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

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Science goals and mission architecture of the Europa Lander mission concept

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Hand, K., Phillips, C., Murray, A., Garvin, J., Maize, E., Gibbs, R., Reeves, G., San Martin, A., Tan-Wang, G., Krajewski, J., Hurst, K., Crum, R., Kennedy, B., McElrath, T., Gallon, J., Sabahi, D., Thurman, S., Goldstein, B., Estabrook, P., Lee, S. W., Dooley, J. A., Brinckerhoff, W. B., Edgett, K. S., German, C. R., Hoehler, T. M., Hörst, S. M., Lunine, J. I., Paranicas, C., Nealson, K., Smith, D. E., Templeton, A. S., Russell, M. J., Schmidt, B., Christner, B., Ehlmann, B., Hayes, A., Rhoden, A., Willis, P., Yingst, R. A., Craft, K., Cameron, M. E., Nordheim, T., Pitesky, J., Scully, J., Hofgartner, J., Sell, S. W., Barltrop, K. J., Izraelevitz, J., Brandon, E. J., Seong, J., Jones, J.-P., Pasalic, J., Billings, K. J., Ruiz, J. P., Bugga, R. V., Graham, D., Arenas, L. A., Takeyama, D., Drummond, M., Aghazarian, H., Andersen, A. J., Andersen, K. B., Anderson, E. W., Babuscia, A., Backes, P. G., Bailey, E. S., Balentine, D., Ballard, C. G., Berisford, D. F., Bhandari, P., Blackwood, K., Bolotin, G. S., Bovre, E. A., Bowkett, J., Boykins, K. T., Bramble, M. S., Brice, T. M., Briggs, P., Brinkman, A. P., Brooks, S. M., Buffington, B. B., Burns, B., Cable, M. L., Campagnola, S., Cangahuala, L. A., Carr, G. A., Casani, J. R., Chahat, N. E., Chamberlain-Simon, B. K., Cheng, Y., Chien, S. A., Cook, B. T., Cooper, M., DiNicola, M., Clement, B., Dean, Z., Cullimore, E. A., Curtis, A. G., Croix, J-P. de la, Pasquale, P. Di, Dodd, E. M., Dubord, L. A., Edlund, J. A., Ellyin, R., Emanuel, B., Foster, J. T., Ganino, A. J., Garner, G. J., Gibson, M. T., Gildner, M., Glazebrook, K. J., Greco, M. E., Green, W. M., Hatch, S. J., Hetzel, M. M., Hoey, W. A., Hofmann, A. E., Ionasescu, R., Jain, A., Jasper, J. D., Johannesen, J. R., Johnson, G. K., Jun, I., Katake, A. B., Kim-Castet, S. Y., Kim, D. I., Kim, W., Klonicki, E. F., Kobeissi, B., Kobie, B. D., Kochocki, J., Kokorowski, M., Kosberg, J. A., Kriechbaum, K., Kulkarni, T. P., Lam, R. L., Landau, D. F., Lattimore, M. A., Laubach, S. L., Lawler, C. R., Lim, G., Lin, J. Y., Litwin, T. E., Lo, M. W., Logan, C. A., Maghasoudi, E., Mandrake, L., Marchetti, Y., Marteau, E., Maxwell, K. A., Namee, J. B. Mc, Mcintyre, O., Meacham, M., Melko, J. P., Mueller, J., Muliere, D. A., Mysore, A., Nash, J., Ono, H., Parker, J. M., Perkins, R. C., Petropoulos, A. E., Gaut, A., Gomez, M. Y. Piette, Casillas, R. P., Preudhomme, M., Pyrzak, G., Rapinchuk, J., Ratliff, J. M., Ray, T. L., Roberts, E. T., Roffo, K., Roth, D. C., Russino, J. A., Schmidt, T. M., Schoppers, M. J., Senent, J. S., Serricchio, F., Sheldon, D. J., Shiraishi, L. R., Shirvanian, J., Siegel, K. J., Singh, G., Sirota, A. R., Skulsky, E. D., Stehly, J. S., Strange, N. J., Stevens, S. U., Sunada, E. T., Tepsuporn, S. P., Tosi, L. P. C., Trawny, N., Uchenik, I., Verma, V., Volpe, R. A., Wagner, C. T., Wang, D., Willson, R. G., Wolff, J. L., Wong, A. T., Zimmer, A. K., Sukhatme, K. G., Bago, K. A., Chen, Y., Deardorff, A. M., Kuch, R. S., Lim, C., Syvertson, M. L., Arakaki, G. A., Avila, A., DeBruin, K. J., Frick, A., Harris, J. R., Heverly, M. C., Kawata, J. M., Kim, S.-K., Kipp, D. M., Murphy, J., Smith, M. W., Spaulding, M. D., Thakker, R., Warner, N. Z., Yahnker, C. R., Young, M. E., Magner, T., Adams, D., Bedini, P., Mehr, L., Sheldon, C., Vernon, S., Bailey, V., Briere, M., Butler, M., Davis, A., Ensor, S., Gannon, M., Haapala-Chalk, A., Hartka, T., Holdridge, M., Hong, A., Hunt, J., Iskow, J., Kahler, F., Murray, K., Napolillo, D., Norkus, M., Pfisterer, R., Porter, J., Roth, D., Schwartz, P., Wolfarth, L., Cardiff, E. H., Davis, A., Grob, E. W., Adam, J. R., Betts, E., Norwood, J., Heller, M. M., Voskuilen, T., Sakievich, P., Gray, L., Hansen, D. J., Irick, K. W., Hewson, J. C., Lamb, J., Stacy, S. C., Brotherton, C. M., Tappan, A. S., Benally, D., Thigpen, H., Ortiz, E., Sandoval, D., Ison, A. M., Warren, M., Stromberg, P. G., Thelen, P. M., Blasy, B., Nandy, P., Haddad, A. W., Trujillo, L. B., Wiseley, T. H., Bell, S. A., Teske, N. P., Post, C., Torres-Castro, L., Grosso, C. Wasiolek, M. Science goals and mission architecture of the Europa Lander mission concept. The Planetary Science Journal, 3(1), (2022): 22, https://doi.org/10.3847/psj/ac4493.Europa is a premier target for advancing both planetary science and astrobiology, as well as for opening a new window into the burgeoning field of comparative oceanography. The potentially habitable subsurface ocean of Europa may harbor life, and the globally young and comparatively thin ice shell of Europa may contain biosignatures that are readily accessible to a surface lander. Europa's icy shell also offers the opportunity to study tectonics and geologic cycles across a range of mechanisms and compositions. Here we detail the goals and mission architecture of the Europa Lander mission concept, as developed from 2015 through 2020. The science was developed by the 2016 Europa Lander Science Definition Team (SDT), and the mission architecture was developed by the preproject engineering team, in close collaboration with the SDT. In 2017 and 2018, the mission concept passed its mission concept review and delta-mission concept review, respectively. Since that time, the preproject has been advancing the technologies, and developing the hardware and software, needed to retire risks associated with technology, science, cost, and schedule.K.P.H., C.B.P., E.M., and all authors affiliated with the Jet Propulsion Laboratory carried out this research at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (grant No. 80NM0018D0004). J.I.L. was the David Baltimore Distinguished Visiting Scientist during the preparation of the SDT report. JPL/Caltech2021

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting & Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (<60, 60-69, and >_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 & PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and >_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research