Specialist referrals and diagnostic delays in motor neurone disease: mapping patients' journey through Hoops and Hurdles in healthcare.

Motor neuron disease (MND) is an uncommon but invariably fatal condition, with a median survival of 24-48 months from symptom onset. Although there is no cure at the moment, early diagnosis is crucial to enable timely access to multidisciplinary care, and enrolment in clinical trials utilising investigational therapies. Unfortunately, diagnostic delays remain common, and the average delay between symptom onset and diagnosis is 12-months. Large numbers of specialist referrals have been suggested as a key contributor to diagnostic delays. We conducted a retrospective review of the medical records of patients diagnosed with MND in Lancashire and South Cumbria, to investigate whether large numbers of specialty referrals are a common occurrence in MND. Our review identified that 35% of patients with MND were seen by two or more specialties before being referred to neurology. This rose to 49% when patients with bulbar onset disease were considered. 9% of cases saw three or more specialists. There was a statistically significant correlation between the number of specialist referrals and delays in neurology referral. We hope our findings will increase awareness of the importance of early diagnosis of MND and promote the use of the MND Red Flag tool as a means of identifying patients in need of prompt neurological referral.

Intracemetery relationships: Non-metric trait combination analysis of Maspalomas of Gran Canaria (Canary Islands, Spain).

Maspalomas is one of the most important archaeological sites in Gran Canaria, Canary Islands. The necropolis is one of the few funerary sites on the island where several the skeletons were found in anatomical position. The burials correspond to graves and cists dated between the 12th and 15th century CE. These graves and cists are clustered together in different formations across the necropolis, giving rise to a complex composition that denotes the existence of possible interpersonal relationships of the people buried there. A total of 135 calcanei and 118 tali were analysed to find non-metric traits and to test whether the clustered burials share a non-metric trait relationship. Trait combinations were formed using talus and calcaneus non-metric traits separately. The results of this study suggest that the individuals of Maspalomas showed a very high prevalence of lateral and medial talar facets, attributed to prolonged squatting position and/or walking on uneven ground. The calcaneal facet pattern (that may be aetiologically genetic) is more closely related to that observed among North-Africans or Indians than to Western Europeans. Calcaneal facet type Ib, and other genetically-determined traits, such as the extra facet extension of Posterior Facet, or the medial root of the inferior extensor retinaculum trait, either as single traits or as the combination of both traits, were significantly associated with individuals buried in different geographical areas of the necropolis defined by differences in burial structures, a finding that may suggest that genetically-linked individuals were buried in a separate area of the necropolis. The use of trait combination analysis in this study shows that the method can be applied to identify relationships among genetically or professionally related individuals that were subjected to a different burial procedure by their contemporaries.

An atlas of anatomical variants of the human calcaneus.

The usefulness of anatomical variation is determined by the knowledge of why nonmetric traits appear. Clear descriptions of the traits are a necessary task, due to the risk of confusing anatomical variants and evidence of trauma. Numerous interpretations of the appearance of calcaneal anatomical variants add to the need of an anatomical atlas of calcaneal nonmetric traits. We have analyzed a total of 886 calcanei; 559 belong to different modern and pre-Hispanic samples, and 327 bones were studied from a reference collection from Athens. In this study, we present the anatomical variations that exist on the calcaneus bone, some of which have rarely been mentioned in previous research. The standardization of methods proposed may be useful to experts working in human anatomy, physical anthropology as well as comparative morphology, due to usefulness of this information during surgery, and bioanthropology to observe and study the lifestyle of past populations.

Transforming growth factor-ß1 and SMAD signalling pathway in the small airways of smokers and patients with COPD: potential role in driving fibrotic type-2 epithelial mesenchymal transition.

Background: COPD is a common disease characterized by respiratory airflow obstruction. TGF-ß1 and SMAD pathway is believed to play a role in COPD pathogenesis by driving epithelial mesenchymal transition (EMT). Methods: We investigated TGF-ß1 signalling and pSmad2/3 and Smad7 activity in resected small airway tissue from patients with; normal lung function and a smoking history (NLFS), current smokers and ex-smokers with COPD GOLD stage 1 and 2 (COPD-CS and COPD-ES) and compared these with normal non-smoking controls (NC). Using immunohistochemistry, we measured activity for these markers in the epithelium, basal epithelium, and reticular basement membrane (RBM). Tissue was also stained for EMT markers E-cadherin, S100A4 and vimentin. Results: The Staining of pSMAD2/3 was significantly increased in the epithelium, and RBM of all COPD groups compared to NC (p <0.0005). There was a less significant increase in COPD-ES basal cell numbers compared to NC (p= 0.02). SMAD7 staining showed a similar pattern (p <0.0001). All COPD group levels of TGF-ß1 in the epithelium, basal cells, and RBM cells were significantly lower than NC (p <0.0001). Ratio analysis showed a disproportionate increase in SMAD7 levels compared to pSMAD2/3 in NLFS, COPD-CS and COPD-ES. pSMAD negatively correlated with small airway calibre (FEF25-75%; p= 0.03 r= -0.36). EMT markers were active in the small airway epithelium of all the pathological groups compared to patients with COPD. Conclusion: Activation of the SMAD pathway via pSMAD2/3 is triggered by smoking and active in patients with mild to moderate COPD. These changes correlated to decline in lung function. Activation of the SMADs in the small airways is independent of TGF-ß1, suggesting factors other than TGF-ß1 are driving these pathways. These factors may have implications for small airway pathology in smokers and COPD through the process of EMT, however more mechanistic work is needed to prove these correlations.

The emerging roles of long non-coding RNA in host immune response and intracellular bacterial infections.

The long non-coding RNAs (lncRNAs) are evolutionarily conserved classes of non-coding regulatory transcripts of > 200 nucleotides in length. They modulate several transcriptional and post-transcriptional events in the organism. Depending on their cellular localization and interactions, they regulate chromatin function and assembly; and alter the stability and translation of cytoplasmic mRNAs. Although their proposed range of functionality remains controversial, there is increasing research evidence that lncRNAs play a regulatory role in the activation, differentiation and development of immune signaling cascades; microbiome development; and in diseases such as neuronal and cardiovascular disorders; cancer; and pathogenic infections. This review discusses the functional roles of different lncRNAs in regulation of host immune responses, signaling pathways during host-microbe interaction and infection caused by obligate intracellular bacterial pathogens. The study of lncRNAs is assuming significance as it could be exploited for development of alternative therapeutic strategies for the treatment of severe and chronic pathogenic infections caused by Mycobacterium, Chlamydia and Rickettsia infections, as well as commensal colonization. Finally, this review summarizes the translational potential of lncRNA research in development of diagnostic and prognostic tools for human diseases.

The effect of performance pressure and error-feedback on anxiety and performance in an interceptive task.

Introduction: Whilst the disruptive effects of anxiety on attention and performance have been well documented, the antecedents to anxiety in motivated performance scenarios are less well understood. We therefore sought to understand the cognitive appraisals that mediate the relationship between pressurised performance situations and the onset of anxiety. Methods: We tested the effects of performance pressure and error feedback on appraisals of the probability and cost of failure, the experience of anxiety, and subsequent impacts on visual attention, movement kinematics, and task performance during a virtual reality interception task. Results: A series of linear mixed effects models indicated that failure feedback and situational pressure influenced appraisals of the probability and cost of failure, which subsequently predicted the onset of anxious states. We did not, however, observe downstream effects on performance and attention. Discussion: The findings support the predictions of Attentional Control Theory Sport, that (i) momentary errors lead to negative appraisals of the probability of future failure; and (ii) that appraisals of both the cost and probability of future failure are important predictors of anxiety. The results contribute to a better understanding of the precursors to anxiety and the feedback loops that may maintain anxious states.

Composite Cold-Formed Steel Beams with Diagonal Rebars for Earthquake-Resistant Buildings.

The construction industry is on the lookout for cost-effective structural members that are also environmentally friendly. Built-up cold-formed steel (CFS) sections with minimal thickness can be used to make beams at a lower cost. Plate buckling in CFS beams with thin webs can be avoided by using thick webs, adding stiffeners, or strengthening the web with diagonal rebars. When CFS beams are designed to carry heavy loads, their depth logically increases, resulting in an increase in building floor height. The experimental and numerical investigation of CFS composite beams reinforced with diagonal web rebars is presented in this paper. A total of twelve built-up CFS beams were used for testing, with the first six designed without web encasement and the remaining six designed with web encasement. The first six were constructed with diagonal rebars in the shear and flexure zones, while the other two with diagonal rebars in the shear zone, and the last two without diagonal rebars. The next set of six beams was constructed in the same manner, but with a concrete encasement of the web, and all the beams were then tested. Fly ash, a pozzolanic waste byproduct of thermal power plants, was used as a 40% replacement for cement in making the test specimens. CFS beam failure characteristics, load-deflection behavior, ductility, load-strain relationship, moment-curvature relationship, and lateral stiffness were all investigated. The results of the experimental tests and the nonlinear finite element analysis performed in ANSYS software were found to be in good agreement. It was discovered that CFS beams with fly ash concrete encased webs have twice the moment resisting capacity of plain CFS beams, resulting in a reduction in building floor height. The results also confirmed that the composite CFS beams have high ductility, making them a reliable choice for earthquake-resistant structures.

Neural network based integration of assays to assess pathogenic potential.

Limited data significantly hinders our capability of biothreat assessment of novel bacterial strains. Integration of data from additional sources that can provide context about the strain can address this challenge. Datasets from different sources, however, are generated with a specific objective and which makes integration challenging. Here, we developed a deep learning-based approach called the neural network embedding model (NNEM) that integrates data from conventional assays designed to classify species with new assays that interrogate hallmarks of pathogenicity for biothreat assessment. We used a dataset of metabolic characteristics from a de-identified set of known bacterial strains that the Special Bacteriology Reference Laboratory (SBRL) of the Centers for Disease Control and Prevention (CDC) has curated for use in species identification. The NNEM transformed results from SBRL assays into vectors to supplement unrelated pathogenicity assays from de-identified microbes. The enrichment resulted in a significant improvement in accuracy of 9% for biothreat. Importantly, the dataset used in our analysis is large, but noisy. Therefore, the performance of our system is expected to improve as additional types of pathogenicity assays are developed and deployed. The proposed NNEM strategy thus provides a generalizable framework for enrichment of datasets with previously collected assays indicative of species.

Biomarkers of Osteoarthritis-A Narrative Review on Causal Links with Metabolic Syndrome.

Development of OA (OA) is multifactorial and is strongly associated with risk factors such as aging, trauma, metabolic disorders, and obesity. Metabolic Syndrome (MetS)-associated OA, collectively coined MetS-OA, is an increasingly recognized entity in which metabolic disorders and low-grade inflammation play a key mechanistic role in the disruption of joint homeostasis and cartilage degradation. Although there have been enormous efforts to discover biomarkers of MetS and OA, studies investigating a pathophysiological link between MetS and OA are relatively limited, and no serum blood marker has proved diagnostic so far. OA biomarkers that are necessary to discriminate and diagnose early disease remain to be elicited, explained in part by limited prospective studies, and therefore limited tools available to utilize in any prognostic capacity. Biomarker validation projects have been established by the Biomarker Consortium to determine biochemical markers demonstrating predictive validity for knee OA. Given that the metabolic constituents of MetS are treatable to varying extents, it stands to reason that treating these, and monitoring such treatment, may help to mitigate deleterious links with OA development. This narrative review will describe the current state of biomarker identification and utility in OA associated with MetS. We discuss the pathophysiological mechanisms of disease according to constituent pathologies of MetS and how identification of biomarkers may guide future investigation of novel targets.

LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein.

The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was functionally restricted to SARS-CoV-2 by accessibility. We localized the interaction to the C-terminus of the S1 domain and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.

Effect of salivary urea, pH and ureolytic microflora on dental calculus formation and its correlation with periodontal status.

Context: Dental calculus, formed by mineralization of plaque predisposes to the development of periodontal disease. Aim: To evaluate the influence of salivary urea and the presence of ureolytic bacteria on dental calculus formation and periodontal status in patients with good, fair and poor oral hygiene. Material and methods: An observational cross-sectional study was carried out on 135 patients, 18-60 years of age. Based on the simplified calculus index, patients were divided into three groups, good oral hygiene, fair oral hygiene and poor oral hygiene. Clinical parameters such as plaque index, gingival index, pocket probing depth and clinical attachment level and salivary pH were recorded for each subject. Saliva samples were collected to evaluate the urea levels using autoanalyzer method. Supragingival calculus samples were collected and presence and quantification of ureolytic bacteria were done by gram staining and bacterial culture and confirmed by biochemical reaction. For statistical analysis, test like Shapiro-Wilk test, Kruskal Wallis and Spearman's rho were used. Results: Increase in salivary pH was associated with increased odds of higher calculus index score (odds ratio = 2.785). There was a non-significant weak correlation between salivary urea and ureolytic bacteria in dental calculus in all the three groups (p > 0.05). Higher calculus index score was associated with increased odds of presence of ureolytic bacteria (odds ratio>1). Conclusions: Higher level of ureolytic bacteria with increasing calculus index score may breakdown the salivary urea to ammonia resulting in a ureolytic pH rise that facilitate calcium phosphate saturation leading to more calculus formation.

Radiomorphological signs and clinical severity of SARS-CoV-2 lineage B.1.1.7.

Objective: We aimed to assess the differences in the severity and chest-CT radiomorphological signs of SARS-CoV-2 B.1.1.7 and non-B.1.1.7 variants. Methods: We collected clinical data of consecutive patients with laboratory-confirmed COVID-19 and chest-CT imaging who were admitted to the Emergency Department between September 1- November 13, 2020 (non-B.1.1.7 cases) and March 1-March 18, 2021 (B.1.1.7 cases). We also examined the differences in the severity and radiomorphological features associated with COVID-19 pneumonia. Total pneumonia burden (%), mean attenuation of ground-glass opacities and consolidation were quantified using deep-learning research software. Results: The final population comprised 500 B.1.1.7 and 500 non-B.1.1.7 cases. Patients with B.1.1.7 infection were younger (58.5 ± 15.6 vs 64.8 ± 17.3; p < .001) and had less comorbidities. Total pneumonia burden was higher in the B.1.1.7 patient group (16.1% [interquartile range (IQR):6.0-34.2%] vs 6.6% [IQR:1.2-18.3%]; p < .001). In the age-specific analysis, in patients <60 years B.1.1.7 pneumonia had increased consolidation burden (0.1% [IQR:0.0-0.7%] vs 0.1% [IQR:0.0-0.2%]; p < .001), and severe COVID-19 was more prevalent (11.5% vs 4.9%; p = .032). Mortality rate was similar in all age groups. Conclusion: Despite B.1.1.7 patients were younger and had fewer comorbidities, they experienced more severe disease than non-B.1.1.7 patients, however, the risk of death was the same between the two groups. Advances in knowledge: Our study provides data on deep-learning based quantitative lung lesion burden and clinical outcomes of patients infected by B.1.1.7 VOC. Our findings might serve as a model for later investigations, as new variants are emerging across the globe.

Potential deleterious effects of paracetamol dose regime used in Nigeria versus that of the United States of America.

Paracetamol, also known as acetaminophen (N-acetyl-para-aminophenol, APAP) is the world's most used over-the-counter analgesic-antipyretic drug. Despite its good safety profile, acetaminophen can cause severe hepatotoxicity in overdose, and poisoning from paracetamol has become a major public health concern. Paracetamol is now the major cause of acute liver failure in the United States and Europe. This systematic review aims at examining the likelihood of paracetamol use in Nigeria causing more liver toxicity vis-à-vis the reduced maximum recommended daily adult dose of 3 g for the 500 mg tablet. Online searches were conducted in the databases of PubMed, Google Scholar and MEDLINE for publications using terms like "paracetamol toxicity," "acetaminophen and liver toxicity," "paracetamol and liver diseases in Nigeria," and other variants. Further search of related references in PubMed was carried out, and synthesis of all studies included in this review finalized. There were 94 studies that met the inclusion criteria. Evaluation of hepatic disorder was predicated mostly on a constellation of clinical features and limited clinical laboratory investigations. Determination of blood paracetamol concentration was rarely reported, thus excluding paracetamol poisoning as one of the likely causes of liver disorders in Nigeria. In Nigeria and elsewhere, several factors are known to increase paracetamol's predisposition to liver injury. They include: the over-the-counter status of paracetamol, use of fixed-dose combinations of paracetamol with other drugs, malnutrition, dose miscalculations, and chronic alcohol consumption. The tendency to exceed the new paracetamol maximum daily dose of 3 g in Nigeria may increase its risk for hepatotoxicity than observed in the United States of America known for emphasizing lower dose of the drug. In addition to recommending the new maximal daily paracetamol dose allowance, the historical maximum daily adult dose of 4 g should be de-emphasized in Nigeria.

Primary Murine Macrophages as a Tool for Virulence Factor Discovery in Coxiella burnetii.

Coxiella burnetii requires a type IVB secretion system (T4SS) to promote intracellular replication and virulence. We hypothesized that Coxiella employs its T4SS to secrete effectors that enable stealthy colonization of immune cells. To address this, we used RNA sequencing to compare the transcriptional response of murine bone marrow-derived macrophages (BMDM) infected with those of wild-type Coxiella and a T4SS-null mutant at 8 and 24 h postinfection. We found a T4SS-independent upregulation of proinflammatory transcripts which was consistent with a proinflammatory polarization phenotype. Despite this, infected BMDM failed to completely polarize, as evidenced by modest surface expression of CD38 and CD11c, nitrate production, and reduced proinflammatory cytokine and chemokine secretion compared to positive controls. As these BMDM permitted replication of C. burnetii, we employed them to identify T4SS effectors that are essential in the specific cellular context of a primary macrophage. We found five Himar1 transposon mutants in T4SS effectors that had a replication defect in BMDM but not J774A.1 cells. The mutants were also attenuated in a SCID mouse model of infection. Among these candidate virulence factors, we found that CBU1639 contributed to the inhibition of macrophage proinflammatory responses to Coxiella infection. These data demonstrate that while T4SS is dispensable for the stealthy invasion of primary macrophages, Coxiella has evolved multiple T4SS effectors that specifically target macrophage function to proliferate within that specific cellular context. IMPORTANCE Coxiella burnetii, the causative agent of Q fever, preferentially infects macrophages of the respiratory tract when causing human disease. This work describes how primary macrophages respond to C. burnetii at the earliest stages of infection, before bacterial replication. We found that while infected macrophages increase expression of proinflammatory genes after bacterial entry, they fail to activate the accompanying antibacterial functions that might ultimately control the infection. This disconnect between initial response and downstream function was not mediated by the bacterium's type IVB secretion system, suggesting that Coxiella has other virulence factors that dampen host responses early in the infection process. Nevertheless, we were able to identify several type IVB secreted effectors that were specifically required for survival in macrophages and mice. This work is the first to identify type IVB secretion effectors that are specifically required for infection and replication within primary macrophages.

Differential airway remodeling changes were observed in patients with asthma COPD overlap compared to patients with asthma and COPD alone.

Management of patients with asthma COPD overlap (ACO) is clinically challenging due to insufficient evidence of pathological changes in these patients. In this cross-sectional study, we evaluated airway remodeling in endobronchial biopsies from a total of 90 subjects, which included 12 ACO, 14 patients with asthma, 12 COPD exsmokers (ES), 11 current smokers (CS), 28 healthy controls (HC), and 13 normal lung function smokers (NLFS). Tissue was stained with Masson's trichrome. Epithelium, goblet cells, reticular basement membrane (RBM), cellularity, lamina propria (LP), and smooth muscle (SM) changes were measured using Image-Pro Plus v7 software. Differential airway remodeling pattern was seen in patients with ACO. A limited change was noted in the ACO epithelium compared with other pathological groups. RBM was substantially thicker in patients with ACO than in HC (P < 0.0002) and tended to be thicker than in patients with asthma and NLFS. The total RBM cells were higher in ACO than in the HC (P < 0.0001), COPD-CS (P = 0.0559), -ES (P = 0.0345), and NLFS (P < 0.0002), but did not differ from patients with asthma. Goblet cells were higher in the ACO than in the HC (P = 0.0028) and COPD-ES (P = 0.0081). The total LP cells in ACO appeared to be higher than in HC, COPD-CS, and NLFS but appeared to be lower than in patients with asthma. Finally, SM area was significantly lower in the ACO than in patients with asthma (P = 0.001), COPD-CS (=0.0290), and NLFS (P = 0.0011). This first comprehensive study suggests that patients with ACO had distinguishable tissue remodeling that appeared to be more severe than patients with asthma and COPD. This study will help in informed decision-making for better patient management in clinical practice.

The first international Delphi consensus statement on Laparoscopic Gastrointestinal surgery.

BACKGROUND: Laparoscopic surgery has almost replaced open surgery in many areas of Gastro-Intestinal (GI) surgery. There is currently no published expert consensus statement on the principles of laparoscopic GI surgery. This may have affected the training of new surgeons. This exercise aimed to achieve an expert consensus on important principles of laparoscopic GI surgery. METHODS: A committee of 38 international experts in laparoscopic GI surgery proposed and voted on 149 statements in two rounds following a strict modified Delphi protocol. RESULTS: A consensus was achieved on 133 statements after two rounds of voting. All experts agreed on tailoring the first port site to the patient, whereas 84.2% advised avoiding the umbilical area for pneumoperitoneum in patients who had a prior midline laparotomy. Moreover, 86.8% agreed on closing all 15 mm ports irrespective of the patient's body mass index. There was a 100% consensus on using cartridges of appropriate height for stapling, checking the doughnuts after using circular staplers, and keeping the vibrating blade of the ultrasonic energy device in view and away from vascular structures. An 84.2% advised avoiding drain insertion through a ≥10 mm port site as it increases the risk of port-site hernia. There was 94.7% consensus on adding laparoscopic retrieval bags to the operating count and ensuring any surgical specimen left inside for later removal is added to the operating count. CONCLUSION: Thirty-eight experts achieved a consensus on 133 statements concerning various aspects of laparoscopic GI Surgery. Increased awareness of these could facilitate training and improve patient outcomes.

Immunogenicity and Reactogenicity in Q Fever Vaccine Development.

Coxiella burnetii is an obligate intracellular bacterium which, in humans, causes the disease Q fever. Although Q fever is most often a mild, self-limiting respiratory disease, it can cause a range of severe syndromes including hepatitis, myocarditis, spontaneous abortion, chronic valvular endocarditis, and Q fever fatigue syndrome. This agent is endemic worldwide, except for New Zealand and Antarctica, transmitted via aerosols, persists in the environment for long periods, and is maintained through persistent infections in domestic livestock. Because of this, elimination of this bacterium is extremely challenging and vaccination is considered the best strategy for prevention of infection in humans. Many vaccines against C. burnetii have been developed, however, only a formalin-inactivated, whole cell vaccine derived from virulent C. burnetii is currently licensed for use in humans. Unfortunately, widespread use of this whole cell vaccine is impaired due to the severity of reactogenic responses associated with it. This reactogenicity continues to be a major barrier to access to preventative vaccines against C. burnetii and the pathogenesis of this remains only partially understood. This review provides an overview of past and current research on C. burnetii vaccines, our knowledge of immunogenicity and reactogenicity in C. burnetii vaccines, and future strategies to improve the safety of vaccines against C. burnetii.

Research priorities in emergency general surgery (EGS): a modified Delphi approach.

BACKGROUND: Emergency general surgery (EGS) patients account for more than one-third of admissions to hospitals in the National Health Service (NHS) in England. The associated mortality of these patients has been quoted as approximately eight times higher than that of elective surgical admissions. This study used a modified Delphi approach to identify research priorities in EGS. The aim was to establish a research agenda using a formal consensus-based approach in an effort to identify questions relevant to EGS that could ultimately guide research to improve outcomes for this cohort. METHODS: Three rounds were conducted using an electronic questionnaire and involved health care professionals, research personnel, patients and their relatives. In the first round, stakeholders were invited to submit clinical research questions that they felt were priorities for future research. In rounds two and three, participants were asked to score individual questions in order of priority using a 5-point Likert scale. Between rounds, an expert panel analysed results before forwarding questions to subsequent rounds. RESULTS: Ninety-two EGS research questions were proposed in Phase 1. Following the first round of prioritisation, forty-seven questions progressed to the final phase. A final list of seventeen research questions were identified from the final round of prioritisation, categorised as condition-specific questions of high interest within general EGS, emergency colorectal surgery, non-technical and health services research. A broad range of research questions were identified including questions on peri-operative strategies, EGS outcomes in older patients, as well as non-technical and technical influences on EGS outcomes. CONCLUSIONS: Our study provides a consensus delivered framework that should determine the research agenda for future EGS projects. It may also assist setting priorities for research funding and multi-centre collaborative strategies within the academic clinical interest of EGS.

Phenotype-Based Threat Assessment.

Bacterial pathogen identification, which is critical for human health, has historically relied on culturing organisms from clinical specimens. More recently, the application of machine learning (ML) to whole-genome sequences (WGSs) has facilitated pathogen identification. However, relying solely on genetic information to identify emerging or new pathogens is fundamentally constrained, especially if novel virulence factors exist. In addition, even WGSs with ML pipelines are unable to discern phenotypes associated with cryptic genetic loci linked to virulence. Here, we set out to determine if ML using phenotypic hallmarks of pathogenesis could assess potential pathogenic threat without using any sequence-based analysis. This approach successfully classified potential pathogenetic threat associated with previously machine-observed and unobserved bacteria with 99% and 85% accuracy, respectively. This work establishes a phenotype-based pipeline for potential pathogenic threat assessment, which we term PathEngine, and offers strategies for the identification of bacterial pathogens.

Early versus delayed defunctioning ileostomy closure after low anterior resection for rectal cancer: a meta-analysis and trial sequential analysis of safety and functional outcomes.

PURPOSE: We performed a systematic review and meta-analysis with trial sequential analysis (TSA) to answer whether early closure of defunctioning ileostomy may be suitable after low anterior resection. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched, up to October 2021, for RCTs comparing early closure (EC ≤ 30 days) and delayed closure (DC ≥ 60 days) of defunctioning ileostomy. The risk ratio (RR) with 95% CI was calculated for dichotomous variables and the mean difference (MD) with 95% CI for continuous variables. The GRADE methodology was implemented for assessing Quality of Evidence (QoE). TSA was implemented to address the risk of random error associated with sparse data and/or multiple testing. RESULTS: Seven RCTs were included for quantitative synthesis. 599 patients were allocated to either EC (n = 306) or DC (n = 293). EC was associated with a higher rate of wound complications compared to DC (RR 2.56; 95% CI 1.33 to 4.93; P = 0.005; I2 = 0%, QoE High), a lower incidence of postoperative small bowel obstruction (RR 0.46; 95% CI 0.24 to 0.89; P = 0.02; I2 = 0%, QoE moderate), and a lower rate of stoma-related complications (RR 0.26; 95% CI 0.16 to 0.42; P < 0.00001; I2 = 0%, QoE moderate). The rate of minor low anterior resection syndrome (LARS) (RR 1.13; 95% CI 0.55 to 2.33; P = 0.74; I2 = 0%, QoE low) and major LARS (RR 0.80; 95% CI 0.59 to 1.09; P = 0.16; I2 = 0%, QoE low) did not differ between the two groups. TSA demonstrated inconclusive evidence with insufficient sample sizes to detect the observed effects. CONCLUSION: EC may confer some advantages compared with a DC. However, TSA advocated a cautious interpretation of the results. PROSPERO REGISTER ID: CRD42021276557.