Evasion of toll-like receptor recognition by Escherichia coli is mediated via population level regulation of flagellin production.

Uropathogenic Escherichia coli is a major cause of urinary tract infections. Analysis of the innate immune response in immortalized urothelial cells suggests that the bacterial flagellar subunit, flagellin, is key in inducing host defenses. A panel of 48 clinical uro-associated E. coli isolates recovered from either cystitis, pyelonephritis asymptomatic bacteriuria (ABU) or UTI-associated bacteraemia infections were characterized for motility and their ability to induce an innate response in urothelial cells stably transfected with a NF-κB luciferase reporter. Thirty-two isolates (67%) were identified as motile with strains recovered from cystitis patients exhibiting an uneven motility distribution pattern; seven of the cystitis isolates were associated with a > 5-fold increase in NF-κB signaling. To explore whether the NF-κB signaling response reflected antigenic variation, flagellin was purified from 14 different isolates. Purified flagellin filaments generated comparable NF-κB signaling responses, irrespective of either the source of the isolate or H-serotype. These data argued against any variability between isolates being related to flagellin itself. Investigations also argued that neither TLR4 dependent recognition of bacterial lipopolysaccharide nor growth fitness of the isolates played key roles in leading to the variable host response. To determine the roles, if any, of flagellar abundance in inducing these variable responses, flagellar hook numbers of a range of cystitis and ABU isolates were quantified. Images suggested that up to 60% of the isolate population exhibited flagella with the numbers averaging between 1 and 2 flagella per bacterial cell. These data suggest that selective pressures exist in the urinary tract that allow uro-associated E. coli strains to maintain motility, but exploit population heterogeneity, which together function to prevent host TLR5 recognition and bacterial killing.

What is empathy? Oncology patient perspectives on empathic clinician behaviors.

BACKGROUND: Oncology patients and physicians value empathy because of its association with improved health outcomes. Common measures of empathy lack consistency and were developed without direct input from patients. Because of their intense engagement with health care systems, oncology patients may have unique perspectives on what behaviors signal empathy in a clinical setting. METHODS: As part of a cross-sectional study of patient perspectives on clinician empathy at an academic cancer center in the northeastern United States, the authors solicited up to 10 free-text responses to an open-ended question about what clinician behaviors define empathy. RESULTS: The authors categorized open-ended responses from 89 oncology patients into 5 categories representing 14 themes. These categories were relationship sensitivity, focus on the whole person, communication, clinician attributes, and institutional resources and care processes. Frequently represented themes, including listening, understanding, and attention to emotions and what matters most, aligned with existing measures of empathy; behaviors that were not well represented among existing measures included qualities of information sharing and other communication elements. Patients also associated clinician demeanor, accessibility, and competence with empathy. CONCLUSIONS: Oncology patients' perspectives on empathy highlight clinician behaviors and attributes that may help to refine patient experience measures and may be adopted by clinicians and cancer centers to enhance patient care and outcomes. High-quality communication skills training can promote active listening and paying attention to the whole person. A system-level focus on delivering empathic care may improve patients' experiences and outcomes. LAY SUMMARY: Oncology patients' responses to an open-ended question about empathic clinician behavior have revealed insights into a variety of behaviors that are perceived as demonstrative of empathy. These include behaviors that imply sensitivity to the clinician-patient relationship, such as listening and understanding and attention to the whole person. Participants valued caring communication and demeanor and clinician accessibility. Perspective taking was not common among answers. Many existing measures of clinical care quality do not include the behaviors cited by patients as empathic. These results can inform efforts to refine quality measures of empathy-associated behaviors in clinical practice. Cancer centers can use skills training to improve elements of communication.

Examining the Vanishing Twin Hypothesis of Neural Tube Defects: Application of an Epigenetic Predictor for Monozygotic Twinning.

Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.

What is clinical empathy? Perspectives of community members, university students, cancer patients, and physicians.

OBJECTIVES: To explore what undergraduates, community members, oncology patients, and physicians consider empathic behavior in a physician. METHODS: 150 undergraduates, 152 community members, 95 physicians, and 89 oncology patients rated 49 hypothetical physician behaviors for how well they fit their personal definition of physician empathy. Dimensions of empathy were explored and compared across groups. RESULTS: Three dimensions of empathy were Conscientious and Reassuring, Relationship Oriented, and Emotionally Involved. Relationship Oriented was the most strongly endorsed, followed by Emotionally Involved, with Conscientious and Reassuring coming in last. There were no group differences for Conscientious and Reassuring, but the Relationship Oriented factor was more endorsed by the clinical groups (physicians and patients) than the non-clinical groups. The Emotionally Involved factor was endorsed by physicians notably more than by patients. CONCLUSION: What is considered clinical empathy is not the same across individuals and stakeholder groups. PRACTICE IMPLICATIONS: Physicians and patients differ in how much they include the physicians' emotionality and emotion-related actions in their definition of empathy. Communication training for physicians that emphasizes behaviors associated with empathy (listening, understanding a person's feelings and perspectives, and showing interest in and concern for the whole person) may enhance patients' perception of clinical empathy.

The spectrum of brain malformations and disruptions in twins.

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.

Topical Estrogen Treatment Augments the Vaginal Response to Escherichia coli Flagellin.

The female climacteric or menopausal process characterised by reduced estrogen, associates with an increased risk of recurrent urinary tract infections (rUTIs) linked to uropathogenic Escherichia coli (UPEC). Clinically, topical vaginal estrogen treatment has a prophylactic effect against such infections. The aim of this study was to investigate, in vitro, the effects of a topical estrogen treatment on vaginal epithelial responses following challenge with E.coli flagellin mimicking an UPEC challenge. Immortalised vaginal epithelial cells (VK2 E6/E7), modelling the vaginal epithelium were treated with either 4 nM 17ß-estradiol (E) for seven days, 50 ng/ml E.coli flagellin (F) for 12 h, or 4 nM 17ß-estradiol plus 50 ng/ml flagellin (E + F(12 h)). RNA was analysed by microarray gene profiling using the Illumina HumanHT-12 v 4 Expression Beadchip. Following E + F treatments expression of genes encoding host defence molecules including DEFß4A, DEFB103A, LCN2 as well as those associated with keratinisation eg CNFN and SPRR family genes were significantly enhanced (P < 0.05) compared to either E or F treatments alone. Mutation of estrogen responsive elements (EREs) identified in the DEFß4 gene promoter abolished the augmented gene expression suggesting estrogen functioned directly through a regulatory mechanism involving ESR1/2. Ingenuity pathway analyses also suggested the pro-inflammatory cytokine IL-17A to regulate the vaginal host defences during infection. Pre-treating VK2 E6/E7 cells with estrogen (4 nM) and challenging with 1L-17A & F (12 h) significantly enhanced DEFß4, DEF103A and S100A7 expression (P < 0.05). Origins of vaginal IL-17 in vivo remain unclear, but patient biopsies support γδ T cells located within the vaginal epithelium. These data suggest that the vaginal antimicrobial response induced by flagellin activation of Toll-like Receptor 5 cell signalling is augmented following topical estrogen application.

Compassionate and Clinical Behavior of Residents in a Simulated Informed Consent Encounter.

BACKGROUND: Compassionate behavior in clinicians is described as seeking to understand patients' psychosocial, physical and medical needs, timely attending to these needs, and involving patients as they desire. The goal of our study was to evaluate compassionate behavior in patient interactions, pain management, and the informed consent process of anesthesia residents in a simulated preoperative evaluation of a patient in pain scheduled for urgent surgery. METHODS: Forty-nine Clinical Anesthesia residents in year 1 and 16 Clinical Anesthesia residents in year 3 from three residency programs individually obtained informed consent for anesthesia for an urgent laparotomy from a standardized patient complaining of pain. Encounters were assessed for ordering pain medication, for patient-resident interactions by using the Empathic Communication Coding System to code responses to pain and nausea cues, and for the content of the informed consent discussion. RESULTS: Of the 65 residents, 56 (86%) ordered pain medication, at an average of 4.2 min (95% CI, 3.2 to 5.1) into the encounter; 9 (14%) did not order pain medication. Resident responses to the cues averaged between perfunctory recognition and implicit recognition (mean, 1.7 [95% CI, 1.6 to 1.9]) in the 0 (less empathic) to 6 (more empathic) system. Responses were lower for residents who did not order pain medication (mean, 1.2 [95% CI, 0.8 to 1.6]) and similar for those who ordered medication before informed consent signing (mean, 1.9 [95% CI, 1.6 to 2.1]) and after signing (mean, 1.9 [95% CI, 1.6 to 2.0]; F (2, 62) = 4.21; P = 0.019; partial η = 0.120). There were significant differences between residents who ordered pain medication before informed consent and those who did not order pain medication and between residents who ordered pain medication after informed consent signing and those who did not. CONCLUSIONS: In a simulated preoperative evaluation, anesthesia residents have variable and, at times, flawed recognition of patient cues, responsiveness to patient cues, pain management, and patient interactions.

The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature.

Arthrogryposis multiplex congenita, or AMC, is a clinical sign defined as congenital contractures of at least two joint levels. These joint contractures are always secondary to diminished fetal movement which can have numerous causes that affect any part of the anatomical structures implicated in movement: the central nervous system, the anterior horn cell, the nerve, the neuromuscular junction, the muscle, or the joint itself. Make a precise diagnosis of the cause in a patient with multiple joint contractures is therefore challenging. The aim of this article is to summarize the use and diagnostic value of common examinations and analyses performed postnatally in patients affected by AMC from a literature review. We also compare this data with results from our clinical practice. Even though it is difficult to give precise guidelines today, it appears that genetic studies, such as whole exome or genome analysis in all patients and chromosomal microarray analysis in patients with intellectual disability and AMC should be preferred as first tier investigations over EMG and muscle biopsy.

Safety of a Restrictive versus Liberal Approach to Red Blood Cell Transfusion on the Outcome of AKI in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

BACKGROUND: Safely reducing red blood cell transfusions can prevent transfusion-related adverse effects, conserve the blood supply, and reduce health care costs. Both anemia and red blood cell transfusion are independently associated with AKI, but observational data are insufficient to determine whether a restrictive approach to transfusion can be used without increasing AKI risk. METHODS: In a prespecified kidney substudy of a randomized noninferiority trial, we compared a restrictive threshold for red blood cell transfusion (transfuse if hemoglobin<7.5 g/dl, intraoperatively and postoperatively) with a liberal threshold (transfuse if hemoglobin<9.5 g/dl in the operating room or intensive care unit, or if hemoglobin<8.5 g/dl on the nonintensive care ward). We studied 4531 patients undergoing cardiac surgery with cardiopulmonary bypass who had a moderate-to-high risk of perioperative death. The substudy's primary outcome was AKI, defined as a postoperative increase in serum creatinine of ≥0.3 mg/dl within 48 hours of surgery, or ≥50% within 7 days of surgery. RESULTS: Patients in the restrictive-threshold group received significantly fewer transfusions than patients in the liberal-threshold group (1.8 versus 2.9 on average, or 38% fewer transfusions in the restricted-threshold group compared with the liberal-threshold group; P<0.001). AKI occurred in 27.7% of patients in the restrictive-threshold group (624 of 2251) and in 27.9% of patients in the liberal-threshold group (636 of 2280). Similarly, among patients with preoperative CKD, AKI occurred in 33.6% of patients in the restrictive-threshold group (258 of 767) and in 32.5% of patients in the liberal-threshold group (252 of 775). CONCLUSIONS: Among patients undergoing cardiac surgery, a restrictive transfusion approach resulted in fewer red blood cell transfusions without increasing the risk of AKI.

Gene expression of AvBD6-10 in broiler chickens is independent of AvBD6, 9, and 10 peptide potency.

The Avian ß-defensin (AvBD) gene cluster contains fourteen genes; within this, two groups (AvBD6/7 and AvBD8 -10) encode charged peptides of >+5 (AvBD6/7), indicative of potent microbial killing activities, and ≤+4 (AvBD8-10), suggestive of reduced antimicrobial activities. Chicken broiler gut tissues are constantly exposed to microbes in the form of commensal bacteria. This study examined whether tissue expression patterns of AvBD6-10 reflected microbial exposure and the encoded peptides a functional antimicrobial hierarchy. Gut AvBD6-10 gene expression was observed in hatch to day 21 birds, although the AvBD8-10 profiles were eclipsed by those detected in the liver and kidney tissues. In vitro challenges of chicken CHCC-OU2 cells using the gut commensal Lactobacillus johnsonii (104 CFU) did not significantly affect AvBD8-10 gene expression patterns, although upregulation (P < 0.05) of IL-Iß gene expression was observed. Similarly, in response to Bacteriodes doreii, IL-Iß and IL-6 gene upregulation were detected (P < 0.05), but AvBD10 gene expression remained unaffected. These data suggested that AvBD8-10 gene expression was not induced by commensal gut bacteria. Bacterial time-kill assays employing recombinant (r)AvBD6, 9 and 10 peptides (0.5µM - 12µM), indicated an antimicrobial hierarchy, linked to charge, of AvBD6 > AvBD9 > AvBD10 against Escherichia coli, but AvBD10 > AvBD9 > AvBD6 using Enterococcus faecalis. rAvBD10, selected due to its reduced cationic charge was, using CHCC-OU2 cells, investigated for cell proliferation and wound healing properties, but none were observed. These data suggest that in healthy broiler chicken tissues AvBD6/7 and AvBD8-10 gene expression profiles are independent of the in vitro antimicrobial hierarchies of the encoded AvBD6, 9 and 10 peptides.

Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery.

BACKGROUND: We reported previously that, in patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery. METHODS: We randomly assigned 5243 adults undergoing cardiac surgery to a restrictive red-cell transfusion strategy (transfusion if the hemoglobin concentration was <7.5 g per deciliter intraoperatively or postoperatively) or a liberal red-cell transfusion strategy (transfusion if the hemoglobin concentration was <9.5 g per deciliter intraoperatively or postoperatively when the patient was in the intensive care unit [ICU] or was <8.5 g per deciliter when the patient was in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery. An expanded secondary composite outcome included all the components of the primary outcome as well as emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the index surgery. The secondary outcomes included the individual components of the two composite outcomes. RESULTS: At 6 months after surgery, the primary composite outcome had occurred in 402 of 2317 patients (17.4%) in the restrictive-threshold group and in 402 of 2347 patients (17.1%) in the liberal-threshold group (absolute risk difference before rounding, 0.22 percentage points; 95% confidence interval [CI], -1.95 to 2.39; odds ratio, 1.02; 95% CI, 0.87 to 1.18; P=0.006 for noninferiority). Mortality was 6.2% in the restrictive-threshold group and 6.4% in the liberal-threshold group (odds ratio, 0.95; 95% CI, 0.75 to 1.21). There were no significant between-group differences in the secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis at 6 months after surgery. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies.

Hemostatic defects are treated using coagulation factors; however, clot formation also requires a procoagulant phospholipid (PL) surface. Here, we show that innate immune cell-derived enzymatically oxidized phospholipids (eoxPL) termed hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) restore hemostasis in human and murine conditions of pathological bleeding. HETE-PLs abolished blood loss in murine hemophilia A and enhanced coagulation in factor VIII- (FVIII-), FIX-, and FX-deficient human plasma . HETE-PLs were decreased in platelets from patients after cardiopulmonary bypass (CPB). To explore molecular mechanisms, the ability of eoxPL to stimulate individual isolated coagulation factor/cofactor complexes was tested in vitro. Extrinsic tenase (FVIIa/tissue factor [TF]), intrinsic tenase (FVIIIa/FIXa), and prothrombinase (FVa/FXa) all were enhanced by both HETE-PEs and HETE-PCs, suggesting a common mechanism involving the fatty acid moiety. In plasma, 9-, 15-, and 12-HETE-PLs were more effective than 5-, 11-, or 8-HETE-PLs, indicating positional isomer specificity. Coagulation was enhanced at lower lipid/factor ratios, consistent with a more concentrated area for protein binding. Surface plasmon resonance confirmed binding of FII and FX to HETE-PEs. HETE-PEs increased membrane curvature and thickness, but not surface charge or homogeneity, possibly suggesting increased accessibility to cations/factors. In summary, innate immune-derived eoxPL enhance calcium-dependent coagulation factor function, and their potential utility in bleeding disorders is proposed.

Risk of Acute Kidney Injury in Patients Randomized to a Restrictive Versus Liberal Approach to Red Blood Cell Transfusion in Cardiac Surgery: A Substudy Protocol of the Transfusion Requirements in Cardiac Surgery III Noninferiority Trial.

BACKGROUND: When safe to do so, avoiding blood transfusions in cardiac surgery can avoid the risk of transfusion-related infections and other complications while protecting a scarce resource and reducing costs. This protocol describes a kidney substudy of the Transfusion Requirements in Cardiac Surgery III (TRICS-III) trial, a multinational noninferiority randomized controlled trial to determine whether the risk of major clinical outcomes in patients undergoing planned cardiac surgery with cardiopulmonary bypass is no greater with a restrictive versus liberal approach to red blood cell transfusion. OBJECTIVE: The objective of this substudy is to determine whether the risk of acute kidney injury is no greater with a restrictive versus liberal approach to red blood cell transfusion, and whether this holds true in patients with and without preexisting chronic kidney disease. DESIGN AND SETTING: Multinational noninferiority randomized controlled trial conducted in 73 centers in 19 countries (2014-2017). PATIENTS: Patients (~4800) undergoing planned cardiac surgery with cardiopulmonary bypass. MEASUREMENTS: The primary outcome of this substudy is perioperative acute kidney injury, defined as an acute rise in serum creatinine from the preoperative value (obtained in the 30-day period before surgery), where an acute rise is defined as ≥26.5 µmol/L in the first 48 hours after surgery or ≥50% in the first 7 days after surgery. METHODS: We will report the absolute risk difference in acute kidney injury and the 95% confidence interval. We will repeat the primary analysis using alternative definitions of acute kidney injury, including staging definitions, and will examine effect modification by preexisting chronic kidney disease (defined as a preoperative estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). LIMITATIONS: It is not possible to blind patients or providers to the intervention; however, objective measures will be used to assess outcomes, and outcome assessors will be blinded to the intervention assignment. RESULTS: Substudy results will be reported by the year 2018. CONCLUSIONS: This substudy will provide generalizable estimates of the risk of acute kidney injury of a restrictive versus liberal approach to red blood cell transfusion in the presence of anemia during cardiac surgery done with cardiopulmonary bypass. TRIAL REGISTRATION: www.clinicaltrials.gov; clinical trial registration number NCT 02042898.

CONTEXTE: En chirurgie cardiaque, éviter les transfusions sanguines, lorsque sécuritaire, contribue à réduire les risques d'infections transfusionnelles et de complications tout en préservant une ressource rare et en réduisant le coût des soins. Ce protocole décrit une étude secondaire qui examine le volet des risques d'insuffisance rénale aiguë (IRA) de l'étude TRICS-III (Transfusion Requirements in Cardiac Surgery III), un essai de non-infériorité multinational, contrôlé et à répartition aléatoire faisant état des exigences applicables à la transfusion sanguine en chirurgie cardiaque. Notre protocole vise plus particulièrement à déterminer si le risque d'atteintes rénales encouru par les patients subissant une chirurgie de pontages coronarien est plus ou moins grand selon que l'on préconise une approche restrictive ou libérale en matière de transfusion sanguine. OBJECTIF: L'objectif de notre étude est de déterminer si le risque d'IRA est plus ou moins grand selon que l'on préconise une approche restrictive ou libérale à l'égard de la transfusion sanguine; et, si c'est le cas, d'établir si ce risque différentiel perdure selon que le patient était ou non atteint d'insuffisance rénale chronique avant l'intervention. CADRE ET TYPE D'ÉTUDE: L'étude consiste en un essai multinational de non-infériorité, contrôlé et à répartition aléatoire, mené entre 2014 et 2017 au sein de 73 centres répartis dans 19 pays. PATIENTS: L'étude compte environ 4 800 patients ayant subi un pontage coronarien. MESURES: Le principal facteur observé est le développement d'une IRA périopératoire, telle que définie par une hausse marquée du taux de créatinine sérique par rapport à la valeur préopératoire (prélevée dans les 30 jours précédant l'intervention). Nous avons défini une « hausse marquée ¼ par un taux de créatinine atteignant au moins 26,5µmol/L dans les 48 heures postopératoires ou son augmentation d'au moins 50 % à l'intérieur des sept premiers jours. MÉTHODOLOGIE: Nous présenterons le risque différentiel absolu d'IRA dans un intervalle de confiance à 95 %. Nous répéterons l'analyse primaire en alternant les définitions de l'IRA (notamment en fonction des différents stades) et examinerons les éventuelles modifications de l'incidence chez des patients atteints d'une insuffisance rénale préexistante (définie par un DFGe préopératoire à moins de 60 ml/min/1,73 m2). LIMITES DE L'ÉTUDE: Il n'est évidemment pas possible de procéder à l'insu des patients ni des fournisseurs de soins lors de l'intervention. Toutefois, des mesures objectives seront utilisées pour évaluer les résultats, et les évaluateurs ne seront aucunement au courant de la répartition des cas. RÉSULTATS: Les résultats de cette étude secondaire seront présentés d'ici 2018. CONCLUSION: Cette étude secondaire fournira des estimations généralisables du risque de développer une IRA lors d'un pontage coronarien selon que, pour traiter l'anémie, l'approche à l'égard de la transfusion sanguine soit restrictive ou libérale.

Transfusion Requirements in Cardiac Surgery III (TRICS III): Study Design of a Randomized Controlled Trial.

OBJECTIVES: To determine if a restrictive transfusion threshold is noninferior to a higher threshold as measured by a composite outcome of mortality and serious morbidity. DESIGN: Transfusion Requirements in Cardiac Surgery (TRICS) III was a multicenter, international, open-label randomized controlled trial of two commonly used transfusion strategies in patients having cardiac surgery using a noninferiority trial design (ClinicalTrials.gov number, NCT02042898). SETTING: Eligible patients were randomized prior to surgery in a 1:1 ratio. PARTICIPANTS: Potential participants were 18 years or older undergoing planned cardiac surgery using cardiopulmonary bypass (CPB) with a preoperative European System for Cardiac Operative Risk Evaluation (EuroSCORE I) of 6 or more. INTERVENTIONS: Five thousand patients; those allocated to a restrictive transfusion group received a red blood cell (RBC) transfusion if the hemoglobin concentration (Hb) was less than 7.5 g/dL intraoperatively and/or postoperatively. Patients allocated to a liberal transfusion strategy received RBC transfusion if the Hb was less than 9.5 g/dL intraoperatively or postoperatively in the intensive care unit or less than 8.5 g/dL on the ward. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite of all-cause mortality, myocardial infarction, stroke, or new onset renal dysfunction requiring dialysis at hospital discharge or day 28, whichever comes first. The primary outcome was analyzed as a per-protocol analysis. The trial monitored adherence closely as adherence to the transfusion triggers is important in ensuring that measured outcomes reflect the transfusion strategy. CONCLUSION: By randomizing prior to surgery, the TRICS III trial captured the most acute reduction in hemoglobin during cardiopulmonary bypass.

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery.

BACKGROUND: The effect of a restrictive versus liberal red-cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS: In this multicenter, open-label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red-cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red-cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red-cell transfusion and other clinical outcomes. RESULTS: The primary outcome occurred in 11.4% of the patients in the restrictive-threshold group, as compared with 12.5% of those in the liberal-threshold group (absolute risk difference, -1.11 percentage points; 95% confidence interval [CI], -2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal-threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red-cell transfusion occurred in 52.3% of the patients in the restrictive-threshold group, as compared with 72.6% of those in the liberal-threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between-group differences with regard to the other secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy regarding red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection.

The identification of the host defence peptides as target effectors in the innate defence of the uro-genital tract creates new translational possibilities for immunomodulatory therapies, specifically vaginal therapies to treat women suffering from rUTI, particularly those carrying the TLR5_C1174T SNP. Urinary tract infections (UTIs) are a microbial disease reported worldwide. Women are particularly susceptible with many suffering debilitating recurrent (r) infections. Treatment is by antibiotics, but such therapy is linked to antibiotic resistance and re-infection. This study explored the innate protective mechanisms of the urogenital tract with the aim of boosting such defences therapeutically. Modelling UTIs in vitro, human vaginal and bladder epithelial cells were challenged with uropathogenic Escherichia coli (CFT073) and microbial PAMPs including flagellin, LPS and peptidoglycan. Flagellin functioning via the TLR5/NFκB pathway was identified as the key UPEC virulence factor causing a significant increase (P < 0.05) in the production of the host-defence peptide (HDP), BD2. BD2-depleted urine samples from bladder infected mice supported increased UPEC growth, strengthening the significance of the HDPs in protecting the urogenital tissues from infection. Clinically, vaginal-douche BD2 concentrations were reduced (p < 0.05) in women suffering rUTIs, compared to age-matched healthy controls with concentrations further decreased (p < 0.05) in a TLR5392Stop SNP rUTI subgroup. Topical vaginal estrogen treatment increased (p < 0.001) BD2 concentrations in all women, including those carrying the SNP. These data identify therapeutic and antibiotic sparing roles for vaginal immunomodulatory agents that specifically target HDP induction, facilitate bacterial killing and disrupt the UPEC infection cycle.

Axillary versus innominate artery cannulation for antegrade cerebral perfusion in aortic surgery: design of the Aortic Surgery Cerebral Protection Evaluation (ACE) CardioLink-3 randomised trial.

INTRODUCTION: Neurological injury remains the major cause of morbidity and mortality following open aortic arch repair. Systemic hypothermia along with antegrade cerebral perfusion (ACP) is the accepted cerebral protection approach, with axillary artery cannulation being the most common technique used to establish ACP. More recently, innominate artery cannulation has been shown to be a safe and efficacious method for establishing ACP. Inasmuch as there is a lack of high-quality data comparing axillary and innominate artery ACP, we have designed a randomised, multi-centre clinical trial to compare both cerebral perfusion strategies with regards to brain morphological injury using diffusion-weighted MRI (DW-MRI). METHODS AND ANALYSIS: 110 patients undergoing elective aortic surgery with repair of the proximal arch requiring an open distal anastamosis will be randomised to either the innominate artery or the axillary artery cannulation strategy for establishing unilateral ACP during systemic circulatory arrest with moderate levels of hypothermia. The primary safety endpoint of this trial is the proportion of patients with new radiologically significant ischaemic lesions found on postoperative DW-MRI compared with preoperative DW-MRI. The primary efficacy endpoint of this trial is the difference in total operative time between the innominate artery and the axillary artery cannulation group. ETHICS AND DISSEMINATION: The study protocol and consent forms have been approved by the participating local research ethics boards. Publication of the study results is anticipated in 2018 or 2019. If this study shows that the innominate artery cannulation technique is non-inferior to the axillary artery cannulation technique with regards to brain morphological injury, it will establish the innominate artery cannulation technique as a safe and potentially more efficient method of antegrade cerebral perfusion in aortic surgery. TRIAL REGISTRATION NUMBER: NCT02554032.

Randomised trial of mitral valve repair with leaflet resection versus leaflet preservation on functional mitral stenosis (The CAMRA CardioLink-2 Trial).

BACKGROUND: The gold-standard treatment of severe mitral regurgitation (MR) due to degenerative disease is valve repair, which is surgically performed with either a leaflet resection or leaflet preservation approach. Recent data suggest that functional mitral stenosis (MS) may occur following valve repair using a leaflet resection strategy, which adversely affects patient prognosis. A randomised comparison of these two approaches to mitral repair on functional MS has not been conducted. METHODS AND ANALYSIS: This is a prospective, multicentre randomised controlled trial designed to test the hypothesis that leaflet preservation leads to better preservation of mitral valve geometry, and therefore, will be superior to leaflet resection for the primary outcome of functional MS as assessed by 12-month mean mitral valve gradient at peak exercise. Eighty-eight patients with posterior leaflet prolapse will be randomised intraoperatively once deemed by the operating surgeon to feasibly undergo mitral repair using either a leaflet resection or leaflet preservation approach. Secondary end points include comparison of repair strategies with regard to mitral valve orifice area, leaflet coaptation height, 6 min walk test and a composite major adverse event end point consisting of recurrent MR ≥2+, death or hospital readmission for congestive heart failure within 12 months of surgery. ETHICS AND DISSEMINATION: Institutional ethics approval has been obtained from all enrolling sites. Overall, there remains clinical equipoise regarding the mitral valve repair strategy that is associated with the least likelihood of functional MS. This trial hopes to introduce high-quality evidence to help surgical decision making in this context. TRIAL REGISTRATION NUMBER: NCT02552771.

Sepsis Prevalence and Outcome on the General Wards and Emergency Departments in Wales: Results of a Multi-Centre, Observational, Point Prevalence Study.

Data on sepsis prevalence on the general wards is lacking on the UK and in the developed world. We conducted a multicentre, prospective, observational study of the prevalence of patients with sepsis or severe sepsis on the general wards and Emergency Departments (ED) in Wales. During the 24-hour study period all patients with NEWS≥3 were screened for presence of 2 or more SIRS criteria. To be eligible for inclusion, patients had to have a high clinical suspicion of an infection, together with a systemic inflammatory response (sepsis) and evidence of acute organ dysfunction and/or shock (severe sepsis). There were 5317 in-patients in the 24-hour study period. Data were returned on 1198 digital data collection forms on patients with NEWS≥3 of which 87 were removed, leaving 1111 for analysis. 146 patients had sepsis and 144 patients had severe sepsis. Combined prevalence of sepsis and severe sepsis was 5.5% amongst all in-patients. Patients with sepsis had significantly higher NEWS scores (3 IQR 3-4 for non-sepsis and 4 IQR 3-6 for sepsis patients, respectively). Common organ dysfunctions in severe sepsis were hypoxia (47%), hypoperfusion (40%) and acute kidney injury (25%). Mortality at 90 days was 31% with a median (IQR) hospital free stay of 78 (36-85) days. Screening for sepsis, referral to Critical Care and completion of Sepsis 6 bundle was low: 26%, 16% and 12% in the sepsis group. Multivariable logistic regression analysis identified higher National Early Warning Score, diabetes, COPD, heart failure, malignancy and current or previous smoking habits as independent variables suggesting the diagnosis of sepsis. We observed that sepsis is more prevalent in the general ward and ED than previously suggested before and that screening and effective treatment for sepsis and severe sepsis is far from being operationalized in this environment, leading to high 90 days mortality.