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Purpose The aim of this study is to compare the use of 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SF) in IV ventricular ependymoma (IVEP) surgical resection. Methods In this retrospective study, six patients with IVEP were enrolled. Gender ratio 2:1 male to female, with mean age 38.9 years old. A 5-ALA oral dose of 20 mg/kg and a SF intravenous dose of 2 mg/kg were administered. Telo-velar approach, operative microscope, and intraoperative monitoring were used in all the operations. We retrospectively compared the two fluorescence techniques at four steps during the surgical procedure: step 1: exposure of the tumor; step 2: dissection of the lesion from the cerebellum; step 3: assessment of the tumor borders and differentiation from normal tissue at the base of implants; and step 4: evaluation of possible residual tissue in the surgical cavity. Results At the first step, the ependymomas resulted well delineated by both fluorescent agents. In this step, 5-ALA was particularly helpful in the case of recurrent ependymoma. At step 2, 5-ALA provided a better identification of the ependymoma boundaries and distinction from cerebellum hemispheres than SF. In steps 3 and 4, SF was really helpful to detect tumor tissue. Conclusion According to our experience, fluorescence-guided surgery of IVEP with 5-ALA and SF is useful to maximize surgical resection with less risk of brainstem injury. Both fluorescence techniques are helpful in different steps of IVEP resection. However, further studies are needed to confirm our preliminary data.

Despite improvements in surgical techniques and perioperative care, cardiac surgery still is burdened by relatively high mortality and frequent major postoperative complications, including myocardial dysfunction, pulmonary complications, neurologic injury, and acute kidney injury. Although the surgeon's skills and volume and patient- and procedure-related risk factors play a major role in the success of cardiac surgery, there is growing evidence that also optimizing perioperative care may improve outcomes significantly. The present review focuses on the aspects of perioperative care that are strictly related to the anesthesia regimen, with special reference to volatile anesthetics and neuraxial anesthesia, whose effect on outcome in adult cardiac surgery has been investigated extensively.

Purpose Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking. Materials and methods Cardiac surgery patients with perioperative myocardial dysfunction were randomized to levosimendan or placebo, in addition to standard inotropic care. One-year mortality data were collected. Results We randomized 506 patients (248 to levosimendan 258 to placebo). At 1-year follow-up, 41 patients (16.5%) died in the levosimendan group, while 47 (18.3%) died in the placebo group (absolute risk difference −1.8; 95% CI −8.4 to 4.9; P = .60). Female sex, history of chronic obstructive pulmonary disease, previous myocardial infarction, serum creatinine, hematocrit, mean arterial pressure, and duration of cardiopulmonary bypass were independently associated with 1-year mortality. Conclusions Levosimendan administration does not improve 1-year survival in cardiac surgery patients with perioperative myocardial dysfunction. One-year mortality in these patients is 17%. Six predictive factors for long-term mortality were identified. Study registration number NCT00994825 ( ClinicalTrials.gov ).

Postoperative acute kidney injury (AKI) is frequent in cardiac surgery patients. Its pathophysiology is complex and involves decreased renal perfusion. Preliminary clinical evidence in critically ill patients shows that amino acids infusion increases renal blood flow and may decrease the incidence and severity of AKI. We designed a study to evaluate the effectiveness of perioperative continuous infusion of amino acids in decreasing AKI.This is a phase III, multi-center, randomized, double-blind, placebo-controlled trial. Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) are included. Patients are randomly assigned to receive either continuous infusion of a balanced mixture of amino acids in a dose of 2 g/kg ideal body weight/day or placebo (balanced crystalloid solution) from the operating room up to start of renal replacement therapy (RRT), or ICU discharge, or 72 h after the first dose. The primary outcome is the incidence of AKI during hospital stay defined by KDIGO (Kidney Disease: Improving Global Outcomes). Secondary outcomes include the need for, and duration of, RRT, mechanical ventilation; ICU and hospital length of stay; all-cause mortality at ICU, hospital discharge, 30, 90, and 180 days after randomization; quality of life at 180 days. Data will be analyzed in 3500 patients on an intention-to-treat basis.The trial is ongoing and currently recruiting. It will be one of the first randomized controlled studies to assess the relationship between amino acids use and kidney injury in cardiac surgery. If our hypothesis is confirmed, this practice could reduce morbidity in the studied population.This trial was registered on ClinicalTrials.gov with the trial identification NCT03709264 in October 2018.

Unlike general anaesthesia, neuraxial anaesthesia (NA) reduces the burden and risk of respiratory adverse events in the post-operative period. However, both patients affected by chronic obstructive pulmonary disease (COPD) and chest wall disorders and/or neuromuscular diseases may experience the development or the worsening of respiratory failure, even during surgery performed under NA; this latter negatively affects the function of accessory respiratory muscles, resulting in a blunted central response to hypercapnia and possibly in an exacerbation of cardiac dysfunction (NA-induced relative hypovolemia). According to European Respiratory Society (ERS) and American Thoracic Society (ATS) guidelines, non-invasive ventilation (NIV) is effective in the post-operative period for the treatment of both impaired pulmonary gas exchange and ventilation, while the intra-operative use of NIV in association with NA is just anecdotally reported in the literature. Whilst NIV does not assure a protected patent airway and requires the patient’s cooperation, it is a handy tool during surgery under NA: NIV is reported to be successful for treatment of acute respiratory failure; it may be delivered through the patient’s home ventilator, may reverse hypoventilation induced by sedatives or inadvertent spread of anaesthetic up to cervical dermatomes, and allow the avoidance of intubation in patients affected by chronic respiratory failure, prolonging the time of non-invasiveness of respiratory support (i.e., neuromuscular patients needing surgery). All these advantages could make NIV preferable to oxygen in carefully selected patients.

Dalton’s law states that the total pressure exerted by a mixture of non-reactive gases (such as air) is equal to the sum of the partial pressures of individual gases. In other words, each component of the mixture exerts a partial pressure equal to the pressure which would exert if it occupied, alone, all the volume available. Fick’s law states that gases diffuse according to a partial pressure gradient. These two laws, which are both important in respiratory physiology, describe how an air bubble left in a syringe may affect blood gas analysis. Moreover, Fick’s law is involved in the mechanism of absorption atelectasis which may be caused by the inhalation of high inspiratory oxygen fractions, and it also regulates gas exchange within the oxygenator during cardiopulmonary bypass or extracorporeal life support.

The physics of oscillations and mechanical waves (such as sound waves) has many applications in our everyday lives, from musical instruments to speeding fines, ultrasonography, radars, and building engineering. The first part of this chapter is between serious and humorous: it discusses the origin and propagation of sound in order to explain something “strange” which might (theoretically) occur during a xenon anesthesia. However, this will also give us the opportunity to introduce important topics, such as simple harmonic motion, resonance, and natural frequency, which will help us to deeply understand what leads to underdamping of invasive pressure monitoring systems. Finally, the notion of damped oscillation is briefly discussed, with reference to the damping coefficient and overdamping of these systems.

Because of viscosity, a real fluid flows through a tube only if there is a pressure difference between its two ends. In fact, it is necessary to do a work (and, hence, apply a net force) against the friction forces in order to maintain the fluid in motion (that’s why we need a heart!). In particular, Hagen–Poiseuille equation states that the volume flow rate of a viscous fluid which moves with laminar flow through a cylindrical conduit is directly proportional to the pressure difference between the two ends of the conduit and to the fourth power of its radius, and inversely proportional to the viscosity of the fluid and to the length of the conduit. Accustomed as we are, as anesthesiologists or intensivists, to deal with any type of “conduit” (tracheal tubes, venous catheters, extracorporeal membrane oxygenation cannulae, and so on), Hagen–Poiseuille equation is probably the physical law to which we are faced more often in our daily clinical practice; the choice of the gauge of a tracheotomy tube, or the decision to use either a central or a peripheral venous catheter, for example, rely also on this law. Moreover, the fundamental relationship between cardiac output and arterial pressure, on which we base hemodynamic monitoring and management, comes from Hagen–Poiseuille equation.

Everyone knows that boats, ships, lifejackets, buoys, and even the human body float in the sea. We also know that ice cubes float in our soft drink, that a balloon filled with helium flies upward, as well as one filled with hot air. Moreover, many people are aware that swimming (or at least stay afloat) in the pool is a bit more exhausting than in the sea. All of this is explained by the same physical law: Archimedes’ principle. This law helps anesthesiologists to protect the brain from air embolism, to facilitate de-airing during open-heart surgery, and to handle a syringe.

In the recently updated international “democracy-based” consensus conference aimed at identifying all nonsurgical strategies which have been shown by sufficiently strong randomized evidence to affect mortality in the perioperative and critical care setting, restrictive inspiratory oxygen fraction (FiO2) was included among interventions reducing mortality. This conclusion was based on the findings of two randomized controlled trials showing a lower intensive care unit (ICU) mortality with a “conservative” FiO2 approach in critically ill patients and an increased long-term mortality in surgical patients receiving high intraoperative FiO2, respectively. However, there is also evidence that high perioperative FiO2 may reduce mortality (possibly through prevention of surgical site infection) among surgical patients, while recent investigations did not confirm (or found a high level of uncertainty about) the survival benefit of restrictive FiO2 strategies in ICU patients. This chapter discusses the main evidences about the topic, the possible mechanisms of the association between FiO2 and mortality, and the implications for clinical practice.

What is temperature and how it can be measured? The conversion of the fuel chemical energy into kinetic energy (i.e., movement) and heat in a car engine. Warm your hands while keeping a cup of tea. The direction in which time flows (i.e., what distinguishes past from future). The choice of the materials with which a pot is constructed. Coolers (e.g., car radiators) and heaters, including heat exchanger of heart–lung machine. All this, in a way or another, has something to do with thermodynamics and its laws. This chapter shows, in particular, how also the Stewart–Hamilton equation, which we use to measure cardiac output by thermodilution, is derived from the first and second laws of thermodynamics.

Lung-protective ventilation (LPV) and prone positioning (PP) are currently the two cornerstones of acute respiratory distress syndrome (ARDS) treatment. LPV with low tidal volumes, moderate-to-high levels of positive end-expiratory pressure (PEEP) and, possibly, recruitment maneuvers has been widely shown in randomized controlled trials (RCTs) to reduce mortality in ARDS patients. However, evidence about the favorable effects in terms of survival of PEEP and recruitment maneuvers is not as conclusive as that about low tidal volumes. PP has been shown for over 40 years to improve oxygenation in ARDS patients but only in recent years a large multicenter RCT succeeded in showing improved survival with this strategy.

Geometrical optics, which deals with light as a set of rays traveling in straight lines (according to the so-called ray model of light) is the oldest part of optics, that is the study of light. This chapter discusses some of its laws (such as the law of reflection and the Snell’s law of refraction) and their applications (e.g., lenses and optical fibers), in order to understand how a bronchoscope works. We will also take the opportunity to discuss the physics behind the fogging of a bronchoscope or of personal protective equipment (PPE) such as goggles.

When you are watering a garden, you can reach the most distant areas by simply partially closing the hose with a thumb. In fact, the water speed increases when it flows through a decreased cross-sectional area (continuity equation). According to Bernoulli’s theorem, the pressure of a fluid that travels along a horizontal streamline decreases as its speed increases: the wings of an airplane are built so as to take advantage of this law and make the airplane fly. Both the continuity equation and the Bernoulli’s equation (in a simplified form) have important echocardiographic applications, while they work together in a Venturi mask, allowing the administration of predictable inspiratory oxygen fractions. Moreover, these two physics laws are involved in the pathophysiology of dynamic left ventricle outflow tract obstruction due to systolic anterior motion, which is a possible cause of severe hemodynamic instability in either the operating room or the intensive care unit.

When you open a can of soda or a bottle of sparkling water and you see a lot of bubbles appear, you are observing the effects of Henry’s law; the degree a gas dissolves into a fluid increases proportionally to the increase in partial pressure above the fluid. Moreover, have you ever noticed that warmer is the drink, larger are the bubbles? Or also, that when it’s hot, drinks left in a glass become “flat” more quickly? This too is due to Henry’s law. In fact, the proportionality coefficient of Henry’s law (the so-called Henry’s constant) depends on temperature. In addition to have a key role in both the pathophysiology and treatment of decompression sickness, Henry’s law explains, at least in part, the respiratory alkalosis which develops at low body temperatures (such as during hypothermic cardiopulmonary bypass or deep hypothermic circulatory arrest), which can be managed according to two different strategies (Alpha-stat or pH-stat).

Laplace’s law correlates the pressure difference between the inside and the outside of a bubble (or of a liquid drop) with its radius and with the so-called surface tension. Approximately, this relationship also applies to hollow objects with an elastic wall (including human organs) which contain a fluid (i.e., a liquid or a gas), provided that the wall is thin enough. Accordingly, examples abound in daily life (raindrops, soap bubbles, beer foam, party balloons, and so on). Moreover, Laplace’s law is often invoked in medicine, being involved in the pathophysiology of air embolism, dilated cardiomyopathy, aortic aneurysm, and alveolar collapse (with due cautions). In the context of clinical anesthesiology, this law explains how the reservoir bag of the anesthesia breathing system may protect the lungs from barotrauma, and probably also why the so-called “finger-pressure” technique fails to correctly assess the inflation pressure of the tracheal tube cuff.

The physics of sound waves has many applications in our everyday lives, from musical instruments to speeding fines, ultrasonography, and radars. This chapter addresses a clinically relevant topic (to anesthesiologists and intensivists) of wave physics: the Doppler Effect and its application to both ultrasonography (e.g., echocardiography) and minimally invasive cardiac output monitoring devices such as the esophageal Doppler.

The part of physics called electricity includes the description of several quantities, phenomena, and devices which are closely related to what anesthesiologists and intensivists daily deal with in their clinical practice. For example, the measurement of a change in the electrical resistance of “something” is involved in invasive pressure monitoring, temperature monitoring, cardiac output estimation, and platelet function testing. Furthermore, body temperature can be measured in clinical practice also using a circuit element, called thermocouple, which relies on a particular thermoelectric effect.

The ideal gas law correlates pressure, volume, and temperature of an ideal gas with one another. As discussed in this chapter, the moka coffee maker works according to this law and popcorn is also made thanks to it; the same physical principle allows to calculate the reserve of oxygen in a cylinder based on the pressure inside it; similarly, volume and pressure of a tracheal tube cuff are affected by both temperature and altitude and, accordingly, adjustments of cuff inflation may be needed (at least theoretically) during intraoperative deep hypothermia or helicopter transportation of intubated patients in order to avoid leakage or tracheal injury, respectively; finally, divers must be very familiar with the behavior of gases to avoid decompression illness, and pressure and volume changes similar to those causing this potentially severe disease during a dive may also be responsible for earache (or other more embarrassing troubles) during an airplane flight.

This chapter points out and discusses the many physical principles which are the basis of the operation and design of vaporizers, with special reference to the so-called variable bypass vaporizers, i.e., those most commonly used for the administration of halogenated anesthetics such as isoflurane and sevoflurane (but not desflurane). Saturated vapor pressure, state changes of matter (particularly vaporization), heat of transformation and evaporative cooling, thermal conductivity, specific heat, Dalton’s law, and thermal expansion are all involved in how vaporizers work and in some of their main features such as calibration, temperature stabilization, and temperature compensation.

The trajectory of an electromagnetic wave which travels through a transparent medium may be deviated in any direction as a result of the interaction between the wave and some obstacle or “inhomogeneity,” such as the particles that are suspended in the medium. This phenomenon, which is referred to as scattering of the electromagnetic wave, explains why the sky is blue. While nonionizing electromagnetic waves such as visible light and infrared radiation mainly undergo elastic scattering (in which the wavelength of the scattered radiation does not change), scattered ionizing radiations undergo a change in wavelength (inelastic scattering). Both types of scattering may have a role in the daily practice of anesthesia and intensive care medicine. For example, the elastic scattering of infrared radiation is one of the principles on which near-infrared spectroscopy (NIRS) cerebral oximetry is based and, at the same time, represents a major technological challenge which accounts for some limitations of this technique. Moreover, the special kind of (inelastic) scattering which ionizing radiations undergo (Compton scattering) has a key role in radiation protection. Finally, although nonionizing electromagnetic waves mainly undergo elastic scattering, inelastic scattering may also occur: this phenomenon, which is known as Raman scattering, is used in some types of respiratory gas analyzers.

The Newton’s laws, also known as laws of dynamics (that is the branch of classical mechanics which studies forces and their effect on motion), account for the motion or motionlessness of any object around us, and deal with our weight as well as with what happens in car engines, jets, rockets, rifles, and cannons. This chapter deals with forces, motion, gravity, and friction, showing (with the help of some trigonometry) how physics may help anesthesiologists to use Trendelenburg position safely.

Physics and mathematics are inextricably linked. In fact, for still partly mysterious reasons, the mathematical language is incredibly effective in describing the “physical world.” Accordingly, in Physics for Anesthesiologists and Intensivists we cannot do without a little mathematics to fully understand the physics that lies behind our “clinical” world, namely that of anesthesiology and intensive care medicine. However, some algebra, a bit of geometry and trigonometry, and just a couple of notions of calculus (very rarely), are all we will need, and are briefly brushed up in this chapter. We will also take the opportunity to immediately make some considerations relating to our daily clinical practice, in particular about the use of geometry and trigonometry to help consolidate our ultrasound-guided central venous catheterization technique, especially when it is performed the first few times.

Have you ever tried to open a heavy door by pushing it from a point very close to its hinges? It takes a lot more force (it is not a coincidence that doorknobs are where they are). In fact, considering a body, such as a metal bar, that is free to rotate about an axis, the ability of a force, applied on it at a given point, to rotate this body depends not only on the magnitude (and direction) of the force, but also on how far from the axis the force is applied (moment of a force or torque). The levers we use every day (e.g., pliers, nutcrackers, and tweezers) rely on this principle. In this chapter, the concepts of vector, vector sum, vector component, and moment of a force are applied to the insertion of a central venous catheter and to laryngoscopy.

The pilot balloon palpation (or 'finger-pressure') method is still widely used to assess the endotracheal tube cuff inflation, despite consistent evidence of its poor sensitivity in recognizing cuff overinflation. It was recently speculated that this may be related to the lower wall tension (due to the smaller radius) of the pilot balloon as compared with the cuff, according to Laplace's law. To verify this hypothesis and, secondarily, to assess whether the use of a 'large' pilot balloon (identical to the cuff) increases the reliability of this technique, 62 anesthetists (41 experienced anesthesiologists and 21 residents) were asked to estimate the pressure of a cuff inflated to 88 mmHg into a simulated trachea by feeling both a usual and a modified 'large' pilot balloon. A similar test was repeated at 40 mmHg. After palpation of the usual pilot balloon, only 35% of participants (49% of experienced anesthesiologists and 10% of residents) recognized considerable overinflation (88 mmHg), as compared with 87% of participants (95% of experienced anesthesiologists and 71% of residents) after palpation of the 'large' pilot balloon. Moreover, 89% of participants (85% of experienced anesthesiologists and 95% of residents) believed that pressure was higher in the 'large' balloon than in the normal one. However, only 32% of participants (51% of experienced anesthesiologists and none of residents) recognized slight overinflation (40 mmHg) after feeling the 'large' balloon. The pilot balloon size affects the sensitivity of the 'finger-pressure' technique, but it remains poorly reliable with a larger pilot balloon.

BACKGROUND Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta-analyses of small trials suggest that levosimendan may result in a higher rate of survival among patients undergoing cardiac surgery. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving patients in whom perioperative hemodynamic support was indicated after cardiac surgery, according to prespecified criteria. Patients were randomly assigned to receive levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 μg per kilogram of body weight per minute) or placebo, for up to 48 hours or until discharge from the intensive care unit (ICU), in addition to standard care. The primary outcome was 30-day mortality. RESULTS The trial was stopped for futility after 506 patients were enrolled. A total of 248 patients were assigned to receive levosimendan and 258 to receive placebo. There was no significant difference in 30-day mortality between the levosimendan group and the placebo group (32 patients [12.9%] and 33 patients [12.8%], respectively; absolute risk difference, 0.1 percentage points; 95% confidence interval [CI], -5.7 to 5.9; P = 0.97). There were no significant differences between the levosimendan group and the placebo group in the durations of mechanical ventilation (median, 19 hours and 21 hours, respectively; median difference, -2 hours; 95% CI, -5 to 1; P = 0.48), ICU stay (median, 72 hours and 84 hours, respectively; median difference, -12 hours; 95% CI, -21 to 2; P = 0.09), and hospital stay (median, 14 days and 14 days, respectively; median difference, 0 days; 95% CI, -1 to 2; P = 0.39). There was no significant difference between the levosimendan group and the placebo group in rates of hypotension or cardiac arrhythmias. CONCLUSIONS In patients who required perioperative hemodynamic support after cardiac surgery, low-dose levosimendan in addition to standard care did not result in lower 30-day mortality than placebo. (Funded by the Italian Ministry of Health; CHEETAH ClinicalTrials.gov number, NCT00994825.).

The antigen-mediated triggering of B cell receptor (BCR) activates the transcription factor NF-κB that regulates the expression of genes involved in B cell differentiation, proliferation, and survival. The tyrosine kinase Btk is essentially required for the activation of NF-κB in BCR signaling through the canonical pathway of IKK-dependent phosphorylation and proteasomal degradation of IκB-α, the main repressor of NF-κB. Here, we provide the evidence of an additional mechanism of NF-κB activation in BCR signaling that is Btk-dependent and IKK-independent. In DeFew B lymphoma cells, the anti-IgM stimulation of BCR activated Btk and NF-κB p50/p65 within 0.5 min in absence of IKK activation and IκB-α degradation. IKK silencing did not affect the rapid activation of NF-κB. Within this short time, Btk associated and phosphorylated IκB-α at Y289 and Y305, and, concomitantly, p65 translocated from cytosol to nucleus. The mutant IκB-α Y289/305A inhibited the NF-κB activation after BCR triggering, suggesting that the phosphorylation of IκB-α at tyrosines 289 and 305 was required for NF-κB activation. In primary chronic lymphocytic leukemia cells, Btk was constitutively active and associated with IκB-α, which correlated with Y305-phosphorylation of IκB-α and increased NF-κB activity compared with healthy B cells. Altogether, these results describe a novel mechanism of NF-κB activation in BCR signaling that could be relevant for Btk-targeted therapy in B-lymphoproliferative disorders. KEY MESSAGES: Anti-IgM stimulation of BCR activates NF-κB p50/p65 within 30 s by a Btk-dependent and IKK-independent mechanism. Btk associates and phosphorylates IκB-α at Y289 and Y305, promoting NF-κB activation. In primary CLLs, the binding of Btk to IκB-α correlates with tyrosine phosphorylation of IκB-α and increased NF-κB activity.

Objective: Reducing mortality is a key target in critical care and perioperative medicine. The authors aimed to identify all nonsurgical interventions (drugs, techniques, strategies) shown by randomized trials to increase mortality in these clinical settings. Design: A systematic review of the literature followed by a consensus-based voting process. Setting: A web-based international consensus conference. Participants: Two hundred fifty-one physicians from 46 countries. Interventions: The authors performed a systematic literature search and identified all randomized controlled trials (RCTs) showing a significant increase in unadjusted landmark mortality among surgical or critically ill patients. The authors reviewed such studies during a meeting by a core group of experts. Studies selected after such review advanced to web-based voting by clinicians in relation to agreement, clinical practice, and willingness to include each intervention in international guidelines. Measurements and main results: The authors selected 12 RCTs dealing with 12 interventions increasing mortality: diaspirin-crosslinked hemoglobin (92% of agreement among web voters), overfeeding, nitric oxide synthase inhibitor in septic shock, human growth hormone, thyroxin in acute kidney injury, intravenous salbutamol in acute respiratory distress syndrome, plasma- derived protein C concentrate, aprotinin in high-risk cardiac surgery, cysteine prodrug, hypothermia in meningitis, methylprednisolone in traumatic brain injury, and albumin in traumatic brain injury (72% of agreement). Overall, a high consistency (ranging from 80% to 90%) between agreement and clinical practice was observed. Conclusion: The authors identified 12 clinical interventions showing increased mortality supported by randomized controlled trials with nonconflicting evidence, and wide agreement upon clinicians on a global scale.

Increasing evidence supports the involvement of IBTK in cell survival and tumor growth. Previously, we have shown that IBTK RNA interference affects the wide genome expression and RNA splicing in cell-type specific manner. Further, the expression of IBTK gene progressively increases from indolent to aggressive stage of chronic lymphocytic leukemia and decreases in disease remission after therapy. However, the role of IBTK in tumorigenesis has not been elucidated. Here, we report that loss of the murine Ibtk gene raises survival and delays tumor onset in Eμ-myc transgenic mice, a preclinical model of Myc-driven lymphoma. In particular, we found that the number of pre-cancerous B cells of bone marrow and spleen is reduced in Ibtk−/−Eμ-myc mice owing to impaired viability and increased apoptosis, as measured by Annexin V binding, Caspase 3/7 cleavage assays and cell cycle profile analysis. Instead, the proliferation rate of pre-cancerous B cells is unaffected by the loss of Ibtk. We observed a direct correlation between Ibtk and myc expression and demonstrated a Myc-dependent regulation of Ibtk expression in murine B cells, human hematopoietic and nonhematopoietic cell lines by analysis of ChIP-seq data. By tet-repressible Myc system, we confirmed a Myc-dependent expression of IBTK in human B cells. Further, we showed that Ibtk loss affected the main apoptotic pathways dependent on Myc overexpression in pre-cancerous Eμ-myc mice, in particular, MCL-1 and p53. Of note, we found that loss of IBTK impaired cell cycle and increased apoptosis also in a human epithelial cell line, HeLa cells, in Myc-independent manner. Taken together, these results suggest that Ibtk sustains the oncogenic activity of Myc by inhibiting apoptosis of murine pre-cancerous B cells, as a cell-specific mechanism. Our findings could be relevant for the development of IBTK inhibitors sensitizing tumor cells to apoptosis.

The authors aimed to identify interventions documented by randomized controlled trials (RCTs) that reduce mortality in adult critically ill and perioperative patients, followed by a survey of clinicians' opinions and routine practices to understand the clinicians' response to such evidence. The authors performed a comprehensive literature review to identify all topics reported to reduce mortality in perioperative and critical care settings according to at least 2 RCTs or to a multicenter RCT or to a single-center RCT plus guidelines. The authors generated position statements that were voted on online by physicians worldwide for agreement, use, and willingness to include in international guidelines. From 262 RCT manuscripts reporting mortality differences in the perioperative and critically ill settings, the authors selected 27 drugs, techniques, and strategies (66 RCTs, most frequently published by the New England Journal of Medicine [13 papers], Lancet [7], and Journal of the American Medical Association [5]) with an agreement ≥67% from over 250 physicians (46 countries). Noninvasive ventilation was the intervention supported by the largest number of RCTs (n = 13). The concordance between agreement and use (a positive answer both to "do you agree" and "do you use") showed differences between Western and other countries and between anesthesiologists and intensive care unit physicians. The authors identified 27 clinical interventions with randomized evidence of survival benefit and strong clinician support in support of their potential life-saving properties in perioperative and critically ill patients with noninvasive ventilation having the highest level of support. However, clinician views appear affected by specialty and geographical location.

Evidence of shared epitopic reactivity among independent B-cell clones in chronic lymphocytic leukemia patients