Impact of the COVID-19 Pandemic on Emergency Adult Surgical Patients and Surgical Services: An International Multi-center Cohort Study and Department Survey.

OBJECTIVES: The PREDICT study aimed to determine how the COVID-19 pandemic affected surgical services and surgical patients and to identify predictors of outcomes in this cohort. BACKGROUND: High mortality rates were reported for surgical patients with COVID-19 in the early stages of the pandemic. However, the indirect impact of the pandemic on this cohort is not understood, and risk predictors are yet to be identified. METHODS: PREDICT is an international longitudinal cohort study comprising surgical patients presenting to hospital between March and August 2020, conducted alongside a survey of staff redeployment and departmental restructuring. A subgroup analysis of 3176 adult emergency patients, recruited by 55 teams across 18 countries is presented. RESULTS: Among adult emergency surgical patients, all-cause in-hospital mortality (IHM) was 3.6%, compared to 15.5% for those with COVID-19. However, only 14.1% received a COVID-19 test on admission in March, increasing to 76.5% by July.Higher Clinical Frailty Scale scores (CFS >7 aOR 18.87), ASA grade above 2 (aOR 4.29), and COVID-19 infection (aOR 5.12) were independently associated with significantly increased IHM.The peak months of the first wave were independently associated with significantly higher IHM (March aOR 4.34; April aOR 4.25; May aOR 3.97), compared to non-peak months.During the study, UK operating theatre capacity decreased by a mean of 63.6% with a concomitant 27.3% reduction in surgical staffing. CONCLUSION: The first wave of the COVID-19 pandemic significantly impacted surgical patients, both directly through co-morbid infection and indirectly as shown by increasing mortality in peak months, irrespective of COVID-19 status.Higher CFS scores and ASA grades strongly predict outcomes in surgical patients and are an important risk assessment tool during the pandemic.

Insights from a global snapshot of the change in elective colorectal practice due to the COVID-19 pandemic.

BACKGROUND: There is a need to understand the impact of COVID-19 on colorectal cancer care globally and determine drivers of variation. OBJECTIVE: To evaluate COVID-19 impact on colorectal cancer services globally and identify predictors for behaviour change. DESIGN: An online survey of colorectal cancer service change globally in May and June 2020. PARTICIPANTS: Attending or consultant surgeons involved in the care of patients with colorectal cancer. MAIN OUTCOME MEASURES: Changes in the delivery of diagnostics (diagnostic endoscopy), imaging for staging, therapeutics and surgical technique in the management of colorectal cancer. Predictors of change included increased hospital bed stress, critical care bed stress, mortality and world region. RESULTS: 191 responses were included from surgeons in 159 centers across 46 countries, demonstrating widespread service reduction with global variation. Diagnostic endoscopy was reduced in 93% of responses, even with low hospital stress and mortality; whilst rising critical care bed stress triggered complete cessation (p = 0.02). Availability of CT and MRI fell by 40-41%, with MRI significantly reduced with high hospital stress. Neoadjuvant therapy use in rectal cancer changed in 48% of responses, where centers which had ceased surgery increased its use (62 vs 30%, p = 0.04) as did those with extended delays to surgery (p<0.001). High hospital and critical care bed stresses were associated with surgeons forming more stomas (p<0.04), using more experienced operators (p<0.003) and decreased laparoscopy use (critical care bed stress only, p<0.001). Patients were also more actively prioritized for resection, with increased importance of co-morbidities and ICU need. CONCLUSIONS: The COVID-19 pandemic was associated with severe restrictions in the availability of colorectal cancer services on a global scale, with significant variation in behaviours which cannot be fully accounted for by hospital burden or mortality.

International Cancer Microbiome Consortium consensus statement on the role of the human microbiome in carcinogenesis.

OBJECTIVE: In this consensus statement, an international panel of experts deliver their opinions on key questions regarding the contribution of the human microbiome to carcinogenesis. DESIGN: International experts in oncology and/or microbiome research were approached by personal communication to form a panel. A structured, iterative, methodology based around a 1-day roundtable discussion was employed to derive expert consensus on key questions in microbiome-oncology research. RESULTS: Some 18 experts convened for the roundtable discussion and five key questions were identified regarding: (1) the relevance of dysbiosis/an altered gut microbiome to carcinogenesis; (2) potential mechanisms of microbiota-induced carcinogenesis; (3) conceptual frameworks describing how the human microbiome may drive carcinogenesis; (4) causation versus association; and (5) future directions for research in the field.The panel considered that, despite mechanistic and supporting evidence from animal and human studies, there is currently no direct evidence that the human commensal microbiome is a key determinant in the aetiopathogenesis of cancer. The panel cited the lack of large longitudinal, cohort studies as a principal deciding factor and agreed that this should be a future research priority. However, while acknowledging gaps in the evidence, expert opinion was that the microbiome, alongside environmental factors and an epigenetically/genetically vulnerable host, represents one apex of a tripartite, multidirectional interactome that drives carcinogenesis. CONCLUSION: Data from longitudinal cohort studies are needed to confirm the role of the human microbiome as a key driver in the aetiopathogenesis of cancer.

Colorectal carcinogenesis: an archetype of gut microbiota-host interaction.

Sporadic colorectal cancer (CRC) remains a major cause of worldwide mortality. Epidemiological evidence of markedly increased risk in populations that migrate to Western countries, or adopt their lifestyle, suggests that CRC is a disease whose aetiology is defined primarily by interactions between the host and his environment. The gut microbiome sits directly at this interface and is now increasingly recognised as a modulator of colorectal carcinogenesis. Bacteria such as Fusobacterium nucleatum and Escherichia coli (E. Coli) are found in abundance in patients with CRC and have been shown in experimental studies to promote neoplasia. A whole armamentarium of bacteria-derived oncogenic mechanisms has been defined, including the subversion of apoptosis and the production of genotoxins and pro-inflammatory factors. But the microbiota may also be protective: for example, they are implicated in the metabolism of dietary fibre to produce butyrate, a short chain fatty acid, which is anti-inflammatory and anti-carcinogenic. Indeed, although our understanding of this immensely complex, highly individualised and multi-faceted relationship is expanding rapidly, many questions remain: Can we define friends and foes, and drivers and passengers? What are the critical functions of the microbiota in the context of colorectal neoplasia?

Pre-, pro- and synbiotics in cancer prevention and treatment-a review of basic and clinical research.

There is a growing appreciation of the role of the human microbiota in the pathophysiology of cancer. Pre-, pro- and synbiotics are some of the best evidenced means of manipulating the microbiota for therapeutic benefit and their potential role in the prevention and treatment of cancer has garnered significant interest. In this review, we discuss how these agents may have oncosuppressive effects by maintaining intestinal barrier function, immunomodulation, metabolism and preventing host cell proliferation. We highlight the epidemiological and trials-based evidence supporting a role for pre-, pro- and synbiotics in the prevention of cancer. Ultimately, there is more evidence in support of these agents as adjuncts in the treatment of cancer. We discuss their roles in optimising the efficacy and/or minimising the adverse effects of chemotherapy and radiotherapy, antibiotics and surgery. Although we see significant promise in the application of pre-, pro- and synbiotics for clinical benefit in oncology patients, the field is very much in its infancy and oncologists face substantial challenges in advising their patients appropriately.

Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection.

OBJECTIVE: To identify the prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and fibrosis in HIV-monoinfected patients. DESIGN: Systematic review and meta-analysis. METHODS: We searched Medline and Embase and included studies that enrolled HIV-monoinfected patients with NAFLD defined by imaging and/or liver histology. Data on prevalence and risk factors for NAFLD, NASH and fibrosis were collected for meta-analysis using random effects models. RESULTS: Ten studies were included from the United States of America (n = 4), Canada (n = 1), France (n = 2), Italy (n = 1), Japan (n = 1) and China (n = 1). The prevalence of NAFLD (Imaging studies), NASH and fibrosis (biopsied populations) were 35% [95% confidence interval (CI) 29-42], 42% (95% CI 22-64) and 22% (95% CI 13-34), respectively. Meta-analysis of risk factors showed that high BMI, waist circumference, type 2 diabetes, hypertension, triglycerides and high CD4 cell count were associated with NAFLD, whereas HIV viral load, duration of HIV infection, duration of antiretroviral therapy and CD4 cell count nadir were not. Patients with high BMI [mean difference (MD) 1.38, 95% CI 0.04-2.71 P = 0.04], fasting glucose (MD 0.80, 95% CI 0.47-1.13 P < 0.00001) and AST level (MD 13.00, 95% CI 4.34-21.65 P = 0.003) were at increased risk of significant liver fibrosis. CONCLUSION: NAFLD is frequently observed in HIV-monoinfected patients, and NASH is a common cause of unexplained abnormal liver function in patients selected for liver biopsy. Metabolic disorders are key risk factors independently of HIV parameters. Future trials on pharmacological interventions in NASH with fibrosis should include patients with HIV.

Longitudinal analysis of serum oxylipin profile as a novel descriptor of the inflammatory response to surgery.

BACKGROUND: Oxylipins are potent lipid mediators demonstrated to initiate and regulate inflammation yet little is known regarding their involvement in the response to surgical trauma. As key modulators of the inflammatory response, oxylipins have the potential to provide novel insights into the physiological response to surgery and the pathophysiology of post-operative complications. We aimed to investigate the effects of major surgery on longitudinal oxylipin profile. METHODS: Adults patients undergoing elective laparoscopic or open colorectal resections were included. Primary outcomes were serum oxylipin profile quantified by ultra high-performance liquid chromatography-mass spectrometry, serum white cell count and C-reactive protein concentration. Serum samples were taken at three time-points: pre-operative (day zero), early post-operative (day one) and late post-operative (day four/five). RESULTS: Some 55 patients were included, of which 33 (60%) underwent surgery that was completed laparoscopically. Pre-operative oxylipin profiles were characterised by marked heterogeneity but surgery induced a common shift resulting in more homogeneity at the early post-operative time-point. By the late post-operative phase, oxylipin profiles were again highly variable. This evolution was driven by time-dependent changes in specific oxylipins. Notably, the levels of several oxylipins with anti-inflammatory properties (15-HETE and four regioisomers of DHET) were reduced at the early post-operative point before returning to baseline by the late post-operative period. In addition, levels of the pro-inflammatory 11-HETE rose in the early post-operative phase while levels of anti-thrombotic mediators (9-HODE and 13-HODE) fell; concentrations of all three oxylipins then remained fairly static from early to late post-operative phases. Compared to those undergoing laparoscopic surgery, patients undergoing open surgery had lower levels of some anti-inflammatory oxylipins (8,9-DHET and 17-HDoHE) in addition to reduced concentrations of anti-thrombotic mediators (9-HODE and 13-HODE) with increased concentration of their pro-thrombotic counterpart (TxB2). CONCLUSIONS: Serum oxylipin profile is modified by surgical intervention and may even be sensitive to the degree of surgical trauma and therefore represents a novel descriptor of the surgical systemic inflammatory response.

Highlights from the Inaugural International Cancer Microbiome Consortium Meeting (ICMC), 5-6 September 2017, London, UK.

The International Cancer Microbiome Consortium (ICMC) is a recently launched collaborative between academics and academic-clinicians that aims to promote microbiome research within the field of oncology, establish expert consensus and deliver education for academics and clinicians. The inaugural two-day meeting was held at the Royal Society of Medicine (RSM), London, UK, 5-6 September 2017. Microbiome and cancer experts from around the world first delivered a series of talks during an educational day and then sat for a day of roundtable discussion to debate key topics in microbiome-cancer research. Talks delivered during the educational day covered a broad range of microbiome-related topics. The potential role of the microbiome in the pathogenesis of colorectal cancer was discussed and debated in detail with experts highlighting the latest data in animal models and humans and addressing the question of causation versus association. The impact of the microbiota on other cancers-such as lung and urogenital tract-was also discussed. The microbiome represents a novel target for therapeutic manipulation in cancer and a number of talks explored how this might be realised through diet, faecal microbiota transplant and chemotherapeutics. On the second day, experts debated pre-agreed topics with the aim of producing a consensus statement with a focus on the current state of our knowledge and key gaps for further development. The panel debated the notion of a 'healthy' microbiome and, in turn, the concept of dysbiosis in cancer. The mechanisms of microbiota-induced carcinogenesis were discussed in detail and our current conceptual models were assessed. Experts also considered co-factors in microbiome-induced carcinogenesis to conclude that the tripartite 'interactome' between genetically vulnerable host, environment and the microbiome is central to our current understanding. To conclude, the roundtable discussed how the microbiome may be exploited for therapeutic benefit in cancer and the safety implications of performing such research in oncology patients.

Robotic surgery: disruptive innovation or unfulfilled promise? A systematic review and meta-analysis of the first 30 years.

BACKGROUND: Robotic surgery has been in existence for 30 years. This study aimed to evaluate the overall perioperative outcomes of robotic surgery compared with open surgery (OS) and conventional minimally invasive surgery (MIS) across various surgical procedures. METHODS: MEDLINE, EMBASE, PsycINFO, and ClinicalTrials.gov were searched from 1990 up to October 2013 with no language restriction. Relevant review articles were hand-searched for remaining studies. Randomised controlled trials (RCTs) and prospective comparative studies (PROs) on perioperative outcomes, regardless of patient age and sex, were included. Primary outcomes were blood loss, blood transfusion rate, operative time, length of hospital stay, and 30-day overall complication rate. RESULTS: We identified 99 relevant articles (108 studies, 14,448 patients). For robotic versus OS, 50 studies (11 RCTs, 39 PROs) demonstrated reduction in blood loss [ratio of means (RoM) 0.505, 95 % confidence interval (CI) 0.408-0.602], transfusion rate [risk ratio (RR) 0.272, 95 % CI 0.165-0.449], length of hospital stay (RoM 0.695, 0.615-0.774), and 30-day overall complication rate (RR 0.637, 0.483-0.838) in favour of robotic surgery. For robotic versus MIS, 58 studies (21 RCTs, 37 PROs) demonstrated reduced blood loss (RoM 0.853, 0.736-0.969) and transfusion rate (RR 0.621, 0.390-0.988) in favour of robotic surgery but similar length of hospital stay (RoM 0.982, 0.936-1.027) and 30-day overall complication rate (RR 0.988, 0.822-1.188). In both comparisons, robotic surgery prolonged operative time (OS: RoM 1.073, 1.022-1.124; MIS: RoM 1.135, 1.096-1.173). The benefits of robotic surgery lacked robustness on RCT-sensitivity analyses. However, many studies, including the relatively few available RCTs, suffered from high risk of bias and inadequate statistical power. CONCLUSIONS: Our results showed that robotic surgery contributed positively to some perioperative outcomes but longer operative times remained a shortcoming. Better quality evidence is needed to guide surgical decision making regarding the precise clinical targets of this innovation in the next generation of its use.

Patient-related risk factors for urinary retention following ambulatory general surgery: a systematic review and meta-analysis.

BACKGROUND: Postoperative urinary retention (POUR) is a source of avoidable patient harm. The aim of this review is to identify and quantify the role of patient-related risk factors in the development of POUR following ambulatory general surgery. METHODS: Studies published until December 2014 were identified by searching MEDLINE, EMBASE, and PsycINFO databases. Risk factors assessed in 3 or more studies were meta-analyzed. RESULTS: Twenty-one studies were suitable for inclusion consisting of 7,802 patients. The incidence of POUR was 14%. Increased age and the presence of lower urinary tract symptoms significantly increased risk with odds ratios [ORs] of 2.11 (95% confidence interval [CI] 1.15 to 3.86) and 2.83 (1.57 to 5.08), respectively. Male sex was not associated with developing POUR (OR .96, 95% CI .62 to 1.50). Preoperative α-blocker use significantly decreased the incidence of POUR with an OR of .37 (95% CI .15 to .91). CONCLUSIONS: Increased age and the presence of lower urinary tract symptoms increase the risk of POUR, while α-blocker use confers protection. Male sex was not associated with POUR. These findings assist in preoperative identification of patients at high risk of POUR.

Monocyte Tumor Necrosis Factor-α-Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation.

OBJECTIVES: To determine the effect of severe sepsis on monocyte tumor necrosis factor-α-converting enzyme baseline and inducible activity profiles. DESIGN: Observational clinical study. SETTING: Mixed surgical/medical teaching hospital ICU. PATIENTS: Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α-converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients' monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α-converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α-converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α-converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α-converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α-converting enzyme activity could be induced in healthy volunteer monocytes using an in vitro two-hit inflammation model. Patients with sepsis also displayed reduced shedding of monocyte tumor necrosis factor receptors upon stimulation with lipopolysaccharide. CONCLUSIONS: Monocyte tumor necrosis factor-α-converting enzyme catalytic activity appeared altered by sepsis and may result in reduced shedding of tumor necrosis factor receptors. Changes seemed specific to sepsis and correlated with illness severity. A better understanding of how tumor necrosis factor-α-converting enzyme function is altered during sepsis will enhance our understanding of sepsis pathophysiology, which will help in the assessment of patient inflammatory status and ultimately may provide new strategies to treat sepsis.

Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumor necrosis factor α-converting enzyme (TACE/ADAM-17) activation in primary human monocytes.

Tumor necrosis factor α-converting enzyme (TACE) is responsible for the shedding of cell surface TNF. Studies suggest that reactive oxygen species (ROS) mediate up-regulation of TACE activity by direct oxidization or modification of the protein. However, these investigations have been largely based upon nonphysiological stimulation of promonocytic cell lines which may respond and process TACE differently from primary cells. Furthermore, investigators have relied upon TACE substrate shedding as a surrogate for activity quantification. We addressed these concerns, employing a direct, cell-based fluorometric assay to investigate the regulation of TACE catalytic activity on freshly isolated primary human monocytes during LPS stimulation. We hypothesized that ROS mediate up-regulation of TACE activity indirectly, by activation of intracellular signaling pathways. LPS up-regulated TACE activity rapidly (within 30 min) without changing cell surface TACE expression. Scavenging of ROS or inhibiting their production by flavoprotein oxidoreductases significantly attenuated LPS-induced TACE activity up-regulation. Exogenous ROS (H(2)O(2)) also up-regulated TACE activity with similar kinetics and magnitude as LPS. H(2)O(2)- and LPS-induced TACE activity up-regulation were effectively abolished by a variety of selective p38 MAPK inhibitors. Activation of p38 was redox-sensitive as H(2)O(2) caused p38 phosphorylation, and ROS scavenging significantly reduced LPS-induced phospho-p38 expression. Inhibition of the p38 substrate, MAPK-activated protein kinase 2, completely attenuated TACE activity up-regulation, whereas inhibition of ERK had little effect. Lastly, inhibition of cell surface oxidoreductases prevented TACE activity up-regulation distal to p38 activation. In conclusion, our data indicate that in primary human monocytes, ROS mediate LPS-induced up-regulation of TACE activity indirectly through activation of the p38 signaling pathway.