Comparison of energy intake in critical illness survivors, general medical patients, and healthy volunteers: A descriptive cohort study.

BACKGROUND: Intensive care unit (ICU) survivors have reduced oral intake; it is unknown whether intake and associated barriers are unique to this group. OBJECTIVE: To quantify energy intake and potential barriers in ICU survivors compared with general medical (GM) patients and healthy volunteers. DESIGN: A descriptive cohort study in ICU survivors, GM patients, and healthy volunteers. Following an overnight fast, participants consumed a 200 ml test-meal (213 kcal) and 180 min later an ad libitum meal to measure energy intake (primary outcome). Secondary outcomes; taste recognition, nutrition-impacting symptoms, malnutrition, and quality of life (QoL). Data are mean ± SD, median (interquartile range [IQR]) or number [percentage]). RESULTS: Twelve ICU survivors (57 ± 17 years, BMI: 30 ± 6), eight GM patients (69 ± 19 years, BMI: 30 ± 6), and 25 healthy volunteers (58 ± 27 years, BMI: 25 ± 4) were included. Recruitment ceased early because of slow recruitment and SARS-CoV-2. Energy intake was lower in both patient groups than in health (ICU: 289 [288, 809], GM: 426 [336, 592], health: 815 [654, 1165] kcal). Loss of appetite was most common (ICU: 78%, GM: 67%). For ICU survivors, GM patients and healthy volunteers, respectively, severe malnutrition prevalence; 40%, 14%, and 0%; taste identification; 8.5 [7.0, 11.0], 8.5 [7.0, 9.5], and 8.0 [6.0, 11.0]; and QoL; 60 [40-65], 50 [31-55], and 90 [81-95] out of 100. CONCLUSIONS: Energy intake at a buffet meal is lower in hospital patients than in healthy volunteers but similar between ICU survivors and GM patients. Appetite loss potentially contributes to reduced energy intake.

Nutrition delivery across hospitalisation in critically ill patients with COVID-19: An observational study of the Australian experience.

BACKGROUND: Data on nutrition delivery over the whole hospital admission in critically ill patients with COVID-19 are scarce, particularly in the Australian setting. OBJECTIVES: The objective of this study was to describe nutrition delivery in critically ill patients admitted to Australian intensive care units (ICUs) with coronavirus disease 2019 (COVID-19), with a focus on post-ICU nutrition practices. METHODS: A multicentre observational study conducted at nine sites included adult patients with a positive COVID-19 diagnosis admitted to the ICU for >24 h and discharged to an acute ward over a 12-month recruitment period from 1 March 2020. Data were extracted on baseline characteristics and clinical outcomes. Nutrition practice data from the ICU and weekly in the post-ICU ward (up to week four) included route of feeding, presence of nutrition-impacting symptoms, and nutrition support received. RESULTS: A total of 103 patients were included (71% male, age: 58 ± 14 years, body mass index: 30±7 kg/m2), of whom 41.7% (n = 43) received mechanical ventilation within 14 days of ICU admission. While oral nutrition was received by more patients at any time point in the ICU (n = 93, 91.2% of patients) than enteral nutrition (EN) (n = 43, 42.2%) or parenteral nutrition (PN) (n = 2, 2.0%), EN was delivered for a greater duration of time (69.6% feeding days) than oral and PN (29.7% and 0.7%, respectively). More patients received oral intake than the other modes in the post-ICU ward (n = 95, 95.0%), and 40.0% (n = 38/95) of patients were receiving oral nutrition supplements. In the week after ICU discharge, 51.0% of patients (n = 51) had at least one nutrition-impacting symptom, most commonly a reduced appetite (n = 25; 24.5%) or dysphagia (n = 16; 15.7%). CONCLUSION: Critically ill patients during the COVID-19 pandemic in Australia were more likely to receive oral nutrition than artificial nutrition support at any time point both in the ICU and in the post-ICU ward, whereas EN was provided for a greater duration when it was prescribed. Nutrition-impacting symptoms were common.

Emergent percutaneous closure of sub-annular aortic root pseudoaneurysm in the setting of composite graft dehiscence: a case report.

Background: Aortic conduit pseudoaneurysms are rare complications of surgical aortic root replacements. These complications are typically treated with a redo-sternotomy, but these surgeries carry high mortality rates, and patients may not always be good surgical candidates. There have been a few reported cases where aortic pseudoaneurysms have been successfully treated percutaneously with both short- and long-term success. We describe a case were a sub-annular aortic root pseudoaneurysm was closed using an Amplatzer Vascular Plug 2 device. Case summary: A 68-year-old man was admitted to the hospital 6 weeks after surgical aortic valve and aortic root replacement undergone for prosthetic valve endocarditis. On computed tomography, he was found to have a large fluid collection with extravasation into a false lumen located on the right side of the ascending aorta. Diagnostic catheterization confirmed flow into the pseudoaneurysm cavity from a sub-annular location. This defect was then closed using an Amplatzer Vascular Plug 2 device, with no residual flow or concern for re-opening at 8 months follow-up. Discussion: This case presents the first documented use of an Amplatzer Vascular Plug 2 to close an aortic root pseudoaneurysm in the sub-annular location. Heart team discussion is crucial in determining whether surgical or percutaneous treatment management should be performed. This case highlights a novel treatment method for sub-annular aortic root pseudoaneurysms which can be considered an alternative to surgery and potentially life-saving for high-risk patients.

Study protocol for TARGET protein: The effect of augmented administration of enteral protein to critically ill adults on clinical outcomes: A cluster randomised, cross-sectional, double cross-over, clinical trial.

Background: It is unknown whether increasing dietary protein to 1.2-2.0 g/kg/day as recommended in international guidelines compared to current practice improves outcomes in intensive care unit (ICU) patients. The TARGET Protein trial will evaluate this. Objective: To describe the study protocol for the TARGET Protein trial. Design setting and participants: TARGET Protein is a cluster randomised, cross-sectional, double cross-over, pragmatic clinical trial undertaken in eight ICUs in Australia and New Zealand. Each ICU will be randomised to use one of two trial enteral formulae for three months before crossing over to the other formula, which is then repeated, with enrolment continuing at each ICU for 12 months. All patients aged ≥16 years in their index ICU admission commencing enteral nutrition will be eligible for inclusion. Eligible patients will receive the trial enteral formula to which their ICU is allocated. The two trial enteral formulae are isocaloric with a difference in protein dose: intervention 100g/1000 ml and comparator 63g/1000 ml. Staggered recruitment commenced in May 2022. Main outcomes measures: The primary outcome is days free of the index hospital and alive at day 90. Secondary outcomes include days free of the index hospital at day 90 in survivors, alive at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. Conclusion: TARGET Protein aims to determine whether augmented enteral protein delivery reduces days free of the index hospital and alive at day 90. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001484831).

TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways.

GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11.

Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement achieved in overall survival. With regards to radiotherapy, GBM is ranked as one of the most radioresistant tumor types. In this study, we wanted to investigate if enriching cells in the most radiosensitive cell cycle phase, mitosis, could improve localized radiotherapy for GBM. To achieve cell cycle arrest in mitosis we used ispinesib, a small molecule inhibitor to the mitotic kinesin, KIF11. Cell culture studies validated that ispinesib radiosensitized patient-derived GBM cells. In vivo, we validated that ispinesib increased the fraction of tumor cells arrested in mitosis as well as increased apoptosis. Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials.

Establishment and characterization of two novel patient-derived lines from canine high-grade glioma.

High-grade glioma is an aggressive cancer that occurs naturally in pet dogs. Canine high-grade glioma (cHGG) is treated with radiation, chemotherapy or surgery, but has no curative treatment. Within the past eight years, there have been advances in our imaging and histopathology standards as well as genetic charactereization of cHGG. However, there are only three cHGG cell lines publicly available, all of which were derived from astrocytoma and established using methods involving expansion of tumour cells in vitro on plastic dishes. In order to provide more clinically relevant cell lines for studying cHGG in vitro, the goal of this study was to establish cHGG patient-derived lines, whereby cancer cells are expanded in vivo by injecting cells into immunocompromized laboratory mice. The cells are then harvested from mice and used for in vitro studies. This method is the standard in the human field and has been shown to minimize the acquisition of genetic alterations and gene expression changes from the original tumour. Through a multi-institutional collaboration, we describe our methods for establishing two novel cHGG patient-derived lines, Boo-HA and Mo-HO, from a high-grade astrocytoma and a high-grade oligodendroglioma, respectively. We compare our novel lines to G06-A, J3T-Bg, and SDT-3G (traditional cHGG cell lines) in terms of proliferation and sensitivity to radiation. We also perform whole genome sequencing and identify an NF1 truncating mutation in Mo-HO. We report the characterization and availability of these novel patient-derived lines for use by the veterinary community.

Nutrition care processes across hospitalisation in critically ill patients with COVID-19 in Australia: A multicentre prospective observational study.

BACKGROUND: The COVID-19 pandemic highlighted major challenges with usual nutrition care processes, leading to reports of malnutrition and nutrition-related issues in these patients. OBJECTIVE: The objective of this study was to describe nutrition-related service delivery practices across hospitalisation in critically ill patients with COVID-19 admitted to Australian intensive care units (ICUs) in the initial pandemic phase. METHODS: This was a multicentre (nine site) observational study in Australia, linked with a national registry of critically ill patients with COVID-19. Adult patients with COVID-19 who were discharged to an acute ward following ICU admission were included over a 12-month period. Data are presented as n (%), median (interquartile range [IQR]), and odds ratio (OR [95% confidence interval {CI}]). RESULTS: A total of 103 patients were included. Oral nutrition was the most common mode of nutrition (93 [93%]). In the ICU, there were 53 (52%) patients seen by a dietitian (median 4 [2-8] occasions) and malnutrition screening occurred in 51 (50%) patients most commonly with the malnutrition screening tool (50 [98%]). The odds of receiving a higher malnutrition screening tool score increased by 36% for every screening in the ICU (1st to 4th, OR: 1.39 [95% CI: 1.05-1.77] p = 0.018) (indicating increasing risk of malnutrition). On the ward, 51 (50.5%) patients were seen by a dietitian (median time to consult: 44 [22.5-75] hours post ICU discharge). The odds of dietetic consult increased by 39% every week while on the ward (OR: 1.39 [1.03-1.89], p = 0.034). Patients who received mechanical ventilation (MV) were more likely to receive dietetic input than those who never received MV. CONCLUSIONS: During the initial phases of the COVID-19 pandemic in Australia, approximately half of the patients included were seen by a dietitian. An increased number of malnutrition screens were associated with a higher risk score in the ICU and likelihood of dietetic consult increased if patients received MV and as length of ward stay increased.

Muscle size, strength, and physical function in response to augmented calorie delivery: A TARGET sub-study.

PURPOSE: Augmented calories may attenuate muscle loss experienced in critical illness. This exploratory sub-study assessed the effect of augmented calorie delivery on muscle mass, strength, and function. MATERIALS AND METHODS: Patients in The Augmented versus Routine approach to Giving Energy Trial (TARGET) randomised to 1.5 kcal/ml or 1.0 kcal/ml enteral formulae at a single-centre were included. Ultrasound-derived muscle layer thickness (MLT) at quadriceps, forearm and mid-upper arm, and handgrip strength, were measured weekly from baseline to hospital discharge, and 3- and 6-months. Physical function was assessed at 3- and 6-months using the 'get up and go' and 6-min walk tests. Data are mean ± SD. RESULTS: Eighty patients were recruited (1.5 kcal: n = 38, 58 ± 14y, 60%M, APACHE II 20 ± 7; 1.0 kcal: n = 42, 54 ± 18y, 66%M, APACHE II 22 ± 10). The 1.5 kcal/ml group received more calories with no difference in quadriceps MLT at any timepoint including ICU discharge (primary outcome) (2.90 ± 1.27 vs 2.39 ± 1.06 cm; P = 0.141). Relationships were similar for all MLT measures, handgrip strength, and 6-min walk test. Patients in the 1.5 kcal/ml group had improved 'get up and go' test at 3-months (6.66 ± 1.33 vs. 9.11 ± 2.94 s; P = 0.014). CONCLUSION: Augmented calorie delivery may not attenuate muscle loss or recovery of strength or function 6-months post-ICU, but this requires exploration in a larger trial.

A sumoylation program is essential for maintaining the mitotic fidelity in proliferating mantle cell lymphoma cells.

BACKGROUND: Mantle cell lymphoma (MCL) is a rare, highly heterogeneous type of B-cell non-Hodgkin's lymphoma. The sumoylation pathway is known to be upregulated in many cancers including lymphoid malignancies. However, little is known about its oncogenic role in MCL. METHODS: Levels of sumoylation enzymes and sumoylated proteins were quantified in MCL cell lines and primary MCL patient samples by scRNA sequencing and immunoblotting. The sumoylation enzyme SAE2 was genetically and pharmacologically targeted with shRNA and TAK-981 (subasumstat). The effects of SAE2 inhibition on MCL proliferation and cell cycle were evaluated using confocal microscopy, live-cell microscopy, and flow cytometry. Immunoprecipitation and orbitrap mass spectrometry were used to identify proteins targeted by sumoylation in MCL cells. RESULTS: MCL cells have significant upregulation of the sumoylation pathway at the level of the enzymes SAE1 and SAE2 which correlated with poor prognosis and induction of mitosis associated genes. Selective inhibition of SAE2 with TAK-981 results in significant MCL cell death in vitro and in vivo with mitotic dysregulation being an important mechanism of action. We uncovered a sumoylation program in mitotic MCL cells comprised of multiple pathways which could be directly targeted with TAK-981. Centromeric localization of topoisomerase 2A, a gene highly upregulated in SAE1 and SAE2 overexpressing MCL cells, was lost with TAK-981 treatment likely contributing to the mitotic dysregulation seen in MCL cells. CONCLUSIONS: This study not only validates SAE2 as a therapeutic target in MCL but also opens the door to further mechanistic work to uncover how to best use desumoylation therapy to treat MCL and other lymphoid malignancies.

MKLP2 functions in early mitosis to ensure proper chromosome congression.

Mitotic kinesin-like protein 2 (MKLP2; also known as KIF20A) is a motor protein with a well-established function in promoting cytokinesis. However, our results with siRNAs targeting MKLP2 and small-molecule inhibitors of MKLP2 (MKLP2i) suggest that it also has a function earlier in mitosis, prior to anaphase. In this study, we provide direct evidence that MKLP2 facilitates chromosome congression in prometaphase. We employed live imaging to observe HeLa cells with fluorescently tagged histones treated with MKLP2i and discovered a pronounced chromosome congression defect. We show that MKLP2 facilitates error correction, as inhibited cells have a significant increase in unstable, syntelic kinetochore-microtubule attachments. We find that the aberrant attachments are accompanied by elevated Aurora kinase (A and B) activity and phosphorylation of the downstream target HEC1 (also known as NDC80) at Ser55. Finally, we show that MKLP2 inhibition results in aneuploidy, confirming that MKLP2 safeguards cells against chromosomal instability. This article has an associated First Person interview with the first author of the paper.

Muscle Protein Synthesis after Protein Administration in Critical Illness.

Rationale: Dietary protein may attenuate the muscle atrophy experienced by patients in the ICU, yet protein handling is poorly understood. Objectives: To quantify protein digestion and amino acid absorption and fasting and postprandial myofibrillar protein synthesis during critical illness. Methods: Fifteen mechanically ventilated adults (12 male; aged 50 ± 17 yr; body mass index, 27 ± 5 kg⋅m-2) and 10 healthy control subjects (6 male; 54 ± 23 yr; body mass index, 27 ± 4 kg⋅m-2) received a primed intravenous L-[ring-2H5]-phenylalanine, L-[3,5-2H2]-tyrosine, and L-[1-13C]-leucine infusion over 9.5 hours and a duodenal bolus of intrinsically labeled (L-[1-13C]-phenylalanine and L-[1-13C]-leucine) intact milk protein (20 g protein) over 60 minutes. Arterial blood and muscle samples were taken at baseline (fasting) and for 6 hours following duodenal protein administration. Data are mean ± SD, analyzed with two-way repeated measures ANOVA and independent samples t test. Measurements and Main Results: Fasting myofibrillar protein synthesis rates did not differ between ICU patients and healthy control subjects (0.023 ± 0.013% h-1 vs. 0.034 ± 0.016% h-1; P = 0.077). After protein administration, plasma amino acid availability did not differ between groups (ICU patients, 54.2 ± 9.1%, vs. healthy control subjects, 61.8 ± 13.1%; P = 0.12), and myofibrillar protein synthesis rates increased in both groups (0.028 ± 0.010% h-1 vs. 0.043 ± 0.018% h-1; main time effect P = 0.046; P-interaction = 0.584) with lower rates in ICU patients than in healthy control subjects (main group effect P = 0.001). Incorporation of protein-derived phenylalanine into myofibrillar protein was ∼60% lower in ICU patients (0.007 ± 0.007 mol percent excess vs. 0.017 ± 0.009 mol percent excess; P = 0.007). Conclusions: The capacity for critically ill patients to use ingested protein for muscle protein synthesis is markedly blunted despite relatively normal protein digestion and amino acid absorption.

Completion peripheral angiography in single-access, Impella-assisted, high-risk PCI: Using a buddy microcatheter sheath after MANTA closure for imaging and potential bailout.

High-risk percutaneous coronary intervention (HR-PCI) is increasingly performed, often with mechanical circulatory support (MCS) provided by devices like the Impella CP. Bleeding and vascular complications remain concerns for HR-PCI, leading to significantly higher in-hospital mortality, duration of stay, and cost, which are important considerations in the decisions surrounding MCS support for HR-PCI. Newly introduced, single-catheter techniques for Impella-supported HR-PCI, along with recent approvals of dedicated large-bore closure devices (MANTA®-Vascular Closure Device) may reduce bleeding and vascular complications, but have limitations with regard to completion of peripheral angiography and/or postclosure percutaneous bailout options. The present technique offers a potential solution to these limitations, and describes a buddy microcatheter approach to postclosure management of HR-PCI with MCS, which was highly successful in a consecutive series of patients at our institution.

The use of smartphone-derived location data to evaluate participation following critical illness: A pilot observational cohort study.

BACKGROUND: Disability is common following critical illness, impacting the quality of life of survivors, and is difficult to measure. 'Participation' can be quantified as involvement in life outside of their home requiring movement from their home to other locations. Participation restriction is a key element of disability, and following critical illness, participation may be diminished. It may be possible to quantify this change using pre-existing smartphone data. OBJECTIVES: The feasibility of extracting location data from smartphones of survivors of intensive care unit (ICU) admission and assessing participation, using location-based outcomes, during recovery from critical illness was evaluated. METHODS: Fifty consecutively admitted, consenting adult survivors of non-elective admission to ICU of greater than 48-h duration were recruited to a prospective observational cohort study where they were followed up at 3 and 6 months following discharge. The feasibility of extracting location data from survivors' smartphones and creating location-derived outcomes assessing participation was investigated over three 28-d study periods: pre-ICU admission and at 3 and 6 months following discharge. The following were calculated: time spent at home; the number of destinations visited; linear distance travelled; and two 'activity spaces', a minimum convex polygon and standard deviation ellipse. RESULTS: Results are median [interquartile range] or n (%). The number of successful extractions was 9/50 (18%), 12/39 (31%), and 13/33 (39%); the percentage of time spent at home was 61 [56-68]%, 77 [66-87]%, and 67 [58-77]% (P = 0.16); the number of destinations visited was 34 [18-64], 38 [22-63], and 65 [46-88] (P = 0.02); linear distance travelled was 367 [56-788], 251 [114-323], and 747 [326-933] km over 28 d (P = 0.02), pre-ICU admission and at 3 and 6 months following ICU discharge, respectively. Activity spaces were successfully created. CONCLUSION: Limited smartphone ownership, missing data, and time-consuming data extraction limit current implementation of mass extraction of location data from patients' smartphones to aid prognostication or measure outcomes. The number of journeys taken and the linear distance travelled increased between 3 and 6 months, suggesting participation may improve over time.

Assessment of physiological barriers to nutrition following critical illness.

BACKGROUND & AIMS: Nutrition may be important for recovery from critical illness. Gastrointestinal dysfunction is a key barrier to nutrition delivery in the Intensive Care Unit (ICU) and metabolic rate is elevated exacerbating nutritional deficits. Whether these factors persist following ICU discharge is unknown. We assessed whether delayed gastric emptying (GE) and impaired glucose absorption persist post-ICU discharge. METHODS: A prospective observational study was conducted in mechanically ventilated adults at 3 time-points: in ICU (V1); on the post-ICU ward (V2); and 3-months after ICU discharge (V3); and compared to age-matched healthy volunteers. On each visit, all participants received a test-meal containing 100 ml of 1 kcal/ml liquid nutrient, labelled with 0.1 g 13C-octanoic acid and 3 g 3-O-Methyl-glucose (3-OMG), and breath and blood samples were collected over 240min to quantify GE (gastric emptying coefficient (GEC)), and glucose absorption (3-OMG concentration; area under the curve (AUC)). Data are mean ± standard error of the mean (SEM) and differences shown with 95% confidence intervals (95%CI). RESULTS: Twenty-six critically ill patients completed V1 (M:F 20:6; 62.0 ± 2.9 y; BMI 29.8 ± 1.2 kg/m2; APACHE II 19.7 ± 1.9), 15 completed V2 and eight completed V3; and were compared to 10 healthy volunteers (M:F 6:4; 60.5 ± 7.5 y; BMI 26.0 ± 1.0 kg/m2). GE was significantly slower on V1 compared to health (GEC difference: -0.96 (95%CI -1.61, -0.31); and compared to V2 (-0.73 (-1.16, -0.31) and V3 (-1.03 (-1.47, -0.59). GE at V2 and V3 were not different to that in health (V2: -0.23 (-0.61, 0.14); V3: 0.10 (-0.27, 0.46)). GEC: V1: 2.64 ± 0.19; V2: 3.37 ± 0.12; V3: 3.67 ± 0.10; health: 3.60 ± 0.13. Glucose absorption (3-OMG AUC0-240) was impaired on V1 compared to V2 (-37.9 (-64.2, -11.6)), and faster on V3 than in health (21.8 (0.14, 43.4) but absorption at V2 and V3 did not differ from health. Intestinal glucose absorption: V1: 63.8 ± 10.4; V2: 101.7 ± 7.0; V3: 111.9 ± 9.7; health: 90.7 ± 3.8. CONCLUSION: This study suggests that delayed GE and impaired intestinal glucose absorption recovers rapidly post-ICU. This requires further confirmation in a larger population. The REINSTATE trial was prospectively registered at www.anzctr.org.au. TRIAL ID: ACTRN12618000370202.

Systematic review of clinicians' knowledge, attitudes, and beliefs about nutrition in intensive care.

Nutrition is a key component of care for critically ill patients; yet nutrition delivery is below international recommendations. In order to improve nutrition delivery to critically ill patients, an understanding of the barriers that prevent guideline adherence is required. It is known that clinicians' knowledge, attitudes, and beliefs of the role of nutrition may act as a potential barrier to nutrition delivery, but whether this remains true in critical care is unknown. The aim of this systematic scoping review was to summarize the literature exploring the knowledge, attitudes, and beliefs of clinicians around nutrition support in critically ill patients. A search of four online databases (MEDLINE via Ovid, Emcare via Ovid, PsycINFO, and CINAHL via EBSCOhost) was conducted on August 14, 2020, to identify literature that reported on clinicians' knowledge, attitudes, and beliefs of nutrition in adult intensive care patients. Data were extracted on study and participant characteristics, methodology, and key study outcomes related to nutrition. Eighteen articles met eligibility criteria and were included in the review. Key findings included the following: nutrition was seen as a priority that ranked below life-saving interventions; differences in perceived clinician responsibilities exist; common barriers to nutrition delivery included inadequate resourcing, lack of nutrition protocols, and gastrointestinal intolerance; and identified facilitators included nutrition education and the presence of a supportive multidisciplinary team. The implementation of nutrition protocols, enhanced clinical nutrition education, and further clarification of roles and responsibilities pertaining to nutrition may assist in improving nutrition delivery in critical care.

A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients.

BACKGROUND: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome. PATIENTS AND METHODS: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10-5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas. RESULTS: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10-7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10-2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10-8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10-2). CONCLUSIONS: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.