The aetiology and burden of myeloproliferative neoplasms in the United Kingdom: the MyelOproliferative neoplasmS: an In-depth case-control (MOSAICC) study protocol.
Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that affect approximately 8 people in every 100,000 individuals in the UK. Little is known about the aetiology of MPNs, as previous studies have been hampered by small sample sizes, thus it is important to understand the cause of MPNs in a larger study to identify prevention strategies and improve treatment strategies. This study aims to determine environmental, lifestyle, genetic and medical causes of MPNs and to assess the relevance of occupational carcinogen exposures and quality of life impacts. A UK-wide case-control study of 610 recently diagnosed MPN patients (within 24 months) receiving clinical care at 21 NHS study sites in Scotland, England, Wales and Northern Ireland and 610 non-blood relative/friend controls is underway. Data on occupational and residential history, medical and environmental factors, and quality of life are being collected from the participants via a structured interview and self-complete questionnaires. Clinical data is being provided by the clinical team. Blood, saliva and toenail samples are also being collected for genetic and elemental analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (95%CI) will be calculated using a p < 0.05 to investigate potential risk factors for the MPN clinical and genetic subtypes, and further analyses will be conducted based on the type of data and outcome of interest at a later stage. The study design is most effective for investigating the aetiology of rare diseases. The study will enable identification of potential causes of MPNs through in-depth assessment of potential risk factors with potential for longer follow-up of a number of outcomes.


The influence of folate antagonists on the metabolism of folic acid and its reduced derivatives in rat liver and kidney.
Uptake and conversion of [3H]folic acid to polyglutamate derivatives by rat liver and kidney were inhibited by methotrexate or aminopterin (15 mg/kg body weight) and DL-tetrahydromethotrexate (30 mg/kg body weight). In contrast, these antagonists did not influence the conversion of L-5-formyl-[3H]tetrahydrofolic acid or L-5-methyl[3H]tetrahydrofolic acid to polyglutamine derivatives and had little effect on the uptake of reduced folate derivatives. When [3H]methotrexate, [3H]aminopterin, and DL-[3H]tetrahydromethotrexate were administered in small amounts (15 mug/kg body wieght), no metabolites of these compounds were observed. However, at higher doses of [3H]methotrexate (300 mug/kg body weight), more than 30% of the radioactivity remaining in the tissue 24 hr after administration could be attributed to a metabolite of methotrexate. This metabolite was tentatively identified as methotrexate diglutamate.


Antibacterial susceptibility of uropathogens in 3 hospitals, Sari, Islamic Republic of Iran, 2002-2003.
To determine the frequency and pattern of antibiotic susceptibility of uropathogens in urinary tract infection (UTI) from 3 university hospitals we carried out a retrospective review of urine culture and antibiotic sensitivity testing from symptomatic outpatients and inpatients during 2002-2003. Of 5600 samples, 703 (12.6%) were culture positive, 38.7% of which were from hospitalized patients. Escherichia coli was the leading cause of UTI in both groups of patients. The rates and roles of other pathogens, including Pseudomonas spp. (5.3%-10.4%), Enterobacter spp. (0%-5.7%), Staphylococcus spp.) 5.4%-26.4%), differed in each hospital. Differences in antibacterial susceptibility patterns were observed. Ampicillin (82%-100%) and co-trimoxazole (50%-90%) resistance were the most frequent. Methicillin resistance in Staphylococcus spp. ranged from 17% to 60%.


H. pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer.
Peptic ulcer is the main cause for upper gastrointestinal haemorrhage, and Helicobacter pylori infection is the main etiologic factor for peptic ulcer disease. Maintenance antisecretory therapy has been the standard long-term treatment for patients with bleeding ulcers to prevent recurrent bleeding. On the other hand, the precise efficacy of H. pylori eradication for the prevention of rebleeding from peptic ulcer is unknown. To compare the efficacy of H. pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. We searched the Cochrane Controlled Trials Register (the Cochrane Library issue 1, 2003), MEDLINE (January 1966 to March 2003), EMBASE (January 1988 to March 2003), CINAHL (January 1982 to March 2003), and reference lists of articles. We also conducted a manual search from several congresses. Controlled clinical trials comparing the efficacy of H. pylori eradication therapy vs. antisecretory non-eradication therapy (with or without long-term maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Extraction and quality assessment of studies were done by two reviewers. Study authors were contacted for additional information. Six studies with a total of 355 patients were included in the first meta-analysis: mean percentage of rebleeding in H. pylori eradication therapy group was 4.5%, and in the non-eradication therapy group without subsequent long-term maintenance antisecretory therapy it was 23.7% (OR 0.18, 95% CI 0.09 to 0.37; there was no statistical evidence of heterogeneity; NNT was 5, 95% CI 4 to 8). Three studies with a total of 470 patients were included in the second meta-analysis: mean percentage of rebleeding in H. pylori eradication therapy group was 1.6%, and in non-eradication therapy group with long-term maintenance antisecretory therapy it was 5.6% (OR 0.25, 95% CI 0.08 to 0.76; heterogeneity was not demonstrated; NNT was 20, 95% CI 12 to 100). Subanalysis. Excluding patients taking non-steroidal anti-inflammatory drugs (NSAIDs) at the time of recurrent bleeding resulted in a rebleeding rate of 4% (first meta-analysis) or 0.78% (second meta-analysis) in the group receiving H. pylori eradication therapy. When only patients with H. pylori eradication success were included, rebleeding rate was 1% in H. pylori eradication therapy group, and NNT decreased from 5 to 4. In some cases, recurrence of H. pylori infection seemed to be responsible for recurrence of bleeding. Treatment of H. pylori infection is more effective than antisecretory non-eradicating therapy (with or without long-term maintenance antisecretory therapy) in preventing recurrent bleeding from peptic ulcer. Consequently, all patients with peptic ulcer bleeding should be tested for H. pylori infection, and eradication therapy should be prescribed to H. pylori-positive patients.


Preliminary Development and Evaluation of an Algorithm to Identify Breast Cancer Chemotherapy Toxicities Using Electronic Medical Records and Administrative Data.
Breast cancer chemotherapy toxicity is not well documented outside of randomized trials. We developed and conducted preliminary evaluation of an algorithm to detect grade 3 and 4 toxicities using electronic data from a large integrated managed care organization. The algorithm used administrative, pharmacy, and electronic data from outpatient, emergency room, and inpatient records of 99 women diagnosed with breast cancer from 2006 to 2009 who underwent chemotherapy. Data were abstracted for 12 months post-treatment initiation (24 months for trastuzumab recipients). An oncology nurse independently blindly reviewed records; these results were the "gold standard." Sensitivity and specificity were calculated for overall toxicity, categories of toxicities, and toxicity by age or regimen. The algorithm was applied to an independent sample of 1,575 patients with breast cancer diagnosed during the study period to estimate prevalence rates. The overall sensitivity for detecting chemotherapy-related toxicity was 89% (95% CI, 77% to 95%). The highest sensitivity was for identification of hematologic toxicities (97%; 95% CI, 84% to 99%). There were good sensitivities for infectious toxicity, but rates dropped for GI and neurological toxicities. Specificity was high within each category (89% to 99%), but when combined to measure any toxicity, it was lower (70%; 95% CI, 57% to 81%). When applied to an independent chemotherapy sample, the algorithm estimates a 26% rate of hematologic toxicity; rates were higher among patients age ≥ 65 years versus less than 65 years. If validated in other samples and health care settings, algorithms to capture toxicity could be useful in comparative and cost-effectiveness evaluations of community practice-delivered treatment.


Cryptococcus pinus sp. nov., an anamorphic basidiomycetous yeast isolated from pine litter.
A novel species of the genus Cryptococcus, isolated from dead needles of Pinus sylvestris, was identified using mycocinotyping and rDNA sequence data. Phylogenetic analysis showed that the novel species was located in the Kwoniella clade of the Tremellales and was closely related to Cryptococcus dejecticola. The type strain of the novel species, Cryptococcus pinus sp. nov., is VKM Y-2958T (=CBS 10737T).


The impact of team-based learning on a foundational pharmacokinetics course.
To assess the impact of team-based learning (TBL) in a foundational pharmacokinetics course. The course was arranged into 5 modules based on the TBL format. Each module contained preclass preparation; readiness-assurance process; and in-class, clinical cases. Survey instruments on professionalism and attitudes of team learning were administered pre- and post-course. Examination grades focused at the evaluation/creation level were significantly higher in the TBL format compared with the previous year. Professionalism scores increased over the course of the semester, particularly in altruism and honesty. Other measures of team-learning attitudes significantly increased over time, although there was no change in major subscales. End-of-semester course evaluations showed improvements in active engagement and in various areas of skill development. The TBL format can be used successfully in a foundational pharmacokinetics course to increase higher levels of learning, team-learning skills, and professionalism in pharmacy students.


An Improved Phenotyping Protocol for Panama Disease in Banana.
Fusarium oxysporum (Fo) belongs to a group of soil-borne hyphomycetes that are taxonomically collated in the Fusarium oxysporum Species Complex (FOSC). Hitherto, those infecting bananas were placed in the forma specialis cubense (Foc). Recently, however, these genetically different Foc lineages were recognized as new Fusarium spp. placed in the Fusarium of Banana Complex (FOBC). A member of this complex F. odoratissimum II-5 that uniquely comprises the so-called Tropical Race 4 (TR4), is a major problem sweeping through production zones of Cavendish banana in several regions of the world. Because of this, there is an urgent need for a phenotyping method that allows the screening for resistance to TR4 of large numbers of banana genotypes. Most Fusarium species produce three types of spores: macroconidia, microconidia and the persistent chlamydospores that can contaminate soils for many years. Inoculum production has been an important bottleneck for efficient phenotyping due to the low or variable number of conidia and the elaborate laboratory procedures requiring specific infrastructure. Here, we report a rapid, simple and high-yielding spore production method for nine F. oxysporum formae speciales as well as the biocontrol species Fo47 and Fo618-12. For Fusarium spp. causing Fusarium wilt or Panama disease of banana, we used the protocol for four species comprising the recognized physiological races, including Tropical Race 4 (TR4). We subsequently tested the produced inoculum in comparative inoculation trials on banana plants to evaluate their efficiency. All assays resulted in typical symptoms within 10 weeks; significant differences in final disease ratings were observed, depending on inoculum concentration. Pouring inoculum directly onto banana plants showed the most consistent and reproducible results, as expressed in external wilting, internal discoloration and determined by real-time PCR assays on entire rhizomes. Moreover, this method allows the inoculation of 250 plants per hour by one individual thereby facilitating the phenotyping of large mutant and breeding populations.


The NADH oxidase system (external) of muscle mitochondria and its role in the oxidation of cytoplasmic NADH.
An exo-NADH oxidase system [NADH oxidase system (external)], effecting intact-mitochondrial oxidation of added NADH, was studied in pigeon heart mitochondria. Breast muscle mitochondria showed an equal specific activity of the system. The exo-NADH oxidase activity (200 micron mol of NADH/min per g of protein) equalled two-thirds of the State-3 respiratory activity with malate + pyruvate or one-seventh of the total NADH oxidase activity of heart mitochondria. The activity was not caused by use of proteinase in the preparation procedure and all measured parameters were very reproducible from preparation to preparation. The activity is therefore most likely not due to preparation artefacts. The exo-NADH oxidase system is present in all mitochondria in the preparation and is not confined to a subpopulation. The system reduced all cytochrome anaerobically and direct interaction with all cytochrome oxidase was demonstrated by interdependent cyanide inhibition. The exo-NADH oxidase system seems to be located at the outer surface of the mitochondrial inner membrane because, for instance, only this system was rapidly inhibited by rotenone, and ferricyanide could act as acceptor in the rotenone-inhibited system (reductase activity = 20 times oxidase activity). In the presence of antimycin, added NADH reduced only a part of the b-cytochromes. Freezing and thawing the mitochondria, one of the methods used for making them permeable to NADH, destroyed this functional compartmentation. The characteristics of the exo-NADH oxidase system and the malate-aspartate shuttle are compared and the evidence for the shuttle's function in heart in vivo is re-evaluated. It is proposed that oxidation of cytoplasmic NADH in red muscles primarily is effected by the exo-NADH oxidase system.


Improving health service management education: the manager speaks.
This paper uses health service manager judgements to discuss educational approaches and environments suitable to the development of required competencies and reports barriers to and opportunities for competency development. Practising managers were found to recognise and value the educational contributions made by academic programs, health service organisations and professional associations to the development of professional competence. Academic programs are seen as the appropriate vehicle for developing conceptual, analytical, problem solving and communication competencies that require considerable maturation time. Health service organisations are seen to have a key role in promoting professional competence through maintaining a culture conductive to encouraging managers to undertake further education, supported by appropriate system strategies. Professional associations are regarded as appropriate sponsors for promoting knowledge and skill update in relation to current issues in management through short courses, conferences and timely educational meetings. Wherever possible, collaboration between professional and educational organisations was seen to be desirable.


Graphene-Based Electrochemical Sensing Platform for Rapid and Selective Ferulic Acid Quantification.
Due to the multitude of physiological functions, ferulic acid (FA) has a wide range of applications in the food, cosmetic, and pharmaceutical industries. Thus, the development of rapid, sensitive, and selective detection tools for its assay is of great interest. This study reports a new electroanalytical approach for the quantification of ferulic acid in commercial pharmaceutical samples using a sulphur-doped graphene-based electrochemical sensing platform. The few-layer graphene material (exf-SGR) was prepared by the electrochemical oxidation of graphite, at a low applied bias (5 V), in an inorganic salt mixture of Na2S2O3/(NH4)2SO4 (0.3 M each). According to the morpho-structural characterization of the material, it appears to have a high heteroatom doping degree, as proved by the presence of sulphur lines in the XRD pattern, and the C/S ratio was determined by XPS investigations to be 11.57. The electrochemical performances of a glassy carbon electrode modified with the exf-SGR toward FA detection were tested by cyclic voltammetry in both standard laboratory solutions and real sample analysis. The developed modified electrode showed a low limit of detection (30.3 nM) and excellent stability and reproducibility, proving its potential applicability as a viable solution in FA qualitative and quantitative analysis.


[Research on the protective effect of hearing protective device for workers exposed to noise in a motor manufacturing enterprise].
Objective: To understand the current situation of noise hazard in a motor manufacturing enterprise, and to explore the protective effect of workers wearing hearing protective device and its possible influencing factors. Methods: In November 2021, a total of 179 noise workers wearing hearing protective devices in a motor manufacturing company in a city were selected as research objects. Personal attenuation rating (PAR) of workers wearing hearing protective devices was measured. Baseline PAR was analyzed for different subgroups of basic demographic information, noise exposure, and the use of hearing protective devices to evaluate the effect of the intervention. Baseline PAR was compared using nonparametric tests. Results: There were 179 workers from 35 positions in 4 types of work, and the over-standard noise rate was 51.2% (42/82), among which the noise exposure intensity of motor equipment debugging workers was the highest [94.4 dB (A) ]. Compared the baseline PAR of different characteristics, it was found that the baseline PAR of male workers, workers whose daily noise exposure time were <8 h, workers who had used the hearing protective devices for 10 to 14 years, and workers who thought the hearing protective devices were comfortable were all higher, and the differences were statistically significant (P<0.05). Baseline PAR passing rate was 43.0% (77/179), and PAR of 102 workers who did not pass baseline test increased from 0 (0, 3) dB before intervention to 14 (12, 16) dB after intervention, with statistical significance (P<0.05) . Conclusion: The noise hazard in this motor manufacturing enterprise is serious, and the protective effect of workers wearing hearing protective devices is not good. Gender, daily noise exposure time, years and comfort of wearing hearing protective device are the possible influencing factors of poor protective effect.


[An app for informal care : User experiences and obstacles from the perspective of family caregivers].
A target group for digital services are people who are involved in informal care arrangements. Family caregivers often undertake the organization and coordination of care, which is associated with a high need for information. The study examined the extent to which family caregivers perceive the use of a mobile digital application as facilitating day to day care, in particular regarding information needs. A market-ready mobile smartphone app was used by 16 informal caregivers over several months. Qualitative interviews were conducted to investigate which app features are being used in real informal care situations and which are perceived as added value. The analysis was carried out with content analysis according to Kuckartz. The app was sporadically used and satisfaction with the information it provides depends on the care situation itself. The participants see added value and facilitation through the app mainly at the beginning of a care situation. They expressed the wish for requirements that have not yet been integrated, e.g., regional information or individual adaptations. For digital support options to develop the desired potential, those involved in informal care must be aware of them at an early stage. Further prerequisites for care apps to be perceived as added value by the target group are a trustworthy presentation of the contents, the customizability and that they are up to date.


Chloride extraction for quality improvement of municipal solid waste incinerator ash for the concrete industry.
Coal ash from power stations has long been used successfully in the cement industry as binders in several Portland formulations. This is not the case for municipal solid waste (MSW) ash as chloride concentrations, ranging from 10 to 200 g kg(-1) dry weight in the bottom and fly ash, respectively, exceed the maximum allowable concentration in most cement mixtures. To reduce chloride content in MSW bottom ash, a laboratory investigation was carried out based on the exhaustive washing in tap water. The influence of operative parameters such as temperature, granulometric properties and solid/liquid ratio of extraction was evaluated. In addition to optimization of the mentioned operative parameters for full-scale application, the paper gives preliminary indications on mechanistic aspects of the washing operation.


IL-2 binding activates a tyrosine-phosphorylated phosphatidylinositol-3-kinase.
IL-2 was shown to induce phosphatidylinositol-3-kinase activity in the CTLL-2 murine lymphocyte line. Tyrosine phosphorylation of phosphatidylinositol-3-kinase was demonstrated by immunoabsorption with antiphosphotyrosine antibody and was coincident with activation of an IL-2R-associated tyrosine kinase. Half-maximal activation of this enzyme, and of cell proliferation, occurred at 30 pM IL-2. Incubation of cells with genistein, a selective tyrosine kinase inhibitor, blocked IL-2-dependent activation of receptor-associated tyrosine kinase and phosphatidylinositol-3-kinase activities, suggesting that tyrosine phosphorylation-dependent activation of phosphatidylinositol-3-kinase is a component of the IL-2R signal transduction process.


Pyramidal neuron number in layer 3 of primary auditory cortex of subjects with schizophrenia.
Individuals with schizophrenia demonstrate impairments of sensory processing within primary auditory cortex. We have previously identified lower densities of dendritic spines and axon boutons, and smaller mean pyramidal neuron somal volume, in layer 3 of the primary auditory cortex in subjects with schizophrenia, all of which might reflect fewer layer 3 pyramidal neurons in schizophrenia. To examine this hypothesis, we developed a robust stereological method based upon unbiased principles for estimation of total volume and pyramidal neuron numbers for each layer of a cortical area. Our method generates both a systematic, uniformly random set of mapping sections as well as a set of randomly rotated sections cut orthogonal to the pial surface, within the region of interest. We applied our approach in twelve subjects with schizophrenia, each matched to a normal comparison subject. Primary auditory cortex volume was assessed using Cavalieri's method. The relative and absolute volume of each cortical layer and, within layer 3, the number and density of pyramidal neurons were estimated using our novel approach. Subject groups did not differ in regional volume, layer volumes, or pyramidal neuron number, although pyramidal neuron density was significantly greater in subjects with schizophrenia. These findings suggest that previously observed lower densities of dendritic spines and axon boutons reflect fewer numbers per neuron, and contribute to greater neuronal density via a reduced neuropil. Our approach represents a powerful new method for stereologic estimation of features of interest within individual layers of cerebral cortex, with applications beyond the current study.


A Cohort Study of Risk Factors That Influence Empirical Treatment of Patients with Acute Pyelonephritis.
The aim of the current study was to compare community-acquired acute pyelonephritis (CA-APN) with health care-associated acute pyelonephritis (HCA-APN), describe the outcomes, and identify variables that could predict antimicrobial susceptibility. We conducted an observational study that included all consecutive episodes of acute pyelonephritis (APN) in adults during 2014 at a Spanish university hospital. From each episode, demographic data, comorbidities, clinical presentation, microbiological data, antimicrobial therapy, and outcome were recorded. A multivariable logistic regression model was performed to define the variables associated with antimicrobial resistance. A total of 607 patients, 503 (82.9%) with CA-APN and 104 (17.1%) with HCA-APN, were included in the study. Patients with HCA-APN were older than patients with CA-APN (70.4 versus 50.6 years; P < 0.001) and had higher rates of previous urinary tract infections (UTIs) (56.5% versus 24.5%; P < 0.001) and previous antibiotic use (56.8% versus 22.8%; P < 0.001). Escherichia coli was more frequently isolated from patients with CA-APN than from patients with HCA-APN (79.9% versus 50.5%; P < 0.001). The rates of resistance of Escherichia coli strains from CA-APN patients versus HCA-APN patients were as follows: amoxicillin-clavulanic acid, 22.4% versus 53.2% (P = 0.001); cefuroxime, 7.7% versus 43.5% (P = 0.001); cefotaxime, 4.3% versus 32.6% (P < 0.001); ciprofloxacin, 22.8% versus 74.5% (P < 0.001); and co-trimoxazole, 34.5% versus 58.7% (P = 0.003). The site of acquisition, recurrent UTIs, and previous antibiotic use were independent risk factors for antimicrobial resistance. Relapse rates were significantly higher when definitive antimicrobial treatment was not adequate (37.1% versus 9.3% when definitive antimicrobial treatment was adequate; P < 0.001). Our study reflects the rise of resistance to commonly used antibiotics in acute pyelonephritis. In order to choose the adequate empirical antibiotic therapy, risk factors for resistance should be considered.


Mechanistic implications of the induction of thermotolerance in Chinese hamster cells by organic solvents.
Several organic solvents were shown to induce thermotolerance. These included: aliphatic alcohols (ethanol to octanol); local anesthetics; dimethyl sulfoxide; and dimethyl formamide. The minimum concentrations of the various alcohols required to induce tolerance were similar to the threshold doses for cytotoxicity. When only intramembrane concentrations were considered (by multiplying by the appropriate membrane:buffer partition coefficient), then the alcohols' threshold dose to induce tolerance was only mildly a function of carbon number. The efficiency increased almost linearly with a membrane dose from propanol to pentanol, but was slightly reduced for octanol. All alcohols induced tolerance rapidly (within a few hours after 30-min exposure), but the thermotolerance ratio decreased with increasing carbon number. Of the three anesthetics examined, lidocaine was a highly efficient inducer, procaine less so, and tetracaine did not induce tolerance even at a concentration mildly cytotoxic. Dimethyl sulfoxide and dimethyl formamide induced tolerance without cytotoxicity, but the kinetics of doing so was different from that seen with the other solvents. Only cells exposed to these water-soluble agents for 18 h or longer showed evidence of induced heat resistance. Our results indicate that membranes likely are the site for the initiation of solvent-induced cell killing and thermotolerance. The minimum dose of induction may be related to the degree of disorder induced by the individual alcohol, but the amount of tolerance induced is inversely related to this. The data on the effects of local anesthetics show that neither their common functional mode of inhibiting nerve transmission nor their similar level of cytotoxicity insures similar efficiency as tolerance inducers. Results with dimethyl sulfoxide and dimethyl formamide suggest that tolerance can be induced by more than one mechanism, or alternately, that a multiple-step mechanism can be activated at different points along this pathway. We also measured heat shock protein synthesis after several treatments; efficient inducers of thermotolerance also induced these proteins.


Reduced antigen production by hepatitis B virus harbouring nucleotide deletions in the overlapping X gene and precore-core promoter.
Hepatitis B virus (HBV) genomes with deletions in the precore-core (preC-C) promoter have been detected in HBV infections without serological markers. To address whether the mutations are responsible for the reduced production of virus antigenes, either an 8 bp (8d, position 1763 to 1770) or a 20 bp (20d, 1753 to 1772) deletion was created in a wild-type (wt) HBV clone. Both mutations cause premature termination of the overlapping X ORF. When introduced into HepG2 cells, both mutants produced reduced amounts of HBsAg, HBcAg and HBeAg, but released the same or more virion-associated DNA compared with the wt. A co-transfection of the 20d mutant with a small amount of intact X gene resulted in a 3-fold increase of HBcAg production compared to transfection with either the 20d or wt alone. When the promoter region was cloned into CAT plasmids, the 8d preC promoter showed weak activity and its initiation site was shifted 6 to 10 bp downstream. The preC promoter activity of 20d was not detectable by CAT ELISA and 5' RACE. The levels of C transcripts of both mutants were higher than that of the wt, and their start sites were not altered. Therefore, the deletions cause the reduction of HBsAg, HBcAg and HBeAg although the mutant viruses can still replicate in cultured cells. The reduction of HBeAg is due to both the reduced preC promoter activity and the defect in HBx. The reduction of HBcAg is due to the disrupted X gene, despite augmented C promoter activity.


The effect of the player's vocal tract on woodwind instrument tone.
Many players of woodwind instruments believe that the tone of the instrument is influenced by the player's vocal tract. If this is so, it would be expected that the vibrating reed in the player's mouth would generate an appreciable sound pressure in his vocal tract. However, measurements of the vocal tract impedance (looking into the mouth) give values an order of magnitude less than the impedances of the clarinet air column resonances. The sound pressure built up in the vocal tract would thus be expected to be much smaller than that in the clarinet. A clarinetlike system was arranged to sound by drawing air through it from the normally open end, the reed being out in the open for easy accessibility. When the mouth was placed around the mouthpiece with the system sounding, the changes in the waveform and harmonic structure of the tone were minimal. When a system with a more sharply tuned resonance was substituted for the vocal tract, the waveform changes were observable but not large. It appears that the player's vocal tract has a negligible influence on the instrument tone.


Visually assessed body condition shows high heritability in a pedigreed great ape population.
Body condition, a measure for relative fat mass, is associated with primate health, fitness, and overall welfare. Body condition is often influenced by dietary factors, age, and/or sex, but several body condition measures (body weight, weight-to-height ratios, and so on) also show high heritability across primate species, indicating a role of genetic effects. Although different measures for body condition exist, many require direct handling of animals, which is invasive, time-consuming, and expensive, making them impractical in wild and captive settings. Therefore, noninvasive visual body condition score (BCS) systems were developed for various animal species, including macaques and chimpanzees, to visually assess relative fat mass. Here we evaluate the utility of a visual BCS system in bonobos by assessing (1) inter-rater reliability, (2) links with body mass, a traditional hands-on measure of condition, and (3) the factors driving individual variation in BCS. We adapted the chimpanzee BCS system to rate 76 bonobos in 11 European zoos (92% of the adult population). Inter-rater reliability was high (s* = 0.948), BCSs were positively associated with body mass (β = 0.075) and not predicted by diet, sex, or age, nor were they associated with a higher abundance of obesity-related diseases. Instead, BCSs showed high levels of heritability (h2 = 0.637), indicating that a majority of body condition variation in bonobos is attributable to genetic similarity of the individuals. This is in line with reported h2 -values for traditional body condition measures in primates and provides support for the reliability of visual BCS systems in great apes. The results of this study emphasize an often unanticipated role of genetics in determining primate body fat and health that has implications for the management of captive primates. Application of this tool in wild populations would aid to unravel environmental from genetic drivers of body condition variation in primates.


Two-phase endolymphatic hydrops: a new dynamic guinea pig model.
The classical guinea pig model for Meniere's disease, in which endolymphatic hydrops was achieved by destruction of the endolymphatic sac and obliteration of the endolymphatic duct, is a non-physiological profound model with shortcomings in relation to Meniere's disease as seen in patients. We developed a more subtle animal model; the two-phase endolymphatic hydrops. This model is based on a combination of chronic endolymphatic sac dysfunction, induced by slight destruction of the most distal part of the endolymphatic sac, and acute stress-induced endolymph production by stimulation of the Na/K-ATPase in the stria vascularis with aldosterone. Light microscopy of the fluid compartments of four groups of cochleas was used to examine them for the presence of endolymphatic hydrops: i) Normal (control) cochleas showed no hydrops; ii) some of the non-operated (no destruction) aldosterone-treated cochleas showed small degrees of hydrops mainly present in the basal turns; iii) mild dissection of the endolymphatic sac without administration of aldosterone produced a hydrops which was mainly present in the cochlear apex; iv) combination of chronic endolymphatic sac dysfunction and acute attacks of endolymph production by aldosterone administration revealed the most severe degrees of hydrops in all cochlear windings, damage to cochlear structures, and cellular disturbances of the epithelial lining of the endolymphatic sac. This new model may represent a more physiologic and dynamic approach to Meniere's disease and may explain the etiology of many symptoms in patients such as the fluctuant nature and the types of sensoneuronal hearing losses.


Xenopus Enhancer of Zeste (XEZ); an anteriorly restricted polycomb gene with a role in neural patterning.
We have identified the Xenopus homologue of Drosophila Enhancer of Zeste using a differential display strategy designed to identify genes involved in early anterior neural differentiation. XEZ codes for a protein of 748 amino acids that is very highly conserved in evolution and is 96% identical to both human and mouse EZ(H)2. In common with most other Xenopus Pc-G genes and unlike mammalian Pc-G genes, XEZ is anteriorly restricted. Zygotic expression of XEZ commences during gastrulation, much earlier than other anteriorly localized Pc-G genes; expression is restricted to the anterior neural plate and is confined later to the forebrain, eyes and branchial arches. XEZ is induced in animal caps overexpressing noggin; up-regulation of XEZ therefore represents a response to inhibition of BMP signalling in ectodermal cells. We show that the midbrain/hindbrain junction marker En-2,and hindbrain marker Krox-20, are target genes of XEZ and that XEZ functions to repress these anteroposterior marker genes. Conversely, XEZ does not repress the forebrain marker Otx-2. XEZ overexpression results in a greatly thickened floor of the forebrain. These results implicate an important role for XEZ in the patterning of the nervous system.


Antifungal resistance and new strategies to control fungal infections.
Despite improvement of antifungal therapies over the last 30 years, the phenomenon of antifungal resistance is still of major concern in clinical practice. In the last 10 years the molecular mechanisms underlying this phenomenon were extensively unraveled. In this paper, after a brief overview of currently available antifungals, molecular mechanisms of antifungal resistance will be detailed. It appears that major mechanisms of resistance are essential due to the deregulation of antifungal resistance effector genes. This deregulation is a consequence of point mutations occurring in transcriptional regulators of these effector genes. Resistance can also follow the emergence of point mutations directly in the genes coding antifungal targets. In addition we further describe new strategies currently undertaken to discover alternative therapy targets and antifungals. Identification of new antifungals is essentially achieved by the screening of natural or synthetic chemical compound collections. Discovery of new putative antifungal targets is performed through genome-wide approaches for a better understanding of the human pathogenic fungi biology.


Growth regulation of a Salmonella plasmid gene essential for virulence.
The Salmonella dublin plasmid gene vsdC is essential for virulence. We have constructed a vsdC-lacZ translational fusion to demonstrate that vsdC is selectively expressed during the stationary phase of bacterial cell growth. This pattern of expression has been confirmed by mRNA hybridization studies. Carbon starvation is able to induce vsdC expression by limiting bacterial growth. The expression of vsdC is dependent upon an upstream gene, vsdA, whose gene product possesses significant amino-terminus homology with the LysR family of transcriptional activator proteins. We have further demonstrated that vsdC expression is not dependent upon the known Salmonella chromosomal virulence regulatory loci ompR, phoP, and cya-crp and that vsdC can be expressed in a range of nontyphoidal Salmonella serovars, including some serovars in which introduction of the virulence plasmid does not confer mouse virulence. The vsd system provides a model for the study of transcriptional activation, a basis for the development of new expression vectors, and a novel mechanism of virulence gene regulation. Bacterial growth limitation within the phagosomes of host phagocytic cells may be the environmental signal inducing plasmid-mediated virulence gene expression in salmonellae.


[Differing microsomal monoxygenase activity in the cells of ascitic and solid forms of transplantable tumors].
Aryl hydroxylase activity has been demonstrated to depend on the pattern of tumor cell structural organization. The activity of microsomal monoxygenases in the ascitic forms of sarcoma MC-11, hepatoma 22a and Ehrlich's tumor was much lower than in the corresponding solid tumors. Aryl hydroxylase was activated after the animals received 3-MC, but the magnitude of the activity induced did not correlate with the basic activity in the different tumors. In in vitro experiments, 7,8-benzoflavone inhibited the enzyme in all the tumors, whereas metyrapone did not affect BP-hydroxylation. It is assumed that all the tumors investigated contain hemoprotein that is similar to cytochrome P1-450.


Target cell-dependent normalization of transmitter release at neocortical synapses.
The efficacy and short-term modification of neocortical synaptic connections vary with the type of target neuron. We investigated presynaptic Ca2+ and release probability at single synaptic contacts between pairs of neurons in layer 2/3 of the rat neocortex. The amplitude of Ca2+ signals in boutons of pyramids contacting bitufted or multipolar interneurons or other pyramids was dependent on the target cell type. Optical quantal analysis at single synaptic contacts suggested that release probabilities are also target cell-specific. Both the Ca2+ signal and the release probability of different boutons of a pyramid contacting the same target cell varied little. We propose that the mechanisms that regulate the functional properties of boutons of a pyramid normalize the presynaptic Ca2+ influx and release probability for all those boutons that innervate the same target cell.


Abnormal Respiratory Sound Identification Using Audio-Spectrogram Vision Transformer.
Respiratory disease, the third leading cause of deaths globally, is considered a high-priority ailment requiring significant research on identification and treatment. Stethoscope-recorded lung sounds and artificial intelligence-powered devices have been used to identify lung disorders and aid specialists in making accurate diagnoses. In this study, audio-spectrogram vision transformer (AS-ViT), a new approach for identifying abnormal respiration sounds, was developed. The sounds of the lungs are converted into visual representations called spectrograms using a technique called short-time Fourier transform (STFT). These images are then analyzed using a model called vision transformer to identify different types of respiratory sounds. The classification was carried out using the ICBHI 2017 database, which includes various types of lung sounds with different frequencies, noise levels, and backgrounds. The proposed AS-ViT method was evaluated using three metrics and achieved 79.1% and 59.8% for 60:40 split ratio and 86.4% and 69.3% for 80:20 split ratio in terms of unweighted average recall and overall scores respectively for respiratory sound detection, surpassing previous state-of-the-art results.


Cardiac oxidative stress determination and myocardial morphology after a single ecstasy (MDMA) administration in a rat model.
Experimental and clinical data indicate that 3,4-methylenedioxy-N-methylamphetamine (MDMA) abuse can produce significant cardiovascular toxicity. A mechanism may be a direct toxic effect of redox active metabolites of MDMA. To evaluate the effect of a single MDMA dose on cellular antioxidant defence system and to investigate the morphology in male albino rats, total glutathione (GSH), oxidised glutathione (GSSG), ascorbic acid (AA), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and malondialdehyde (MDAL) were studied. The effects were evaluated at 3, 6, 16 and 24 h after MDMA administration. Antioxidant enzymes activity was significantly reduced: GPx (-24%) and SOD (-50%) after 3 h and GR (-19%) after 6 h from treatment. AA levels decrease (-37%) after 3 h and (-30%) after 6 h; MDAL level increased (+119%) after 3 h; GSH levels decreased after 3 (31.3%) and 6 h (37.9%) from MDMA treatment. GSSG content was not affected by ecstasy administration. Myocardial contraction band necrosis (CBN) was already visible in rats killed at 6 h. After 16 h, macrophagic monocytes around the necrotic myocardial cells were observed, and within 24 h, this infiltrate became more widespread with an early removal of the necrotic material. Calcium deposits were observed within ventricular cardiomyocytes with intact nuclei and sarcomeres. Single administration of MDMA can significantly alter the cellular antioxidant defence system and produce oxidative stress which may result in lipid peroxidation and disruption of Ca(2 +) homeostasis. The depression in Ca(2+) regulatory mechanism by reactive oxygen species ultimately results in intracellular Ca(2 +) overload, CBN and cell death.


Parathyroid Adenoma in a Young Female Presenting Multiple Fractures and Postoperative Hungry Bone Syndrome.
A young 18-year-old female patient with general bone pain and history of multiple fractures brought her to our medical attention. Laboratory work showed hypercalcemia and high parathyroid hormone levels in the blood. Radiograph imaging revealed severe scoliosis with multiple vertebrae fractures with decreased bone mineral density. Sestamibi showed parathyroid adenoma. This case emphasizes the importance of maintaining a primary hyperparathyroidism as a differential diagnosis when a young patient presents with a multiple pathologic fractures history.


Association of leisure-time physical activity with cardiorespiratory fitness in Indian men.
The relationship between leisure-time physical activity (LTPA) and cardiorespiratory fitness (CRF) is not clearly understood in Indian men. It is important to elucidate whether the duration or intensity of LTPA is responsible for increasing CRF. This will help in designing better physical activity intervention strategies for improving CRF in Indian men. Healthy nondiabetic urban Indian men with no history of coronary heart disease (CHD) were selected (n = 603; aged 22-64 years) and their energy intake and physical activity was determined using a questionnaire. Body fat (percent) was determined by leg-to-leg bioelectrical impedance analysis while CRF was measured on multistage, continuous treadmill test using Bruce protocol. Intensity of physical activity (METs) emerged as the best independent predictor of CRF (β = 0.217; P < .001). Using univariate General Linear Model, it was found that CRF is more a function of LTPA intensity than LTPA duration, since LTPA duration was not related to CRF when controlled for LTPA intensity. However, LTPA intensity remained significantly associated with CRF even after adjustment for LTPA duration. LTPA of preferably higher intensity should be incorporated in the lifestyle to improve CRF and prevent CHD in Indian men.


The importance of scale for spatial-confounding bias and precision of spatial regression estimators.
Residuals in regression models are often spatially correlated. Prominent examples include studies in environmental epidemiology to understand the chronic health effects of pollutants. I consider the effects of residual spatial structure on the bias and precision of regression coefficients, developing a simple framework in which to understand the key issues and derive informative analytic results. When unmeasured confounding introduces spatial structure into the residuals, regression models with spatial random effects and closely-related models such as kriging and penalized splines are biased, even when the residual variance components are known. Analytic and simulation results show how the bias depends on the spatial scales of the covariate and the residual: one can reduce bias by fitting a spatial model only when there is variation in the covariate at a scale smaller than the scale of the unmeasured confounding. I also discuss how the scales of the residual and the covariate affect efficiency and uncertainty estimation when the residuals are independent of the covariate. In an application on the association between black carbon particulate matter air pollution and birth weight, controlling for large-scale spatial variation appears to reduce bias from unmeasured confounders, while increasing uncertainty in the estimated pollution effect.


Do DRG reimbursement rates reflect nursing costs?
The assumption underlying diagnosis related group (DRG) reimbursement is that the prospective, diagnosis-determined rates reflect actual costs incurred during a hospital stay. The nursing component represents a significant percentage of the costs associated with a patient's hospital stay. However, a study of actual nursing labor costs for 240 acute care patients in five DRG categories showed that some DRGs vary in daily nursing labor costs up to 500% over the course of a patient's stay. For some DRGs, the patient's DRG classification is not an adequate measure for determining, assigning, or allocating nursing costs within the institution. Hospitals that do not track actual nursing costs risk unanticipated cost overruns for some diagnoses that may have a significant effect on hospital finances.


Adverse drug events in intensive care units: risk factors, impact, and the role of team care.
Advances in diagnostic tests, technological interventions, and pharmacotherapy have resulted in spectacular results for many intensive care unit (ICU) patients who, in earlier generations, would have succumbed to their critical illness. At the same time, the complexity and intensity of care required for ICU patients is also associated with greater risks for harm resulting from care. As in other inpatient areas, medications are the most common type of therapy in ICUs and are also associated with the most frequent type of ICU adverse events. Critically ill patients are at high risk for adverse drug events for many reasons, including the complexity of their disease that creates challenges in drug dosing, their vulnerability to rapid changes in pharmacotherapy, the intensive care environment providing ample distractions and opportunity for error, the administration of complex drug regimens, the numerous high-alert medications that they receive, and the mode of drug administration. The clinical outcomes of adverse drug events can result in end-organ damage and even death. The costs of an adverse drug event can be substantial to healthcare systems with an additional $6,000-$9,000 for each event. The multiprofessional patient care team is one approach to promoting patient safety in the ICU.


[Frequency and characteristics of aspirin resistance in Chilean cardiovascular patients].
Studies performed in Anglo-Saxon countries show that 5% of patients are resistant to the antiplatelet effects of aspirin. To assess the prevalence of aspirin resistance in a sample of Chilean cardiovascular patients and its association with clinical and laboratory characteristics. Ninety nine patients (30 women, 63+/-10 years) treated for stable cardiovascular diseases with aspirin 100-325 mg/day were studied. Clinical and basic coagulation variables were assessed. Platelet aggregation was studied with platelet rich plasma using three different agonists in an optical aggregometer. Aspirin resistance was defined as an aggregation 20% with arachidonic acid and an aggregation 70% with ADP or collagen. Eleven patients (11.11%, 95% CI= 4.95-17.27%) complied with both criteria and were classified as aspirin resistant. Current smoking was more common in aspirin resistant patients (63.6 vs 29.6%, p=0.039). Aspirin resistance was found in a significant proportion of cardiovascular patients and was more common among current smokers.


Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer.
The prevalence and risk factors for thromboembolism (TE) in children with cancer are largely unknown. This retrospective cohort study aims to determine the epidemiology of TE and to identify potential risk factors for TE in children with cancer. We used logistic regression to determine the association of age (<10 years vs. > or =10 years), gender, type of cancer, presence or absence of intra-thoracic disease (mediastinal mass or any primary or metastatic pulmonary disease), type of central venous line (CVL) and CVL-dysfunction (difficulty of blood draw, infusion or documented CVL infection) on the risk of developing TE. Fifty-seven of 726 patients [7.9%; 95% confidence intervals (CI); 6.0,10.0] developed TE; children with brain tumors (n = 201) had significantly lower prevalence of TE (0.5%; P < 0.001). Older patients had increased risk of developing TE compared to younger patients [Odds ratios (OR) 1.8; 95% CI; 1.0,3.2; P = 0.036]. Children with acute lymphoblastic leukemia (ALL) (OR 4.6; 95% CI; 1.8, 12.3; P = 0.002), lymphoma (OR 3.8; 95% CI; 1.3, 11.1; P = 0.016), and sarcoma (OR 4.3; 95% CI; 1.4, 13.3; P = 0.012) had an increased risk of TE. Subgroup analyses showed that patients with CVL-dysfunction and intra-thoracic disease had a higher prevalence of TE compared to those without CVL-dysfunction (22.8% vs. 8.8%; 95% CI; 4.0, 24.3; P = 0.006) and intra-thoracic disease (18.0% vs. 6.1%; 95% CI; 2.4, 21.4; P = 0.02). TE is common in children with cancer. Age and type of cancer are independent risk factors for TE in children with non-CNS cancers. CVL-dysfunction and intra-thoracic disease are significantly associated with the diagnosis of TE.


Reading Level and Suitability of Congestive Heart Failure (CHF) Education in a Mobile App (CHF Info App): Descriptive Design Study.
Education at the time of diagnosis or at discharge after an index illness is a vital component of improving outcomes in congestive heart failure (CHF). About 90 million Americans have limited health literacy and have a readability level at or below a 5th-grade level, which could affect their understanding of education provided at the time of diagnosis or discharge from hospital. The aim of this paper was to assess the suitability and readability level of a mobile phone app, the CHF Info App. A descriptive design was used to assess the reading level and suitability of patient educational materials included in the CHF Info App. The suitability assessment of patient educational materials included in the CHF Info App was independently assessed by two of the authors using the 26-item Suitability Assessment of Materials (SAM) tool. The reading grade level for each of the 10 CHF educational modules included in the CHF Info App was assessed using the comprehensive online Text Readability Consensus Calculator based on the seven most-common readability formulas: the Flesch Reading Ease Formula, the Gunning Fog Index, the Flesch-Kincaid Grade Level Formula, the Coleman-Liau Index, the Simplified Measure of Gobbledygook Index, the Automated Readability Index, and the Linsear Write Formula. The reading level included the text-scale score, the ease-of-reading score, and the corresponding grade level. The educational materials included in the CHF Info App ranged from a 5th-grade to an 8th-grade reading level, with a mean of a 6th-grade level, which is recommended by the American Medical Association. The SAM tool result demonstrated adequate-to-superior levels in all four components assessed, including content, appearance, visuals, and layout and design, with a total score of 77%, indicating superior suitability. The authors conclude that the CHF Info App will be suitable and meet the recommended health literacy level for American adult learners. Further testing of the CHF Info App in a longitudinal study is warranted to determine improvement in CHF knowledge.


The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreading.
Vinculin is a conserved actin binding protein localized in focal adhesions and cell-cell junctions. Here, we report that vinculin is tyrosine phosphorylated in platelets spread on fibrinogen and that the phosphorylation is Src kinases dependent. The phosphorylation of vinculin on tyrosine was reconstituted in vanadate treated COS-7 cells coexpressing c-Src. The tyrosine phosphorylation sites in vinculin were mapped to residues 100 and 1065. A phosphorylation-specific antibody directed against tyrosine residue 1065 reacted with phosphorylated platelet vinculin but failed to react with vinculin from unstimulated platelet lysates. Tyrosine residue 1065 located in the vinculin tail domain was phosphorylated by c-Src in vitro. When phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail. In contrast, the phosphorylation did not affect the binding of vinculin to actin in vitro. A double vinculin mutant protein Y100F/Y1065F localized to focal adhesion plaques. Wild-type vinculin and single tyrosine phosphorylation mutant proteins Y100F and Y1065F were significantly more effective at rescuing the spreading defect of vinculin null cells than the double mutant Y100F/Y1065F. The phosphorylation of vinculin by Src kinases may be one mechanism by which these kinases regulate actin filament assembly and cell spreading.


[Determination of paraquat residue in plant-derived foodstuffs by high performance liquid chromatography-tandem mass spectrometry].
A sensitive and selective method is presented for the determination of paraquat residue in fruits, vegetables, beans and grain by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Paraquat in samples was extracted with water and cleaned-up with a weak cation exchange (WCX) column to obtain an extract suitable for analysis using HPLC-MS/MS. The paraquat was separated by a CAPCELL PAK ST column (150 mm x 2.0 mm) and with acetonitrile-10 mmol/L ammonium acetate solution (adjusted to pH 4.0 by formic acid) as the mobile phase, and multiple reaction monitoring (MRM) was used with electrospray ionization in the positive ion mode. The calibration curve was linear between the peak area and the mass concentration of paraquat from 0.01 to 0.1 mg/L with the correlation coefficient of 0.993. Recoveries of paraquat spiked in samples at three levels ranged from 84.0% to 106.0% with the relative standard deviations of 7.8% - 18.8%. The limits of detection (LODs) of paraquat were 0.01 mg/kg in fruits and vegetables and 0.05 mg/kg in beans and grain. The LODs can meet the requirements of international maximum residue limit.


Characterization of an epithelial and a tumor-associated human small cell lung carcinoma glycoprotein antigen.
The small cell carcinoma (SCC) antigens recognized by LAM2 and LAM8 antibody were characterized by comparison of their tissue expression and analysis of their biochemical composition. LAM2, but not LAM8 antigen could be demonstrated in lipid extracts of SCC cells. By immunohistochemical staining the SCC antigen LAM2 was shown to be an epithelial type membrane antigen. Immunoblotting experiments and competition solid phase radioimmunoassays showed LAM2 antigen to be a native conformation of a glycoprotein with major bands at Mr 100,000-120,000 and a minor band at Mr 210,000. L-Fucose was a dominant part of the epitope which appeared to be closely related to the carbohydrate epitope of the blood group antigen H(O). The tumor-associated membrane antigen LAM8 was shown to be a glycoprotein with major bands at Mr 90,000-135,000 and a minor band at Mr 200,000. Neuraminic acid was the predominant part of the carbohydrate epitope. LAM8 antibody recognized a structure in the saliva of Lea positive probands, but untreated and neuraminidase-treated SCC extracts were unreactive with anti-Lea antibody. Anti CA 19-9 (sialo-Lea antigen) and LAM2 antibodies did not compete for LAM8 binding in direct radioimmunoassays. The sialo-GP90-135 antigen recognized by LAM8 antibody therefore is likely to represent a novel tumor antigen.


QSAR: an in silico approach for predicting the partitioning of pesticides into breast milk.
The aim of this study was to develop an in silico Quantitative Structure Activity Relationship (QSAR) model capable of predicting partitioning of pesticides into breast milk from their respective chemical structures. A large data set of 190 diverse compounds, including drugs and their active metabolites (87%), and pesticides (13%) with experimentally derived milk/plasma (M/P) ratios taken from the literature, was used to train, test and validate a predictive model. Each compound was encoded with 65 calculated chemical structure descriptors. Sensitivity analysis was then used to select a subset of the descriptors that best describe the transfer of pesticides into breast milk and Artificial neural networks modeling was applied to correlate selected descriptors (inputs) with the M/P ratio (output) in order to develop a predictive QSAR. The developed QSAR model included 26 molecular descriptors related to the molecular size, polarity and hydrogen binding capacity. Together with aromatic rings, these descriptors account for molecule's size and hydrophobic interaction capabilities. The average correlation for the final model (incorporating training, testing, and validation) was 0.85. The developed model provides a useful method for predicting the M/P ratios of pesticides from just a sketch of their respective molecular structures. However, these predictions should only be used to assist in the evaluation of risk in conjunction with an assessment of the infant's response to a given drug/pesticide.


Iodixanol in multidetector-row computed tomography angiography (MDCTA): diagnostic accuracy for abdominal aorta and abdominal aortic major-branch diseases using four-, eight- and 16-detector-row CT scanners.
To compare iodixanol-enhanced multidetector-row computed tomography angiography (MDCTA) with digital subtraction angiography (DSA), perioperative angiography, or surgical findings in the evaluation of the abdominal aorta and its main branches. 173 patients with known or suspected aortic aneurysms or stenosis/occlusion of the abdominal aorta or its major branches were enrolled. The iso-osmolar contrast medium iodixanol (320 mg Iota/ml) was used, and data were acquired using four-, eight-, or 16-active-detector-row scanners. Reference diagnoses were provided by surgical findings, interventional findings, or DSA. Diagnostic accuracy was estimated with reference to surgery or interventional arteriography or DSA. Image quality was assessed as excellent, good, sufficient, or insufficient, and correlations were made with attenuation values in the aortic lumen. Tolerability of iodixanol was monitored during the injection for discomfort and other adverse events, and for 72 hours after contrast injection. In 132 of 136 evaluable cases, MDCTA diagnosis matched the reference diagnosis, yielding an agreement rate of 97.1% (95% CI 92.6-99.2%). The quality of most MDCTA scans (147/173) was rated as excellent. Overall mean attenuation was 305.7 HU. MDCTA appeared more accurate than DSA for identification of lesion calcification, thrombus, irregularity, and ulceration. Tolerability of iodixanol was good, and no serious adverse events were reported. MDCTA using iodixanol is a promising, noninvasive alternative for evaluating patients with abdominal aortic disease.


Dissociated neurons regenerate into sciatic but not optic nerve explants in culture irrespective of neurotrophic factors.
Explants of adult or 10-day-old rat sciatic and optic nerves were implanted as "bridges" through a silicon grease seal in a three-compartment chamber culture system, leading from a narrow center chamber to two adjacent side chambers. Dissociated newborn rat sympathetic or sensory neurons were plated into the center chamber and grown in the presence of optimal concentrations of nerve growth factor (NGF). By light microscopy, nerve fibers were seen to grow out of the sciatic nerve explants in the side chambers after 2 to 3 weeks. Electron microscopy showed large numbers of axons present inside the sciatic nerves, irrespective of the presence and number of living Schwann cells. Besides their tendency to fasciculate, axons grew with high preference on Schwann cell membranes and the Schwann cell side of the basal lamina, a situation identical to in vivo regeneration. In contrast to the sciatic nerves, no axons could be found under any condition in the optic nerves. This result points to the existence of extremely poor, non-permissive substrate conditions in the differentiated optic nerves which cannot be overcome by the strong fiber outgrowth-promoting effects of NGF.


[Ultrastructure of liver cells of shrews].
It was established that the hepatocytes of least shrew (Sorex minutissimus) contained 1-2 nucleus with wide nuclear pores and big nucleolus. There are abundant mitochondria with numerous crists in their matrix (many organelles were divided along the crists). Each mitochondrion was surrounded by the cistern of granular endoplasmic reticulum. The ultrastructure of Golgi complex (1-2 flat cisterns, small vesicles] indicated that the bile was secreted often, by small portions, that was the adaptation to repeated fractional feeding. There were many peroxisomes in the cytoplasm of hepatocytes. Lipid droplets were absent, glycogen granules were not at all hepatocytes. Sinusoidal cells had the usual structure. All sinusoids were open and consisted of the erythrocytes, fragments of hepatocyte cytoplasm and myelin figures in its lumen.


Dental erosion among 12 year-old Libyan schoolchildren.
As there are limited data on dental erosion in Libya, the aim of this study was to assess the prevalence and severity of dental erosion in a sample of 12 year-old children in Benghazi, Libya. Cross-sectional observational study. Elementary schools in Benghazi, Libya. A random sample of 791 12 year-old children (397 boys and 394 girls) attending 36 schools. Clinical dental examination for erosion using UK National Diet and Nutrition Survey (2000) criteria and self-completion questionnaire. The area and depth of dental erosion affecting the labial and palatal surfaces of the upper permanent incisors and occlusal surfaces of the first permanent molars. Dental erosion was observed in 40.8% of subjects; into enamel affecting 32.5%, into dentine affecting 8.0% and into pulp affecting 0.3% of subjects. Based on area affected, 323 subjects (40.8%) exhibited dental erosion (code > 0), with 32.6% of these subjects having erosion affecting more than two thirds of one or more surfaces examined. Mean total scores for dental erosion for all surfaces per mouth by area and by depth were both 2.69 (sd 3.81). Of the 9492 tooth surfaces examined, 2128 surfaces (22.4%) had dental erosion. Girls had more experience of erosion than boys at all levels of severity (p = 0.001). In a cohort of 12 year-old Libyan schoolchildren, more than one third of children examined showed dental erosion, requiring clinical preventive counselling. Significantly more erosion occurred in girls than boys.


Impact of Haemophilus influenzae Type b conjugate vaccine in Mongolia: prospective population-based surveillance, 2002-2010.
Bacterial meningitis is associated with high mortality and long-term complications. This study assessed the impact of Haemophilus influenzae type b (Hib) conjugate vaccine on childhood bacterial meningitis in Ulaanbaatar, Mongolia. Prospective, active, population-based surveillance for suspected meningitis in children aged 2-59 months was conducted (February 2002-January 2011) in 6 hospitals. Clinical data, blood, and cerebrospinal fluid were collected. The impact of Hib conjugate vaccine was assessed by comparing Hib and all cause meningitis data in the 3 years preceding pentavalent conjugate vaccine implementation (2002-2004) with 3 years postimplementation (2008-2010). Five hundred eleven cases of suspected meningitis were identified from 2002-2011. Pentavalent conjugate vaccine coverage in December 2005 in Ulaanbaatar city was 97%. The proportion of suspected cases confirmed as Hib meningitis decreased from 25% (50/201) in the prevaccination era to 2% (4/193) in the postvaccination era (P < .0001). The annual incidence of Hib decreased from 28 cases per 100,000 children in 2002-2005 to 2 per 100,000 in 2008-2010 (P < .0001). This article demonstrates the marked impact of Hib conjugate vaccine introduction on meningitis in Mongolia. It is important to sustain this surveillance system to monitor the long-term impact of Hib conjugate vaccine, as well as other interventions such as pneumococcal and meningococcal vaccines.


Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia.
Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) alpha1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric alpha1 or heteromeric alpha1beta GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.


Validation of quantitative attenuation and backscattering coefficient measurements by optical coherence tomography in the concentration-dependent and multiple scattering regime.
Optical coherence tomography (OCT) has the potential to quantitatively measure optical properties of tissue such as the attenuation coefficient and backscattering coefficient. However, to obtain reliable values for strong scattering tissues, accurate consideration of the effects of multiple scattering and the nonlinear relation between the scattering coefficient and scatterer concentration (concentration-dependent scattering) is required. We present a comprehensive model for the OCT signal in which we quantitatively account for both effects, as well as our system parameters (confocal point spread function and sensitivity roll-off). We verify our model with experimental data from controlled phantoms of monodisperse silica beads (scattering coefficients between 1 and 30 mm(−1) and scattering anisotropy between 0.4 and 0.9). The optical properties of the phantoms are calculated using Mie theory combined with the Percus–Yevick structure factor to account for concentration-dependent scattering. We demonstrate excellent agreement between the OCT attenuation and backscattering coefficient predicted by our model and experimentally derived values. We conclude that this model enables us to accurately model OCT-derived parameters (i.e., attenuation and backscattering coefficients) in the concentration-dependent and multiple scattering regime for spherical monodisperse samples.


Gene Expression Analysis Reveals Genes Common to Cerebral Malaria and Neurodegenerative Disorders.
Cerebral malaria, a reversible encephalopathy affecting young children, is a medical emergency requiring urgent clinical assessment and treatment. We performed a whole-transcriptomic analysis of blood samples from Malian children with cerebral or uncomplicated malaria. We focused on transcripts from pathways for which dysfunction has been associated with neurodegenerative disorders. We found that SNCA, SIAH2, UBB, HSPA1A, TUBB2A, and PINK1 were upregulated (fold-increases, ≥2.6), whereas UBD and PSMC5 were downregulated (fold-decreases, ≤4.39) in children with cerebral malaria, compared with those with uncomplicated malaria. These findings provide the first evidence for pathogenic mechanisms common to human cerebral malaria and neurodegenerative disorders.


Intra-unit-cell electronic nematicity of the high-T(c) copper-oxide pseudogap states.
In the high-transition-temperature (high-T(c)) superconductors the pseudogap phase becomes predominant when the density of doped holes is reduced. Within this phase it has been unclear which electronic symmetries (if any) are broken, what the identity of any associated order parameter might be, and which microscopic electronic degrees of freedom are active. Here we report the determination of a quantitative order parameter representing intra-unit-cell nematicity: the breaking of rotational symmetry by the electronic structure within each CuO(2) unit cell. We analyse spectroscopic-imaging scanning tunnelling microscope images of the intra-unit-cell states in underdoped Bi(2)Sr(2)CaCu(2)O(8 +) (delta) and, using two independent evaluation techniques, find evidence for electronic nematicity of the states close to the pseudogap energy. Moreover, we demonstrate directly that these phenomena arise from electronic differences at the two oxygen sites within each unit cell. If the characteristics of the pseudogap seen here and by other techniques all have the same microscopic origin, this phase involves weak magnetic states at the O sites that break 90 degrees -rotational symmetry within every CuO(2) unit cell.


Assessment of occupational genotoxic risk among Brazilian hairdressers.
To evaluate the genotoxic risk to hairdressers exposed daily to chemical substances such as hair dyes, waving and straightening preparations and manicurists' products by the Comet assay test (single-cell gel electrophoresis). The Comet assay was performed on blood samples from 69 female hairdressers (36.4 +/- 10.7 years old) currently employed in 21 different beauty institutes in São Paulo, Brazil, and on 55 female control blood donors (32.6 +/- 10.0 years old) from the São Paulo University Clinical Hospital blood bank. All the control subjects had occupations other than hairdresser. Comet assays were performed by evaluating 100 blood lymphocytes per individual and graded by visual score according to comet tail length. The hairdressers showed a higher frequency of DNA damage revealed by Comet Score (159.8 +/- 71) when compared to the control group (125.4 +/- 64.1), and the difference was statistically significant by the Student's t-test (P = 0.005). Multiple regression analysis showed that in addition to the hairdressers' profession, tobacco use contributed to the higher frequency of cells with comets (P < 0.05). The observed DNA damage could be associated with the hairdressers' occupational environment, where different chemicals are chronically manipulated and inhaled. Considering that this profession in many countries, including Brazil, is not officially regulated, more attention should focus on these professionals not only by legislative bodies but also by multidisciplinary teams able to develop and implement risk prevention and control strategies for chemical, physical and biological agents to which hairdressers are exposed.


UAV-Based Volumetric Measurements toward Radio Environment Map Construction and Analysis.
Unmanned aerial vehicle (UAV)-empowered communications have gained significant attention in recent years due to the promise of agile coverage provision for a large number of various mobile nodes on the ground and in three-dimensional (3D) space. Consequently, there is a need for efficient spectrum utilization in these dense aerial networks, which is characterized through radio environment maps (REMs), the construction of which is an important research area. Nevertheless, due to the difficult collection of radio frequency (RF) data, there are limited works that are based on real-world measurement campaigns. This paper presents a novel experimental setup that includes a constellation of three UAVs, the communication signals of which are measured by a software-defined radio (SDR) mounted on a separate UAV. It follows a trajectory that defines the REM's two-dimensional (2D) area on a plane, executed at four altitudes, to extend the REM to 3D. The measurements are then processed and their features (received mean power level, average difference of the mean power, percentage of meaningful correlations) are analyzed in the temporal, spatial, and frequency domains to determine the utilization of a 20 MHz band in the 2.4 GHz spectrum, as well as their variation with altitude. This analysis provides a base for research in reducing the amount of measurements (by identifying the regions of low and of high interest) and spectrum occupancy prediction for UAV-based communication coexistence.


Critical issues in the pathophysiology and management of peptic ulcer disease.
To discuss some of the critical issues in the pathophysiology and management of peptic ulcer disease. Peptic ulcer disease has multiple causes, although gastric acid has traditionally been considered the primary aggressive factor. Helicobacter pylori infection is established as a major causative factor, but some aspects of the mechanisms by which H. pylori causes peptic ulceration remain unclear. Treatment with proton pump inhibitors (PPIs) is the most effective means of healing peptic ulcers. In addition to healing a higher proportion of ulcers than H2-receptor antagonists, PPIs provide faster healing and relief of symptoms. The ability of PPIs to produce effective and sustained inhibition of gastric acid secretion suggests that they may also become the treatment of choice for gastric ulcers caused by non-steroidal anti-inflammatory drugs. However, eradication of H. pylori infection is more effective than maintenance therapy with antisecretory agents in reducing the rate of recurrence of peptic ulcers initially healed using antisecretory therapy. H. pylori eradication is therefore the optimal, and almost certainly the most cost-effective, approach to the long-term management of patients with peptic ulcer disease. Despite the fact that 90-95% of patients with demonstrable duodenal ulceration are probably infected with H. pylori, it is recommended that, in routine clinical practice, infection is diagnosed before eradication therapy is instituted. H. pylori testing 4-6 weeks after the completion of eradication therapy is also recommended to check that the infection has been successfully cured. For routine clinical practice, the highly sensitive and specific rapid urease test is probably the most useful diagnostic approach. The most appropriate H. pylori eradication regimen remains to be defined. However, 1-2 weeks of treatment with a combination of a PPI and two antimicrobial agents achieves eradication rates in excess of 90%, which are similar to those attained using standard triple therapy, but with the advantage of better patient compliance and greater tolerability. Preliminary evidence also suggests that H. pylori eradication prevents the recurrence of peptic ulcer bleeding, although further studies are required. H. pylori eradication by 1-2 weeks' treatment with a combination of a PPI and two antimicrobial agents appears to be the optimal (and probably the most cost-effective) approach to the long-term management of patients with peptic ulcer disease, and represents a major advance in the management of such patients.


[Use of 131 iodine for the treatment of hyperthyroidism in adults].
The authors report on their experience with the treatment of hyperthyroidism using radioiodine (RI) over a period of 15 years in 516 patients. RI dosimetry was calculated from thyroid 24 hr uptake and weight, using linearly increasing RI doses (from 40 to 100 microCi/g) with increasing thyroid weight (between 10 and 100 g) for both diffuse (D) and multinodular (MN) toxic goiters. For solitary toxic (ST) nodules, a fixed dose of 250 microCi/g was used. In severe hyperthyroidism, antithyroid drugs (ATD) and KI (15 mg/d) were added 24 hours after RI and given during 1-4 months and 21 days, respectively. Combining RI + ATD/KI therapy allowed for a reduction of RI recirculation and release from the gland and also for more rapid return to a euthyroid status. The results showed that 88% of patients with ST, 68% with D, and 55% with MN were cured with a single dose of RI. Furthermore, the incidence of late hypothyroidism was relatively low, reaching 7% in ST, 36% in D, and 28% in MN after a follow-up period of fifteen years. Annual follow-up, however, showed that an additional 2.7% of patients (3.5% of D; 1.6% of MN; 2.4% of ST) exhibited--per year--an exaggerated TSH response to TRH even though these patients remained clinically and biochemically euthyroid (normal circulating basal hormones and TSH levels). In conclusion, 1) low doses RI combined with ATD/KI yielded a high success rate: less than 30% of patients required more than 1 dose and only 30% became hypothyroid after prolonged follow-up; 2) abnormalities of TRH test were not infrequent in patients with D and MN goiters, as well as ST nodules, thereby fully justifying the need for careful and prolonged follow-up of all hyperthyroid patients receiving RI therapy.


Conclusions and future directions for the REiNS International Collaboration.
The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established with the goal to develop consensus recommendations for the use of endpoints in neurofibromatosis (NF) clinical trials. This supplement includes the first series of REiNS recommendations for the use of patient-reported, functional, and visual outcomes, and for the evaluation of imaging response in NF clinical trials. Recommendations for neurocognitive outcome measures, the use of whole-body MRI in NF, the evaluation of potential biomarkers of disease, and the comprehensive evaluation of functional and patient-reported outcomes in NF are in development. The REiNS recommendations are made based on current knowledge. Experience with the use of the recommended endpoints in clinical trials, development of new tools and technologies, new knowledge of the natural history of NF, and advances in the methods used to analyze endpoints will likely lead to modifications of the currently proposed guidelines, which will be shared with the NF research community through the REiNS Web site www.reinscollaboration.org. Due to the clinical complexity of NF, there is a need to seek expertise from multiple medical disciplines, regulatory agencies, and industry to develop trial endpoints and designs, which will lead to the identification and approval of effective treatments for NF tumor and nontumor manifestations. The REiNS Collaboration welcomes anyone interested in providing his or her expertise toward this effort.


Birth Weight and Diabetic Retinopathy: Results From the Population-Based Gutenberg Health Study (GHS).
This study investigates the relationship between diabetic retinopathy (DR) and birth weight (BW) in diabetic subjects sampled from the general population. The Gutenberg Health Study (GHS) is a population-based, observational cohort study in participants aged from 35 to 74 years. Criteria for diabetes diagnosis were HbA1c ≥6.5% at study entry, a doctor-diagnosis of diabetes, or diabetes medication. The presence of DR was determined by evaluating fundus photographs. BW was assessed by self-reports. GHS participants were divided into three different BW groups (low: <2500 g; normal: 2500-4000 g; high:>4000 g). Logistic regression analysis was conducted as uni- and multivariable analysis with adjustment for age and sex. Effect mediators were separately investigated. A total of 1,124 GHS participants (7.5% of the cohort) had diabetes at study entry. Of these, 402 subjects (35.8%) had gradable fundus photographs, reported BW data and were included into this study. Overall, 91/402 subjects (23%) had DR. With regard to BW groups, DR was descriptively more frequent in subjects with low (28.1% [95%-CI: 14.4-47.0%; n = 32]) and high BW (30.8% [95%-CI: 19.1-45.3%; n = 52]) compared to normal BW (20.8% [95%-CI: 16.5-25.7%; n = 318]). Both high and low BW were associated with DR in multivariable analysis (high: OR = 1.68, p = .037; low: OR = 1.81, p = .05). The BW effect was mediated by duration of diabetes in both BW groups and by arterial hypertension in the low BW group. Low and high BW in persons with diabetes is related to higher risk of diabetic retinopathy. Longer duration of diabetes and higher prevalence of arterial hypertension are factors in these subjects explaining the elevated risk.


Absence of p21 expression is associated with abnormal p53 in human breast carcinomas.
The p53 tumour-suppressor gene is important in the regulation of cell growth and apoptosis, and loss of functional wild-type activity may be associated with tumour formation and resistance to therapy. Differentiation of functionally normal wild-type protein from mutant or abnormal protein remains difficult using either immunohistochemical assays or mutational DNA sequencing. p21(WAF1/CIP1) (p21) is induced by wild type p53 and plays an important role in promoting cell cycle arrest. To test the hypothesis that p21 protein expression may act as a downstream marker of tumours from patients with locally advanced breast cancer before treatment with doxorubicin, pretreatment p53 status had been characterized in 63 tumours by p53 protein immunostaining and DNA mutational analysis. There was a significant association between immunostaining for p53 and the presence of p53 mutations (P = 0.01). Of 56 patients available for determination of p21, 31 (55%) expressed p21 protein. Twenty-eight out of 31 patients (90%) positive for p21 had low negative p53 protein expression, whereas only 3 of 13 patients (23%) with high p53 expressed p21 (P = 0.009). No association was seen between p21 protein expression and p53 mutations (P = 0.24). The combination of p53 and p21 immunostaining results improved the specificity of the immunostaining but at a cost of significant reduction in sensitivity. Immunohistochemical assessment of p21 protein expression is inversely associated with abnormal p53 protein in human breast cancer. The detection of p21 protein expression in combination with p53 protein expression did not improve the ability of immunohistochemistry (IHC) to differentiate between normal and mutant p53 protein.


A novel approach to the management of acute tracheal tear.
We describe the emergency use of a covered, expandable, removable tracheal stent in a patient who developed a large posterior tracheal tear complicating endobronchial therapy for large airway obstruction. Case report and review of the literature concerning management of acute tracheal tear. Our patient demonstrates that endotracheal stenting is an option for managing acute large airway tear. Moreover, the use of a removable stent allows not only for rapid closure of the defect but also removal once the defect has healed, thus avoiding long-term complications of stent deployment.


Cytomegalovirus pneumonitis is a risk for bronchiolitis obliterans syndrome in lung transplantation.
Cytomegalovirus pneumonitis is one of the most prevalent opportunistic infections after lung transplantation. Early studies reported that cytomegalovirus pneumonitis was a risk factor for chronic allograft dysfunction. More recently, in the era of routine prophylaxis and ganciclovir treatment, the adverse impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome has been challenged. We hypothesized that cytomegalovirus pneumonitis contributes to adverse outcomes in the current antiviral era. We sought to define the impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome and survival in a large single-center cohort (n = 231) of consecutive patients undergoing lung transplantation from 2000 to 2004, all receiving short-course ganciclovir prophylaxis. Transbronchial biopsies were performed at defined intervals with prospective cytomegalovirus immunostaining on every biopsy (n = 1,887). Cox proportional hazards models were used to assess the relationship between treated cytomegalovirus pneumonitis and clinical outcomes. Forty-nine (21%) recipients developed cytomegalovirus pneumonitis a median of 106 days after transplantation. Treated cytomegalovirus pneumonitis within the first 6 months after transplantation significantly increased the risk for bronchiolitis obliterans syndrome (P = 0.001; hazard ratio, 2.19; 95% confidence interval, 1.36-3.51) and post-transplantation death (P = 0.02; hazard ratio, 1.89; 95% confidence interval, 1.11-3.23). This risk persisted when cytomegalovirus pneumonitis was considered as a time-dependent predictor as well as in multivariable models controlling for other risk factors. Cytomegalovirus pneumonitis affects more than 20% of lung transplant recipients. Despite treatment, it increases the risk for bronchiolitis obliterans syndrome and death. More effective preventive strategies for cytomegalovirus pneumonitis are needed to improve long-term outcomes after lung transplantation.


Prioritizing Evidence-based Interventions for Dissemination and Implementation Investments: AHRQ's Model and Experience.
The Agency for Healthcare Research and Quality (AHRQ) is mandated to implement patient-centered outcomes research (PCOR) to promote safer, higher quality care. With this goal, we developed a process to identify which evidence-based PCOR interventions merit investment in implementation. We present our process and experience to date. AHRQ developed and applied a systematic, transparent, and stakeholder-driven process to identify, evaluate, and prioritize PCOR interventions for broad dissemination and implementation. AHRQ encouraged public nominations, and assessed them against criteria for quality of evidence, potential impact, and feasibility of successful implementation. Nominations with sufficient evidence, impact, and feasibility were considered for funding. Between June 2016 and June 2018, AHRQ received 35 nominations from researchers, nonprofit corporations, and federal agencies. Topics covered diverse settings, populations, and clinical areas. Twenty-eight unique PCOR interventions met minimum criteria; 16 of those had moderate to high evidence/impact and were assessed for feasibility. Fourteen topics either duplicated other efforts or lacked evidence on implementation feasibility. Two topics were prioritized for funding (cardiac rehabilitation after myocardial infarction and screening/treatment for unhealthy alcohol use). AHRQ developed replicable criteria, and a transparent and stakeholder-driven framework that attracted a diverse array of nominations. We identified 2 evidence-based practice interventions to improve care with sufficient evidence, impact, and feasibility to justify an AHRQ investment to scale up practice. Other funders, health systems or institutions could use or modify this process to guide prioritization for implementation.


Cost-effectiveness of the use of transvaginal sonography in the evaluation of postmenopausal bleeding.
To assess the cost-effectiveness of transvaginal sonography (TVS) in the diagnostic work-up of women with postmenopausal bleeding. We performed a decision analysis in which we estimated life expectancy and cost of four strategies for the evaluation of postmenopausal bleeding: TVS (I), TVS and office endometrial biopsy (II), TVS and hysteroscopy (III), and endometrial biopsy (IV). In strategies incorporating TVS, calculations were performed for three different cut-off values between 3 and 9 mm double layer. Expectant management, i.e. no diagnosis or treatment was considered to be the reference strategy to which the other four strategies were compared. Data were obtained from the published literature. In extensive sensitivity analyses, we varied patient's age, discount rate, prevalence of endometrial carcinoma and atypical hyperplasia, and costs. The strategy with endometrial biopsy and the strategy with TVS followed by endometrial biopsy in case of an increased endometrial thickness were the most cost-effective strategies. The strategy starting with endometrial biopsy was the most cost-effective when the prevalence of endometrial carcinoma was > or =15.3%, whereas the strategy with TVS and endometrial biopsy was the most cost-effective for women in which the prevalence of endometrial carcinoma was lower. In these strategies, a cut-off level for abnormality of 9 mm resulted in lowest cost per life-year gained. TVS is of use in women with postmenopausal bleeding and a probability of endometrial carcinoma below 15%.


Fabrication of high-aspect-ratio Fresnel zone plates by e-beam lithography and electroplating.
The fabrication of gold Fresnel zone plates, by a combination of e-beam lithography and electrodeposition, with a 30 nm outermost zone width and a 450 nm-thick structure is described. The e-beam lithography process was implemented with a careful evaluation of applied dosage, tests of different bake-out temperatures and durations for the photoresist, and the use of a developer without methylisobutylketone. Electrodeposition with a pulsed current mode and with a specially designed apparatus produced the desired high-aspect-ratio nanostructures. The fabricated zone plates were examined by electron microscopy and their performances were assessed using a transmission X-ray microscope. The results specifically demonstrated an image resolution of 40 nm.


The Down syndrome critical region regulates retinogeniculate refinement.
Down syndrome (DS) is a developmental disorder caused by a third chromosome 21 in humans (Trisomy 21), leading to neurological deficits and cognitive impairment. Studies in mouse models of DS suggest that cognitive deficits in the adult are associated with deficits in synaptic learning and memory mechanisms, but it is unclear whether alterations in the early wiring and refinement of neuronal circuits contribute to these deficits. Here, we show that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome. Specifically, we find excessive eye-specific segregation of retinal axons in the dorsal lateral geniculate nucleus. Indeed, the degree of refinement scales with defects in the "Down syndrome critical region" (DSCR) in a dose-dependent manner. We further identify Dscam (Down syndrome cell adhesion molecule), a gene within the DSCR, as a regulator of eye-specific segregation of retinogeniculate projections. Although Dscam is not the sole gene in the DSCR contributing to enhanced refinement in trisomy, Dscam dosage clearly regulates cell spacing and dendritic fasciculation in a specific class of retinal ganglion cells. Thus, altered developmental refinement of visual circuits that occurs before sensory experience is likely to contribute to visual impairment in individuals with Down syndrome.


Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality.
More information is needed about the long-term effects of low-dose aspirin (≤160 mg) on incident hepatocellular carcinoma, liver-related mortality, and gastrointestinal bleeding in persons with chronic hepatitis B or hepatitis C virus infection. Using nationwide Swedish registries, we identified all adults who received a diagnosis of chronic hepatitis B or hepatitis C from 2005 through 2015 and who did not have a history of aspirin use (50,275 patients). Patients who were starting to take low-dose aspirin (14,205 patients) were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin. We constructed a propensity score and applied inverse probability of treatment weighting to balance baseline characteristics between groups. Using Cox proportional-hazards regression modeling, we estimated the risk of hepatocellular carcinoma and liver-related mortality, accounting for competing events. With a median of 7.9 years of follow-up, the estimated cumulative incidence of hepatocellular carcinoma was 4.0% among aspirin users and 8.3% among nonusers of aspirin (difference, -4.3 percentage points; 95% confidence interval [CI], -5.0 to -3.6; adjusted hazard ratio, 0.69; 95% CI, 0.62 to 0.76). This inverse association appeared to be duration-dependent; as compared with short-term use (3 months to <1 year), the adjusted hazard ratios were 0.90 (95% CI, 0.76 to 1.06) for 1 to less than 3 years of use, 0.66 (95% CI, 0.56 to 0.78) for 3 to less than 5 years of use, and 0.57 (95% CI, 0.42 to 0.70) for 5 or more years of use. Ten-year liver-related mortality was 11.0% among aspirin users and 17.9% among nonusers (difference, -6.9 percentage points [95% CI, -8.1 to -5.7]; adjusted hazard ratio, 0.73 [95% CI, 0.67 to 0.81]). However, the 10-year risk of gastrointestinal bleeding did not differ significantly between users and nonusers of aspirin (7.8% and 6.9%, respectively; difference, 0.9 percentage points; 95% CI, -0.6 to 2.4). In a nationwide study of patients with chronic viral hepatitis in Sweden, use of low-dose aspirin was associated with a significantly lower risk of hepatocellular carcinoma and lower liver-related mortality than no use of aspirin, without a significantly higher risk of gastrointestinal bleeding. (Funded by the National Institutes of Health and others.).


Effects of a Long-Term Adapted Judo Program on the Health-Related Physical Fitness of Children with ASD.
Physical fitness is one of the most important physical and mental health aspects for children with Autism Spectrum Disorder (ASD). This study aimed to test the effects of a long-term adapted judo program on the health-related physical fitness of children with ASD. The participants were recruited from various associations of families and schools for children with special needs. Twenty-one children were assigned to an experimental group and nineteen to a control group. The experimental group participated in a six-month adapted judo program consisting of 90 min of practice each week. Health-related physical fitness was measured using the indicators obtained from the ALPHA-fitness battery, the estimated VO2max and the waist/height ratio0.5. Changes within and between groups were analyzed using linear mixed models for repeated measures designs and test-retest reliability of tests requiring a maximum score using the Intraclass Correlation Coefficient (ICC). A judo program tailored for children with ASD can improve the cardio-metabolic health and cardiorespiratory fitness of its participants. The problems involved with administering physical aptitude tests that involve maximum effort or performance in children with ASD cast serious doubts on the reproducibility of their results.