The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity.

The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver.

Clinical Reasoning Behind Antibiotic Use in PICUs: A Qualitative Study.

OBJECTIVES: To describe the reasoning processes used by pediatric intensivists to make antibiotic-related decisions. DESIGN: Grounded theory qualitative study. SETTING: Three Canadian university-affiliated tertiary medical, surgical, and cardiac PICUs. PATIENTS: Twenty-one PICU physicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We conducted field observation during morning rounds followed by semistructured interviews with participants to examine the clinical reasoning behind antibiotic-related decisions (starting/stopping antibiotics, or treatment duration) made for patients with a suspected/proven bacterial infection. We used a grounded theory approach for data collection and analysis. Thematic saturation was reached after 21 interviews. Of the 21 participants, 10 (48%) were female, 15 (71%) were PICU attending staff, and 10 (48%) had greater than 10 years in clinical practice. Initial clinical reasoning involves using an analytical approach to determine the likelihood of bacterial infection. In case of uncertainty, an assessment of patient safety is performed, which partly overlaps with the use of intuitive clinical reasoning. Finally, if uncertainty remains, physicians tend to consult infectious diseases experts. Factors that override this clinical reasoning process include disease severity, pressure from consultants, and the tendency to continue antibiotic treatment initiated by colleagues. CONCLUSIONS: Antibiotic-related decisions for critically ill children are complex, and pediatric intensivists use several clinical reasoning strategies to decrease the uncertainty around the bacterial etiology of infections. However, disease severity and patient safety concerns may overrule decisions based on clinical evidence and lead to antibiotic use. Several cognitive biases were identified in the clinical reasoning processes.

Frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and benzodiazepines in critically Ill neonates, children and adults: A systematic review of clinical studies.

WHAT IS KNOWN AND OBJECTIVE: Many critically ill patients are exposed to opioids and benzodiazepines at high doses for prolonged periods, and upon discontinuation of these drugs, they may be at risk for iatrogenic withdrawal. Although this syndrome was associated with worse outcomes in the critically ill, limited guidance exists regarding its evaluation, prevention and treatment. This systematic review examined the frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and/or benzodiazepines in critically ill neonates, children and adults. METHODS: The literature search was conducted in PubMed, Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane register of systematic reviews, DARE, CINAHL, Trip database, CMA infobase and NICE evidence from inception to February 2018. Grey literature was examined. We included studies reporting frequency, risk factors or symptomatology of iatrogenic withdrawal of opioids, benzodiazepines (or both) in critically ill patients. We considered all study designs except case reports and case series. We excluded studies on neonatal abstinence syndrome, alcohol withdrawal, studies on chronic opioid and/or benzodiazepine users and studies on prevention or treatment of withdrawal in critical care patients. Two independent reviewers applied the inclusion and exclusion criteria. Pairs of reviewers independently abstracted data and evaluated methodological quality using the Cochrane Collaboration Tool, Newcastle-Ottawa or QUADAS-2. Details regarding study design, outcomes, definition, evaluation and type of withdrawal (opioid, benzodiazepine or mixed) were collected. Cumulative doses and duration of opioids and benzodiazepines were collected. RESULTS AND DISCUSSION: We identified 21 866 unique citations and 153 full texts were assessed for eligibility. Thirty-four studies were included; the majority were observational and few included adults. In prospective studies, mixed withdrawal was observed in 7.5%-100% of patients in paediatric studies and ranged from 16.7% to 55% in adults. Symptomatology of withdrawal was not well described. Risk factors included higher cumulative dose and prolonged administration of opioids and benzodiazepines. WHAT IS NEW AND CONCLUSION: Iatrogenic withdrawal appears to be a frequent syndrome in critical care patients who received regular doses of opioids and/or benzodiazepines for ≥72 hours. Larger studies are required, especially in critically ill adults, to better define the syndrome and its symptomatology.

The impact of a quality improvement project to standardize pain, agitation, and withdrawal assessments on the use of morphine and midazolam in the Pediatric Intensive Care Unit.

BACKGROUND: This study aims to assess the impact of a quality improvement initiative to increase assessments of pain, agitation, and iatrogenic withdrawal syndrome, on the use of sedative and analgesic medication in a pediatric intensive care unit. METHODS: This is a retrospective pre and post, observational, quality improvement study conducted in an 18-bed medical-surgical-cardiac, tertiary intensive care unit. We included patients consecutively admitted from October 1 to March 31 (pre-period 2015-2016, post-period 2016-2017) who were mechanically ventilated beyond 48 hours. A multidisciplinary team, including a family advisor, implemented the following interventions using rapid "Plan-Do-Study-Act cycles:" (a) standardized pain and sedation assessments, (b) standardized sedation goal setting, and (c) non-pharmacological strategies to manage pain and agitation. We did not implement any specific sedation protocol. We used audit and feedback to reinforce change. RESULTS: The post-intervention phase started once sedation scores were documented q12h for >60% of patients. The groups (n = 45 per group) were similar regarding demographics, severity of illness, and mechanical ventilation duration, but different in length of intensive care stay. The cumulative dose of midazolam equivalent was significantly lower in the post-intervention period (3.71 vs 2.65 mg/kg/mechanical ventilation day, P = 0.009, 95% CI: -1.12 (-1.89, -0.31)). Morphine equivalent usage went from 3.51 to 2.57 mg/kg/mechanical ventilation day (P = 0.066, 95% CI: -0.67 [-1.44, 0.05]). There were no significant pre-post-differences in the use of other sedative agents, rates of iatrogenic withdrawal syndrome or severe pain, nor medication cost. CONCLUSION: Implementation of a multifaceted QI project was successful at increasing standardized assessments of pain and agitation, and was associated with a significant reduction in midazolam use. We also observed a decrease in morphine use without increasing rates of severe pain. Incidence of iatrogenic withdrawal syndrome and cost were unchanged.

Ability to Assent in Pediatric Critical Care Research: A Prospective Environmental Scan of Two Canadian PICUs.

OBJECTIVES: To determine the number of patients considered not appropriate to approach for assent within the first 24 hours of PICU admission. DESIGN: Exploratory prospective 1-month environmental scan. SETTING: Two tertiary Canadian PICUs. PATIENTS: Ninety patients age newborn to 17 years old admitted to the PICU during September 2016 (Site 1) or May 2017 (Site 2). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At PICU admission, 81% of patients were deemed not appropriate to approach for assent most commonly due to age, influence of psychotropic medications, and/or mechanical ventilation. At PICU discharge, 74% of patients were considered not appropriate to approach, most commonly due to age and/or developmental delay. There was moderate to good agreement between the research team and care team assessments of appropriateness for assent. Only 8% of patients considered not approachable at admission become appropriate to approach for assent by PICU discharge. CONCLUSIONS: Very few patients were considered approachable for assent during the first 24 hours of PICU admission. Those who were considered appropriate to approach were less ill, spent less time in PICU, and were unlikely to be considered for enrollment in pediatric critical care research.

Role of programmed necrosis and cell death in intestinal inflammation.

PURPOSE OF REVIEW: To critically review recent advances on the role of programmed necrosis and other cell death modalities in intestinal health and inflammatory bowel disease. RECENT FINDINGS: Tight regulation of intestinal epithelial cell proliferation and cell death is required for intestinal physiology, and to maintain an integral barrier that restricts microbiota translocation and ensures immune tolerance. Apoptosis has long been considered as a normal part of intestinal epithelial cell turnover. However, recent studies have demonstrated that excessive cell death leads to deleterious intestinal inflammation, as is observed in inflammatory bowel disease. Additionally, a novel form of cell death dubbed programmed necrosis, or necroptosis, has been recently shown to be pathological in the gut. SUMMARY: The role of cell death in the intestine is complex and its potential implication in intestinal diseases, and inflammatory bowel disease in particular, needs to be reevaluated.

Strategies for the Prevention and Treatment of Iatrogenic Withdrawal from Opioids and Benzodiazepines in Critically Ill Neonates, Children and Adults: A Systematic Review of Clinical Studies.

BACKGROUND: Critically ill patients are at high risk of iatrogenic withdrawal syndrome (IWS), due to exposure to high doses or prolonged periods of opioids and benzodiazepines. PURPOSE: To examine pharmacological management strategies designed to prevent and/or treat IWS from opioids and/or benzodiazepines in critically ill neonates, children and adults. METHODS: We included non-randomised studies of interventions (NRSI) and randomised controlled trials (RCTs), reporting on interventions to prevent or manage IWS in critically ill neonatal, paediatric and adult patients. Database searching included: PubMed, CINAHL, Embase, Cochrane databases, TRIP, CMA Infobase and NICE evidence. Additional grey literature was examined. Study selection and data extraction were performed in duplicate. Data collected included: population, definition of opioid, benzodiazepine or mixed IWS, its assessment and management (drug or strategy, route of administration, dosage and titration), previous drug exposures and outcomes measures. Methodological quality assessment was performed by two independent reviewers using the Cochrane risk of bias tool for RCTs and the ROBINS-I tool for NRSI. A qualitative synthesis of the results is provided. For the subset of studies evaluating multifaceted protocolised care, we meta-analysed results for 4 outcomes and examined the quality of evidence using GRADE post hoc. RESULTS: Thirteen studies were eligible, including 10 NRSI and 3 RCTs; 11 of these included neonatal and paediatric patients exclusively. Eight studies evaluated multifaceted protocolised interventions, while 5 evaluated individual components of IWS management (e.g. clonidine or methadone at varying dosages, routes of administration and duration of tapering). IWS was measured using an appropriate tool in 6 studies. Ten studies reported upon occurrence of IWS, showing significant reductions (n = 4) or no differences (n = 6). Interventions failed to impact duration of mechanical ventilation, ICU length of stay, and adverse effects. Impact on opioid and/or benzodiazepine total doses and duration showed no differences in 4 studies, while 3 showed opioid and benzodiazepine cumulative doses were significantly reduced by 20-35% and 32-66%, and treatment durations by 1.5-11 and 19 days, respectively. Variable effects on intervention drug exposures were found. Weaning durations were reduced by 6-12 days (n = 4) for opioids and/or methadone and by 13 days (n = 1) for benzodiazepines. In contrast, two studies using interventions centred on transition to enteral routes or longer tapering durations found significant increases in intervention drug exposures. Interventions had overall non-significant effects on additional drug requirements (except for one study). Included studies were at high risk of bias, relating to selection, detection and reporting bias. CONCLUSION: Interventions for IWS management fail to impact duration of mechanical ventilation or ICU length of stay, while effect on occurrence of IWS and drug exposures is inconsistent. Heterogeneity in the interventions used and methodological issues, including inappropriate and/or subjective identification of IWS and bias due to study design, limited the conclusions.

The Interleukin (IL)-1R1 pathway is a critical negative regulator of PyMT-mediated mammary tumorigenesis and pulmonary metastasis.

Breast cancer is the most common cancer in women and the second leading cause of female cancer-related deaths worldwide. Inflammation is an established hallmark of tumorigenesis and an important determinant of tumor outcome and response to therapy. With advances in cancer immunotherapy, there is an urgent need to dissect the contribution of specific immune effectors in cancer development. Here, we genetically investigated the role of the Interleukin-1 (IL-1) receptor 1 (IL-1R1) pathway in breast cancer tumorigenesis and metastasis using the MMTV-PyMT mouse model. Our results indicate that IL-1R1 signaling suppresses mammary tumor cell proliferation early in tumorigenesis and curbs breast cancer outgrowth and pulmonary metastasis. We show that PyMT/Il1r1-/- mice had a higher primary tumor burden and increased mortality rate compared with IL-1R1-sufficient PyMT control mice. This phenotype was independent of the inflammatory caspases-1/-11 but driven by IL-1α, as PyMT/Il1a-/- mice phenocopied PyMT/Il1r1-/- mice. Collectively, our results suggest that IL-1α-mediated IL-1R1 signaling is tumor-suppressive in PyMT-driven breast cancer.

Linking cancer-induced Nlrp3 inflammasome activation to efficient NK cell-mediated immunosurveillance.

We have recently demonstrated that the Nlrp3 inflammasome can detect the presence of colorectal cancer (CRC) metastatic growth in the liver and limit its growth. Inflammasome signaling primed natural killer (NK) cells through Interleukin (IL)-18 and activated their ability to trigger FasL-induced apoptosis of the tumor.

Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival.

Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. The corresponding contributions of IAPs to infectious disease outcomes are relatively unexplored. We find that mice deficient in cIAP2 exhibit increased susceptibility and mortality to influenza A virus infection. The lethality was not due to impaired antiviral immune functions, but rather because of death-receptor-induced programmed necrosis of airway epithelial cells that led to severe bronchiole epithelial degeneration, despite control of viral replication. Pharmacological inhibition of RIPK1 or genetic deletion of Ripk3, both kinases involved in programmed necrosis, rescued cIAP2-deficient mice from influenza-induced lethality. Genetic deletion of the death receptor agonists Fas ligand or TRAIL from the hematopoietic compartment also reversed the susceptibility of cIAP2-deficient mice. Thus, cIAP2-dependent antagonism of RIPK3-mediated programmed necrosis critically protects the host from influenza infection through maintenance of pulmonary tissue homeostasis rather than through pathogen control by the immune system.

Crosstalk between the intestinal microbiota and the innate immune system in intestinal homeostasis and inflammatory bowel disease.

: Inflammatory bowel diseases are a set of complex and chronic disorders that arise in genetically predisposed individuals due to a lack of tolerance to the gut microflora. Although the intestinal microbiota is required for the proper development of the host and the maintenance of intestinal homeostasis, its dysbiosis is associated with inflammatory bowel diseases pathogenesis. In this review, we focus the discussion on the crosstalk between the innate immune system and the microbiota. We examine new findings from genetic and functional studies investigating the critical role of the intestinal epithelial cell layer and the processes that maintain its integrity in health and disease. We further explore the mechanisms of the mucosal innate immune system including dendritic cells, macrophages, and innate-like lymphocytes in mediating immunological tolerance at the steady state or pathogenic inflammatory responses in inflammatory bowel diseases.

Function of NOD-like receptors in immunity and disease.

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are cytosolic pattern-recognition receptors that sense microbial invasion, cell stress and physiological perturbations, and elicit an inflammatory response to alert the system to the presence of danger. Most NLRs exert their functions by assembling inflammasomes that recruit and activate caspase-1, whereas a few engage the NFκB and MAPK pathways. In the past few years, significant insights have been gained into the regulatory mechanisms of these innate immunity effectors and their role in health and disease that, notably, have led to direct therapeutic applications in the clinic. This review discusses the biology of NLRs, focusing on recent advances in the field that indicate a broader role for these proteins than had been previously anticipated, such as in priming systemic innate immunity, driving adaptive immunity, maintaining tissue homeostasis and inducing tissue repair following injury.