Development and external validation of preoperative clinical prediction models for postoperative outcomes including preoperative aerobic fitness in patients approaching elective colorectal cancer surgery.

INTRODUCTION: Preoperative aerobic fitness is associated with postoperative outcomes after elective colorectal cancer (CRC) surgery. This study aimed to develop and externally validate two clinical prediction models incorporating a practical test to assess preoperative aerobic fitness to distinguish between patients with and without an increased risk for 1) postoperative complications and 2) a prolonged time to in-hospital recovery of physical functioning after elective colorectal cancer (CRC) surgery. MATERIALS AND METHODS: Models were developed using prospective data from 256 patients and externally validated using prospective data of 291 patients. Postoperative complications were classified according to Clavien-Dindo. The modified Iowa level of assistance scale (mILAS) was used to determine time to postoperative in-hospital physical recovery. Aerobic fitness, age, sex, body mass index, American Society of Anesthesiologists (ASA) classification, neoadjuvant treatment, surgical approach, tumour location, and preoperative haemoglobin level were potential predictors. Areas under the curve (AUC), calibration plots, and Hosmer-Lemeshow tests evaluated predictive performance. RESULTS: Aerobic fitness, sex, age, ASA, tumour location, and surgical approach were included in the final models. External validation of the model for complications and postoperative recovery presented moderate to fair discrimination (AUC 0.666 (0.598-0.733) and 0.722 (0.651-0.794), respectively) and good calibration. High sensitivity and high negative predictive values were observed in the lower predicted risk categories (<40 %). CONCLUSION: Both models identify patients with and without an increased risk of complications or a prolonged time to in-hospital physical recovery. They might be used for improving patient-tailored preoperative risk assessment and targeted and cost-effective application of prehabilitation interventions.

Accelerated enhanced recovery after colon cancer surgery with discharge within one day after surgery: a systematic review.

BACKGROUND: Recent studies have demonstrated that accelerated enhanced recovery after colorectal surgery is feasible for specific patient populations. The accelerated enhanced recovery protocols (ERP) tend to vary, and the majority of studies included a small study population. This hampers defining the optimal protocol and establishing the potential benefits. This systematic review aimed to determine the effect of accelerated ERPs with intended discharge within one day after surgery. METHODS: PubMed (MEDLINE), Embase, Cochrane and Web of Science databases were searched using the following search terms: colon cancer, colon surgery, accelerated recovery, fast track recovery, enhanced recovery after surgery. Clinical trials published between January 2005 - February 2023, written in English or Dutch comparing accelerated ERPs to Enhanced Recovery After Surgery (ERAS) care for adult patients undergoing elective laparoscopic or robotic surgery for colon cancer were eligible for inclusion. RESULTS: Thirteen studies, including one RCT were included. Accelerated ERPs after colorectal surgery was possible as LOS was shorter; 14 h to 3.4 days, and complication rate varied from 0-35.7% and readmission rate was 0-17% in the accelerated ERP groups. Risk of bias was serious or critical in most of the included studies. CONCLUSIONS: Accelerated ERPs may not yet be considered the new standard of care as the current data is heterogenous, and data on important outcome measures is scarce. Nonetheless, the decreased LOS suggests that accelerated recovery is possible for selected patients. In addition, the complication and readmission rates were comparable to ERAS care, suggesting that accelerated recovery could be safe.

Volatile organic compounds in headspace characterize isolated bacterial strains independent of growth medium or antibiotic sensitivity.

INTRODUCTION: Early and reliable determination of bacterial strain specificity and antibiotic resistance is critical to improve sepsis treatment. Previous research demonstrated the potential of headspace analysis of volatile organic compounds (VOCs) to differentiate between various microorganisms associated with pulmonary infections in vitro. This study evaluates whether VOC analysis can also discriminate antibiotic sensitive from resistant bacterial strains when cultured on varying growth media. METHODS: Both antibiotic-sensitive and -resistant strains of Pseudomonas aeruginosa, Staphylococcus aureus and Klebsiella pneumonia were cultured on 4 different growth media, i.e. Brain Heart Infusion, Marine Broth, Müller-Hinton and Trypticase Soy Agar. After overnight incubation at 37°C, the headspace air of the cultures was collected on stainless steel desorption tubes and analyzed by gas chromatography time-of-flight mass spectrometry (GC-tof-MS). Statistical analysis was performed using regularized multivariate analysis of variance and cross validation. RESULTS: The three bacterial species could be correctly recognized based on the differential presence of 14 VOCs (p<0.001). This discrimination was not influenced by the different growth media. Interestingly, a clear discrimination could be made between the antibiotic-resistant and -sensitive variant of Pseudomonas aeruginosa (p<0.001) based on their species-specific VOC signature. CONCLUSION: This study demonstrates that isolated microorganisms, including antibiotic-sensitive and -resistant strains of Pseudomonas aeruginosa, could be identified based on their excreted VOCs independent of the applied growth media. These findings suggest that the discriminating volatiles are associated with the microorganisms themselves rather than with their growth medium. This study exemplifies the potential of VOC analysis as diagnostic tool in medical microbiology. However, validation of our results in appropriate in vivo models is critical to improve translation of breath analysis to clinical applications.

Lipidomic Phenotyping Of Human Small Intestinal Organoids Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging.

In the past decade, interest in organoids for biomedical research has surged, resulting in a higher demand for advanced imaging techniques. Traditional specimen embedding methods pose challenges, such as analyte delocalization and histological assessment. Here, we present an optimized sample preparation approach utilizing an Epredia M-1 cellulose-based embedding matrix, which preserves the structural integrity of fragile small intestinal organoids (SIOs). Additionally, background interference (delocalization of analytes, nonspecific (histological) staining, matrix ion clusters) was minimized, and we demonstrate the compatibility with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). With our approach, we can conduct label-free lipid imaging at the single-cell level, thereby yielding insights into the spatial distribution of lipids in both positive and negative ion modes. Moreover, M-1 embedding allows for an improved coregistration with histological and immunohistochemical (IHC) stainings, including MALDI-IHC, facilitating combined untargeted and targeted spatial information. Applying this approach, we successfully phenotyped crypt-like (CL) and villus-like (VL) SIOs, revealing that PE 36:2 [M - H]- (m/z 742.5) and PI 38:4 [M - H]- (m/z 885.5) display higher abundance in CL organoids, whereas PI 36:1 [M - H]- (m/z 863.6) was more prevalent in VL organoids. Our findings demonstrate the utility of M-1 embedding for advancing organoid research and unraveling intricate biological processes within these in vitro models.

A systematic review on the detection of volatile organic compounds in exhaled breath in experimental animals in the context of gastrointestinal and hepatic diseases.

BACKGROUND: Analysis of volatile organic compounds (VOCs) in exhaled breath has the potential to serve as an accurate diagnostic tool for gastro-intestinal diseases. Animal studies could be instrumental as a preclinical base and subsequent clinical translation to humans, as they are easier to standardize and better equipped to relate specific VOCs to metabolic and pathological processes. This review provides an overview of the study design, characteristics and methodological quality of previously published animal studies on analysis of exhaled breath in gastrointestinal and hepatic diseases. Guidelines are provided for standardization in study design and breath collection methods to improve comparability, avoid duplication of research and reduce discomfort of animals in future studies. METHODS: PubMed and Embase database were searched for animal studies using exhaled breath analysis to detect gastro-intestinal diseases. Risk of bias was assessed using the SYRCLE's risk of bias tool for animal studies. Information on study design, standardization methods, animal models, breath collection methods and identified VOCs were extracted from the included studies. RESULTS: 10 studies were included (acute liver failure n = 1, non-alcoholic steatohepatitis n = 1, hepatic ischemia n = 2, mesenteric ischemia n = 2, sepsis and peritonitis n = 3, colitis n = 1). Rats were used in most of the studies. Exhaled breath was mostly collected using invasive procedures as tracheal cannulation or tracheostomy. Poor reporting on standardization, breath collection methods, analytical techniques, as well as heterogeneity of the studies, complicate comparison of the different studies. CONCLUSION: Poor reporting of essential methodological details impaired comprehensive summarizing the various studies on exhaled breath in gastrointestinal and hepatic diseases. Potential pitfalls in study design, and suggestions for improvement of study design are discussed which, when applied, lead to consistent and generalizable results and a reduction in the use of laboratory animals. Refining the methodological quality of animal studies has the potential to improve subsequent clinical trial design.

Diagnostic potential of plasma biomarkers and exhaled volatile organic compounds in predicting the different stages of acute mesenteric ischaemia: protocol for a multicentre prospective observational study (TACTIC study).

INTRODUCTION: Acute mesenteric ischaemia (AMI) is a life-threatening condition with short-term mortality of up to 80%. The diagnosis of AMI has remained troublesome due to the non-specific clinical presentation, symptoms and laboratory findings. Early unambiguous diagnosis of AMI is critical to prevent progression from reversible to irreversible transmural intestinal damage, thereby decreasing morbidity and improving survival. The present study aims to validate a panel of plasma biomarkers and investigate volatile organic compound (VOC) profiles in exhaled air as a tool to timely and accurately diagnose AMI. METHODS AND ANALYSIS: In this international multicentre prospective observational study, 120 patients (>18 years of age) will be recruited with clinical suspicion of AMI. Clinical suspicion is based on: (1) clinical manifestation, (2) physical examination, (3) laboratory measurements and (4) the physician's consideration to perform a CT scan. The patient's characteristics, repetitive blood samples and exhaled air will be prospectively collected. Plasma levels of mucosal damage markers intestinal fatty acid-binding protein and villin-1, as well as transmural damage marker smooth muscle protein 22-alpha, will be assessed by ELISA. Analysis of VOCs in exhaled air will be performed by gas chromatography time-of-flight mass spectrometry. Diagnosis of AMI will be based on CT, endovascular and surgical reports, clinical findings, and (if applicable) verified by histopathological examination. ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Research Ethics Committee (METC) of Maastricht University Medical Centre+ and Maastricht University (METC azM/UM), the Netherlands (METC19-010) and the Ethics Committee Research UZ/KU Leuven, Belgium (S63500). Executive boards and local METCs of other Dutch participating centres Gelre Ziekenhuizen (Apeldoorn), Medisch Spectrum Twente (Enschede), and University Medical Centre Groningen have granted permission to carry out this study. Study results will be disseminated via open-access peer-reviewed scientific journals and national/international conferences. TRIAL REGISTRATION NUMBER: NCT05194527.

Diagnostic Performance of Magnetic Resonance Imaging for Parathyroid Localization of Primary Hyperparathyroidism: A Systematic Review.

Accurate preoperative localization is crucial for successful minimally invasive parathyroidectomy in primary hyperparathyroidism (PHPT). Preoperative localization can be challenging in patients with recurrent and/or multigland disease (MGD). This has led clinicians to investigate multiple imaging techniques, most of which are associated with radiation exposure. Magnetic resonance imaging (MRI) offers ionizing radiation-free and accurate imaging, making it an attractive alternative imaging modality. The objective of this systematic review is to provide an overview of the diagnostic performance of MRI in the localization of PHPT. PubMed and Embase libraries were searched from 1 January 2000 to 31 March 2023. Studies were included that investigated MRI techniques for the localization of PHPT. The exclusion criteria were (1) secondary/tertiary hyperparathyroidism, (2) studies that provided no diagnostic performance values, (3) studies published before 2000, and (4) studies using 0.5 Tesla MRI scanners. Twenty-four articles were included in the systematic review, with a total of 1127 patients with PHPT. In 14 studies investigating conventional MRI for PHPT localization, sensitivities varied between 39.1% and 94.3%. When employing more advanced MRI protocols like 4D MRI for PHPT localization in 11 studies, sensitivities ranged from 55.6% to 100%. The combination of MR imaging with functional techniques such as 18F-FCH-PET/MRI yielded the highest diagnostic accuracy, with sensitivities ranging from 84.2% to 100% in five studies. Despite the limitations of the available evidence, the results of this review indicate that the combination of MR imaging with functional imaging techniques such as 18F-FCH-PET/MRI yielded the highest diagnostic accuracy. Further research on emerging MR imaging modalities, such as 4D MRI and PET/MRI, is warranted, as MRI exposes patients to minimal or no ionizing radiation compared to other imaging modalities.

Detection of differentiated thyroid carcinoma in exhaled breath with an electronic nose.

This proof-of-principle study investigates the diagnostic performance of the Aeonose in differentiating malignant from benign thyroid diseases based on volatile organic compound analysis in exhaled breath. All patients with a suspicious thyroid nodule planned for surgery, exhaled in the Aeonose. Definitive diagnosis was provided by histopathological determination after surgical resection. Breath samples were analyzed utilizing artificial neural networking. About 133 participants were included, 48 of whom were diagnosed with well-differentiated thyroid cancer. A sensitivity of 0.73 and a negative predictive value (NPV) of 0.82 were found. The sensitivity and NPV improved to 0.94 and 0.95 respectively after adding clinical variables via multivariate logistic regression analysis. This study demonstrates the feasibility of the Aeonose to discriminate between malignant and benign thyroid disease. With a high NPV, low cost, and non-invasive nature, the Aeonose may be a promising diagnostic tool in the detection of thyroid cancer.

The patient perspective on the preoperative colorectal cancer care pathway and preparedness for surgery and postoperative recovery-a qualitative interview study.

BACKGROUND AND OBJECTIVES: This study aimed to explore colorectal cancer (CRC) patients' perspectives and experiences regarding the preoperative surgical care pathway and their subsequent preparedness for surgery and postoperative recovery. METHODS: CRC patients were recruited using purposive sampling and were interviewed three times (preoperatively, and 6 weeks and 3 months postoperatively) using semistructured telephone interviews. Interviews were audiotaped, transcribed verbatim and analysed independently by two researchers using thematic analysis with open coding. RESULTS: Data saturation was achieved after including 18 patients. Preoperative factors that contributed to a feeling of preparedness for surgery and recovery were patient-centred- and professional healthcare organization, sincere and personal guidance, and thorough information provision. Postoperatively, patients with complications or physical complaints experienced unmet information needs regarding the impact of complications and what to expect from postoperative recovery. CONCLUSIONS: The preoperative period is a vital period to prepare patients for surgery and recovery in which patients most value personalized information, personal guidance and professionalism. According to CRC patients, the feeling of preparedness for surgery and recovery can be improved by continually providing dosed information. This information should provide the patient with patient-tailored perspectives regarding the impact of (potential) complications and what to expect during recovery.

Quality and clinical generalizability of feasibility outcomes in exercise prehabilitation before colorectal cancer surgery - A systematic review.

Suboptimal quality of feasibility assessments might partially explain inconsistencies observed in the effectiveness of exercise prehabilitation before colorectal cancer (CRC) surgery. This systematic review aimed to assess the reporting quality and clinical generalizability of feasibility outcomes in feasibility studies addressing exercise prehabilitation before CRC surgery. PubMed/Medline, Embase, Cochrane, and CINAHL were searched to identify all feasibility studies focussing on exercise prehabilitation in CRC surgery. Reporting quality was assessed using the Thabane et al. checklist and the Consolidated Standards of Reporting Trials extension for feasibility studies. Clinical generalizability was evaluated by appraising patient participation in all steps of the study and intervention. Twelve studies were included. The main feasibility outcome in all studies was adherence to the intervention by the study sample. Based on adherence, 10 studies (83%) concluded exercise prehabilitation to be feasible. Six studies (50%) reported all details to assess patient participation showing retention rates between 18.4% and 58.2%, which was caused by non-participation and drop-out. Three feasibility studies (25%) discussed patient-reported barriers to participation and five additional studies (41%) described potential selection bias. Four studies (33%) reported lessons learned to solve issues hampering feasibility and clinical generalizability. Results suggest that true feasibility of exercise prehabilitation before CRC surgery remains questionable due to poor reporting quality, insufficient clarity regarding the representativeness of the study sample for the target population, and limited attention for clinical generalizability. Feasibility of exercise prehabilitation might be improved by offering supervised community- or home-based interventions tailored to the physical and mental abilities of the patient.

Aerobic fitness and muscle density play a vital role in postoperative complications in colorectal cancer surgery.

BACKGROUND AND OBJECTIVES: To assess the association of preoperative aerobic fitness and body composition variables with a patient's resilience to the development and impact of postoperative complications after elective colorectal cancer (CRC) surgery. METHODS: Preoperative aerobic fitness was assessed by steep ramp test performance. Preoperative body composition was assessed by muscle mass and density determined from preoperative computed tomography scan analysis at the L3-level. Complication development and severity was graded according to Clavien-Dindo. Complication impact was assessed by the time to recovery of physical functioning after complications. Multivariable logistic regression analyses adjusted for age, sex, comorbidities and tumour location was performed. RESULTS: Of 238 included patients, 96 (40.3%) developed postoperative complications. Better preoperative aerobic fitness decreased the likelihood to develop complications, independent of muscle mass (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.35-0.85) or muscle density (OR: 0.57, 95% CI: 0.36-0.89). A prolonged time to recovery following complications was associated with lower preoperative muscle density (OR: 4.14, 95% CI: 1.28-13.41), independent of aerobic fitness. CONCLUSIONS: Lower aerobic fitness increases the risk of complication development, while low muscle density seems associated with a prolonged recovery from complications. Aerobic fitness and muscle density could be valuable additives to preoperative risk assessment.

Self-perceived recovery and quality of life in elderly patients surviving ICU-admission for abdominal sepsis.

INTRODUCTION: Concern for loss of physical performance and Health-Related Quality of Life (HRQoL) may raise doubts regarding the meaningfulness of an Intensive Care (ICU) admission in elderly patients. We evaluated self-perceived long-term recovery and satisfaction in elderly surviving an abdominal sepsis related ICU-admission and related this to objective measures of HRQoL. METHODS: A cross-sectional survey study was performed in all ICU-survivors with age ≥70 admitted with abdominal sepsis. HRQoL, frailty and self-perceived long-term recovery were measured using the EQ-5D-3L, Groningen Frailty Indicator, and a self-developed questionnaire, respectively. RESULTS: Of 144 patients admitted, 48 were alive at follow up (2.42 [0.92; 3.83] years), and 29 (60%) returned the survey. Eleven patients out of 29 (38%) recovered to baseline functioning, and reported higher HRQoL compared to unrecovered patients (0.861 [0.807; 1.000] and 0.753 [0.499; 0.779] respectively, p=0.005). Of the unrecovered patients, 53% were satisfied with their functioning, and 94% were willing to return to ICU. CONCLUSIONS: Mortality in elderly patients with abdominal sepsis is high and ICU-admission should be weighed carefully. However, despite substantial functional decline in survivors, it does not necessarily cause self-perceived unsatisfactory functioning, poor HRQoL and unwillingness to receive life-sustaining therapy again. Caution is advised to use an anticipated loss of functioning as an argument to deny an ICU-admission.

Applying the electronic nose for pre-operative SARS-CoV-2 screening.

BACKGROUND: Infection with SARS-CoV-2 causes corona virus disease (COVID-19). The most standard diagnostic method is reverse transcription-polymerase chain reaction (RT-PCR) on a nasopharyngeal and/or an oropharyngeal swab. The high occurrence of false-negative results due to the non-presence of SARS-CoV-2 in the oropharyngeal environment renders this sampling method not ideal. Therefore, a new sampling device is desirable. This proof-of-principle study investigated the possibility to train machine-learning classifiers with an electronic nose (Aeonose) to differentiate between COVID-19-positive and negative persons based on volatile organic compounds (VOCs) analysis. METHODS: Between April and June 2020, participants were invited for breath analysis when a swab for RT-PCR was collected. If the RT-PCR resulted negative, the presence of SARS-CoV-2-specific antibodies was checked to confirm the negative result. All participants breathed through the Aeonose for five minutes. This device contains metal-oxide sensors that change in conductivity upon reaction with VOCs in exhaled breath. These conductivity changes are input data for machine learning and used for pattern recognition. The result is a value between - 1 and + 1, indicating the infection probability. RESULTS: 219 participants were included, 57 of which COVID-19 positive. A sensitivity of 0.86 and a negative predictive value (NPV) of 0.92 were found. Adding clinical variables to machine-learning classifier via multivariate logistic regression analysis, the NPV improved to 0.96. CONCLUSIONS: The Aeonose can distinguish COVID-19 positive from negative participants based on VOC patterns in exhaled breath with a high NPV. The Aeonose might be a promising, non-invasive, and low-cost triage tool for excluding SARS-CoV-2 infection in patients elected for surgery.

Can Electric Nose Breath Analysis Identify Abdominal Wall Hernia Recurrence and Aortic Aneurysms? A Proof-of-Concept Study.

Introduction. This pilot study evaluates if an electronic nose (eNose) can distinguish patients at risk for recurrent hernia formation and aortic aneurysm patients from healthy controls based on volatile organic compound analysis in exhaled air. Both hernia recurrence and aortic aneurysm are linked to impaired collagen metabolism. If patients at risk for hernia recurrence and aortic aneurysms can be identified in a reliable, low-cost, noninvasive manner, it would greatly enhance preventive options such as prophylactic mesh placement after abdominal surgery. Methods. From February to July 2017, a 3-armed proof-of-concept study was conducted at 3 hospitals including 3 groups of patients (recurrent ventral hernia, aortic aneurysm, and healthy controls). Patients were measured once at the outpatient clinic using an eNose with 3 metal-oxide sensors. A total of 64 patients (hernia, n = 29; aneurysm, n = 35) and 37 controls were included. Data were analyzed by an automated neural network, a type of self-learning software to distinguish patients from controls. Results. Receiver operating curves showed that the automated neural network was able to differentiate between recurrent hernia patients and controls (area under the curve 0.74, sensitivity 0.79, and specificity 0.65) as well as between aortic aneurysm patients and healthy controls (area under the curve 0.84, sensitivity 0.83, and specificity of 0.81). Conclusion. This pilot study shows that the eNose can distinguish patients at risk for recurrent hernia and aortic aneurysm formation from healthy controls.

Exciton diffusion in two-dimensional metal-halide perovskites.

Two-dimensional layered perovskites are attracting increasing attention as more robust analogues to the conventional three-dimensional metal-halide perovskites for both light harvesting and light emitting applications. However, the impact of the reduced dimensionality on the optoelectronic properties remains unclear, particularly regarding the spatial dynamics of the excitonic excited state within the two-dimensional plane. Here, we present direct measurements of exciton transport in single-crystalline layered perovskites. Using transient photoluminescence microscopy, we show that excitons undergo an initial fast diffusion through the crystalline plane, followed by a slower subdiffusive regime as excitons get trapped. Interestingly, the early intrinsic diffusivity depends sensitively on the choice of organic spacer. A clear correlation between lattice stiffness and diffusivity is found, suggesting exciton-phonon interactions to be dominant in the spatial dynamics of the excitons in perovskites, consistent with the formation of exciton-polarons. Our findings provide a clear design strategy to optimize exciton transport in these systems.

Feasibility of indocyanine green fluorescence imaging for intraoperative identification of parathyroid glands during thyroid surgery.

BACKGROUND: This study assessed the feasibility of near-infrared fluorescence imaging with indocyanine green (ICG) to identify the parathyroid glands (PGs) intraoperatively and to assess their perfusion after thyroid resection. METHODS: Patients undergoing elective thyroidectomy were enrolled in this prospective study. An intravenous bolus of 7.5 mg ICG was administered twice: the first bolus to identify the PGs before resection of the thyroid and the second to assess vascularization of the PGs after resection. RESULTS: A total of 30 operations in 26 patients were included. In 17 surgeries (56.7%), fluorescence imaging was of added value, especially to confirm the presence of a suspected PG. No intraoperative or postoperative complications occurred because of the use of ICG. CONCLUSION: Near-infrared fluorescence imaging with the use of ICG for intraoperative identification of the PGs and the assessment of its vascularization is feasible and safe and can provide more certainty about the location of the PGs.

Predictive Factors for Anastomotic Leakage After Colorectal Surgery: Study Protocol for a Prospective Observational Study (REVEAL Study).

BACKGROUND: Anastomotic leakage (AL) remains the most important complication following colorectal surgery, and is associated with high morbidity and mortality rates. Previous research has focused on identifying risk factors and potential biomarkers for AL, but the sensitivity of these tests remains poor. OBJECTIVE: This prospective multicenter observational study aims at combining multiple parameters to establish a diagnostic algorithm for colorectal AL. METHODS: This study aims to include 588 patients undergoing surgery for colorectal carcinoma. Patients will be eligible for inclusion when surgery includes the construction of a colorectal anastomosis. Patient characteristics will be collected upon consented inclusion, and buccal swabs, breath, stool, and blood samples will be obtained prior to surgery. These samples will allow for the collection of information regarding patients' inflammatory status, genetic predisposition, and intestinal microbiota. Additionally, breath and blood samples will be taken postoperatively and patients will be strictly observed during their in-hospital stay, and the period shortly thereafter. RESULTS: This study has been open for inclusion since August 2015. CONCLUSIONS: An estimated 8-10% of patients will develop AL following surgery, and they will be compared to non-leakage patients. The objectives of this study are twofold. The primary aim is to establish and validate a diagnostic algorithm for the pre-operative prediction of the risk of AL development using a combination of inflammatory, immune-related, and genetic parameters. Previously established risk factors and novel parameters will be incorporated into this algorithm, which will aid in the recognition of patients who are at risk for AL. Based on these results, recommendations can be made regarding the construction of an anastomosis or deviating stoma, and possible preventive strategies. Furthermore, we aim to develop a new algorithm for the post-operative diagnosis of AL at an earlier stage, which will positively reflect on short-term survival rates. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02347735; https://clinicaltrials.gov/ct2/show/NCT02347735 (archived by WebCite at http://www.webcitation.org/6hm6rxCsA).

Lipid-rich enteral nutrition improves the defense against an opportunistic infection during polymicrobial sepsis.

The development of an immunosuppressive state during the protracted course of sepsis is associated with opportunistic infections and is considered to correlate with the extent of the proinflammatory response during early sepsis. Short-term intervention with enteral lipid-rich nutrition was shown to attenuate the acute inflammatory response. This study investigates the effects of lipid-rich nutrition on the immunosuppression induced by polymicrobial sepsis. Female BALB/c mice were either fasted or fed liquid lipid-rich nutrition or isocaloric control nutrition before and shortly after induction of polymicrobial sepsis through cecal ligation and puncture (CLP) or sham operation. After 4 days, mice were intranasally infected with Pseudomonas aeruginosa. Twenty-four hours after P. aeruginosa infection, fasted and control nutrition-fed CLP mice displayed a significantly higher bacterial load in the lungs than did corresponding sham-operated mice (P < 0.001 and P < 0.05, respectively). Fasted CLP mice expressed reduced pulmonary levels of proinflammatory cytokines interleukin 12 (IL-12) and interferon γ (IFN-γ) in comparison to sham mice (both P < 0.05). Lipid-rich nutrition prevented the increase in bacteria, promoted the IL-12 and IFN-γ production (IL-12 and IFN-γ [P < 0.05] vs. fasted and IFN-γ [P < 0.05] vs. control nutrition), and prevented the expression of the immunosuppressive cytokine IL-10 (P < 0.05 vs. control nutrition) in lungs of CLP mice. The preserved immune defense during late sepsis in lipid-rich fed mice was preceded by attenuation of the early inflammatory response (IL-6 [P = 0.05] and IL-10 [P < 0.01] vs. fasted CLP mice) at 6 h after CLP. In conclusion, short-term treatment with lipid-rich enteral nutrition improves the pulmonary antimicrobial defense during polymicrobial sepsis.

Prevention of hemolysis-induced organ damage by nutritional activation of the vagal anti-inflammatory reflex*.

OBJECTIVES: Acute hemolysis is associated with organ damage, inflammation, and impaired vascular function. Stimulation of the cholecystokinin-1 receptor-dependent vagal anti-inflammatory reflex with lipid-rich enteral nutrition was demonstrated to prevent tissue damage and attenuate inflammation. This study investigates the effects of nutritional activation of the vagal anti-inflammatory reflex on organ integrity, systemic inflammation, and microcirculation during hemolysis. DESIGN: Prospective randomized controlled study. SETTING: University research unit. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Intravascular hemolysis was simulated by infusion of prelysed erythrocytes. Animals were fasted or received lipid-rich enteral nutrition. Pegylated (PEG)-CCK9A, A70104 (a cholecystokinin-1 receptor antagonist), and chlorisondamine (a nicotinic acetylcholine receptor antagonist) were applied to investigate involvement of the vagal reflex. MEASUREMENTS AND MAIN RESULTS: Nutritional intervention reduced hemolysis-related renal tubular cell damage, hepatocyte damage, ileal leakage of horseradish peroxidase, and bacterial translocation compared with food deprivation (all p < 0.05). Also circulating interleukin (IL)-6 levels were decreased by enteral nutrition (p < 0.05). Blockage of the cholecystokinin-1 receptor or the nicotinic acetylcholine receptor reversed the protective nutritional effects compared with vehicle (p < 0.05), whereas PEG-CCK9 mimicked the impact of enteral feeding in fasted animals (p < 0.05). Furthermore, nutritional intervention increased renal, hepatic, and intestinal blood flow compared with fasting (all p < 0.05), as evaluated using fluorescent microspheres. CONCLUSIONS: Nutritional activation of the vagal anti-inflammatory reflex preserves tissue integrity and attenuates systemic inflammation in a rodent model of acute hemolysis. In addition, lipid-rich nutrition improves renal, hepatic, and intestinal microcirculation. These findings implicate stimulation of the autonomic nervous system by nutritional means as a potential therapy to prevent complications of acute hemolysis. (Crit Care Med 2013; 41:e361-e367).