Synthesis and toxicity of some metabolites of the microbial degradation of synthetic naphthenic acids.
Some ill-defined carboxylic acids, termed 'naphthenic acids' (NA), are best known as important constituents of the >720billionlitres of process-affected water associated with the expanding oil sands industries. Other NA are components of some immature and biodegraded crude oils and these may enter the environment via produced water discharges from oil production platforms. Yet others are used as biocides and in the manufacture of steel radial tyres and these may also enter the environment through disposal and/or weathering. The environmental fate of NA, including the mechanisms of biodegradation, therefore needs to be better understood. In order to better elucidate such mechanisms, previously we studied the biodegradation in the laboratory of some alkylcyclohexylbutanoic synthetic NA. However, we could only tentatively identify the metabolites produced. In the present study we report the synthesis and characterisation of six alkylcyclohexylethanoic NA. Each was characterised by gas chromatography-mass spectrometry (GC-MS; trimethylsilyl esters) and we show by co-chromatography that these were indeed the metabolites. Also, a preferential degradation of the trans- isomers was revealed. Assessment of the toxicity of the synthetic NA (Microtox assay), revealed that the relative toxicity of the alkylcyclohexylbutanoic acids was reduced by biotransformation to the alkylcyclohexylethanoic acids, as observed recently for the corresponding aromatic acids. Very recent studies have shown that at least one commercial NA mixture contains cyclohexylbutanoic and alkylcyclohexylethanoic acids, suggesting that the biotransformation of the acids studied herein may be quite relevant to the environmental fate of such acids. A similar study of the acid extractables of one oil sands process-affected water sample suggests that the synthetic acids may be less good 'models' for oil sands NA. The consortia of microbes present in oil sands process-affected water may also be different to those used herein. However, the heterogeneity of oil sands process water is well-known and further detailed studies will need to be made in order to establish whether degradation of oil sands NA proceeds by beta oxidation as observed for the acids herein, or whether the oil sands acids are more resistant to bioremediation.


Protein synthesis in rat liver: influence of amino acids in diet on microsomes and polysomes.
Rats were killed 1 hour after having been fed by stomach tube with amino acid mixtures that were either nutritionally complete or lacked tryptophan. Microsomes isolated from the livers of animals fed the incomplete mixture showed a reduced capacity to incorporate (14)C-leucine in vitro, and polysomes prepared from the same livers showed an increased proportion of monosomes and disomes. Prior treatment with actinomycin D did not prevent these differences in response to the two amino acid mixtures, an indication that synthesis of messenger RNA may not be involved in the cell mechanism which recognizes differences in amino acid pattern.


Antireflective surface structures in glass by self-assembly of SiO2 nanoparticles and wet etching.
We describe the fabrication of an antireflective surface structure with sub-wavelength dimensions on a glass surface using scalable low-cost techniques involving sol-gel coating, thermal annealing, and wet chemical etching. The glass surface structure consists of sand dune like protrusions with 250 nm periodicity and a maximum peak-to-valley height of 120 nm. The antireflective structure increases the transmission of the glass up to 0.9% at 700 nm, and the transmission remains enhanced over a wide spectral range and for a wide range of incident angles. Our measurements reveal a strong polarization dependence of the transmission change.


A Systematic Review Investigating the Relation Between Animal-Source Food Consumption and Stunting in Children Aged 6-60 Months in Low and Middle-Income Countries.
Animal-source foods (ASFs) are a food group of interest for interventions aimed at reducing stunting and other inadequate growth measures in early childhood. The aim of this systematic review was to examine the relation between ASF consumption and stunting in children aged 6-60 mo in low- and middle-income countries (LMICs). The secondary aim was to examine the relation between ASF consumption and other indicators of growth and development (length/height, weight, head circumference, and anemia). A search of the peer-reviewed and grey literature published from January 1980 to June 2017 was conducted. Databases searched included CINAHL, Embase, Global Index Medicus, PubMed, and Web of Science. There were 14,783 records and 116 full text articles dual screened; 21 studies were included in the review and were dual evaluated for risk of bias (RoB). The relation between ASF and stunting (length- or height-for-age z-score←2) was examined in randomized-controlled trials [(RCTs), n = 3] and cross-sectional studies (n = 4) only; ASF reduced stunting in 1 RCT and was associated with reduced stunting in 1 cross-sectional study. We did not identify any longitudinal cohorts that examined this relation. The relation between ASF and secondary indicators length/height, weight, head circumference, and anemia were largely nonsignificant across study designs. The intervention/exposure, comparator, outcome measures, methods, and analyses were highly heterogeneous. Although we did not find a consistent relation between ASF consumption and our primary and secondary outcomes, this may have been a function of inconsistencies in study design. Foods in the whole diet, particularly combination dishes, are inherently difficult to assess. To quantitatively assess the relation between ASF and stunting and other indicators of growth and iron status in early childhood, future research should provide consistency in the definition and quantification of the exposure and outcomes allowing for interstudy quantitative comparisons.


Dysregulated but not decreased salience network activity in schizophrenia.
Effective estimation of the salience of environmental stimuli underlies adaptive behavior, while related aberrance is believed to undermine rational thought processes in schizophrenia. A network including bilateral frontoinsular cortex (FIC) and dorsal anterior cingulate cortex (dACC) has been observed to respond to salient stimuli using functional magnetic resonance imaging (fMRI). To test the hypothesis that activity in this salience network (SN) is less discriminately modulated by contextually-relevant stimuli in schizophrenia than in healthy individuals, fMRI data were collected in 20 individuals with schizophrenia and 13 matched controls during performance of a modified monetary incentive delay (MID) task. After quantitatively identifying spatial components representative of the FIC and dACC features of the SN, two principal analyses were conducted. In the first, modulation of SN activity by salience was assessed by measuring response to trial outcome. First-level general linear models were applied to individual-specific time-courses of SN activity identified using spatial independent component analysis (ICA). This analysis revealed a significant salience-by-performance-by-group interaction on the best-fit FIC component's activity at trial outcome, whereby healthy individuals but not individuals with schizophrenia exhibited greater distinction between the response to hits and misses in high salience trials than in low salience trials. The second analysis aimed to ascertain whether SN component amplitude differed between the study groups over the duration of the experiment. Independent-samples T-tests on back-projected, percent-signal-change scaled SN component images importantly showed that the groups did not differ in the overall amplitude of SN expression over the entire dataset. These findings of dysregulated but not decreased SN activity in schizophrenia provide physiological support for mechanistic conceptual frameworks of delusional thought formation.


Use of a simulation game for HIV/AIDS education with pre-service teachers.
The article describes the use of a simulation game in HIV/AIDS education with pre-service teachers in Johannesburg, South Africa. The use of a simulation game, as novel experiential pedagogy, was an attempt to raise awareness about HIV and AIDS and to demonstrate that anyone can be at risk of HIV infection. Using a generic qualitative research design, the data were collected over a three-year period by way of video recordings of the simulation game, recordings of large and small group discussions afterwards, and via questionnaires and written reflections by the education students four weeks afterwards. Content analysis and discourse analysis led to the construction of three main themes. First, we found that the novelty factor of the simulation game for raising HIV/AIDS awareness was confirmed both during the game itself and after a period of time had elapsed. Second, in light of many education students' naivety about the intersection of biological, socio-cultural and economic issues at play in the spread of HIV, the game prompted more reflexivity about the disease and helped to broaden the participants' discussions. Lastly, the data revealed the disjuncture between theory and practice in HIV/AIDS education. We propose that in raising awareness of HIV and AIDS, educators should move towards more engaging and challenging pedagogies that address the learning needs of the 'new' generation of university students.


Co-developing climate services for public health: Stakeholder needs and perceptions for the prevention and control of Aedes-transmitted diseases in the Caribbean.
Small island developing states (SIDS) in the Caribbean region are challenged with managing the health outcomes of a changing climate. Health and climate sectors have partnered to co-develop climate services to improve the management of emerging arboviral diseases such as dengue fever, for example, through the development of climate-driven early warning systems. The objective of this study was to identify health and climate stakeholder perceptions and needs in the Caribbean, with respect to the development of climate services for arboviruses. Stakeholders included public decision makers and practitioners from the climate and health sectors at the regional (Caribbean) level and from the countries of Dominica and Barbados. From April to June 2017, we conducted interviews (n = 41), surveys (n = 32), and national workshops with stakeholders. Survey responses were tabulated, and audio recordings were transcribed and analyzed using qualitative coding to identify responses by research topic, country/region, and sector. Health practitioners indicated that their jurisdiction is currently experiencing an increased risk of arboviral diseases associated with climate variability, and most anticipated that this risk will increase in the future. National health sectors reported financial limitations and a lack of technical expertise in geographic information systems (GIS), statistics, and modeling, which constrained their ability to implement climate services for arboviruses. National climate sectors were constrained by a lack of personnel. Stakeholders highlighted the need to strengthen partnerships with the private sector, academia, and civil society. They identified a gap in local research on climate-arbovirus linkages, which constrained the ability of the health sector to make informed decisions. Strategies to strengthen the climate-health partnership included a top-down approach by engaging senior leadership, multi-lateral collaboration agreements, national committees on climate and health, and shared spaces of dialogue. Mechanisms for mainstreaming climate services for health operations to control arboviruses included climatic-health bulletins and an online GIS platform that would allow for regional data sharing and the generation of spatiotemporal epidemic forecasts. Stakeholders identified a 3-month forecast of arboviral illness as the optimal time frame for an epidemic forecast. These findings support the creation of interdisciplinary and intersectoral 'communities of practice' and the co-design of climate services for the Caribbean public health sector. By fostering the effective use of climate information within health policy, research and practice, nations will have greater capacity to adapt to a changing climate.


[Huangdi Neijing: a classic book of traditional Chinese medicine].
According to the data of the recent archaeological excavations, the history of traditional Chinese medicine begins in the neolithic period (10,000-4,000 years ago). The fundamental principles of the traditional Chinese medicine may be interpreted on the basis of two classic theories of Chinese thought: the Yin-Yang theory and the five phases theory. The former stated that our reality is the product of the continuous interaction and transformation of the Yin and Yang principles. The latter recognise the existence of five emblematic groups in which everything regarding humankind and nature may be classified. The five phases interact in two different ways: the cycle of production (Sheng) and the cycle of control (Ke). Theoretical basis of traditional Chinese medicine are described on the Huangdi Neijing (The Book of Yellow Emperor's: a classic of internal medicine) written during the period 475-225 b.C. as a dialogue between the mythical Emperor Huangdi and his physician Qibo. The book is divided into two parts: the Suwen (Questions about living matter) and Lingshu (The vital axe). Each part is composed of 81 sections. In this book are set correspondences between phases and organs, viscera, feelings, body fluids, flavours, foods, colours, and so on. We can also find the description of blood (Xue) and energy (Qi) circulation and the pathways of main, collateral and curious vessels. The origins of disease are also reported on the Huangdi Neijing. As regards the psychological point of view, special attention is dedicated to dreams and their possible causes and to the description of various kind of mental illness. The unknown Authors underline the five defects and the four mistakes of the physician, pointing out the importance to avoid them. Finally, it must be mentioned their special care to the principles of preventive medicine.


Optical Society of America's 2010 Topical Meeting on Optical Interference Coatings: introduction by the feature editors.
This Applied Optics feature issue is dedicated to the eleventh topical meeting on Optical Interference Coatings held on 6-11 June 2010 in Tucson, Arizona, USA. This topical conference is held in a three year rotation with conferences in Europe and Asia and is a premier opportunity to discuss advances in research and development within the field of optical interference coatings. Papers from this meeting cover a broad range of topics ranging from deposition processes, thin film design, materials, metrology, and a wide array of practical applications.


Determination of Colorectal Cancer Risk Levels, Colorectal Cancer Screening Rates, and Factors Affecting Screening Participation of Individuals Working in Agriculture in Turkey.
Colorectal cancer (CRC) is the fourth ranked malignancy leading to death in Turkey. Agricultural workers with low socioeconomic level are particularly at risk due to the intense use of pesticides. The aim of this study was to determine CRC risk levels, status of participation in CRC screenings, and the factors affecting participation in screenings among individuals between 50 and 70 years old working in agriculture. Data in this cross-sectional study were collected from 244 agricultural workers in Turkey. The rate of participation in CRC screenings among these workers at high risk was low. Their knowledge and health beliefs did not affect their participation in CRC screenings. Having a friend or neighbor with CRC and knowing which doctor to consult increased participation in CRC screenings 10 times, and having abdominal pain increased participation in CRC screenings 4 times. The rate of participation in CRC screenings is low in this group of workers, but rates may increase when these individuals are directed to be screened. Health professionals should advise agricultural workers to participate in CRC screenings and should inform workers about the locations where screenings are conducted.


Insulin-like growth factor binding protein-3 (IGFBP-3) genetic variant and the risk of esophageal squamous cell carcinoma in a Chinese population.
Insulin-like growth factor binding protein-3 (IGFBP-3) exerts anti-proliferative or pro-apoptotic effects through IGF-dependent as well as IGF-independent mechanisms in vitro. The purpose of this study was to examine the association between genetic variants in IGFBP-3 (rs2270628) and the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese Han population. Five hundred ESCC cases and 500 cancer-free controls of the Chinese Han population were involved in this study. The IGFBP-3 single-nucleotide polymorphism (SNP) rs2270628 was genotyped and the estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for its association with the risk of ESCC were determined using unconditional logistic regression analysis. Compared with the rs2270628 CC genotype, TT genotype was associated with a significantly increased ESCC risk with OR (95%CI) of 2.07 (1.05-4.09), but CT genotype was not (OR = 1.25, 95%CI =0.94-1.66). IGFBP-3 SNP rs2270628 may contribute to the risk of ESCC in the Chinese Han population.


Influence of source and concentrations of dietary fiber on in vivo nitrogen excretion pathways in pigs as reflected by in vitro fermentation and nitrogen incorporation by fecal bacteria.
The inclusion of dietary fiber (DF) in diets has been suggested as a way to reduce NH(3) emission in pig barns because it contributes to a shift in N excretion from urine to feces owing to enhanced bacterial growth in the intestines. This study compared an in vitro method to measure bacterial protein synthesis during fermentation with an in vivo N excretion shift induced by diets differing in DF concentrations and solubility. The first experiment measured the effect of graded concentrations of sugar beet pulp (SBP; 0, 10, 20, and 30%) in corn- and soybean meal-based diets on in vivo N excretion partitioning between the urine and feces. A second experiment investigated the replacement of SBP, rich in soluble DF, with oat hulls (OH), rich in insoluble DF (20:0, 10.5:10.5, and 0:22%, respectively). In parallel, the fermentation characteristics of the dietary carbohydrates not digested in the small intestine were evaluated in an in vitro gas test, based on their incubation with colonic microbiota, using a mineral buffer solution enriched with (15)N. The N originating from the buffer solution incorporated into the bacterial proteins (BNI) was measured when half the final gas volume was produced (8.5 to 14.5 h of fermentation) and after 72 h of fermentation. Short-chain fatty acids were determined in the liquid phase. In the first experiment, the inclusion of SBP linearly decreased urinary N excretion from 0.285 to 0.215 g of N excreted in the urine per gram of N ingested and decreased the urinary-N:fecal-N excretion ratio from 2.171 to 1.177 (P < 0.01). In the second experiment, substituting SBP with OH linearly increased the urinary-N:fecal-N excretion ratio (P = 0.009). Unlike short-chain fatty acid production, BNI was greater at half-time to asymptotic gas production than at 72 h of fermentation. Sugar beet pulp enhanced BNI linearly (P < 0.001), 2.01, 2.06, and 2.35 mg g(-1) of diet with 10, 20, and 30% SBP, respectively, as compared with 1.51 mg for the control diet. The substitution of SBP with OH decreased BNI (P < 0.01). With the exception of final gas production, all in vitro kinetic characteristics and BNI were correlated with in vivo N excretion parameters, and regression equations for the prediction of N excretion pathways from in vitro data were identified. Even if the presence of resistant starch in the diet might alter the composition of the fibrous residue that is fermented, the in vitro method is a possible useful tool for the formulation of diets, reducing the effects of pig production on the environment.


Hominoid dietary evolution.
During the later Palaeocene and early Miocene, catarrhine primates and the evolving hominoids had adaptations for frugivorous diets, with the emphasis on soft foods. Early in the middle Miocene the hominoids underwent a major shift, both in morphology and in habitat, with the morphology characterized by thickened enamel on the molars, enlarged incisors and massive jaws. The diet indicated by this morphology is interpreted as still mainly frugivorous but with changed emphasis, possibly towards harder objects. The thick-enamelled hominoids are found associated with more open forest habitats, and the distribution of food resources in equivalent habitats today is discontinuous both in time and in space, leading to evolutionary pressures particularly affecting locomotion, brain size and social behaviour. The earliest known hominid fossils differed little in dental and mandibular morphology from the middle Miocene apes, and the implied dietary similarity, together with ape-like patterns of dental development and retained arboreal adaptations of the postcrania, suggests little change in the foraging strategies of the earliest hominids compared with their ape ancestors and further suggests similarity in evolutionary grade. This similarity may have extended to other aspects of behaviour, for example to patterns of tool making and use, which may have been similar in the common ancestor of apes and humans to the pattern shared by the earliest australopithecines and chimpanzees.


Effect of combined aspirin and extended-release dipyridamole versus clopidogrel on functional outcome and recurrence in acute, mild ischemic stroke: PRoFESS subgroup analysis.
Long-term antiplatelet therapy is effective at reducing recurrence after ischemic stroke. However, the relative safety and efficacy of combined aspirin-dipyridamole or clopidogrel are not known in patients with acute ischemic stroke. The factorial PRoFESS secondary prevention trial assessed antiplatelet and blood pressure-lowering strategies in 20,332 patients, 1360 of whom were randomized within 72 hours of ischemic stroke to combined aspirin (Asp; 25 mg BID) and extended-release dipyridamole (ER-DP; 200 mg BID, n=672) or clopidogrel (75 mg/d, n=688). The primary outcome for this post hoc subgroup analysis was functional outcome at 30 days; secondary outcomes included recurrence and death by 90 days. Analyses were adjusted for baseline prognostic variables and blood pressure treatment assignment. Patients were representative of the whole trial (age 67 years, National Institutes of Health Stroke Scale score 3, small-artery occlusion 59%), and baseline variables were similar between treatment groups. The mean time from stroke to recruitment was 58 hours. By 90 days, treatment was no longer being taken in 121 (18%) patients randomized to Asp/ER-DP and in 86 (12.5%) assigned to clopidogrel (P=0.006). Combined death or dependency (shift analysis of modified Rankin Scale score at day 30) did not differ between treatment groups (odds ratio [OR]=0.97; 95% CI, 0.79 to 1.19). Nonsignificant trends to reduced recurrence (OR=0.56; 95% CI, 0.26 to 1.18) and vascular events (OR=0.71; 95% CI, 0.36 to 1.37) were present with Asp/ER-DP. Rates of death, major bleeding, and serious adverse events did not differ between treatment groups. Treatment with combined Asp/ER-DP vs clopidogrel in 1360 patients with acute, mild ischemic stroke did not differ in terms of effects on functional outcome, recurrence, death, bleeding, or serious adverse events. Both treatments were practical to administer.


Coxsackievirus group B replication in cultured fetal baboon aortic smooth muscle cells.
All six coxsackievirus B (CVB) serotypes replicated to various extents in fetal baboon aortic smooth muscle cells (SMC) in culture. CVB3 and CVB4 replicated to the highest titers and induced no cytopathology at the level of light microscopy. Maximum yields of CVB3 were produced between 12 and 24 hr postinoculation. Up to 15% of SMC cells became infected, as determined by immunofluorescence assays with anti-CVB3 antiserum, yet overall cell division in infected cultures did not differ from infected SMC cultures. Electron microscopy of CVB3-inoculated SMC cultures revealed changes in some cells: viruslike particles, secondary lysosomes containing dense bodies, and peripheral nuclear chromatin condensation. CVB3 replicated well in SMC passages up to the eighth, but did not replicate in eleventh-passage cells. Because of the cardiotropic and myotropic potential of this virus and its ability to replicate in aortic SMC with associated ultrastructural alterations, CVB3 (and other CVB) should be further examined as an etiologic agent(s) that could induce atherosclerosis.


Modulation of intein activity by its neighboring extein substrates.
Inteins comprise a large family of phylogenetically widespread self-splicing protein catalysts that colonize diverse host proteins. The evolutionary and functional relationship between the intein and the split-host protein, the exteins, is largely unknown. To probe an association, we developed an in vivo and in vitro intein assay based on FRET. The FRET assay reports cleavage of the intein from its N-terminal extein. Applying this assay to randomized extein libraries, we show that the nature of the extein substrate bordering the intein can profoundly influence intein activity. Residues proximal to the intein-splicing junction in both N- and C-terminal exteins can accelerate the N-terminal cleavage rate by >4-fold or attenuate cleavage by 1,000-fold, both resulting in compromised self-splicing efficiency. The existence and the magnitude of extein effects require consideration for maximizing the utility of inteins in biotechnological applications, and they predict biases in intein integration sites in nature.


Restless Legs Syndrome: clinical features, diagnosis and a practical approach to management.
Restless legs syndrome (RLS) is a chronic neurological disorder that interferes with rest and sleep. It has a wide spectrum of symptom severity, and treatment is started when symptoms become bothersome. Dopamine agonists and calcium channel apha-2-delta antagonists (gabapentin, gabapentin enacarbil and pregabalin) are first-line treatments; calcium channel alpha-2-deltas are preferred over dopamine agonists because they give less augmentation, a condition with symptom onset earlier in the day and intensification of RLS symptoms. Dopamine agonists can still be used as first-line therapy, but the dose should be kept as low as possible. Iron supplements are started when the serum ferritin concentration is ≤75 µg/L, or if the transferrin saturation is less than 20%. For severe or resistant RLS, a combined treatment approach can be effective. Augmentation can be very challenging to treat and lacks evidenced-based guidelines.


Angiomatoid "malignant" fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype.
Angiomatoid "malignant" fibrous histiocytoma (AMFH) has been considered to be a low-grade sarcoma of childhood, and, with its fibrous pseudocapsule, angiomatoid change, dense lymphoplasmacytic response, and proliferation of spindled or round cells, has been classified as a fibrohistiocytic neoplasm. We wanted to study the clinicopathologic and immunophenotypic features of a large number of these tumors and to especially further explore their myoid differentiation. Cases coded as AMFH from 1979 to 1995 were retrieved from the Soft Tissue Registry of the AFIP. Only cases that met the criteria for AMFH by light microscopy were included, a total of 158 cases. Immunohistochemistry was obtained on 98 cases. Clinical history on 92% of all cases revealed a gender ratio of 1.3 females: males, age range of 2 to 71 years, median size of 2.0 cm, and a distribution of extremities > trunk > head and neck, with 66% lesions occurring in areas of normal lymphoid tissue. All tumors with available margins were well-circumscribed. Eighty percent of cases had some degree of lymphoplasmacytic infiltration; 50% cases had pseudovascular spaces filled with blood. Fifty-two percent had predominantly round cell morphology; 48% had a predominantly spindle cell pattern. Desmin positivity was noted in 51% cases and occurred in both predominantly round cell and spindle cell tumors. Most of the desmin-positive cases with adjacent lymphoid infiltrate (67%) showed scattered similar, desmin-positive cells in the surrounding lymphoid infiltrate, adjacent to the tumor. Muscle-specific and smooth-muscle actins were seen in 14% cases. Heavy-caldesmon was strongly positive in 3%, and calponin was focally positive in 73% and extensively positive in 12% cases. MyoD1, myoglobin, and myogenin (myf4) were negative in all tumors studied. Forty-five percent of cases were positive for CD99; 52% of these had round cell morphology. Fifteen percent of cases were positive for KP-1. All tumors were positive for vimentin and negative for CD21, CD35, S100 protein, CD34, keratins 8/18, and lysozyme. Clinical follow-up on 86 patients indicated that only 1 patient was alive with a local nodal metastasis (1% frequency of metastasis) within 1 year, and 2 others had local recurrence, all over a mean follow-up period of 6 years. The myoid, primarily myofibroblastic, phenotype of these lesions is supported by desmin, calponin, and occasional actin positivity. The occasional heavy-caldesmon and smooth muscle actin additionally suggest rare smooth muscle phenotype; however, lack of skeletal muscle markers indicate no relationship of AMFH to skeletal muscle tumors. The resemblance of these lesions to lymph nodes, clinically and morphologically, the finding of similar desmin positive cells in the adjacent lymphoid infiltrate, and the fact that 66% cases were found in sites of normal lymphoid tissue raise the possibility that some of these lesions may arise from or be related to myoid cells of lymphoid tissue. AMFH has an almost invariably benign behavior, but the 1% metastatic rate warrants its classification as low-grade "malignant." The predominantly round cell, CD99-positive and desmin positive AMFH cases, respectively, should not be confused with Ewing's sarcoma/PNET or rhabdomyosarcoma, respectively.


5-Aminolevulinic acid coated microneedles for photodynamic therapy of skin tumors.
This study evaluated the potential of coated microneedles for improved dermal delivery of 5-aminolevulinic acid (5-ALA), which naturally gets converted by cells of the tissue in to a photosensitizer called protoporphyrin IX (PPIX). Microneedle patches containing 57 microneedles were coated with 5-ALA using an in-house developed micro-precision dip coater. The coating process was optimized to achieve higher 5-ALA loading on microneedles and a high delivery efficiency into porcine cadaver skin. Using 5 dips with 25% w/v 5-ALA solution, a mass of about 350μg of 5-ALA was coated per patch, which gave a delivery efficiency of about 90% in porcine cadaver skin. Bright-field and scanning electron microscopy established that coatings of 5-ALA on microneedles of the patch were uniform. In vivo dermal pharmacokinetics showed that delivery of just 350μg of 5-ALA using coated microneedles led to about 3.2-fold higher PPIX formation after 4h, as compared to topical application of 20% w/w 5-ALA in a conventional cream formulation (25mg cream). Furthermore, with use of coated microneedles, PPIX was observed in deeper regions of the skin (~480μm) as compared to topical 5-ALA cream formulation (~150μm). The potential of PPIX for photodynamic therapy was tested in vivo. After light exposure (633nm; 118J/cm(2)), PPIX got photosensitized, and due to higher initial amount of PPIX in the coated microneedle group, about twice the amount of PPIX was photobleached compared to topical cream application. Finally, even with a lower dose of just 1.75mg 5-ALA, coated microneedles suppressed the growth of subcutaneous tumors by ~57%, while a topical cream containing 5mg of 5-ALA did not suppress the tumor volume and led to tumor growth comparable to the untreated control group. Overall, the strategy of delivering 5-ALA using coated microneedles could be a promising approach for photodynamic therapy of skin tumors.


Fluorescence resonance energy transfer based MCM-EDTA-Tb3+-MES sensor.
An in situ mesopourous surface imprinted polymeric (SIP) sensor was synthesized for a highly sensitive, selective, and kinetically faster detection of the high-vapor-pressure nerve gas surrogate methyl salicylate (MES). Visual detection occurred on the filtrate thin films at 25 pM. Other nerve gas surrogates, TP, DMP, DMMP, PMP, and 1,4-thioxane, were tested and showed a decrease in sensitivity compared to MES. In addition, 2,6-dipicolinic acid (DPA), a biological indicator, was also investigated and showed a decrease in sensitivity compared to MES. Finally, the detection plateau was reached at 40 s and at 1.5 x 10(-4) M from pH 6-11.


Self-harm in the UK: differences between South Asians and Whites in rates, characteristics, provision of service and repetition.
Rates of self-harm appear high in South Asian young women in the United Kingdom (UK) although previous studies were mostly small. Data on treatment and outcomes for South Asians are lacking. This study compared rates of self-harm, socio-demographic and clinical characteristics, provision of services and risk of repetition by ethnicity. A prospective cohort of adult self-harm attendees (n = 7185), aged 15 and over presenting to four emergency departments in the cities of Manchester and Salford, UK over a 4-year period. The study included 299 South Asians. South Asian women aged 16-24 years were more likely to self-harm than Whites of the same age group (1010.9 vs. 754 per 100,000). Across all age groups the rates of self-harm were lower in South Asian men compared to White men and to South Asian women. South Asian women were significantly more likely to report relationship problems within the family than White women (32% vs. 19%, P = <0.001). South Asians were less likely than Whites to report depressive symptoms and to be offered specialist mental health services (Rate ratio = 0.75), and more likely to be referred back to the GP (Rate ratio = 1.83). South Asians were less likely to attend with a repeat episode (Rate ratio = 0.56). Young South Asian women are at high risk of self-harm, but their clinical risk appears to be lower in terms of the accepted contextual factors contributing to risk. Potentially useful service provision may include an interpersonal problem solving approach although to be effective, interventions would need to be acceptable to South Asian women and culturally appropriate.


Glucocorticoids and myosin5b loss of function induce heightened PKA signaling in addition to membrane traffic defects.
Loss-of-function mutations in the nonconventional myosin Vb (Myo5b) result in microvillus inclusion disease (MVID) and massive secretory diarrhea that often begins at birth. Myo5b mutations disrupt the apical recycling endosome (ARE) and membrane traffic, resulting in reduced surface expression of apical membrane proteins. ARE disruption also results in constitutive phosphoinositide-dependent kinase 1 gain of function. In MVID, decreased surface expression of apical anion channels involved in Cl- extrusion, such as cystic fibrosis transmembrane conductance regulator (CFTR), should reduce fluid secretion into the intestinal lumen. But the opposite phenotype is observed. To explain this contradiction and the onset of diarrhea, we hypothesized that signaling effects downstream from Myo5b loss of function synergize with higher levels of glucocorticoids to activate PKA and CFTR. Data from intestinal cell lines, human MVID, and Myo5b KO mouse intestine revealed changes in the subcellular redistribution of PKA activity to the apical pole, increased CFTR phosphorylation, and establishment of apical cAMP gradients in Myo5b-defective cells exposed to physiological levels of glucocorticoids. These cells also displayed net secretory fluid fluxes and transepithelial currents mainly from PKA-dependent Cl- secretion. We conclude that Myo5b defects result in PKA stimulation that activates residual channels on the surface when intestinal epithelia are exposed to glucocorticoids at birth.


Immunoglobulin G fragment C receptor polymorphisms and KRAS mutations: are they useful biomarkers of clinical outcome in advanced colorectal cancer treated with anti-EGFR-based therapy?
KRAS mutations have been identified as a strong predictor of resistance to anti-epidermal growth factor receptor (EGFR) therapies. Besides inhibiting the EGFR pathway, anti-EGFR monoclonal antibodies may exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC). Through this mechanism, the antibody fragment C portion (Fcγ) interacts with Fc receptors (FcγRs) expressed by immune effectors cells. We investigated the association of FcγR polymorphisms and KRAS mutation with the clinical outcome of 104 refractory metastatic colorectal cancer (mCRC) patients treated with anti-EGFR antibodies. FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed in genomic DNA using a 48.48 dynamic array on the BioMark system (Fluidigm, South Sanfrancisco, CA, USA). Tumor tissues from 96 cases were screened for KRAS mutations. KRAS mutation was associated with a lower response rate (RR) (P = 0.035) and a shorter progression-free survival (PFS) (3 vs 7 months; P = 0.36). FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms did not show statistically significant associations with response, PFS, or KRAS status. In the logistic regression analysis, KRAS status (P = 0.04) and skin toxicity (P = 0.03) were associated with RR. By multivariate analysis, the clinical risk classification (P = 0.006) and skin toxicity (P < 0.0001) were found to be independent risk factors for PFS. In conclusion, the FcγRIIa and FcγRIIIa polymorphisms are not useful as molecular markers for clinical outcome in mCRC patients. To date, the EORTC (European Organization for Research and Treatment of Cancer Classification), skin toxicity, and KRAS status are the only reliable biomarkers to identify patients that would benefit from anti-EGFR therapy.


Infarct volume is a pivotal biomarker after intra-arterial stroke therapy.
Pretreatment infarct volume appears to predict clinical outcome after intra-arterial therapy. To confirm the importance of infarct size in patients undergoing intra-arterial therapy, we sought to characterize the relationship between final infarct volume (FIV) and long-term functional outcome in a prospective cohort of endovascularly treated patients. From our prospective intra-arterial therapy database, we identified 107 patients with acute ischemic stroke with anterior circulation proximal artery occlusions who underwent final infarct imaging and had 3-month modified Rankin Scale scores. Clinical, imaging, treatment, and outcome data were analyzed. Mean age was 66.6 years. Median admission National Institutes of Health Stroke Scale score was 17. Reperfusion (Thrombolysis In Cerebral Infarction 2A-3) was achieved in 78 (72.9%) patients. Twenty-seven (25.2%) patients achieved a 3-month good outcome (modified Rankin Scale 0-2), and 30 (28.0%) died. Median FIV was 71.4 cm(3). FIV independently correlated with functional outcome across the entire modified Rankin Scale. In receiver operating characteristic analysis, it was the best discriminator of both good outcome (area under the curve=0.857) and mortality (area under the curve=0.772). A FIV of approximately 50 cm(3) demonstrated the greatest accuracy for distinguishing good versus poor outcome, and a FIV of approximately 90 cm(3) was highly specific for a poor outcome. The interaction term between FIV and age was the only independent predictor of good outcome (P<0.0001). The impact of FIV was accentuated in patients <80 years. Among patients with anterior circulation acute ischemic stroke who undergo intra-arterial therapy, final infarct volume is a critical determinant of 3-month functional outcome and appears suitable as a surrogate biomarker in proof-of-concept intra-arterial therapy trials.


Eukaryotic initiation factor 5A activity and HIV-1 Rev function.
Eukaryotic initiation factor 5A (eIF-5A) is the only cellular protein known to contain the unusual amino acid hypusine, a modification that appears to be required for cell proliferation. This hypusine-modified protein stimulates synthesis of methionyl-puromycin in an in vitro assay which mimics the formation of the first peptide bond during protein synthesis, although the exact role of eIF-5A in vivo is still unknown. The unexpected finding that eIF-5A is a cellular cofactor of the HIV-1 Rev trans-activator protein may, however, provide a novel opportunity to reveal precisely what function eIF-5A performs in eukaryotic cells. In this review article, we first present a brief description of HIV-1 Rev function, followed by an overview of the data that identified eIF-5A as a Rev cofactor and, finally, discuss novel findings with respect to cellular eIF-5A activities.


Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI.
The goal of this study is to investigate the relationship between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and body mass index (BMI) in two sizable and well-characterized populations of British women: the British Women's Heart and Health Study (BWHHS) (age 60-79 years) and the mothers from the Avon Longitudinal Study of Parents and Children (age 16-44 years). We genotyped the Val66Met polymorphism (rs6265) in these two populations, and conducted a linear regression analysis to test for an association between this polymorphism and BMI. Both study populations indicated an association between BMI and the Val66Met polymorphism, with individuals carrying the Met-Met genotype having a lower mean BMI than those with the Val-Met or Val-Val genotypes (in the BWHHS): mean BMI difference=-0.911 kg/m(2), 95% confidence interval (CI): -1.70 to -0.12, P=0.023; in the mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC): mean BMI difference=-0.57 kg/m(2), 95%CI: -1.08 to -0.054, P=0.03). In a pooled analysis of these two studies, together with one further published study that provided data in a suitable format for inclusion in our meta-analysis, we found a pooled difference of -0.76 (95% CI: -1.16, -0.036) for adult women; I(2)-test for heterogeneity=51%, P=0.13. Our study indicated an association between BDNF and BMI in two general population studies of women. The exact role of BDNF in weight regulation merits further investigation.


Personality disorder types proposed for DSM-5.
The Personality and Personality Disorders Work Group has proposed five specific personality disorder (PD) types for DSM-5, to be rated on a dimension of fit: antisocial/psychopathic, avoidant, borderline, obsessive-compulsive, and schizotypal. Each type is identified by core impairments in personality functioning, pathological personality traits, and common symptomatic behaviors. The other DSM-IV-TR PDs and the large residual category of personality disorder not otherwise specified (PDNOS) will be represented solely by the core impairments combined with specification by individuals' unique sets of personality traits. This proposal has three main features: (1) a reduction in the number of specified types from 10 to 5; (2) description of the types in a narrative format that combines typical deficits in self and interpersonal functioning and particular configurations of traits and behaviors; and (3) a dimensional rating of the degree to which a patient matches each type. An explanation of these modifications in approach to diagnosing PD types and their justifications--including excessive co-morbidity among DSM-IV-TR PDs, limited validity for some existing types, lack of specificity in the definition of PD, instability of current PD criteria sets, and arbitrary diagnostic thresholds--are the subjects of this review.


Case management accountability for safe, smooth, and sustained transitions: a plea for building "wrap-around" case management services now.
The purpose is to encourage hospital administrations to address readmissions immediately and to restructure and significantly enhance case management services once and for all so that they can provide a "wraparound" service for the full clinical course from admission to transition for all patients and families. If 10 basic interventions cannot be provided because of staffing limitations or processes, case management will continue to operate in a crisis mode and hospitals will suffer potentially large financial, quality, and satisfaction losses. If further customization cannot be provided to patients and their families, hospitals will be at risk to fail both their margin and their mission. Although other professionals and support staff will have distinct responsibilities, case management must be built, resourced, and restructured to be the authorized and accountable central control operation between level-of -care transitions. Acute care hospitals. The national length of stay (LOS) has lowered from 7.8 days in 1970 to 5.2 days (males) and 4.5 days (females) in 2006 (DeFrances, C., Lucas, C., Buie, V., & Golosinskiy, A., 2008), whereas the national readmission rate for adult medical-surgical patients, depending on the diagnosis and the payer, has risen from a range of 5%-29% after 30 days (The Center for Case Management, 2009) to an average of 19% (Jencks, S., Williams, M., & Coleman, E., 2009). Of the key results for return on investment claimed by case management, the largest combined measure of quality, financial, and satisfaction outcomes lies in the delivery of safe, smooth, and sustained discharges/transitions. In other words, readmission rates should be the conscience of the hospital, especially of case management services. 2010 is the year for case management services and departments to adamantly request the authority and take the accountability that will be required to prevent readmissions while maintaining or continuing to decrease LOS, thus increasing flow and capacity. To achieve full accountability for 100% of patients' transitions from admission to transition, case management must build a wraparound service that covers 10 basic interventions and a handful of best practices to customize each transition. Two principles pertain: (1) If you have not met the patient or family until the discharge day, you don't know them and will make mistakes, and (2) there is no such thing as a simple discharge! If hospitals do not undertake the full support of case management as the accountable agent for preventing readmissions as their biggest challenge (potentially larger than Retrospective Audit Contractors' financial take-backs) and provide case management with a full contingent of strategically positioned full time equivalents (FTEs), hospitals and their patients and families will suffer from a predictable imbalance in LOS, readmissions, and the greater community's loss of confidence.


Slow infusion for the prevention of akathisia induced by prochlorperazine: a randomized controlled trial.
The utility of intravenous prochlorperazine (PCZ) in the treatment of nausea, vomiting, and headache may be limited by the akathisia that occurs frequently with the recommended 2-min infusion rate. We tested the hypothesis that decreasing the rate of PCZ infusion to 15 min reduces the incidence of akathisia at 1 hour. This double-blinded, randomized, controlled trial was conducted in the Emergency Department of an academic tertiary-care medical center with an annual census of 95,000 emergency patient visits. We enrolled a convenience sample of adult patients who received 10 mg i.v. PCZ for the treatment of nausea, vomiting, or headache. Subjects were randomized to receive either a 2-min infusion of PCZ (10 mg) followed by a 15-min infusion of saline, or a 2-min infusion of saline followed by a 15-min infusion of prochlorperazine. The incidence of akathisia at 1 hour was measured by using explicit diagnostic criteria. One hundred sixty patients were randomly enrolled into two groups, which were comparable with respect to age, gender, weight, and complaint. Akathisia developed in 31 of 84 patients (36.9%) who received the 2-min infusion of PCZ and in 18 of 76 patients (23.7%) who received the 15-min infusion of PCZ (p = 0.07), a 36% (95% CI, -5% to 61%) relative reduction. The delta from pre-infusion to postinfusion scores between the two groups was not significant (p = 0.19). We conclude that slowing the rate of PCZ infusion does not decrease akathisia.


Communicating about the risks and benefits of genetically modified foods: the mediating role of trust.
Recent research suggests that public attitudes toward emerging technologies are mainly driven by trust in the institutions promoting and regulating these technologies. Alternative views maintain that trust should be seen as a consequence rather than a cause of such attitudes. To test its actual role, direct as well as mediating effects of trust were tested in an attitude change experiment involving 1,405 consumers from Denmark, Germany, Italy, and the United Kingdom. After prior attitudes to genetic modification in food production had been assessed, participants received different information materials (either product-specific information or balanced/general information about genetic modification in food production) and were asked to evaluate different types of genetically modified foods (either beer or yoghurt). The information materials were attributed to different information sources (either an industry association, a consumer organization, or a government source). After completion, perceived risk and perceived benefit were assessed, and participants indicated their trust in the information sources to which the materials had been attributed. Direct and trust-mediated attitude change effects were estimated in a multi-sample structural equation model. The results showed that information provision had little effect on people's attitudes toward genetically modified foods, and that perceptions of information source characteristics contributed very little to attitude change. Furthermore, the type of information strategy adopted had almost no impact on postexperimental attitudes. The extent to which people trusted the information sources appeared to be driven by people's attitudes to genetically modified foods, rather than trust influencing the way that people reacted to the information. Trust was not driving risk perception-rather, attitudes were informing perceptions of the motivation of the source providing the information.


Renoprotective effect of vildagliptin following hepatic ischemia/reperfusion injury.
Remote renal injury is a drastic consequence of hepatic ischemia/reperfusion (IR) injury. Vildagliptin (V) is a dipeptidyl peptidase-4 inhibitor that has a hepatorenal protective effect against models of liver and renal IR. This research was done to explore the protective role of vildagliptin against renal injury following hepatic IR injury as well as the possible involvement of transforming growth factor-beta (TGF-β)/Smad/alpha-smooth muscle actin (α-SMA) expressions in the pathophysiological mechanism of the remote renal injury. Three groups of male Wistar rats were organized into: sham group, IR group, and V + IR group in which 10 mg/kg/day of vildagliptin was pretreated for 10 days intraperitoneally. Blood in addition to renal and hepatic tissue samples was used for biochemical and histopathological studies. Hepatic IR induced a marked increase in serum creatinine, blood urea nitrogen, liver enzymes, renal nitric oxide, malondialdehyde, tumor necrosis factor-alpha levels with a marked upregulation of renal mRNA expressions of TGF-β, Smad2, Smad3, and α-SMA in addition to a marked decline in renal catalase content comparing to the sham group. Abnormal histopathological findings of hepatic and renal injury were detected in the IR group. Vildagliptin significantly improved these biochemical markers as well as the histopathological changes. The upregulation of renal TGF-β/Smad/α-SMA mRNA expressions was involved for the first time in the pathogenesis of the renal injury following hepatic IR and vildagliptin ameliorated this renal injury through blocking these expressions.


A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury.
Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI.


Competition at the range boundary in the slimy salamander: using reciprocal transplants for studies on the role of biotic interactions in spatial distributions.
1. Determining the factors that influence the distribution of species has been a longstanding goal in the field of ecology. New techniques such as ecological niche modelling have the potential to aid in addressing many broad questions in ecology, evolutionary biology, and behavioural ecology. 2. This study combines broad-scale ecological niche models with fine-scaled studies of biotic interactions to examine how abiotic and biotic interactions affect the spatial distribution of the terrestrial salamander species Plethodon glutinosus (northern slimy salamander), in a potential contact zone shared with Plethodon mississippi (Mississippi slimy salamander). 3. The core habitat in the interior portion of the range of P. glutinosus and the contact zone are distributed in unique environmental niche space. 4. The form of competition, inter- or intraspecific, significantly affected mass loss of adult salamanders. Salamanders lost more mass when interacting with a heterospecific. 5. Abiotic conditions strongly influenced the impact of competition on salamanders. Under stressful environmental conditions at the field site located in the contact zone, salamanders lost more mass than at the field site located in the interior of the range. 6. Furthermore, adult salamanders from range-edge populations and core populations (from the interior of the range) differed in their respective abilities to compete under the abiotic conditions in the contact zone.


Novel Use of Cangrelor With Heparin During Cardiopulmonary Bypass in Patients With Heparin-Induced Thrombocytopenia Who Require Cardiovascular Surgery: A Case Series.
Optimal anticoagulation strategy during cardiopulmonary bypass (CPB) remains uncertain in patients with heparin-induced thrombocytopenia (HIT) who require urgent/emergent cardiac surgery. We describe our strategy and experience with utilizing cangrelor in combination with heparin for anticoagulation during CPB in patients with different phases of HIT undergoing a wide range of urgent/emergent cardiovascular surgery. Cangrelor is an intravenous direct-acting P2Y12 platelet receptor antagonist that achieves therapeutic effect and eliminates rapidly. Its antiplatelet activity is unaffected by stagnation of blood, nor is it influenced by patient's sex, age, renal status, or hepatic function. Our institutional alternative intraoperative anticoagulation strategy for HIT patients is to administer cangrelor with a loading dose of 30 μg/kg, followed by continuous infusion of 4 μg/kg/min throughout CPB via a dedicated intravenous access. VerifyNow P2Y12 reaction unit point-of-care assay is utilized to monitor platelet inhibition throughout surgery. Cangrelor infusion is discontinued 10 minutes prior to heparin reversal with protamine. Ten urgent/emergent cardiovascular surgeries were performed at our institution using cangrelor with heparin for anticoagulation during CPB, and the majority were pulmonary thromboendarterectomy (60%). HIT was confirmed in 3 cases and was suspected in 4 which was found to be negative after the operation. One case of subacute B HIT and 2 cases of remote HIT were included in this series. This novel alternative intraoperative anticoagulation strategy was well tolerated by all patients. There was neither serious postoperative thrombotic event nor major postoperative bleeding complication that required reoperation. One death occurred in a patient with advanced intracardiac malignancy, whose life support was ultimately withdrawn postoperatively. Median postoperative intensive care unit stay was 7.2 ± 5.5 days, while median postoperative hospital stay was 16.3 ± 10.8 days. In patients with various phases of HIT who require urgent/emergent on-pump cardiovascular surgery, the use of cangrelor with heparin may be a convenient, safe, and effective alternative intraoperative anticoagulation strategy providing acceptable outcomes.


Glomerular filtration rate in schoolgirls with covert bacteriuria.
Clearance of technetium-99m-labelled diethylenetriaminepenta-acetic acid was used to measure total and individual kidney glomerular filtration rates in 48 girls with covert bacteriuria. The mean (+/- SD) of the total rates of 18 girls with scarred kidneys (99 +/- 24 ml/min/1.73 m2) was significantly (0.005 greater than p greater than 0.002) lower than that in 30 girls with unscarred kidneys (119 +/- 18 ml/min/1.73 m2). This reduction in glomerular filtration was related to the loss of kidney substance associated with scarring rather than to vesicoureteric reflux. The glomerular filtration rate was unrelated to the duration of bacteriuria. These findings suggest that in girls aged 4 and over neither vesicoureteric reflux nor covert bacteriuria contributes to the progression of kidney damage.


Cytomegalovirus infection in patients with AIDS.
Advances in the field of antiviral therapy are now occurring with increasing frequency and rapidity and often generate varying degrees of confusion among those of us whose practices are focused primarily on therapy with antibacterial agents. How to treat cytomegalovirus infections in patients infected with the human immunodeficiency virus constitutes one of the best examples of the quandaries engendered by these advances, and the topic is reviewed in this first AIDS Commentary update. Given the U.S. Food and Drug Administration's recent approval of foscarnet, this discussion is very timely; it is particularly relevant for clinicians to be made aware of current lines of thought regarding induction versus maintenance therapy, the benefits of efficacy versus adverse effects of drug-related toxicity, and the interactions between antiretroviral drugs and ganciclovir or foscarnet. Dr. W. Lawrence Drew's career in this area has been long-standing and productive, and he is one of the leading experts in the field. In this update he addresses these perplexing issues.


Development and characterization of EST-SSR markers in Bombax ceiba (Malvaceae).
Bombax ceiba (Malvaceae), commonly known as silk cotton tree, is a multipurpose tree species of tropical forests. Novel expressed sequence tag-simple sequence repeat (EST-SSR) markers were developed and characterized for the species using transcriptome analysis. A total of 33 new EST-SSR markers were developed for B. ceiba, of which 13 showed polymorphisms across the 24 individuals from four distant populations tested in the study. The results showed that the number of alleles per polymorphic locus ranged from two to four, and the expected heterozygosity and observed heterozygosity per locus varied from 0.043 to 0.654 and from 0 to 0.609, respectively. These newly developed EST-SSR markers can be used in phylogeographic and population genetic studies to investigate the origin of B. ceiba populations. Furthermore, these EST-SSR markers could also greatly promote the development of molecular breeding studies pertaining to silk cotton tree.


Dietary Inflammatory Index and Renal Cell Carcinoma Risk in an Italian Case-Control Study.
The relation between diet-related inflammation and renal cell carcinoma (RCC) has not been investigated. In this study, we explored the association between the dietary inflammatory index (DII) and RCC in an Italian case-control study conducted between 1992 and 2004. Cases were 767 patients with incident, histologically confirmed RCC. Controls were 1534 subjects admitted to the same hospitals as cases for various acute, nonneoplastic conditions. The DII was computed based on dietary intake assessed using a reproducible and valid 78-item food frequency questionnaire. Odds ratios (ORs) were estimated through logistic regression models conditioned on age, sex, and center, and adjusted for recognized confounding factors, including total energy intake. Subjects in the highest quartile of DII scores (i.e., with the most proinflammatory diets) had a higher risk of RCC compared to subjects in the lowest quartile [OR 1.41, 95% confidence interval (CI) 1.02, 1.97; p-trend = 0.04)]. Apparently stronger associations were observed among females (OR 1.68, 95% CI 0.93, 3.03), subjects aged <60 yr (OR 1.77, 95% CI 1.05, 2.98), body mass index ≥25 kg/m2 (OR 1.64, 95% CI 1.07, 2.51), and ever smokers (OR 1.66, 95% CI 1.08, 2.57), in the absence of significant heterogeneity. A proinflammatory diet is associated with increased RCC risk.


Effects of mental imagery technique in addition to conventional physical therapy to improve hand functions in chronic stroke patients.
To observe the effect of mental imagery and conventional physical therapy for the treatment of hand function in chronic stroke patients. The study was conducted at Rana and Alvi welfare society. A sample of 50 stroke patients was selected and divided in two groups; group A (experimental) and group B (control). Inclusion and exclusion criteria were established and patients meeting inclusion criteria were included in the study. A p-value of <0.05 was considered significant. Group A was treated with conventional physical therapy combined with mental imagery whereas Group B was treated with conventional physical therapy alone. Wolf motor function test and action research arm test was used as outcome measures. Group A consisted of 17 (68%) females and 8 (32%) males and group B comprised of 11 (44%) females and 14 (56%) males. Mean age of group A and B were 59.68±2.37 and 58.52±2.46 years respectively. Mean duration (in months) of stroke for group A was 16.32±3.77 (minimum and maximum duration 13 and 23 months respectively). The stroke mean duration of group B was 16.00±2.34 (minimum and maximum duration 13 and 20 months respectively). Both groups did not show significant difference at 5th week (p=0.721) whereas a significant difference was observed at 10th week (p<0.001). It was concluded that mental imagery technique in combination with conventional physical therapy is significantly effective to improve hand function among chronic stroke patients in comparison to conventional physical therapy alone.


Positive effects of cerebrolysin on electroencephalogram slowing, cognition and clinical outcome in patients with postacute traumatic brain injury: an exploratory study.
The potential effects of Cerebrolysin (EBEWE Pharma, Unterach, Austria), a peptide preparation with neurotrophic activity, on brain bioelectrical activity, cognitive performance and clinical outcome in postacute traumatic brain injury (TBI) patients, were investigated in an exploratory study. A decrease in slow electroencephalogram (EEG) activity and an increase in fast frequencies were observed after the administration of Cerebrolysin. This EEG-activating effect was not influenced by TBI time course or severity, nor by the chronic treatment with nootropic compounds. Cognitive performance, evaluated with the Syndrome Kurztest test, improved in TBI patients after Cerebrolysin treatment, independent of disease severity, time course or disability. A significant improvement in the patients' clinical outcome, only evident during the first year after brain trauma, was also found following Cerebrolysin infusions. No relevant changes in biological parameters nor drug-related adverse events were observed. These promising preliminary results suggest that Cerebrolysin might be a useful treatment to improve the recovery of patients with traumatic brain damage, and encourage the conduction of confirmatory clinical trials.


[Disasters and emergency situations: what have we learned from the past to prepare for the future?].
Israel has gained extensive experience in the mass casuaLty field, especially from dealing with terrorism events. This special issue of "Harefuah" includes articles that describe and analyze several aspects and approaches related to mass casualty event (MCE) preparedness and response strategies, based on Israel's experience. Feigenberg reports that Magen David Adom (MDA) was able to evacuate all urgent injuries during an MCE from the site to a hospital in 28 minutes, on average. Of the MCE casualties, 71% were evacuated directly to level 1 trauma centers. Rafalowski notes that the ability of MDA to implement organizational and operational Learning processes close to the time of the incident, as well as their modular operational approach, which allows flexibility in responding to simultaneous events, are probably among the reasons that have helped MDA reach a high Level of success in dealing with MCEs. Analysis of terrorism injury data demonstrates that these injuries, suffered by both children and adults, are characterized by increased complexity, with higher severity, higher in-patient mortality rates, and significantly greater use of precious hospital resources such as intensive care, operating rooms, CT, and days of hospitalization. Extensive experience dealing with MCEs has brought managerial insights to the entire health system, for instance in the hospitalization system and clinical management of injuries. In her article, Adini defines five major components for assessing the Israeli health system in emergencies. Shasha's article discusses the principles of hospital preparedness while working under fire. The importance of this subject has in recent years helped bring a more academic approach to emergency and disaster management in the world and in Israel, as enacted at Tel Aviv University's Multidisciplinary Master's Program in Emergency and Disaster Management, and also in other universities that focus on specific disciplines. In summary, achieving improvement requires continuous focus on preparedness, integration of new technologies, routine debriefings, and developing new coping strategies, education, training, and drills. These should all be part of daily preparedness routines. Only in this way can a high quality level of preparedness be maintained over time.


Present state and developments in the production of inactivated poliomyelitis vaccine.
A review is given on the present state and developments in the production of inactivated poliomyelitis vaccine. Various aspects of the production such as cell substrates, large scale culture techniques, seed viruses and processing of virus harvests are discussed in view of safety, potency and economics. As far as cell substrates are concerned subcultured monkey kidney cells from captive-bred monkeys or non-tumorigenic continuous cell lines both cultivated in microcarrier culture are at the moment considered to be the best cell substrates in substitution for primary monkey kidney cells. Although with the present seed viruses highly potent vaccines can be prepared attention should be paid to the antigenicity and stability of the seed viruses especially type 1 seed virus. For processing of virus harvests concentration by ultrafiltration followed by purification with column chromatography is giving very pure virus suspensions. The results regarding yields and economics on the processing of virus harvests may be improved by application of affinity chromatography on immobilized antibodies. Inactivation by formalin has proved to be a reliable and safe method for the inactivation of the concentrated and purified virus suspensions.


The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity.
C-Circles, self-primed telomeric C-strand templates for rolling circle amplification, are the only known alternative-lengthening-of-telomeres (ALT)-specific molecule. However, little is known about the biology of C-Circles and if they may be clinically useful. Here we show that C-Circles are secreted by ALT+ cancer cells inside exosomes, and that a blood-based C-Circle Assay (CCA) can provide an accurate diagnostic for ALT activity. Extracellular vesicles were isolated by differential centrifugation from the growth media of lung adenocarcinoma, glioblastoma, neuroblastoma, osteosarcoma, and soft tissue sarcoma cell lines, and C-Circles were detected in the exosome fraction from all eleven ALT+ cancer cell lines and not in any extracellular fraction from the eight matching telomerase positive cancer cell lines or the normal fibroblast strain. The existence of C-Circles in ALT+ exosomes was confirmed with exosomes isolated by iodixanol gradient separation and CD81-immunoprecipitation, and C-Circles in the exosomes were protected from nucleases. On average, 0.4% of the total ALT+ intracellular C-Circles were secreted in the exosomes every 24 h. Comparing the serum-based and tumor-based CCAs in 35 high risk neuroblastoma patients divided randomly into ALT+ threshold derivation and validation groups, we found the serum-based CCA to have 100% sensitivity (6/6), 70% specificity (7/10), and 81% concordance (13/16). We conclude that the secretion of C-Circles by ALT+ cancer cells in the exosomes provides a stable blood-based biomarker and a potential clinical diagnostic for ALT activity.


A Scoping Review of Investment Cases for Vaccines and Immunization Programs.
Many investment cases have recently been published intending to show the value of new health investments, but without consistent methodological approaches. To conduct a scoping review of existing investment cases (using vaccines and immunization programs as an example), identify common characteristics that define these investment cases, and examine their role within the broader context of the vaccine development and introduction. A systematic search was conducted from January 1980 to November 2017 to identify investment cases in the area of vaccines and immunization programs from gray literature and electronic bibliographic databases. Investment case outcomes, objectives, key variables, target audiences, and funding sources were extracted and analyzed according to their reporting frequency. We found 24 investment cases, and most of them aim to provide information for decisions (12 cases) or advocate for a specific agenda (9 cases). Outcomes presented fell into 4 broad categories-burden of disease, cost of investment, impact of investment, and other considerations for implementation. Number of deaths averted (70%), incremental cost-effectiveness ratios (67%), and reduction in health and socioeconomic inequalities (54%) were the most frequently reported outcome measures for impact of investment. Health system capacity (79%) and vaccine financing landscape (75%) were the most common considerations for implementation. A sizable proportion (41.4%) of investment cases did not reveal their funding sources. This review describes information that is critical to decision making about resource mobilization and allocation concerning vaccines. Global efforts to harmonize investment cases more broadly will increase transparency and comparability.


The Effect of Lycopene Supplementation on Mood Status and Quality of Life in Infertile Men: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Infertility is a major worldwide problem which is caused by several factors such as environmental, physiological, and genetic conditions. Lycopene is considered to be one of the most important antioxidants that can contribute to reducing or preventing the psychological damage that leads to infertility. Thus, the aim of this study was to evaluate the effect of lycopene supplementation on depression, anxiety and stress scales and quality of life in infertile men. In this randomized clinical trial, 44 infertile men with oligozoospermia were randomly divided into the following two groups: the experimental group was supplemented with 25 mg lycopene, once per day for 12 weeks, and the control group received a placebo, for 12 weeks. Anthropometric and dietary data, physical activity, mood status, including depression, anxiety, stress, and quality of life scores were recorded pre- and post-intervention. Depression, anxiety and stress were assessed using a 21-item questionnaire (DASS-21) and quality of life was examined using the WHO 26-qustion questionnaire (WHOQOL). The baseline age and body mass index (BMI) were not significantly different between the two groups (age: 31.89 ± 2.51 and 32.15 ± 2.16 years old for intervention and placebo, respectively; P=0.732 and BMI: 27.20 ± 1.68 and 26.53 ± 1.53; for intervention and placebo, respectively; P=0.206). There were no significant differences in depression, anxiety and stress values between the two groups; however, depression score significantly decreased in both groups compared to the baseline levels (P=0.028 and P=0.031). No significant differences were observed in four domains of quality of life, except for psychological domain that was improved in the lycopene group compared to the baseline values (P=0.049). Short term supplementation of lycopene had no effect on mood status and quality of life, except for psychological status in infertile men (Registration number: IRCT20171105037249N1).


The costs and outcomes of paediatric tuberculosis treatment at primary healthcare clinics in Johannesburg, South Africa.
Little up-to-date information is available about the costs of providing drug-susceptible tuberculosis (DS-TB) treatment to paediatric patients in South Africa (SA), nor have actual costs incurred at clinics been compared with costs expected from guidelines. To estimate actual and guideline treatment costs by means of a retrospective cohort analysis. We report patient characteristics, outcomes and treatment costs from a retrospective cohort of paediatric and adolescent (<18 years) DS-TB patients registered for treatment from 1 April 2011 to 31 March 2013 at three primary healthcare clinics in Johannesburg, SA. Actual treatment costs in 2015 SA rands and US dollars were estimated from the provider perspective using a standard bottom-up microcosting approach and compared with an estimate of guideline costs. We enrolled 88 DS-TB patients (median age 4 years (interquartile range 1.0 - 9.5), 44.3% female, 22.7% HIV co-infected, 92.0% pulmonary TB). Treatment success was high (89.8%; 13.6% cured, 76.1% completed treatment), and the mean (standard deviation (SD)) cost per patient with treatment success was ZAR1 820/USD143 (ZAR593/USD46), comprising fixed costs (44.0%), outpatient visits (30.7%), medication (19.3%) and laboratory investigations (6.0%). This was 17% more than the mean (SD) cost estimated by applying treatment guidelines (ZAR1 553/USD122 (ZAR1 620/USD127)), with differences due mainly to higher laboratory costs and more outpatient visits taking place than were recommended in national guidelines. These results are the first reported estimates of paediatric DS-TB treatment costs in SA and show the potential cost savings of closer adherence to national treatment guidelines. The findings were robust in sensitivity analyses and are lower than previous cost estimates in adults.


Numerical models for assessing the risk of leaflet thrombosis post-transcatheter aortic valve-in-valve implantation.
Leaflet thrombosis has been suggested as the reason for the reduced leaflet motion in cases of hypoattenuated leaflet thickening of bioprosthetic aortic valves. This work aimed to estimate the risk of leaflet thrombosis in two post-valve-in-valve (ViV) configurations, using five different numerical approaches. Realistic ViV configurations were calculated by modelling the deployments of the latest version of transcatheter aortic valve devices (Medtronic Evolut PRO, Edwards SAPIEN 3) in the surgical Sorin Mitroflow. Computational fluid dynamics simulations of blood flow followed the dry models. Lagrangian and Eulerian measures of near-wall stagnation were implemented by particle and concentration tracking, respectively, to estimate the thrombogenicity and to predict the risk locations. Most of the numerical approaches indicate a higher leaflet thrombosis risk in the Edwards SAPIEN 3 device because of its intra-annular implantation. The Eulerian approaches estimated high-risk locations in agreement with the wall sheer stress (WSS) separation points. On the other hand, the Lagrangian approaches predicted high-risk locations at the proximal regions of the leaflets matching the low WSS magnitude regions of both transcatheter aortic valve implantation models and reported clinical and experimental data. The proposed methods can help optimizing future designs of transcatheter aortic valves with minimal thrombotic risks.


Using individual-based bioenergetic models to predict the aggregate effects of disturbance on populations: A case study with beaked whales and Navy sonar.
Anthropogenic activities can lead to changes in animal behavior. Predicting population consequences of these behavioral changes requires integrating short-term individual responses into models that forecast population dynamics across multiple generations. This is especially challenging for long-lived animals, because of the different time scales involved. Beaked whales are a group of deep-diving odontocete whales that respond behaviorally when exposed to military mid-frequency active sonar (MFAS), but the effect of these nonlethal responses on beaked whale populations is unknown. Population consequences of aggregate exposure to MFAS was assessed for two beaked whale populations that are regularly present on U.S. Navy training ranges where MFAS is frequently used. Our approach integrates a wide range of data sources, including telemetry data, information on spatial variation in habitat quality, passive acoustic data on the temporal pattern of sonar use and its relationship to beaked whale foraging activity, into an individual-based model with a dynamic bioenergetic module that governs individual life history. The predicted effect of disturbance from MFAS on population abundance ranged between population extinction to a slight increase in population abundance. These effects were driven by the interaction between the temporal pattern of MFAS use, baseline movement patterns, the spatial distribution of prey, the nature of beaked whale behavioral response to MFAS and the top-down impact of whale foraging on prey abundance. Based on these findings, we provide recommendations for monitoring of marine mammal populations and highlight key uncertainties to help guide future directions for assessing population impacts of nonlethal disturbance for these and other long-lived animals.


Normal intelligibility functions for the Auditec CID W-22 test at 30% and 60% time-compression.
Time-compressed speech has been used to identify the site of central auditory disorders and auditory processing problems. Some authors suggest that the determination of audiometric normalcy should include satisfactory performance on a speech intelligibility test sensitive to central auditory dysfunction, such as time-compressed speech. Before scores from patients with auditory disorders can be meaningfully interpreted, however, it is necessary to establish normal performance on standardized recordings. Thus, this study was undertaken to generate speech intelligibility functions in a normal-hearing population using the Auditec CID W-22 recordings with 30% and 60% time-compression. The 30% condition revealed a slope of 3.24% per decibel and the function approached a plateau at 35 dB sensation level (SL). The 60% condition produced a function that increased gradually at 1.8% per decibel over the 20 to 80% intelligibility range. An intelligibility score of 82% was observed at 46 dB SL where the function approached an asymptote. These functions provide a standard against which subjects with central auditory dysfunctions can be compared. The relative difficulty that normal subjects had with the 60% time-compressed speech suggests that this condition may be too difficult for some subjects with central auditory disorders.


Prevalence and clinical significance of systolic impairment in hypertrophic cardiomyopathy.
To determine the frequency of systolic impairment (SI) and its impact on the natural history of hypertrophic cardiomyopathy (HCM). 1080 patients (mean (SD) age 43 (15) years, 660 men) with HCM were evaluated. Initial assessment included history, examination, 48 hour Holter monitoring, cardiopulmonary exercise testing, and echocardiography; SI was defined as a fractional shortening (FS) < or = 25%. Survival data were collected at clinic visits or by direct communication with patients and their general practitioners. The results of serial echocardiography in 462 patients with normal FS at presentation are also reported. 26 (2.4%) patients (49 (14) years, 18 men) had SI at the initial visit. During follow up (58 (49) months), nine (34.6%) died or underwent cardiac transplantation compared with 108 (10.2%) patients with normal FS (p = 0.01). Five year survival from death (any cause) or transplantation was 90.1% (95% confidence interval (CI) 87.8 to 92.4) in patients with normal systolic function versus 52.4% (95% CI 25.2 to 79.6, p < 0.0001) in patients with SI. In patients who underwent serial echocardiography, 22 (4.8%, aged 41 (15) years) developed SI over 66 (40) months; the annual incidence of SI was 0.87% (95% CI 0.54 to 1.31). On initial evaluation patients who developed SI had a higher frequency of syncope (67 (15.2%) v 10 (45.5%) of those who did not develop SI, p = 0.001), non-sustained ventricular tachycardia (91 (20.6%) v 11 (50%), p = 0.002), and an abnormal blood pressure response on exercise (131 (29.7%) v 15 (68.2%), p = 0.001). Patients with SI had greater wall thinning (p = 0.001), left ventricular cavity enlargement (p < 0.0005), and deterioration in New York Heart Association functional class (p = 0.001) during follow up. Thirteen (59.1%) patients who progressed to SI died or underwent transplantation compared with 38 (8.6%) patients who maintained normal systolic function. SI is an infrequent complication of HCM but, when present, is associated with a poor prognosis.


[Non adherence to cancer screening guidelines for cervical cancer among women who attended prenatal care].
To estimate the prevalence and identify the factors associated with delayed pap smear test of the cervix (carried out more than three years ago) among mothers with sons under two years of age, who attended the prenatal care. Cross-sectional, population-based household survey. Women with sons under two years old, living in the northern area of the city of Juiz de Fora (MG), Brazil, were interviewed. Stratification and clustering were used in a complex sampling procedure. We applied a survey questionnaire to capture women's demographic and socioeconomic characteristics of women and information about prenatal and practices for preventing cancer of the cervix. For statistical analysis of the possible bivariate association of factors, we used χ² test and a logistic regression model with the explanatory variables that had a significance less than or equal to 0.05 in the bivariate analysis. We found a delayed test prevalence of 26.6% (95%CI 21.3 - 32.6), including women who were never submitted to the exam. The variables associated with the non-adherence to the examination within the stipulated time were: to be married (OR 0.5; 95%CI 0.2 - 0.9), and divorced/widowed (OR 0.1; 95%CI 0.02 - 0,8), having performed gynecological examination in prenatal care (OR 0.3; 95%CI 0.1 - 0.6) and number of prenatal visits (OR 0.09; 95%CI 0.03 - 0.25 for more than 11 visits), being all protection factors. The prevalence of adherence to Pap smear guidelines is slightly lower than the percentage recommended by the World Health Organization. Apart from that, the fact that the woman was submitted to the prenatal care did not guarantee the adherence to Pap smear frequency guidelines.


Reconfiguring practice: the interdependence of experimental procedure and computing infrastructure in distributed earthquake engineering.
When transitioning local laboratory practices into distributed environments, the interdependent relationship between experimental procedure and the technologies used to execute experiments becomes highly visible and a focal point for system requirements. We present an analysis of ways in which this reciprocal relationship is reconfiguring laboratory practices in earthquake engineering as a new computing infrastructure is embedded within three laboratories in order to facilitate the execution of shared experiments across geographically distributed sites. The system has been developed as part of the UK Network for Earthquake Engineering Simulation e-Research project, which links together three earthquake engineering laboratories at the universities of Bristol, Cambridge and Oxford. We consider the ways in which researchers have successfully adapted their local laboratory practices through the modification of experimental procedure so that they may meet the challenges of coordinating distributed earthquake experiments.


The duration of antibiotic treatment is associated with carriage of toxigenic and non-toxigenic strains of Clostridioides difficile in dogs.
Clostridioides difficile is a leading cause of human antibiotic-associated diarrhoeal disease globally. Zoonotic reservoirs of infection are increasingly suspected to play a role in the emergence of this disease in the community and dogs are considered as one potential source. Here we use a canine case-control study at a referral veterinary hospital in Scotland to assess: i) the risk factors associated with carriage of C. difficile by dogs, ii) whether carriage of C. difficile is associated with clinical disease in dogs and iii) the similarity of strains isolated from dogs with local human clinical surveillance. The overall prevalence of C. difficile carriage in dogs was 18.7% (95% CI 14.8-23.2%, n = 61/327) of which 34% (n = 21/61) were toxigenic strains. We found risk factors related to prior antibiotic treatment were significantly associated with C. difficile carriage by dogs. However, the presence of toxigenic strains of C. difficile in a canine faecal sample was not associated with diarrhoeal disease in dogs. Active toxin was infrequently detected in canine faecal samples carrying toxigenic strains (2/11 samples). Both dogs in which active toxin was detected had no clinical evidence of gastrointestinal disease. Among the ten toxigenic ribotypes of C. difficile detected in dogs in this study, six of these (012, 014, 020, 026, 078, 106) were ribotypes commonly associated with human clinical disease in Scotland, while nontoxigenic isolates largely belonged to 010 and 039 ribotypes. Whilst C. difficile does not appear commonly associated with diarrhoeal disease in dogs, antibiotic treatment increases carriage of this bacteria including toxigenic strains commonly found in human clinical disease.


Cluster headache and the hypothalamus: causal relationship or epiphenomenon?
Typical clinical features of cluster headache (CH) include circadian/circannual rhythmicity and ipisilateral cranial autonomic features. This presentation has led to the assumption that the hypothalamus plays a pivotal role in this primary headache disorder. Several studies using neuroimaging techniques or measuring hormone levels supported the hypothesis of a hypothalamic involvement in the underlying pathophysiology of CH. Animal studies added further evidence to this hypothesis. Based on previous data, even invasive treatment methods, such as hypothalamic deep brain stimulation, are used for therapy. However, the principal question of whether these alterations are pathognomonic for CH or whether they might be detected in trigeminal pain disorders in general, in terms of an epiphenomenon, is still unsolved. This article summarizes studies on hypothalamic involvement in CH pathophysiology, demonstrates the involvement of the hypothalamus in other diseases and tries to illuminate the role of the hypothalamus based on this synopsis.


Tunneling current modulation in atomically precise graphene nanoribbon heterojunctions.
Lateral heterojunctions of atomically precise graphene nanoribbons (GNRs) hold promise for applications in nanotechnology, yet their charge transport and most of the spectroscopic properties have not been investigated. Here, we synthesize a monolayer of multiple aligned heterojunctions consisting of quasi-metallic and wide-bandgap GNRs, and report characterization by scanning tunneling microscopy, angle-resolved photoemission, Raman spectroscopy, and charge transport. Comprehensive transport measurements as a function of bias and gate voltages, channel length, and temperature reveal that charge transport is dictated by tunneling through the potential barriers formed by wide-bandgap GNR segments. The current-voltage characteristics are in agreement with calculations of tunneling conductance through asymmetric barriers. We fabricate a GNR heterojunctions based sensor and demonstrate greatly improved sensitivity to adsorbates compared to graphene based sensors. This is achieved via modulation of the GNR heterojunction tunneling barriers by adsorbates.


Reversible diffusion-weighted imaging lesions in acute ischemic stroke: A systematic review.
To systematically review the literature for reversible diffusion-weighted imaging (DWIR) lesions and to describe its prevalence, predictors, and clinical significance. Studies were included if the first DWI MRI was performed within 24 hours of stroke onset and follow-up DWI or fluid-attenuated inversion recovery (FLAIR)/T2 was performed within 7 or 90 days, respectively, to measure DWIR. We abstracted clinical, imaging, and outcomes data. Twenty-three studies met the study criteria. The prevalence of DWIR was 26.5% in DWI-based studies and 6% in FLAIR/T2-based studies. DWIR was associated with recanalization or reperfusion of the ischemic tissue with or without the use of tissue plasminogen activator (t-PA) or endovascular therapy, earlier treatment with t-PA, shorter time to endovascular therapy after MRI, and absent or less severe perfusion deficit within the DWI lesion. DWIR was associated with early neurologic improvement in 5 of 6 studies (defined as improvement in the NIH Stroke Scale (NIHSS) score by 4 or 8 points from baseline or NIHSS score 0 to 2 at 24 hours after treatment or at discharge or median NIHSS score at 7 days) and long-term outcome in 6 of 7 studies (defined as NIHSS score ≤1, improvement in the NIHSS score ≥8 points, or modified Rankin Scale score up to ≤2 at 30 or 90 days) likely due to reperfusion. DWIR is seen in up to a quarter of patients with acute ischemic stroke, and it is associated with good clinical outcome following reperfusion. Our findings highlight the pitfalls of DWI to define ischemic core in the early hours of stroke.


Oral anticoagulant use in octogenarian European patients with atrial fibrillation: A subanalysis of PREFER in AF.
Few studies describe oral anticoagulant (OAC) prescription practices in very elderly patients with atrial fibrillation (AF). In this sub-analysis of the PREFER in AF study, performed in 2012, patients were stratified according to age (<80 [n=5565] and ≥80years [n=1660]) and OAC treatment. Factors associated with OAC prescription were analyzed in a multivariate logistic regression model with backward elimination of variables least associated with OAC use. Patients ≥80years presented with permanent AF more often (p<0.0001) and reported fatigue and dyspnea more frequently (p<0.0001) and palpitations less frequently (p<0.0001) than patients <80years. Hypertension, stroke, heart failure, coronary heart disease, peripheral arterial disease, cancer, chronic kidney disease, and prior major bleeding were significantly more frequent in ≥80years. Most patients were treated with OACs in both age groups. The overall use of vitamin K antagonists was similar in both groups (78.2% vs.78.2% p=0.98), while the use of non-vitamin K antagonist OACs was lower in the ≥80years old group than in the <80years group (4.5% vs. 6.6% p=0.001). Among patients ≥80years, prior stroke and heart failure were significantly associated with OAC use, whereas higher age, prior bleeding, paroxysmal AF, chronic hepatic disease, and difficulties with self-care were associated with no OAC use. The current use of OAC in European AF patients was satisfactorily high in octogenarians, suggesting reasonable implementation of current guidelines. Interestingly, patients with poor quality of life were less often anticoagulated. This may warrant further studies.


Out of Sight, out of Mind? An Audit Which Proposes a Follow-Up and Management Pathway for Inferior Vena Cava Filters.
Insertion of an IVC filter can be a safe and effective way to avoid PE in thrombosis patients who cannot be anticoagulated. If temporary filters are not promptly removed they can become difficult to remove, causing avoidable complications and often requiring lifelong warfarin. In this study, two sequential audits of retrieval of temporary IVC filters were conducted before and after the implementation of a coordinated management strategy for IVC filter follow-up. 33 filter placements were examined over a 15-month period (Group A). Following implementation of the strategy a comparable 15-month period in which 33 IVC filters were placed was audited (Group B). Following implementation, failed retrievals dropped from 15% to 9%. The number successfully retrieved did not change at 45%. The number made permanent from the outset following expert discussion increased from 12% to 39%. The number of filters with no attempted retrieval and no consultation about retrieval decreased from 27% to 9% (these patients were lost to follow-up with multiple contact attempts made). In Group B 100% of placed IVC filters were followed up appropriately. The proposed model is an easily implemented plan to avoid patient morbidity caused by temporary IVC filters made unintentionally permanent by loss to follow-up.


Harry and Louise go to Washington: political advertising and health care reform.
Political advertising by interest groups trying to influence public policy has proliferated recently. Formerly the preserve of election campaigns, advertising has spread to policy arenas, such as abortion, trade, and health care. This article examines group lobbying for and against President Clinton's health care reform plan. Using a study of advertisements, a content analysis of news coverage, interviews with half a dozen leading figures in the debate during the spring of 1995, and an analysis of three national public opinion surveys designed to gauge the public response to health care ads, we investigate the media campaign on health care. Ads directed against the Clinton plan played a crucial role in the public's attaching negative connotations to some of its key elements. Grassroots campaigns can work either by mobilizing public opinion or by persuading political leaders that grassroots opposition exists to a particular program.


Transposon mutagenesis identifies genetic drivers of Braf(V600E) melanoma.
Although nearly half of human melanomas harbor oncogenic BRAF(V600E) mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in Braf(V600E) mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAF(V600E) melanoma and discover new genes with potential clinical importance in human melanoma.