China Studies Review

In our first section, we introduce three short pieces that examine important issues in U.S.-China investment relations, public opinion in China and Japan, and the Hong Kong pro-democracy move-ment. Benjamin Pollock examines the progression of negotiations between the United States and China in adopting a high-quality bilateral investment treaty. Cheng Zhang uses data from Genron to understand the reasons behind mutual dis-trust between China and Japan. Adrienne Dalton looks at the role of Hong Kong triads in the suppression of the 2014 Hong Kong pro-democracy demonstrations. Our second section features six research articles covering a wide range of topics. Jakob Bund explores U.S.-China relations in cyberspace and provides an alternative framework by which the two countries can cooperate in the absence of trust. Patrick Lozada discusses China’s “creative indus-tries”, and the shortcomings of China’s creative special economic zones in foster-ing an innovation economy. David Rubin builds upon Bruce Gilley’s spectrum of democratic and authoritarian environ-mentalism and finds that in the context of environmental policymaking, China is transitioning towards more inclusivity and grassroots engagement. Peter Kim also examines China’s environmental policy and uses dust and sandstorms, also known as “yellow dust”, to examine the challenges and opportunities for environmental coop-eration in Northeast Asia. Shuxian Luo conducts a comparative analysis of China and India’s naval modernization efforts, noting that while China’s rapid economic development has spurred its naval modern-ization at a more rapid pace, there are other important elements such as differing threat perceptions and alliance options that help to explain India’s relative lag in naval mod-ernization. Finally, Winston Kung presents a Taiwan Straits crisis scenario analysis that examines the legal, diplomatic, strategic, and domestic opinion factors that would likely affect a U.S. response, concluding that U.S. diplomatic and military leverage would eventually lead China and Taiwan to de-escalate tensions in the region

China Studies Review

The first section of this issue features two brief issue papers. Ned Collins-Chase examines the Qianhai Free Trade Zone and considers its prospects as a tool for Chinese capital account liberalization. Minh Joo Yi surveys China’s foreign policy calculus under Presi-dent Xi Jinping and notes Beijing’s growing assertiveness in foreign affairs. In the second section of this issue, we pres-ent three research articles spanning China’s environment, nuclear weapons strategy, and economy. Miaosu Li analyzes a little understood aspect of China’s wind energy development - the associated environmen-tal costs of rare-earth metal processing - and calls for a more nuanced assessment of Chinese energy policy and implemen-tation. Amanda Van Gilder provides a comprehensive analysis of the nuclear bal-ance between the United States and China. She concludes that while the United States will maintain nuclear superiority for the next one to two decades, the gap will close as China gradually attains doctrinal and tech-nological parity. Benjamin Pollok compares the homeward investment patterns of the diaspora populations of China and India. Pollok attributes China’s greater success in attracting this investment to its active dias-pora engagement policies — a strategy not yet meaningfully pursued by India

Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis

Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD.

OBJECTIVE: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine. DESIGN: Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine. RESULTS: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine. CONCLUSION: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab. TRIAL REGISTRATION NUMBER: ISRCTN45176516

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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Barrier Enclosure for Endotracheal Intubation in a Simulated COVID-19 Scenario: A Crossover Study

Introduction: Barrier enclosures have been developed to reduce the risk of COVID-19 transmission to healthcare providers during intubation, but little is known about their impact on procedure performance. We sought to determine whether a barrier enclosure delays time to successful intubation by experienced airway operators.Methods: We conducted a crossover simulation study at a tertiary academic hospital. Participants watched a four-minute video, practiced one simulated intubation with a barrier enclosure, and then completed one intubation with and one without the barrier enclosure (randomized to determine order). The primary outcome measure was time from placement of the video laryngoscope at the lips to first delivered ventilation. Secondary outcomes were periprocedural complications and participant responses to a post-study survey.Results: Proceduralists (n = 50) from emergency medicine and anesthesiology had median intubation times of 23.6 seconds with practice barrier enclosure, 20.5 seconds with barrier enclosure, and 16.7 seconds with no barrier. Intubation with barrier enclosure averaged 4.5 seconds longer (95% confidence interval, 2.7-6.4, p &lt; .001) than without, but was less than the predetermined clinical significance threshold of 10 seconds. Three complications occurred, all during the practice intubation. Barrier enclosure made intubation more challenging according to 48%, but 90% indicated they would consider using it in clinical practice.Conclusion: Experienced airway operators performed intubation using a barrier enclosure with minimal increased time to procedure completion in this uncomplicated airway model. Given potential to reduce droplet spread, use of a barrier enclosure may be an acceptable adjunct to endotracheal intubation for those familiar with its use

Barrier Enclosure for Endotracheal Intubation in a Simulated COVID-19 Scenario: A Crossover Study

Introduction: Barrier enclosures have been developed to reduce the risk of COVID-19 transmission to healthcare providers during intubation, but little is known about their impact on procedure performance. We sought to determine whether a barrier enclosure delays time to successful intubation by experienced airway operators.Methods: We conducted a crossover simulation study at a tertiary academic hospital. Participants watched a four-minute video, practiced one simulated intubation with a barrier enclosure, and then completed one intubation with and one without the barrier enclosure (randomized to determine order). The primary outcome measure was time from placement of the video laryngoscope at the lips to first delivered ventilation. Secondary outcomes were periprocedural complications and participant responses to a post-study survey.Results: Proceduralists (n = 50) from emergency medicine and anesthesiology had median intubation times of 23.6 seconds with practice barrier enclosure, 20.5 seconds with barrier enclosure, and 16.7 seconds with no barrier. Intubation with barrier enclosure averaged 4.5 seconds longer (95% confidence interval, 2.7-6.4, p &lt; .001) than without, but was less than the predetermined clinical significance threshold of 10 seconds. Three complications occurred, all during the practice intubation. Barrier enclosure made intubation more challenging according to 48%, but 90% indicated they would consider using it in clinical practice.Conclusion: Experienced airway operators performed intubation using a barrier enclosure with minimal increased time to procedure completion in this uncomplicated airway model. Given potential to reduce droplet spread, use of a barrier enclosure may be an acceptable adjunct to endotracheal intubation for those familiar with its use

Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma

Malignant glioma, the most common primary brain tumor, is generally incurable. Although phosphatidylinositol-3-kinase (PI3K) signaling features prominently in glioma, inhibitors generally block proliferation rather than induce apoptosis. Starting with an inhibitor of both lipid and protein kinases that induced prominent apoptosis and that failed early clinical development because of its broad target profile and overall toxicity, we identified protein kinase targets, the blockade of which showed selective synthetic lethality when combined with PI3K inhibitors. Prioritizing protein kinase targets for which there are clinical inhibitors, we demonstrate that cyclin-dependent kinase (CDK)1/2 inhibitors, siRNAs against CDK1/2, and the clinical CDK1/2 inhibitor roscovitine all cooperated with the PI3K inhibitor PIK-90, blocking the antiapoptotic protein Survivin and driving cell death. In addition, overexpression of CDKs partially blocked some of the apoptosis caused by PIK-75. Roscovitine and PIK-90, in combination, were well tolerated in vivo and acted in a synthetic-lethal manner to induce apoptosis in human glioblastoma xenografts. We also tested clinical Akt and CDK inhibitors, demonstrating induction of apoptosis in vitro and providing a preclinical rationale to test this combination therapy in patients