The current fertility preservation consultation model: are we adequately informing cancer patients of their options?
There is very limited information about the amount of information that cancer patients retain after a fertility preservation (FP) consultation (FPC). Our objective was to assess patients' knowledge following FPC and to examine predictors of increased knowledge. We conducted a multi-center, cross-sectional, web-based survey at academic IVF centers, including women aged 18-43 years seen for comprehensive FPC between April 2009 and December 2010. The primary outcome measure was a knowledge score designed to assess comprehension of FP options. Analysis was performed to assess which patient variables were associated with higher knowledge scores. A 13-item knowledge tool about FP was developed (Kuder-Richardson 20=0.64). Among 90 eligible subjects, 66 were successfully contacted and 52 completed the survey (79% response rate). Participant's median age was 30.7 (interquartile range (IQR) 24.9-36.9) years and most were Caucasian, college graduates, nulliparous and in a committed relationship. The median knowledge post-FPC score was 6 (IQR: 5-9). Higher knowledge scores were associated with a college education, higher income, a primary diagnosis of breast cancer, additional contact with the FP specialist following the initial FPC and use of specific reference websites such as www.fertilehope.org. Parity, marital status and completion of FP treatment were not associated with knowledge scores. FP knowledge following comprehensive FPC remains limited. Modifications to the current single visit FPC, such as a standard follow-up visit or additional educational tools, may be needed to improve patient comprehension of complex FP treatment options. Further research is needed to validate the knowledge scale in broader populations of cancer patients receiving FPC.


Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation.
Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated with Pseudomonas aeruginosa colonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17. Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected with P. aeruginosa had robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed with P. aeruginosa infection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency of Cftr and ongoing inflammation. These studies demonstrate the in vivo contribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis.


Application of image cytometry to characterize heterologous lipid flippases in yeast.
Lipid flippases are integral membrane proteins that play a central role in moving lipids across cellular membranes. Some of these transporters are ATPases that couple lipid translocation to ATP hydrolysis, whereas others function without any discernible metabolic energy input. A growing number of lipid flippases has been identified but key features of their activity remain to be elucidated. A well-established method to characterize ATP-driven flippases is based on their heterologous expression in yeast, followed by incubation of the cells with fluorescent lipids. Internalization of these probes is typically monitored by flow cytometry, a costly and maintenance-intensive method. Here, we have optimized a protocol to use an automated image-based cell counter to accurately measure lipid uptake by heterologous lipid flippases expressed in yeast. The method was validated by comparison with the classical flow cytometric evaluation of lipid-labeled cells. In addition, we demonstrated that expression of fluorescently tagged flippase complexes can be directly co-related with fluorescent lipid uptake using the image-based cell counter system. The method extends the number of techniques available for characterization of lipid flippase activity, and should be readily adaptable to analyze a variety of other transport systems in yeast, parasites, and mammalian cells. © 2016 International Society for Advancement of Cytometry.


Chaplaincy placements will highlight role of patient spirituality.
UNIVERSITY OF Hull nursing students are undertaking placements with chaplains to find out more about the importance of patient spirituality. Lead chaplain for Northern Lincolnshire and Goole NHS Foundation Trust, the Rev Charles Thody, is working with chaplains at Hull and East Yorkshire Hospitals NHS Trust to provide placements and run lectures and tutorials. 'Spiritual care is a huge element of palliative and end of life care,' he said.


Adaptive, locally linear models of complex dynamics.
The dynamics of complex systems generally include high-dimensional, nonstationary, and nonlinear behavior, all of which pose fundamental challenges to quantitative understanding. To address these difficulties, we detail an approach based on local linear models within windows determined adaptively from data. While the dynamics within each window are simple, consisting of exponential decay, growth, and oscillations, the collection of local parameters across all windows provides a principled characterization of the full time series. To explore the resulting model space, we develop a likelihood-based hierarchical clustering, and we examine the eigenvalues of the linear dynamics. We demonstrate our analysis with the Lorenz system undergoing stable spiral dynamics and in the standard chaotic regime. Applied to the posture dynamics of the nematode Caenorhabditis elegans, our approach identifies fine-grained behavioral states and model dynamics which fluctuate about an instability boundary, and we detail a bifurcation in a transition from forward to backward crawling. We analyze whole-brain imaging in C. elegans and show that global brain dynamics is damped away from the instability boundary by a decrease in oxygen concentration. We provide additional evidence for such near-critical dynamics from the analysis of electrocorticography in monkey and the imaging of a neural population from mouse visual cortex at single-cell resolution.


Investigating adsorption/desorption of carbon dioxide in aluminum compressed gas cylinders.
Between June 2010 and June 2011, the National Institute of Standards and Technology (NIST) gravimetrically prepared a suite of 20 carbon dioxide (CO2) in air primary standard mixtures (PSMs). Ambient mole fraction levels were obtained through six levels of dilution beginning with pure (99.999%) CO2. The sixth level covered the ambient range from 355 to 404 μmol/mol. This level will be used to certify cylinder mixtures of compressed dry whole air from both the northern and southern hemispheres as NIST standard reference materials (SRMs). The first five levels of PSMs were verified against existing PSMs in a balance of air or nitrogen with excellent agreement observed (the average percent difference between the calculated and analyzed values was 0.002%). After the preparation of a new suite of PSMs at ambient level, they were compared to an existing suite of PSMs. It was observed that the analyzed concentration of the new PSMs was less than the calculated gravimetric concentration by as much as 0.3% relative. The existing PSMs had been used in a Consultative Committee for Amount of Substance-Metrology in Chemistry Key Comparison (K-52) in which there was excellent agreement (the NIST-analyzed value was -0.09% different from the calculated value, while the average of the difference for all 18 participants was -0.10%) with those of other National Metrology Institutes and World Meteorological Organization designated laboratories. In order to determine the magnitude of these losses at the ambient level, a series of "daughter/mother" tests were initiated and conducted in which the gas mixture containing CO2 from a "mother" cylinder was transferred into an evacuated "daughter" cylinder. These cylinder pairs were then compared using cavity ring-down spectroscopy under high reproducibility conditions (the average percent relative standard deviation of sample response was 0.02). A ratio of the daughter instrument response to the mother response was calculated, with the resultant deviation from unity being a measure of the CO2 loss or gain. Cylinders from three specialty gas vendors were tested to find the appropriate cylinder in which to prepare the new PSMs. All cylinders tested showed a loss of CO2, presumably to the walls of the cylinder. The vendor cylinders exhibiting the least loss of CO2 were then purchased to be used to gravimetrically prepare the PSMs, adjusting the calculated mole fraction for the loss bias and an uncertainty calculated from this work.


High-mix insulins.
Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid-acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high-mix insulin can be used, including once daily, twice daily, thrice daily, hetero-mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use.


Perceived stress and quality of life of pharmacy students in University of Ghana.
Stress among pharmacy students could greatly affect their learning activities and general well-being. It is therefore necessary to investigate how stress relates with the quality of life of students to maintain and/or improve their personal satisfaction and academic performance. A school-based longitudinal study was used to investigate the relationship between stress and quality of life of undergraduate pharmacy students. The 10-item perceived stress scale and the shorter version of the WHO quality of life scale were administered to the same participants at two time points i.e. Time 1 (4 weeks into the semester) and Time 2 (8 weeks afterwards). The correlations and differences between the study variables were tested using the Pearson's coefficient and independent sample t test. The mean stress scores were higher at Time 2 compared to Time 1 for the first and second years. However, there was no significant difference in stress for different year groups-Time 1 [F (3) = 0.410; p = 0.746] and Time 2 [F(3) = 0.909; p = 0.439]. Female students had higher stress scores at Time 2 compared to male students. The main stressors identified in the study were; large volume of material to be studied (88.2%), laboratory report writing (78.2%), constant pressure to maintain good grades (66.4%) and the lack of leisure time (46.4%). Even though most students employed positive stress management strategies such as time management (68.2%), other students resorted to emotional eating (9.1%) and alcohol/substance use (1.8%). At Time 2, perceived stress scores were significantly negatively correlated with social relationship (r = -0.40, p ≤ 0.0001), environmental health (r = -0.37, p ≤ 0.0001), physical health (r = -0.49, p ≤ 0.0001) and psychological health (r = -0.51, p ≤ 0.0001). The study reported significant correlations between stress and various domains of quality of life of undergraduate pharmacy students. It is thus necessary to institute some personal and institutional strategies to ameliorate the effect of stress on the quality of life of pharmacy students while encouraging the use of positive stress management strategies.


Simultaneous separation of triterpenoid saponins and flavonoid glycosides from the roots of Glycyrrhiza uralensis Fisch by pH-zone-refining counter-current chromatography.
Glycosides including triterpenoid saponins and flavonoid glycosides are the main constituents of Glycyrrhiza uralensis Fisch (licorice) and exhibit prominent pharmacological activities. However, conventional methods for the separation of glycosides always cause irreversible adsorption and unavoidable loss of sample due to their high hydrophilicities. The present paper describes a convenient method for the simultaneous separation of triterpenoid saponins and flavonoid glycosides from licorice by pH-zone-refining counter-current chromatography. Ethyl acetate/n-butanol/water (2:3:5, v/v) with 10 mM TFA in the upper organic stationary phase and 10 mM ammonia in the lower aqueous mobile phase was used as the biphasic solvent system. Three triterpenoid saponins and two flavonoid glycosides including licorice-saponin A3 (63.3 mg), glycyrrhizic acid (342.2 mg), 3-O-[β-D-glucuronopyranosyl-(1 → 2)-β-D-galactopyranosyl]glycyrrhetic acid (56.0 mg), liquiritin apioside (232.6 mg), and liquiritin (386.5 mg) were successfully obtained from licorice ethanol extract (2 g) in one step. This method subtly takes advantage of the common acidic properties of triterpenoid saponins and flavonoid glycosides, and obviously is much more efficient and convenient than the previous methods. It is also the first time that the separation of acidic triterpenoid saponins by using pH-zone-refining counter-current chromatography has been reported.


LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent.
The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAβ, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAβ and oTau requires expression of APP. Finally, the toxic effect of both extracellular oAβ and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oAβ- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of Aβ and/or Tau.


Participation in interventions and recommended follow-up for non-attendees in cervical cancer screening -taking the women's own preferred test method into account-A Swedish randomised controlled trial.
Cervical cancer is a highly preventable disease. To not attend an organized cervical cancer screening program increases the risk for cervical dysplasia and cervical cancer. The aim was to investigate the participation rate in three different intervention groups for non- attendees in the Swedish national program for cervical screening. The participation in the recommended follow up, and the histology found were also examined. Population-based randomized control trial. It included10,614 women that had not participated in the cervical cancer screening programme during the last six years (ages 30-49) and the last eight years (ages 50-64) were randomised 1:1:1(telephone call from a midwife (offering the choice between a visit for a pap smear or an HPV self-sampling test); an HPV self-sampling test only; or the routine procedure with a yearly invitation). In the intention to treat analysis the participation rates were 25.5% (N = 803/3146) vs 34.1% (N = 1047/3068) and 7.0% (N = 250/3538) (p<0.001) for telephone, HPV self-test and control groups respectively. In the by protocol analysis including women that answered the phone call the participation rates were 31.7% (N = 565/1784) vs 26.1% (N = 788/3002) and 7.0% (N = 250/3538) (p<0.001) for telephone, HPV self-test and control groups. The corresponding results in the by protocol analysis including women that did not answer the phone call was 19.7% (N = 565/2870) vs 26.1% (N = 788/3002) and 7.0% (N = 250/3538) (p< 0.001). The majority of the women 63,4% (1131/1784) who answered the telephone wanted to participate either by booking a visit for pap smear (38,5%) or to be sent a HPV self- sampling test (24,9%) (p<0.001). Women who chose an HPV self-test were older and gave anxiety/ fear as a reason to decline participation, and they were also less likely to participate in the follow-up if found to be HPV-positive compared to the women who chose a Pap smear. The attendance to the recommended follow-up after abnormality was in total 87%. The non-attendees had a three or eight times higher risk of having a cytology result of HSIL or suspected SCC respectively, in the index sample compared to women screened as recommended (OR 3.3 CI 95% 1.9-5.2, OR 8.6 CI 1.6-30). A total of ten SCC and one adenocarcinoma were found in the histopathology results from the non-attendee group with a study intervention, while there was only one SCC in the non-attendee group without any study intervention (p = 0.02, OR 8.1 CI 95% 1.2-350). Our study suggests, according to intention to treat analysis, that the best intervention to get as many non-attendees as possible to participate is to send an HPV self-sampling test together with an invitation letter. Almost 90% of women in the study with an abnormal index sample attended follow-up. This is high enough to indicate that interventions to increase the participation among non-attendees are meaningful. International Standard Randomised Controlled Trial Number (ISRCTN) Registration number ISRCTN78719765.


Ferroelectricity and Ferromagnetism Achieved via Adjusting Dimensionality in BiFeO3/BiMnO3 Superlattices.
Integrating characteristics of materials through constructing artificial superlattices (SLs) has raised extensive attention in multifunctional materials. Here, we report the synthesis of BiFeO3/BiMnO3 SLs with considerable ferroelectric polarizations and tunable magnetic moments. The polarization of BiFeO3/BiMnO3 SLs presents a decent value of 12 μC/cm2, even as the dimensionality of BiFeO3 layers per period is reduced to about five-unit cells when keeping the BiMnO3 layers same. Moreover, it is found that the tunable magnetic moments of SLs are linked intimately to the dimensionality of BiFeO3 layers. Our simulations demonstrate that the superexchange interaction of Fe-O-Mn tends to be antiferromagnetic (AFM) with a lower magnetic domain formation energy rather than ferromagnetic (FM). Therefore, as the dimensionality of BiFeO3 per period is reduced, the AFM superexchange interaction between BiFeO3 and BiMnO3 in the SLs becomes weak, promoting a robust magnetization. This interlayer modulation effect in SLs presents an alluring way to accurately control the multiple order parameters in a multiferroic oxide system.


Oncogene induction of metastases.
A metastatic colony is the end result of a complex series of steps involving multiple gene products. In some cases, the augmented metastatic potential of certain tumour cells may be due to the increased expression of specific gene products which confer a selective advantage. Transfection of the c-Ha-ras oncogene into suitable recipient cells constitutes a powerful experimental model with which to identify putative gene products augmented in highly metastatic tumour cells compared to their non-metastatic counterparts. Transfection of the activated ras oncogene into 3T3 and 10T1/2 embryo fibroblasts, and adult rat fibroblasts, results in transformants which produce high numbers of spontaneous metastases in nude mice or syngeneic recipients. The ras oncogene will also increase the metastatic aggressiveness of murine tumours with low metastatic potential. However, the ras oncogene will not induce the metastatic phenotype in all recipient cells. Furthermore, specific genes such as adenovirus 2 E1A suppress the ability of ras to induce the metastatic phenotype. Natural 'suppressor' gene products may exist which render certain cells resistant to the induction of metastases by ras. Ras oncogene transfection induces the production of type IV collagenase, motility factors and growth factors. The ras oncogene therefore induces a cascade of gene functions leading to rapid progression to the metastatic phenotype. The mechanism of the induction probably involves complex interactions between the ras p21 product and multiple cellular gene products.


Contribution of electrophysiological studies to cerebellar physiology.
Electrical stimulation and the recording of electrical potentials have made important contributions to the classic formulations of cerebellar function. These electrical methods also have contributed to a re-appraisal, now underway, of the cerebellar role in the human brain. Beyond its accepted role in motor function, the cerebellum seems to contribute to some nonmotor functions. It is now known to communicate with the prefrontal cortex as well as with the motor cortex of the frontal lobe, and it seems to be involved in some prefrontal cognitive and language functions as well as in motor function. Investigations of cerebellar involvement in such functions are now being carried out, with encouraging results. If confirmed by further clinical evidence, this broader concept of cerebellar function would explain the mystery of why the most lateral parts of the cerebellum enlarged dramatically in the human brain, concomitantly with the enlargement of the cerebral association areas.


Pain relief at the end of life: nurses' experiences regarding end-of-life pain relief in patients with dementia.
Patients with dementia receive suboptimal palliative care, and this patient group is at risk to have pain at the end of life. Because communicative impairments are common in this patient group, nurses play an important caregiver role in identifying, assessing, and relieving patients' pain. This study aimed to describe nurses' experiences regarding end-of-life pain relief in patients with dementia. This descriptive exploratory qualitative study was based on seven semistructured interviews. Burnard's content analysis inspired the data analysis. Two main categories were identified: (1) nurses' experience of difficulties concerning pain relief and (2) nurses' experience of resources concerning pain relief. Nurses experienced difficulties, such as feeling of powerlessness because of difficulties in obtaining adequate prescriptions for analgesics, ethical dilemmas, feeling of inadequacy because analgesia did not have the desired effect, and a feeling of not being able to connect with the patient. Factors, including knowledge about the patient, professional experience, utilization of pain assessment tools, interpersonal relationships, and interprofessional cooperation, served as resources and enabled end-of-life pain relief. The results of this study highlight the complexity of pain relief in patients with dementia at the end of life from a nursing perspective. The inability of patients with dementia to verbally communicate their pain makes them a vulnerable patient group, dependent on their caregivers. Knowing the life story of the patient, professional experience, teamwork based on good communication, and use of a pain assessment tool were reported by the nurses to improve pain relief at the end of life for patients with dementia.


Vancomycin-resistant enterococcus (VRE) carriage and infection in intensive care units.
From July, 1997, through December, 2001, patients who were admitted to intensive care units (ICUs) were enrolled in the study of vancomycin resistance enterococcus (VRE) colonization. Among 4,538 patients admitted to the ICUs, 363 (8.0%) patients were found to have positive culture of VRE at the day of admission to the ICUs and 453 (10.0%) of patients were negative to the first day of admission but became colonized with VRE during the stay in ICU. Among 816 patients, 9 (1.1%) with VRE isolated from sterile sites were selected for further analysis. Pulsed-field gel electrophoresis (PFGE) revealed a total of four PFGE banding patterns in the colonized and infected Enterococcus faecium isolates. Six of nine 9 were found to have an identical PFGE type Ia, suggesting the circulation of an endemic strain. All of these type Ia isolates also contained two potential virulence genes, the esp and hly genes and were first identified in Asia. After the further typing of 540 isolates that were randomly selected from each month, the endemic strain was not identified before the first patient was colonized and infected with this strain in November, 1998, but was isolated from other ICU patients during each month thereafter throughout the remainder of the study period. Although colonization of VRE is the first step toward infection, a low infection rate was observed, except in patients with prolonged hospitalization and severe illness. Use of the isolation room and reminders regarding hand hygiene failed to prevent the circulation of endemic strain. Thus, the SHEA guideline (Muto et al., Infect. Control Hosp. Epidemiol. 2003;24:362-386) for preventing nosocomial transmission of VRE should be enforced.


[Antagonistic effects of estrogen on iron-induced bone resorption and its mechanism].
To explore the antagonistic effect of estrogen on iron-induced bone resorption and the role of oxidative stress. In vivo, 8-week-old female imprinting control region mice were randomly divided into 3 groups of ferritin (F), ovariectomy (OVX) and F+OVX. Intervention was made by ferric ammonium citrate (FAC) and OVX. Serum levels of ferritin, malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. The expression changes of TRAP, CTR, matrix metallopeptidase 9 (MMP9) and CTK derived from murine bilateral tibia were detected by reverse transcription-polymerase chain reaction (RT-PCR). A high-resolution micro-computed tomography was utilized for scanning distal femur. In vitro, RAW264.7 cells were used and intervened by FAC and estradiol. Tartrate resistant acid phosphatase (TRAP) staining was performed and wine-red TRAP positive cells were counted. ROS level was detected by 2', 7'-dichloro-dihydrofluorescein diacetate (DCFH-DA) with a multi-detection reader. The serum ferritin were heightened in F and F+OVX groups [(335.30 ± 44.10) vs (41.38 ± 5.56) µg/L, (324.80 ± 38.60) vs (41.38 ± 5.56) µg/L respectively, P < 0.01]. The trend of MDA level was F+OVX>OVX>F while SOD level was quite opposite. Body mass density of F+OVX group was lower than that of OVX group (0.114 ± 0.013 vs 0.187 ± 0.029 mg/mm³, P < 0.05) or F group (0.114 ± 0.013 vs 0.902 ± 0.064 mg/mm³, P < 0.05). TRAP and CTK gene expression of OVX group was lower than that of F+OVX group. However, TRAP, CTR and CTK gene expression of F+OVX group was higher than that of F group. TRAP staining: FAC increased the number of TRAP positive cells (41.7 ± 5.5 vs 20.0 ± 4.0, P < 0.05) while estradiol decreased it (14.8 ± 5.1 vs 41.7 ± 5.5, P < 0.05). DCFH-DA test show that reactive oxygen species was elevated by FAC (160% ± 8% vs 100% ± 9%, P < 0.05) and reduced by estradiol (53% ± 13% vs 160% ± 8%, P < 0.05). The antagonistic effect of estrogen on iron-induced bone resorption is probably regulated by oxidative stress.


[Clinical and pathological correlation in fatal dengue cases found in Maracaibo, Venezuela].
Given the importance of dengue in America, it is indispensable to know the cause of death of the infected people and to evaluate the few necropsy studies available. To describe and to analyze the relevant clinical and pathological findings in fatal dengue cases of dengue in a Venezuelan endemic area. Eight fatal cases, according to clinical and epidemiological dengue criteria and/or confirmed by complete serological tests were studied after complete clinical necropsy. The tissues were processed by standard histopathological techniques. All these cases showed severe lung disease (diffuse alveolar damage, non cardiogenic pulmonary edema, thromboembolism, bronchopneumonia, pneumonitis, intralveolar hemorrhage). Six presented with pleural or abdominal effusion. Focal hepatic necrosis was found in two cases. The cause of death was related to respiratory failure in six (6) cases secondary to lung disease; two with hypovolemic shock, and one developed liver failure. the studied dengue cases showed fatal severe pulmonary compromise leading to death, unlike those reported in other studies of autopsies in The Americas. They also developed multiple organ failure, which in most cases led to death not directly associated to hypovolemic shock. These findings in autopsies will allow designing therapeutic strategies to avoid mortality.


Preoperative Opioid Use Disorder Is Associated With Poorer Outcomes After Coronary Bypass and Valve Surgery: A Multistate Analysis, 2007-2014.
To determine the effect of preoperative opioid use disorder (OUD) on postoperative outcomes in patients undergoing coronary artery bypass grafting (CABG) and heart valve surgery. Retrospective, observational study using data from the State Inpatient Database and the Healthcare Cost and Utilization Project. Inpatient data from Florida, California, New York, Maryland, and Kentucky between 2007 and 2014. A total of 377,771 CABG patients and 194,469 valve surgery patients age ≥18 years. None. The prevalence of OUD was 2,136 (0.57%) in the CABG group and 2,020 (1.04%) in the valve surgery group. There was no significant difference in mortality between the OUD and non-OUD groups in both surgical cohorts (both p > 0.05). On adjusted analyses, preoperative OUD was significantly associated with increased adjusted odds ratios (aORs) of 30-day hospital readmission (CABG aOR 1.47 [95% confidence interval {CI} 1.30-1.66]; valve surgery aOR 1.41 [95% CI 1.27-1.56]) and 90-day hospital readmission (CABG aOR 1.47 [95% CI 1.31-1.64]; valve surgery aOR 1.33 [95% CI 1.23-1.43]). Preoperative OUD was significantly associated with increased adjusted risk ratios (aRRs) of hospital length of stay (CABG aRR 1.13 [95% CI 1.10-1.16]; valve surgery aRR 1.63 [95% CI 1.54-1.72]) and total hospitalization charges (CABG aRR 1.05 [95% CI 1.03-1.07]; valve surgery aRR 1.28 [95% CI 1.24-1.32]). Preoperative OUD is significantly associated with poorer outcomes after cardiac surgery, including increased 30- and 90-day readmissions, hospital length of stay, and total hospitalization charges. Opioid use should be considered a modifiable risk factor in cardiac surgery, and interventions should be attempted preoperatively.


Slot waveguide ring resonators coated by an atomic layer deposited organic/inorganic nanolaminate.
In this study, slot waveguide ring resonators patterned on a silicon-on-insulator (SOI) wafer and coated with an atomic layer deposited nanolaminate consisting of alternating layers of tantalum pentoxide and polyimide were fabricated and characterized. To the best of our knowledge, this is the first demonstration of atomic layer deposition (ALD) of organic materials in waveguiding applications. In our nanolaminate ring resonators, the optical power is not only confined in the narrow central air slot but also in several parallel sub-10 nm wide vertical polyimide slots. This indicates that the mode profiles in the silicon slot waveguide can be accurately tuned by the ALD method. Our results show that ALD of organic and inorganic materials can be combined with conventional silicon waveguide fabrication techniques to create slot waveguide ring resonators with varying mode profiles. This can potentially open new possibilities for various photonic applications, such as optical sensing and all-optical signal processing.


Clinicopathological analysis of primary central nervous system NK/T cell lymphoma: rare and localized aggressive tumour among extranasal NK/T cell tumours.
The central nervous system (CNS) is a rare primary site of non-Hodgkin lymphoma. Although direct invasion of nasal natural killer (NK)/T cell tumours into CNS is reported occasionally, primary CNS NK/T cell lymphoma is extremely rare, and the clinicopathological features of primary CNS NK/T cell lymphoma remain largely unknown. We identified four cases from our consultation files and analysed the clinicopathological features. Three were immunocompetent and one was immunosuppressed. There were three males and one female and their ages ranged from 21 to 77 years (median: 46 years). Radiotherapy was rendered for all patients, and methotrexate was administered to two patients. The overall survival was 4-29 months (median, 19 months) for the three immunocompetent patients. Neoplastic cells exhibited medium to large atypical nuclei. Angiocentric growth and necrosis were observed. The immunophenotype was typical of NK cell tumours: CD3ε, 100%; CD56, 67%; CD5, 50%; cytotoxic molecules, 100%; Epstein-Barr virus encoded small RNA (EBER), 100% and T cell receptor (TCR)-β or γ, 0%. No TCR-gene rearrangements were detected. Reviewing 10 additional cases from the literature and comparing with extranasal NK/T cell lymphoma of the more frequent origins (skin or gastrointestinal tract), primary CNS NK/T cell lymphoma was diagnosed at an earlier stage without B symptoms but exhibited aggressive clinical behaviours. Although extremely rare, primary CNS NK/T cell lymphoma does occur and should always be included in the differential diagnosis and we should apply relevant markers routinely in conjunction with exploring the patient background. The accumulation of cases is indispensable to establish an effective treatment strategy for this rare and aggressive malignancy.


Virioplankton dynamics are related to eutrophication levels in a tropical urbanized bay.
Virioplankton are an important and abundant biological component of marine and freshwater ecosystems. Often overlooked, aquatic viruses play an important role in biogeochemical cycles on a global scale, infecting both autotrophic and heterotrophic microbes. Viral diversity, abundance, and viral interactions at different trophic levels in aqueous environments are not well understood. Tropical ecosystems are less frequently studied than temperate ecosystems, but could provide new insights into how physical and chemical variability can shape or force microbial community changes. In this study, we found high viral abundance values in Guanabara Bay relative to other estuaries around the world. Viral abundance was positively correlated with bacterioplankton abundance and chlorophyll a concentrations. Moreover, prokaryotic and viral abundance were positively correlated with eutrophication, especially in surface waters. These results provide novel baseline data on the quantitative distribution of aquatic viruses in tropical estuaries. They also provide new information on a complex and dynamic relationship in which environmental factors influence the abundance of bacterial hosts and consequently their viruses. Guanabara Bay is characterized by spatial and seasonal variations, and the eutrophication process is the most important factor explaining the structuring of virioplankton abundance and distribution in this tropical urbanized bay.


Ankle-foot orthosis has limited effect on walking test parameters among patients with peripheral ankle dorsiflexor paresis.
The aim of this study was to determine the relationship between ankle dorsiflexor strength and performances on several walking tests and to determine the effect of ankle-foot orthosis (AFO) use on walking tests. The following tests were used: 10-metre walking test (with and without three stairs), a complex walking task (6-minute walk with cognitive loading) and a subjective evaluation (SIP68 mobility scale and questionnaire). Isometric strength of the ankle dorsiflexors was measured. All walking tests were performed with and without AFO in random order. When relating torque values to walking performances, the highest correlation was found with the "10 metre" and "10 metre with stairs" test (r = -0.51, i.e. an inverse relationship). No threshold in the degree of paresis was found below which walking disability suddenly increased. No significant improvement could be demonstrated from AFO use on the 10-metre tests. Improvement on the 6-minute test was nearly significant (p = 0.06), the questionnaire revealed a positive opinion on AFO use related to overall walking function and effort. Thus, we have to conclude that these walking tests do not aid the clinician in estimating the severity of (progression of) the paresis nor to detect differences in degree of paresis between subjects.


Telomerase is upregulated in irreversible preneoplastic lesions during bladder carcinogenesis in rats.
Multiple occurrence or recurrence after transurethral resection is an important characteristic of superficial bladder tumors. To study bladder carcinogenesis, we focused on detection of telomerase activation, which was investigated in several human cancers, including bladder tumors. We experimentally examined the telomerase activity during bladder carcinogenesis, especially in precancerous lesions, induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in rats. Male Wistar rats were given 0.05% BBN in water from the age of 8 weeks to 24 weeks. Subgroups were euthanized at 4, 8, 10, 12, 18, and 24 weeks after BBN administration. Using the stretch PCR method, telomerase activity was semiquantified in exfoliated bladder epithelial cells. In addition, telomere length in each subgroup was measured by southern hybridization for the terminal restriction fragment using a (TTAGGG)(4) probe. Statistical analyses were performed using analysis of variance and Fisher's PLSD test. Epithelial cells of normal bladder in the control groups and those of diffuse hyperplasia, which was a reversible change at 4 weeks, expressed no telomerase activity. In contrast, telomerase activity significantly increased in the stage after nodular hyperplasia, an irreversible change at 8 weeks, then elevated with carcinogenesis. However, telomere length was still preserved by the 12th week, and was shortened at 18 and 24 weeks. These results suggest that telomerase activation is probably induced independent of telomere shortening during bladder carcinogenesis in the rat, and might be a biological tumor marker of irreversible preneoplastic lesions, which evolve into bladder tumors in the rat.


TRANSECTION OF INFERIOR ALVEOLAR NERVE IN THE RAT - NEUROANATOMICAL STUDY AND EXPERIMENTAL MODEL.
Experimental lesions in the inferior alveolar nerve (IAN) are used for the study of peripheral and central alterations. The objective of our study was to contribute to a more precise description of the approach to the IAN and creating a lesion. Twenty-six males of Wistar laboratory rats were used for the study. The animals were divided into three groups: control group (6 rats), experimental group (12 rats - a part of the bone above the mandibular canal was removed under general anaesthesia using extraoral approach, after exposing a part of the IAN, the nerve was excised in a length of 3 mm), and a sham group (8 rats - the nerve was only dissected but not transected). Persisting denervation was verified using surgical revision and histological and immunohistochemical analysis after the observation period (4 weeks). No evidence of re-innervation after 4 weeks. We found no statistically significant differences in mean weight gains between individual groups during the observation period. The described technique used in the study is one of the possible ways to create a nerve lesion at the site of the main trunk of the nerve. At the same time, the study provides a more precise description of the anatomical situation and approach to the IAN in the mandibular canal.


Three-dimensional reconstruction of statistically optimal unit cells of polydisperse particulate composites from microtomography.
In this paper, we present a systematic approach for characterization and reconstruction of statistically optimal representative unit cells of polydisperse particulate composites. Microtomography is used to gather rich three-dimensional data of a packed glass bead system. First-, second-, and third-order probability functions are used to characterize the morphology of the material, and the parallel augmented simulated annealing algorithm is employed for reconstruction of the statistically equivalent medium. Both the fully resolved probability spectrum and the geometrically exact particle shapes are considered in this study, rendering the optimization problem multidimensional with a highly complex objective function. A ten-phase particulate composite composed of packed glass beads in a cylindrical specimen is investigated, and a unit cell is reconstructed on massively parallel computers. Further, rigorous error analysis of the statistical descriptors (probability functions) is presented and a detailed comparison between statistics of the voxel-derived pack and the representative cell is made.


[Progress in research of risk factors of iron deficiency and intervention in blood donors].
Long-term repeated regular blood donation may result in the loss and deficiency of iron. Epidemiological studies have indicated that blood donation frequency, demographical characteristics, and genetic factors are associated with iron deficiency. Our review summarizes the progress in research of etiology of iron deficiency in blood donors and intervention measures to provide evidence for the health management of non-remunerated blood donors in China.


The long-term results of a randomized clinical trial of laparoscopy-assisted versus open surgery for colon cancer.
The aim of this study was to compare the long-term outcome of laparoscopy-assisted colectomy (LAC) and open colectomy (OC) for nonmetastatic colon cancer. From November 1993 to July 1998 all patients with adenocarcinoma of the colon were assessed for entry in this single center, clinically randomized trial. Adjuvant therapy and postoperative follow-up were similar in both groups. The primary endpoint was cancer-related survival and secondary endpoints were probability of overall survival and probability of being free of recurrence. Data were analyzed according the intention-to-treat principle. Two hundred and nineteen patients entered the study (111 LAC group and 108 OC group). The median follow-up was 95 months (range, 77-133). There was a tendency of higher cancer-related survival (P = 0.07, NS) and overall survival (P = 0.06, NS) for the LAC group. Probability of cancer-related survival was higher in the LAC group (P = 0.02) when compared with OC. The regression analysis showed that LAC was independently associated with a reduced risk of tumor relapse (hazard ratio 0.47, 95% CI 0.23-0.94), death from a cancer-related cause (0.44, 0.21-0.92) and death from any cause (0.59, 0.35-0.98). LAC is more effective than OC in the treatment of colon cancer.


Undiagnosed diseases: Needs and opportunities in 20 countries participating in the Undiagnosed Diseases Network International.
Rare diseases (RD) are a health priority worldwide, overall affecting hundreds of millions of people globally. Early and accurate diagnosis is essential to support clinical care but remains challenging in many countries, especially the low- and medium-income ones. Hence, undiagnosed RD (URD) account for a significant portion of the overall RD burden. In October 2020, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) launched a survey among its members, belonging to 20 countries across all continents, to map unmet needs and opportunities for patients with URD. The survey was based on questions with open answers and included eight different domains. Conflicting interpretations were resolved in contact with the partners involved. All members responded to the survey. The results indicated that the scientific and medical centers make substantial efforts to respond to the unmet needs of patients. In most countries, there is a high awareness of RD issues. Scarcity of resources was highlighted as a major problem, leading to reduced availability of diagnostic expertise and research. Serious equity in accessibility to services were highlighted both within and between participating countries. Regulatory problems, including securing informed consent, difficulties in sending DNA to foreign laboratories, protection of intellectual property, and conflicts of interest on the part of service providers, remain issues of concern. Finally, most respondents stressed the need to strengthen international cooperation in terms of data sharing, clinical research, and diagnostic expertise for URD patients in low and medium income countries. The survey highlighted that many countries experienced a discrepancy between the growing expertise and scientific value, the level of awareness and commitment on the part of relevant parties, and funding bodies. Country-tailored public health actions, including general syllabus of medical schools and of the education of other health professionals, are needed to reduce such gaps.


Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens.
We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound E showed low nanomolar inhibition of DNA gyrase (IC50 < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.03 μg/mL for most Gram-positive strains and 4-16 μg/mL against Gram-negative E. coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, a combination of docking calculations, molecular dynamics (MD) simulations, and MD-derived structure-based pharmacophore modeling was performed. The computational analysis has revealed that the substitution at position C5 can be used to modify the physicochemical properties and antibacterial spectrum and enhance the inhibitory potency of the compounds. Additionally, a discussion of challenges associated with the synthesis of 5-substituted 2-aminobenzothiazoles is presented.


Immune modulation effect of porcine placenta extracts in weaned the pig.
In a previous study, we established a collection of appropriate porcine placental extracts using PBS at 80°C (PE-PBS80) as a food supplement to increase immune activities in a mice model. In this study, piglets were treated with 0.1%, 0.3%, and 0.5% PE-PBS80 for 3 wk after weaning. Experiments were performed at 2 separate farms using 2 different pig varieties. Composition of white blood cells, lymphocyte activation, and cytokine concentrations were analyzed to assess the immune modulation effect. In Exp. 1, the number of white blood cells increased significantly in the PE-PBS80 treatment and T- and B-cell activation increased as well (P < 0.01). Interestingly, piglets in all treatments in Exp. 2 were naturally infected by a rotavirus at the third day of the experiment but recovered after d 10. Increased lymphocyte activation was observed in the PE-PBS80 treatment (P < 0.01) regardless of viral infection. Additionally, unlike in Exp. 1, the percentage of granulocytes and concentrations of interferon-γ, IL-1β, and IgG increased in the PE-PBS80 treatment (P < 0.01) and were more active in the 0.3% PE-PBS80 treatment compared with the control and the other treatment. In conclusion, 0.3% PE-PBS80 treatment modulated immune activities in antigen-infected piglets. Therefore, the PE-PBS80 pig placental extract, particularly the 0.3% supplement to the normal diet, could be useful as an alternative feed supplement to modulate immune activity during the early piglet period.


Structural differences in the DNA binding domains of human p53 and its C. elegans ortholog Cep-1.
The DNA binding domains of human p53 and Cep-1, its C. elegans ortholog, recognize essentially identical DNA sequences despite poor sequence similarity. We solved the three-dimensional structure of the Cep-1 DNA binding domain in the absence of DNA and compared it to that of human p53. The two domains have similar overall folds. However, three loops, involved in DNA and Zn binding in human p53, contain small alpha helices in Cep-1. The alpha helix in loop L3 of Cep-1 orients the side chains of two conserved arginines toward DNA; in human p53, both arginines are mutation hotspots, but only one contacts DNA. The alpha helix in loop L1 of Cep-1 repositions the entire loop, making it unlikely for residues of this loop to contact bases in the major groove of DNA, as occurs in human p53. Thus, during evolution there have been considerable changes in the structure of the p53 DNA binding domain.


Ticagrelor mitigates ischaemia-reperfusion induced vascular endothelial dysfunction in healthy young males - a randomized, single-blinded study.
Animal data suggest that ticagrelor but not clopidogrel protects against tissue injury. It is unclear if this effect of ticagrelor is also detectable in humans. We studied the effect of ticagrelor and clopidogrel at standard clinical doses on endothelial dysfunction in an experimental model of forearm vascular ischaemia-reperfusion (IR) injury. In a randomized, single-blinded trial, 24 subjects underwent forearm blood flow (FBF) measurements in response to the endothelium-dependent vasodilator acetylcholine (ACh) and to glyceryltrinitrate (GTN; endothelium-independent) before and after a 20 min forearm ischaemia. FBF reactivity was assessed after an oral loading dose of ticagrelor or clopidogrel and after 14 days of regular intake of maintenance doses of the study medicines. In addition, the effect on platelet inhibition was evaluated using multiple electrode aggregometry. ACh-induced vasodilation was impaired during reperfusion and not completely normalized by acute or chronic treatment with ticagrelor or clopidogrel (post- vs. pre-ischaemia). However, ticagrelor mitigated endothelial dysfunction compared to clopidogrel after loading (FBF AChAUC ratio post- vs. pre-ischaemia: 0.83 [0.70; 0.96] vs. 0.64 [0.56; 0.72]; P = 0.024) and after chronic administration (FBF AChAUC ratio: 0.86 [0.71; 1.00] vs. 0.66 [0.55; 0.77]; P = 0.027). As expected, GTN-induced vasodilation was not affected by ischaemia. Ticagrelor or clopidogrel treatment inhibited platelet activation to a similar degree. Our data indicate that ticagrelor treatment exerts a greater vascular salutary effect than clopidogrel during reperfusion after an acute vascular occlusion. IR-induced vascular injury cannot be prevented completely by administration of these antiplatelet agents at standard clinical doses.


Early diagnostics and therapeutics for Alzheimer's disease--how early can we get there?
Alzheimer's disease (AD) is a major threat for the rapidly aging world population. AD is the leading cause of dementia and a major cause of death in developed countries. The disease puts a tremendous practical, emotional and financial burden on individuals and governments. Clinicians and researchers in the AD field face great challenges: the pathophysiological processes that cause AD are not well understood, definite diagnosis of AD requires autopsy, and therapeutic options are limited to treating the symptoms rather than the cause of the disease. Nevertheless, new insights into the earliest events that lead to development of AD increase hope that reliable diagnostics and efficacious therapies may emerge.


De novo transcriptome analysis and glucosinolate profiling in watercress (Nasturtium officinale R. Br.).
Watercress (Nasturtium officinale R. Br.) is an aquatic herb species that is a rich source of secondary metabolites such as glucosinolates. Among these glucosinolates, watercress contains high amounts of gluconasturtiin (2-phenethyl glucosinolate) and its hydrolysis product, 2-phennethyl isothiocyanate, which plays a role in suppressing tumor growth. However, the use of N. officinale as a source of herbal medicines is currently limited due to insufficient genomic and physiological information. To acquire precise information on glucosinolate biosynthesis in N. officinale, we performed a comprehensive analysis of the transcriptome and metabolome of different organs of N. officinale. Transcriptome analysis of N. officinale seedlings yielded 69,570,892 raw reads. These reads were assembled into 69,635 transcripts, 64,876 of which were annotated to transcripts in public databases. On the basis of the functional annotation of N. officinale, we identified 33 candidate genes encoding enzymes related to glucosinolate biosynthetic pathways and analyzed the expression of these genes in the leaves, stems, roots, flowers, and seeds of N. officinale. The expression of NoMYB28 and NoMYB29, the main regulators of aliphatic glucosinolate biosynthesis, was highest in the stems, whereas the key regulators of indolic glucosinolate biosynthesis, such as NoDof1.1, NoMYB34, NoMYB51, and NoMYB122, were strongly expressed in the roots. Most glucosinolate biosynthetic genes were highly expressed in the flowers. HPLC analysis enabled us to detect eight glucosinolates in the different organs of N. officinale. Among these glucosinolates, the level of gluconasturtiin was considerably higher than any other glucosinolate in individual organs, and the amount of total glucosinolates was highest in the flower. This study has enhanced our understanding of functional genomics of N. officinale, including the glucosinolate biosynthetic pathways of this plant. Ultimately, our data will be helpful for further research on watercress bio-engineering and better strategies for exploiting its anti-carcinogenic properties.


The application of 19F nuclear magnetic resonance to investigate microbial biotransformations of organofluorine compounds.
Fluorinated organic compounds, although rare in nature, are significant environmental contaminants owing to the numerous applications for which this class of compounds is employed. It is important that biodegradation of these compounds can be readily assessed in order to provide information on their fate in the environment. Fluorine-19 nuclear magnetic resonance (19F NMR) spectroscopy has emerged as a very useful technique to readily determine the catabolism of fluorinated aromatic compounds by microorganisms, either in whole cell or cell-free systems. The principal advantage of this technique is that fluorinated compounds can be observed directly in the culture supernatant or enzyme assay, without purification or derivatization. In this review an account of the application of 19F NMR in the study of microbial metabolism of organofluorine compounds is presented.


A Compact Microwave Microfluidic Sensor Using a Re-Entrant Cavity.
A miniaturized 2.4 GHz re-entrant cavity has been designed, manufactured and tested as a sensor for microfluidic compositional analysis. It has been fully evaluated experimentally with water and common solvents, namely methanol, ethanol, and chloroform, with excellent agreement with the expected behaviour predicted by the Debye model. The sensor's performance has also been assessed for analysis of segmented flow using water and oil. The samples' interaction with the electric field in the gap region has been maximized by aligning the sample tube parallel to the electric field in this region, and the small width of the gap (typically 1 mm) result in a highly localised complex permittivity measurement. The re-entrant cavity has simple mechanical geometry, small size, high quality factor, and due to the high concentration of electric field in the gap region, a very small mode volume. These factors combine to result in a highly sensitive, compact sensor for both pure liquids and liquid mixtures in capillary or microfluidic environments.


The calcimimetic R-568 increases vitamin D receptor expression in rat parathyroid glands.
We previously demonstrated that extracellular calcium regulates vitamin D receptor (VDR) expression by parathyroid cells. Since the calcimimetic R-568 potentiates the effects of calcium on the calcium-sensing receptor, it was hypothesized that administration of R-568 may result in increased VDR expression in parathyroid tissue. In vitro studies of the effect of R-568 on VDR mRNA and protein were conducted in cultures of whole rat parathyroid glands and human hyperplastic parathyroid glands. In vivo studies in Wistar rats examined the effect of R-568 and calcitriol alone and in combination. Incubation of rat parathyroid glands in vitro with R-568 (0.001-1 microM) resulted in a dose-dependent decrease in parathyroid hormone (PTH) secretion and an increase in VDR expression (mean +/- SE). Incubation in 1 mM calcium + 0.001 microM R-568 elicited an increase in VDR mRNA (306 +/- 46%) similar to the maximum increase detected with 1.5 mM calcium (330 +/- 42%). In vivo, VDR mRNA was increased after administration of R-568 (168 +/- 9%, P < 0.001 vs. control) or calcitriol (198 +/- 16%, P < 0.001 vs. control). Treatment with R-568 also increased VDR protein in normal rat parathyroid glands and in human parathyroid glands with diffuse, but not nodular, hyperplasia. In conclusion, the present study shows that the calcimimetic R-568 exerts a stimulatory effect on VDR expression in the parathyroid glands of study models and provides additional evidence for the use of calcimimetics in the treatment of secondary hyperparathyroidism.


Evaluation of surgery and surgical results of Baha® Attract system implantations - single centre experience of hundred twenty five cases.
Bone-anchored hearing aids are currently well-established solutions for treatment of hearing-impaired patients. To evaluate the surgery of the Baha® Attract system, healing process and soft tissue condition after the processor activation. 125 patients implanted with the Baha® Attract system during a 3 year period in a single ENT department were analysed. Evaluated parameters comprised: details of surgery, healing process and soft tissue condition at the time of the processor activation and on subsequent follow-up visits. The implantation was conducted under local anaesthesia in 96% of patients. The mean surgery time was 42min. Soft tissue reduction was performed in 43.2% of cases; bone polishing in 23.2% and bipolar coagulation in all the cases. Healing was uneventful in 92.8%. 10 days after the surgery, pain was reported in 48% of cases. On subsequent follow-up visits, 1 month and 3 months after the surgery, pain was present in 18.4% and 2.4% of cases respectively. Similarly, numbness and paresthesia, initially reported in 84% and 15.2%, were present in 60% and 11.2% after a month, and in 17.6% and 1.6% after three months. After the processor attachment, no serious problems were observed in the analysed group during follow-up visits. However, mild redness and/or mild pain over the magnet were observed in 9.6% of patients. Implantation of the Baha® Attract system is an easy and safe procedure. It can be performed under local anaesthesia in adults. There are no major surgical problems or complications, and the healing process proceeds efficiently in most patients. Postoperative pain is usually mild and gradually decreases in the following months. Numbness in the operated area is frequent, but as reinnervation occurs in time, the numb patch decreases in size and finally completely disappears in most cases.


Evidence-based dentistry: a clinician's perspective.
Evidence-based dentistry is a discipline that provides best, explicit-based evidence to dentists and their patients in shared decision-making. Currently, dentists are being trained and directed to adopt the role of translational researchers in developing evidence-based dental practices. Practically, evidence-based dentistry is not usable in its current mode for the provision of labor-intensive services that characterize current dental practice. The purpose of this article is to introduce a model of evidence-based dental practice. This model conceptualizes a team approach in explaining problems and solutions to change current dental practice. These changes constitute an evidence-based dental practice that involves the electronic chart, centralized database, knowledge management software, and personnel in optimizing effective oral health care to dental patients.


Estimating Densities of the Pest Halotydeus destructor (Acari: Penthaleidae) in Canola.
Development of sampling techniques to effectively estimate invertebrate densities in the field is essential for effective implementation of pest control programs, particularly when making informed spray decisions around economic thresholds. In this article, we investigated the influence of several factors to devise a sampling strategy to estimate Halotydeus destructor Tucker densities in a canola paddock. Direct visual counts were found to be the most suitable approach for estimating mite numbers, with higher densities detected than the vacuum sampling method. Visual assessments were impacted by the operator, sampling date, and time of day. However, with the exception of operator (more experienced operator detected higher numbers of mites), no obvious trends were detected. No patterns were found between H. destructor numbers and ambient temperature, relative humidity, wind speed, cloud cover, or soil surface conditions, indicating that these factors may not be of high importance when sampling mites during autumn and winter months. We show further support for an aggregated distribution of H. destructor within paddocks, indicating that a stratified random sampling program is likely to be most appropriate. Together, these findings provide important guidelines for Australian growers around the ability to effectively and accurately estimate H. destructor densities.


Tuning your priors to the world.
The idea that perceptual and cognitive systems must incorporate knowledge about the structure of the environment has become a central dogma of cognitive theory. In a Bayesian context, this idea is often realized in terms of "tuning the prior"-widely assumed to mean adjusting prior probabilities so that they match the frequencies of events in the world. This kind of "ecological" tuning has often been held up as an ideal of inference, in fact defining an "ideal observer." But widespread as this viewpoint is, it directly contradicts Bayesian philosophy of probability, which views probabilities as degrees of belief rather than relative frequencies, and explicitly denies that they are objective characteristics of the world. Moreover, tuning the prior to observed environmental frequencies is subject to overfitting, meaning in this context overtuning to the environment, which leads (ironically) to poor performance in future encounters with the same environment. Whenever there is uncertainty about the environment-which there almost always is-an agent's prior should be biased away from ecological relative frequencies and toward simpler and more entropic priors.


Routine use of backscattered electron imaging to visualize cytochemical and autoradiographic reactions in semi-thin plastic sections.
The scanning electron microscope (SEM) was used to examine cytochemical and autoradiographic reactions in 2-microns semi-thin sections of tissues conventionally fixed and embedded in various resins. The sections were examined using both the secondary and backscatter modes of the SEM at magnifications within the range attainable with the light microscope. Both modes allowed the imaging of phosphatase reaction product using cerium and lead capture, lectin-gold, and immunogold labeling, with and without silver enhancement, and autoradiography. Backscattered electron imaging (BEI), however, provided images with more contrast and structural details. This approach allows examination of large sections, with more contrast and resolution than the light microscope, and visualization of reactions not visible with this instrument. The improved imaging and the simple and conventional preparation of specimens indicate that BEI can be used routinely to examine tissue organization, cell structure, and the content of the various cell compartments with a resolution approaching that of transmission electron microscopy.


How can the safety of biotherapy products be ensured for patients?
The topic of the round table being very broad, it was agreed with the participants that the discussion should be focused on autologous cell therapy (CT) used in tissue repair, immunomodulation or gene transduction. Autologous CT is actually comprised of both very innovative procedures as well as of products used in routine clinical practice. In France, the regulatory framework for CT has now been finalised, underlining the fact that a CT product (CTP) is intrinsically linked to the process used in its preparation. The objective of this round table was to define the essential prerequisites for the development of therapies involving ex vivo cell preparations and, more specifically, to address the issues associated with patient safety during the course of product development. The different stages of CTP development were considered: (i) requirements for CTP manufacturing in order to guarantee product quality; (ii) nonclinical development, and selection of appropriate animal models to provide the proof of the concept and support the definition of CTP specifications; and (iii) clinical development and methodological specificities of CTP development. The specific problems associated with the use of ancillary therapeutic products (ATPs) during the development of a CTP were discussed. Actions were proposed to ensure long-term supply of ATPs, which may be a significant bottleneck for the development of CT in France. Eventually, new regulatory provisions will come into force in the area of biovigilance, and it was deemed necessary for healthcare and industry professionals to be appropriately involved in the implementation phase.


Comparison of two individualized antithrombotic protocols in HeartWare HVAD recipients.
We previously reported low rates of pump thrombosis and hemorrhagic stroke, but increased bleeding, under our original antithrombosis protocol (P1) in HeartWare recipients. We designed and implemented a revised protocol (P2) to reduce complexity and bleeding. Thrombelastography and PFA-100 guide antiplatelet titration. Goals for P2 were altered to decrease antiplatelet use and anticoagulation intensity. We compared the incidence and rates of gastrointestinal bleeding (GIB), embolic (eCVA) and hemorrhagic (hCVA) stroke, pump thrombosis (PT), and total bleeding (GIB+hCVA), total thrombosis (eCVA+PT), and total events between P1 and P2. Laboratory and medication data were assessed. Patients with and without hemocompatibility-related adverse events (HRAEs) were compared. The study included 123 patients (P1: 65; P2: 58). GIB rate decreased (P1: 0.66; P2 0.30 EPPY, P = .003). CVA rates and incidence were statistically similar, although hCVA incidence increased (P1: 3%; P2: 12%, P = .06). Incidence (P1: 3%; P2: 16%, P = .02) and rate (P1: 0.03; P2: 0.12 EPPY, P = .08) of PT increased. Incidence and rate of overall HRAEs and thrombotic events were similar, while bleeding rate decreased (P1: 0.69; P2: 0.40 EPPY, P = .02). Twelve-month medication burden decreased. Compared to non-HRAE patients, patients with bleeding HRAEs had more antiplatelet and pentoxifylline use, but less statin use; and lower PFAs. Patients with thrombotic HRAEs had less dual antiplatelet use, lower INRs, R-times, and PFA-ADP values. A revised antithrombotic protocol decreased GIB and overall hemorrhagic HRAE rate and medication burden. Unfortunately, PT increased. Non-HRAE and HRAE patients differed in anticoagulation and antiplatelet intensity. These differences will guide the revision of P2.


Linkage between theory-based measurement of organizational readiness for change and lessons learned conducting quality improvement-focused research.
Organizations have different levels of readiness to implement change in the patient care process. The Hypertension Telemedicine Nurse Implementation Project for Veterans (HTN-IMPROVE) is an example of an innovation that seeks to enhance delivery of care for patients with hypertension. We describe the link between organizational readiness for change (ORC), assessed as the project began, and barriers and facilitators occurring during the process of implementing a primary care innovation. Each of 3 Veterans Affairs medical centers provided a half-time nurse and implemented a nurse-delivered, telephone-based self-management support program for patients with uncontrolled hypertension. As the program was starting, we assessed the ORC and factors associated with ORC. On the basis of consensus of medical center and research partners, we enumerated implementation process barriers and facilitators. The primary ORC barrier was unclear long-term commitment of nursing to provide continued resources to the program. Three related barriers included the need to address: (1) competing organizational demands, (2) differing mechanisms to integrate new interventions into existing workload, and (3) methods for referring patients to disease and self-management support programs. Prior to full implementation, however, stakeholders identified a high level of commitment to conduct nurse-delivered interventions fully using their skills. There was also a significant commitment from the core implementation team and a desire to improve patient outcomes. These facilitators were observed during the implementation of HTN-IMPROVE. As demonstrated by the link between barriers to and facilitators of implementation anticipated though the evaluation of ORC and what was actually observed during the process of implementation, this project demonstrates the practical utility of assessing ORC prior to embarking on the implementation of significant new clinical innovations.


Identification of Leptospira Species in Environmental Soil of Urban Settlements in Cambodia.
Background: Leptospirosis represents a major public health threat in Cambodia. To help establish preventive strategies for leptospirosis, we isolated and identified Leptospira from soil collected in Phnom Penh and its neighboring province during the dry and rainy seasons. Materials and Methods: Soil samples were collected from 15 sites in the Phnom Penh metropolitan area and Kandal Province in 2019 and 2020. A total of 120 soil samples were collected and analyzed after culturing. Cultured isolates were identified at the species level using 16S rRNA and gyrB gene sequencing analysis. Results: The positive culture rate for Leptospira was significantly higher for samples collected during the rainy season (31 out of 60 samples, 51.7%) than during the dry season (19 out of 60 samples; p < 0.05, chi-squared test). In terms of sampling area, 10 (35.7%) and 13 (46.9%) soil samples from Phnom Penh and 9 (28.1%) and 18 (56.3%) soil samples from Kandal Province were culture-positive when collected during the dry and rainy seasons, respectively. Three isolates from the Kandal samples collected during the dry season were categorized as pathogenic clade type P1 according to 16S rRNA and gyrB sequence analyses. In addition, samples collected during the rainy season from Phnom Penh and Kandal Province (three each) were categorized as clade type P1. The samples with isolates in clade type P1 were collected from riverbanks during both the dry and rainy seasons and from a hospital garden during the rainy season. Conclusions: This is the first report on the isolation of clade P1 Leptospira species in environmental soil samples from Cambodia. Environmental soil appears to be a reservoir for Leptospira in the capital city and surrounding areas of Cambodia. This study contributes to the understanding of Leptospira species distribution in Asian countries.


3-Aryl-2-quinolone derivatives: synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a new therapeutical target connected with cell migration.
Among 25 3-aryl-2-quinolone derivatives synthesized, the antitumor activity of some of them was characterized both in vitro and in vivo. In this series, no compound appeared to be cytotoxic in vitro, as was known by the colorimetric MTT assay carried out on 12 distinct human cancer cell lines obtained from the American Type Culture Collection. Indeed, the concentration values decreasing the growth of the 12 cell lines by at least 50% (IC(50) index) were always higher than 10(-5) M. We then made use of a computer-assisted phase-contrast videomicroscopy system to quantitatively determine in vitro the level of migration of living MCF-7 human breast cancer cells. For example, at 10(-7) M, compounds 7, 13, 16, and 28 markedly decreased the migration level of these MCF-7 human breast cancer cells. The in vivo determination of the maximum tolerated dose showed that all compounds tested were definitively nontoxic. When the nontoxic, antimigratory compound 16 was combined with either doxorubicin or etoposide, two cytotoxic compounds routinely used in the clinic, this led to additive in vivo benefits from this treatment (as compared to individual administrations of the drugs) when the MXT mouse mammary adenocarcinoma was used. Thus, nontoxic antimigratory compounds, including the 2-quinolone derivatives synthesized here, can actually improve the efficiency of antitumor treatment when combined with conventional cytotoxic agents.


Paternal imprints can be established on the maternal Igf2-H19 locus without altering replication timing of DNA.
Genomic imprinting in mammals marks the parental alleles in gametes, resulting in differential gene expression in offspring. A number of epigenetic features are associated with imprinted genes. These include differential DNA methylation, histone acetylation and methylation, subnuclear localization and DNA replication timing. While DNA methylation has been shown to be necessary both for establishment and maintenance of imprinting, the connections with the other types of epigenetic marking systems are not clear. Specifically, it is not known whether the other marking systems, either on their own or in conjunction with DNA methylation, are required for imprinting. Here we show that in the mouse mutant Minute (Mnt) the Igf2-H19 locus acquires a paternal methylation imprint in the maternal germline. DNA methylation of the H19 DMR is established in oogenesis, maintained during postzygotic development on the maternal allele, and erased in primordial germ cells. The fact that a paternal type methylation imprint can also be established in the maternal germline indicates that trans-acting factors that target methylation to this imprinted region are likely to be the same in both germlines. Surprisingly, however, asynchrony of DNA replication of the locus is maintained despite the altered expression and methylation imprint of Igf2 and H19. These results show clearly that replication asynchrony of this region is neither the determinant factor for, nor a consequence of, epigenetic modifications that are critical for genomic imprinting. Replication asynchrony may thus be regulated differently from methylation imprints and have a separate function.


Early Childhood Caries, Mouth Pain, and Nutritional Threats in Vietnam.
We investigated the relationships among early childhood caries (ECC), mouth pain, and nutritional status in children aged 1 to 6 years in Southern and Central Vietnam. A total of 593 parent-child pairs were recruited from 5 kindergartens or preschools in Ho-Chi Minh City and Da Nang. Parents completed surveys about dietary habits, oral health practices, and children's mouth pain experience; children received anthropometric assessment and dental examinations. There was a high prevalence of dental caries (74.4%), mostly untreated, and mouth pain (47.1%). Moderate correlations were found between parents' and children's consumption of soda (ρ = 0.361; P < .001) and salty snacks (ρ = 0.292; P < .001). Severity of ECC was associated with decreased weight- and body mass index-for-age z-scores. Presence of pulp-involved caries was associated with strikingly lower height-for-age (mean difference = 0.66; P = .001), weight-for-age (mean difference = 1.17; P < .001), and body mass index-for-age (mean difference = 1.18; P < .001) z-scores. Mouth pain was associated with lower body mass index-for-age z-scores (mean difference = 0.29; P = .013). ECC might negatively affect children's nutritional status, which might be mediated by the depth of decay, chronic inflammation, and mouth pain. Family-based and prevention-oriented nutrition and oral health programs are needed and should start during pregnancy and infancy.


Total synthesis of indole-3-acetonitrile-4-methoxy-2-C-β-D-glucopyranoside. Proposal for structural revision of the natural product.
Indole-3-acetonitrile-4-methoxy-2-C-β-D-glucopyranoside (1), a novel C-glycoside from Isatis indigotica with important cytotoxic activity, has been prepared in ten steps from ethynyl-β-C-glycoside 3 and 2-iodo-3-nitrophenyl acetate 6. Key steps in the synthesis include a Sonogashira coupling and a CuI-mediated indole formation. NMR spectroscopic data for synthetic 1 differs from that reported for the natural product. A revised structure for the natural product, containing an alternate carbohydrate substituent, is proposed.


Enaminone-directed ruthenium(II)-catalyzed C-H activation and annulation of arenes with diazonaphthoquinones for polycyclic benzocoumarins.
The weakly coordinating enaminone functionality has been leveraged for a C-H bond activation strategy under ruthenium catalysis and employed in the regioselective annulative coupling of arenes with diazonaphthoquinones, offering polycyclic benzocoumarins in very high yields. The enaminone motif plays a dual role and the protocol operates through a Ru(II)/Ru(IV) catalytic pathway which is amenable to the diversification of various pharmacophore-coupled substrates.


Titanium and niobium imido complexes stabilized by heteroscorpionate ligands.
The reaction of [Ti(NR)Cl(2)(py)(3)](R = (t)Bu, p-tolyl, 2,6-C(6)H(3)(i)Pr(2)) with [{Li(bdmpza)(H(2)O)}(4)][bdmpza = bis(3,5-dimethylpyrazol-1-yl)acetate] and [{Li(bdmpzdta)(H(2)O)}(4)][bdmpzdta = bis(3,5-dimethylpyrazol-1-yl)dithioacetate] affords the corresponding complexes [Ti(NR)Cl(kappa(3)-bdmpzx)(py)](x = a, R = (t)Bu 1, p-tolyl 2, 2,6-C(6)H(3)(i)Pr(2) 3; x = dta, R =(t)Bu 4, p-tolyl , 2,6-C(6)H(3)(i)Pr(2) 6), which are the first examples of imido Group 4 complexes stabilized by heteroscorpionate ligands. The solid-state X-ray crystal structure of 1 has been determined. The titanium centre is six-coordinate with three fac-sites occupied by the heteroscorpionate ligand and the remainder of the coordination sphere being completed by chloride, imido and pyridine ligands. The complexes are 1-6 fluxional at room temperature. The pyridine ortho- and meta-proton resonances show evidence of dynamic behaviour for this ligand and variable-temperature NMR studies were carried out in order to study their dynamic behaviour in solution. The complexes [Nb(NR)Cl(3)(py)(2)](R = (t)Bu, p-tolyl, 2,6-C(6)H(3)(i)Pr(2)) reacted with [{Li(bdmpza)(H(2)O)}(4)] and (Hbdmpze)[bdmpze = 2,2-bis(3,5-dimethylpyrazol-1-yl)ethoxide], the latter with prior addition of (n)BuLi, to give the complexes [Nb(NR)Cl(2)(kappa(3)-bdmpzx)](x = a, R =(t)Bu 7, p-tolyl 8, 2,6-C(6)H(3)(i)Pr(2) 9; x = e, R = (t)Bu 10, p-tolyl 11, 2,6-C(6)H(3)(i)Pr(2)) 12 and these are the first examples of imido Group 5 complexes with heteroscorpionate ligands. The structures of these complexes have been determined by spectroscopic methods.


Agitated older patients: nurses' perceptions and reality.
Management of agitation is an increasingly common duty in the nursing care of older patients. Agitation describes a range of behavioural symptoms including aggressiveness and hyperactivity, and can be a sign of severe illness. In a series of focus groups in a large teaching hospital, nurses' feelings and actions in regard to nursing agitated older people were recorded and analysed. The results demonstrated that agitation is not well understood and is often not well-managed. Despite recent efforts to provide more supportive staffing structures, nurses felt particularly stressed and unsupported in relation to this phenomenon. Recommendations are made for the instigation of enhanced education programmes as well as ongoing attention to improved workload initiatives.


Mussel-Inspired Wet-Adhesive Multifunctional Organohydrogel with Extreme Environmental Tolerance for Wearable Strain Sensor.
As a flexible artificial material, the conductive hydrogel has broad application prospects in flexible wearable electronics, soft robotics, and biomedical monitoring. However, traditional hydrogels still face many challenges, such as long-term stability, availability in extreme environments, and long-lasting adhesion to the skin surface under sweaty or humid conditions. To circumvent the above issues, one kind of ionic conductive hydrogel was prepared by a simple one-pot method that dissolved chitosan (CS), 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS), tannic acid (TA), and 2-methoxy-ethyl acrylate (MEA) into dimethyl sulfoxide (DMSO)/H2O solvent. The resulting hydrogel showed excellent tensile properties (1440%), extreme environmental tolerance (-40-60 °C), adhesion (72 KPa at porcine skin), ionic conductivity (0.87 S m-1), and high-efficiency antibacterial property. Furthermore, the produced organohydrogel strain sensor exhibited high strain sensitivity (GF = 4.07), excellent signal sensing capabilities (human joint movement, microexpression, and sound signals), and long-term cyclic stability (400 cycles). Looking beyond, this work provides a simple and promising strategy for using hydrogel sensors in extreme environments for e-skin, health monitoring, and wearable electronic devices.


The structure of genetic and environmental risk factors for DSM-IV personality disorders: a multivariate twin study.
Although both genetic and environmental factors affect risk of individual personality disorders (PDs), we know little of how they contribute to the pattern of comorbidity between the PDs in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV). To clarify the structure of the genetic and environmental risk factors for the 10 DSM-IV PDs. Assessment of PDs at personal interview and multivariate twin modeling with the Mx program. General community. A total of 2794 young adult members of the Norwegian Institute of Public Health Twin Panel. Main Outcome Measure Number of endorsed criteria for the 10 DSM-IV PDs. The best-fit multivariate twin model required 3 genetic and 3 individual-specific environmental factors and genetic and individual-specific factors unique to each PD. The first genetic factor had high loadings on PDs from all 3 clusters including paranoid, histrionic, borderline, narcissistic, dependent, and obsessive-compulsive. The second genetic factor had substantial loadings only on borderline and antisocial PD. The third genetic factor had high loadings only on schizoid and avoidant PD. Several PDs had substantial disorder-specific genetic risk factors. The first, second, and third individual-specific environmental factors had high loadings on the cluster B, A, and C PDs, respectively, with 1 exception: obsessive-compulsive PD loaded with cluster B and not cluster C PDs. Genetic risk factors for DSM-IV PDs do not reflect the cluster A, B, and C typology. Rather, 1 genetic factor reflects a broad vulnerability to PD pathology and/or negative emotionality. The 2 other genetic factors are more specific and reflect high impulsivity/low agreeableness and introversion. Unexpectedly, the cluster A, B, and C typology is well reflected in the structure of environmental risk factors, suggesting that environmental experiences may be responsible for the tendency of cluster A, B, and C PDs to co-occur.


How Specific Is Site-Specific? A Review and Guidance for Selecting and Evaluating Approaches for Deriving Local Water Quality Benchmarks.
Existing prescriptive guidance on the derivation of local water quality benchmarks (WQBs; e.g., guideline values, criteria, standards) for protecting aquatic ecosystems is limited to only 3 to 4 specific approaches. These approaches do not represent the full suite available for deriving local WQBs for multiple types of water quality-related issues. The general lack of guidance is inconsistent with the need for, and benefits of, local WQBs, and can constrain the appropriate selection and subsequent evaluation of derivation approaches. Consequently, the defensibility of local WQBs may not be commensurate with the nature of the issues for which they are derived. Moreover, where local WQBs are incorporated into regulatory requirements, the lack of guidance presents a potential risk to the derivation of appropriate WQBs and the achievement of desired environmental outcomes. This review addresses the deficiency in guidance by 1) defining local WQBs and outlining initial considerations for deciding if one is required; 2) summarizing the existing regulatory context; 3) summarizing existing guidance and identifying gaps; 4) describing strengths, weaknesses, and potential applications of a range of derivation approaches based on laboratory and/or field data; and 5) presenting a conceptual framework for appropriately selecting and evaluating a derivation approach to best suit the need. The guidance incorporates an existing set of guiding principles for deriving local WQBs and reinforces an existing categorization of site-adapted and site-specific WQBs. The conceptual framework recognizes the need to strike an appropriate balance between effort and ecological risk and, thus, embeds the concept of fit-for-purpose by considering both the significance of the issue being assessed and the extent to which the approach provides confidence that the ecosystem will be appropriately protected. The guidance can be used by industry, regulators, and others for both the a priori selection and the post hoc evaluation of appropriate approaches for deriving local WQBs. Integr Environ Assess Manag 2019;15:683-702. © 2019 The Authors.


Sentinel node detection with the blue dye technique in early cervical cancer.
The aim of this study was to investigate the feasibility of sentinel node detection with the blue dye technique in early cervical cancer. In a retrospective study conducted between January 2000 and February 2005, 47 women with early cervical cancer (6 patients FIGO Stage I A, 38 patients FIGO Stage I B, 2 patients FIGO Stage II A, 1 patient FIGO Stage II B) who underwent class II-III radical hysterectomy with pelvic lymphadenectomy were identified. Prior to surgery 1 ml of blue dye (lymphazurin 1%) was injected into the four quadrants of the cervix. The detection rate for sentinel nodes was 83% (39/47 patients). The median number of sentinel lymph nodes per patient was two. Nine patients had positive sentinel nodes. In one patient the sentinel lymph node procedure revealed to be false-negative. Positive predictive value and specificity were both 100%. The sensitivity and negative predictive value were 90% and 97%, respectively. Sentinel node detection has become a main field of interest in gynecological oncology. Our detection rate and sensitivity rate using the blue dye technique in cervical cancer are comparable to those in previously published data. However, recent data on a combined radioactively labeled albumin and blue dye technique show even more promising results. The clinical validity of the combined techniques must be evaluated prospectively in larger studies.


Analytical probabilistic modeling for radiation therapy treatment planning.
This paper introduces the concept of analytical probabilistic modeling (APM) to quantify uncertainties in quality indicators of radiation therapy treatment plans. Assuming Gaussian probability densities over the input parameters of the treatment plan quality indicators, APM enables the calculation of the moments of the induced probability density over the treatment plan quality indicators by analytical integration. This paper focuses on analytical probabilistic dose calculation algorithms and the implications of APM regarding treatment planning. We derive closed-form expressions for the expectation value and the (co)variance of (1) intensity-modulated photon and proton dose distributions based on a pencil beam algorithm and (2) the standard quadratic objective function used in inverse planning. Complex correlation models of high dimensional uncertain input parameters and the different nature of random and systematic uncertainties in fractionated radiation therapy are explicitly incorporated into APM. APM variance calculations on phantom data sets show that the correlation assumptions and the difference of random and systematic uncertainties of the input parameters have a crucial impact on the uncertainty of the resulting dose. The derivations regarding the quadratic objective function show that APM has the potential to enable robust planning at almost the same computational cost like conventional inverse planning after a single probabilistic dose calculation. Beneficial applications of APM in the context of radiation therapy treatment planning are feasible.


IL-17A promotes the proliferation of human nasopharyngeal carcinoma cells through p300-mediated Akt1 acetylation.
Interleukin (IL)-17A is a T helper (Th)17 cell-secreted cytokine that is able to induce various inflammatory responses. There is emerging evidence that IL-17A is generated in the cancer microenvironment of human nasopharyngeal carcinoma (NPC). However, the role of IL-17A in NPC remains unclear. Thus, the present study aimed to examine the direct influence of IL-17A stimulation on the proliferation of human NPC cells and identify the underlying molecular mechanisms. Furthermore, E1A binding protein p300 (p300)-mediated AKT serine/threonine kinase 1 (Akt1) acetylation and its role in regulating the proliferation of NPC cells was investigated. The results of the current study demonstrated that IL-17A stimulation in vitro increased the proliferation of human NPC cells. Furthermore, Akt1 acetylation was identified to be enhanced in human NPC cells induced by IL-17A. Additionally, p300 induction was demonstrated to be required for Akt1 acetylation in human NPC cells following exposure to IL-17A. Functionally, p300-mediated Akt1 acetylation contributed to the proliferation of human NPC cells stimulated by IL-17A. In conclusion, the results of the present demonstrate a novel activity of IL-17A that promotes human NPC cell proliferation via p300-mediated Akt1 acetylation. This may provide a potential strategy for the treatment of patients with NPC through the inhibition of IL-17A or its receptors.


The effect of taurolidine on brain tumor cells.
Although an inhibiting effect of the antibacterial substance taurolidine on several tumor cell lines was suggested in 1990, no specific research has been performed concerning its effect on brain tumor cells. Monolayers of rat-derived C6 glioma, mouse-derived HT22 neuronal tumor, and human-derived U373 astrocytoma/glioblastoma cell lines were cultured and incubated with 1 microg/ml to 4 mg/ml of taurolidine. Neuronal and glial brain cells were obtained from rat fetuses at day 15 of gestation and incubated with taurolidine to investigate its effect on normal brain cells. Following incubation with taurolidine, the tumor cells started to shrink and to become denser. Ultrastructurally, shrinkage of cytoplasm and condensation and marginalization of chromatin could be observed. Exposure to taurolidine at concentrations of 2.8 microg/ml to 2 mg/ml led to cell death of the evaluated tumor cell types. Results of flow cytometry suggested a fragmentation of DNA. Phosphatidylserine expression increased from 6% to 25% following exposure to taurolidine at a concentration of 25 microg/ml. Normal brain cells did not show any significant changes following incubation with taurolidine. The characteristics identified by light and electron microscopy and the data obtained by flow cytometry indicate an apoptotic mechanism of cell death via currently unknown pathways. Taurolidine was found to have a direct and selective antineoplastic effect on glial and neuronal brain tumor cells in vitro.


Imprinting genes associated with endometriosis.
Much work has been carried out to investigate the genetic and epigenetic basis of endometriosis and proposed that endometriosis has been described as an epigenetic disease. The purpose of this study was to extract the imprinting genes that are associated with endometriosis development. The information on the imprinting genes can be accessed publicly from a web-based interface at http://www.geneimprint.com/site/genes-by-species. In the current version, the database contains 150 human imprinted genes derived from the literature. We searched gene functions and their roles in particular biological processes or events, such as development and pathogenesis of endometriosis. From the genomic imprinting database, we picked 10 genes that were highly associated with female reproduction; prominent among them were paternally expressed genes (DIRAS3, BMP8B, CYP1B1, ZFAT, IGF2, MIMT1, or MIR296) and maternally expressed genes (DVL1, FGFRL1, or CDKN1C). These imprinted genes may be associated with reproductive biology such as endometriosis, pregnancy loss, decidualization process and preeclampsia. This study supports the possibility that aberrant epigenetic dysregulation of specific imprinting genes may contribute to endometriosis predisposition.


Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?
Hypertrophic cardiomyopathy and pathological cardiac hypertrophy are characterized by mitochondrial structural and functional abnormalities. In this issue of the JCI, Zhuang et al. discovered 1-deoxynojirimycin (DNJ) through a screen of mitochondrially targeted compounds. The authors described the effects of DNJ in restoring mitochondria and preventing cardiac myocyte hypertrophy in cellular models carrying a mutant mitochondrial gene, MT-RNR2, which is causally implicated in familial hypertrophic cardiomyopathy. DNJ worked via stabilization of the mitochondrial inner-membrane GTPase OPA1 and other, hitherto unknown, mechanisms to preserve mitochondrial crista and respiratory chain components. The discovery is likely to spur development of a class of therapeutics that restore mitochondrial health to prevent cardiomyopathy and heart failure.


Psychometric properties of the translated Spanish version of the Pain Self-Efficacy Questionnaire.
Some patients with rotator cuff injuries do not report significant changes in pain-related outcomes. Pain self-efficacy, which is commonly assessed using the Pain Self-Efficacy Questionnaire, may contribute toward this outcome. However, a Spanish adaptation of this questionnaire is currently lacking. Therefore, this study's purpose was developing the Spanish version of this questionnaire, and assess its psychometric properties. The Spanish version of the Pain Self-Efficacy Questionnaire was translated and culturally adapted, and a sample of 107 patients with rotator cuff injuries completed the questionnaire to examine its convergent validity (analyzing its correlation with the Tampa Scale of Kinesiophobia), its test-retest reliability, for which a subset of 40 participants completed again the questionnaire, and its internal consistency. Translation was conducted without any problems, and 107 participants completed the study. Mean scores for the Pain Self-Efficacy Questionnaire were 45.2 points (standard deviation, 11.4). The Pain Self-Efficacy Questionnaire showed a moderate negative correlation with the Tampa Scale of Kinesiophobia (Pearson's correlation index r = -0.48) supporting its convergent validity. High test-retest reliability (Intraclass Correlation Coefficient of 0.90) and excellent internal consistency (Cronbach's α value of 0.92) were also found. The Spanish version of the Pain Self-Efficacy Questionnaire presents high validity, test-retest reliability, and internal consistency to assess pain self-efficacy in patients suffering rotator cuff injuries in Spanish-speaking settings.


Evaluability Assessment of an immunization improvement strategy in rural Burkina Faso: intervention theory versus reality, information need and evaluations.
An innovative immunization improvement strategy was proposed by the CRSN (Centre de Recherche en Santé de Nouna) to improve the low coverage rate for children aged 0-11 months in the health district of Nouna in Burkina Faso. This article reports on the Evaluability Assessment (EA) study that aimed to orient decisions for its evaluation in close relationship with the information needs of the stakeholders. Various methods were used, including document reviews, individual interviews, focus group discussions, meetings, literature reviews and site visits. A description of the intervention theory and philosophy is provided with its logic models and its reality documented. Lessons on the procedure include the importance of the position of the evaluability assessor, the value of replicating some steps of the assessment and the relationships between EA and process evaluation. The evaluability study concludes that the intervention had some evaluable components. To satisfy the stakeholders' needs, the initially planned community randomized controlled trial can be maintained and complemented with a process evaluation. There is a need to provide sufficient information on the cost of the intervention. This will inform decision makers on the possibility of replicating the intervention in other contexts.