Prolonged interval to surgery following neoadjuvant chemoradiotherapy in locally advanced rectal cancer: A meta-analysis of randomized controlled trials.

BACKGROUND: Long-course neoadjuvant chemoradiotherapy (NCRT), followed by surgery after an interval of 6-8 weeks, represents standard of care for patients with locally advanced rectal cancer (LARC). Increasing this interval may improve rates of complete pathological response (pCR) and tumour downstaging. We performed a meta-analysis comparing standard (SI, within 8 weeks) versus longer (LI, after 8 weeks) interval from NCRT to surgery. METHODS: PubMed, Embase, and Cochrane databases were searched up to 31 August 2022. Randomized controlled trials (RCTs) comparing SI with LI after NCRT for LARC were included. The primary endpoint was pCR rate. Secondary endpoints included rates of R0 resection, circumferential resection margin positivity (+CRM), TME completeness, lymph node yield (LNY), operative duration, tumour downstaging (TD), sphincter preservation, mortality, postoperative complications, surgical site infection (SSI) and anastomotic leak (AL). Random effects models were used to calculate pooled effect size estimates. RESULTS: Four RCTs encompassing 867 patients were included. There were 539 males (62.1%). LI was associated with a higher pCR rate (OR 0.61, 95%CI â€‹= â€‹0.39-0.95, p â€‹= â€‹0.03), and more TD (OR 0.60, 95%CI â€‹= â€‹0.37-0.97, p â€‹= â€‹0.04) compared to SI. However, there was no difference in rates of R0 resection (p â€‹= â€‹0.87), +CRM (p â€‹= â€‹0.66), sphincter preservation (p â€‹= â€‹0.26), incomplete TME (p â€‹= â€‹0.49), LNY (p â€‹= â€‹0.55), SSI (p â€‹= â€‹0.33), AL (p â€‹= â€‹0.20), operative duration (p â€‹= â€‹0.07), mortality (p â€‹= â€‹0.89) or any surgical complication (p â€‹= â€‹0.91). CONCLUSIONS: A LI to surgery after NCRT for LARC increases pCR and TD rates. Local recurrence or survival were not assessed due to unavailable data. We recommend deferring TME until after an interval of 8 weeks following completion of NCRT.

Measures of performance and proficiency in robotic assisted surgery: a systematic review.

Robotic assisted surgery (RAS) has seen a global rise in adoption. Despite this, there is not a standardised training curricula nor a standardised measure of performance. We performed a systematic review across the surgical specialties in RAS and evaluated tools used to assess surgeons' technical performance. Using the PRISMA 2020 guidelines, Pubmed, Embase and the Cochrane Library were searched systematically for full texts published on or after January 2020-January 2022. Observational studies and RCTs were included; review articles and systematic reviews were excluded. The papers' quality and bias score were assessed using the Newcastle Ottawa Score for the observational studies and Cochrane Risk Tool for the RCTs. The initial search yielded 1189 papers of which 72 fit the eligibility criteria. 27 unique performance metrics were identified. Global assessments were the most common tool of assessment (n = 13); the most used was GEARS (Global Evaluative Assessment of Robotic Skills). 11 metrics (42%) were objective tools of performance. Automated performance metrics (APMs) were the most widely used objective metrics whilst the remaining (n = 15, 58%) were subjective. The results demonstrate variation in tools used to assess technical performance in RAS. A large proportion of the metrics are subjective measures which increases the risk of bias amongst users. A standardised objective metric which measures all domains of technical performance from global to cognitive is required. The metric should be applicable to all RAS procedures and easily implementable. Automated performance metrics (APMs) have demonstrated promise in their wide use of accurate measures.

The Association of Surgeons in Training (ASiT) Consensus Statement on Major Trauma Training in the UK.

INTRODUCTION: Since the establishment of the Major Trauma Networks in 2012, it is estimated that an extra 1,600 lives have been saved across England. Although the delivery of trauma care has improved significantly, the provision of trauma training has not and remains fragmented. The Association of Surgeons in Training (ASiT), an independent organisation run by trainees, is dedicated to excellence in surgical training within the United Kingdom (UK) and Republic of Ireland (ROI). The aim of this study was to develop a consensus statement representing the views of the ASiT on the future of trauma surgery training. METHODS: A modified nominal group technique was used in five stages: 1, scoping exercise; 2, virtual consultation; 3, nominal group consensus meeting; 4, virtual feedback from stakeholders; and 5, virtual confirmation by the ASiT Council. The design and reporting of the consensus followed best practice methodology for consensus research. RESULTS: Overall, 62 participants gave 90 statements across stages 1-3. Eleven key themes were identified, all of which met the consensus of the ASiT Council. The key findings were widespread support for increased exposure to trauma for medical students and early surgical trainees as well as an increased use of simulation methods and improved focus on non-technical skills within trauma surgery. CONCLUSIONS: This study sets out the position of the ASiT on the future of trauma surgery training and how training in major trauma surgery in the UK and ROI could be improved.

Animal factors that affect enteric methane production measured using the GreenFeed monitoring system in grazing dairy cows.

Similar to all dairy systems internationally, pasture-based dairy systems are under increasing pressure to reduce their greenhouse gas (GHG) emissions. Ireland and New Zealand are 2 countries operating predominantly pasture-based dairy production systems where enteric CH4 contributes 23% and 36% of total national emissions, respectively. Ireland currently has a national commitment to reduce 51% of total GHG emissions by 2030 and 25% from agriculture by 2030, as well as striving to achieve climate neutrality by 2050. New Zealand's national commitment is to reduce 10% of methane emissions by 2030 and between 24% and 47% reduction in methane emissions by 2050. To achieve these reductions, factors that affect enteric methane (CH4) production in a pasture-based system need to be investigated. The objective of this study was to assess the relationship between enteric CH4 and other animal traits (feed intake, metabolic liveweight, energy corrected milk yield, milk urea concentration, and body condition score [BCS]) in a grazing dairy system. Enteric CH4 emissions were measured on 45 late lactation (213.8 ± 29 d after calving) grazing Holstein-Friesian and Holstein-Friesian × Jersey crossbred cows (lactation number 3.01 ± 1.65, 538.64 ± 59.37 kg live weight, and 3.14 ± 0.26 BCS) using GreenFeed monitoring equipment for 10 wk. There was a training period for the cows to use the GreenFeed of 3 wk before the 10-wk study period. The average enteric CH4 produced in the study was 352 g ± 45.7 g per day with an animal to animal coefficient of variation of 13%. Dry matter intake averaged 16.6 kg ± 2.23 kg per day, while milk solids (fat plus protein) averaged 1.62 kg ± 0.29 kg per day. A multiple linear regression model indicated that each one unit increase in energy corrected milk yield, metabolic liveweight and milk urea concentration, resulted in an increase in enteric CH4 production per day by 3.9, 1.74, and 1.38 g, respectively. Although each one unit increase in BCS resulted in a decrease in 39.03 g CH4 produced per day. When combined, these factors explained 47% of the variation in CH4 production, indicating that there is a large proportion of variation not included in the model. The repeatability of the CH4 measurements was 0.66 indicating that cows are relatively consistently exhibiting the same level of CH4 throughout the study. Therefore, enteric CH4 production is suitable for phenotyping.

Computational Expansion of High-Resolution-MSn Spectral Libraries.

Commonly, in MS-based untargeted metabolomics, some metabolites cannot be confidently identified due to ambiguities in resolving isobars and structurally similar species. To address this, analytical techniques beyond traditional MS2 analysis, such as MSn fragmentation, can be applied to probe metabolites for additional structural information. In MSn fragmentation, recursive cycles of activation are applied to fragment ions originating from the same precursor ion detected on an MS1 spectrum. This resonant-type collision-activated dissociation (CAD) can yield information that cannot be ascertained from MS2 spectra alone, which helps improve the performance of metabolite identification workflows. However, most approaches for metabolite identification require mass-to-charge (m/z) values measured with high resolution, as this enables the determination of accurate mass values. Unfortunately, high-resolution-MSn spectra are relatively rare in spectral libraries. Here, we describe a computational approach to generate a database of high-resolution-MSn spectra by converting existing low-resolution-MSn spectra using complementary high-resolution-MS2 spectra generated by beam-type CAD. Using this method, we have generated a database, derived from the NIST20 MS/MS database, of MSn spectral trees representing 9637 compounds and 19386 precursor ions where at least 90% of signal intensity was converted from low-to-high resolution.

Protocol for mapping the metabolome and lipidome of medulloblastoma cells using liquid chromatography-mass spectrometry.

Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and lipidomics have recently been used to show that MYC-amplified group 3 medulloblastoma tumors are driven by metabolic reprogramming. Here, we present a protocol to extract metabolites and lipids from human medulloblastoma brain tumor-initiating cells and normal neural stem cells. We describe untargeted LC-MS methods that can be used to achieve extensive coverage of the polar metabolome and lipidome. Finally, we detail strategies for metabolite identification and data analysis. For complete details on the use and execution of this protocol, please refer to Gwynne et al.1.

Comparing nasopharyngeal apnoeic oxygenation at 18 l/min to preoxygenation alone in obese patients - A randomised controlled study.

STUDY OBJECTIVE: Investigate a low-cost, nasopharyngeal apnoeic oxygenation technique, establish its efficacy, and compare it to preoxygenation only in an obese population. The study's hypothesis was that nasopharyngeal apnoeic oxygenation at 18 l.min-1 would significantly prolong safe apnoea time compared to preoxygenation alone. DESIGN: Randomised controlled study. SETTING: Theatre complex of a resource constrained hospital. PATIENTS: 30 adult, obese (BMI ≥ 35 kg.m-2) patients presenting for elective surgery. Patients with limiting cardio-respiratory disease, suspected difficult airway, risk of aspiration, and that were pregnant, were excluded. Patients were allocated by block randomisation in a 1:2 ratio to a preoxygenation-only (No-AO) and an intervention group (NPA-O2). INTERVENTIONS: All patients were preoxygenated to an Et-O2 > 80%, followed by a standardised induction. The intervention group received oxygen at 18 l.min-1 via the nasopharyngeal catheter intervention. The desaturation process was documented until an SpO2 of 92% or 600 s was reached. MEASUREMENTS: Baseline demographic and clinical characteristics were collected. The primary outcome was safe apnoea time, defined as the time taken to desaturate to an SpO2 of 92%. Secondary outcomes were rate of carbon dioxide accumulation and factors affecting the risk of desaturation. MAIN RESULTS: The study was conducted in a morbidly obese population (NoAO = 41,1 kg.m-2; NPA-O2 = 42,5 kg.m-2). The risk of desaturation was signifantly lower in the intervention group (Hazzard Ratio = 0,072, 95% CI[0,019-0,283]) (Log-Rank test, p < 0.001). The median safe apnoea time was significantly longer in the intervention group (NoAO = 262 s [IQR 190-316]; NPA-O2 = 600 s [IQR 600-600]) (Mann-Whitney-U test, p < 0.001). The mean rate of CO2 accumalation was significantly slower in the intervention group (NoAO = 0,47 ± 0,14 kPa.min-1; NPA-O2 = 0,3 ± 0,09 kPa.min-1) (t-test, p = 0.003). There were no statistically significant risk factors associated with an increased risk of desaturation found. CONCLUSIONS: Nasopharyngeal apnoeic oxygenation at 18 l/min prolongs safe apnoea time, compared to preoxygenation alone, and reduces the risk of desaturation in morbidly obese patients. CLINICAL TRIAL REGISTRATION: PACTR202202665252087; WC/202004/007.

The effect of anaesthetic use on healing in sub cutaneous abscess management: a retrospective before and after cohort study.

INTRODUCTION: There is wide variation in the management of simple subcutaneous abscesses in the UK and no national guidelines describing best practice. During the SARS-CoV-2 pandemic, regional or local anaesthesia (LA) use was recommended instead of general anaesthesia. This study aimed to assess the effect of anaesthetic use on outcomes following incision and drainage (I&D) of simple subcutaneous abscesses. METHODS: Two cohorts of patients undergoing abscess incision and drainage at St. James' University Hospital in Leeds were identified retrospectively over a 14-week period before (P1) and after (P2) the introduction of the COVID-19 anaesthetic guidelines. The number of follow-up appointments for repacking and representation to healthcare services 30 days after I&D were used as surrogate endpoints for wound healing. RESULTS: A total of 133 patients were included (n=70, P1 and n=63, P2). Significantly more procedures were performed under LA after the intervention (84.1% vs 5.7%; p<0.0001) with a significant reduction in wound packing (68.3% vs 87.1%; p=0.00473). Follow-up analysis found no significant difference in the median number of follow-up appointments (7.46 vs 5.11; p=0.0731) and the number of patients who required ongoing treatment after 30 days (n=14, P1 vs n=14, P2; p=0.921). CONCLUSIONS: Drainage of simple subcutaneous abscess under 5cm in diameter is safe under LA, with no significant difference in surrogate endpoints of wound healing observed in this patient cohort. Recurrent packing may not be required. Future work should explore patient-reported outcomes, including pain management, cosmesis and the cost and sustainability implications of a change in this common procedure.

Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma.

MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.

The Trisubstituted Isoxazole MMV688766 Exerts Broad-Spectrum Activity against Drug-Resistant Fungal Pathogens through Inhibition of Lipid Homeostasis.

Candida species are among the most prevalent causes of systemic fungal infection, posing a growing threat to public health. While Candida albicans is the most common etiological agent of systemic candidiasis, the frequency of infections caused by non-albicans Candida species is rising. Among these is Candida auris, which has emerged as a particular concern. Since its initial discovery in 2009, it has been identified worldwide and exhibits resistance to all three principal antifungal classes. Here, we endeavored to identify compounds with novel bioactivity against C. auris from the Medicines for Malaria Venture's Pathogen Box library. Of the five hits identified, the trisubstituted isoxazole MMV688766 emerged as the only compound displaying potent fungicidal activity against C. auris, as well as other evolutionarily divergent fungal pathogens. Chemogenomic profiling, as well as subsequent metabolomic and phenotypic analyses, revealed that MMV688766 disrupts cellular lipid homeostasis, driving a decrease in levels of early sphingolipid intermediates and fatty acids and a concomitant increase in lysophospholipids. Experimental evolution to further probe MMV688766's mode of action in the model fungus Saccharomyces cerevisiae revealed that loss of function of the transcriptional regulator HAL9 confers resistance to MMV688766, in part through the upregulation of the lipid-binding chaperone HSP12, a response that appears to assist in tolerating MMV688766-induced stress. The novel mode of action we have uncovered for MMV688766 against drug-resistant fungal pathogens highlights the broad utility of targeting lipid homeostasis to disrupt fungal growth and how screening structurally-diverse chemical libraries can provide new insights into resistance-conferring stress responses of fungi. IMPORTANCE As widespread antimicrobial resistance threatens to propel the world into a postantibiotic era, there is a pressing need to identify mechanistically distinct antimicrobial agents. This is of particular concern when considering the limited arsenal of drugs available to treat fungal infections, coupled with the emergence of highly drug-resistant fungal pathogens, including Candida auris. In this work, we demonstrate that existing libraries of drug-like chemical matter can be rich resources for antifungal molecular scaffolds. We discovered that the small molecule MMV688766, from the Pathogen Box library, displays previously undescribed broad-spectrum fungicidal activity through perturbation of lipid homeostasis. Characterization of the mode of action of MMV688766 provided new insight into the protective mechanisms fungi use to cope with the disruption of lipid homeostasis. Our findings highlight that elucidating the genetic circuitry required to survive in the presence of cellular stress offers powerful insights into the biological pathways that govern this important phenotype.

Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation.

Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between energy intake and consumption, therefore balancing energy homeostasis is an attractive target for metabolic diseases. One therapeutic approach consists of increasing the number of brown-like adipocytes in the white adipose tissue (WAT). Whereas WAT stores excess energy, brown adipose tissue (BAT) can dissipate this energy overload in the form of heat, increasing energy expenditure and thus inhibiting metabolic diseases. To facilitate BAT production a high-throughput screening approach was developed on previously known drugs using human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes. The screening allowed us to discover that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased adipocytes into functional brown adipocytes. However, zafirlukast is toxic to human cells at higher dosages. Drug-Initiated Activity Metabolomics (DIAM) was used to investigate zafirlukast as a BAT inducer, and the endogenous metabolite myristoylglycine was then discovered to mimic the browning properties of zafirlukast without impacting cell viability. Myristoylglycine was found to be bio-synthesized upon zafirlukast treatment and was unique in inducing brown adipocyte differentiation, raising the possibility of using endogenous metabolites and bypassing the exogenous drugs to potentially alleviate disease, in this case, obesity and other related metabolic diseases.

Chemical genomics with pyrvinium identifies C1orf115 as a regulator of drug efflux.

Pyrvinium is a quinoline-derived cyanine dye and an approved anti-helminthic drug reported to inhibit WNT signaling and have anti-proliferative effects in various cancer cell lines. To further understand the mechanism by which pyrvinium is cytotoxic, we conducted a pooled genome-wide CRISPR loss-of-function screen in the human HAP1 cell model. The top drug-gene sensitizer interactions implicated the malate-aspartate and glycerol-3-phosphate shuttles as mediators of cytotoxicity to mitochondrial complex I inhibition including pyrvinium. By contrast, perturbation of the poorly characterized gene C1orf115/RDD1 resulted in strong resistance to the cytotoxic effects of pyrvinium through dysregulation of the major drug efflux pump ABCB1/MDR1. Interestingly, C1orf115/RDD1 was found to physically associate with ABCB1/MDR1 through proximity-labeling experiments and perturbation of C1orf115 led to mis-localization of ABCB1/MDR1. Our results are consistent with a model whereby C1orf115 modulates drug efflux through regulation of the major drug exporter ABCB1/MDR1.

Centralisation of rectal cancer care has improved patient survival in the republic of Ireland.

BACKGROUND: Centralisation of rectal cancer surgery to designated centres was a key objective of the Irish national cancer control program. A national audit of rectal cancer surgery indicated centralisation was associated with improved early surgical outcomes. This study aimed to determine the impact of implementation of the national cancer strategy on survival from rectal cancer. MATERIALS AND METHODS: Data were collected from the National Cancer Registry of Ireland to include all patients with Stage I-III rectal cancer undergoing rectal cancer surgery with curative intent between 2003 and 2012. Five-year overall survival and cancer-specific survival was compared between patients in the pre-centralisation (2003-2007) and post-centralisation period (2008-2012) and between patients receiving surgery in designated cancer centres and non-cancer centres. RESULTS: The proportion of rectal cancer surgery performed in a designated cancer centre increased from 42% during 2003-2007 to 58% during 2008-2012. Five-year overall survival increased from 66.1% in 2003-2007 to 73.5% in 2008-2012 (p < 0.001). Five-year cancer-specific survival increased from 75.3% in 2003-2007 to 81.9% in 2008-2012 (p < 0.001). Surgery in a cancer centre and surgery post-centralisation were significantly associated with overall and cancer specific survival using Cox proportional hazards regression. CONCLUSION: Survival following resection of rectal cancer was significantly improved following implementation of a national cancer strategy incorporating centralisation of rectal cancer surgery.

Mapped Predictions of Manganese and Arsenic in an Alluvial Aquifer Using Boosted Regression Trees.

Manganese (Mn) concentrations and the probability of arsenic (As) exceeding the drinking-water standard of 10 µg/L were predicted in the Mississippi River Valley alluvial aquifer (MRVA) using boosted regression trees (BRT). BRT, a type of ensemble-tree machine-learning model, were created using predictor variables that affect Mn and As distribution in groundwater. These variables included iron (Fe) concentrations and specific conductance predicted from previously developed BRT models, groundwater flux and age estimates from MODFLOW, and hydrologic characteristics. The models also included results from the first airborne geophysical survey conducted in the United States to target an entire aquifer system. Predictions of high Mn and As occurred where Fe was high. Predicted high Mn concentrations were correlated with fraction of young groundwater (less than 65 years) computed from MODFLOW results. High probabilities of As exceedance were predicted where groundwater was relatively old and airborne electromagnetic resistivity was high, typically proximal to streams. Two-variable partial-dependence plots and sensitivity analysis were used to provide insight into the factors controlling Mn and As distribution in groundwater. The maps of predicted Mn concentrations and As exceedance probabilities can be used to identify areas where these constituents may be high, and that could be targeted for further study. This paper shows that incorporation of a selected set of process-informed data, such as MODFLOW results and airborne geophysics, into a machine-learning model improves model interpretability. Incorporation of process-rich information into machine-learning models will likely be useful for addressing a wide range of problems of interest to groundwater hydrologists.

A statistical evaluation of associations between reproductive performance and milk composition and animal factors on grazing dairy cows in two New Zealand dairy farms.

AIMS: To determine if milk composition, milk yield, live weight, live weight change, breed and heterosis are associated with reproductive performance in dairy cows from two dairy farms under New Zealand grazing conditions. METHODS: Milk composition was determined in herd tests from 205 Holstein-Friesian (F), 77 Jersey (J) and 351 F × J crossbred cows from two Massey University dairy herds in the 2016 and 2017 production seasons. Mating occurred from October to December in each production season. The start of breeding to first service (SBFS), start of breeding to conception (SBCO), submission rate at 21 days (SR21), pregnancy rate at 21 (PR21) and 42 days (PR42) were calculated for each cow. These traits were analysed using mixed linear models that included fixed effects for herd, production season, regression coefficients of deviation from median calving date, lactation number, proportion of F, F × J heterosis, energy-corrected milk yield (ECMY), percentages of fat, protein and lactose, milk urea nitrogen (MUN), live weight and change in live weight, with random effects for cow and residual error. The variables with binomial distribution were analysed using logistic regression. RESULTS: Deviation from the herd's median calving date had a significant effect (p < 0.05) on all reproductive traits. Proportion of F was significant (p = 0.022) on PR21, and F × J heterosis effects were significant on PR21 (p = 0.049) and PR42 (p = 0.046). F cows had 17.8% higher PR21 than J cows, and F × J cows had higher reproductive performance than the mean of the two purebreeds. ECMY was negatively associated with SBFS (p = 0.001) and SBCO (p = 0.001) and positively associated with PR21 (p = 0.002) and PR42 (p = 0.001). Protein percentage was positively associated (p < 0.05) with PR21 and PR42, whereas lactose percentage was negatively associated (p < 0.05) with PR21 and PR42. Cows gaining live weight were more likely to become pregnant within 21 days of the start of breeding (p = 0.020). Milk urea nitrogen was negatively associated (p = 0.042) with SR21. CONCLUSIONS AND CLINICAL RELEVANCE: This study confirms that breed, heterosis, ECMY, protein and lactose percentages, live weight change and calving date are associated with the reproductive performance of grazing cows. Results from this study contrast with the historical antagonism between milk production and reproductive performance in dairy cattle, demonstrating that well managed cows can achieve high levels of production and good reproductive performance. MUN was not associated with reproductive performance traits, except with SR21.

Metabolomics activity screening of T cell-induced colitis reveals anti-inflammatory metabolites.

Untargeted metabolomics of disease-associated intestinal microbiota can detect quantitative changes in metabolite profiles and complement other methodologies to reveal the full effect of intestinal dysbiosis. Here, we used the T cell transfer mouse model of colitis to identify small-molecule metabolites with altered abundance due to intestinal inflammation. We applied untargeted metabolomics to detect metabolite signatures in cecal, colonic, and fecal samples from healthy and colitic mice and to uncover differences that would aid in the identification of colitis-associated metabolic processes. We provided an unbiased spatial survey of the GI tract for small molecules, and we identified the likely source of metabolites and biotransformations. Several prioritized metabolites that we detected as being altered in colitis were evaluated for their ability to induce inflammatory signaling in cultured macrophages, such as NF-κB signaling and the expression of cytokines and chemokines upon LPS stimulation. Multiple previously uncharacterized anti-inflammatory and inflammation-augmenting metabolites were thus identified, with phytosphingosine showing the most effective anti-inflammatory activity in vitro. We further demonstrated that oral administration of phytosphingosine decreased inflammation in a mouse model of colitis induced by the compound TNBS. The collection of distinct metabolites we identified and characterized, many of which have not been previously associated with colitis, may offer new biological insight into IBD-associated inflammation and disease pathogenesis.

Delay to surgery in acute perforated and ischaemic gastrointestinal pathology: a systematic review.

BACKGROUND: Patients with acute abdominal pathology requiring emergency laparotomy who experience a delay to theatre have an increased risk of morbidity, mortality and complications. The timeline between symptom onset and operation is ill defined with international variance in assessment and management. This systematic review aims to define where delays to surgery occur and assess the evidence for interventions trialled across Europe. METHODS: A systematic review was performed searching MEDLINE and EMBASE databases (1 January 2005 to 6 May 2020). All studies assessing the impact of time to theatre in patients with acute abdominal pathology requiring emergency laparotomy were considered. RESULTS: Sixteen papers, involving 50 653 patients, were included in the analysis. Fifteen unique timepoints were identified in the patient pathway between symptom onset and operation which are classified into four distinct phases. Time from admission to theatre (1-72 hours) and mortality rate (10.6-74.5 per cent) varied greatly between studies. Mean time to surgery was significantly higher in deceased patients compared with that in survivors. Delays were related to imaging, diagnosis, decision making, theatre availability and staffing. Four of five interventional studies showed a reduced mortality rate following introduction of an acute laparotomy pathway. CONCLUSION: Given the heterogeneous nature of the patient population and pathologies, an assessment and management framework from onset of symptoms to operation is proposed. This could be incorporated into mortality prediction and audit tools and assist in the assessment of interventions.

Kidney biopsy practice amongst Australasian nephrologists.

BACKGROUND: Percutaneous kidney biopsy is the gold standard investigation for the diagnosis of kidney diseases. The associated risks of the procedure depend on the skill and experience of the proceduralist as well as the characteristics of the patient. The Kidney Health Australia - Caring for Australasians with Renal Impairment (KHA-CARI) guidelines on kidney biopsies, published in 2019, are the only published national kidney biopsy guidelines. As such, this study surveys current kidney biopsy practices in Australasia and examines how they align with the Australian guidelines, as well as international biopsy practice. METHODS: A cross-sectional, multiple-choice questionnaire was developed examining precautions prior to kidney biopsy; rationalisation of medications prior to kidney biopsy; technical aspects of kidney biopsy; complications of kidney biopsy; and indications for kidney biopsy. This was distributed to all members of the Australian and New Zealand Society of Nephrology (ANZSN). RESULTS: The response rate for this survey is approximately 21.4 % (182/850). Respondents found agreement (> 75.0 %) in only six out of the twelve questions (50.0 %) which assessed their practice against the KHA-CARI guidelines. CONCLUSIONS: This is the first study of its kind where kidney biopsy practices are examined against a clinical guideline. Furthermore, responses showed that practices were incongruent with guidelines and that there was a lack of consensus on many issues.