Micro- and macrocirculatory effects of norepinephrine on anaesthesia-induced hypotension: a prospective preliminary study.

BACKGROUND: Intraoperative arterial hypotension (IOH) leads to increased postoperative morbidity. Norepinephrine is often use to treat IOH. The question regarding the mode of administration in either a bolus or continuous infusion remains unanswered. The aim of the present study was to describe and compare the effects on macrocirculation and microcirculation of a bolus and a continuous infusion of norepinephrine to treat IOH. METHODS: We conducted a prospective observational study with adult patients who underwent neurosurgery. Patients with invasive arterial blood pressure and cardiac output (CO) monitoring were screened for inclusion. All patients underwent microcirculation monitoring by video-capillaroscopy, laser doppler, near-infrared spectroscopy technology, and tissular CO2. In case of IOH, the patient could receive either a bolus of 10 µg or a continuous infusion of 200 µg/h of norepinephrine. Time analysis for comparison between bolus and continuous infusion were at peak of MAP. The primary outcome was MFI by videocapillaroscopy. RESULTS: Thirty-five patients were included, with 41 boluses and 33 continuous infusion. Bolus and continuous infusion induced an maximal increase in mean arterial pressure of +30[20-45] and +23[12-34] %, respectively (P=0,07). For macrocirculatory parameters, continuous infusion was associated with a smaller decrease in CO and stroke volume (p<0.05). For microcirculatory parameters, microvascular flow index (-0,1 vs. + 0,3, p=0,03), perfusion index (-12 vs. +12%, p=0,008), total vessel density (-0,2 vs. +2,3 mm2/mm2, p=0,002), showed significant opposite variations with bolus and continuous infusion, respectively. CONCLUSIONS: These results on macro and microcirculation enlighten the potential benefits of a continuous infusion of norepinephrine rather than a bolus to treat anaesthesia-induced hypotension. TRIAL REGISTRATION: (NOR-PHARM: 1-17-42 Clinical Trials: NCT03454204), 05/03/2018.

Estimation of cardiac output variations induced by hemodynamic interventions using multi-beat analysis of arterial waveform: a comparative off-line study with transesophageal Doppler method during non-cardiac surgery.

Multi-beat analysis (MBA) of the radial arterial pressure (AP) waveform is a new method that may improve cardiac output (CO) estimation via modelling of the confounding arterial wave reflection. We evaluated the precision and accuracy using the trending ability of the MBA method to estimate absolute CO and variations (ΔCO) during hemodynamic challenges. We reviewed the hemodynamic challenges (fluid challenge or vasopressors) performed when intra-operative hypotension occurred during non-cardiac surgery. The CO was calculated offline using transesophageal Doppler (TED) waveform (COTED) or via application of the MBA algorithm onto the AP waveform (COMBA) before and after hemodynamic challenges. We evaluated the precision and the accuracy according to the Bland & Altman method. We also assessed the trending ability of the MBA by evaluating the percentage of concordance with 15% exclusion zone between ΔCOMBA and ΔCOTED. A non-inferiority margin was set at 87.5%. Among the 58 patients included, 23 (40%) received at least 1 fluid challenge, and 46 (81%) received at least 1 bolus of vasopressors. Before treatment, the COTED was 5.3 (IQR [4.1-8.1]) l min-1, and the COMBA was 4.1 (IQR [3-5.4]) l min-1. The agreement between COTED and COMBA was poor with a 70% percentage error. The bias and lower and upper limits of agreement between COTED and COMBA were 0.9 (CI95 = 0.82 to 1.07) l min-1, -2.8 (CI95 = -2.71 to-2.96) l min-1 and 4.7 (CI95 = 4.61 to 4.86) l min-1, respectively. After hemodynamic challenge, the percentage of concordance (PC) with 15% exclusion zone for ΔCO was 93 (CI97.5 = 90 to 97)%. In this retrospective offline analysis, the accuracy, limits of agreements and percentage error between TED and MBA for the absolute estimation of CO were poor, but the MBA could adequately track induced CO variations measured by TED. The MBA needs further evaluation in prospective studies to confirm those results in clinical practice conditions.

Velocity-pressure loops can estimate intrinsic and pharmacologically induced changes in cardiac afterload during non-cardiac surgery. An observational study.

PURPOSE: Continuous measurement of aortic pressure and aortic flow velocity signals in the operating theatre allows us to draw velocity-pressure (Vel-Pre) loops. The global afterload angle (GALA), derived from the Vel-Pre loops, has been linked to cardiac afterload indicators. As age is the major determinant of constitutive arterial stiffness, we aimed to describe (1) the evolution of the GALA according to age in a large cohort of anesthetized patients and (2) GALA variations induced by haemodynamic interventions. METHODS: We included patients for whom continuous monitoring of arterial pressure and cardiac output were indicated. Fluid challenges or vasopressors were administered to treat intra-operative hypotension. The primary endpoint was the comparison of the GALA values between young and old patients. The secondary endpoint was the difference in the GALA values before and after haemodynamic interventions. RESULTS: We included 133 anaesthetized patients: 66 old and 67 young patients. At baseline, the GALA was higher in the old patients than in young patients (38 ± 6 vs. 25 ± 4 degrees; p < 0.001). The GALA was positively associated with age (p < 0.001), but the mean arterial pressure (MAP) and cardiac output were not. The GALA did not change after volume expansion, regardless of the fluid response, but it did increase after vasopressor administration. Furthermore, while a vasopressor bolus led to a similar increase in MAP, phenylephrine induced a more substantial increase in the GALA than noradrenaline (+ 12 ± 5° vs. + 8 ± 5°; p = 0.01). CONCLUSION: In non-cardiac surgery, the GALA seems to be associated with both intrinsic rigidity (reflected by age) and pharmacologically induced vasoconstriction changes (by vasopressors). In addition, the GALA can discriminate the differential effects of phenylephrine and noradrenaline. These results should be confirmed in a prospective, ideally randomized, trial.

Characteristics of the convergent angles of tapered implants based on a premolar root model.

STATEMENT OF PROBLEM: Developing tapered implants with the most appropriate angular characteristics requires an improved analysis of the anatomy of premolar roots. PURPOSE: The purpose of this observational study was to analyze the 3D anatomy of premolar roots by determining the tapered slope and convergent angle (TS/CA), to transform the TS/CA patterns into those in which the tapered implants mimic natural tooth roots, and to provide TS/CA references for future investigations. MATERIAL AND METHODS: A total of 73 human single-rooted premolars were surveyed and analyzed by microcomputed tomography and an associated software program. The 3D root surface area (RSA), the radius/diameter (R/D) at the planned first to tenth millimeter levels apical to the cementoenamel junction (CEJ), and the TS/CA at corresponding levels were calculated. The results were statistically analyzed by using an independent samples t test to assess the general differences of tested parameters between maxillary and mandibular premolars. A paired t test was used to examine the significant intragroup TS/CA differences between sequential coronoapical levels. One-way ANOVA was applied to study the general significance of developmental patterns in maxillary and/or mandibular groups. Two-way ANOVA was used to inspect the TS/CA significance at various measurements coronoapically between the maxillary and mandibular premolars (α=.05). RESULTS: Generally, the RSA, root length, R/D, and TS/CA parameters examined for the maxillary premolar roots differed significantly from those for the mandibular roots at the evaluated levels (P<.05). According to the measurements, the maxillary premolar roots generally exhibited nonsignificant RSA and R/D reduction patterns, with a decreasing angle of TS=13.44 degrees and CA=24.53 degrees coronoapically. However, mandibular premolar roots exhibited a significant reduction pattern, with TS=11.25 degrees and CA=21.06 degrees coronoapically according to both individual and general evaluations. CONCLUSIONS: Based on the developmental patterns of the evaluated TSs/CAs, tapered implants imitating premolar root anatomy should have a conical rather than a cylindrical shape, and the R/D of these models should be reduced to half at the apical third. However, further studies are warranted to identify more TS/CA characteristics related to the tapered implants, including the TSs/CAs of other tooth types.

Psychological torture: definitions, clinical sequelae and treatment principles.

Psychological torture, in its broadest sense, is the intentional infliction of suffering without resorting to direct physical violence, in what is known as 'no-touch' torture. While several other definitions of psychological torture have been suggested, there is no one precise definition. Given the rapidly evolving current global political climate and the intensification of conflict, war and asylum seeking, the need for better recognition of psychological torture among clinicians, followed by the provision of appropriate treatment support for victims, has become increasingly pertinent. This article raises awareness of the concept of psychological torture among clinicians, through an overview of its debated definitions, the modalities which constitute this form of torture, and its clinical sequelae and treatment approach.

Convergent angles of a tapered implant referred from the root profile of premolars.

Background/purpose: Limited studies have discussed the convergent profiles regarding tapered implants based on biological considerations. This study analyzed the convergent angles (CAs) of premolar roots and imitated a tapered implant according to the anatomy of tooth roots. Materials and methods: A total of 60 single-rooted premolars were explored by micro-computed tomography. Every individual root was divided into 10 segments corono-apically, and the roots' buccolingual (BL) and mesiodistal (MD) CAs were measured by sections. To mimic a dental implant, the irregular shape of examined root cross-sections was transformed into a circular shape with equal areas. A biomimetic dental implant (BDI) was reconstructed and its CAs were compared with those of the natural roots' BL and MD at the examined levels and overall estimation. Results: In general, the maxillary and mandibular premolars demonstrated comparable CA patterns. However, significantly different CA patterns of BL, MD, and BDI were developed for both the maxillary and mandibular roots at the examined levels. The BL's CAs were greater than those CAs measured from the BDI and MD aspects, particularly for the sections at the middle and apical thirds of the roots. For overall CAs, the BDI's CAs were comparable with the average CAs of the BL and MD for both premolar groups. Conclusion: Instead of a cylindrical configuration, the BDI prototype demonstrated a tapered model with a continuous slope. The average CA of BDI was 14°-24°, serving as a biological reference for future tapered implant design and research.

The developing patterns of calibrated implant stability quotients of posterior implants.

BACKGROUND/PURPOSE: Many surgical protocols were modified to improve implant stability. However, the conclusions of applying osteotome condensation technique could enhance implant stability were controversial. The evaluated implant stability quotients (ISQ) were calibrated to differentiate the implant stability improvement that applied by varied surgical techniques and the bone quality at recipient sites. Therefore, this study examine the developing patterns of calibrated ISQ values induced by osteotome bone condensation and conventional drilling technique at the posterior ridges. MATERIALS AND METHODS: The ISQ values of 4.1/4.8-mm diameter implants were calibrated by 3.3-mm diameter implants (ISQb). Osteotome condensation technique was applied on the sites with ISQb ≤ 65 while those with ISQb > 65 were treated with conventional drilling technique. The implant ISQ values at Week 0, 1, 2, 3, 4, 6, 8, 10, 12 were recorded. The detected and calibrated ISQ values were statistically analyzed. RESULTS: Maxillary 14 implants and mandibular 16 implants using osteotome technique, maxillary 15 implants and mandibular 16 implants with conventional drilling technique were studied. Both techniques showed a generally similar ISQ developing pattern at both arches. Without calibration, significantly less ISQ values were noted for the osteotome technique of posterior maxilla at initial four weeks; subsequently, both techniques presented a comparable ISQ developing pattern. Osteotome technique demonstrated a greater ISQ increase after calibration on both arches (p < 0.05). All implants reached an ISQ stability plateau between Week 8 and 10. CONCLUSION: With calibration, osteotome condensation technique could enhance greater primary and secondary implant stability for both arches.

Pembrolizumab-Induced Pancreatic Exocrine Insufficiency Complicated by Severe Hepatic Steatosis.

Anti-programmed death receptor-1 (anti-PD-1) monoclonal antibodies (mAbs) are used to treat an increasing range of cancers. However, the distinct toxicity profile of immune-related adverse events (irAEs) is a frequent drawback of their clinical application. Among the more common irAEs are hepatitis and colitis, which are diagnosed and graded in patients based on elevated serum liver enzyme levels and increased stool frequency, respectively, and both of which often require treatment with high-dose corticosteroids. Herein, we describe the case of a patient who developed severe transaminase elevation and diarrhoea due to an unusual irAE, which was successfully treated without corticosteroids.

Calcitriol and enamel matrix derivative differentially regulated cemento-induction and mineralization in human periodontal ligament-derived cells.

BACKGROUND: Alveolar bone and cementum share many biological and developmental similarities. The mineralizing effect of calcitriol has been previously reported. Yet, its cemento-inductivity has not been confirmed. This study evaluated the potential cemento-inductivity effect of calcitriol and enamel matrix derivative (EMD) on human periodontal ligament-derived cells (hPDLCs). METHODS: The hPDLCs obtained from extracted third molars or premolars were cultured with calcitriol, or EMD. Cementogenic gene expression was examined using real-time quantitative reverse transcription polymerase chain reaction. Expression analysis also included cementoblast-specific markers, cementum protein 1 (CEMP1), cementum attachment protein (CAP), and recently reported cementoblast-enriched genes, secreted frizzled related protein 1 (SFRP1), and Dickkopf-related protein 1 (DKK1). Mineralization capacities were evaluated by alkaline phosphatase (ALP) activity, Alizarin Red, and Von Kossa staining followed by scanning electron microscope imaging and element mapping. RESULTS: Among tested conditions, 10 nM calcitriol enhanced most cementogenic gene expression, transforming growth factor-ß1, bone morphogenetic proteins (BMP-2 and BMP-4), core-binding factor subunit alpha-1/Runt-related transcription factor 2, Type I collagen, ALP, bone sialoprotein, osteopontin), osteocalcin, CEMP1, and CAP, and Wnt signaling negative modulators, SFRP1 and DKK1, along with highest ALP activity and mineralization formation in hPDLCs. However, only moderate CEMP1 protein was observed. In contrast, EMD stimulated stronger CEMP1 and CAP protein, but presented weaker mineralization capacity, hinting at the possibility that strong stimulation of mineralization might dominate cemetogenic specific factors and vice versa. CONCLUSIONS: Calcitriol demonstrated not only great osteoinductivity, but also the potential to induce cementogenic gene expression by initiating hPDLC differentiation and promoting mineralization. Compared with calcitriol, EMD promoted cemento-inductivity in hPDLCs at a later time point via highly expressed CEMP1 and CAP protein, but with less mineralization. Thus, calcitriol and EMD could provide differential enhancement of cemento-induction and mineralization, likely acting at various differentiation stages.

Influence of noninvasive central blood pressure devices for afterload monitoring with aortic velocity-pressure Loop in anesthetized patients.

BACKGROUND: Global afterload angle (GALA) is a parameter derived from velocity-pressure loop (VP Loop), for continuous assessment of cardiac afterload in the operating room. It has been validated with invasive measure of central pressure. The aim of this study was to evaluate the feasibility of noninvasive VP Loop obtained with central pressure measured with two different noninvasive tonometers. METHODS: A prospective, observational, monocentric study was conducted in 51 patients under general anesthesia. Invasive central pressure (cPINV) was measured with a fulfilled intravascular catheter, and noninvasive central pressure signals were obtained with two applanation tonometry devices: radial artery tonometry (cPSHYG: Sphygmocor tonometer) and carotid tonometry (cPCOMP: Complior tonometer). Three VP Loops were built: VP LoopINV, VP LoopSPHYG and VP LoopCOMP. Patients were separated according to cardiovascular risk factors. RESULTS: In the 51 patients under general anesthesia, cPSHYG was adequately obtained in 48 patients (89%) but, compared to cPINV, SBP was underestimated (-4 ± 6 mmHg, P < 0.0001), augmentation index (AIXSPHYG) and a GALASPHYG were overestimated (+13 ± 19%, P = 0.0077 and +4 ± 8°, P = 0.0024, respectively) with large limit of agreement (LOA) (-21 to 47% and -13 to 21° for AIXSPHYG and GALASPHYG, respectively). With the Complior, the failure rate of measurement for cPCOMP was 41%. SBP was similar (3 ± 17 mmHg, P = 0.32), AIXCOMP was underestimated (-11 ± 19%, P = 0.0046) and GALACOMP was similar but with large LOA (-50 to 26% and -20 to 18° for AIXCOMP and GALACOMP, respectively). CONCLUSION: In anesthetized patient, the reliability of noninvasive central pressure monitoring by tonometry seems too limited to monitor cardiac afterload with VP Loop.

Assessment of blood flow velocities and venous pressures using a dual-sensor guidewire in symptomatic dural sinus stenoses.

Lateral venous sinus stenoses have been associated with idiopathic intracranial hypertension and venous pulsatile tinnitus. Venous pressure measurement is traditionally performed to assess the indications for stenting in patients with idiopathic intracranial hypertension. However, its reliability has recently been questioned by many authors. The dual-sensor guidewire was first developed for advanced physiological assessment of fractional and coronary flow reserves in coronary artery stenoses. It allows measurement of both venous pressure and blood flow velocities. The authors used this device in 14 consecutively treated patients to explore for symptomatic lateral sinus stenosis. They found that venous blood flow was significantly accelerated inside the stenotic lesion. This acceleration, as well as the pulsatile tinnitus, resolved in all patients following stent placement. According to the authors' results, this guidewire can be helpful for establishing an indication for stenting in patients with pulsatile tinnitus and idiopathic intracranial hypertension.

Perioperative management of patients with coronary artery disease undergoing non-cardiac surgery: Summary from the French Society of Anaesthesia and Intensive Care Medicine 2017 convention.

This review summarises the specific stakes of preoperative, intraoperative, and postoperative periods of patients with coronary artery disease undergoing non-cardiac surgery. All practitioners involved in the perioperative management of such high cardiac risk patients should be aware of the modern concepts expected to decrease major adverse cardiac events and improve short- and long-term outcomes. A multidisciplinary approach via a functional heart team including anaesthesiologists, cardiologists and surgeons must be encouraged. Rational and algorithm-guided management of those patients should be known and implemented from preoperative to postoperative period.

Directional cerebrospinal fluid movement between brain ventricles in larval zebrafish.

BACKGROUND: Cerebrospinal fluid (CSF) contained within the brain ventricles contacts neuroepithelial progenitor cells during brain development. Dynamic properties of CSF movement may limit locally produced factors to specific regions of the developing brain. However, there is no study of in vivo CSF dynamics between ventricles in the embryonic brain. We address CSF movement using the zebrafish larva, during the major period of developmental neurogenesis. METHODS: CSF movement was monitored at two stages of zebrafish development: early larva [pharyngula stage; 27-30 h post-fertilization (hpf)] and late larva (hatching period; 51-54 hpf) using photoactivatable Kaede protein to calculate average maximum CSF velocity between ventricles. Potential roles for heartbeat in early CSF movement were investigated using tnnt2a mutant fish (tnnt2a (-/-)) and chemical [2,3 butanedione monoxime (BDM)] treatment. Cilia motility was monitored at these stages using the Tg(ßact:Arl13b-GFP) transgenic fish line. RESULTS: In wild-type early larva there is net CSF movement from the telencephalon to the combined diencephalic/mesencephalic superventricle. This movement directionality reverses at late larval stage. CSF moves directionally from diencephalic to rhombencephalic ventricles at both stages examined, with minimal movement from rhombencephalon to diencephalon. Directional movement is partially dependent on heartbeat, as indicated in assays of tnnt2a (-/-) fish and after BDM treatment. Brain cilia are immotile at the early larval stage. CONCLUSION: These data demonstrate directional movement of the embryonic CSF in the zebrafish model during the major period of developmental neurogenesis. A key conclusion is that CSF moves preferentially from the diencephalic into the rhombencephalic ventricle. In addition, the direction of CSF movement between telencephalic and diencephalic ventricles reverses between the early and late larval stages. CSF movement is partially dependent on heartbeat. At early larval stage, the absence of motile cilia indicates that cilia likely do not direct CSF movement. These data suggest that CSF components may be compartmentalized and could contribute to specialization of the early brain. In addition, CSF movement may also provide directional mechanical signaling.

Epstein-Barr Virus Infection of Mammary Epithelial Cells Promotes Malignant Transformation.

Whether the human tumor virus, Epstein-Barr Virus (EBV), promotes breast cancer remains controversial and a potential mechanism has remained elusive. Here we show that EBV can infect primary mammary epithelial cells (MECs) that express the receptor CD21. EBV infection leads to the expansion of early MEC progenitor cells with a stem cell phenotype, activates MET signaling and enforces a differentiation block. When MECs were implanted as xenografts, EBV infection cooperated with activated Ras and accelerated the formation of breast cancer. Infection in EBV-related tumors was of a latency type II pattern, similar to nasopharyngeal carcinoma (NPC). A human gene expression signature for MECs infected with EBV, termed EBVness, was associated with high grade, estrogen-receptor-negative status, p53 mutation and poor survival. In 11/33 EBVness-positive tumors, EBV-DNA was detected by fluorescent in situ hybridization for the viral LMP1 and BXLF2 genes. In an analysis of the TCGA breast cancer data EBVness correlated with the presence of the APOBEC mutational signature. We conclude that a contribution of EBV to breast cancer etiology is plausible, through a mechanism in which EBV infection predisposes mammary epithelial cells to malignant transformation, but is no longer required once malignant transformation has occurred.