Opioid-free versus opioid-sparing anaesthesia in ambulatory total hip arthroplasty: a randomised controlled trial.

BACKGROUND: Enhanced recovery after surgery pathways are essential for ambulatory surgery. They usually recommend lower intraoperative opioid use to avoid opioid-related adverse effects. This has led to opioid-sparing anaesthesia (OSA) techniques, with the extreme approach of opioid-free anaesthesia (OFA) mostly with dexmedetomidine. As evidence is lacking in day-case primary total hip arthroplasty, this study was performed to assess the potential benefits in postoperative analgesia of OFA over OSA. METHODS: In this single-centre, prospective, triple blind study, we randomly allocated 80 patients undergoing day-case primary THA under general anaesthesia. Patients received a total intravenous anaesthesia with a laryngeal mask and multimodal analgesic regimen with non-opioid analgesics. The OSA group received low dose of sufentanil, and the OFA group received dexmedetomidine The primary outcome was the opioid consumption in the first 24 h in oral morphine equivalents (OME). RESULTS: There was no difference in median cumulative OME consumption at 24 h between the OSA and OFA groups (12 [0-25] mg vs 16 [0-30] mg, respectively; P=0.7). Pain scores were similar and low in both groups with comparable walking recovery time. Adverse events were sparse and equivalent in both groups except for dizziness, which was more frequent in the OSA group (P<0.05). CONCLUSIONS: In day-case total hip arthoplasty under general anaesthesia, opioid-free anaesthesia and opioid-sparing anaesthesia both provide early recovery and effective postoperative pain relief. When compared with opioid-sparing anaesthesia, opioid-free anaesthesia does not decrease opioid consumption in the first 24 h. These findings do not suggest any significant benefit from complete intraoperative avoidance of opioids. CLINICAL TRIAL REGISTRATION: NCT0507270.

Persistent diaphragm dysfunction after cardiac surgery is associated with adverse respiratory outcomes: a prospective observational ultrasound study.

BACKGROUND: Transient diaphragm dysfunction is common during the first week after cardiac surgery; however, the precise incidence, risk factors, and outcomes of persistent diaphragm dysfunction are not well described. METHODS: In a single-centre prospective cohort study, we included all consecutive patients over 18 yr who underwent elective cardiac surgery. Diaphragm function was evaluated with ultrasound (M-mode) by recording the excursion of both hemidiaphragms at two different time points: preoperatively and after the seventh postoperative day in patients breathing without assistance. Significant diaphragm dysfunction after the seventh day of the index cardiac surgery was defined as a decrease in diaphragm excursion below the lower limit of normal: at rest, < 9 mm for women and < 10 mm for men; after a sniff test, < 16 mm for women and < 18 mm for men. RESULTS: Overall, 122 patients were included in the analysis. The median [interquartile range (IQR)] age was 69 [59-74] years and 96/122 (79%) were men. Ten (8%) patients had diaphragm dysfunction after the seventh postoperative day. We did not identify risk factors for persistent diaphragm dysfunction. Persistent diaphragm dysfunction was associated with a longer median [IQR] duration of noninvasive (8 [0-34] vs 0 [0-0] hr; difference in medians, 8 hr; 95% confidence interval [CI], 0 to 22; P < 0.001) and invasive mechanical ventilation (5 [3-257] vs 3[2-4] hr; difference in medians, 2 hr; 95% CI, 0.5 to 41; P = 0.008); a higher reintubation rate (4/10, 40% vs 1/112, 0.9%; relative risk, 45; 95% CI, 7.1 to 278; P < 0.0001), a higher incidence of pneumonia (4/10 [40%] vs 7/112 [6%]; relative risk, 6; 95% CI, 2 to 16; P < 0.001), and longer median [IQR] length of stay in the intensive care unit (8 [5-29] vs 4 [2-6] days; difference in medians, 4 days; 95% CI, 2 to 12; P = 0.002). CONCLUSION: The incidence of persistent diaphragm dysfunction was 8% in patients undergoing elective cardiac surgery and was associated with adverse respiratory outcomes. STUDY REGISTRATION: ClinicalTrials.gov (NCT04276844); prospectively registered 19 February 2020.

RéSUMé: CONTEXTE: Un dysfonctionnement transitoire du diaphragme est fréquent au cours de la première semaine après une chirurgie cardiaque. Toutefois, l'incidence précise, les facteurs de risque et les devenirs liés à un dysfonctionnement persistant du diaphragme ne sont pas bien décrits. MéTHODE: Dans une étude de cohorte prospective monocentrique, nous avons inclus tous les patients consécutifs de plus de 18 ans qui ont bénéficié d'une chirurgie cardiaque non urgente. La fonction du diaphragme a été évaluée à l'échographie (mode M) en enregistrant l'excursion des deux hémidiaphragmes à deux moments différents : avant l'opération et après le septième jour postopératoire chez les patients respirant sans assistance. Un dysfonctionnement significatif du diaphragme après le septième jour de la chirurgie cardiaque initiale a été défini comme une diminution de l'excursion diaphragmatique en dessous de la limite inférieure de la normale, soit : au repos, < 9 mm pour les femmes et < 10 mm pour les hommes; après un test de reniflement, < 16 mm pour les femmes et < 18 mm pour les hommes. RéSULTATS: Au total, 122 patients ont été inclus dans l'analyse. L'âge médian des patients (écart interquartile [ÉIQ]) était de 69 ans [59-74] ans et 96/122 (79 %) étaient des hommes. Dix (8 %) patients ont présenté un dysfonctionnement du diaphragme après le septième jour postopératoire. Nous n'avons pas identifié de facteurs de risque de dysfonctionnement persistant du diaphragme. Un dysfonctionnement persistant du diaphragme était associé à : une durée médiane [ÉIQ] de ventilation non invasive (8 [0­34] vs 0 [0­0] h; différence dans les médianes, 8 heures; intervalle de confiance [IC] à 95 %, 0 à 22; P < 0,001) et de ventilation mécanique invasive (5 [3­257] vs 3[2­4] h; différence dans les médianes, 2 heures; IC 95 %, 0,5 à 41; P = 0,008) plus longues, un taux de réintubation plus élevé (4/10, 40 % vs 1/112, 0,9 %; risque relatif, 45; IC 95 %, 7,1 à 278; P < 0,0001), une incidence plus élevée de pneumonie (4/10 [40 %] vs 7/112 [6 %]; risque relatif, 6; IC 95 %, de 2 à 16; P < 0,001), et une durée de séjour médiane [ÉIQ] plus longue à l'unité de soins intensifs (8 [5-29] vs 4 [2­6] jours; différence en médianes, 4 jours; IC 95 %, 2 à 12; P = 0,002). CONCLUSION: L'incidence de dysfonctionnement persistant du diaphragme était de 8 % chez les patients bénéficiant d'une chirurgie cardiaque non urgente et était associée à des issues respiratoires indésirables. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT04276844); enregistrée prospectivement le 19 février 2020.

Combined proximal or distal nerve blocks for postoperative analgesia after total knee arthroplasty: a randomised controlled trial.

BACKGROUND: Many regional anaesthetic techniques have been proposed to manage pain after total knee arthroplasty, but the best approach is unclear. We compared opioid consumption in the first 48 h between two different regional anaesthesia strategies in patients undergoing total knee arthroplasty. METHODS: In this single-centre, prospective study, we randomly allocated 90 patients to a combination of IPACK (interspace between popliteal artery and capsule of the posterior knee), triangle femoral and obturator nerve blocks (distal group), or a combination of sciatic, femoral, obturator, and lateral femoral cutaneous nerve blocks (proximal group). All patients received an opioid-sparing general anaesthesia regimen. The primary outcome was opioid consumption in the first 48 h. Secondary outcomes included opioid consumption in the first 24 h and verbal rating pain scores in the first 48 h. RESULTS: There was no difference in median cumulative oral morphine equivalent consumption at 48 h between the distal and the proximal block groups (33 [18-78] mg vs 30 [22-51] mg, respectively; P=0.29). Median oral morphine equivalent consumption at 24 h was higher in the distal group compared with the proximal group (30 [13-59] vs 15 [0-18], respectively; P<0.001). Verbal rating pain scores were lower in the proximal group compared with the distal group on arrival to the postanaesthesia care unit and at 6 and 12 h. CONCLUSIONS: In patients undergoing total knee arthroplasty under total intravenous general anaesthesia with a multimodal analgesia regimen, proximal nerve blocks resulted in improved pain scores in the first 12 h and reduced opioid consumption in the first 24 h when compared with distal nerve blocks. No difference in pain scores or opioid consumption was seen at 48 h. CLINICAL TRIAL REGISTRATION: NCT04499716.

Protective reactive thymus hyperplasia in COVID-19 acute respiratory distress syndrome.

BACKGROUND: Patients with COVID-19 (COVID) may develop acute respiratory distress syndrome with or without sepsis, coagulopathy and visceral damage. While chest CT scans are routinely performed in the initial assessment of patients with severe pulmonary forms, thymus involvement and reactivation have not been investigated so far. METHODS: In this observational study, we systematically scored the enlargement of the thymus and the lung involvement, using CT scans, in all adult patients admitted to the ICU for COVID or any other cause (control group) at one centre between March and April 2020. Initial biological investigations included nasal detection of SARS-CoV-2 ribonucleic acid by polymerase chain reaction (PCR). In a subgroup of 24 patients with different degrees of pulmonary involvement and thymus hypertrophy, plasma cytokine concentrations were measured and the export of mature T cells from the thymus was estimated simultaneously by PCR quantification of T cell receptor excision circles (TRECs). RESULTS: Eighty-seven patients were studied: 50 COVID patients and 37 controls. Non-atrophic or enlarged thymus was more commonly observed in COVID patients than in controls (66% vs. 24%, p < 0.0001). Thymus enlargement in COVID patients was associated with more extensive lung injury score on CT scans (4 [3-5] vs. 2 [1.5-4], p = 0.01), but a lower mortality rate (8.6% vs. 41.2%, p < 0.001). Other factors associated with mortality were age, lymphopaenia, high CRP and co-morbidities. COVID patients had higher concentrations of IL-7 (6.00 [3.72-9.25] vs. 2.17 [1.76-4.4] pg/mL; p = 0.04) and higher thymic production of new lymphocytes (sj/ßTREC ratio = 2.88 [1.98-4.51] vs. 0.23 [0.15-0.60]; p = 0.004). Thymic production was also correlated with the CT scan thymic score (r = 0.38, p = 0.03) and inversely correlated with the number of lymphocytes (r = 0.56, p = 0.007). CONCLUSION: In COVID patients, thymus enlargement was frequent and associated with increased T lymphocyte production, which appears to be a beneficial adaptation to virus-induced lymphopaenia. The lack of thymic activity/reactivation in older SARS-CoV-2 infected patients could contribute to a worse prognosis.

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells.

RNA-binding proteins (RBPs) have emerged as important regulators of invertebrate adult stem cells, but their activities remain poorly appreciated in mammals. Using a short hairpin RNA strategy, we demonstrate here that the 2 mammalian RBPs, PUMILIO (PUM)1 and PUM2, members of the PUF family of posttranscriptional regulators, are essential for hematopoietic stem/progenitor cell (HSPC) proliferation and survival in vitro and in vivo upon reconstitution assays. Moreover, we found that PUM1/2 sustain myeloid leukemic cell growth. Through a proteomic approach, we identified the FOXP1 transcription factor as a new target of PUM1/2. Contrary to its canonical repressive activity, PUM1/2 rather promote FOXP1 expression by a direct binding to 2 canonical PUM responsive elements present in the FOXP1-3' untranslated region (UTR). Expression of FOXP1 strongly correlates with PUM1 and PUM2 levels in primary HSPCs and myeloid leukemia cells. We demonstrate that FOXP1 by itself supports HSPC and leukemic cell growth, thus mimicking PUM activities. Mechanistically, FOXP1 represses the expression of the p21-CIP1 and p27-KIP1 cell cycle inhibitors. Enforced FOXP1 expression reverses shPUM antiproliferative and proapoptotic activities. Altogether, our results reveal a novel regulatory pathway, underscoring a previously unknown and interconnected key role of PUM1/2 and FOXP1 in regulating normal HSPC and leukemic cell growth.

Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL.

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones.

Wide Awake Local Anesthesia No Tourniquet (WALANT) technique improves the efficiency of distal nerve blocks for carpal tunnel release.

BACKGROUND: Axillary block is the standard for carpal tunnel release (CTR), providing effective anesthesia, and tolerance of tourniquet. Conversely, distal blocks are less used due to poor tolerance of tourniquet. Wide Awake Local Anesthesia No Tourniquet (WALANT), proposed for hand and wrist surgeries, avoids its use. This study assesses the benefits of the addition of WALANT to distal blocks during endoscopic CTR (eCTR). METHODS: This randomized, open-label, controlled trial prospectively enrolled 60 patients scheduled for eCTR. Patients were randomized to receive distal blocks at the wrist combined to either a high arm tourniquet (Distal block group) or a WALANT in the area of surgery (Distal + Walant group). The primary endpoint was the global pain score summing pain scores related to puncture, local anesthetic injection, pneumatic tourniquet, surgical procedure, tourniquet deflation, and residual sensitivity after surgery. RESULTS: Mean global pain score was significantly reduced in the Distal + Walant group (0.5 ± 1.4 vs. 2.2 ± 2.4; p < 0.001). No need for an additional anesthetic procedure was required in the Distal + Walant group. Even if the quality of visualization was high in both groups, it was better in the Distal block group (5 [5-5] vs. 4 [4-5]; p < 0.001). No rescue tourniquet was necessary for the Distal + Walant group. The rate of hematoma 15 days post-surgery was significantly reduced in the Distal + Walant group (20% vs. 57%; p < 0.01). CONCLUSIONS: The addition of WALANT to distal blocks is adapted for eCTR. This combined technique decreases perioperative pain scores, provides good surgery conditions, and reduces the risk of postoperative hematoma. CLINICAL TRIAL NUMBER AND REGISTRY URL: The trial was registered on ClinicalTrials.gov (NCT04494100) on July 31, 2020 https://clinicaltrials.gov/ct2/show/NCT04494100?term=CMC+ambroise+pare&cntry=FR&draw=4&rank=28.

Genetically determined thymic function affects strength and duration of immune response in COVID patients with pneumonia.

Thymic activation improves the outcome of COVID-19 patients with severe pneumonia. The rs2204985 genetic polymorphism within the TCRA-TCRD locus, which affects thymic output in healthy individuals, was found here to modify SARS-CoV-2-specific immunity and disease severity in COVID-19 patients with severe pneumonia. Forty patients with severe COVID-19 pneumonia were investigated. The GG genotype at the rs2204985 locus was associated, independently of age and sex, with stronger and long-lasting anti-SARS-CoV-2 helper and cytotoxic T cell responses 6 months after recovery. The GG genotype was also associated with less severe lung involvement, higher thymic production, and higher counts of blood naïve T lymphocytes, including recent thymic emigrants, and a larger population of activated stem cell memory CD4+ T cells. Overall, GG patients developed a more robust and sustained immunity to SARS-CoV-2. Polymorphism at rs2204985 locus should be considered as an additional predictive marker of anti-SARS-CoV-2 immune response.

[Assessment of Teleconsultation for planned orthopaedic surgery]. / Faisabilité d'une téléconsultation d'anesthésie en chirurgie orthopédique programmée.

The COVID-19 pandemic has motivated the development of teleconsultation in anaesthesia. We have conducted a single centre prospective study in patients scheduled for planned orthopaedic surgery during 9 weeks between may and july 2020 to assess its practicability. The quality of the consultation and patients' satisfaction, were evaluated during this period. The teleconsultation was successful in 90% of the patients without the need of attendance to the hospital for assessment before anaesthesia. The process was satisfactory for 97% of these patients. The mean duration was 15 minutes. The support of a third party was required in 46% of patients older than 65 years. The main cause of failure was the poor quality of the connection. Only two patients were cancelled for surgery because they did not understand fasting rule. The teleconsultation is now an integral part of preoperative assessment of patients for anaesthesia with good practicability and reliability.

Virtual reality vs. Kalinox® for management of pain in intensive care unit after cardiac surgery: a randomized study.

INTRODUCTION: The management of pain and anxiety remains a challenge in the intensive care unit. By distracting patients, virtual reality (VR) may have a role in painful procedures. We compared VR vs. an inhaled equimolar mixture of N2O and O2 (Kalinox®) for pain and anxiety management during the removal of chest drains after cardiac surgery. METHODS: Prospective, non-inferiority, open-label study. Patients were randomized, for Kalinox® or VR session during drain removal. The analgesia/nociception index (ANI) was monitored during the procedure for objective assessment of pain and anxiety. The primary endpoint was the ΔANI (ANImin - ANI0) during the procedure, based on ANIm (average on 4 min). We prespecified VR as non-inferior to Kalinox® with a margin of 3 points. Self-reported pain and anxiety were also analysed using numeric rate scale (NRS). RESULTS: 200 patients were included, 99 in the VR group and 101 in the Kalinox® group; 90 patients were analysed in both groups in per-protocol analysis. The median age was 68.0 years [60.0-74.8]. The ΔANI was - 15.1 ± 12.9 in the Kalinox® group and - 15.7 ± 11.6 in the VR group (NS). The mean difference was, therefore, - 0.6 [- 3.6 to 2.4], including the non-inferiority margin of 3. Patients in the VR group had a significantly higher pain NRS scale immediately after the drain removal, 5.0 [3.0-7.0] vs. 3.0 [2.0-6.0], p = 0.009, but no difference 10 min after. NRS of anxiety did not differ between the two groups. CONCLUSION: Based on the ANI, the current study showed that VR did not reach the statistical requirements for a proven non-inferiority vs. Kalinox® in managing pain and anxiety during chest drain removal. Moreover, VR was less effective based on NRS. More studies are needed to determine if VR might have a place in the overall approach to pain and anxiety in intensive care units. Trial registration NCT, NCT03956264. Registered 20 May 2019, https://clinicaltrials.gov/ct2/show/NCT03956264.

Total knee arthroplasty under quadruple nerve block with ropivacaine 0.32%: effect of addition of intravenous dexmedetomidine to intravenous dexamethasone on analgesic duration.

BACKGROUND AND OBJECTIVES: Peripheral nerve blocks reduce postoperative pain and enhance recovery after total knee arthroplasty (TKA). This study aims to assess the benefits of addition of intravenous dexmedetomidine (DexM) to intravenous dexamethasone on the analgesic duration of quadruple nerve blocks. METHODS: This double-blind, randomized, controlled trial prospectively enrolled 90 patients scheduled for TKA under quadruple nerve blocks (sciatic, femoral, obturator, and lateral femoral cutaneous nerves blocks) with 70 mL, 0.32% ropivacaine. All patients received systemic dexamethasone 10 mg. Patients were randomized to receive DexM (2 µg/kg, intravenous) or placebo (1:1 ratio). The primary endpoint was the duration of analgesia defined as the time to first request for rescue analgesia (oxycodone). RESULTS: Kaplan-Meier curves for the first analgesic request were similar between groups (log-rank test; p=0.27). Median (IQR) duration of analgesia was similar between placebo (1575 min (1211-1952)) and DexM (1470 min (1263-1700)) groups (p=0.56). Cumulative consumption of oxycodone at the 48th hour was 20 mg (10-30) and 30 mg (20-40) in placebo and DexM groups, respectively (p=0.14). The day after surgery, 93% and 89% of patients were able to walk in placebo and DexM groups, respectively (p=0.46). Intravenous DexM was associated with bradycardia, hypotension and longer recovery room stay (p<0.05 for all comparisons). CONCLUSIONS: In a multimodal analgesic regimen, addition of systemic DexM (2 µg/kg) to systemic dexamethasone does not prolong the analgesic duration of quadruple nerve block with ropivacaine 0.32% after TKA. TRIAL REGISTRATION NUMBER: NCT03834129.

Low Tidal Volume Mechanical Ventilation Against No Ventilation During Cardiopulmonary Bypass in Heart Surgery (MECANO): A Randomized Controlled Trial.

BACKGROUND: Postoperative pulmonary complications are common after cardiac surgery and have been related to lung collapse during cardiopulmonary bypass (CPB). No consensus exists regarding the effects of maintaining mechanical ventilation during CPB to decrease these complications. RESEARCH QUESTION: To determine whether maintaining low-tidal ventilation (3 mL/kg 5 times/min, with positive end expiratory pressure of 5 cm H2O) during CPB (ventilation strategy) was superior to a resting-lung strategy with no ventilation (no ventilation strategy) regarding postoperative pulmonary complications, including mortality. STUDY DESIGN AND METHODS: In a randomized controlled trial, patients undergoing cardiac surgery at a single center from May 2017 through August 2019 were randomized to the ventilation or no ventilation strategy during CPB (1:1 ratio). Apart from the CPB phase, perioperative ventilation procedures were standardized. RESULTS: The study included 1,501 patients (mean age, 68.8 ± 10.3 years; 1,152 (76.7%) men; mean EuroSCORE II, 2.3 ± 2.7). Seven hundred fifty-six patients were in the ventilation strategy group, and no differences existed in baseline characteristics and types of procedures between the two groups. An intention-to-treat analysis yielded no significant difference between the ventilation and no ventilation groups regarding incidence of the primary composite outcome combining death, early respiratory failure, ventilation support beyond day 2, and reintubation, with 112 of 756 patients (14.8%) in the ventilation group vs 133 of 745 patients (17.9%) in the no ventilation group (OR, 0.80; 95% CI, 0.61-1.05; P = .11). Strict per-protocol analyses of 1,338 patients (89.1%) with equally distributed preoperative characteristics yielded similar results (OR, 0.81; 95% CI, 0.60-1.09; P = .16). Post hoc analysis of the subgroup who underwent isolated coronary artery bypass graft procedures (n = 725) showed that the ventilation strategy was superior to the no ventilation strategy regarding the primary outcome (OR, 0.56; 95% CI, 0.37-0.84; P = .005). INTERPRETATION: Among patients undergoing cardiac surgery with CPB, continuation of low tidal volume ventilation was not superior to no ventilation during CPB with respect to postoperative complications, including death, early respiratory failure, ventilation support beyond day 2, and reintubation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03098524; URL: www.clinicaltrials.gov.

Efficacy of parasternal block to decrease intraoperative opioid use in coronary artery bypass surgery via sternotomy: a randomized controlled trial.

OBJECTIVE: This study aims to assess the effect of a preoperative parasternal plane block (PSB) on opioid consumption required to maintain hemodynamic stability during sternotomy for coronary artery bypass graft surgery. METHODS: This double-blind, randomized, placebo-controlled trial prospectively enrolled 35 patients scheduled for coronary artery bypass graft surgery under general anesthesia with propofol and remifentanil. Patients were randomized to receive preoperative PSB using either ropivacaine (PSB group) or saline solution (placebo group) (1:1 ratio). The primary endpoint was the maximal effect-site concentration of remifentanil required to maintain heart rate and blood pressure within the recommended ranges during sternotomy. RESULTS: Median maximum concentration of remifentanil necessary to maintain adequate hemodynamic status during sternotomy was significantly reduced in PSB group (4.2 (2.5-6.0) ng/mL) compared with placebo group (7.0 (5.2-8.0) ng/mL) (p=0.02). Mean maximum concentration of propofol used to control depth of anesthesia was also reduced (3.9±1.1 µg/mL vs 5.0±1.5 µg/mL, PSB vs placebo, respectively; p=0.02). This reduction in propofol consumption during sternotomy enabled a more adequate level of sedation to be maintained in patients (minimum patient state index was 11.7±8.7 in placebo group and 18.3±6.8 in PSB group; p=0.02). PSB reduced postoperative inflammatory response by limiting concentrations of proinflammatory cytokines IL-8, IL-18, IL-23, IL-33 and MCP-1 measured in the first 7-day after surgery (p<0.05). CONCLUSIONS: Preoperative PSB reduced the maximum concentrations of remifentanil and propofol required to maintain hemodynamic stability and depth of anesthesia during sternotomy. TRIAL REGISTRATION NUMBER: NCT03734159.Sébastien Bloc, M.D.1,2; Brieuc P. Pérot, Ph.D.3; Hadrien Gibert, M.D.1; Jean-Dominique Law Koune, M.D.1; Yannick Burg, M.D.1; Didier Leclerc, M.D.1; Anne-Sophie Vuitton, M.D.1; Christophe De La Jonquière, M.D.1; Marine Luka, L.S.3; Thierry Waldmann, M.D.4; Nicolas Vistarini, M.D.4; Stéphane Aubert, M.D.4; Mickaël M. Ménager, Ph.D.3; Messaouda Merzoug, Ph.D.2; Cécile Naudin, Ph.D.2; Pierre Squara, M.D.2,5.

Smart bracelet to assess physical activity after cardiac surgery: A prospective study.

OBJECTIVES: Little is known about the physical activity of patients after cardiac surgery. This study was designed to assess this activity using a connected bracelet. METHODS: In this prospective, monocentric study, patients scheduled for cardiac surgery were offered to wear an electronic bracelet. The main objective was to measure the physical activity recovery. Secondary objectives were the predictors of the correct use of the monitoring system, of the physical recovery and, if any, the relationship between physical activity and out-of-hospital morbidity. RESULTS: One hundred patients were included. Most patients (86%) were interested in participating in the study. The compliance to the device and to the study protocol was good (94%). At discharge, the mean number of daily steps was 1454 ± 145 steps, increasing quite homogeneously, reaching 5801±1151 steps at Day 60. The best fit regression curve gave a maximum number of steps at 5897±119 (r2 = 0.97). The 85% level of activity was achieved at Day 30±3. No predictor of noncompliance was found. At discharge, age was independently associated with a lower number of daily steps (p <0.001). At Day 60, age, peripheral arterial disease and cardio-pulmonary bypass duration were independently associated with a lower number of daily steps (p = 0.039, p = 0.041 and p = 0.033, respectively). CONCLUSIONS: After cardiac surgery, wearing a smart bracelet recording daily steps is simple, well tolerated and suitable for measuring physical activity. Standard patients achieved around 6000 daily steps 2 months after discharge. 85% of this activity is reached in the first month. CLINICAL TRIAL REGISTRY NUMBER: NCT03113565.

The role of small adaptor proteins in the control of oncogenic signalingr driven by tyrosine kinases in human cancer.

Protein phosphorylation on tyrosine (Tyr) residues has evolved as an important mechanism to coordinate cell communication in multicellular organisms. The importance of this process has been revealed by the discovery of the prominent oncogenic properties of tyrosine kinases (TK) upon deregulation of their physiological activities, often due to protein overexpression and/or somatic mutation. Recent reports suggest that TK oncogenic signaling is also under the control of small adaptor proteins. These cytosolic proteins lack intrinsic catalytic activity and signal by linking two functional members of a catalytic pathway. While most adaptors display positive regulatory functions, a small group of this family exerts negative regulatory functions by targeting several components of the TK signaling cascade. Here, we review how these less studied adaptor proteins negatively control TK activities and how their loss of function induces abnormal TK signaling, promoting tumor formation. We also discuss the therapeutic consequences of this novel regulatory mechanism in human oncology.

SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2.

The adaptor SLAP is a negative regulator of receptor signalling in immune cells but its role in human cancer is ill defined. Here we report that SLAP is abundantly expressed in healthy epithelial intestine but strongly downregulated in 50% of colorectal cancer. SLAP overexpression suppresses cell tumorigenicity and invasiveness while SLAP silencing enhances these transforming properties. Mechanistically, SLAP controls SRC/EPHA2/AKT signalling via destabilization of the SRC substrate and receptor tyrosine kinase EPHA2. This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2. SRC phosphorylates EPHA2 on Tyr594, thus creating a feedback loop that promotes EPHA2 destruction and thereby self-regulates its transforming potential. SLAP silencing enhances SRC oncogenicity and sensitizes colorectal tumour cells to SRC inhibitors. Collectively, these data establish a tumour-suppressive role for SLAP in colorectal cancer and a mechanism of SRC oncogenic induction through stabilization of its cognate substrates.

Suppressor of cytokine signaling 1 modulates invasion and metastatic potential of colorectal cancer cells.

Suppressor of cytokine signaling (SOCS) 1 is an inducible negative regulator of cytokine signaling but its role in human cancer is not completely established. Here we report that, while SOCS1 is expressed in normal colonic epithelium and colon adenocarcinomas, its level decreases during progression of colon adenocarcinomas, the lowest level being found in the most aggressive stage and least differentiated carcinomas. Forced expression of SOCS1 in metastatic colorectal SW620 cells reverses many characteristics of Epithelial-Mesenchymal Transition (EMT), as highlighted by the disappearance of the transcription factor ZEB1 and the mesenchymal form of p120ctn and the re-expression of E-cadherin. Furthermore, miRNA profiling indicated that SOCS1 also up-regulates the expression of the mir-200 family of miRNAs, which can promote the mesenchymal-epithelial transition and reduce tumor cell migration. Accordingly, overexpression of SOCS1 induced cell morphology changes and dramatically reduced tumor cell invasion in vitro. When injected in nude mice, SOCS1-expressing SW620 cells induced metastases in a smaller number of animals than parental SW620 cells, and did not generate any adrenal gland or bone metastasis. Overall, our results suggest that SOCS1 controls metastatic progression of colorectal tumors by preventing the mesenchymal-epithelial transition (MET), including E-cadherin expression. This pathway may be associated with survival to colorectal cancer by reducing the capacity of generating metastases.