Cardiopulmonary exercise variables and their association with postoperative morbidity and mortality after major oesophagogastric cancer surgery-a multicentre observational study.

Background: Outcomes after oesophagogastric cancer surgery remain poor. Cardiopulmonary exercise testing (CPET) used for risk stratification before oesophagogastric cancer surgery is based on conflicting evidence. This study explores the relationship between CPET and postoperative outcomes, specifically for patients undergoing neoadjuvant treatment. Methods: Patients undergoing oesophagogastric cancer resection and CPET (pre- or post-neoadjuvant treatment, or both) were retrospectively enrolled into a multicentre pooled cohort study. Oxygen uptake at peak exercise (VO2 peak) was compared with 1-yr postoperative survival. Secondary analyses explored relationships between patient characteristics, tumour pathology characteristics, CPET variables (absolute, relative to weight, ideal body weight, and body surface area), and postoperative outcomes (morbidity, 1-yr and 3-yr survival) were assessed using logistic regression analyses. Results: Seven UK centres recruited 611 patients completing a 3-yr postoperative follow-up period. Oesophagectomy was undertaken in 475 patients (78%). Major complications occurred in 25%, with 18% 1-yr and 43% 3-yr mortality. No association between VO2 peak or other selected CPET variables and 1-yr survival was observed in the overall cohort. In the overall cohort, the anaerobic threshold relative to ideal body weight was associated with 3-yr survival (P=0.013). Tumour characteristics (ypT/ypN/tumour regression/lymphovascular invasion/resection margin; P<0.001) and Clavien-Dindo ≥3a (P<0.001) were associated with 1-yr and 3-yr survival. On subgroup analyses, pre-neoadjuvant treatment CPET; anaerobic threshold (absolute; P=0.024, relative to ideal body weight; P=0.001, body surface area; P=0.009) and VE/VCO2 at anaerobic threshold (P=0.026) were associated with 3-yr survival. No other CPET variables (pre- or post-neoadjuvant treatment) were associated with survival. Conclusions: VO2 peak was not associated with 1-yr survival after oesophagogastric cancer resection. Tumour characteristics and major complications were associated with survival; however, only some selected pre-neoadjuvant treatment CPET variables were associated with 3-yr survival. CPET in this cohort of patients demonstrates limited outcome predictive precision. Clinical trial registration: NCT03637647.

Identification of a macrocyclic compound targeting the lassa virus polymerase.

There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC50 against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.

Shiftless Is a Novel Member of the Ribosome Stress Surveillance Machinery That Has Evolved to Play a Role in Innate Immunity and Cancer Surveillance.

A longstanding paradox in molecular biology has centered on the question of how very long proteins are synthesized, despite numerous measurements indicating that ribosomes spontaneously shift reading frame at rates that should preclude their ability completely translate their mRNAs. Shiftless (SFL; C19orf66) was originally identified as an interferon responsive gene encoding an antiviral protein, indicating that it is part of the innate immune response. This activity is due to its ability to bind ribosomes that have been programmed by viral sequence elements to shift reading frame. Curiously, Shiftless is constitutively expressed at low levels in mammalian cells. This study examines the effects of altering Shiftless homeostasis, revealing how it may be used by higher eukaryotes to identify and remove spontaneously frameshifted ribosomes, resolving the apparent limitation on protein length. Data also indicate that Shiftless plays a novel role in the ribosome-associated quality control program. A model is proposed wherein SFL recognizes and arrests frameshifted ribosomes, and depending on SFL protein concentrations, either leads to removal of frameshifted ribosomes while leaving mRNAs intact, or to mRNA degradation. We propose that SFL be added to the growing pantheon of proteins involved in surveilling translational fidelity and controlling gene expression in higher eukaryotes.

The health burden of air pollution in the UK: a modelling study using updated exposure-risk associations.

BACKGROUND: Long-term exposure to ambient air pollution, in particular fine particles or PM2·5, is a leading global disease burden. PM2·5 in the UK, dominated by agricultural emissions of ammonia (NH3), has been estimated to be responsible for 29 000-34 000 adult early deaths a year. These estimates use models that relate exposure to health risk that predate cohort studies that have identified a supralinear relationship between exposure and risk at relatively low PM2·5 concentrations typical of the UK (5-12 mg m-3). Here we used this new knowledge to estimate adult premature mortality in the UK in 2019. METHODS: For this modelling study, we used the GEOS-Chem model nested over the UK to simulate ambient PM2·5 concentrations, UK Office for National Statistics (ONS) health data provided by the Global Burden of Disease (GBD), and a hybrid health-risk assessment model. The hybrid model fuses a well established linear relationship between PM2·5 and risk for PM2·5 exceeding 10 mg m-3 with a supralinear curve at lower concentrations that is constrained with cohort studies conducted in Canada and confirmed with similar relationships from cohort studies in the USA and Europe. FINDINGS: We estimated that adult premature mortality attributable to exposure to ambient PM2·5 in the UK totalled 48 625 deaths in 2019 (95% CI 45 118-52 595); 15 000-20 000 more deaths than those estimated using outdated health-risk assessment models. Older people (aged 65 years or older) account for most UK deaths (86%). All adult premature mortality (in people aged 25 years and older) in Greater London (4861, 95% CI 4549-5247) exceeded that in Scotland (3673, 3214-4073), Wales (2462, 2270-2660), and Northern Ireland (1052, 934-1156). INTERPRETATION: According to our findings, PM2·5 is more hazardous to UK adults than previously reported, but a supralinear exposure-response curve also suggests that there are substantial public health gains in targeting dominant source contributors to PM2·5, in particular the unregulated agricultural sector. FUNDING: Department for the Environment, Food and Rural Affairs (DEFRA).

Impact of Legislated and Best Available Emission Control Measures on UK Particulate Matter Pollution, Premature Mortality, and Nitrogen-Sensitive Habitats.

Past emission controls in the UK have substantially reduced precursor emissions of health-hazardous fine particles (PM2.5) and nitrogen pollution detrimental to ecosystems. Still, 79% of the UK exceeds the World Health Organization (WHO) guideline for annual mean PM2.5 of 5 µg m-3 and there is no enforcement of controls on agricultural sources of ammonia (NH3). NH3 is a phytotoxin and an increasingly large contributor to PM2.5 and nitrogen deposited to sensitive habitats. Here we use emissions projections, the GEOS-Chem model, high-resolution data sets, and contemporary exposure-risk relationships to assess potential human and ecosystem health co-benefits in 2030 relative to the present day of adopting legislated or best available emission control measures. We estimate that present-day annual adult premature mortality attributable to exposure to PM2.5 is 48,625 (95% confidence interval: 45,188-52,595), that harmful amounts of reactive nitrogen deposit to almost all (95%) sensitive habitat areas, and that 75% of ambient NH3 exceeds levels safe for bryophytes and lichens. Legal measures decrease the extent of the UK above the WHO guideline to 58% and avoid 6,800 premature deaths by 2030. This improves with best available measures to 36% of the UK and 13,300 avoided deaths. Both legal and best available measures are insufficient at reducing the extent of damage of nitrogen pollution to sensitive habitats. Far more ambitious reductions in nitrogen emissions (>80%) than is achievable with best available measures (34%) are required to halve the amount of excess nitrogen deposited to sensitive habitats.

UK cost-effectiveness analysis of endoscopic sleeve gastroplasty versus lifestyle modification alone for adults with class II obesity.

BACKGROUND: Endoscopic sleeve gastroplasty (ESG) is a minimally invasive procedure that has been demonstrated in the MERIT randomised, controlled trial to result in substantial and durable additional weight loss in adults with obesity compared with lifestyle modification (LM) alone. We sought to conduct the first cost-effectiveness analysis of ESG versus LM alone in adults with class II obesity (BMI 35.0-39.9 kg/m2) from a national healthcare system perspective in England based on results from this study. METHODS: A 6-state Markov model was developed comprising 5 BMI-based health states and an absorbing death state. Baseline characteristics, utilities, and transition probabilities were informed by patient-level data from the subset of patients with class II obesity in MERIT. Adverse events (AEs) were based on the MERIT safety population. Mortality was estimated by applying BMI-specific hazard ratios from the published literature to UK general population mortality rates. Utilities for the healthy weight and overweight health states were informed from the literature; disutility associated with increasing BMI in the class I-III obesity health states was estimated using MERIT utility data. Disutility due to AEs and the prevalence of obesity-related comorbidities were based on the literature. Costs included intervention costs, AE costs, and comorbidity costs. RESULTS: ESG resulted in higher overall costs than LM alone but led to an increase in quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) for ESG vs LM alone was £2453/QALY gained. ESG was consistently cost effective across a wide range of sensitivity analyses, with no ICER estimate exceeding £10,000/QALY gained. In probabilistic sensitivity analysis, the mean ICER was £2502/QALY gained and ESG remained cost effective in 98.25% of iterations at a willingness-to-pay threshold of £20,000/QALY. CONCLUSION: Our study indicates that ESG is highly cost effective versus LM alone for the treatment of adults with class II obesity in England.

EGR1 Upregulation during Encephalitic Viral Infections Contributes to Inflammation and Cell Death.

Early growth response 1 (EGR1) is an immediate early gene and transcription factor previously found to be significantly upregulated in human astrocytoma cells infected with Venezuelan equine encephalitis virus (VEEV). The loss of EGR1 resulted in decreased cell death but had no significant impact on viral replication. Here, we extend these studies to determine the impacts of EGR1 on gene expression following viral infection. Inflammatory genes CXCL3, CXCL8, CXCL10, TNF, and PTGS2 were upregulated in VEEV-infected cells, which was partially dependent on EGR1. Additionally, transcription factors, including EGR1 itself, as well as ATF3, FOS, JUN, KLF4, EGR2, and EGR4 were found to be partially transcriptionally dependent on EGR1. We also examined the role of EGR1 and the changes in gene expression in response to infection with other alphaviruses, including eastern equine encephalitis virus (EEEV), Sindbis virus (SINV), and chikungunya virus (CHIKV), as well as Zika virus (ZIKV) and Rift Valley fever virus (RVFV), members of the Flaviviridae and Phenuiviridae families, respectively. EGR1 was significantly upregulated to varying degrees in EEEV-, CHIKV-, RVFV-, SINV-, and ZIKV-infected astrocytoma cells. Genes that were identified as being partially transcriptionally dependent on EGR1 in infected cells included ATF3 (EEEV, CHIKV, ZIKV), JUN (EEEV), KLF4 (SINV, ZIKV, RVFV), CXCL3 (EEEV, CHIKV, ZIKV), CXCL8 (EEEV, CHIKV, ZIKV, RVFV), CXCL10 (EEEV, RVFV), TNF-α (EEEV, ZIKV, RVFV), and PTGS2 (EEEV, CHIKV, ZIKV). Additionally, inhibition of the inflammatory gene PTGS2 with Celecoxib, a small molecule inhibitor, rescued astrocytoma cells from VEEV-induced cell death but had no impact on viral titers. Collectively, these results suggest that EGR1 induction following viral infection stimulates multiple inflammatory mediators. Managing inflammation and cell death in response to viral infection is of utmost importance, especially during VEEV infection where survivors are at-risk for neurological sequalae.

The Parallel Transformations of Polycyclic Aromatic Hydrocarbons in the Body and in the Atmosphere.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) emitted from combustion sources are known to be mutagenic, with more potent species also being carcinogenic. Previous studies show that PAHs can undergo complex transformations both in the body and in the atmosphere, yet these transformation processes are generally investigated separately. OBJECTIVES: Drawing from the literature in atmospheric chemistry and toxicology, we highlight the parallel transformations of PAHs that occur in the atmosphere and the body and discuss implications for public health. We also examine key uncertainties related to the toxicity of atmospheric oxidation products of PAHs and explore critical areas for future research. DISCUSSION: We focus on a key mode of toxicity for PAHs, in which metabolic processes (driven by cytochrome P450 enzymes), leads to the formation of oxidized PAHs that can damage DNA. Such species can also be formed abiotically in the atmosphere from natural oxidation processes, potentially augmenting PAH toxicity by skipping the necessary metabolic steps that activate their mutagenicity. Despite the large body of literature related to these two general pathways, the extent to which atmospheric oxidation affects a PAH's overall toxicity remains highly uncertain. Combining knowledge and promoting collaboration across both fields can help identify key oxidation pathways and the resulting products that impact public health. CONCLUSIONS: Cross-disciplinary research, in which toxicology studies evaluate atmospheric oxidation products and their mixtures, and atmospheric measurements examine the formation of compounds that are known to be most toxic. Close collaboration between research communities can help narrow down which PAHs, and which PAH degradation products, should be targeted when assessing public health risks. https://doi.org/10.1289/EHP9984.

Identifying Inhibitors of -1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses.

Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use -1 programmed ribosomal frameshifting (-1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates -1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of -1 PRF in SARS-CoV-2 also inhibited -1 PRF in a range of bat CoVs-the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on -1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed -1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit -1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics.

Cancer Care in the Wake of a Cyberattack: How to Prepare and What to Expect.

PURPOSE: Cyberattacks targeting health care organizations are becoming more frequent and affect all aspects of care delivery. Cancer care is particularly susceptible to major disruptions because of the potential of immediate and long-term consequences for patients who often rely on timely diagnostic testing and regular administration of systemic therapy in addition to other local treatment modalities to cure or control their diseases. On October 28, 2020, a cyberattack was launched on the University of Vermont Health Network with wide-ranging consequences for oncology, including loss of access to all network intranet servers, e-mail communications, and the electronic medical record (EMR). METHODS: This review details the immediate challenges faced by hematology and oncology during the cyberattack. The impact and response on inpatient, outpatient, and special patient populations are described. Steps that other academic- and community-based oncology practices can take to lessen the brunt of such an assault are suggested. RESULTS: The two areas of immediate impact after the cyberattack were communications and lack of EMR access. The oncology-specific impact included loss of the individualized EMR chemotherapy plan templates and electronic safeguards built into multistep treatment preparation and delivery. With loss of access to schedules, basic patient information, encrypted communications platforms and radiology, and laboratory and pharmacy services, clinical outpatient care delivery was reduced by 40%. The infusion visit volume dropped by 52% in the first week and new patients could not access necessary services for timely diagnostic evaluation, requiring the creation of command centers to oversee ethical and transparent triage and allocation of systemic therapies and address new patient referrals. This included appropriate transfer of patients to alternate sites to minimize delays. Inpatient care including transitions of care was particularly challenging and addressing patient populations whose survival might be affected by delays in care. CONCLUSION: Oncology health care leaders and providers should be aware of the potential impact of a cyberattack on cancer care delivery and preventively develop processes to mitigate the impact.

Global Cancer Risk From Unregulated Polycyclic Aromatic Hydrocarbons.

In assessments of cancer risk from atmospheric polycyclic aromatic hydrocarbons (PAHs), scientists and regulators rarely consider the complex mixture of emitted compounds and degradation products, and they often represent the entire mixture using a single emitted compound-benzo[a]pyrene. Here, we show that benzo[a]pyrene is a poor indicator of PAH risk distribution and management: nearly 90% of cancer risk worldwide results from other PAHs, including unregulated degradation products of emitted PAHs. We develop and apply a global-scale atmospheric model and conduct health impact analyses to estimate human cancer risk from 16 PAHs and several of their N-PAH degradation products. We find that benzo[a]pyrene is a minor contributor to the total cancer risks of PAHs (11%); the remaining risk comes from other directly emitted PAHs (72%) and N-PAHs (17%). We show that assessment and policy-making that relies solely on benzo[a]pyrene exposure provides misleading estimates of risk distribution, the importance of chemical processes, and the prospects for risk mitigation. We conclude that researchers and decision-makers should consider additional PAHs as well as degradation products.

Safety and feasibility of revisional bariatric surgery following Laparoscopic Adjustable Gastric Band - Outcomes from a large UK private practice.

BACKGROUND: Revisional bariatric surgery is unavoidable in a proportion of patients. Despite its need, the development of this speciality has been hampered by its complexity and preferred delivery in institutional set ups. Although primary bariatric surgery can be delivered in the private sector; safety and feasibility of revisional bariatric surgery remains unexplored in this setting. MATERIALS AND METHODS: Patients undergoing revisional bariatric surgery following previous Laparoscopic Adjustable Gastric Band (LAGB) between 2008 and 2019 at a single private bariatric unit with a minimum follow up of at least 6 months were included. The primary aim was safety outcomes and 30-day morbidity. RESULTS: 178 patients with BMI of 45.6 ± 8.2 kg/m2 underwent revisional bariatric surgery. One stage conversion was performed for 86.5% of the cases. At 9.5 ± 5.3 months follow up, BMI and percentage excess BMI loss were 31.8 ± 6.2 kg/m2 and 62.6 ± 40% respectively. There was no mortality, and the major complication rate was 2.8%. There was no statistically significant difference in the incidence of complications based on one-stage vs. two-stage conversion (p = 0.52). There were no differences in weight loss outcomes post-revisional surgery according to the indication for revision (p = 0.446) or weight loss following primary surgery (p = 0.12). CONCLUSION: Revisional bariatric surgery can be delivered safely in the private sector with good outcomes. One-stage conversions are feasible and do not detrimentally affect the morbidity of the procedure or the weight loss outcomes. More importantly, success following revisional surgery is independent of the indication for revision and weight loss outcomes following primary surgery.

Systematic Review of Innovation Reporting in Endoscopic Sleeve Gastroplasty.

BACKGROUND: Endoscopic sleeve gastroplasty (ESG) is a novel endoscopic procedure used to treat obesity-related comorbidities. Whilst its use is increasing in clinical practice, there is comparatively little understanding about how it has been evaluated. This study aimed to systematically summarize and appraise the reporting of ESG in the context of guidelines for evaluating innovative surgical devices and procedures. METHODS: Systematic searches were used to identify all published studies reporting ESG insertion. Data collected included patient selection, governance arrangements, proceduralist expertise, technique description and outcome reporting. RESULTS: Searches identified 2289 abstracts; 37 full-text papers were included (one prospective comparative cohort study, 16 retrospective cohort studies, 17 prospective cohort studies and three case reports). No randomized trials were identified. Eighteen studies were conducted prospectively. The number of patients in the included studies ranged from 1 to 1000. The lower BMI limit ranged from 27 to 35 kg/m2. Research approvals were reported in 26 studies. Two studies reported on the learning curve. All studies reported some aspect of technical implementation, but many variations were noted. Suturing device used and suture pattern were the most commonly reported aspects (32 studies). Follow-up ranged from 1 to 24 months, but was 12 months or less in 28 studies. Forty-eight different outcomes were reported across all studies. CONCLUSION: The literature on ESG has demonstrated some progression in reporting and analysis and the next stage of assessment should be a randomized controlled trial to demonstrate efficacy.

Enhanced photocatalytic degradation of 2-methyl-4-chlorophenoxyacetic acid (MCPA) by the addition of H2O2.

Photocatalytic remediation technology has been shown to be a favorable approach for the removal of a range of environmental pollutants in water treatment. While this approach can often achieve complete degradation, often overlooked are reaction intermediates that are potentially as harmful as the original parent compound. In the case of photocatalytic oxidation of the herbicide 2-methyl-4-chlorophenoxyacetic acid (MCPA), we have recently shown that 4-chloro-2-methylphenol (CMP) is formed as the primary intermediate. To ensure the continued development of the technology, it is crucial to ensure the removal of both MCPA and CMP can be achieved by photocatalysis. Reported here is the enhanced photocatalytic removal and subsequent suppression of MCPA and CMP respectively, by the addition of small quantities of H2O2. While the addition of H2O2 often accelerates degradation rates (via increased OH radical production), it was found to restrict the formation of CMP in this study through competitive adsorption at the surface of TiO2. Based on the combination of MCPA removal coupled with supressed CMP formation, 0.5% H2O2 was determined to be an optimal loading for the process. Under these conditions 100% MCPA removal was achieved (to the limit of HPLC detection) after 45 min irradiation at a degradation rate of ∼1 mg L-1 min-1 (ƞphoton = 4.4), which also resulted in a ∼83% reduction in CMP formation when compared to a system with no H2O2 present.

Minimally Invasive Approach in Boerhaave's Syndrome: Case Series and Systematic Review.

Introduction: Boerhaave's syndrome is a life-threatening spontaneous perforation of the esophagus associated with significant morbidity and mortality. Historically, thoracotomy has been the mainstay of treatment, but is associated with high morbidity and pain. Minimally invasive approaches provide alternative treatment possibilities. This systematic review together with inclusion of a case series from a tertiary esophagogastric unit assesses current evidence focused on minimally invasive surgical management of this condition. Methods: A systematic review was conducted in line with MOOSE (Meta-analyses Of Observational Studies in Epidemiology) guidelines. Electronic databases PubMed, MEDLINE, and Cochrane Library were searched, and articles focusing on the minimally invasive management of Boerhaave's syndrome were identified and scrutinized. We also report demographics and outcomes for a consecutive case series of patients with acute Boerhaave's syndrome managed via thoracoscopy. Results: Fifteen studies were included comprising 5 retrospective cohort studies and 10 case reports. Management strategies were divided into three categories: thoracoscopic, endoscopic, and laparoscopic. Overall mortality rates for each treatment modality were 2%, 13%, and 33%, and treatment success rates 98%, 38%, and 67%, respectively. Postoperative infective complications were seen in 79% of patients, with only 2 patients requiring salvage thoracotomy. In our local case series, we report 4 consecutive patients managed with thoracoscopy, with a 100% treatment success rate. Conclusion: Minimally invasive approaches in the management of Boerhaave's syndrome are safe and effective. We propose a selective management algorithm involving a minimally invasive approach to management of this life-threatening condition. Registered with local clinical outcomes team as service evaluation. (Approval number sev/0171).

Programmed -1 Ribosomal Frameshifting in coronaviruses: A therapeutic target.

Human population growth, climate change, and globalization are accelerating the emergence of novel pathogenic viruses. In the past two decades alone, three such members of the coronavirus family have posed serious threats, spurring intense efforts to understand their biology as a way to identify targetable vulnerabilities. Coronaviruses use a programmed -1 ribosomal frameshift (-1 PRF) mechanism to direct synthesis of their replicase proteins. This is a critical switch in their replication program that can be therapeutically targeted. Here, we discuss how nearly half a century of research into -1 PRF have provided insight into the virological importance of -1 PRF, the molecular mechanisms that drive it, and approaches that can be used to manipulate it towards therapeutic outcomes with particular emphasis on SARS-CoV-2.

The effects of cancer therapies on physical fitness before oesophagogastric cancer surgery: a prospective, blinded, multi-centre, observational, cohort study.

Background: Neoadjuvant cancer treatment is associated with improved survival following major oesophagogastric cancer surgery. The impact of neoadjuvant chemo/chemoradiotherapy on physical fitness and operative outcomes is however unclear. This study aims to investigate the impact of neoadjuvant chemo/chemoradiotherapy on fitness and post-operative mortality. Methods: Patients with oesophagogastric cancer scheduled for chemo/chemoradiotherapy and surgery were recruited to a prospective, blinded, multi-centre, observational cohort study. Primary outcomes were changes in fitness with chemo/chemoradiotherapy, measured using cardiopulmonary exercise testing and its association with mortality one-year after surgery. Patients were followed up for re-admission at 30-days, in-hospital morbidity and quality of life (exploratory outcomes). Results: In total, 384 patients were screened, 217 met the inclusion criteria, 160 consented and 159 were included (72% male, mean age 65 years). A total of 132 patients (83%) underwent chemo/chemoradiotherapy, 109 (71%) underwent chemo/chemoradiotherapy and two exercise tests, 100 (63%) completed surgery and follow-up. A significant decline in oxygen uptake at anaerobic threshold and oxygen uptake peak was observed following chemo/chemoradiotherapy: -1.25ml.kg -1.min -1 (-1.80 to -0.69) and -3.02ml.kg -1.min -1 (-3.85 to -2.20); p<0.0001). Baseline chemo/chemoradiotherapy anaerobic threshold and peak were associated with one-year mortality (HR=0.72, 95%CI 0.59 to 0.88; p=0.001 and HR=0.85, 0.76 to 0.95; p=0.005). The change in physical fitness was not associated with one-year mortality. Conclusions: Chemo/chemoradiotherapy prior to oesophagogastric cancer surgery reduced physical fitness. Lower baseline fitness was associated with reduced overall survival at one-year. Careful consideration of fitness prior to chemo/chemoradiotherapy and surgery is urgently needed.

BACKGROUND: Cancer treatments such as chemotherapy and radiotherapy given to people with oesophageal and gastric cancer (also known as cancer of the food pipe/stomach) before surgery can improve survival. However, the impact such treatments have on fitness and recovery after surgery is unclear. The aim of this research was to understand the impact cancer treatments has on fitness and any complications after surgery. METHODS: Patients with oesophageal and gastric cancer (also known as cancer of the food pipe/stomach) who were being treated by cancer treatment and surgery were recruited from different hospitals in the UK. All participants were asked to undertake an exercise test to measure fitness and fill out questionnaires to measure quality of life before and after cancer treatment. Complications patients experienced after surgery, the number of patients who had to be readmitted to hospital 30 days after surgery and one-year survival was recorded. RESULTS: A total of 160 consented to participate in this study and 159 were included in the study (72% male, average age 65 years). In total, 132 patients (83%) had cancer treatment, 109 (71%) had cancer treatment and the two exercise tests and 100 (63%) had surgery and were followed-up after surgery. Study findings show that fitness reduced after cancer treatment. Patient's fitness levels at the start of the study (or before cancer treatment) were linked to one-year survival. The fall in fitness after cancer treatment was not linked to death at the one-year follow-up. CONCLUSION: Cancer treatments before oesophageal and gastric cancer reduce fitness. Patients with a lower fitness level before cancer treatment had a reduced overall survival at one-year. Careful consideration of fitness prior to such cancer treatments and surgery is urgently needed.

Outcomes and survival following neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the esophagus: Inverse propensity score weighted analysis.

BACKGROUND: Esophageal cancer is increasingly common and carries a poor prognosis. The optimal treatment modality for locally advanced cancer is unknown, with current guidance recommending either neoadjuvant chemotherapy (CT) or chemoradiotherapy (CRT) followed by surgery. There is a lack of adequately powered trials comparing CT against CRT. We retrospectively compared CT versus CRT using a propensity score weighting approach. METHODS: Demographic, disease, treatment and outcome data were retrieved from a local database for patients who received neoadjuvant CT or CRT followed by surgery. Inverse probability of treatment weighting (IPTW) was used to balance groups using a propensity score-weighting approach. Groups were assessed for differences in postoperative outcomes and survival. Kaplan-Meier and non-parametric tests were used to compare survival and outcome data as appropriate. RESULTS: Data for 284 patients were retrieved. Following IPTW groups were well matched. No significant differences were seen for postoperative complications (CT 64.9% vs. CRT 63.3%, p = 0.807), including major complications (24.0% vs. 23.6%, p = 0.943) and anastomotic leak (7.8% vs. 5.6%, p = 0.526). Significantly higher rates of clinical regression and complete pathological response were seen following CRT (p = 0.002 for both). Rates of R0 resection were higher with CRT, CT 79.1% vs. CRT 93.1%, p = 0.006. There was no difference between groups for overall or disease-free survival. CONCLUSION: This study suggests that the significant improvements in local tumour response seen after neoadjuvant CRT compared to CT may not translate to different survival outcomes. However, it must be stressed that adequately powered prospective trials are still lacking.

Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS coronavirus 2 (SARS-CoV-2).

Approximately 17 years after the severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic, the world is currently facing the COVID-19 pandemic caused by SARS corona virus 2 (SARS-CoV-2). According to the most optimistic projections, it will take more than a year to develop a vaccine, so the best short-term strategy may lie in identifying virus-specific targets for small molecule-based interventions. All coronaviruses utilize a molecular mechanism called programmed -1 ribosomal frameshift (-1 PRF) to control the relative expression of their proteins. Previous analyses of SARS-CoV have revealed that it employs a structurally unique three-stemmed mRNA pseudoknot that stimulates high -1 PRF rates and that it also harbors a -1 PRF attenuation element. Altering -1 PRF activity impairs virus replication, suggesting that this activity may be therapeutically targeted. Here, we comparatively analyzed the SARS-CoV and SARS-CoV-2 frameshift signals. Structural and functional analyses revealed that both elements promote similar -1 PRF rates and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablate -1 PRF activity. We noted that the upstream attenuator hairpin activity is also functionally retained in both viruses, despite differences in the primary sequence in this region. Small-angle X-ray scattering analyses indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 have the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit -1 PRF was similarly effective against -1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may be promising lead compounds to combat the current COVID-19 pandemic.

Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS-CoV-2.

17 years after the SARS-CoV epidemic, the world is facing the COVID-19 pandemic. COVID-19 is caused by a coronavirus named SARS-CoV-2. Given the most optimistic projections estimating that it will take over a year to develop a vaccine, the best short-term strategy may lie in identifying virus-specific targets for small molecule interventions. All coronaviruses utilize a molecular mechanism called -1 PRF to control the relative expression of their proteins. Prior analyses of SARS-CoV revealed that it employs a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of -1 PRF, and that it also harbors a -1 PRF attenuation element. Altering -1 PRF activity negatively impacts virus replication, suggesting that this molecular mechanism may be therapeutically targeted. Here we present a comparative analysis of the original SARS-CoV and SARS-CoV-2 frameshift signals. Structural and functional analyses revealed that both elements promote similar rates of -1 PRF and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablated -1 PRF activity. The upstream attenuator hairpin activity has also been functionally retained. Small-angle x-ray scattering indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 had the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit -1 PRF was similarly effective against -1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may provide promising lead compounds to counter the current pandemic.