Optimizing Moxifloxacin Dose in MDR-TB Participants with or without Efavirenz Coadministration Using Population Pharmacokinetic Modeling.

Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic and MIC distribution in participants with MDR-TB. Participants enrolled at two TB hospitals in South Africa underwent intensive pharmacokinetic sampling approximately 1 to 6 weeks after treatment initiation. Plasma drug concentrations and clinical data were analyzed using nonlinear mixed-effects modeling with simulations to evaluate doses for different scenarios. We enrolled 131 participants (54 females), with median age of 35.7 (interquartile range, 28.5 to 43.5) years, median weight of 47 (42.0 to 54.0) kg, and median fat-free mass of 40.1 (32.3 to 44.7) kg; 79 were HIV positive, 29 of whom were on efavirenz-based antiretroviral therapy. Moxifloxacin pharmacokinetics were described with a 2-compartment model, transit absorption, and elimination via a liver compartment. We included allometry based on fat-free mass to estimate disposition parameters. We estimated an oral clearance for a typical patient to be 17.6 L/h. Participants treated with efavirenz had increased clearance, resulting in a 44% reduction in moxifloxacin exposure. Simulations predicted that, even at a median MIC of 0.25 (0.06 to 16) mg/L, the standard daily dose of 400 mg has a low probability of attaining the ratio of the area under the unbound concentration-time curve from 0 to 24 h to the MIC (fAUC0-24)/MIC target of >53, particularly in heavier participants. The high-dose WHO regimen (600 to 800 mg) yielded higher, more balanced exposures across the weight ranges, with better target attainment. When coadministered with efavirenz, moxifloxacin doses of up to 1,000 mg are needed to match these exposures. The safety of higher moxifloxacin doses in clinical settings should be confirmed.

Creation of a new genus in the family Secoviridae substantiated by sequence variation of newly identified strawberry latent ringspot virus isolates.

To obtain insight into the sequence diversity of strawberry latent ringspot virus (SLRSV), isolates from collections and diagnostic samples were sequenced by high-throughput sequencing. For five SLRSV isolates, the complete genome sequences were determined, and for 18 other isolates nearly complete genome sequences were determined. The sequence data were analysed in relation to sequences of SLRSV and related virus isolates available in the NCBI GenBank database. The genome sequences were annotated, and sequences of the protease-polymerase (Pro-Pol) region and coat proteins (CPs) (large and small CP together) were used for phylogenetic analysis. The amino acid sequences of the Pro-Pol region were very similar, whereas the nucleotide sequences of this region were more variable. The amino acid sequences of the CPs were less similar, which was corroborated by the results of a serological comparison performed using antisera raised against different isolates of SLRSV. Based on these results, we propose that SLRSV and related unassigned viruses be assigned to a new genus within the family Secoviridae, named "Stralarivirus". Based on the phylogenetic analysis, this genus should include at least three viruses, i.e., SLRSV-A, SLRSV-B and lychnis mottle virus. The newly generated sequence data provide a basis for designing molecular tests to screen for SLRSV.

Determining the radial distribution function of water using electron scattering: A key to solution phase chemistry.

High energy electron scattering of liquid water (H2O) at near-ambient temperature and pressure was performed in a transmission electron microscope (TEM) to determine the radial distribution of water, which provides information on intra- and intermolecular spatial correlations. A recently developed environmental liquid cell enables formation of a stable water layer, the thickness of which is readily controlled by pressure and flow rate adjustments of a humid air stream passing between two silicon nitride (Si3N4) membranes. The analysis of the scattering data is adapted from the x-ray methodology to account for multiple scattering in the H2O:Si3N4 sandwich layer. For the H2O layer, we obtain oxygen-oxygen (O-O) and oxygen-hydrogen (O-H) peaks at 2.84 Å and 1.83 Å, respectively, in good agreement with values in the literature. This demonstrates the potential of our approach toward future studies of water-based physics and chemistry in TEMs or electron probes of structural dynamics.

[ACE-inhibition and bradykinin-mediated angioedema]. / Cas clinique. Angioedème bradykininique induit par inhibition de l'enzyme de conversion de l'angiotensine.

Angiotensin converting enzyme inhibitors (ACE-i) are the most common cause of bradykininin angioedema. These bradykinin-mediated angioedemas are sometimes confused with histamine-induced angioedema, which may cause a late diagnosis and hence poor initial management, deleterious to the patient. This report describes a patient with a bradykinin-mediated angioedema soon after the initiation of perindopril, with laryngeal involvement requiring orotracheal intubation in emergency. The diagnosis was confirmed later and the assay of the activity of the enzymes involved in the catabolism of kinins - aminopeptidase P (APP), carboxypeptidase N (CPN) and Angiotensin-Converting Enzyme (ACE) - demonstrated a decrease of activity of both APP and ACE. As the diagnosis was not made initially, the specific treatments - concentrate of C1 inhibitor or antagonist of the B2 receptor of bradykinin (Icatibant) - were not administered. Any angioedema occurring during a treatment with ACE-i should be considered as a bradykinin-mediated angioedema.

Les inhibiteurs de l'enzyme de conversion de l'angiotensine (IEC) sont la cause la plus fréquente d'angioedème bradykininique. Ceux-ci se confondent facilement avec l'angioedème histaminique, pouvant causer un retard diagnostique et donc une mauvaise prise en charge initiale, délétère pour le patient. Nous rapportons le cas d'un patient présentant un angioedème induit par le périndopril, avec une atteinte laryngée nécessitant une intubation orotrachéale en urgence. Le diagnostic a été posé a posteriori et le dosage des activités des enzymes du catabolisme des kinines - aminopeptidase P (APP), carboxypeptidase N (CPN) et enzyme de conversion de l'angiotensine (ECA) - a démontré une diminution des activités APP et ECA. Le diagnostic n'étant pas posé initialement, les traitements spécifiques - concentré de C1 inhibiteur ou antagoniste des récepteurs B2 de la bradykinine (Icatibant) - n'ont pas été administrés. Tout angioedème sous IEC doit être considéré comme un angioedème bradykininique.

Why should the anesthesiologist evaluate nutritional status?

BACKGROUND: The anesthesiologist's involvement in perioperative medicine has significantly changed. In order to identify patients at risks of perioperative complications, the anesthesiologist has to consider, amongst others, screening and management of undernutrition. For this purpose knowledge of prevalence and risk factors, along with screening tools and guidelines for an adapted nutritional management and outcomes of renutrition are mandatory. The present review intends to provide these tools to the Anesthesiologists. METHOD: We conduct a literature review in Pubmed, Direct Science and Cochrane Library without limit of time related to undernutrition in the perioperative period. RESULTS: Undernutrition is common in surgical patients. Undernutrition is associated with an increase of morbidity, mortality, length of hospital stay and costs. Undernutrition could probably be detected during the anesthetic consultation with simple and rapid tests, such as SNAQ, MST, MUST and NRS-2002. Nevertheless, further studies are needed to validate such tests in surgical patients. Waiting for these results, we prefer MUST. The implementation of nutritional support recommendations would reduce postoperative complications. CONCLUSION: The anesthesiologist could play an important role in undernutrition screening and its management in order to reduce perioperative morbidity.

Preoperative frailty assessment: a review.

Elderly surgical population is growing faster than the rate of population ageing. The risk of postoperative complication is higher in this population, the type of complication and the risk indicators are different from younger patients. There is also a huge heterogeneity in the elderly population. The concept of frailty-emerges to explain these specific aspects and to risk stratify older patients. The present work intends to help the anaesthesiologist to take into account the concept of frailty at the preoperative visit. We reviewed, in the light of surgical context, the physiopathology of ageing, the definitions of frailty concept,the current existing strategies for peri-operational optimisation and the different frailty assessment tools. Our conclusions are that preoperative frailty assessment is essential in modern perioperative medicine practice and that the Edmonton Frail Scale stands out from other tools even though it cannot yet be considered as a gold standard.

Intraoperative use of ketorolac or diclofenac is associated with improved disease-free survival and overall survival in conservative breast cancer surgery.

BACKGROUND: An association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and better outcome after mastectomy and lung surgery for cancer has been recently suggested. In a retrospective analysis, we investigated the association between intraoperative NSAIDs use in conservative breast cancer surgery and breast cancer disease-free survival (DFS). Similarly, we also evaluated the association between breast cancer DFS and preoperative neutrophil:lymphocyte ratio (NLR). METHODS: A retrospective analysis of a single-centre cohort was performed in breast cancer patients (n=720) with uni- and multivariate analyses, using a Cox regression model. RESULTS: In conservative breast cancer surgery, the intraoperative use of NSAIDs (ketorolac or diclofenac) was associated with an improved DFS {hazard ratio (HR)=0.57 [95% confidence interval (CI): 0.37-0.89], P=0.01} and an improved overall survival (OS) [HR=0.35 (95% CI: 0.17-0.70), P=0.03]. In these patients, an NLR >3.3 (identified by a receiver-operating characteristic curve) was associated with a shorter DFS [HR=1.99 (95% CI: 1.16-3.41), P=0.01] and OS [HR=2.35 (95% CI: 1.02-5.43), P=0.046]. CONCLUSIONS: Intraoperative NSAIDs and higher preoperative NLR are associated with improved outcome in conservative breast cancer surgery. Prospective, randomized trials to evaluate if these associations are causal are warranted.

Is the "in situ" simulation for teaching anesthesia residents a lower cost, feasible and satisfying alternative to simulation center ? A 24 months prospective observational study in a university hospital.

BACKGROUND: The value of simulation in medical education is increasingly obvious. Nevertheless, the high cost of running a simulation center and the time's availability for students to get to simulation center remain a major problem. Technological developments and miniaturization of computer systems now allow handling of simulation manikins. Therefore, "in situ" simulation seems a valuable alternative to center simulation. OBJECTIVE(S): To identify the costs and feasibility of "in situ" simulation. To conduct an evaluation of the sessions by participants in order to adapt the educational objectives. DESIGN: Observational study. SETTING: 118 "in situ" simulation sessions were organized between March 2011 and February 2013 in the university hospital of Université Catholique de Louvain. Sessions took place in OR facilities. At the end of each session, a questionnaire was given to each participant. PARTICIPANTS: 357 of 368 participants completed a questionnaire. For each session, one or two nurses and 2 residents in anesthesia were invited. MAIN OUTCOME MEASURES: Total costs for organizing the sessions. Number of realized sessions. Global satisfaction of participants. RESULTS: Total cost for organizing the sessions is 18 414 Euro. One hundred and one among the 118 scheduled sessions were performed, which corresponds to a rate of 85%. Three hundred and sixty-five people participated in training simulations. During the sessions, 357 questionnaires were completed. The global satisfaction was high with a median Likert scale of 5 (5-5) to the question "I would like to participate in other sessions in the future". CONCLUSION: The "in situ" simulation in anesthesia is feasible in a university hospital using the available facilities of the operating theater during the working hours of both participants and trainers. However, the number of annual sessions may be limited by the availability of the simulation room or staff.

Should the "in situ" simulation become the new way in Belgium? Experience of an academic hospital.

The place of simulation in medical education, particularly in anesthesia, appears to be more and more evident. However, the history of simulation in Belgium showed that the associated costs remain a barrier. The use of 'in situ' simulation, defined as the practice of simulation in the usual workplace, could solve the problem of providing access to this educational tool. Indeed, it allows reducing equipment and manpower costs: the needed equipment comes from the hospital, and supervision and organization are provided by staff members. It also provides access to simulation for a larger number of individuals on site. The environment is more realistic because the participants operate in their usual workplace, with their customary equipment and team. Furthermore, 'in situ' simulation allows participation of the paramedical staff. This allows developing skills related to teamwork and communication. Despite those numerous advantages, several difficulties persist. The associated logistic and organizational constraints can be cumbersome.

Is there a rationale for an anesthesiologist's role against cancer recurrence?

Growth of tumors can accelerate during the peri-operative period. Accordingly, early relapse of cancer occurs in some patients during the first two postoperative years. Temporal and biologic analyses of cancer pathophysiology suggest a link between peri-operative pathophysiological changes and acceleration of tumor growth. Understanding the role of inflammation and its consequences (i.e., immune response, growth factors, dissemination of tumor cells) could lead to define a role of anesthesiologists in reducing cancer recurrence following surgery. We argue for peri-operative pharmacological interventions to reduce cancer relapse, with a focus on non-steroidal anti-inflammatory drugs.

In vivo optical spectroscopy monitoring in a new model of muscular compartment syndrome.

BACKGROUND: Muscular compartment syndrome (MCS) is a rare but serious postoperative complication. In vivo optical spectroscopy (INVOS) monitors continuously and non-invasively regional oxygen saturation (rSO(2)), and could predict the development of MCS. METHODS: In 10 healthy volunteers, we inflated a tourniquet to the mean arterial pressure to produce slight venous congestion and arterial hypoperfusion. Comparisons were made between the relative reduction in rSO(2) with baseline (deltaINVOS) and the time to observe motor nerve block (with non-invasive electromyography). Neurological symptoms, pain, and invasive intracompartmental pressure (ICP) were assessed. RESULTS: In the eight volunteers completing the protocol, we observed a profound motor nerve conduction block, immediately reversible. Baseline values were: [mean (sd)] INVOS: 73.3 (8.9)% and ICP: 16.9 (8.6) mm Hg. At the time of the block, values were: INVOS: 46.4 (10.9)%, deltaINVOS: 28.7 (10.6)%, and ICP: 70.0 (5.5) mm Hg. The time to reach the block was 33.0 (10.9) min, and to a deltaINVOS>10%: 27.4 (10.4) min. Receiver-operating characteristic curves demonstrated a similar accuracy of ICP and INVOS to predict the occurrence of the block. Twenty minutes with a deltaINVOS>10% or ICP>30 mm Hg were associated with a sensitivity and a specificity of 95% and 70%; or 91% and 65%, respectively. CONCLUSIONS: We have developed a model of acute immediately reversible MCS. Monitoring using the INVOS technology is as accurate as measurement of ICP, and could be a useful tool to prevent development of intraoperative MCS.

Ideal versus corrected body weight for dosage of sugammadex in morbidly obese patients.

To date, the dosing of sugammadex is based on real body weight without taking fat content into account. We compared the reversal of profound rocuronium-induced neuromuscular blockade in morbidly obese patients using doses of sugammadex based on four different weight corrections. One hundred morbidly obese patients, scheduled for laparoscopic bariatric surgery under propofol-sufentanil anaesthesia, were randomly assigned four groups: ideal body weight; ideal body weight + 20%; ideal body weight + 40%; and real body weight. Patients received sugammadex 2 mg.kg(-1), when adductor pollicis monitoring showed two responses. The primary endpoint was full decurarisation. Secondary endpoints were the ability to get into bed independently on arrival to the post-anaesthetic care unit and clinical signs of residual paralysis. There was no residual paralysis in any patient. Morbidly obese patients can safely be decurarised from rocuronium-induced neuromuscular blockade T1-T2 with sugammadex dosed at 2 mg.kg(-1) ideal body weight + 40% (p < 0.0001).

The anti-inflammatory effects of ketamine: state of the art.

Inflammation is a major component in keeping the body in homeostasis. However, an overwhelmed inflammatory response may be associated to a loss of this homeostatic status, which may lead to tissue injury or organ dysfunction. A huge number of drugs interacts with the inflammatory response in a positive, negative or "dual" manner. Among these drugs, ketamine seems to have a significant positive effect on the regulation of inflammation. This NMDA-receptor antagonist acts at different levels of inflammation, interacting with inflammatory cells recrutment, cytokins production, and inflammatory mediators regulation. The resultant effect of these interactions confers to ketamine a anti-proinflammatory effect by limiting exacerbation of systemic inflammation without affecting local healing processes. This review makes a complete overview of the immunomodulatory properties of this complex anesthetic substance.

Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion.

Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens. The influence of human TLR6 polymorphisms on susceptibility to infection is only partially understood. Most microbes contain lipopeptides recognized by TLR2/1 or TLR2/6 heterodimers. Our aim was to determine whether single nucleotide polymorphisms in TLR6 are associated with altered immune responses to lipopeptides and whole mycobacteria. We sequenced the TLR6 coding region in 100 healthy South African adults to assess genetic variation and determined associations between polymorphisms and lipopeptide- and mycobacteria-induced interleukin (IL)-6 production in whole blood. We found two polymorphisms, C745T and G1083C, that were associated with altered IL-6 secretion. G1083C was associated with altered IL-6 levels in response to lipopeptides, Mycobacterium tuberculosis lysate (Mtb lysate, P=0.018) and Bacille Calmette-Guerin (BCG P=0.039). The 745T allele was also associated with lower NF-κB signaling in response to di-acylated lipopeptide, PAM2 (P=0.019) or Mtb (P=0.026) in an HEK293 cell line reconstitution assay, compared with the 745C allele. We conclude that TLR6 polymorphisms may be associated with altered lipopeptide-induced cytokine responses and recognition of Mtb. These studies provide new insight into the role of TLR6 variation and the innate immune response to human infection.

Does the KCE restrictive policy for preoperative testing lead to increased postoperative complications rate?

The majority of the industrialized country tries to contain the health care costs. One of the solutions applied was to restrict preoperative routine testing. To determine whether such policy was safe for the patient, we conducted a retrospective study related to 659 women, classified ASA 1 or 2, admitted for gynaecological surgery. In this study we have not observed an increased complications rate related to this restrictive policy. We conclude that for the population selected, the KCE recommendations for preoperative testing are secure and do not induce an increased postoperative complications rate.

Pleth variability index combined with passive leg raising-induced pulse pressure variation to detect hypovolemia in spontaneously breathing patients.

The combination of Pleth Variability Index (PVI) and passive leg raising (PLR)-induced pulse pressure variation may help to diagnose hypovolemia in spontaneously breathing patients. In 44 subjects, PVI and Pulse Pressure (PP) variation after PLR were measured before and after induced hypovolemia (blood gift or hemodialysis session). PVI values were significantly greater after hemodialysis session or blood gift (22% vs 18%, P = 0.03); in contrast PP variation did not change significantly (7% vs 4%, P = 0.49). The accuracy of these parameters or of their combination to identify the "after hypovolemia induction" period was weak. In spontaneous ventilation, PVI value is greater after induced hypovolemia, whereas PP variation does not change significantly. The combination of PVI and PLR does not improve the accuracy of the detection of induced hypovolemia.

Abnormal sensations evoked over the chest and persistent peri-incisional chest pain after cardiac surgery.

Risk factors for developing Persistent peri-incisional Chest Pain (PCP) after sternotomy are multiple. We examined whether hypoesthesia, hyperalgesia or dysesthesia, evoked in the postoperative period might be associated with PCP after sternotomy. One hundred patients undergoing a sternotomy were evaluated on day 5. Peri-incisional sensory testing was performed using von Frey filament. Presence and severity of PCP were assessed at 2 and 6 months. PCP was present in 29% and 15% of patients respectively at 2 and 6 months. Hyperalgesia on day 5 was present in 43% of patients with PCP at 6 months compared to 15% without PCP. Hypoesthesia was present in 57% of patients with PCP at 6 months compared to 22% without PCP. There was no significant difference in the incidence of dysesthesia. On day 5, hyperalgesia was correlated with a risk to develop PCP at 6 months. Among sensory abnormalities, the presence of hyperalgesia is associated with PCP at 6 months postoperatively.

Clinical Practice: Should we Radically Alter our Sedation of Critical Care Patients, Especially Given the COVID-19 Pandemics?

The high number of patients infected with the SARS-CoV-2 virus requiring care for ARDS puts sedation in the critical care unit (CCU) to the edge. Depth of sedation has evolved over the last 40 years (no-sedation, deep sedation, daily emergence, minimal sedation, etc.). Most guidelines now recommend determining the depth of sedation and minimizing the use of benzodiazepines and opioids. The broader use of alpha-2 adrenergic agonists ('alpha-2 agonists') led to sedation regimens beginning at admission to the CCU that contrast with hypnotics+opioids ("conventional" sedation), with major consequences for cognition, ventilation and circulatory performance. The same doses of alpha-2 agonists used for 'cooperative' sedation (ataraxia, analgognosia) elicit no respiratory depression but modify the autonomic nervous system (cardiac parasympathetic activation, attenuation of excessive cardiac and vasomotor sympathetic activity). Alpha-2 agonists should be selected only in patients who benefit from their effects ('personalized' indications, as opposed to a 'one size fits all' approach). Then, titration to effect is required, especially in the setting of systemic hypotension and/or hypovolemia. Since no general guidelines exist for the use of alpha-2 agonists for CCU sedation, our clinical experience is summarized for the benefit of physicians in clinical situations in which a recommendation might never exist (refractory delirium tremens; unstable, hypovolemic, hypotensive patients, etc.). Because the physiology of alpha-2 receptors and the pharmacology of alpha-2 agonists lead to personalized indications, some details are offered. Since interactions between conventional sedatives and alpha-2 agonists have received little attention, these interactions are addressed. Within the existing guidelines for CCU sedation, this article could facilitate the use of alpha-2 agonists as effective and safe sedation while awaiting large, multicentre trials and more evidence-based medicine.