The safety of high-dose dexmedetomidine after cardiac surgery: a historical cohort study.

PURPOSE: The off-label use of dexmedetomidine beyond the monograph-recommended maximum dose of 0.7 µg·kg-1·hr-1 is common in postoperative cardiac surgical units; however, limited data exist on the association of higher doses and adverse hemodynamic effects. We sought to compare the rate of hypotension or bradycardia in cardiac surgery patients receiving peak infusion doses below and above 0.7 µg·kg-1·hr-1 for any indication or duration. METHODS: In this historical cohort study, we reviewed all patients who received dexmedetomidine infusion after cardiac surgery between June 2013 and July 2017 at a single centre. Regardless of the duration of exposure at the peak infusion dose, patients were categorized into high- or standard-dose groups using 0.7 µg·kg-1·hr-1 as the cutoff value. We compared rates of the primary composite outcome of hypotension or bradycardia, and secondary outcomes (i.e., arrhythmia and hyperglycemia) between groups using the two-proportion z test. Exploratory regression models were fitted to adjust for potential confounders. RESULTS: The median [interquartile range (IQR)] peak infusion dose was 1.0 [1.0-1.4] µg·kg-1·hr-1 in the high-dose group (N = 121) and 0.5 [0.4-0.7] µg·kg-1·hr-1 in the standard-dose group (N = 124). The rates of the primary composite outcome were 73% and 65%, respectively (absolute risk difference, 8%; 95% confidence interval, -3 to 20; P = 0.17). There was no significant difference in primary or secondary outcomes between groups. CONCLUSION: There was a high overall rate of hypotension or bradycardia in patients receiving dexmedetomidine after cardiac surgery; infusion rates below or above 0.7 µg·kg-1·hr-1 had similar rates of adverse hemodynamic events.

RéSUMé: OBJECTIF: L'utilisation non conforme (off-label) de la dexmédétomidine au-delà de la dose maximale recommandée dans la monographie de 0,7 µg·kg−1·h−1 est fréquente dans les unités de chirurgie cardiaque postopératoire; cependant, il n'existe que peu de données sur l'association entre des doses plus élevées et des effets hémodynamiques indésirables. Nous avons cherché à comparer le taux d'hypotension ou de bradycardie chez les patients de chirurgie cardiaque recevant des doses de perfusion maximales inférieures ou supérieures à 0,7 µg·kg−1·h−1 pour toute indication ou durée. MéTHODE: Dans cette étude de cohorte historique, nous avons passé en revue tous les patients qui ont reçu une perfusion de dexmédétomidine après une chirurgie cardiaque entre juin 2013 et juillet 2017 dans un seul centre. Quelle que soit la durée de l'exposition à la dose de perfusion maximale, les patients ont été classés en groupes à dose élevée ou standard selon une valeur seuil de 0,7 µg·kg−1·h−1. Nous avons comparé les taux d'hypotension ou de bradycardie, notre critère d'évaluation principal composite, et les taux des critères d'évaluation secondaires (soit l'arythmie et l'hyperglycémie) entre les groupes à l'aide du test z à deux proportions. Des modèles de régression exploratoire ont été ajustés pour tenir compte des facteurs de confusion potentiels. RéSULTATS: La dose de perfusion maximale médiane [écart interquartile (ÉIQ)] était de 1,0 [1,0­1,4] µg·kg−1·h−1 dans le groupe à forte dose (n = 121) et de 0,5 [0,4­0,7] µg·kg−1·h−1 dans le groupe à dose standard (n = 124). Les taux pour le critère d'évaluation principal composite étaient de 73% et 65%, respectivement (différence de risque absolue, 8%; intervalle de confiance à 95%, -3 à 20; P = 0,17). Aucune différence intergroupe significative n'a été observée dans les critères d'évaluation primaires ou secondaires. CONCLUSION: Nous avons observé un taux global élevé d'hypotension ou de bradycardie chez les patients recevant de la dexmédétomidine après une chirurgie cardiaque; les taux de perfusion inférieurs ou supérieurs à 0,7 µg·kg−1·h−1 ont entraîné des taux similaires d'événements hémodynamiques indésirables.

The mycoestrogen zeranol at high dosage antagonizes transient receptor potential channel activities in 3T3 L1 cells.

Recent findings have revealed that exposure to environmental contaminants may result in obesity and pose a health threat to the general public. As the activity of transient receptor potential channels (TRPs) plays a permissive role in adipogenesis, the interactions between TRPs and some food pollutants, i.e. bisphenol A, di (2-ethylhexyl) phthalate, zearalenone, and zeranol at 10 µM were investigated in the present study. TRP-V1,-V3, -C4 and -C6 are reported to be differentially expressed in the adipocyte differentiation, and immunoblotting was performed to quantify changes in these TRPs affected by the pollutants. Our result indicated that the mycoestrogen zeranol or α-zearalanol suppressed the expression of the V1 and C6 isoforms. Subsequently, confocal microscopy was used to measure the calcium inflow repressed by zeranol from 0.1 µM to 10 µM. Oil Red O staining was used to determine the differentiation of 3T3 L1 preadipocytes. Zeranol could suppress the expression of TRP-V1 and -C6 protein and inhibit the associated flow of calcium into the cytosol of 3T3 L1 cells. Its IC50 value for inhibiting calcium inflow stimulated by 40 µM capsaicin or 10 µM GSK1702934A was estimated to be around 6 µM. Reduced TRP-V1 or -C6 activity might result in promoting adipogenesis. In conclusion, this study demonstrated that zeranol could potentiate fat cell differentiation through antagonizing TRP-V1 and -C6 activities.

Toward the Scale-Up of a Bicyclic Homopiperazine via Schmidt Rearrangement and Photochemical Oxaziridine Rearrangement in Continuous-Flow.

The scale-up of a chiral bicyclic homopiperazine of pharmaceutical interest was investigated. The outcome and safety profile of a key batch ring-expansion step via Schmidt rearrangement was improved using continuous-flow chemistry. The selectivity of nitrogen insertion for the ring expansion was improved via an alternative photochemical oxaziridine rearrangement under mild conditions, which when converted to continuous-flow in a simple and efficient flow reactor allowed the first photochemical scale-up of a homopiperazine.

The livestock growth-promoter zeranol facilitates GLUT4 translocation in 3T3 L1 adipocytes.

Zeranol is an approved but controversial growth-promoting agent for livestock in North America. It is a mycotoxin metabolite secreted by the Fusarium family fungi. The regulatory bodies in this region have established the acceptable daily intake and exposure below the level would not significantly increase the health risk for humans. However, their European counterparts have yet to establish an acceptable level and do not permit the use of this agent in farm animals. Given the growth-promoting ability of zeranol, its effect on energy metabolism was investigated in the current study. Our results indicated that zeranol could induce glucose transporter type 4 (GLUT4) expression in 3T3 L1 cells at 10 µM and initiate the translocation of the glucose transporter to the membrane as assayed by confocal microscopy. The translocation was likely triggered by the increase of GLUT4 and p-Akt. The insulin signal transduction pathway of glucose translocation was analyzed by Western blot analysis. Since no increase in the phosphorylated insulin receptor substrate in zeranol-treated cells was evidenced, the increased p-Akt and GLUT4 amount should be the mechanism dictating the GLUT4 translocation. In summary, this study showed that zeranol could perturb glucose metabolism in differentiated 3T3 L1 adipocytes. Determining the growth-promoting mechanism is crucial to uncover an accepted alternative to the general public.

2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth.

The lysyl oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation of cross-links in fibrillar elastin and collagens leading to extracellular matrix (ECM) stabilization. These enzymes have also been implicated in tumor progression and metastatic disease and have thus become an attractive therapeutic target for many types of invasive cancers. Following our recently published work on the discovery of aminomethylenethiophenes (AMTs) as potent, orally bioavailable LOX/LOXL2 inhibitors, we report herein the discovery of a series of dual LOX/LOXL2 inhibitors, as well as a subseries of LOXL2-selective inhibitors, bearing an aminomethylenethiazole (AMTz) scaffold. Incorporation of a thiazole core leads to improved potency toward LOXL2 inhibition via an irreversible binding mode of inhibition. SAR studies have enabled the discovery of a predictive 3DQSAR model. Lead AMTz inhibitors exhibit improved pharmacokinetic properties and excellent antitumor efficacy, with significantly reduced tumor growth in a spontaneous breast cancer genetically engineered mouse model.

Social and cultural construction processes involved in HPV vaccine hesitancy among Chinese women: a qualitative study.

BACKGROUND: HPV vaccine is a prophylactic vaccine to prevent HPV infections. Recommended by the World Health Organization, this vaccine is clinically proven to be one of the most effective preventive measures against the prevalence of cervical cancer and other HPV-associated cancers and chronic genital conditions. However, its uptake rate among women in Hong Kong is insignificant-only approximately 2.9% adolescent girls and 9.7% female university students received HPV vaccination in 2014. With the notion of Critical Medical Anthropology, we aimed to identify if different influential factors, ranging from individual, societal, and cultural, are involved in the decision-making process of whether to receive HPV vaccination. METHODS: We adopted a qualitative approach and conducted in-depth individual semistructured interviews with 40 women in Hong Kong between May and August 2017. RESULTS: We noted that the following factors intertwined to influence the decision-making process: perceptions of HPV and HPV vaccine; perceived worthiness of HPV vaccines, which was in turn influenced by vaccine cost, marriage plans, and experiences of sexual activities; history of experiencing gynecological conditions, stigma associated with HPV vaccination, acquisition of information on HPV vaccines, distrust on HPV vaccines, and absence of preventive care in the healthcare practice. CONCLUSIONS: HPV vaccination is promoted in a manner that is "feminized" and "moralized" under the patriarchal value system, further imposing the burden of disease on women, and leading to health inequality of women in pursuing the vaccination as a preventive health behaviour as a result. We believe that this ultimately results in an incomplete understanding of HPV, consequently influencing the decision-making process. The "mixed-economy" medical system adopting capitalist logic also molds a weak doctor-patient relationship, leading to distrust in private practice medical system, which affects the accessibility of information regarding HPV vaccination for participants to make the decision.

Author Correction: Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure-Activity Relationships.

Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided the initial hits. Structure-activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half-maximal inhibitory concentrations (IC50) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.

Barriers to Receiving HPV Vaccination Among Men in a Chinese Community: A Qualitative Study in Hong Kong.

Human papillomavirus (HPV) can cause various diseases; low-risk strains can cause genital warts, whereas high-risk strains can cause cervical cancer and cancer of the vulva in women and cancers of the penis, anus, and oropharynx in men. Although HPV affects men, literature has reported that the prevalence of HPV vaccination is far lower among men than among women. Few studies have examined perceptions and acceptability of the HPV vaccine among men, particularly in Chinese communities. In this study, the acceptability of the HPV vaccine to men was investigated using Hong Kong men as a case group. A qualitative research approach was adopted. Thirty-nine men were purposively sampled for the in-depth individual semistructured interviews from June to October 2017 to investigate their perceptions of the HPV vaccine and the barriers for them to receive the vaccination. Limited knowledge and awareness of HPV-related issues, low perceived risk of HPV infection, perceived association between HPV vaccine and promiscuity, and lack of accessible official information on HPV-related topics were identified as the key barriers. These barriers intermingled with the sociocultural environment, cultural values of sexuality, and patriarchal gender values. HPV vaccine is shown to be socially constructed as a vaccine for women exclusively and for promiscuity. The participants were discouraged from receiving HPV vaccination because of its signaling of socially deviant promiscuity. Cultural taboo on sex served as a social oppression of open discussion about HPV vaccine and affected the participants' perceived need of vaccination. Perceived insignificance of reproductive organs also influenced the participants' perceived need of vaccination.

Bridging the gap: An evaluation of self-paced online transition modules for advanced pharmacy practice experience students.

BACKGROUND AND PURPOSE: A three module online self-paced educational resource was developed for entry to practice students transitioning from the classroom to their inpatient practicums. The objective of this study was to determine the benefits of the transition modules on students' self-perceived competency as related to onsite performance and reduction in anxiety during their inpatient practicum. EDUCATIONAL ACTIVITY AND SETTING: Evaluations of the three transition modules were conducted in two phases via electronic surveys distributed to final year advanced pharmacy practice students and focus group members including faculty, pharmacy practice educators, and pharmacy residents. FINDINGS: Based on our findings, the modules addressed common learning needs. While 69.7% of student respondents from Phase II of the evaluation found the modules to have positively impacted their onsite performance, only 24.7% believed the modules reduced their anxiety. DISCUSSION: The study indicates that students found the modules to be relevant to inpatient practice and of appropriate difficulty. Although most students perceived the modules to enhance performance on practicum, student anxiety levels appeared to remain unchanged. SUMMARY: Based on feedback and results, it may be beneficial to expose students to transition modules earlier in the curriculum in tandem with other inpatient preparatory activities. The results from this study may be of interest or benefit other universities and healthcare educators pursuing work on transition activities.

The citrus flavonone hesperetin attenuates the nuclear translocation of aryl hydrocarbon receptor.

The environmental polycyclic aromatic hydrocarbons (PAH) and dioxins are carcinogens and their adverse effects have been largely attributed to the activation of AhR. Hesperetin is a flavonone found abundantly in citrus fruits and has been shown to be a biologically active agent. In the present study, the effect of hesperetin on the nuclear translocation of AhR and the downstream gene expression was investigated in MCF-7 cells. Confocal microscopy indicated that 7, 12-dimethylbenz[α]anthracene (DMBA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) -induced nuclear translocation of AhR was deterred by hesperetin treatment. The reduced nuclear translocation could also be observed in Western analysis. Reporter-gene assay further illustrated that the induced XRE transactivation was weakened by the treatment of hesperetin. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated that the gene expressions of CYP1A1, 1A2, and 1B1 followed the same pattern of AhR translocation. These results suggested that hesperetin counteracted AhR transactivation and suppressed the downstream gene expression.

Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.

Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFß1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.

Improving the stability of 11C-labeled L-methionine with ascorbate.

BACKGROUND: Carbon-11 labeled L-methionine (11C-MET) is a popular tracer used in the clinic for imaging brain tumors with positron emission tomography. However, the stability of 11C-MET in its final formulation is not well documented in literature. Recently, we observed fast degradation of HPLC-purified 11C-MET over time, and systematic investigation was conducted to identify the cause. RESULTS: In this study, we verified the degraded product as 11C-labeled methionine sulfoxide (11C-METSO). To minimize oxidation, ascorbate (100 ppm) was added to the HPLC eluant, and the resulting HPLC-purified 11C-MET was stable in the final formulation solution without noticeable degradation for up to 1 h after the end of synthesis. CONCLUSIONS: Our data suggest that to minimize degradation, ascorbate can be added to the 11C-MET formulation solution especially if it is not administered into patients soon after the end of synthesis.

Repeatability of a novel corneal indentation device for corneal biomechanical measurement.

PURPOSE: The aim of the study was to evaluate the repeatability of a new device for measuring corneal biomechanics. METHODS: Twenty-nine normal subjects aged 20-28 years (23.4 ± 1.7 years) underwent measurements of corneal stiffness and tangent elastic modulus using a novel corneal indentation device. Corneal topography, axial biometry and Goldmann applanation tonometry were also performed during the visit. Subjects returned after about 1 week, at approximately the same time, and with the corneal biomechanics, corneal topography and Goldmann applanation tonometry measured again. Both the intrasession and intersession repeatability was assessed. RESULTS: Both the corneal stiffness and tangent elastic modulus demonstrated good intrasession repeatability (corneal stiffness: coefficient of variation = 7.32%, intraclass correlation coefficient = 0.75; tangent elastic modulus: coefficient of variation = 7.34%, intraclass correlation coefficient = 0.84). The mean modulus after normalised to normal intraocular pressure of 15.5 mmHg was 0.755 ± 0.159 MPa. There was no significant difference between the two visits (paired t-tests: p > 0.05). The repeatability [1.96 times the standard deviation (S.D.) of the intersession difference] of the corneal stiffness and the tangent elastic modulus was 0.0022 N mm(-1) and 0.197 MPa, respectively. CONCLUSION: The corneal indentation device has good intrasession and intersession repeatability. It has good potential to measure corneal biomechanics clinically, even at different corneal regions.

Soft wearable contact lens sensor for continuous intraocular pressure monitoring.

Intraocular pressure (IOP) is a primary indicator of glaucoma, but measurements from a single visit to the clinic miss the peak IOP that may occur at night during sleep. A soft chipless contact lens sensor that allows the IOP to be monitored throughout the day and at night is developed in this study. A resonance circuit composed of a thin film capacitor coupled with a sensing coil that can sense corneal curvature deformation is designed, fabricated and embedded into a soft contact lens. The resonance frequency of the sensor is designed to vary with the lens curvature as it changes with the IOP. The frequency responses and the ability of the sensor to track IOP cycles were tested using a silicone rubber model eye. The results showed that the sensor has excellent linearity with a frequency response of ∼8 kHz/mmHg, and the sensor can accurately track fluctuating IOP. These results showed that the chipless contact lens sensor can potentially be used to monitor IOP to improve diagnosis accuracy and treatment of glaucoma.

Comparative study of corneal tangent elastic modulus measurement using corneal indentation device.

The aim of this study is to examine the corneal tangent modulus measurement repeatability and performance of the corneal indentation device (CID). Twenty enucleated porcine eyes were measured and the eyes were pressurized using saline solution-filled manometer to 15 and 30 mmHg. Corneal tangent moduli measured using the CID were compared with those measured using high precision universal testing machine (UTM). The within-subject standard deviation (Sw), repeatability (2.77×Sw), coefficient of variation (CV) (Sw/overall mean), and intraclass correlation coefficient (ICC) were determined. The mean corneal tangent moduli measured using UTM and CID were 0.094±0.030 and 0.094±0.028 MPa at 15 mmHg, and 0.207±0.056 and 0.207±0.055 MPa at 30 mmHg, respectively, with a difference less than 0.13%. The 95% limit of agreement was between -0.009 and 0.009 MPa. The Sw, repeatability, CV and ICC of corneal tangent moduli measured by the CID were 0.006 MPa, 0.015 MPa, 4.3% and 0.993, respectively. The results showed that the corneal tangent moduli measured by the CID are repeatable and are in good agreement with the results measured by the high precision UTM.

Noninvasive measurement of scleral stiffness and tangent modulus in porcine eyes.

PURPOSE: We investigated an indentation technique to measure the scleral stiffness and tangent modulus of porcine eyes. METHODS: The scleral load-displacement responses were measured with a universal testing machine as a function of IOP in 15 porcine eyes ex vivo using a 5-mm diameter cylindrical flat-punch indenter. The scleral radius of curvature and scleral thickness were measured using a DSLR camera (Alpha 900) and a camera-mounted stereomicroscope (M205C), respectively. The relationships between scleral stiffness, tangent modulus, and IOP were examined. RESULTS: The mean local scleral radius of curvature and scleral thickness were 7.86 ± 0.49 and 1.03 ± 0.14 mm, respectively. The average scleral stiffness and scleral tangent modulus of porcine eyes were 0.13 ± 0.02 N/mm and 0.20 ± 0.04 MPa at 15 mm Hg, respectively. The scleral stiffness and scleral tangent modulus were correlated positively with IOP (scleral stiffness, 0.989 < r < 0.999, P < 0.001; scleral tangent modulus, 0.989 < r < 0.999, P < 0.001). CONCLUSIONS: The scleral indentation technique can provide a noninvasive approach to measure scleral stiffness and tangent modulus.

Individual-specific tonometry on porcine eyes.

Intraocular pressure (IOP) monitoring is important in the diagnosis and management of glaucoma. The measurement of IOP is affected by corneal properties, but the effect of corneal stiffness on IOP measurement is unaccounted for in pressure measurement instruments such as the Goldmann Applanation Tonometer (GAT). A new instrumented non-invasive indentation tonometry that can measure IOPIST, a corneal stiffness-corrected intraocular pressure is developed. The inter-individual corneal variations of 12 porcine eyes ex vivo were independently characterized; and their true intraocular pressure, IOPT's, were set using a manometer before indentation using the new indentation tonometry. Analyses of the load-displacement data showed that porcine corneal stiffness varied more than five times from 0.045 to 0.253N/mm. Analysis showed that, without individual stiffness correction, inter-individual variation of IOPGAT can vary up to 8mmHg from IOPT at 15mmHg; the error becomes larger at high IOPT. In comparison when corneal stiffness is accounted for, IOPIST has a significantly smaller error of 1.82±1.70mmHg for IOPT between 12 and 40mmHg than IOPGAT. The results showed that the new tonometry successfully accounted for inter-individual variations in IOP measurement.

Characterization of pressure reduction in coil-filled aneurysm under flow of human blood with and without anti-coagulant.

Filling aneurysms with embolization coils is a widely used part of the treatment to stop intracranial aneurysm from rupturing. However, the effect of coiling on aneurysmal pressure has not been established. In this study, the effect of intra-aneurysmal coiling on pressure reduction was characterized. Coil deployment in the aneurysm will disturb flow and may induce aneurysmal coagulation. These effects were experimentally examined in this study using silicone rubber saccular aneurysm models. Changes in aneurysmal blood pressure under pulsatile flow were characterized. With coils in the aneurysm, results showed that flow reduction of anti-coagulated blood in the aneurysm did not reduce aneurysmal pressure. Significant pressure reduction was observed only when the blood's coagulation ability is restored to normal. These results suggest that blood coagulation is pivotal to pressure reduction and concomitant with rupture risk reduction in treatments of aneurysm with coils.

Characterization of corneal tangent modulus in vivo.

PURPOSE: Intraocular pressure (IOP) measured using Goldmann Applanation Tonometry (GAT) changes with individual's corneal properties, but the method to measure the in vivo corneal material properties to account for individual variation in GAT IOP is not available. In this study, a new method to measure the IOP-dependent corneal tangent modulus in vivo is developed to address this research gap. METHODS: Instrumented indentation and analysis were developed to measure the corneal tangent modulus. The validity of the method and procedure was verified using model silicone eye pressurized to different IOP. In addition, 15 porcine eyes and 3 rabbit eyes were tested using the corneal indentation at different set intraocular pressure and different indentation rates. RESULTS: The results from silicone eye showed that the measured tangent modulus is in good agreement with the standard silicone rubber modulus. The results on the porcine eyes and rabbit eyes showed that the method can be used to measure corneal tangent modulus in vivo in the human range of intraocular pressure from 10 to 40 mmHg. CONCLUSIONS: An indentation method to measure the corneal tangent modulus in vivo was developed, and the IOP dependence of the corneal tangent modulus was characterized. The developed indentation method provides a new means to measure the in vivo corneal tangent modulus to account for individual and pressure variations in measurement of intraocular pressure.