intracardiac Ganglia reverses vagal impairment in hypertensive rats.

Hypertension is associated with reduced cardiac vagal activity and decreased atrial guanylate cyclase and cGMP levels. Neuronal production of NO facilitates cardiac parasympathetic transmission, although oxidative stress caused by hypertension may disrupt this pathway. We tested the hypothesis that peripheral vagal responsiveness is attenuated in the spontaneously hypertensive rat (SHR) because of impaired NO-cGMP signaling and that gene transfer of neuronal NO synthase (nNOS) into cholinergic intracardiac ganglia can restore neural function. Cardiac vagal heart rate responses in the isolated SHR atrial/right vagus preparation were significantly attenuated compared with age-matched normotensive Wistar-Kyoto rats. [(3)H] acetylcholine release was also significantly lower in the SHR. The NO donor, sodium nitroprusside, augmented vagal responses to nerve stimulation and [(3)H] acetylcholine release in the Wistar-Kyoto rat, whereas the soluble guanylate cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxaline-1-one attenuated [(3)H] acetylcholine release in Wistar-Kyoto atria. No effects of sodium nitroprusside or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxaline-1-one were seen in the SHR during nerve stimulation. In contrast, SHR atria were hyperresponsive to carbachol-induced bradycardia, with elevated production of atrial cGMP. After gene transfer of adenoviral nNOS into the right atrium, vagal responsiveness in vivo was significantly increased in the SHR compared with transfection with adenoviral enhanced green fluorescent protein. Atrial nNOS activity was increased after gene transfer of adenoviral nNOS, as was expression of alpha(1)-soluble guanylate cyclase in both groups compared with adenoviral enhanced green fluorescent protein. In conclusion, a significant component of cardiac vagal dysfunction in hypertension is attributed to an impairment of the postganglionic presynaptic NO-cGMP pathway and that overexpression of nNOS can reverse this neural phenotype.

Remodeling of the cardiac pacemaker L-type calcium current and its beta-adrenergic responsiveness in hypertension after neuronal NO synthase gene transfer.

Hypertension is associated with abnormal neurohumoral activation. We tested the hypothesis that beta-adrenergic hyperresponsiveness in the sinoatrial node (SAN) of the spontaneously hypertensive rat occurs at the level of the L-type calcium current because of altered cyclic nucleotide-dependent signaling. Furthermore, we hypothesized that NO, a modulator of cGMP and cAMP, would normalize the beta-adrenergic phenotype in the hypertensive rat. Chronotropic responsiveness to norepinephrine (NE), together with production of cAMP and cGMP, was assessed in isolated atrial preparations from age-matched hypertensive and normotensive rats. Right atrial/SAN pacemaking tissue was injected with adenovirus encoding enhanced green fluorescent protein (control vector) or neuronal NO synthase (nNOS). In addition, L-type calcium current was measured in cells isolated from the SAN of transfected animals. Basal levels of cGMP were lower in hypertensive rat atria. These atria were hyperresponsive to NE at all of the concentrations tested, with elevated production of cAMP. This was accompanied by increased basal and norepinephrine-stimulated L-type calcium current. Using enhanced green fluorescent protein, we observed transgene expression within both tissue sections and isolated pacemaking cells. Adenoviral nNOS increased right atrial nNOS protein expression and cGMP content. NE-stimulated cAMP concentration and L-type calcium current were also attenuated by adenoviral nNOS, along with the chronotropic responsiveness to NE in hypertensive rat atria. Decreased calcium current after cardiac nNOS gene transfer contributes to the normalization of beta-adrenergic hyperresponsiveness in the SAN from hypertensive rats by modulating cyclic nucleotide signaling.