Scarborough General Hospital

Abstract Background This review aims to present a consensus for optimal perioperative care in rectal/pelvic surgery, and to provide graded recommendations for items for an evidenced‐based enhanced recovery protocol. Methods Studies were selected with particular attention paid to meta‐analyses, randomized controlled trials and large prospective cohorts. For each item of the perioperative treatment pathway, available English‐language literature was examined, reviewed and graded. A consensus recommendation was reached after critical appraisal of the literature by the group. Results For most of the protocol items, recommendations are based on good‐quality trials or meta‐analyses of good‐quality trials (evidence grade: high or moderate). Conclusions Based on the evidence available for each item of the multimodal perioperative care pathway, the Enhanced Recovery After Surgery (ERAS) Society, European Society for Clinical Nutrition and Metabolism (ESPEN) and International Association for Surgical Metabolism and Nutrition (IASMEN) present a comprehensive evidence‐based consensus review of perioperative care for rectal surgery.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Abstract Background This review aims to present a consensus for optimal perioperative care in colonic surgery and to provide graded recommendations for items for an evidenced‐based enhanced perioperative protocol. Methods Studies were selected with particular attention paid to meta‐analyses, randomised controlled trials and large prospective cohorts. For each item of the perioperative treatment pathway, available English‐language literature was examined, reviewed and graded. A consensus recommendation was reached after critical appraisal of the literature by the group. Results For most of the protocol items, recommendations are based on good‐quality trials or meta‐analyses of good‐quality trials (quality of evidence and recommendations according to the GRADE system). Conclusions Based on the evidence available for each item of the multimodal perioperative care pathway, the Enhanced Recovery After Surgery (ERAS) Society, International Association for Surgical Metabolism and Nutrition (IASMEN) and European Society for Clinical Nutrition and Metabolism (ESPEN) present a comprehensive evidence‐based consensus review of perioperative care for colonic surgery.

AIMS: To investigate the "gut origin of sepsis" hypothesis. METHODS: Prospective controlled study of 279 surgical patients in which cultures of nasogastric aspirates were compared with those obtained from mesenteric lymph nodes taken at laparotomy and the organisms cultured from subsequent septic complications. Bacterial translocation was confirmed if positive cultures were obtained from mesenteric lymph nodes. Postoperative sepsis was defined as any positive culture in the postoperative period. Bacterial species obtained in gastric microflora, mesenteric lymph nodes, and postoperative septic complications were compared. RESULTS: Only 85/279 patients (31%) had a sterile nasogastric aspirate; the most frequently identified organism was Candida spp. (54%) and the most common enteric organism cultured was E coli (20%). Multiple organisms were isolated in 39% and occurred more frequently in patients aged over 70 years, those undergoing non-elective surgery, and in those requiring proximal gastrointestinal surgery. Postoperative sepsis was more common in these patients. Bacterial translocation occurred in 21% and was significantly more frequent in those with multiple organisms in their nasogastric aspirates. E coli was the commonest organism isolated from the lymph node specimens (48%) and septic foci (53%). Fungal translocation did not occur. An identical genus was identified in the nasogastric aspirate and the septic focus in 30% of patients, in the nasogastric aspirate and the lymph node in 31%, and in the lymph node and a postoperative septic focus in 45%. CONCLUSIONS: Proximal gut colonisation is associated with both increased bacterial translocation and septic morbidity. The commonality of organisms identified supports the gut origin of sepsis hypothesis.

BACKGROUND: Gut translocation of bacteria has been shown in both animal and human studies. Evidence from animal studies that links bacteria translocation to the development of postoperative sepsis and multiple organ failure has yet to be confirmed in humans. AIMS: To examine the spectrum of bacteria involved in translocation in surgical patients undergoing laparotomy and to determine the relation between nodal migration of bacteria and the development of postoperative septic complications. METHODS: Mesenteric lymph nodes (MLN), serosal scrapings, and peripheral blood from 448 surgical patients undergoing laparotomy were analysed using standard microbiological techniques. RESULTS: Bacterial translocation was identified in 69 patients (15.4%). The most common organism identified was Escherichia coli (54%). Both enteric bacteria, typical of indigenous intestinal flora, and non-enteric bacteria were isolated. Postoperative septic complications developed in 104 patients (23%). Enteric organisms were responsible in 74% of patients. Forty one per cent of patients who had evidence of bacterial translocation developed sepsis compared with 14% in whom no organisms were cultured (p < 0.001). Septic morbidity was more frequent when a greater diversity of bacteria resided within the MLN, but this was not statistically significant. CONCLUSION: Bacterial translocation is associated with a significant increase in the development of postoperative sepsis in surgical patients. The organisms responsible for septic morbidity are similar in spectrum to those observed in the mesenteric lymph nodes. These data strongly support the gut origin hypothesis of sepsis in humans.

BACKGROUND: Multimodal optimization of surgical care has been associated with reduced hospital stay and improved physical function. The aim of this randomized trial was to compare multimodal optimization with standard care in patients undergoing colonic resection. METHODS: Twenty-five patients requiring elective right or left hemicolectomy were randomized to receive a ten-point optimization programme (14 patients) or conventional care (11). The groups were similar in terms of age (64 versus 68 years), male : female sex ratio (6 : 8 versus 5 : 6) and Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) score (both 26). Outcome measures were recorded before operation and on postoperative days 1, 7 and 30. They included hand grip strength, lung spirometry, and pain and fatigue scores. Further outcome measures included time to achieve a predetermined mobilization target, time to resumption of normal diet, and length of stay. RESULTS: Optimization was associated with maintained grip strength, earlier mobilization (46 versus 69 h; P = 0.043), and significantly lower pain and fatigue scores. Patients in the optimization group tolerated a regular hospital diet significantly earlier than controls (48 versus 76 h; P < 0.001). Optimization significantly reduced the median length of hospital stay (3 versus 7 days; P = 0.002). CONCLUSION: Optimization of surgical care significantly improved patients' physical and psychological function in the early postoperative period and facilitated early hospital discharge.

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.

BACKGROUND: The aim of this trial was to compare multimodal optimization with conventional perioperative management in a consecutive series of patients undergoing a wide range of colorectal procedures. METHODS: Thirty-nine patients undergoing major elective colonic resection were recruited prospectively. Patients were randomized to receive a ten-point multimodal optimization package or conventional perioperative care. All patients were administered epidural analgesia and opiates were avoided. Outcome measures recorded related to length of hospital stay, physical and mental function, and gut function. RESULTS: Optimization was associated with a significantly shorter median (interquartile range) hospital stay compared with conventional care (5 (4-9) versus 7.5 (6-10) days; P = 0.027). Duration of catheterization (P = 0.022) and duration of intravenous infusion (P = 0.007) were also less. Optimization was associated with a quicker recovery of gut function (P = 0.042). Grip strength was maintained in the postoperative period in the optimized group (P = 0.241) but not in the control group (P = 0.049). There were no differences in morbidity or mortality between the groups. CONCLUSION: Optimization is safe and results in a significant reduction in postoperative stay along with other improved endpoints. This cannot be directly attributed to improvement in any single outcome measure or to the use of epidural analgesia. Improvements are more likely to be multifactorial and may relate to an earlier return of gut function.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Phenomenologists seeking to explicate “lived experience” need above all to do justice to the phenomenon under study; research methods need to be responsive to the phenomenon, towards capturing something of its “is-ness.” This article aims to clarify some processes involved in doing phenomenological analysis, whatever the variant of phenomenology. A phenomenological sensibility is suggested rather than offering cookbook guidelines. Four key processes are identified: seeing afresh, dwelling, explicating, and languaging. Specific examples of research and writing are provided, with special attention to the principal phenomenological sources used in psychology: the “descriptive phenomenology” of Giorgi and Wertz, van Manen’s “hermeneutic phenomenology,” and Smith et al.’s “Interpretative Phenomenological Analysis.” The article ends with my personal top ten tips for novice researchers.

Background: Acute appendicitis (AA) is the most common surgical disease, and appendectomy is the treatment of choice in the majority of cases. A correct diagnosis is key for decreasing the negative appendectomy rate. The management can become difficult in case of complicated appendicitis. The aim of this study is to describe the worldwide clinical and diagnostic work-up and management of AA in surgical departments. Methods: This prospective multicenter observational study was performed in 116 worldwide surgical departments from 44 countries over a 6-month period (April 1, 2016-September 30, 2016). All consecutive patients admitted to surgical departments with a clinical diagnosis of AA were included in the study. Results: A total of 4282 patients were enrolled in the POSAW study, 1928 (45%) women and 2354 (55%) men, with a median age of 29 years. Nine hundred and seven (21.2%) patients underwent an abdominal CT scan, 1856 (43.3%) patients an US, and 285 (6.7%) patients both CT scan and US. A total of 4097 (95.7%) patients underwent surgery; 1809 (42.2%) underwent open appendectomy and 2215 (51.7%) had laparoscopic appendectomy. One hundred eighty-five (4.3%) patients were managed conservatively. Major complications occurred in 199 patients (4.6%). The overall mortality rate was 0.28%. Conclusions: The results of the present study confirm the clinical value of imaging techniques and prognostic scores. Appendectomy remains the most effective treatment of acute appendicitis. Mortality rate is low.

BACKGROUND: Delayed sepsis, systemic inflammatory response syndrome (SIRS) and multiorgan failure remain major causes of morbidity and mortality on intensive care units. One factor thought to be important in the aetiology of SIRS is failure of the intestinal barrier resulting in bacterial translocation and subsequent sepsis. AIM: This review summarizes the current knowledge about bacterial translocation and methods to prevent it. METHODS: Relevant studies during 1966-2006 were identified from a literature search. Factors, which detrimentally affect intestinal barrier function, are discussed, as are methods that may attenuate bacterial translocation in the critically ill patient. RESULTS: Methodological problems in confirming bacterial translocation have restricted investigations to patients undergoing laparotomy. There are only limited data available relating to specific interventions that might preserve intestinal barrier function or limit bacterial translocation in the intensive care setting. These can be categorized broadly into pre-epithelial, epithelial and post-epithelial interventions. CONCLUSIONS: A better understanding of factors that influence translocation could result in the implementation of interventions which contribute to improved patient outcomes. Glutamine supplementation, targeted nutritional intervention, maintaining splanchnic flow, the judicious use of antibiotics and directed selective gut decontamination regimens hold some promise of limiting bacterial translocation. Further research is required.

BACKGROUND: Bacterial translocation (BT) describes the passage of bacteria from the gastrointestinal tract to normally sterile tissues such as the mesenteric lymph nodes (MLNs) and other internal organs. The clinical and pathophysiological significance of BT remains controversial. This report describes results obtained over a 13-year period of study. METHODS: MLNs were obtained from 927 patients undergoing laparotomy. Nasogastric aspirates were obtained from 458 (49.4 per cent) of 927 patients for culture; pH was measured in 172 (37.6 per cent) of 458. Preoperative clinical variables were evaluated and factors that influenced BT were included in a multivariate logistic regression analysis. RESULTS: BT was identified in 130 (14.0 per cent) of 927 patients. Postoperative sepsis was more common in patients with BT (42.3 versus 19.9 per cent; P < 0.001). Independent preoperative variables associated with BT were emergency surgery (P = 0.001) and total parenteral nutrition (TPN) (P = 0.015). Gastric colonization was confirmed in 248 (54.1 per cent) of 458 patients, and was associated with both BT (P = 0.015) and postoperative sepsis (P = 0.029). A gastric pH of less than 4 was associated with a significant reduction in gastric colonization (53 versus 80 per cent; P < 0.001) and postoperative sepsis (46 versus 70.3 per cent; P = 0.018) but not BT. CONCLUSION: BT is associated with postoperative sepsis. Emergency surgery and TPN are independently associated with an increased prevalence of BT.

AIM: Although there are numerous studies on the efficacy of enhanced recovery after surgery (ERAS) protocols in reducing length of stay, the long-term compliance to such protocols in routine clinical practice has not been well documented. The aim of this study was to review the published literature on compliance to ERAS in patients undergoing colorectal surgery in routine clinical practice. METHOD: Medline, Embase and PubMed databases were searched to identify studies that focused on compliance to ERAS protocols during routine clinical practice. Fourteen studies fulfilled the inclusion criteria and a total of 19 perioperative ERAS modalities were identified across these studies. RESULTS: None of the studies used all 19 ERAS modalities within their ERAS protocols. Compliance to the various modalities varied considerably between studies and, in general, was poorest during the postoperative period. The use of epidural had the highest compliance (between 67 and 100%), whereas the use of transverse incisions (25%) had the lowest compliance. Length of stay in hospital ranged from 2 to 13 days. Higher compliance was associated with a reduced length of hospital stay. However, reduced length of hospital stay was associated with a high rate of readmission. CONCLUSION: There is significant variation in the components of, as well as in compliance to, ERAS protocols in daily practice. This may contribute to the observed variation between the studies in length of hospital stay. A standardized and practically feasible ERAS protocol should be established in order to improve the implementation and optimal outcome.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

BACKGROUND: It is possible to manipulate the composition of the gastrointestinal microflora by administration of pre- and probiotics. This may help to preserve gut barrier function and reduce the incidence of septic morbidity. AIMS: To assess the effects of a combination of pre- and probiotics (synbiotic) on bacterial translocation, gastric colonisation, systemic inflammation, and septic morbidity in elective surgical patients. PATIENTS: Patients were enrolled two weeks prior to elective abdominal surgery. Seventy two patients were randomised to the synbiotic group and 65 to the placebo group. Patients were well matched regarding age and sex distribution, diagnoses, and POSSUM scores. METHODS: Patients in the synbiotic group received a two week preoperative course of Lactobacillus acidophilus La5, Bifidobacterium lactis Bb-12, Streptococcus thermophilus, and Lactobacillus bulgaricus, together with the prebiotic oligofructose. Patients in the placebo group received placebo capsules and sucrose powder. At surgery, a nasogastric aspirate, mesenteric lymph node, and scrapings of the terminal ileum were harvested for microbiological analysis. Serum was collected preoperatively and on postoperative days 1 and 7 for measurement of C reactive protein, interleukin 6, and antiendotoxin antibodies. Septic morbidity and mortality were recorded. RESULTS: There were no significant differences between the synbiotic and control groups in bacterial translocation (12.1% v 10.7%; p = 0.808, chi(2)), gastric colonisation (41% v 44%; p = 0.719), systemic inflammation, or septic complications (32% v 31%; p = 0.882). CONCLUSIONS: In this study, synbiotics had no measurable effect on gut barrier function in elective surgical patients. Further studies investigating the place of pre- and probiotics in clinical practice are required.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for an ongoing human pandemic (COVID-19). There is a massive international effort underway to develop diagnostic reagents, vaccines, and antiviral drugs in a bid to slow down the spread of the disease and save lives. One part of that international effort involves the research community working with plants, bringing researchers from all over the world together with commercial enterprises to achieve the rapid supply of protein antigens and antibodies for diagnostic kits, and scalable production systems for the emergency manufacturing of vaccines and antiviral drugs. Here, we look at some of the ways in which plants can and are being used in the fight against COVID-19.

BACKGROUND: Despite limited evidence, closed suction drainage is often used to reduce the risk of seroma formation after breast cancer surgery. The aim of this study was to evaluate the effect of drains and fibrin sealant on the incidence of seroma formation. METHODS: A total of 116 patients undergoing surgery for breast cancer were randomized to receive suction drainage (group 1; n = 58), or to receive no drain (n = 58). Patients allocated to receive no drain were further randomized to have fibrin sealant applied to the dissected area (group 2; n = 29), or to no intervention (group 3; n = 29). Outcome measures were incidence and volume of postoperative seroma, length of hospital stay and postoperative pain scores. RESULTS: There was no significant difference in the incidence of seroma between group 1 (15 of 58) and either group with no drains (ten of 29 in group 2; 12 of 29 in group 3). There was a significant reduction in hospital stay and postoperative pain scores in patients who did not have a drain. Following mastectomy without a drain, the use of fibrin sealant was associated with a significant reduction in the incidence and total volume of seroma (190 versus 395 ml; P = 0.012). CONCLUSION: Drains did not prevent seroma formation, and were associated with a longer postoperative stay and higher pain scores after surgery for breast cancer. In patients who had mastectomy the use of fibrin sealant reduced the rate of seroma formation.

Incisional (ventral) hernias may not be discovered until many months after operation','. This has led to the belief that aponeuroses that have healed edge to edge may gradually part and permit the development of a hernia'. An alternative hypothesis is that a gap forms between the edges of the divided aponeurosis soon after operation, and that the weak fibrous tissue filling that gap gradually stretches until a hernia becomes detectable. The present study was carried out to test the validity of this hypothesis.

BACKGROUND: We recently observed mutations in ADAR1 to cause a phenotype of bilateral striatal necrosis (BSN) in a child with the type I interferonopathy Aicardi-Goutières syndrome (AGS). We therefore decided to screen patients with apparently non-syndromic BSN for ADAR1 mutations, and for an upregulation of interferon-stimulated genes (ISGs). METHODS: We performed Sanger sequencing of ADAR1 in a series of patients with BSN presenting to us during our routine clinical practice. We then undertook detailed clinical and neuroradiological phenotyping in nine mutation-positive children. We also measured the expression of ISGs in peripheral blood from these patients, and in children with BSN who did not have ADAR1 mutations. RESULTS: Nine ADAR1 mutation-positive patients from seven families demonstrated an acute (five cases) or subacute (four cases) onset of refractory, four-limb dystonia starting between 8 months and 5 years of age. Eight patients were developmentally normal at initial presentation. In seven cases, the disease was inherited as an autosomal recessive trait, while two related patients were found to have a heterozygous (dominant) ADAR1 mutation. All seven mutation-positive patients assayed showed an upregulation of ISGs (median: 12.50, IQR: 6.43-36.36) compared to controls (median: 0.93, IQR: 0.57-1.30), a so-called interferon signature, present many years after disease onset. No interferon signature was present in four children with BSN negative for mutations in ADAR1 (median: 0.63, IQR: 0.47-1.10). CONCLUSIONS: ADAR1-related disease should be considered in the differential diagnosis of apparently non-syndromic BSN with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR1 mutations in this context, and may suggest novel treatment approaches.