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

Factors associated with developing symptomatic HIV-associated sensory neuropathy

HIV-associated sensory neuropathy (HIV-SN) is one of the most common neurological problems of HIV. It is frequently painful and reduces quality of life. HIV-SN can be caused both by HIV itself and by exposure to neurotoxic antiretrovirals such as stavudine. The South African Department of Health now recommends use of tenofovir in place of stavudine as first line treatment. However many people remain on stavudine and or live with the side effects. Stavudine is still prescribed in many other resource-poor countries. This thesis presents the first systematic study of clinical and genetic risk factors for the development of symptomatic HIV-SN in Black Southern Africans. I recruited 404 Black HIV-positive Africans from the Virology Clinic of the Charlotte Maxeke Academic Hospital, Johannesburg and assessed HIV-SN using the AIDS Clinical Trials Group (ACTG) Brief Peripheral Neuropathy Screen. HIV-SN was defined as present if the patient had both symptoms and signs of peripheral neuropathy. If present, the distribution and intensity of symptoms were recorded. Of those exposed to stavudine, 57% (226/395) had HIV-SN. Pain was the most common symptom and was experienced by 74% (172/226). Of these, 76% (128/172) reported their pain as moderate to severe. As in previous studies, increasing age and height were independently associated with risk of HIV-SN. However nadir and current CD4 T-cell counts and sex were not associated with SN. Patients donated blood for DNA extraction and single nucleotide polymorphisms (SNPs) were selected from the literature and genotyped using Illumina Golden GateTM technology. 342 individuals were assessed for genetic associations with HIV-SN and a subset of 159 positive for HIV-SN were assessed for associations with painful HIV-SN. I completed four genetic analyses: SNPs and haplotypes from TNF and adjacent genes from the major histocompatability complex on chromosome six were assessed for association with HIV-SN. I found no association with TNF-1031, even though this had associated with risk of HIV-SN in Caucasian, Chinese and Malay cohorts. Novel associations were identified between HIV-SN protection and 5 other SNPs (BAT1 rs3130059, rs2523504; ATP6V1G2 rs2071594; NFKBIL1 rs2071592, rs2071591). Associations were also found with haplotypes: FV15-23 weakly associated with risk and FV30-31 associated with protection against HIV-SN in this cohort. Analysis of 8 SNPs not previously assessed produced two novel associations with LTA SNPs (rs1041981, rs909253), where the minor alleles conferred protection against HIV-SN. Analysis of linkage disequilibrium (LD) suggests that there is linkage disequilibrium within the TNF block, that it differs between ethnicities and that TNF-1031 is unlikely to be a causative SNP for risk of HIV-SN. SNPs from other cytokines and chemokines implicated in the pathogenesis of HIVSN and the associated pain were assessed in Chapter 5. The major allele of the antiinflammatory gene IL4 (rs2243250) associated with risk of HIV-SN. This allele has been associated with higher CD4 T-cell counts, so I have proposed a role for high IL- 4 in early stage HIV-SN. A 3-SNP haplotype of IL10 associated with protection against HIV-SN whilst another IL10 haplotype showed a trend for risk of painful HIVSN. These data and the involvement of TNF haplotype (Chapter 4) suggest an inflammatory etiology for HIV-SN. Polymorphisms of UCP2 (rs659366) and UCP3 (rs1800849) have previously associated with risk of diabetic neuropathy. These SNPs encode uncoupling proteins 2 and 3 which regulate reactive oxygen species and may affect development of neuropathy via the effects of oxidative stress and mitochondrial dysfunction. Alleles of these SNPs did not associate with HIV-SN in this cohort. Patterns of linkage disequilibrium may differ between the two ethnicities or UCP2 and UCP3 may associate with a mechanism particular to diabetic neuropathy. I also assessed a ‘pain protective haplotype’ and SNPs of GCH1 which have been associated with decreased pain intensity in radicular pain following lumbar discectomy. Associations of the 3-SNP ‘pain protective’ haplotype (rs10483639*C, rs3783641*A and rs8007267*T) and a 6-SNP haplotype containing this motif with protection against pain were significant but dependent on age, sex and CD4 T-cell count. Association of another 3-SNP haplotype (rs10483639*G, rs3783641*T and rs8007267*C) with increased risk of pain in HIV-SN was also not independent of age, sex and CD4 T-cell count. The weaker associations here compared to Caucasian cohorts may be a result of differing LD between ethnicities or demonstrate different pain mechanisms between HIV-SN and radicular pain following lumbar discectomy. My results highlight the prevalence of HIV-SN and frequency of pain in this Southern African cohort. The genetic studies identify a likely inflammatory component and identify genes worthy of further investigation both in HIV-SN and the associated pain

The Southern Ocean Observing System

Due to its position as the principal connector of the major ocean basins, the Southern Ocean strongly impacts climate, sea level, biogeochemical cycles and biological productivity on a global scale. The Southern Ocean influences the global distribution and movement of heat and carbon (e.g. Rintoul et al., 2001), and it features a vigorous overturning circulation that drives deep-water carbon and nutrients to the surface and draws down anthropogenic carbon from the atmosphere, with implications for global climate change and large-scale productivity (Sarmiento et al., 2004; le Quere et al., 2007; Meredith et al., 2012). The Southern Ocean exerts a strong influence on sea levels via melting of glacial ice (Rignot and Jacobs, 2002; Rignot et al., 2011), and it encompasses a sea-ice system that provides an important habitat for marine organisms, and which influences surface albedo and air-sea gas and heat exchange (Thomas and Dieckmann, 2002). The Southern Ocean also includes some of the most productive and vulnerable marine ecosystems on Earth, many of which support economically important species

Establishing Consensus for the Core Concepts of Physiology in the Australian Higher Education Context using the Delphi Method

A set of core concepts ("big ideas") integral to the discipline of physiology are important for students to understand and demonstrate their capacity to apply. We found poor alignment of learning outcomes in programs with physiology majors (or equivalent) from 17 Australian universities and the 15 core concepts developed by a team in the United States. The objective of this project was to reach Australia-wide consensus on a set of core concepts for physiology, which can be embedded in curricula across Australian universities. A four-phase Delphi method was employed, starting with the assembling of a Task Force of physiology educators with extensive teaching and curriculum development expertise from 25 Australian universities. After two online meetings and a survey, the Task Force reached agreement on seven core concepts of physiology and their descriptors, which were then sent out to the physiology educator community across Australia for agreement. The seven core concepts and their associated descriptions were endorsed through this process (n = 138). In addition, embedding the core concepts across the curriculum was supported by both Task Force members (85.7%) and educators (82.1%). The seven adopted core concepts of human physiology were Cell Membrane, Cell-Cell Communication, Movement of Substances, Structure and Function, Homeostasis, Integration, and Physiological Adaptation. The core concepts were subsequently unpacked into themes and subthemes. If adopted, these core concepts will result in consistency across curricula in undergraduate physiology programs and allow for future benchmarking.NEW &amp; NOTEWORTHY This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.</p