Uncovering the role of hydrophobic residues in cytochrome P450-cytochrome P450 reductase interactions.
Cytochrome P450 (CYP or P450)-mediated drug metabolism requires the interaction of P450s with their redox partner, cytochrome P450 reductase (CPR). In this work, we have investigated the role of P450 hydrophobic residues in complex formation with CPR and uncovered novel roles for the surface-exposed residues V267 and L270 of CYP2B4 in mediating CYP2B4--CPR interactions. Using a combination of fluorescence labeling and stopped-flow spectroscopy, we have investigated the basis for these interactions. Specifically, in order to study P450--CPR interactions, a single reactive cysteine was introduced in to a genetically engineered variant of CYP2B4 (C79SC152S) at each of seven strategically selected surface-exposed positions. Each of these cysteine residues was modified by reaction with fluorescein-5-maleimide (FM), and the CYP2B4-FM variants were then used to determine the K(d) of the complex by monitoring fluorescence enhancement in the presence of CPR. Furthermore, the intrinsic K(m) values of the CYP2B4 variants for CPR were measured, and stopped-flow spectroscopy was used to determine the intrinsic kinetics and the extent of reduction of the ferric P450 mutants to the ferrous P450--CO adduct by CPR. A comparison of the results from these three approaches reveals that the sites on P450 exhibiting the greatest changes in fluorescence intensity upon binding CPR are associated with the greatest increases in the K(m) values of the P450 variants for CPR and with the greatest decreases in the rates and extents of reduced P450--CO formation.


Mean-field crack networks on desiccated films and their applications: Girl with a Pearl Earring.
Usual requirements for bulk and fissure energies are considered in obtaining the interdependence among external stress, thickness and area of crack polygons in desiccated films. The average area of crack polygons increases with thickness as a power-law of 4/3. The sequential fragmentation process is characterized by a topological factor related to a scaling finite procedure. Non-sequential overly tensioned (prompt) fragmentation is briefly discussed. Vermeer's painting, Girl with a Pearl Earring, is considered explicitly by using computational image tools and simple experiments and applying the proposed theoretical analysis. In particular, concerning the source of lightened effects on the girl's face, the left/right thickness layer ratio (≈1.34) and the stress ratio (≈1.102) are evaluated. Other master paintings are briefly considered.


A Health Need Satisfaction Instrument for Taiwan's single-living older people with chronic disease in the community.
The aims of this study were to explore health needs and need satisfaction of Taiwan's single-living older people with chronic disease in the community, develop a culturally sensitive Health Need Satisfaction Instrument and examine the relationships between health needs and need satisfaction. Until now, there has been no reliable instrument for health professionals to assess, comprehensively, health needs and needs satisfaction for Chinese single-living older people with chronic disease in the community. Between-method triangulation design was used. The first phase explored the contextual content of health needs from the perspectives of a purposive sampling (n = 44) using the explorative qualitative method. The second phase developed the Health Need Satisfaction Instrument and established its reliability and validity. The final phase implemented the instrument in a cohort study (n = 110) and examined the relationship between the respective/overall health needs and need satisfaction. A Health Need Satisfaction Instrument with good validity and reliability encompassing tangible, psychospiritual and informational needs was developed. A significant correlation between tangible and psychospiritual needs (r = 0.238, p < 0.05) and between tangible and informational needs (r = 0.306, p < 0.01) was found. Three types of need satisfaction were inter-related (p < 0.01). A negative correlation between global health needs and need satisfaction (r = -0.223, p < 0.05) was found. Each domain of need satisfaction was negatively correlated with that particular type of health needs (p < 0.01), except for psychospiritual need (r = 0.339, p < 0.01). A measurement model between health needs and need satisfaction was established. This study set a successful example of a rigorous, cross-cultural instrument development process for community-based Taiwan's single-living older people. Using Health Need Satisfaction Instrument, the less satisfied multidimensional health needs of community-based Taiwan's single-living older people with chronic disease can be more accurately assessed and met.


Divergent evolution and niche differentiation within the common peatmoss Sphagnum magellanicum.
Populations with phenotypic polymorphism in discrete characters may be good models for investigating genome evolution and speciation. Sphagnum magellanicum Brid. is found throughout the northern hemisphere, and despite considerable variation in morphological characters, it is considered one of the least taxonomically controversial peatmoss species. We have observed two main morphs of the species associated with different microhabitats. Here we investigated the genomic and environmental basis of this intraspecific morphological variation. We conducted transplant and common garden experiments to test whether the two morphs are genetically differentiated. We then used RAD-sequencing to quantify the genomic divergence between the morphs and approximate Bayesian computation (ABC) to infer the most likely demographic scenario explaining the genome-wide differentiation of the two morphs. We found that genomic differentiation between the two morphs is unexpectedly high and that several of the differentiated morphological characters have a genetic basis. Using simulation approaches, we found support for a scenario of ancient divergence followed by recent secondary contact. We show that the two morphs represent the two main genetic clusters previously found worldwide. Our results demonstrate that relatively minor morphological differentiation in a presumed phenotypically plastic peatmoss may be associated with massive divergence across the genome.


Fluid dynamic induced break-up during volcanic eruptions.
Determining whether magma fragments during eruption remains a seminal challenge in volcanology. There is a robust paradigm for fragmentation of high viscosity, silicic magmas, however little is known about the fragmentation behaviour of lower viscosity systems-the most abundant form of volcanism on Earth and on other planetary bodies and satellites. Here we provide a quantitative model, based on experiments, for the non-brittle, fluid dynamic induced fragmentation of low viscosity melts. We define the conditions under which extensional thinning or liquid break-up can be expected. We show that break-up, both in our experiments and natural eruptions, occurs by both viscous and capillary instabilities operating on contrasting timescales. These timescales are used to produce a universal break-up criterion valid for low viscosity melts such as basalt, kimberlite and carbonatite. Lastly, we relate these break-up instabilities to changes in eruptive behaviour, the associated natural hazard and ultimately the deposits formed.


Laboratory sampling. Alternate site perspectives.
Laboratory test results are a major diagnostic tool in the determination of a patient's condition. Clinical decisions and treatment regimens are based on these results. Laboratory testing requires a complex combination of skill, knowledge, planning, and attention to details for the end result to be an accurate representation of the patient's condition at a specific point in time. Competency in techniques, knowledge of the purpose of the testing, effects of variables on laboratory results, and the importance of following quality standards are imperative. Alternate sites present many challenges to laboratory testing. Physicians' offices, clinics, and patient's homes are rapidly replacing the traditionally controlled laboratory setting. Point-of-care technology has addressed many of the logistical problems inherent in laboratory testing for the alternate site; however, competence and quality assurance remain important parts of laboratory testing and the analysis of results.


Insulin treatment of patients with gestational diabetes: does dosage play a role?
In nonpregnant patients high insulin requirements are associated with hypoglycemia and weight gain but not with improvement in glucose control. The effect of insulin requirement on maternal and neonatal outcomes in gestational diabetes mellitus (GDM) is yet unknown. We conducted a retrospective cohort study of maternal and neonatal outcomes of pregnancy according to insulin requirements in women with GDM who were followed and delivered at the Yitzhak Shamir Medical Center between 2006 and 2016. The daily insulin dose in units per body weight was divided into quartiles and analyses were performed to compare the lowest, highest, and two middle quartiles. The primary outcome was a composite of any of the following: cesarean-section (CS), preeclampsia, macrosomia and large for gestational age (LGA) birth weight, neonatal intensive care unit admission, need for phototherapy, and neonatal hypoglycemia. Women were divided according to their insulin requirements as follows: 79 (24.8%) women who needed <0.13 IU/kg/day of insulin (insulin-sensitive group), 160 (50%) women who needed 0.14-0.42 IU/kg/day of insulin (comparison-group), and the rest who needed >0.43 IU/kg/day of insulin (insulin resistant group). There were no differences in the composite outcome between the groups (64.6, 61.3, and 69.6% for the insulin sensitive-, comparison- and resistant- groups, respectively, p = .44). Women in the insulin-resistant group had higher fasting glucose levels in the first trimester (91, 98 and 102 mg/dL for women in the insulin sensitive-, comparison- and insulin-resistant groups, respectively; p = .01). Women in the insulin-sensitive group had significantly better glycemic control (fasting glucose levels ≤90 mg/dL and 1-hour and 2-hour postprandial glucose levels ≤140 mg/dL and ≤120 mg/dL for more than 80% of measurements) than those in the insulin-resistant group (70.3 versus 29.9%; p < .001). The rate of CS was significantly higher in the insulin-resistant group (42.3 versus 24.1%; p = .03), but the rate of LGA birth weight was surprisingly higher in the insulin-sensitive group (29.5 versus 16.7%, p = .04). After controlling for confounders, women in the insulin-sensitive group had a decreased risk for CS in relation to the comparison group (OR = 0.46, 95%CI 0.23-0.9, p = .025). We found no association between insulin requirements and adverse composite outcome in women with GDM. However, those with higher insulin requirements have poorer glucose control and higher rates of CS than those with lower insulin requirements. Larger studies are needed to inquire short- and long-term outcomes of insulin requirements on fetal and maternal outcomes.


Experimental parameters of the photoemitter membrane spatial light modulator.
Experimental parameters of the photoemitter membrane spatial light modulator (PEMLM) photocathode, microchannel plate (MCP), and membrane are measured to determine the constraints they impose on the fabrication and performance of the device. An analysis of the PEMLM has shown that the ratio of the MCP strip current to the membrane tension is proportional to the ultimate limit of the device time response. Experimental measurements indicate that the ultimate performance has not been obtained. A different selection of the membrane material can improve the time response by lowering the tension. But the material selection is greatly restricted by the need to incorporate a visible photocathode for applications utilizing feedback. The use of high temperature stable membranes with low tensions and high strip current MCPs should enhance the PEMLM's time response.


Development and Validation of a Score to Predict Acute Care Use After Initiation of Systemic Therapy for Cancer.
Emergency department visits and hospitalizations after starting systemic therapy for cancer are frequent, undesirable, and costly. A score to quantify the risk of needing acute care can inform decision-making and facilitate the development of preventive interventions. To develop and validate a score to predict early use of acute care after initiating systemic therapy for cancer. A retrospective population-based cohort study was conducted between July 1, 2014, and June 30, 2015. Patients with cancer were eligible if they started a new systemic therapy for cancer, regardless of line of therapy. A total of 12 162 patients in Southwestern Ontario, Canada, formed the development cohort and 15 845 patients in Northeastern Ontario formed the validation cohort. Data analysis was conducted from December 1, 2016, to August 10, 2019. The Prediction of Acute Care Use During Cancer Treatment (PROACCT) score was created based on logistic regression in the development cohort. Combinations of cancer type and regimens were grouped into quintiles based on risk of needing acute care. The score was assessed in the validation cohort. At least 1 emergency department visit or hospitalization within 30 days after starting systemic therapy for cancer identified from administrative databases. Among the 12 162 patients in the development cohort, 6903 were women and 5259 were men (mean [SD] age, 62.9 [12.6] years); among the 15 845 patients in the validation cohort, 9025 were women and 6820 were men (mean [SD] age, 62.9 [12.6] years). Use of acute care occurred within 30 days after initiation of systemic therapy in 3039 patients (25.0%) in the development cohort and 4212 patients (26.6%) in the validation cohort. Three characteristics predicted early use of acute care and formed the PROACCT score: combination of cancer type and treatment regimen, age, and emergency department visits in the prior year (C statistic, 0.67; 95% CI, 0.66-0.69; P < .001). Other characteristics including patient-reported symptoms did not improve performance. In the validation cohort, the PROACCT score was associated with use of acute care (odds ratio per point increase, 1.22; 95% CI, 1.20-1.24; P < .001), had a C statistic of 0.61 (95% CI, 0.60-0.62; P < .001), was reasonably calibrated, and provided net benefit in decision curve analysis. The PROACCT score predicted the risk of early use of acute care in patients starting systemic treatment for cancer and could be incorporated at the point of care to select patients for preventive interventions. Future studies should validate the PROACCT score in other settings.


Current perspective on protein S-acylation in plants: more than just a fatty anchor?
Membranes are an important signalling platform in plants. The plasma membrane is the point where information about the external environment must be converted into intracellular signals, while endomembranes are important sites of protein trafficking, organization, compartmentalization, and intracellular signalling. This requires co-ordinating the spatial distribution of proteins, their activation state, and their interacting partners. This regulation frequently occurs through post-translational modification of proteins. Proteins that associate with the cell membrane do so through transmembrane domains, protein-protein interactions, lipid binding motifs/domains or use the post-translational addition of lipid groups as prosthetic membrane anchors. S-acylation is one such lipid modification capable of anchoring proteins to the membrane. Our current knowledge of S-acylation function in plants is fairly limited compared with other post-translational modifications and S-acylation in other organisms. However, it is becoming increasingly clear that S-acylation can act as more than just a simple membrane anchor: it can also act as a regulatory mechanism in signalling pathways in plants. S-acylation is, therefore, an ideal mechanism for regulating protein function at membranes. This review discusses our current knowledge of S-acylated proteins in plants, the interaction of different lipid modifications, and the general effects of S-acylation on cellular function.


Study on a linear relationship between limited pressure difference and coil current of on/off valve and its influential factors.
On/off solenoid valves with PWM control are widely used in all types of vehicle electro-hydraulic control systems respecting to their desirable properties of reliable, low cost and fast acting. However, it can hardly achieve a linear hydraulic modulation by using on/off valves mainly due to the nonlinear behaviors of valve dynamics and fluid, which affects the control accuracy significantly. In this paper, a linear relationship between limited pressure difference and coil current of an on/off valve in its critical closed state is proposed and illustrated, which has a great potential to be applied to improve hydraulic control performance. The hydraulic braking system of case study is modeled. The linear correspondence between limited pressure difference and coil current of the inlet valve is simulated and further verified experimentally. Based on validated simulation models, the impacts of key parameters are researched. The limited pressure difference affected by environmental temperatures is experimentally studied, and the amended linear relation is given according to the test data.


Type 2 diabetes and the metabolic syndrome in children and adolescents.
The prevalence rates of obesity, metabolic syndrome, and type 2 diabetes in children are increasing at an alarming rate. The potential impact of these conditions on the individual, the family, and society, especially in regard to the costs and utilization of health care resources, are very serious. Strategies aimed at reducing caloric intake, increasing caloric expenditure through regular exercise, and treating cardiovascular risk factors and type 2 diabetes early and aggressively are necessary to meet the challenges they impose.


Vestibular input to brain monoamine neurons--a review.
Yates et al. reported that serotonergic RN neurons are associated with vestibulo-sympathetic responses and may control BP changes during body repositioning (Yates et al., 1992; 1993). Pompeiano et al. demonstrated that LC-NA neurons participate in the postural control and modify the vestibulo-spinal reflex (Pompeiano et al., 1990; 1991a; 2001). Nishiike et al. (1996a) examined the effects of caloric vestibular stimulation on the neuronal activity of LC-NA neurons in rats. The predominant effect of CA with both hot- and cold-water on the electrical activity of LC neurons is inhibitory and persists for several minutes. GABAA receptors located on the postsynaptic membrane of LC neurons are responsible for these inhibitory responses. The VLM may inhibit LC neuronal activity in response to the CA via GABAA receptors (Nishiike et al., 1997). It is suggested that LC-NA inhibition is involved in the development of motion sickness (Nishiike et al., 2001).


WarpDrive: Improving spatial normalization using manual refinements.
Spatial normalization-the process of mapping subject brain images to an average template brain-has evolved over the last 20+ years into a reliable method that facilitates the comparison of brain imaging results across patients, centers & modalities. While overall successful, sometimes, this automatic process yields suboptimal results, especially when dealing with brains with extensive neurodegeneration and atrophy patterns, or when high accuracy in specific regions is needed. Here we introduce WarpDrive, a novel tool for manual refinements of image alignment after automated registration. We show that the tool applied in a cohort of patients with Alzheimer's disease who underwent deep brain stimulation surgery helps create more accurate representations of the data as well as meaningful models to explain patient outcomes. The tool is built to handle any type of 3D imaging data, also allowing refinements in high-resolution imaging, including histology and multiple modalities to precisely aggregate multiple data sources together.


What do anxious patients think? An exploratory investigation of anxious dental patients' thoughts.
According to BECK's cognitive model of emotional disorders (1976) anxiety is associated with negative and threatening thoughts concerning the likelihood of personal danger. In the present study the content of thoughts of 32 anxious dental patients was investigated. Patients' mean score for the Dental Anxiety Scale was 17.1 (SD = 2.0). The average time period patients had not visited a dentist was 9.1 yr (SD = 8.7). Using semi-structured interviews 132 thoughts were explored. The mean number of thoughts reported per patient was 4.1 (SD = 1.6). Almost all patients reported thoughts in some way related to their fear. All patients except one reported self-verbalizations of a negative or catastrophizing nature. Nine different categories of the content of the thoughts were identified. Nine percent of the thoughts consisted of visual images. The largest category (23%) consisted of catastrophic thoughts about the patient's own functioning during dental treatment, e.g., thoughts about losing control, panicking and dying. Fifty-nine percent of the patients reported thoughts of this type. The findings provide support for BECK's cognitive model of emotional disorders.


Caring for frail patients: best practice.
Frailty has become synonymous with vulnerability and is a state caused by many factors, including disability, recurrent infection and multiple co-morbidities. The Gwent frailty service recognises the importance of an interdisciplinary approach to care, including timely recognition of frailty in patients and referral to the most appropriate services to optimise management and treatment.


Triphlorethol-A from Ecklonia cava protects V79-4 lung fibroblast against hydrogen peroxide induced cell damage.
In the present study, triphlorethol-A, a phlorotannin, was isolated from Ecklonia cava and its antioxidant properties were investigated. Triphlorethol-A was found to scavenge intracellular reactive oxygen species (ROS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, and thus prevented lipid peroxidation. The radical scavenging activity of triphlorethol-A protected the Chinese hamster lung fibroblast (V79-4) cells exposed to hydrogen peroxide (H2O2) against cell death, via the activation of ERK protein. Furthermore, triphlorethol-A reduced the apoptotic cells formation induced by H2O2. Triphlorethol-A increased the activities of cellular antioxidant enzymes like, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Hence, from the present study, it is suggestive that triphlorethol-A protects V79-4 cells against H2O2 damage by enhancing the cellular antioxidative activity.


Image formation in holographic tomography: high-aperture imaging conditions.
Three-dimensional (3D) imaging by holographic tomography can be performed for a fixed detector through rotation of either the object or the illumination beam. We have previously presented a paraxial treatment to distinguish between these two approaches using transfer function analysis. In particular, the cutoff of the transfer function when rotating the illumination about one axis was calculated analytically using one-dimensional Fourier integration of the defocused transfer function. However, high numerical aperture objectives are usually used in experimental arrangements, and the previous paraxial model is not accurate in this case. Hence, in this analysis, we utilize 3D analytical geometry to derive the imaging behavior for holographic tomography under high-aperture conditions. As expected, the cutoff of the new transfer function leads to a similar peanut shape, but we found that there was no line singularity as was previously observed in the paraxial case. We also present the theory of coherent transfer function for holographic tomography under object rotation while the detector is kept stationary. The derived coherent transfer functions offer quantitative insights into the image formation of a diffractive tomography system.


A local time-dependent sverdrup balance in the eastern north pacific ocean.
Direct observations of the dynamic balance between time-dependent winds and deep ocean currents are described for the eastern North Pacific Ocean at 42 degrees N, 152 degrees W. Currents from 150 to 4000 meters below the surface at frequencies from 0.01 to 0.1 cycle per day are significantly correlated with the wind stress curl derived from U.S. Navy operational wind fields. The horizontal currents are depth-independent below 300 meters, and they flow parallel to the potential vorticity gradient derived from the earth's rotation and the large-scale bottom topography. These characteristics are expected for such periodic motions with horizontal scales larger than 500 kilometers and represent a generalized Sverdrup balance between the atmospheric forcing and the oceanic response.


A new edible coating of fish gelatin incorporated into açaí oil to increase the post-harvest shelf life of tomatoes.
Açaí oil (Euterpe oleracea) is a new active ingredient, originating from the Amazon Forest, which offers numerous benefits as an antioxidant and antimicrobial agent. Here, we report how açaí oil can be used as an active ingredient in gelatin coatings to increase the shelf life of tomatoes. The optimized viscosity and gel strength conditions were 5.40 % gelatin, 17.25 % açaí oil and 18 % plasticizer. FTIR, XRD and zeta potential analysis reveals that repulsive forces dominate the interactions between açaí oil and gelatin. The optimized coating (GAO) reduced mass loss by 8 % and achieved greater firmness (25 N), proving its effectiveness in maintaining tomato quality during storage. For the first time, it was found that the addition of açaí oil to fish gelatin improves the percentage of acidity and firmness of the tomato, delaying ripening, making it a promising alternative as packaging for climacteric fruits.


Mycobacterial infections after kidney transplant.
We looked at mycobacterial infections occurring after a kidney transplant to determine incidence, risk factors, and outcomes. Of 3921 kidney transplants performed between 1984 and 2002, 18 (0.45%) (10 men, eight women; 11 cadaveric donor, seven living donor graft) were identified as having mycobacterial infection at some time posttransplant. Mean age at transplant was 38.3 years. Racial background was: Caucasian (n = 12), African-American (n = 2), Native Indian (n = 2), Hispanic (n = 1), and Middle Eastern (n = 1). The majority had a kidney alone (n = 14). Four recipients had simultaneous transplant of a second organ: pancreas (n = 2), islets (n = 1), and liver (n = 1). None of the 18 recipients had documented mycobacterial infection pretransplant. One recipient had a positive Mantoux test at the time of transplant and then developed pulmonary tuberculosis 4 months posttransplant; the remaining 17 patients had either negative (n = 10) or unavailable (n = 7) pretransplant Mantoux results. Mean time to infection was 3.2 years (range 1 week to 12 years). The most common site of infection was respiratory (n = 8). Other sites included musculoskeletal (n = 4), skin (n = 3), gyn (n = 1), and other (n = 2). Only three of the infections were with mycobacterial tuberculi; the others were with avium (n = 5), chelonae (n = 2), or other nontuberculous mycobacteria. Risk factors included previous TB exposure, occupational exposure, or accidental soft tissue injury. Soft tissue infections often presented as chronic unhealed wounds and required extensive surgical debridements. With mean follow-up of 12.5 years since transplant and 9.2 years since infection, 13 of the recipients are alive and well; causes of death included cardiovascular (n = 3) and sepsis (n = 2).


Association of self-reported sleep duration with eating behaviors of American adults: NHANES 2005-2010.
Published evidence suggests an inverse association between sleep duration and body weight status. We examined the association of sleep duration with eating behaviors reported by adult Americans to understand the relation between sleep duration and body weight status. This cross-sectional study used sleep duration and dietary data from the continuous NHANES conducted from 2005 to 2010 (n = 15,199, age ≥20 y). Eating behaviors examined included the following: reporting of and energy from main meals (breakfast, lunch, and dinner) and snacks (before breakfast, after dinner, and after 2000 h), intermeal intervals, time of day of main meal reporting, and intakes of macronutrients and beverages. Multiple regression methods were used to examine the independent association of hours of sleep duration grouped as short (≤6 h), average (7-8 h), and long (≥9 h) with eating behavior outcomes. Relative to average-duration sleepers, a smaller percentage of short-duration sleepers mentioned breakfast, lunch (women only), and dinner in the recall (P ≤ 0.04). They also reported a lower mean percentage of energy from main meals but higher energy from all snacks (P ≤ 0.0004) and after 2000 h (P = 0.03). Short-duration sleepers reported the earliest eating time of the first episode and the latest time of the last eating episode. Absolute amounts of sugar and caffeine and percentage of energy from beverages (women only) were higher in short-duration sleepers. However, the total number of eating episodes and energy intake were not related with sleep duration. Short-duration sleepers began eating earlier and ended their eating later in the day, but despite the longer eating period, they did not report more eating events. Profiles of the relative contribution of main meals and snacks, at or after 2000 h eating, and beverages in short-duration sleepers were suggestive of eating behaviors that may increase energy intake, but 24-h energy intake did not differ among categories of sleep duration.


Polypodium Leucotomos Extract (PLE): New Study Gives Evidence-based Insight into "Ain't Nothing Like the Real Thing".
Polypodium leucotomos is widely available as an oral supplement and has been shown to exhibit photoprotective properties which might provide adjunctive benefit when used along with topically applied suncreens. However, data are lacking with the majority of Polypodium leucotomos formulations (including extracts) related to their quantitative and qualitative polyphenol content and specific photoprotective properties. This article reviews results from a study of six different Polypodium leucotomos extract formulations, comparing their polyphenol and excipient contents and specific photoprotective properties. Consistency was observed primarily with one specific brand of Polypodium leucotomos extract oral capsules, which is also supported by a large body of published evidence.


Safety evaluation of naringenin upon experimental exposure on rat gastrointestinal epithelium for novel optimal drug delivery.
To assess the effect of naringenin on the intestinal biochemical composition, function and histology for gastrointestinal toxicity since it has not yet been adequately exploited for safety through standard assays. Here, we describe naringenin (1 mM, 10 mM and 100 mM, respectively) or sodium deoxycholate (10 mM) effects on isolated brush border membrane from intestinal segments with single pass intestinal perfusion using lactate dehydrogenase, alkaline phosphatase and protein assays. MTT assay was used for cytotoxicity studies. Everted gut sac studies were used for evaluating the transport of nutrients across the intestinal segments. Lucifer yellow was used for paracellular permeability, followed by histological changes and surface characteristic studies of intestinal sacs. The results indicated no significant alterations with naringenin, although significant (p < 0.01) changes were noticed with sodium deoxycholate in the activity of the rat intestinal brush border associated enzymes such as LDH, followed by intact cell viability with marked decrease in the villi height of the intestinal segments. These observations indicate that naringenin was harmless upon exposure to rat gastrointestinal epithelium, clearly demonstrating the potential use of naturally occurring bioflavonoid as safe and novel pharmaceutical adjuvant in oral dosage forms as P-gp inhibitor.


Causes of blindness among adult Jordanians: a hospital-based study.
To assess the causes of blindness among adults aged 20 years and over who attended two big general ophthalmic clinics in Jordan. This hospital-based study was undertaken at Jordan University Hospital in Amman (the capital of Jordan) and Princess Basma Teaching Hospital which is affiliated with Jordan University of Science and Technology in Irbid, the third largest city in the country. A total of 2732 patients seen consecutively over 26 months were examined and the ophthalmic findings were recorded. Using standard Snellen charts, subjects were placed in one of three categories according to their best corrected visual acuity: (1) unilateral blindness: less than 6/60 in the worst eye, 6/60 or more in the better eye; (2) moderate bilateral blindness: less than 6/60 in the worst eye, less than 6/60 to 3/60 or more the better eye; and (3) severe bilateral blindness: less than 3/60 in both eyes. Of the totalpatients seen, 373 were blind according to the selection criteria. Among 248 patients with unilateral blindness, diabetic retinopathy, cataract and trauma were the leading causes. Among the 81 patients with moderate bilateral blindness, diabetic retinopathy and cataract were the leading causes. Diabetic retinopathy and glaucoma were the leading causes in patients with severe bilateral blindness. These data could be used in planning blindness prevention and treatment programs while awaiting a national survey on the prevalence and causes of blindness in Jordan.


Assessing the Quality of Outpatient Pain Care and Opioid Prescribing in the Military Health System.
Pain conditions are the leading cause of disability among active-duty service members. Given the significant implications for force readiness and service member well-being, the Military Health System (MHS) has made it a strategic priority to provide service members with the highest-quality treatment for pain conditions. RAND researchers assessed MHS outpatient care for acute and chronic pain, including opioid prescribing. The assessment involved developing a set of 14 quality measures designed to assess aspects of outpatient care for pain, including care associated with dental and ambulatory procedures, acute low back pain, chronic pain, opioid prescribing, and medication treatment for opioid use disorder. This research offers the most comprehensive examination to date of the quality and safety of pain care in the MHS and its alignment with evidence-based clinical practice guidelines. It identifies several areas of strength in pain care delivery, along with some areas for improvement, and provides recommendations to support the MHS in continuing to improve pain care for service members.


Mortality risk and associated factors in HIV-exposed, uninfected children.
With increasing maternal antiretroviral treatment (ART), the number of children newly infected with HIV has declined. However, the possible increased mortality in the large number of HIV-exposed, uninfected (HEU) children may be of concern. We quantified mortality risks among HEU children and reviewed associated factors. Systematic search of electronic databases (PubMed, Scopus). We included all studies reporting mortality of HEU children to age 60 months and associated factors. Relative risk of mortality between HEU and HIV-unexposed, uninfected (HUU) children was extracted where relevant. Inverse variance methods were used to adjust for study size. Random-effects models were fitted to obtain pooled estimates. A total of 14 studies were included in the meta-analysis and 13 in the review of associated factors. The pooled cumulative mortality in HEU children was 5.5% (95% CI: 4.0-7.2; I(2) = 94%) at 12 months (11 studies) and 11.0% (95% CI: 7.6-15.0; I(2) = 93%) at 24 months (four studies). The pooled risk ratios for the mortality in HEU children compared to HUU children in the same setting were 1.9 (95% CI: 0.9-3.8; I(2) = 93%) at 12 months (four studies) and 2.4 (95% CI: 1.1-5.1; I(2) = 93%) at 24 months (three studies). Compared to HUU children, mortality risk in HEU children was about double at both age points, although the association was not statistically significant at 12 months. Interpretation of the pooled estimates is confounded by considerable heterogeneity between studies. Further research is needed to characterise the impact of maternal death and breastfeeding on the survival of HEU infants in the context of maternal ART, where current evidence is limited.


Nonlinear Features from Multi-Modal Signals for Continuous Stress Monitoring.
Continuous monitoring of stress in individuals during their daily activities has become an inevitable need in present times. Unattended stress is a silent killer and may lead to fatal physical and mental disorders if left unidentified. Stress identification based on individual judgement often leads to under-diagnosis and delayed treatment possibilities. EEG-based stress monitoring is quite popular in this context, but impractical to use for continuous remote monitoring.Continuous remote monitoring of stress using signals acquired from everyday wearables like smart watches is the best alternative here. Non-EEG data such as heart rate and ectodermal activity can also act as indicators of physiological stress. In this work, we have explored the possibility of using nonlinear features from non-EEG data such as (a) heart rate, (b) ectodermal activity, (c) body temperature (d) SpO2 and (e) acceleration in detecting four different types of neurological states; namely (1) Relaxed state, (2) State of Physical stress, (3) State of Cognitive stress and (4) State of Emotional stress. Physiological data of 20 healthy adults have been used from the noneeg database of PhysioNet.Results: We used two machine learning models; a linear logistic regression and a nonlinear random forest to detect (a) stress from relaxed state and (4) the four different neurological states. We trained the models using linear and nonlinear features separately. For the 2-class and 4-class problems, using nonlinear features increased the accuracy of the models. Moreover, it is also proved in this study that by using nonlinear features, we can avoid the use of complex machine learning models.


Differential stereoselectivity of methotrimeprazine enantiomers for selected central nervous system receptor types.
Optical isomers of methotrimeprazine, an analgesic/neuroleptic, were investigated with respect to their ability to interact with six receptor types or subtypes. Bovine caudate nucleus tissue homogenates provided the dopamine, opiate, and serotonin receptor populations studied in these experiments. The radioligands used in saturation and binding competition experiments were tritiated dopamine, spiperone, dihydromorphine, 5-L-methionine enkephalin, naloxone, and 5-hydroxytryptamine. Saturation experiments verified acceptable performance of these in vitro receptor assay systems and indicated that a one-site binding model was adequate for each of these ligands under the experimental conditions employed. The competition experiments exhibited statistically significant (p less than 0.05) differences in isomeric effects only for dopamine and 5-hydroxytryptamine receptors. The more active isomer, levorotatory methotrimeprazine, was shown to be pharmacodynamically equivalent to chlorpromazine at these receptor types. When the magnitude of receptor stereoselectivity is plotted against an estimate of the more active isomer's affinity for that particular receptor, an excellent correlation is observed. This suggests that a high degree of stereoselectivity characterizes a highly specific drug/receptor interaction. These findings are compatible with the conclusion that methotrimeprazine does not produce analgesia via a direct action upon opiate receptors.


Metal-organic frameworks as efficient heterogeneous catalysts for the regioselective ring opening of epoxides.
An iron-based metal-organic framework, [Fe(BTC)] (BTC: 1,3,5-benzenetricarboxylate) is an efficient catalyst in the ring opening of styrene oxide with alcohols and aniline under mild reaction conditions. Out of the various alcohols tested for ring opening of styrene oxide, methanol was found to be the most reactive in terms of percentage conversion and reactivity. The rate of the ring-opening reaction of styrene oxide decreases as the size of the alcohol is increased, suggesting the location of active sites in micropores. [Fe(BTC)] was a truly heterogeneous catalyst and could be reused without loss of activity. The analogous compound [Cu(3)(BTC)(2)] was also found to be effective, although with somewhat lower activity than [Fe(BTC)]. The present heterogeneous protocol is compared with a homogeneous catalyst to give an insight into the reaction mechanism.


Influence of surface coating on the intracellular behaviour of gold nanoparticles: a fluorescence correlation spectroscopy study.
In the biomedical applications of nanoparticles (NPs), the proper choice of surface chemistry is a crucial aspect in their design. The nature of the coating can heavily impact the interaction of NPs with biomolecules, affect the state of aggregation, and ultimately determine their biological fate. As such, protein corona formation and the aggregation behaviour of gold NPs (Au NPs) are studied here. Au NPs are prepared with four distinct surface functionalisations, namely mercaptosuccinic acid (MSA), N-4-thiobutyroil glucosamine, HS-PEG5000 and HS-alkyl-PEG600. Corona formation, aggregation, and the intracellular behaviour of the Au NPs are then investigated by means of Fluorescence Correlation Spectroscopy (FCS) in cell culture media and in live cells. To evaluate the state of aggregation and the formation of a protein corona, the Au NPs are incubated in cell media and the diffusion coefficient is determined via FCS. The in vitro behaviour is compared with the level of aggregation of the NPs in cells. Diffusion times of the NPs are estimated at different positions in the cell after a one hour incubation period. It is found that the majority of MSA and glucose-Au NPs are present inside the cell as slowly diffusing species with diffusion times (τD) greater than 6000 μs (hydrodynamic diameter >250 nm). PEGylated Au NPs adsorb a small amount of protein and manifest low agglomeration both in media and in living cells. In particular, the HS-alkyl-PEG600 coating shows an excellent correlation between lower protein adsorption, 4-fold lower compared to the MSA coated NPs, and limited intracellular aggregation. In the case of single HS-alkyl-PEG600 coated NPs, it is found that typical intracellular τD values range from 500 to 1500 μs, indicating that these particles display reduced aggregation in the intracellular environment.


Hormonal manipulation for rising PSA after radical prostatectomy.
PSA recurrence after radical prostatectomy usually indicates recurrent prostate cancer. Identification of the recurrence site is difficult, but pathological and clinical features may suggest local versus distant recurrence. Radiographic techniques including transrectal ultrasonography, and 111indium capromab pendetide scans may help identify recurrences. The use of hormonal manipulation for rising PSA after radical prostatectomy is controversial. Androgen deprivation has been a mainstay of the management for advanced prostate cancer. The timing of such therapy is debatable, and early therapy in an asymptomatic patient may not correlate with improved survival. Maximal androgenic blockade with castration and nonsteroidal antiandrogens may offer a modest survival benefit in selected patients. Novel potency-sparing therapies with antiandrogens and finasteride afford an improved patient lifestyle, with questionable effects on survival. Intermittent androgen suppression is an experimental treatment modality that may reduce the side effects of castration. Ongoing studies are being performed to clarify these controversies, and the variety of treatment options allows patients great flexibility in considering quality of life and effective cancer control.


[Clinical characteristics and short-term prognosis of 22 cases with SARS-CoV-2 infection associated acute encephalopathy].
Objective: To investigate the clinical features and short-term prognosis of patients with SARS-CoV-2 infection associated acute encephalopathy (AE). Methods: Retrospective cohort study. The clinical data, radiological features and short-term follow-up of 22 cases diagnosed with SARS-CoV-2 infection associated AE in the Department of Neurology, Beijing Children's Hospital from December 2022 to January 2023 were retrospectively analyzed. The patients were divided into cytokine storm group, excitotoxic brain damage group and unclassified encephalopathy group according to the the clinicopathological features and the imaging features. The clinical characteristics of each group were analyzed descriptively. Patients were divided into good prognosis group (≤2 scores) and poor prognosis group (>2 scores) based on the modified Rankin scale (mRS) score of the last follow-up. Fisher exact test or Mann-Whitney U test was used to compare the two groups. Results: A total of 22 cases (12 females, 10 males) were included. The age of onset was 3.3 (1.7, 8.6) years. There were 11 cases (50%) with abnormal medical history, and 4 cases with abnormal family history. All the enrolled patients had fever as the initial clinical symptom, and 21 cases (95%) developed neurological symptoms within 24 hours after fever. The onset of neurological symptoms included convulsions (17 cases) and disturbance of consciousness (5 cases). There were 22 cases of encephalopathy, 20 cases of convulsions, 14 cases of speech disorders, 8 cases of involuntary movements and 3 cases of ataxia during the course of the disease. Clinical classification included 3 cases in the cytokine storm group, all with acute necrotizing encephalopathy (ANE); 9 cases in the excitotoxicity group, 8 cases with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and 1 case with hemiconvulsion-hemiplegia syndrome; and 10 cases of unclassified encephalopathy. Laboratory studies revealed elevated glutathione transaminase in 9 cases, elevated glutamic alanine transaminase in 4 cases, elevated blood glucose in 3 cases, and elevated D-dimer in 3 cases. Serum ferritin was elevated in 3 of 5 cases, serum and cerebrospinal fluid (CSF) neurofilament light chain protein was elevated in 5 of 9 cases, serum cytokines were elevated in 7 of 18 cases, and CSF cytokines were elevated in 7 of 8 cases. Cranial imaging abnormalities were noted in 18 cases, including bilateral symmetric lesions in 3 ANE cases and "bright tree appearance" in 8 AESD cases. All 22 cases received symptomatic treatment and immunotherapy (intravenous immunoglobulin or glucocorticosteroids), and 1 ANE patient received tocilizumab. The follow-up time was 50 (43, 53) d, and 10 patients had a good prognosis and 12 patients had a poor prognosis. No statistically significant differences were found between the two groups in terms of epidemiology, clinical manifestations, biochemical indices, and duration of illness to initiate immunotherapy (all P>0.05). Conclusions: SARS-CoV-2 infection is also a major cause of AE. AESD and ANE are the common AE syndromes. Therefore, it is crucial to identify AE patients with fever, convulsions, and impaired consciousness, and apply aggressive therapy as early as possible.


Are bacteriophage defence and virulence two sides of the same coin in Campylobacter jejuni?
The continuous battle for survival in the environment has led to the development or acquisition of sophisticated defence systems in bacteria. These defence systems have contributed to the survival of the bacterial species in the environment for millions of years. Some systems appear to have evolved in a number of pathogenic bacteria towards a role in virulence and host immune evasion. Recently, different bacterial cell envelope components from diverse bacterial species have been linked not only to bacteriophage defence, but also to virulence features. In the present review we focus specifically on the bacterial cell envelope-expressed sialic-acid-containing LOS (lipo-oligosaccharide) structures and Type II CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) genes that both occur in specific Gram-negative pathogens. In Campylobacter jejuni circumstantial evidence points at a potential intertwined dual function between sialylated LOS structures and subtype II-C CRISPR-Cas, i.e. in phage defence and virulence. In the present review we discuss whether a dual functionality of sialylated LOS and subtype II-C CRISPR-Cas is exclusive to C. jejuni only or could be more widespread within the group of Type II CRISPR-Cas-harbouring bacteria. We conclude from the literature that, at least in C. jejuni, circumstantial evidence exists for a complex intertwined dual functionality between sialylated LOS and Type II CRISPR-Cas, and that other bacteria show similar genomic signatures.


Fabrication of biodegradable poly(ester-amide)s based on tyrosine natural amino acid.
N,N'-Bis[2-(methyl-3-(4-hydroxyphenyl)propanoate)]isophthaldiamide (5), a novel diol monomer containing chiral group, was prepared by the reaction of S-tyrosine methyl ester (3) with isophthaloyl dichloride (4a). A new family of optically active and potentially biodegradable poly(ester-amide)s (PEAs) based on tyrosine amino acid were prepared by the polycondensation reaction of diol monomer 5 with several aromatic diacid chlorides. The resulting new polymers were obtained in good yields with inherent viscosities ranging between 0.25 and 0.42 dL/g and are soluble in polar aprotic solvents. They showed good thermal stability and high optical purity. The synthetic compounds were characterized and studied by FT-IR, 1H-NMR, specific rotation, elemental and thermogravimetric analysis (TGA) techniques and typical ones by 13C-NMR, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and field emission scanning electron microscopy (FE-SEM) analysis. Soil burial test of the diphenolic monomer 5, and obtained PEA6a, and soil enzymatic assay showed that the synthesized diol and its polymer are biologically active and probably biodegradable in soil environment.


An investigation of bone resorption and Dictyostelium discoideum growth inhibition by bisphosphonate drugs.
We report the results of 3D-QSAR/CoMFA investigations of the activity of bisphosphonate drugs, farnesyl pyrophosphate synthase (FPPSase) inhibitors, in the inhibition of bone resorption as well as the growth of Dictyostelium discoideum. In the case of D. discoideum, we find an experimental versus QSAR predicted pIC(50) R(2) value of 0.94 for 16 bisphosphonates over the 9-1200 microM range of IC(50) values, a cross-validated R(2) = 0.90, and a bootstrapped R(2) = 0.94, and we demonstrate that this approach has predictive utility (a 0.18 pIC(50) rms error for three test sets of 3 predictions). In bone resorption, we find an experimental versus predicted pLED (lowest effective dose) R(2) = 0.79 for 35 bisphosphonates over the 0.0001-1 mg of P/kg LED range, a cross-validated R(2) = 0.75, and a bootstrapped R(2) = 0.79. Two sets of 31 compounds were used as training sets for the predicted pLED values for two sets of 4 compounds which have an rms error of 0.44, larger than that found with D. discoideum. However, this can be attributed to the rather large uncertainties in the experimental bone resorption data which are almost all reported in decade steps (DeltapLED = 1). The CoMFA predicted (rat) bone antiresorptive pLED values are in agreement with literature (human recombinant) FPPSase inhibition results with an rms error of 0.45 (a factor of 2.8 error in activity prediction). We also report the single-crystal X-ray crystallographic structure of the compound most active in D. discoideum growth inhibition, 2-(3-picolyl)-aminomethylene-1,1-bisphosphonic acid. The structure clearly shows the presence of bond length alternation in the picolyl ring and a planar amino group linked by a very short (1.346 A) bond to the picolyl group, an amidinium-like structure which is also expected to occur in other highly active species such as minodronate and zoledronate. Overall, these results show that it is now possible to predict the activity of bisphosphonates using 3D-QSAR/CoMFA methods, although bone resorption studies should benefit from additional, accurate information on enzyme inhibition.


Nurse workforce scheduling: A qualitative study of Indonesian nurse managers' experiences during the COVID-19 pandemic.
The increase in COVID-19 cases in Indonesia has resulted in changes in the hospital workflow, including the staffing process and scheduling, especially in the isolation units. Nurse managers are working hard in the scheduling system to ensure high-quality care is provided with the best human resources. This study aimed to explore the experiences of nurse managers in managing staff nurses' work schedules during the COVID-19 pandemic. A qualitative descriptive design was used in this study. Eleven nurse managers from three COVID-19 referral hospitals were selected using purposive sampling. Data were collected using online semi-structured interviews. Thematic analysis was used for data analysis, and data were presented using a thematic tree. Consolidated criteria for reporting qualitative research (COREQ) checklist was used as a reporting guideline of the study. Four themes were developed: (i) Nurse shortage, (ii) Strategically looking for ways to fulfill the workforce, (iii) Change of shift schedule, and (iv) Expecting guidance from superiors and compliance from staff. The lack of nurse staff is a problem during a pandemic. Thus, managing personnel effectively, mobilizing and rotating, and recruiting volunteers are strategies to fulfill the workforce during the pandemic. Using a sedentary shift pattern and sufficient holidays could prevent nurses from falling ill and increase compliance with scheduling. In addition, a staffing calculation formula is needed, and top nursing managers are suggested to provide guidance or direction to the head nurses to reduce confusion in managing the work schedule during the pandemic.


Platelet membrane calmodulin-stimulated calcium-adenosine triphosphatase. Altered activity in essential hypertension.
Platelet free Ca2+ concentration has been found to be elevated in essential hypertension and to correlate with blood pressure level. Free cytoplasmic calcium concentration is determined by calcium influx, pooling, and efflux. The present study found a Ca2+-ATPase in platelet membranes that has a high affinity for Ca2+ (Km approximately 1 microM), is inhibited by low concentrations of orthovanadate (Ki approximately 1 microM), and can be stimulated by calmodulin (Km approximately 5 nM). The absolute increase in calmodulin-stimulated Ca2+-ATPase activity was not different between normotensive and hypertensive subjects; however, the degree of stimulation of Ca2+-ATPase activity at saturating calmodulin concentrations apparently was diminished in calmodulin-deficient membranes from subjects with established essential hypertension (40%) as compared to that in normotensive subjects of similar age (135%; p less than 0.001). Affinities for calmodulin and Ca2+ were comparable between the two groups, while the capacity for Ca2+-ATPase activity (basal and calmodulin-stimulated) was markedly greater (1.5- to 1.8-fold) in both native and calmodulin-deficient membranes from hypertensive subjects. On the other hand, the defective calcium efflux pump activity, as assessed by a decreased degree of calmodulin stimulation, may have contributed to elevated cytoplasmic calcium concentrations and the associated enhanced hormone sensitivity in platelets from essential hypertensive subjects. This may represent an adaptive negative feedback control mechanism to protect the cell against Ca2+ overload.


Laparoscopic Sleeve Gastrectomy for Morbid Obesity in Patients After Orthotopic Liver Transplant: a Matched Case-Control Study.
Obesity is frequently encountered in patients with orthotopic liver transplant (OLT). The role of bariatric surgery is still unclear for this specific population. The aim of this study was to review our experience with laparoscopic sleeve gastrectomy (LSG) after OLT. We performed a retrospective case-control study of patients undergoing LSG after OLT from 2010 to 2016. OLT-LSG patients were matched by age, sex, body mass index (BMI), and year to non-OLT patients undergoing LSG. Demographics, operative variables, postoperative events, and long-term weight loss with comorbidity resolution were collected and compared between cases and controls. Of 303 patients undergoing LSG, 12 (4%) had previous OLT. They were matched to 36 non-OLT patients. No difference was found between groups in the American Society of Anesthesiologists class, mean operative time, or postoperative morbidity. The non-OLT group, however, had a significantly shorter mean hospital stay than the OLT group (1.7 vs 3.1 days; P < .001). There were no conversions to open procedures. For patients with long-term follow-up, change in BMI after LSG was similar between the groups, but the non-OLT patients had significantly more excess body weight loss at 2 years (53.7 vs 45.2%; P < .001). Similar resolution of comorbid conditions was noted in both groups. LSG caused no changes in dosage of immunosuppressive medications, and no liver complications occurred. LSG after OLT in appropriately selected patients appears to have similar outcomes to LSG in non-OLT patients.


Scope of practice issues for occupational and environmental health nurses.
This article discusses scope of practice issues among various levels of professional nurses within the United States. It raises awareness that all occupational and environmental health nurses must be knowledgeable about workplace activities that may be permitted or prohibited by their state practice acts.


Prevalence and Clinical Correlates of Intracranial Dolichoectasia in Individuals With Ischemic Stroke.
Acute ischemic stroke is a known complication of intracranial dolichoectasia (IDE). However, the frequency of IDE causing brain infarction is unknown. We aim to determine the prevalence and clinical correlates of IDE in acute ischemic stroke by employing an objective IDE definition for major intracranial arteries of the anterior and posterior circulation. Consecutive patients with acute ischemic stroke admitted to a tertiary-care hospital during a 4-month period were analyzed. Intracranial arterial diameter, length, and tortuosity were determined by semiautomatic vessel segmentation and considered abnormal if ≥2 SDs from the study population mean. Either ectasia (increased diameter) or dolichosis (increased length or tortuosity) of at least one proximal intracranial artery defined IDE. Symptomatic IDE was considered when the infarct was located in the territory supplied by an affected artery in the absence of any alternative pathogenic explanation. Multivariate models were fitted to determine IDE clinical correlates. Among 211 cases screened, 200 patients (mean age 67±14 years, 47.5% men) with available intracranial vessel imaging were included. IDE was identified in 24% cases (5% with isolated ectasia, 9.5% with isolated dolichosis, and 9.5% with both ectasia and dolichosis). IDE was considered the most likely pathogenic mechanism in 12 cases (6% of the entire cohort), which represented 23.5% of strokes initially categorized as undetermined cause. In addition, 21% of small-artery occlusion strokes had the infarct territory supplied by a dolichoectatic vessel (3% of the entire cohort). IDE was independently associated with male sex (odds ratio, 4.2 [95% CI, 1.7–10.6]) and its component of ectasia was associated with advanced age (odds ratio, 3.5 [95% CI, 1.3–9.5]). Vascular risk profile was similar across patients with stroke with and without IDE. Our findings suggest that IDE is an arteriopathy frequently found in patients with acute ischemic stroke and is likely responsible for a sizable fraction of strokes initially categorized as of undetermined cause and perhaps also in those with small-artery occlusion.


Pharmacogenomic information in drug labels: European Medicines Agency perspective.
Pharmacogenomics (PGx) has a growing impact on healthcare and constitutes one of the major pillars of personalised medicine. For the purpose of improved individualised drug treatment, there is an increasing effort to develop drugs suitable for specific subpopulations and to incorporate pharmacogenomic drug labels in existing and novel medicines. Here, we review the pharmacogenomic drug labels of all 517 medicinal products centrally approved in the European Union (EU) since the establishment of the European Medicines Agency in 1995. We identified all pharmacogenomic-related information mentioned in the product labels and classified it according to its main effect and function on drug treatment, that is, metabolism, transport and pharmacodynamics, and according to the place of the respective section of the Summary of Product Characteristics (SmPC). The labels are preferentially present in drugs having antineoplastic properties. We find that the number of drugs with pharmacogenomic labels in EU increases now steadily and that it will be an important task for the future to refine the legislation on how this information should be utilised for improvement of drug therapy.


Malignant germ cell-like tumors, expressing Ki-1 antigen (CD30), are revealed during in vivo differentiation of partially reprogrammed human-induced pluripotent stem cells.
Because many of the genes used to produce induced pluripotent stem cells (iPSCs) from somatic cells are either outright established oncogenes, such as c-myc and Klf4, or potentially related to tumorigenesis in various cancers, both the safety and the risks of tumorigenesis linked to iPSC generation require evaluation. In this work, we generated, by lentivirus-mediated gene transfer of Oct4, Sox2, Nanog, and Lin28, two types of iPSCs from human mesenchymal stem cells and human amniotic fluid-derived cells: fully reprogrammed iPSCs with silencing of the four transgenes and partially reprogrammed iPSCs that still express one or several transgenes. We assessed the behavior of these cells during both their differentiation and proliferation using in vivo teratoma assays in nonobese diabetic mice with severe combined immunodeficiency. In contrast to fully reprogrammed iPSCs, 43% of partially reprogrammed iPSC cases (6 of 14 teratomas) generated major dysplasia and malignant tumors, with yolk sac tumors and embryonal carcinomas positive for α-fetoprotein, cytokeratin AE1/AE3, and CD30. This correlated with the expression of one or several transgenes used for the reprogramming, down-regulation of CDK 1A mRNA (p21/CDKN1A), and up-regulation of antiapoptotic Bcl-2 mRNA. Therefore, the oncogenicity of therapeutically valuable patient-specific iPSC-derived cells should be scrupulously evaluated before they are used for any clinical applications.


Molecular markers in the surgical margin of oral carcinomas.
Local or regional lymph node recurrence is the most common pattern of treatment failure in oral squamous cell carcinoma (SCC). The local recurrence rate is 30% even when the surgical resection margin is diagnosed as tumour free. Accumulation of genetic changes in histologically normal epithelium in the surgical resection margin may explain the local recurrence rate. The purpose of this study is to investigate the presence of senescence markers, which may represent early malignant changes in the margin that in routine pathological evaluations are classified as histologically normal. Formalin-fixed, paraffin-embedded surgical specimens from 16 consecutive patients with oral SCC and a clear surgical margin were obtained. The margin was analysed by immunohistochemistry for p53, p16, Chk2, Laminin-5 and glycosylated oncofetal fibronectin. Two patterns of p53 expression were found in the histologically normal epithelium in the surgical resection margin. One was characterized by no protein expression in the majority of cells, except for small clusters of basal and parabasal cells with nuclear staining. The other was characterized by p53 expression in the nuclei of most basal cells. The expression of p16 was confined to small groups of cells in the basal cell layer whereas Chk2 was only seen in one case. Upregulation of the stromal proteins, Laminin-5 or glycosylated oncofetal fibronectin, was only seen at regions of invasion. Small groups of cells expressing p53 and p16 were found in the surgical resection margin that appeared to be histologically normal and may represent early malignant changes.


Direct Observation of Aryl Gold(I) Carbenes that Undergo Cyclopropanation, C-H Insertion, and Dimerization Reactions.
Mesityl gold(I) carbenes lacking heteroatom stabilization or shielding ancillary ligands have been generated and spectroscopically characterized from chloro(mesityl)methylgold(I) carbenoids bearing JohnPhos-type ligands by chloride abstraction with GaCl3 . The aryl carbenes react with PPh3 and alkenes to give stable phosphonium ylides and cyclopropanes, respectively. Oxidation with pyridine N-oxide and intermolecular C-H insertion to cyclohexane have also been observed. In the absence of nucleophiles, a bimolecular reaction, similar to that observed for other metal carbenes, leads to a symmetrical alkene.


Clinical neurophysiology in the diagnosis of peroneal nerve palsy.
Peroneal neuropathy is one of the common focal mononeuropathies in the lower extremities occurring in both adults and children. Foot drop due to weakness of ankle dorsiflexion is the most common presentation of a peroneal neuropathy. It may also result from other causes involving the upper or lower motor neurons. Disorders that must be distinguished from peroneal neuropathy include sciatic mononeuropathy, lumbosacral plexopathy, motor neuron disease, polyneuropathy, and an L5 radiculopathy. To establish a diagnosis, electrodiagnostic studies have been used to localize the level of the abnormality and to establish prognosis. The most common site of injury is the fibular head, but focal neuropathies have also been reported at the level of the calf, ankle, and foot. In this article, we overviewed the peroneal nerve palsy, and its diagnosis by neurophysiologic evaluation, conduction study and needle EMG. The neurophysiologic information gives us the underlying pathophysiology and its prognosis. Therefore the neurophysiologic evaluation must be performed not only for the differential diagnosis, but also for planning the treatment strategy.


Interferon alfa treatment of HCV RNA carriers with persistently normal transaminase levels: a pilot randomized controlled study.
Most patients with serum hepatitis C virus (HCV) RNA and persistently normal alanine transaminase (ALT) levels show histological features of mild to moderately active chronic hepatitis. Some cirrhosis has also been reported. To assess whether interferon (IFN) treatment led to long-term HCV suppression in these patients, 31 previously untreated patients (15 men, 16 women; mean age, 44 years) with serum HCV RNA, persistently normal ALT levels on at least four consecutive occasions 2 months apart, and histological features of chronic hepatitis (21 mild activity, 10 moderate activity) were randomized to receive 1FN-alpha-2a, 3 MU three times a week for 6 months (n = 16), or no treatment (n = 15). All patients were followed up for at least 6 months after treatment ended. HCV RNA was tested by nested reverse-transcription polymerase chain reaction (RT-PCR) using 5'-untranslated region complementary primers, quantified by branched-DNA assay, and typed by nested RT-PCR testing for the HCV core region. Treated and untreated patients had similar epidemiological, virological, and histological characteristics. At the end of treatment, serum HCV RNA was still detected in 15 patients (94%) and 14 controls (93%). ALT levels flared up in 10 patients receiving IFN (62%) and in 1 control (62% vs. 7%; P < .005, chi2 test). In conclusion, 6 months' treatment with IFN-alpha-2a did not eradicate HCV RNA from serum in carriers with persistently normal ALT levels but caused ALT flare-ups in two thirds of them. Until more is known about the natural history of HCV RNA carriers with normal ALT levels, these patients should not be treated with IFN.


Successful Aging Among Community-Dwelling Older Adults in Urban Areas of Liaoning Province: The Crucial Effect of Visual Ability.
Successful aging is an effective approach to coping with population aging; however, the definition and associated factors vary due to culture and demographic distribution differences. This study was designed to assess successful aging of the older adults in China and explore the associated factors. A community-based cross-sectional study was performed in Liaoning, China. After double-cognitive function screening, 3558 older adults (1656 males and 1902 females) ≥65 years of age served as our subjects. Successful aging was assessed based on the following: physical disability; cognitive function; activities of daily living; and self-rated psychological/mood status. The rate of successful aging was 31.7% in males and 29.4% in females. After adjustment for age, multivariate logistic regression showed that successful aging was significantly associated with, in odds ratio sequence, visual ability, self-rated chronic disease, marital status, and filial piety in males, and with visual ability, self-rated chronic disease, watching television, and ethnicity in females. The level of successful aging in China is lower than in other countries. Demographic characteristics, health status, individual behavior, and social-psychological factors are all associated with successful aging. Overall, visual ability had the most crucial role in successful aging for the older adults, whether males or females.


[Impacts of non-transmissible chronic diseases on social security benefits].
This paper strives to identify the current impact of Non-Transmissible Chronic Diseases (NTCDs) on sickness and disability benefits paid out by Brazil's National Social Security Institute (INSS) between 2000 and 2002. A total of 17,970 new cases were studied, registered at the two local agencies in Recife, Pernambuco State, Northeast Brazil. Initially the cases were divided up according by major diseases groups, following the CID-10 classification. Osteomuscular diseases (OMDs) and cardiovascular diseases (CVDs) were among the main reasons for granting sickness benefits. Among the disability benefits, CVDs, mental disorders (MDs), and OMDs, were the main reasons. In terms of specific diseases within the major DCNT groups, the main reasons for granting sickness benefits were high blood pressure, diabetes mellitus, arthrosis, breast and intestinal cancer, mood disorders and schizophrenia. For disability benefits, the main causes were cerebrovascular diseases, diabetes mellitus, cancer of the gastro-intestinal tract and schizophrenia. Most (66%) of the recipients were men between 39 and 58 years of age, and the initial value of the benefit was of up to three minimum wages per month.


Fast empirical Bayesian LASSO for multiple quantitative trait locus mapping.
The Bayesian shrinkage technique has been applied to multiple quantitative trait loci (QTLs) mapping to estimate the genetic effects of QTLs on quantitative traits from a very large set of possible effects including the main and epistatic effects of QTLs. Although the recently developed empirical Bayes (EB) method significantly reduced computation comparing with the fully Bayesian approach, its speed and accuracy are limited by the fact that numerical optimization is required to estimate the variance components in the QTL model. We developed a fast empirical Bayesian LASSO (EBLASSO) method for multiple QTL mapping. The fact that the EBLASSO can estimate the variance components in a closed form along with other algorithmic techniques render the EBLASSO method more efficient and accurate. Comparing with the EB method, our simulation study demonstrated that the EBLASSO method could substantially improve the computational speed and detect more QTL effects without increasing the false positive rate. Particularly, the EBLASSO algorithm running on a personal computer could easily handle a linear QTL model with more than 100,000 variables in our simulation study. Real data analysis also demonstrated that the EBLASSO method detected more reasonable effects than the EB method. Comparing with the LASSO, our simulation showed that the current version of the EBLASSO implemented in Matlab had similar speed as the LASSO implemented in Fortran, and that the EBLASSO detected the same number of true effects as the LASSO but a much smaller number of false positive effects. The EBLASSO method can handle a large number of effects possibly including both the main and epistatic QTL effects, environmental effects and the effects of gene-environment interactions. It will be a very useful tool for multiple QTL mapping.


Ombitasvir, paritaprevir, and ritonavir plus dasabuvir for 8 weeks in previously untreated patients with hepatitis C virus genotype 1b infection without cirrhosis (GARNET): a single-arm, open-label, phase 3b trial.
Clinical studies have shown high rates of sustained virological response (hepatitis C virus [HCV] RNA <15 IU/mL) at post-treatment week 12 (SVR12) in patients with genotype 1b infection with and without cirrhosis who received coformulated ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin, for 12 weeks. In this study, we aimed to assess 8-week treatment with ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin in patients infected with HCV genotype 1b without cirrhosis. We did a multicentre, open-label, single-arm, phase 3b study (GARNET) in 20 hospitals or clinics in Australia, Canada, France, Germany, Israel, Italy, Spain, and the UK, to assess the safety and efficacy of an 8-week treatment duration of once-daily oral ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg, plus twice-daily oral dasabuvir 250 mg in previously untreated patients with chronic HCV genotype 1b infection without cirrhosis (as assessed by liver biopsy, transient elastography, or serum markers). Eligible patients were aged at least 18 years, with more than 1000 IU/mL HCV RNA, and a laboratory result at screening indicating infection with HCV genotype 1b subtype only. Patients were excluded if they had evidence of HCV genotype or subtype other than genotype 1b, if they tested positive for hepatitis B surface antigen or anti-HIV antibody at screening, or if they had previously been treated for HCV. The primary endpoint was the proportion of patients with SVR12; the primary endpoint and safety were assessed in all patients who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, number NCT02582632. Patients were screened between Nov 24, 2015, and March 1, 2016, and 166 patients were enrolled. 163 (98%) of 166 enrolled patients had HCV genotype 1b infection, and three (2%) of 166 had other genotypes or subtypes (genotype 1a, genotype 1d, and genotype 6). All enrolled patients received at least one dose of study drugs. 162 (98% [95% CI 95·3-99·9]) of 166 patients achieved SVR12. One patient discontinued treatment on day 45 due to adverse events. Most adverse events were mild in severity, and the most common adverse events were headache (35 [21%] of 166) and fatigue (28 [17%] of 166). Two (1%) of 166 patients had serious adverse events; neither were considered related to study drug treatment. Treatment with ombitasvir, paritaprevir, and ritonavir, plus dasabuvir, without ribavirin, for 8 weeks was efficacious and well tolerated. 8-week treatment options for previously untreated patients with HCV genotype 1b infection without cirrhosis are limited; shortening the treatment duration might reduce the burden associated with medical visits and procedures, thereby improving access to care and enabling the treatment of more patients. AbbVie.


Development of realistic environmental release factors based on measured data: approach and lessons from the EU metal industry.
The assessment of environmental exposure and risks associated with the production or use of a substance on an industrial site includes the estimation of the releases to the environment. In the absence of measured release data on the specific substance, a risk assessor would rely on default release factors to the environmental compartments as developed in international, national, or regional context. Because a wide variety of substances, processes, and uses has to be covered, default release factors are as a rule conservative, usually leading to significant overprediction of releases and hence to overpredicted environmental exposure concentrations and risks. In practice, unrealistic and worst-case predictions do not support a more efficient management of releases and risk. The objective of this article is to propose a more realistic approach to characterize the environmental releases from manufacture, processing, and downstream uses of the metals and their compounds. Although developed in the European Union (EU), this approach can also be used in other regions and in other chemical management systems addressing metals. A database consisting of more than 1300 recent (1993-2010), site-specific measured release factors to air and water of 18 different metals from various EU Member States was compiled and used to calculate average and reasonable worst-case release factors for multiple metal manufacture and industrial use processes. The parameters influencing releases to water were found to depend predominantly on life cycle step (manufacture and/or use), the sector and/or the solid-water partition coefficient (K(d)). The release factors can be used as advanced tier instrument in environmental safety assessments, increasing the realism of the estimates while still keeping a sufficient level of conservatism.


The evolutionary history of an accidental model organism, the leopard gecko Eublepharis macularius (Squamata: Eublepharidae).
The leopard gecko, Eublepharis macularius, is a widely used model organism in laboratory and experimental studies. The high phenotypic diversity in the pet trade, the fact that the provenance of different breeding lines is unknown, and that distinct Eublepharis species are known to hybridize, implies that the continued use of E. macularius as a model requires clarity on the origin of the lineages in the pet trade. We combine multi-locus sequence data and the first range-wide sampling of the genus Eublepharis to reconstruct the evolutionary history of the Eublepharidae and Eublepharis, with an updated time-tree for the Eublepharidae. Our sampling includes five of the six recognized species and additional nominal taxa of uncertain status comprising 43 samples from 34 localities plus 48 pet-trade samples. The Eublepharidae began diversifying in the Cretaceous. Eublepharis split from its sister genera in Africa in the Palaeocene-Eocene, and began diversifying in the Oligocene-Miocene, with late Miocene-Pliocene cladogenesis giving rise to extant species. The current species diversity within this group is moderately underestimated. Our species delimitation suggests 10 species with four potentially unnamed divergent lineages in Iran, India and Pakistan. All 30 individuals of E. macularius that we sampled from the pet trade, which include diverse morphotypes, come from a few shallow E. macularius clades, confirming that lab and pet trade strains are part of a single taxon. One of the wild-caught haplotypes of E. macularius, from near Karachi, Pakistan, is identical to (10) pet-trade samples and all other captive populations are closely related to wild-caught animals from central/southern Pakistan (0.1-0.5 % minimum pairwise uncorrected ND2 sequence divergence).


Electrochemical multi-analyte point-of-care perspiration sensors using on-chip three-dimensional graphene electrodes.
Multi-analyte sensing using exclusively laser-induced graphene (LIG)-based planar electrode systems was developed for sweat analysis. LIG provides 3D structures of graphene, can be manufactured easier than any other carbon electrode also on large scale, and in form of electrodes: hence, it is predestinated for affordable, wearable point-of-care sensors. Here, it is demonstrated that LIG facilitates all three electrochemical sensing strategies (voltammetry, potentiometry, impedance) in a multi-analyte system for sweat analysis. A potentiometric potassium-ion-selective electrode in combination with an electrodeposited Ag/AgCl reference electrode (RE) enabled the detection of potassium ions in the entire physiologically relevant range (1 to 500 mM) with a fast response time, unaffected by the presence of main interfering ions and sweat-collecting materials. A kidney-shaped interdigitated LIG electrode enabled the determination of the overall electrolyte concentration by electrochemical impedance spectroscopy at a fixed frequency. Enzyme-based strategies with amperometric detection share a common RE and were realized with Prussian blue as electron mediator and biocompatible chitosan for enzyme immobilization and protection of the electrode. Using glucose and lactate oxidases, lower limits of detection of 13.7 ± 0.5 μM for glucose and 28 ± 3 μM for lactate were obtained, respectively. The sensor showed a good performance at different pH, with sweat-collecting tissues, on a model skin system and furthermore in synthetic sweat as well as in artificial tear fluid. Response time for each analytical cycle totals 75 s, and hence allows a quasi-continuous and simultaneous monitoring of all analytes. This multi-analyte all-LIG system is therefore a practical, versatile, and most simple strategy for point-of-care applications and has the potential to outcompete standard screen-printed electrodes. Graphical abstract.


Regulation of sexual development of Plasmodium by translational repression.
Translational repression of messenger RNAs (mRNAs) plays an important role in sexual differentiation and gametogenesis in multicellular eukaryotes. Translational repression and mRNA turnover were shown to influence stage-specific gene expression in the protozoan Plasmodium. The DDX6-class RNA helicase, DOZI (development of zygote inhibited), is found in a complex with mRNA species in cytoplasmic bodies of female, blood-stage gametocytes. These translationally repressed complexes are normally stored for translation after fertilization. Genetic disruption of pbdozi inhibits the formation of the ribonucleoprotein complexes, and instead, at least 370 transcripts are diverted to a degradation pathway.


Squeezed Light Induced Symmetry Breaking Superradiant Phase Transition.
We theoretically investigate the quantum phase transition in the collective systems of qubits in a high quality cavity, where the cavity field is squeezed via the optical parametric amplification process. We show that the squeezed light induced symmetry breaking can result in quantum phase transition without the ultrastrong coupling requirement. Using the standard mean field theory, we derive the condition of the quantum phase transition. Surprisingly, we show that there exists a tricritical point where the first- and second-order phase transitions meet. With specific atom-cavity coupling strengths, both the first- and second-order phase transition can be controlled by the nonlinear gain coefficient, which is sensitive to the pump field. These features also lead to an optical switching from the normal phase to the superradiant phase by just increasing the pump field intensity. The signature of these phase transitions can be observed by detecting the phase space Wigner function distribution with different profiles controlled by the squeezed light intensity. Such superradiant phase transition can be implemented in various quantum systems, including atoms, quantum dots, and ions in optical cavities as well as the circuit quantum electrodynamics system.


Ocular Pathogens and Antibiotic Sensitivity in Bacterial Keratitis Isolates at King Khaled Eye Specialist Hospital, 2011 to 2014.
To investigate prevalence and in vitro susceptibility trends of bacteria isolated from patients with bacterial keratitis from 2011 to 2014 in a tertiary care eye hospital in Saudi Arabia. Retrospective review of bacterial isolates from corneal scraping of eyes with microbial keratitis. The most common isolates and their antibiotic resistance profiles were identified; trend analysis was performed over the study period. A total of 2037 bacterial isolates met inclusion criteria during the study period. Gram positives accounted for 91.4% of isolates, including Staphylococcus epidermidis 962 (27.4%), other coagulase-negative staphylococci 289 (8.2%), Staphylococcus aureus 237 (6.8%), and Streptococcus pneumoniae 159 (4.5%). Pseudomonas aeruginosa was the most common gram-negative isolate (38.4%). All tested Gram positive isolates were sensitive to vancomycin. As a whole, isolates were most sensitive to moxifloxacin and ciprofloxacin with resistance of 3.7% and 3.3%, respectively. Oxacillin resistance was increasingly found in S. aureus (14.8% in 2011, 27.8% in 2014, P = 0.06), but was without significant change in S. epidermidis and other coagulase-negative Staphylococci (range 19.4%-32.0%). There was an increase in moxifloxacin resistance among S. epidermidis, increasing from 0.9% to 12.7%. Using a logistic regression model, the overall change in resistance of bacteria to antibiotics by year was not significant. Gram-positive bacteria represented the majority of bacteria isolated, with a possibly increasing prevalence of oxacillin resistance in S. aureus. Fluoroquinolone resistance is uncommon, and no vancomycin-resistant gram-positive strains were identified. There was no overall significant trend in antibiotics resistance; however, future surveillance studies are recommended.


Bacterial vaginosis: a review.
Bacterial vaginosis (BV) is a clinically definable condition that is frequently diagnosed in the primary care setting. Changes in the nomenclature, causative microorganisms, as well as treatment have caused confusion over the last century. BV is currently viewed as a shift in the normal vaginal ecosystem from a predominance of aerobic bacteria to anaerobic bacteria (Soper, 1993), resulting in a malodorous discharge. However, more than one half of clinically diagnosed patients are asymptomatic. Recent evidence indicates that the anaerobes identified as components of BV have been implicated in obstetric complications, postoperative pelvic infections, and pelvic inflammatory disease. Practice issues resulting from this research include the appropriate treatment of asymptomatic women, especially in pregnancy. This article reviews BV from a historical perspective, provides a summary of recent research findings identifying BV as a possible risk factor in various serious medical conditions and their sequelae, and discusses related practice concerns resulting from the implications of these findings.


Characterization of Charge Transfer in Excited States of Extended Clusters of π-Stacked Donor and Acceptor Complexes in Lock-Arm Supramolecular Ordering.
Lock-arm supramolecular ordering cocrystals formed by π-stacked materials constitute an interesting class of materials, which exhibits ferroelectric behavior at room temperature. To characterize the charge transfer in excited states, two complexes with π-stacked donors and acceptors, the 1,5-naphthalene diol (NDI) donor and pyromellitic diimide with diethylene glycol arms (PDIA) acceptor, 5-amino-1-naphthol (AMN) donor and PDIA acceptor, were investigated. The electronic excitations were calculated using the scaled opposite-spin variant of ADC(2), time-dependent density functional theory (TD-DFT) using a long-range corrected (LC) functional (ωB97xD), and the TD-LC approach within density-functional-based tight binding (TD-LC-DFTB). Face-to-face mixed stacks and edge-to-face crossed stacks up to hexamers were investigated. The calculations show that the ground state of the complexes does not possess significant CT character. On the other hand, the lowest excited state (S1) shows in all clusters a strong charge transfer. In several cases, the second excited state and also higher excited singlet states possess significant CT character. The orbitals involved in the excitation are mostly well localized and located on adjacent donor/acceptor pairs. Comparing different stacking directions, the vertical excitation energies for the NDI-PDIA crossed stacks are larger than those for the mixed stacks by 0.2-0.4 eV. In the case of the AMN-PDIA system, the energy differences are smaller (∼0.1 eV) with mostly the same energetic ordering as for the NDI-PDIA case. Strong red shifts in vertical fluorescence emission transitions have been computed, which could even lead to intersection between ground and first excited states, resulting in ultrafast radiationless decay and fluorescence quenching.


Phosphorylated insulin-like growth factor-1 receptor (pIGF1R) is a poor prognostic factor in brain metastases from lung adenocarcinomas.
A greater understanding of brain metastases is imperative for developing novel therapeutic strategies. Our previous study showed that insulin-like growth factor (IGF) signaling pathway was activated in brain-tropic cancer cells. In this study, we investigated the clinical relevance of activated (phosphorylated) IGF-1 receptor (pIGF1R) expression in brain metastases originating from lung adenocarcinomas. All pathologically confirmed brain metastases from lung adenocarcinomas, with available archived specimens from January 1998 to December 2009 at National Taiwan University Hospital, were assessed immunohistochemically for pIGF1R expression using H-score criteria. A median H-score was used as a cutoff point to define high or low pIGF1R expression. The mutation status in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) was examined using direct sequencing. The prognostic significance of pIGF1R expression, its correlations with clinicopathological characteristics, and EGFR status were evaluated. In the 86 cases, high membranous/cytoplasmic pIGF1R expression in brain metastases correlated with a shorter median survival (10.8 vs 27.8 mo, P = 0.003). This correlation was more significant in patients with EGFR mutations [hazard ratio (HR) 2.38, 95 % confidence interval (CI) 1.19-4.77 for EGFR mutations; HR 1.99, 95 % CI 0.95-4.15 for EGFR wild type] and remained statistically significant in multivariate analysis after adjusting for the effects of other potential prognostic factors, including the graded prognostic assessment score, solitary brain metastasis, extracranial metastatic status, EGFR mutations, and treatment using EGFR tyrosine kinase inhibitors. Although we also identified nuclear pIGF1R expression, this result was prognostically non-significant. Our study results showed that high membranous/cytoplasmic pIGF1R expression in brain metastases was a poor prognostic factor, more significantly in patients with EGFR mutations than in those with wild-type EGFRs.


The impact of health plan delivery system organization on clinical quality and patient satisfaction.
The purpose of this study was to examine the extent to which measures of health plan clinical performance and measures of patient perceptions of care are associated with health plan organizational characteristics, including the percentage of care provided based on a group or staff model delivery system, for-profit (tax) status, and affiliation with a national managed care firm. Data describing health plans on region, age of health plan, for-profit status, affiliation with a national managed care firm, percentage of Medicare business, total enrollment, ratio of primary care physicians to specialists, HMO penetration, and form of health care delivery system (e.g., IPA, network, mixed, staff, group) were obtained from InterStudy. Clinical performance measures for women's health screening rates, child and adolescent immunization rates, heart disease screening rates, diabetes screening rates, and smoking cessation were developed from HEDIS data. Measures of patient perceptions of care are obtained from CAHPS survey data submitted as Healthplan Employer Data and Information Set, Consumer Assessment of Health Plans 2.0 H. Multivariate regression cross-sectional analysis of 272 health plans was used to evaluate the relationship of health plan characteristics with measures of clinical performance and patient perceptions of care. The form of delivery system, measured by percent of care delivered by staff and group model systems, is significantly related (p < or = .05) with four of the five clinical performance indices but none of the three satisfaction performance indices. Other variables significantly associated with performance were being geographically located in the Northeast, having nonprofit status, and for patient satisfaction, not being part of a larger insurance company. These comparative results provide evidence suggesting that the type of delivery system used by health plans is related to many clinical performance measures but is not related to patient perceptions of care. These findings underscore the importance of the form of the delivery system and the need for further inquiry that examines the relationship between organizational form and performance.


Cell Wall Pectin Content Refers to Favored Delivery of Negatively Charged Carbon Dots in Leaf Cells.
In this work, we systematically investigated how cell wall and cell wall components affect the delivery of charged carbon quantum dots (CDs, from -34 to +41 mV) to leaf cells of cucumber and Arabidopsis plants. Four different types of leaf cells in cucumber and Arabidopsis were used, i.e., protoplasts (without cell wall), isolated individual cells (cell wall hydrolyzed with pectinase), regenerated individual cells (cell wall regenerated from protoplast), and intact leaf cells (intact cell wall, in planta). Leaf cells were incubated with charged CDs (0.5 mg/mL) for 2 h. Confocal imaging results showed that protoplasts, regenerated individual cells, and leaf cells showed favored uptake of the negatively charged CDs (-34 mV) compared to the PEI (polyethylenimine) coated and positively charged carbon dots [PEI600-CDs (17 mV) and PEI10K-CDs (41 mV)], while in isolated individual cells, the trend is opposite. The results of the content of the cell wall components showed that no significant changes in the total cell wall content were found between isolated individual cells and regenerated individual cells (1.28 vs 1.11 mg/106 cells), while regenerated individual cells showed significant higher pectin content [water-soluble pectin (0.13 vs 0.06 mg/106 cells, P < 0.01), chelator-soluble pectin (0.04 vs 0.01 mg/106 cells, P < 0.01), and alkaline pectin (0.02 vs 0.01 mg/106 cells, P < 0.01)] and significant lower cellulose content (0.13 vs 0.32 mg/106 cells, P < 0.01) than the isolated individual cells. No difference of the hemicellulose content was found between isolated individual cells and regenerated individual cells (0.20 vs 0.21 mg/106 cells). Our results suggest that compared with cellulose and hemicellulose in the cell wall, the pectin is a more important factor referring to the favored uptake of negatively charged carbon dots in leaf cells. Overall, this work provides a method to study the role of cell wall components in the uptake of nanoparticles in plant cells and also points out the importance of understanding the interactions between cell barriers and nanoparticles to design nanoparticles for agricultural use.


Topic search filters: a systematic scoping review.
Searching for topics within large biomedical databases can be challenging, especially when topics are complex, diffuse, emerging or lack definitional clarity. Experimentally derived topic search filters offer a reliable solution to effective retrieval; however, their number and range of subject foci remain unknown. This systematic scoping review aims to identify and describe available experimentally developed topic search filters. Reports on topic search filter development (1990-) were sought using grey literature sources and 15 databases. Reports describing the conception and prospective development of a database-specific topic search and including an objectively measured estimate of its performance ('sensitivity') were included. Fifty-four reports met inclusion criteria. Data were extracted and thematically synthesised to describe the characteristics of 58 topic search filters. Topic search filters are proliferating and cover a wide range of subjects. Filter reports, however, often lack clear definitions of concepts and topic scope to guide users. Without standardised terminology, filters are challenging to find. Information specialists may benefit from a centralised topic filter repository and appraisal checklists to facilitate quality assessment. Findings will help information specialists identify existing topic search filters and assist filter developers to build on current knowledge in the field.