Diagnostic Value of Aortic Valve Calcification Levels in the Assessment of Low-Gradient Aortic Stenosis.

BACKGROUND: In patients with low-gradient aortic stenosis (AS) and low transvalvular flow, dobutamine stress echocardiography (DSE) is recommended to determine AS severity, whereas the degree of aortic valve calcification (AVC) supposedly correlates with AS severity according to current European and American guidelines. OBJECTIVES: The purpose of this study was to assess the relationship between AVC and AS severity as determined using echocardiography and DSE in patients with aortic valve area <1 cm2 and peak aortic valve velocity <4.0 m/s. METHODS: All patients underwent DSE to determine AS severity and multislice computed tomography to quantify AVC. Receiver-operating characteristics curve analysis was used to assess the diagnostic value of AVC for AS severity grading as determined using echocardiography and DSE in men and women. RESULTS: A total of 214 patients were included. Median age was 78 years (25th-75th percentile: 71-84 years) and 25% were women. Left ventricular ejection fraction was reduced (<50%) in 197 (92.1%) patients. Severe AS was diagnosed in 106 patients (49.5%). Moderate AS was diagnosed in 108 patients (50.5%; in 77 based on resting transthoracic echocardiography, in 31 confirmed using DSE). AVC score was high (≥2,000 for men or ≥1,200 for women) in 47 (44.3%) patients with severe AS and in 47 (43.5%) patients with moderate AS. AVC sensitivity was 44.3%, specificity was 56.5%, and positive and negative predictive values for severe AS were 50.0% and 50.8%, respectively. Area under the receiver-operating characteristics curve was 0.508 for men and 0.524 for women. CONCLUSIONS: Multi-slice computed tomography-derived AVC scores showed poor discrimination between grades of AS severity using DSE and cannot replace DSE in the diagnostic work-up of low-gradient severe AS.

Physical and Computational Modeling for Transcatheter Structural Heart Interventions.

Structural heart disease interventions rely heavily on preprocedural planning and simulation to improve procedural outcomes and predict and prevent potential procedural complications. Modeling technologies, namely 3-dimensional (3D) printing and computational modeling, are nowadays increasingly used to predict the interaction between cardiac anatomy and implantable devices. Such models play a role in patient education, operator training, procedural simulation, and appropriate device selection. However, current modeling is often limited by the replication of a single static configuration within a dynamic cardiac cycle. Recognizing that health systems may face technical and economic limitations to the creation of "in-house" 3D-printed models, structural heart teams are pivoting to the use of computational software for modeling purposes.

Sequential Alcohol Septal Ablation to Resolve LV Outflow Tract Obstruction After Transcatheter Mitral Valve Replacement.

Left ventricular outflow tract obstruction (LVOTO) is a notorious complication of transcatheter mitral valve replacement (TMVR). Computed tomography-derived simulations can predict neo-LVOTO post-TMVR, whereas alcohol septal ablation (ASA) can mitigate neo-LVOTO risk. We report a case of sequential ASA of 2 adjacent septal branches to resolve unexpected neo-LVOTO post-TMVR.

Transcatheter Aortic Valve Replacement for Pure Native Aortic Valve Regurgitation: The PANTHEON International Project.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) in patients with pure severe native aortic valve regurgitation (NAVR) has been associated with suboptimal results. The available evidence concerns mostly outdated transcatheter heart valves (THVs). OBJECTIVES: The aim of this study was to investigate the performance of new-generation THVs in patients treated for pure severe NAVR. METHODS: The PANTHEON (Performance of Currently Available Transcatheter Aortic Valve Platforms in Inoperable Patients With Pure Aortic Regurgitation of a Native Valve) study retrospectively included patients who underwent TAVR with currently available devices (both self-expanding [SE] and balloon expandable [BE]) for severe NAVR. Technical and device success rates as well as a composite of all-cause mortality and heart failure rehospitalization at 1 year were evaluated. The rate and clinical consequences of acute transcatheter valve embolization or migration (TVEM) were also considered. RESULTS: A total of 201 patients were included. Overall technical and device success rates were 83.6% and 76.1%, respectively, and did not differ between SE and BE devices. These figures were due mostly to TVEM occurrence (14.6% vs 16.1%; P = 0.47) and residual moderate or greater aortic regurgitation (9.2% vs 10.1%; P = 0.87). Patients who experienced TVEM compared with those without TVEM had a significantly higher incidence of the composite endpoint at 1 year (25.7% vs 15.8%; P = 0.05). CONCLUSIONS: Despite improved THV platforms and techniques, TAVR for pure severe NAVR remains a challenging procedure, with significant risk for TVEM. SE and BE platforms demonstrated comparable performance in this setting. (Performance of Currently Available Transcatheter Aortic Valve Platforms in Inoperable Patients With Pure Aortic Regurgitation of a Native Valve [PANTHEON]; NCT05319171).

Invasive Real Time Biventricular Pressure-Volume Loops to Monitor Dynamic Changes in Cardiac Mechanoenergetics During Structural Heart Interventions: Design and Rationale of a Prospective Single-Center Study.

Background: Transcatheter valvular interventions affect cardiac and hemodynamic physiology by changing ventricular (un-)loading and metabolic demand as reflected by cardiac mechanoenergetics. Real-time quantifications of these changes are scarce. Pressure-volume loop (PVL) monitoring appraises both load-dependent and load-independent compounds of cardiac physiology including myocardial work, ventricular unloading, and ventricular-vascular interactions. The primary objective is to describe changes in physiology induced by transcatheter valvular interventions using periprocedural invasive biventricular PVL monitoring. The study hypothesizes transcatheter valve interventions modify cardiac mechanoenergetics that translate into improved functional status at 1-month and 1-year follow-up. Methods: In this single-center prospective study, invasive PVL analysis is performed in patients undergoing transcatheter aortic valve replacement or tricuspid or mitral transcatheter edge-to-edge repair. Clinical follow-up is per standard of care at 1 and 12 months. This study aims to include 75 transcatheter aortic valve replacement patients and 41 patients in both transcatheter edge-to-edge repair cohorts. Results: The primary outcome is the periprocedural change in stroke work, potential energy, and pressure-volume area (mmHg mL-1). The secondary outcomes comprise changes in a myriad of parameters obtained by PVL measurements, including ventricular volumes and pressures and the end-systolic elastance-effective arterial elastance ratio as a reflection of ventricular-vascular coupling. A secondary endpoint associates these periprocedural changes in cardiac mechanoenergetics with functional status at 1 month and 1 year. Conclusions: This prospective study aims to elucidate the fundamental changes in cardiac and hemodynamic physiology during contemporary transcatheter valvular interventions.

Development of a sterile morphine hydrogel for the local treatment of painful skin ulcers.

OBJECTIVES: It is often difficult to relieve the pain from skin ulcers. In several patients, topical morphine, applied as a hydrogel, has been described as useful. There is no such product commercially available. We present a solution for compounding, packaging, sterilisation and chemical stability of a morphine containing hydrogel. METHODS: We developed a morphine containing poloxamer 407 thermoreversible hydrogel with a concentration of 5 mg/g (0.5% w/w) morphine hydrochloride. The hydrogel was packaged into a plastic prefillable syringe system: BD Sterifill SCF. This syringe can be steam sterilised after it has been filled. RESULTS: Sterility tests according to the European Pharmacopoeia showed the product to be sterile directly after production and sterilisation and after 20 months of storage. The stability of the morphine hydrochloride was assessed by monthly analysis of the concentration with a stability indicating HPLC-UV method. Morphine hydrochloride concentrations remained between 90% and 110% of the theoretical concentration for a period of 36 months, when stored at room temperature outside the influence of light. CONCLUSION: With the described formulation, packaging, sterilisation and stability data, together with the previously reported biopharmaceutical dissolution profile, we present a complete solution for a morphine containing poloxamer 407 hydrogel that can be compounded in any pharmacy with a steam or hot water steriliser at their disposal. This might improve the availability of a sterile morphine hydrogel for the treatment of painful skin ulcers.

Transcranial Doppler-derived indices of cerebrovascular haemodynamics are independent of depth and angle of insonation.

Continuous measurement of cerebral blood flow velocity (CBFV) of the middle cerebral artery (MCA) using transcranial Doppler (TCD) and arterial blood pressure (ABP) monitoring enables assessment of cerebrovascular haemodynamics. Further indices describing cerebrovascular function can be calculated from ABP and CBFV, such as the mean index (Mxa) of cerebrovascular autoregulation, the 'time constant of the cerebral arterial bed' (tau), the 'critical closing pressure' (CrCP) and a 'non-invasive estimator of ICP' (nICP). However, TCD is operator-dependent and changes in angle and depth of MCA insonation result in different readings of CBFV. The effect of differing CBFV readings on the calculated secondary indices remains unknown. The aim of this study was to investigate variation in angle and depth of MCA insonation on these secondary indices. In eight patients continuous ABP and ipsilateral CBFV monitoring was performed using two different TCD probes, resulting in four simultaneous CBFV readings at different angles and depths per patient. From all individual recordings, the K-means clustering algorithm was applied to the four simultaneous longitudinal measurements. The average ratios of the between-clusters, sum-of-squares and total sum-of-squares were significantly higher for CBFV than for the indices Mxa, tau and CrCP (p < 0.001, p = 0.007 and p = 0.016) but not for nICP (p = 0.175). The results indicate that Mxa, tau and CrCP seemed to be not affected by depth and angle of TCD insonation, whereas nICP was.

Nitric Oxide Attenuates the Inflammatory Effects of Air During Extracorporeal Circulation.

Cardiopulmonary bypass causes a systemic inflammatory response reaction that may contribute to postoperative complications. One cause relates to the air/blood interface from the extracorporeal circuit. The modulatory effects of blending nitric oxide (NO) gas into the ventilation/sweep gas of the membrane lung was studied in a porcine model of air-induced inflammation in which NO gas was added and compared with controls with or without an air/blood interface. Healthy swine were supported on partial bypass under four different test conditions. Group 1: no air exposure, group 2: air alone, group 3: air plus 50 ppm NO, and group 4: air plus 500 ppm NO. The NO gas was blended into the ventilation/sweep site of the membrane lung. The platelets and leucocytes were activated by air alone. Addition of NO to the sweep gas attenuated the inflammatory response created by the air/blood interface in this model.

Tidal Flow Perfusion for the Artificial Placenta: A Paradigm Shift.

The modalities of vascular access for the extracorporeal artificial placenta (AP) have undergone many iterations over the past decade. We hypothesized that single lumen cannulation (SLC) of the jugular vein using tidal flow extracorporeal life (ECLS) support is a feasible alternative to venovenous (VV) umbilical-jugular cannulation and double lumen cannulation (DLC) and can maintain fetal circulation, stable hemodynamics, and adequate gas exchange for 24 hours. After in vitro evaluation of the tidal flow system, six preterm lambs at estimated gestational age 118-124 days (term 145 days) were delivered and underwent VV-ECLS. Three were supported using DLC and three with SLC utilizing tidal flow AP support. Hemodynamics, circuit flow, and gas exchange were monitored. Target fetal parameters were as follows: mean arterial pressure 40-60 mmHg, heart rate 140-240 beats per minute (bpm), SatO2% 60-80%, PaO2 25-50 mmHg, PaCO2 30-55 mmHg, oxygen delivery >5 ml O2/dl/kg/min, and circuit flow 100 ± 25 ml/kg/min. All animals survived 24 hours and maintained fetal circulation with stable hemodynamics and adequate gas exchange. Parameters of the tidal flow group were comparable with those of DLC. Single lumen jugular cannulation using tidal flow is a promising vascular access strategy for AP support. Successful miniaturization holds great potential for clinical translation to support extremely premature infants.

Early detection of left ventricular diastolic dysfunction using conventional and speckle tracking echocardiography in a large animal model of metabolic dysfunction.

Left ventricular (LV) diastolic dysfunction is one of the important mechanisms responsible for symptoms in patients with heart failure. The aim of the current study was to identify parameters that may be used to detect early signs of LV diastolic dysfunction in diabetic pigs on a high fat diet, using conventional and speckle tracking echocardiography. The study population consisted of 16 healthy Göttingen minipigs and 18 minipigs with experimentally induced metabolic dysfunction. Echocardiography measurements were performed at baseline and 3-month follow-up. The ratio of peak early (E) and late filling velocity (E/A ratio) and the ratio of E and the velocity of the mitral annulus early diastolic wave (E/Em ratio) did not change significantly in both groups. Peak untwisting velocity decreased in the metabolic dysfunction group (- 30.1 ± 18.5 vs. - 23.4 ± 15.5 °/ms) but not in controls (- 38.1 ± 23.6 vs. - 42.2 ± 23.0 °/ms), being significantly different between the groups at the 3-month time point (p < 0.05). In conclusion, whereas E/A ratio and E/Em ratio did not change significantly after 3 months of metabolic dysfunction, peak untwisting velocity was significantly decreased. Hence, peak untwisting velocity may serve as an important marker to detect early changes of LV diastolic dysfunction.

Root cause analysis of critical events in neurosurgery, New South Wales.

BACKGROUND: Adverse events reportedly occur in 5% to 10% of health care episodes. Not all adverse events are the result of error; they may arise from systemic faults in the delivery of health care. Catastrophic events are not only physically devastating to patients, but they also attract medical liability and increase health care costs. Root cause analysis (RCA) has become a key tool for health care services to understand those adverse events. METHOD: This study is a review of all the RCA case reports involving neurosurgical patients in New South Wales between 2008 and 2013. The case reports and data were obtained from the Clinical Excellence Commission database. The data was then categorized by the root causes identified and the recommendations suggested by the RCA committees. RESULTS: Thirty-two case reports were identified in the RCA database. Breaches in policy account for the majority of root causes identified, for example, delays in transfer of patients or wrong-site surgery, which always involved poor adherence to correct patient and site identification procedures. The RCA committees' recommendations included education for staff, and improvements in rostering and procedural guidelines. CONCLUSION: RCAs have improved the patient safety profile; however, the RCA committees have no power to enforce any recommendation or ensure compliance. A single RCA may provide little learning beyond the unit and staff involved. However, through aggregation of RCA data and dissemination strategies, health care workers can learn from adverse events and prevent future events from occurring.

Controlled release of morphine from a poloxamer 407 gel.

Treatment of painful ulcers is discouraging. Topical morphine has been described as a useful therapeutic adjunct in some patients. In the development of a new analgesic product, we studied the in vitro release characteristics of a new topical formulation containing 0.5% (w/w) morphine-HCl in a poloxamer 407 (P407) based gel. A diffusion cell was used for measurement of in vitro release characteristics. The donor compartment (DC) and the receptor compartment (RC) were separated by a 5000 Da cellulose acetate membrane. The morphine-HCl release from this developed P407 based gel followed zero-order kinetics with a constant release of 150 µg cm(-2)h(-1). Our results support the use of this P407 gel as a sustained release topical formulation in the pharmacological treatment of painful ulcers. Future research welcomes a formulation with release characteristics leading to less frequent application.

Identification of drug-related problems by a clinical pharmacist in addition to computerized alerts.

BACKGROUND: Both clinical pharmacists and computerized physician order entry systems with clinical decision support (CPOE/CDSS) can reduce drug-related problems (DRPs). However, the contribution of a clinical pharmacist in addition to CPOE/CDSS has not been established in a prospective study. OBJECTIVE: To determine which DRPs can be identified by a clinical pharmacist in a setting with routine use of CPOE/CDSS. SETTING: Two surgical and two neurological wards in St. Elisabeth hospital, a 600-bed teaching hospital in the Netherlands. METHODS: In this observational prospective follow-up study a clinical pharmacist reviewed the pharmacotherapy of patients admitted to surgical and neurological wards to identify DRPs (i.e. medication errors and adverse drug events) and discussed the relevance of identified problems and interventions to resolve these with the responsible physician. Acceptance of the proposed interventions and the presence of alerts in CPOE/CDSS were assessed. Primary outcome was the proportion of DRPs identified by the clinical pharmacist that also triggered a CPOE/CDSS alert. Differences between the DRPs that generated an alert and those that did not were expressed as relative risks or analyzed with Chi square statistics or Mann-Whitney U tests. MAIN OUTCOME MEASURE: The proportion of drug-related problems identified by the clinical pharmacist that also generated an alert in the CPOE/CDSS. RESULTS: During 1206 medication reviews, 442 potential DRPs were identified; 286 (65 %) DRPs were considered relevant and 247 (56 %) of the proposed interventions were accepted. A CPOE/CDSS alert was generated for 35 (8 %) of the DRPs the clinical pharmacist identified. The only difference between problems that triggered an alert and those that did not was the class of the DRP (indication 23 vs. 36 %, effectiveness 23 vs. 13 %, safety 23 vs. 10 % and pharmaceutical care issues 31 vs. 42 %, p = 0.02). CPOE/CDSS triggered 623 additional alerts that were handled during routine pharmacy service. CONCLUSIONS: As most DRPs identified by a clinical pharmacist were not detected in daily clinical practice by CPOE/CDSS, a clinical pharmacist contributes to reducing DRPs. The sensitivity of CPOE/CDSS to detect certain classes of problems should be optimized.

Is postoperative intensive care unit admission a prerequisite for elective craniotomy?

OBJECT: Routine postoperative admission to the intensive care unit (ICU) is often considered a necessity in the treatment of patients following elective craniotomy but may strain already limited resources and is of unproven benefit. In this study the authors investigated whether routine postoperative admission to a regular stepdown ward is a safe alternative. METHODS: Three hundred ninety-four consecutive patients who had undergone elective craniotomy over 54 months at a single institution were retrospectively analyzed. Indications for craniotomy included tumor (257 patients) and transsphenoidal (63 patients), vascular (31 patients), ventriculostomy (22 patients), developmental (13 patients), and base of skull conditions (8 patients). Recorded data included age, operation, reason for ICU admission, medical emergency team (MET) calls, in-hospital mortality, and postoperative duration of stay. RESULTS: Three hundred forty-three patients were admitted to the regular ward after elective craniotomy, whereas there were 43 planned and 8 unplanned ICU admissions. The most common reasons for planned ICU admissions were anticipated lengthy operations (42%) and anesthetic risks (40%); causes for unplanned ICU admissions were mainly unexpected slow neurological recovery and extensive intraoperative blood loss. Of the 343 regular ward admissions, 10 (3%) required a MET call; only 3 of these MET calls occurred within the first 48 postoperative hours and did not lead to an ICU admission. The overall mortality rate in the investigated cohort was 1%, with no fatalities in patients admitted to the normal ward postoperatively. CONCLUSIONS: Routine ward admission for patients undergoing elective craniotomies with selective ICU admission appears safe; however, approximately 2% of patients may require a direct postoperative unplanned ICU admission. Patients with anticipated long operation times, extensive blood loss, and high anesthetic risks should be selected for postoperative ICU admission, but further study is needed to determine the preoperative factors that can aid in identifying and caring for these groups of patients.

The general pharmacy work explored in The Netherlands.

OBJECTIVE: To determine the frequency and nature of general pharmacy work at three Dutch community pharmacies. METHODS: In a purposive and convenience sample of three Dutch community pharmacies the general work was investigated. Multi-dimensional work sampling (MDWS) was used. The study took six weeks: two weeks at each pharmacy. MAIN OUTCOME MEASURE: The number of care related items emerging in the general work. RESULTS: Care related work represented 34% of all pharmacy activities. CONCLUSION: Although care related work was present at all three studied pharmacies, this part of the work still needs serious attention of Dutch pharmacists in order to advance pharmaceutical care. It is suggested that an efficient pharmacy organization in combination with robotization, task specialization, and interior design can expand the care related work at the pharmacy.

In vitro effects of retinoic acid on mouse incisor development.

The developing dentition is known to express the complete set of retinoic acid (RA) nuclear receptors and cytoplasmic RA-binding proteins (CRABPI and II), and RA is required for in vitro mouse molar morphogenesis, so the role of RA during in vitro mouse incisor development was investigated. Histological procedures, immunocytochemical detection of proliferating cells, immunofluorescence detection of laminin, and in situ hybridization with RNA probes for CRABPI and II were done on the tooth-germ cultures either in the presence or in the absence of RA. RA appeared to control initial morphogenesis, particularly the asymmetrical growth of the cervical loop, and to regulate required differential mitotic activity. RA seemed also to be involved in asymmetrical laminin deposition. The distribution of the CRABP gene transcripts was similar during in vivo and in vitro incisor development. However, CRABPI gene transcript distribution in the labial part of the epithelial loop was detected in vitro only in the presence of RA. A direct role of the CRABPs during tooth development is, however, unlikely because Ch55, a synthetic RA analogue that does not bind to CRABP, had the same effects as RA on in vitro incisor development.

Expression of nuclear retinoic acid receptors during mouse odontogenesis.

The developmental expression of retinoic acid (RA) nuclear receptors RAR(alpha, beta, gamma) and RXR(alpha, beta, gamma) was analysed during mouse odontogenesis by in situ hybridization on frozen sections and compared with the expression patterns of the cellular retinoic acid binding proteins CRABPI and II. The transcripts distribution of each RAR and RXR was basically similar in developing molars and incisors. RAR alpha and RXR alpha were preferentially expressed in dental epithelia, whereas RAR gamma and RXR gamma were transcribed in the dental mesenchyme. RAR beta, RAR gamma and RXR beta displayed both epithelial and mesenchymal expression. RAR beta expression was initiated during bell stage. RXR gamma transcripts were observed only at day 19.5 post coitum in the mitogenic mesenchyme facing the epithelial loops. Odontoblasts expressed RAR beta and RAR gamma, RXR alpha and RXR beta. Preameloblasts expressed RXR alpha and RXR beta and ameloblasts RXR gamma, RXR alpha and RXR beta. RAR alpha transcription in the incisor preameloblasts and ameloblasts was not observed in the first molar. The coexpression between RARs and RXRs might be important to form RAR/RXR heterodimers which are necessary to activate the transcriptions of target genes. CRABPI and CRABPII demonstrated graded variation of expression during odontogenesis in the mesenchyme and in the inner dental epithelium respectively. The pattern of CRABPI transcripts overlapped at least partially with expressions of all the studied nuclear receptors whereas CRABPII epithelial expression was superimposed with the transcription of RAR alpha, RXR alpha and RXR beta. These cytoplasmic proteins might participate in the storage and/or metabolism of RA and then distribute RA to colocalized nuclear receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of suramin, a polyanionic drug inducing lysosomal storage disorders on tooth germs in vitro.

Suramin, a potent inhibitor of lysosomal enzymes, is commonly employed as a tool for inducing experimental mucopolysaccharidosis and lipidosis. The effects of the drug on embryonic mouse molars were analysed. Presecretory ameloblasts and odontoblasts were loaded with lysosome-like vacuoles. Staining with MC22-33F, an antibody to choline phospholipids and sphingomyelin, was completely reversed in the suramin-treated germs, in that it stained only presecretory ameloblasts (versus odontoblasts and some pulpal cells in the control group), according to a developmentally regulated pattern. The suramin-induced cytoplasmic changes were reminiscent of the features of mucopolysaccharidoses and lipidoses. The basement membrane, separating the enamel organ from the dental papilla, displayed suramin-induced patches, and in predentin collagen fibrillogenesis was found to be disturbed. Furthermore, autoradiography was employed to reveal uptake and distribution of [3H] suramin in the cells and predentin. Finally, a suramin-induced disturbance of the metabolism of sulphated macromolecules was found. The results imply that suramin effects in vitro on tooth germs can be used as a useful experimental model with to study both the action of the drug as well as cell and extracellular matrix perturbations in a mucopolysaccharidosis-like condition.

Immunocytochemical localization of choline-phospholipids in postnatal mouse molars.

This localization was studied using anti-choline phospholipid monoclonal IgM antibody (MC22-33F). By immunofluorescence, the apical portions of enamel-secreting ameloblasts and dentine-secreting odontoblasts were positively stained with MC22-33F. By immunoelectron microscopy, lysosomes in preodontoblasts, odontoblasts, preameloblasts and ameloblasts as well as matrix vesicles in dentine were strongly stained with MC22-33F. On the other hand, plasma membrane of these cells did not stain with MC22-33F. The frequency of positively reacting lysosomes in ameloblasts and odontoblasts and of matrix vesicles increased with cell maturation and mineral deposition.