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.

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.

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.

Patient-Reported Outcome Measures may optimize shared decision-making for cancer risk management in BRCA mutation carriers.

PURPOSE: The aim of this study was to compare patient-reported outcomes (PROs) of BRCA1/2 mutation carriers, either after bilateral prophylactic mastectomy (BPM) or during breast surveillance, to improve shared decision-making in their cancer risk management. METHODS: Unaffected BRCA1/2 mutation carriers at least one year after BPM followed by immediate breast reconstruction (BPM-IBR) or one year under surveillance were eligible. After informed consent, the Hospital Anxiety and Depression Scale (HADS) and BREAST-Q were administered and compared between the different strategies. PROs were also compared to available normative data. RESULTS: Ninety-six participants were analyzed in this study and showed significant differences between strategies in age, age at genetic testing, and time since BPM or starting breast surveillance. All HADS scores were below 8 suggesting no signs of anxiety or depression in both groups. Higher mean 'Q-physical well-being' scores were reported by the surveillance group (81.78 [CI 76.99-86.57]) than the BPM group (76.96 [CI 73.16 - 80.75]; p = 0.011). Overall, for both questionnaires better scores were seen when compared to age-matched normative data. CONCLUSIONS: No signs of anxiety or depression were seen in the surveillance or BPM-IBR group. Slightly better mean BREAST-Q scores were seen for the surveillance group in comparison to BPM-IBR, except for 'Q-psychological well-being'. The difference in 'Q-physical well-being' was significantly worse for BPM-IBR. Approaches to obtain longitudinal PROs and reference values should be explored in the future, which could add value to shared decision-making in regards to breast cancer risk management in this specific patient population.

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.

Pharmacokinetics of Sulfadoxine and Pyrimethamine for Intermittent Preventive Treatment of Malaria During Pregnancy and After Delivery.

Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98 women during pregnancy and 77 after delivery in four African countries were analyzed using nonlinear mixed-effects modeling to characterize the effects of pregnancy, postpartum duration, and other covariates such as body weight and hematocrit on sulfadoxine/pyrimethamine pharmacokinetic properties. During pregnancy, clearance increased 3-fold for sulfadoxine but decreased by 18% for pyrimethamine. Postpartum sulfadoxine clearance decreased gradually over 13 weeks. This finding, together with hematocrit-based scaling of plasma to whole-blood concentrations and allometric scaling of pharmacokinetics parameters with body weight, enabled site-specific differences in the pharmacokinetic profiles to be reduced significantly but not eliminated. Further research is necessary to explain residual site-specific differences and elucidate whether dose-optimization, to address the 3-fold increase in clearance of sulfadoxine in pregnant women, is necessary, viable, and safe with the current fixed dose combination of sulfadoxine/pyrimethamine.

Primitive Tumour of the Pulmonary Valve: Discussion of the Differential Diagnosis.

There is a paucity of information concerning cardiac tumours of the pulmonary valve due to their rarity at this location. We report a case of a 47-year-old patient suffering from haemoptysis, asthenia, and acute kidney injury (AKI). A transthoracic echocardiography (TTE) revealed a mass on the pulmonary valve. Further diagnostic investigation was completed until he exhibited worsening hemodynamic instability. This case emphasizes the lack of information regarding the management of a pulmonary valve tumour.

Do we feel pain during anesthesia? A critical review on surgery-evoked circulatory changes and pain perception.

The difficulty of defining the three so-called components of « an-esthesia ¼ is emphasized: hypnosis, absence of movement, and adequacy of anti-nociception (intraoperative « analgesia ¼). Data obtained from anesthetized animals or humans delineate the activation of cardiac and vasomotor sympathetic reflex (somato-sympathetic reflex) and the cardiac parasympathetic deactivation observed following somatic stimuli. Sympathetic activation and parasympathetic deactivation are used as monitors to address the adequacy of intraoperative anti-nociception. Finally, intraoperative nociception through the administration of nonopioid analgesics vs. opioid analgesics is considered to achieve minimal postoperative side effects.

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.

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.

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 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.

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.

[Postoperative pain trajectories to identify risk of chronic postsurgical pain in living donors for liver transplantation]. / Identification du risque de douleur chronique après hépatectomie pour don de foie par les trajectoires de douleur.

OBJECTIVES: To assess pain trajectories in predicting risk of chronic postoperative pain (CPP) after liver resection for living donor transplantation. STUDY DESIGN: Retrospective analysis of patients undergoing liver resection for living donor transplantation during 3years. PATIENTS AND METHODS: After recording perioperative data, patients presenting CPP at 3months were separated from patients without postsurgical pain problem in order to build a pain trajectory for liver donor patients without CPP. Postoperative course of liver donors with CPP was then compared to that standard pain trajectory. RESULTS: Sixty-five patients (30 females, 35 males) were included. Epidural analgesia was used in 66%; others received autocontrolled analgesia by morphine. Severe acute pain was expressed by 11% and 37% at rest and movement respectively on the first day. Chronic pain involved six patients without any link with gender or type of analgesia. Analysis of pain trajectories shown that these patients presented either higher initial pain at day 1 or positive slopes with worsening of pain. CONCLUSION: Acute postoperative pain is a risk factor of developing CPP. Identification of those people by pain trajectories can be useful to treat them early.