Associations of subclinical cardiovascular disease with frailty.
Frail health in old age has been conceptualized as a loss of physiologic reserve associated with loss of lean mass, neuroendocrine dysregulation, and immune dysfunction. Little work has been done to define frailty and describe the underlying pathophysiology. Frailty status was defined in participants of the Cardiovascular Health Study (CHS), a cohort of 5,201 community-dwelling older adults, based on the presence of three out of five clinical criteria. The five criteria included self-reported weight loss, low grip strength, low energy, slow gait speed, and low physical activity. We examined the spectrum of clinical and subclinical cardiovascular disease in those who were frail (3/5 criteria) or of intermediate frailty status (1 or 2/5 criteria), compared to those who were not frail (0/5). We hypothesized that the severity of frailty would be related to a higher prevalence of reported cardiovascular disease (CVD), as well as to a greater extent of CVD, measured by noninvasive testing. Of 4,735 eligible participants, 2,289 (48%) were not frail, 299 (6%) were frail, and 2.147 (45%) were of intermediate frailty status. Those who were frail were older (77.2 yrs) compared to those who were not frail (71.5 yrs) or intermediate (73.4 yrs) (p < .001). Frailty status was associated with clinical CVD and most strongly with congestive heart failure (odds ratio [OR] = 7.51 (95% confidence interval [CI] = 4.66-12.12). In those without a history of a CVD event (n = 1.259), frailty was associated with many noninvasive measures of CVD. Those with carotid stenosis >75% (adjusted OR = 3.41), ankle-arm index <0.8 (adjusted OR = 3.17) or 0.8-0.9 (adjusted OR = 2.01), major electrocardiography (ECG) abnormalities (adjusted OR = 1.58), greater left ventricular (LV) mass by echocardiography (adjusted OR = 1.16), and higher degree of infarct-like lesions in the brain (adjusted OR = 1.71), were more likely to be frail compared to those who were not frail. The overall associations of each of these noninvasive measures of CVD with frailty level were significant (all p < .05). Cardiovascular disease was associated with an increased likelihood of frail health. In those with no history of CVD, the extent of underlying cardiovascular disease measured by carotid ultrasound and ankle-arm index, LV hypertrophy by ECG and echocardiography, was related to frailty. Infarct-like lesions in the brain on magnet resonance imaging were related to frailty as well.


Undue industry influences that distort healthcare research, strategy, expenditure and practice: a review.
Expenditure on industry products (mostly drugs and devices) has spiraled over the last 15 years and accounts for substantial part of healthcare expenditure. The enormous financial interests involved in the development and marketing of drugs and devices may have given excessive power to these industries to influence medical research, policy, and practice. Review of the literature and analysis of the multiple pathways through which the industry has directly or indirectly infiltrated the broader healthcare systems. We present the analysis of the industry influences at the following levels: (i) evidence base production, (ii) evidence synthesis, (iii) understanding of safety and harms issues, (iv) cost-effectiveness evaluation, (v) clinical practice guidelines formation, (vi) healthcare professional education, (vii) healthcare practice, (viii) healthcare consumer's decisions. We located abundance of consistent evidence demonstrating that the industry has created means to intervene in all steps of the processes that determine healthcare research, strategy, expenditure, practice and education. As a result of these interferences, the benefits of drugs and other products are often exaggerated and their potential harms are downplayed, and clinical guidelines, medical practice, and healthcare expenditure decisions are biased. To serve its interests, the industry masterfully influences evidence base production, evidence synthesis, understanding of harms issues, cost-effectiveness evaluations, clinical practice guidelines and healthcare professional education and also exerts direct influences on professional decisions and health consumers. There is an urgent need for regulation and other action towards redefining the mission of medicine towards a more objective and patient-, population- and society-benefit direction that is free from conflict of interests.


Being enjoyably challenged is the key to an enjoyable gaming experience: an experimental approach in a first-person shooter game.
Applied to video games, Csikszentmihalyi's work on flow evidences that a positive gaming experience is intrinsically self-rewarding and primarily determined by the skill/challenge balance. A multi-layered measure of enjoyment is built to take these components into account. Gamers were asked to report the concentration-enjoyment they experienced during a first-person shooter game, and to better assess the gap between skill and challenge, the challenge enjoyment was also rated. Along with concentration level, concentration enjoyment is used to build a gaming experience typology that accounts for the self-rewarding component. An enjoyment-based challenge mapping is also drawn up, crossing challenge enjoyment and challenge level. The results show that this integrative enjoyment measure strengthens the causal link between challenge and gaming experience. Most importantly, the findings suggest that challenge or concentration-based enjoyment measures outweigh the standard concentration and difficulty measures as they are more likely to ensure a pleasant and positive experience (flow or relaxation) for the gamers. Indeed, regardless of the reported level of challenge, a gamer is more likely to have a positive experience when challenged at a level she perceives as pleasant. This article emphasizes the importance for game publishers of gathering enjoyment-based concentration and challenge assessments to ensure a positive gaming experience and gamers' commitment.


Cytochrome-oxidase blobs and intrinsic horizontal connections of layer 2/3 pyramidal neurons in primate V1.
Pyramidal neurons in superficial layers of cerebral cortex have extensive horizontal axons that provide a substrate for lateral interactions across cortical columns. These connections are believed to link functionally similar regions, as suggested by the observation that cytochrome-oxidase blobs in the monkey primary visual cortex (V1) are preferentially connected to blobs and interblobs to interblobs. To better understand the precise relationship between horizontal connections and blobs, we intracellularly labeled 20 layer 2/3 pyramidal neurons in tangential living brain slices from V1 of macaque monkeys. The locations of each cell body and the cell's synaptic boutons relative to blobs were quantitatively analyzed. We found evidence for two cell types located at characteristic distances from blob centers: (1) neurons lacking long-distance, clustered axons (somata 130-200 microm from blob centers) and (2) cells with clustered, long-distance axon collaterals (somata < 130 microm or >200 microm from blob centers). For all cells, synaptic boutons close to the cell body were located at similar distances from blob centers as the cell body. The majority of boutons from cells lacking distal axon clusters were close to their cell bodies. Cells located more than 200 microm from blob centers were in interblobs and had long-distance clustered axon collaterals selectively targeting distant interblob regions. Cells located less than 130 microm from blob centers were found within both blobs and interblobs, but many were close to traditionally defined borders. The distant synaptic boutons from these cells were generally located relatively near to blob centers, but the neurons closest to blob centers had synaptic boutons closer to blob centers than those farther away. There was not a sharp transition that would suggest specificity for blobs and interblobs as discrete, binary entities. Instead they appear to be extremes along a continuum. These observations have important implications for the function of lateral interactions within V1.


New species of Trichomycterus (Siluriformes: Trichomycteridae) from the High Andean Plateau of Argentina.
Trichomycterus varii new species, is described from a small tributary of the High Andean Plateau Region, Jujuy, Argentina. The new species is distinguished from other species of Trichomycterus by the following characters: the caudal peduncle expanded in the area of procurrent caudal-fin rays, distal tip of pelvic fin not reaching the anus when depressed, the presence of fronto-lachrymal tendon bone without lateral process, the first pectoral-fin ray terminating at the margin of the fin, the distal margin of pectoral-fin rounded, seven pectoral fin rays, 15-19 interopercular odontodes, the supraorbital sensory canal with the presence of pore s3, the infraorbital sensory canal segment with the presence of pores i1 and i3, the laterosensory canal of trunk with three sensory pores, 16 pairs of ribs, 11 precaudal vertebrae, and 25 caudal vertebrae. It closely resembles T. yuska and T. pseudosilvinichthys from northwestern Argentina and western Bolivia, but differs in head canal sensory pattern.


Holographic disk with high data transfer rate: its application to an audio response memory.
This paper describes a memory realized with a high data transfer rate using the holographic parallel-processing function and its application to an audio response system that supplies many audio messages to many terminals simultaneously. Digitalized audio messages are recorded as tiny 1-D Fourier transform holograms on a holographic disk. A hologram recorder and a hologram reader were constructed to test and demonstrate the holographic audio response memory feasibility. Experimental results indicate the potentiality of an audio response system with a 2000-word vocabulary and 250-Mbit/sec bit transfer rate.


Individual variation in locomotor behavior and maximal oxygen consumption in mice.
Individual differences in open-field activity and emotionality (number of defecations and urinations), voluntary wheel running, voluntary and forced maximal sprint running speed on a photocell-timed racetrack, swimming endurance, and maximal oxygen consumption (VO2max) were studied in 35 random bred male ICR mice. With the exception of latency in the open field and voluntary speed on a racetrack, all measurements were significantly repeatable on two successive trial days. Maximal oxygen consumption (corrected for body size) was positively correlated with amount of wheel running during each day of a 7-day test, and the correlation became stronger throughout the testing period; however, none of the daily correlations reached statistical significance. The first factor from a principal components (PC) analysis showed positive loadings (component correlations) for all measures of speed in the open field, for both voluntary and forced maximal speeds on the racetrack, and for VO2max, but a negative loading for emotionality. Wheel running and VO2max loaded positively on PC 2. Only swimming endurance loaded strongly on PC 3; this trait was uncorrelated with any other measure of physiology or behavior. These results suggest that measures of both voluntary and forced locomotor speed, as well as amount of voluntary wheel running, may be related to aerobic physiological capacities in untrained mice.


Neurocognitive and psychopathological correlates of self-monitoring ability in schizophrenia.
In a previous study reported by our group one salient finding was that many patients with schizophrenia appeared to be unable to judge their own quality of life (QoL) and that this inability was associated with negative symptoms. The association between negative symptoms, poor self-monitoring capacity and lack of insight might be explained by a common underlying factor, i.e. neurocognitive impairment. Fifty schizophrenic patients were examined by symptom ratings and a comprehensive neuropsychological test battery. The cognitive performance of the patients was very poor. The major findings of the present study were the association between clinically rated Lack of judgement (PANSS G12) and 1) a set of standard performance and executive indices of the computerised tests, and 2) difference scores between objective performance/strategies and self-ratings of the same attributes. There appears to be a substantial contribution of cognitive and executive problems to the poor judgement and lack of insight of schizophrenic patients, and these problems can to some extent be assessed objectively.


Spectral super-resolution reflectance retrieval from remotely sensed imaging spectrometer data.
Existing atmospheric correction methods retrieve surface reflectance keeping the same nominal spectral response functions (SRFs) as that of the airborne/spaceborne imaging spectrometer radiance data. Since the SRFs vary dependent on sensor type and configuration, the retrieved reflectance of the same ground object varies from sensor to sensor as well. This imposes evident limitations on data validation efforts between sensors at surface reflectance level. We propose a method to retrieve super-resolution reflectance at the surface, by combining the first-principles atmospheric correction method FLAASH (fast line-of-sight atmospheric analysis of spectral hypercubes) with spectral super-resolution of imaging spectrometer radiance data. This approach is validated by comparing airborne AVIRIS (airborne visible/infrared imaging spectrometer) and spaceborne Hyperion data. The results demonstrate that the super-resolution reflectance in spectral bands with sufficiently high signal-to-noise ratio (SNR) serves as intermediate quantity to cross validate data originating from different imaging spectrometers.


[Droperidol for the treatment of acutely agitated patients: still an option].
In Flemish emergency psychiatry droperidol is still an option for the treatment of agitation. However, its efficacy and safety are contested. To find out whether the continuing use of droperidol to treat agitation is justified on scientific grounds. Randomised controlled trials of droperidol (intramuscular or intravenous) were traced via a systematic search of the literature. These data were supplemented with a description of the drug's most important pharmacological properties and a survey of the literature on cardiac side-effects and of the place accorded to droperidol in some guidelines. The efficacy and safety of droperidol (IM/IV) were studied in 8 randomised control-led trials: 352 patients treated with droperidol. Droperidol was compared with benzodiazepines, antipsychotics and combination treatment. A single injection of droperidol was successful in 64-92% of patients. Droperidol tended to act faster and be more effective than haloperidol and lorazepam. There were very few side-effects. No clinically important cardiac side-effects were reported; this is also in keeping with evidence revealed in systematic reviews on the subject. The ecological validity of the trials was high. In spite of a decline in the popularity of droperidol in most guidelines, the drug still seems to play a valuable role in the treatment of the agitated patient. Because it acts rapidly over a short period of time and is safe to use in patients with high (co)morbidity, it is still in favour with many health professionals.


Factors determining access to oral health services among children aged less than 12 years in Peru.
Background: Understanding problems of access to oral health services requires knowledge of factors that determine access. This study aimed to evaluate factors that determine access to oral health services among children aged <12 years in Peru between 2014 and 2015. Methods: We performed a secondary data analysis of 71,614 Peruvian children aged <12 years and their caregivers. Data were obtained from the Survey on Demography and Family Health 2014-2015 (Encuesta Demográfica y de Salud Familiar - ENDES). Children's access to oral health services within the previous 6 months was used as the dependent variable (i.e. Yes/No), and the Andersen and col model was used to select independent variables. Predisposing (e.g., language spoken by tutor or guardian, wealth level, caregivers' educational level, area of residence, natural region of residence, age, and sex) and enabling factors (e.g. type of health insurance) were considered. Descriptive statistics were calculated, and multivariate analysis was performed using generalized linear models (Poisson family). Results: Of all the children, 51% were males, 56% were aged <5 years, and 62.6% lived in urban areas. The most common type of health insurance was Integral Health Insurance (57.8%), and most respondents were in the first quintile of wealth (31.6%). Regarding caregivers, the most common educational level was high school (43.02%) and the most frequently spoken language was Spanish (88.4%). Univariate analysis revealed that all variables, except sex and primary educational level, were statistically significant. After adjustment, sex, area of residence, and language were insignificant, whereas the remaining variables were statistically significant. Conclusions: Wealth index, caregivers' education level, natural region of residence, age, and type of health insurance are factors that determine access to oral health services among children aged <12 years in Peru. These factors should be considered when devising strategies to mitigate against inequities in access to oral health services.


Analysis of bacterial communities and bacterial pathogens in a biogas plant by the combination of ethidium monoazide, PCR and Ion Torrent sequencing.
The present study investigated the changes of bacterial community composition including bacterial pathogens along a biogas plant, i.e. from the influent, to the biogas reactor and to the post-digester. The effects of post-digestion temperature and time on the changes of bacterial community composition and bacterial pathogens were also studied. Microbial analysis was made by Ion Torrent sequencing of the PCR amplicons from ethidium monoazide treated samples, and ethidium monoazide was used to cleave DNA from dead cells and exclude it from PCR amplification. Both similarity and taxonomic analysis showed that the bacterial community composition in the influent was changed after anaerobic digestion. Firmicutes were dominant in all the samples, while Proteobacteria decreased in the biogas reactor compared with the influent. Variations of bacterial community composition in the biogas reactor with time were also observed. This could be attributed to varying composition of the influent. Batch experiments showed that the methane recovery from the digested residues (obtained from biogas reactor) was mainly related with post-digestion temperature. However, post-digestion time rather than temperature had a significant effect on the changes of bacterial community composition. The changes of bacterial community composition were also reflected in the changes of relative abundance of bacterial pathogens. The richness and relative abundance of bacterial pathogens were reduced after anaerobic digestion in the biogas reactor. It was found in batch experiments that bacterial pathogens showed the highest relative abundance and richness after 30 days' post-digestion. Streptococcus bovis was found in all the samples. Our results showed that special attention should be paid to the post-digestion since the increase in relative abundance of bacterial pathogens after post-digestion might reflect regrowth of bacterial pathogens and limit biosolids disposal vectors.


Efficacy of individual computer-based auditory training for people with hearing loss: a systematic review of the evidence.
Auditory training involves active listening to auditory stimuli and aims to improve performance in auditory tasks. As such, auditory training is a potential intervention for the management of people with hearing loss. This systematic review (PROSPERO 2011: CRD42011001406) evaluated the published evidence-base for the efficacy of individual computer-based auditory training to improve speech intelligibility, cognition and communication abilities in adults with hearing loss, with or without hearing aids or cochlear implants. A systematic search of eight databases and key journals identified 229 articles published since 1996, 13 of which met the inclusion criteria. Data were independently extracted and reviewed by the two authors. Study quality was assessed using ten pre-defined scientific and intervention-specific measures. Auditory training resulted in improved performance for trained tasks in 9/10 articles that reported on-task outcomes. Although significant generalisation of learning was shown to untrained measures of speech intelligibility (11/13 articles), cognition (1/1 articles) and self-reported hearing abilities (1/2 articles), improvements were small and not robust. Where reported, compliance with computer-based auditory training was high, and retention of learning was shown at post-training follow-ups. Published evidence was of very-low to moderate study quality. Our findings demonstrate that published evidence for the efficacy of individual computer-based auditory training for adults with hearing loss is not robust and therefore cannot be reliably used to guide intervention at this time. We identify a need for high-quality evidence to further examine the efficacy of computer-based auditory training for people with hearing loss.


Chemically induced virus resistance in Arabidopsis thaliana is independent of pathogenesis-related protein expression and the NPR1 gene.
Salicylic acid (SA) treatment triggers inhibition of replication or movement of several positive-sense RNA plant viruses in tobacco. This resistance can also be stimulated by nonlethal concentrations of cyanide and antimycin A (AA) without triggering induction of pathogenesis-related PR-1 protein genes. In two ecotypes of Arabidopsis thaliana (Columbia and Nössen), SA-induced resistance to a tobamovirus, Turnip vein clearing virus (TVCV), was also induced by nonlethal concentrations of cyanide and AA without concomitant induction of PR-1 gene expression. Furthermore, chemically induced resistance to TVCV, as well as the induction of the plant mitochondrial alternative oxidase (a potential target for the chemicals), was independent of NPR1, a gene that plays a key role downstream of SA in the induction of PR proteins. The chemically induced resistance to TVCV appeared to be due to inhibition of replication at the site of inoculation. Taken together, these results show that in Arabidopsis, as in tobacco, resistance to viruses can be induced via a distinct branch of the defensive signal transduction pathway. This suggests that the existence of this virus-specific branch may be widespread among plants.


Recommendations for implementation of high dose rate 192Ir brachytherapy in developing countries by the Advisory Group of International Atomic Energy Agency.
To provide recommendations for the implementation of high dose rate (HDR) 192Ir brachytherapy technology in developing countries. An Advisory Group Meeting of the International Atomic Energy Agency (IAEA) met to address the implementation of HDR 192Ir brachytherapy technology in developing countries. These recommendations reflect only the personal opinions of the authors and do not necessarily represent the opinion of the IAEA. An HDR treatment system should be purchased as a complete unit that includes the 192Ir radioactive source, source loading unit, applicators, treatment planning system, and control console. Infrastructure support may require additional or improved buildings and procurement of or access to new imaging facilities. A supportive budget is needed for quarterly source replacement and the annual maintenance necessary to keep the system operational. The radiation oncologist, medical physicist, and technologist should be specially trained before HDR can be introduced. Training for the oncologist and medical physicist is an ongoing process as new techniques or sites of treatment are introduced. Procedures for quality assurance (QA) of patient treatment, and the planning system must be introduced. Emergency procedures with adequate training of all associated personnel must be in place. The decision to select HDR in preference to alternate methods of brachytherapy is influenced by the ability of the machine to treat a wide variety of clinical sites. In departments with personnel and budgetary resources to support this equipment appropriately, economic advantage becomes evident only if large numbers of patients are treated. Intangible benefits of source safety, personnel safety, and easy adaptation to fluctuating demand for treatments also require consideration when evaluating the need to introduce this treatment system.


A mouse-to-man candidate gene study identifies association of chronic otitis media with the loci TGIF1 and FBXO11.
Chronic otitis media with effusion (COME) is the most common cause of hearing loss in children, and known to have high heritability. Mutant mouse models have identified Fbxo11, Evi1, Tgif1, and Nisch as potential risk loci. We recruited children aged 10 and under undergoing surgical treatment for COME from 35 hospitals in the UK, and their nuclear family. We performed association testing with the loci FBXO11, EVI1, TGIF1 and NISCH and sought to replicate significant results in a case-control cohort from Finland. We tested 1296 families (3828 individuals), and found strength of association with the T allele at rs881835 (p = 0.006, OR 1.39) and the G allele at rs1962914 (p = 0.007, OR 1.58) at TGIF1, and the A allele at rs10490302 (p = 0.016, OR 1.17) and the G allele at rs2537742 (p = 0.038, OR 1.16) at FBXO11. Results were not replicated. This study supports smaller studies that have also suggested association of otitis media with polymorphism at FBX011, but this is the first study to report association with the locus TGIF1. Both FBX011 and TGIF1 are involved in TGF-β signalling, suggesting this pathway may be important in the transition from acute to chronic middle ear inflammation, and a potential molecular target.


Emerging developments in RNA therapeutics.
Exciting developments have recently emerged in the field of RNA therapeutics, with potential applications in the treatment of human diseases. The second International Conference on RNA in drug development was held to highlight several novel RNA-based technologies, including different approaches to silence gene expression, the broad range of diagnostic and therapeutic applications for aptamers, and the targeting of RNA with small molecules. Highlights of the meeting included the utilisation of RNA interference to silence genes, with applications for the treatment of both cancer and viral infections, and for systemic silencing of gene expression. Novel approaches to safer drug design using aptamers were presented, which would enable control of their therapeutic activity to be achieved with antidote oligonucleotides. Updates were also presented on the clinical and preclinical development of ribozymes and aptamers, including good progress in increasing the half-life of these molecules in serum.


Whole-Slide Image Focus Quality: Automatic Assessment and Impact on AI Cancer Detection.
Digital pathology enables remote access or consults and powerful image analysis algorithms. However, the slide digitization process can create artifacts such as out-of-focus (OOF). OOF is often only detected on careful review, potentially causing rescanning, and workflow delays. Although scan time operator screening for whole-slide OOF is feasible, manual screening for OOF affecting only parts of a slide is impractical. We developed a convolutional neural network (ConvFocus) to exhaustively localize and quantify the severity of OOF regions on digitized slides. ConvFocus was developed using our refined semi-synthetic OOF data generation process and evaluated using seven slides spanning three different tissue and three different stain types, each of which were digitized using two different whole-slide scanner models ConvFocus's predictions were compared with pathologist-annotated focus quality grades across 514 distinct regions representing 37,700 35 μm × 35 μm image patches, and 21 digitized "z-stack" WSIs that contain known OOF patterns. When compared to pathologist-graded focus quality, ConvFocus achieved Spearman rank coefficients of 0.81 and 0.94 on two scanners and reproduced the expected OOF patterns from z-stack scanning. We also evaluated the impact of OOF on the accuracy of a state-of-the-art metastatic breast cancer detector and saw a consistent decrease in performance with increasing OOF. Comprehensive whole-slide OOF categorization could enable rescans before pathologist review, potentially reducing the impact of digitization focus issues on the clinical workflow. We show that the algorithm trained on our semi-synthetic OOF data generalizes well to real OOF regions across tissue types, stains, and scanners. Finally, quantitative OOF maps can flag regions that might otherwise be misclassified by image analysis algorithms, preventing OOF-induced errors.


Stable isotopes in atmospheric water vapor and applications to the hydrologic cycle.
The measurement and simulation of water vapor isotopic composition has matured rapidly over the last decade, with long-term datasets and comprehensive modeling capabilities now available. Theories for water vapor isotopic composition have been developed by extending the theories that have been used for the isotopic composition of precipitation to include a more nuanced understanding of evaporation, large-scale mixing, deep convection, and kinetic fractionation. The technologies for in-situ and remote sensing measurements of water vapor isotopic composition have developed especially rapidly over the last decade, with discrete water vapor sampling methods, based on mass spectroscopy, giving way to laser spectroscopic methods and satellite- and ground-based infrared absorption techniques. The simulation of water vapor isotopic composition has evolved from General Circulation Model (GCM) methods for simulating precipitation isotopic composition to sophisticated isotope-enabled microphysics schemes using higher-order moments for water- and ice-size distributions. The incorporation of isotopes into GCMs has enabled more detailed diagnostics of the water cycle and has led to improvements in its simulation. The combination of improved measurement and modeling of water vapor isotopic composition opens the door to new advances in our understanding of the atmospheric water cycle, in processes ranging from the marine boundary layer, through deep convection and tropospheric mixing, and into the water cycle of the stratosphere. Finally, studies of the processes governing modern water vapor isotopic composition provide an improved framework for the interpretation of paleoclimate proxy records of the hydrological cycle.


Apparent inhibition by arginine of macrocyclic b ion formation from singly charged protonated peptides.
There is now strong evidence for the existence of macrocyclic isomers of b(n)(+) ions, the formation and subsequent opening of which can lead to loss of sequence information from protonated peptides in multiple-stage tandem mass spectrometry experiments. In this study, the fragmentation patterns of protonated YARFLG and permuted isomers of the model peptide were investigated by collision-induced dissociation. Of interest was the potential influence of the arginine residue, and its position in the peptide sequence, on formation of the presumed macrocyclic b(5) ion isomer and potential loss of sequence information. We find that regardless of the sequence position (either internal or at the N- or C-terminus), only direct sequence ions or ions directly related to fragmentation of the arginine side chain are observed.


Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease.
Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.


Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.
The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone. MifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m2vs ≥35 kg/m2), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024. Between Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54-0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53-0·95; p=0·021). We found no difference in incidence of adverse events between the study groups. Treatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery. UK National Institute for Health Research Health Technology Assessment Programme.


Pd-Co nanoalloys nested on CuO nanosheets for efficient electrocatalytic N2 reduction and room-temperature Suzuki-Miyaura coupling reaction.
Due to their synergistic and tunable effects, bimetallic alloy systems have recently attracted considerable attention as superior catalysts. Herein, Pd-Co bimetallic alloy nanoparticles were uniformly deposited onto CuO nanosheet supports. This nanostructured catalyst was first shown to be an effective catalyst to convert N2 to NH3 in 0.1 M KOH with a yield of 10.04 μg h-1 mg-1cat. and a faradaic efficiency of 2.16%. The catalyst also performed well in the Suzuki-Miyaura coupling reaction at room temperature without an inert atmosphere and any toxic solvents. Thus, the catalyst is consistent with the principles of green chemistry. Due to the synergistic effects, this bimetallic Pd-Co catalyst shows higher catalytic activity than its monometallic counterparts. Moreover, the Pd/Co ratio was tuned to achieve the best catalytic performance. Finally, the Pd-Co/CuO catalyst presented good stability and recyclability. The superior catalytic activity of the bimetallic alloy catalyst make it an alternative material for catalytic applications in the future.


Comprehending the multiple 'values' of green infrastructure - Valuing nature-based solutions for urban water management from multiple perspectives.
The valuation of urban water management practices and associated nature-based solutions (NBS) is highly contested, and is becoming increasingly important to cities seeking to increase their resilience to climate change whilst at the same time facing budgetary pressures. Different conceptions of 'values' exist, each being accompanied by a set of potential measures ranging from calculative practices (closely linked to established market valuation techniques) - through to holistic assessments that seek to address wider concerns of sustainability. Each has the potential to offer important insights that often go well beyond questions of balancing the costs and benefits of the schemes concerned. However, the need to address - and go beyond - economic considerations presents policy-makers, practitioners and researchers with difficult methodological, ethical and practical challenges, especially when considered without the benefit of a broader theoretical framework or in the absence of well-established tools (as might apply within more traditional infrastructural planning contexts, such as the analysis of transport interventions). Drawing on empirical studies undertaken in Sheffield over a period of 10 years, and delivered in partnership with several other European cities and regions, we compare and examine different attempts to evaluate the benefits of urban greening options and future development scenarios. Comparing these different approaches to the valuation of nature-based solutions alongside other, more conventional forms of infrastructure - and indeed integrating both 'green and grey' interventions within a broader framework of infrastructures - throws up some surprising results and conclusions, as well as providing important sign-posts for future research in this rapidly emerging field.


Respiratory cryptosporidiosis in a patient with malignant lymphoma. Report of a case and review of the literature.
Respiratory cryptosporidiosis is a rare complication of intestinal infection by cryptosporidia, with only six cases reported (to our knowledge) since its first description in 1983. We report the first case of respiratory cryptosporidiosis recognized at the National Institutes of Health, Bethesda, Md. An antemortem diagnosis was made based on recognition of acid-fast cryptosporidia in an induced sputum specimen obtained from a 64-year-old woman with malignant lymphoma and an associated profound immunodeficiency. Autopsy confirmed the presence of cryptosporidia along the apical aspect of the respiratory epithelium lining the trachea, bronchi, and bronchioles. Cryptosporidia were also identified in the duodenum and gallbladder. Immunohistochemical staining of the paraffin-embedded autopsy lung sections using a monoclonal antibody verified the diagnosis of cryptosporidiosis. Review of our case and the literature suggests that respiratory cryptosporidiosis is characterized by a chronic tracheitis, bronchitis, and bronchiolitis but generally does not cause severe pulmonary dysfunction.


Antitumor Effects of Ethanol Extracts from Hyptis Rhomboidea in H22 Tumor-bearing Mice.
Research the antitumor effects of ethanol extracts from Hyptis rhomboidea in H22 tumor-bearing mice. At the fist-stage of the experiments, the research team took MTT method to measure the antitumor activity in vitro, then selected the most inhibitory tumor cell strain as the test object of antitumor activity in vivo, established three models of a solid tumor H22 liver cancer, ascites tumor, and immunodeficiency in male mice. From inflammatory factor, liver toxicity, in vivo antioxidant index to observe antitumor activity of ethanol extracts from H. rhomboidea. Hundred and twenty ICR male mice were used to establish three models of a solid tumor H22 liver cancer, ascites tumor, and immunodeficiency in male mice and models group of a solid tumor H22 liver cancer randomly divided into six groupshe normal control group, the model control group, the positive group (cyclophosphamide), the sample treated group (high - 1.300 g/kg, medium - 0.750 g/kg, low - 0.373 g/kg). The animals were sacrificed 15d after oral administration and tumors were taken out for the tumor weights and antitumor rates. Blood in eyeball was collected for the determination of aspartate transaminase, alanine transaminase, malondialdehyde (MDA), superoxide dismutase (SOD), interleukin (IL)-2, and tumor necrosis factor (TNF)-α in serum. Sections of tumor issue were prepared, and morphological changes in tumor tissue cells were observed using hematoxylin and eosin staining technique. The results showed that ethanol extracts from H. rhomboidea have a certain inhibitory effect on the digestive tumor cells. In solid tumor model, the inhibitory rate is up to 68.84% of the high dose of treated group from H. rhomboidea, and H. rhomboidea could improve the immune organ index, decrease the concentration of TNF-α and IL-2 in serum. In ascites tumor model, H. rhomboidea could slow down weight gain in mice and prolong the survival time; in immunodeficiency model, H. rhomboidea could improve the serum TNF-α and, IL-2 levels, increase SOD activity, and reduce MDA content, so as to achieve antitumor effect. Ethanol extracts from H. rhomboidea have obvious antitumor activity in vivo and can improve a tumor-burdened mice inflammation factors, improve the survival quality of H22 tumor mice, and enhance immunity and antitumor activity. Ethanol extracts from Hyptis rhomboidea have obvious antitumor activity without obviously liver damageThe experiment results prompt that the antitumor activity probably caused by decreasing the inflammatory factors, improve the survival quality, enhance the abnormal cytokines and scavenging free radicals, and raising autoimmune function in H22 tumor bearing mice. Abbreviations used: H. rhomboidea: Hyptis rhomboidea; AST: Aspartate transaminase; ALT: Alanine transaminase; MDA: Malondialdehyde; SOD: Superoxide dismutase; IL-2: Interleukin 2; TNF-α: Tumor Necrosis Factor-α; CTX: Cyclophosphamide.


Small Alcohols Revisited: CCSD(T) Relative Potential Energies for the Minima, First- and Second-Order Saddle Points, and Torsion-Coupled Surfaces.
The elucidation of conformations and relative potential energies (rPEs) of small molecules has a long history across a diverse range of fields. Periodically, it is helpful to revisit what conformations have been investigated and to provide a consistent theoretical framework for which clear comparisons can be made. In this paper, we compute the minima, first- and second-order saddle points, and torsion-coupled surfaces for methanol, ethanol, propan-2-ol, and propanol using consistent high-level MP2 and CCSD(T) methods. While for certain molecules more rigorous methods were employed, the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pV5Z theory level was used throughout to provide relative energies of all minima and first-order saddle points. The rPE surfaces were uniformly computed at the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVTZ level. To the best of our knowledge, this represents the most extensive study for alcohols of this kind, revealing some new aspects. Especially for propanol, we report several new conformations that were previously not investigated. Moreover, two metrics are included in our analysis that quantify how the selected surfaces are similar to one another and hence improve our understanding of the relationship between these alcohols.


A novel lysis system in PM2, a lipid-containing marine double-stranded DNA bacteriophage.
In this study we investigated the lysis system of the lipid-containing double-stranded DNA bacteriophage PM2 infecting Gram-negative marine Pseudoalteromonas species. We analysed wt and lysis-deficient phage-induced changes in the host physiology and ascribed functions to two PM2 gene products (gp) involved in lysis. We show that bacteriophage PM2 uses a novel system to disrupt the infected cell. The novelty is based on the following findings: (i) gp k is needed for the permeabilization of the cytoplasmic membrane and appears to play the role of a typical holin. However, its unique primary structure [53 aa, 1 transmembrane domain (TMD)] places it into a new class of holins. (ii) We have proposed that, unlike other bacteriophages studied, PM2 relies on lytic factors of the cellular origin for digestion of the peptidoglycan. (iii) gp l (51 aa, no TMDs) is needed for disruption of the outer membrane, which is highly rigidified by the divalent cations abundant in the marine environment. The gp l has no precedent in other phage lytic systems studied so far. However, the presence of open reading frame l-like genes in genomes of other bacterial viruses suggests that the same system might be used by other phages and is not unique to PM2.


Molecular classification as prognostic factor and guide for treatment decision of pancreatic cancer.
Clinico-pathological factors fail to consistently predict the outcome after pancreatic resection for pancreatic ductal adenocarcinoma (PDAC). PDACs show a high level of inter- and intra- tumor genetic heterogeneity. A molecular classification should help sort patients into less heterogeneous and more appropriate groups regarding the metastatic risk and the therapeutic response, with the consequences of better predicting evolution and better orienting the treatment. PDAC can be classified based on mutational subtypes and 18gene alterations. Whole-genome sequencing identified mutational signatures, mutational burden and hyper-mutated tumors with specific DNA repair defects. Their overlap/similarities allow the definition of molecular subtypes. DNA and RNA classifications can be used in prognosis assessment. They are useful in therapeutic choice for they allow the design of approaches that can predict the respective drug sensitivity of each molecular subtype. This review provides a comprehensive analysis of available molecular classifications in PDAC and how this can help guide clinical decisions.


Choosing Wisely Campaign: Valuable For Providers Who Knew About It, But Awareness Remained Constant, 2014-17.
Together with physician specialty societies, the Choosing Wisely® campaign has codified recommendations of which health care services' use should be questioned and discussed with patients. The ABIM Foundation administered surveys in 2014 and 2017 to examine physicians' attitudes toward and awareness of the use of low-value care. The surveys included questions on the factors driving that use, physicians' comfort in having conversations with patients about that use, and physicians' exposure to the Choosing Wisely campaign. Despite continued publicity and physician outreach efforts, there were no significant changes between 2014 and 2017 in awareness of the campaign among physicians (awareness increased from 21 percent to 25 percent) or physician-reported difficulty in talking to patients about avoiding a low-value service (42 percent reported that such conversations had gotten harder in 2014, and 46 percent did so in 2017). Barriers to the adoption of recommendations included malpractice concerns, patient demand and satisfaction, and physicians' desire for more information to reduce uncertainty. Multifaceted interventions that reinforce guidelines through personalized education, follow-up, and feedback, as well as aligned financial incentives, should be pursued to reduce the use of low-value services.


Evaluation of correlative coding and DP-16QAM n-channel 112Gbit/s coherent transmission: digital non-linear compensation perspective.
We numerically report on the complexity reduction of digital backward propagation (DBP) by utilizing correlative encoded transmission (dual-polarization quadrature duobinary) at a bit-rate of 112Gbit/s over 1640km fiber link. The single channel (N=1) and multi-channel (N=10) transmission performances are compared in this paper. In case of multi-channel system, 10 transmitters are multiplexed with 25GHz channel spacing. The fiber link consists of Large A(eff) Pure-Silica core fiber with 20 spans of 82km each. No in-line optical dispersion compensator is employed in the link. The system performances are evaluated by monitoring the bit-error-ratio and the forward error correction limit corresponds to bit-error-ratio of 3.8×10(-3). The DBP algorithm is implemented after the coherent detection and is based on the logarithmic step-size based split-step Fourier method. The results depict that dual-polarization quadrature duobinary can be used to transmit 112Gbit/s signals with an spectral efficiency of 4-b/s/Hz, but at the same time has a higher tolerance to nonlinear transmission impairments. By utilizing dual-polarization quadrature duobinary modulation, comparative system performance with respect to dual-polarization 16-quadrature amplitude modulation transmission can be achieved with 60% less computations and with a step-size of 205km.


Differential effects of interspecific interactions and water availability on survival, growth and fecundity of three congeneric grassland herbs.
Fitness of individual plants and of populations depends on the rates of survival, growth and fecundity. This study tested whether vital rates were differentially affected by biotic interactions and water availability. The effects of manipulations of above-ground competition (through clipping) and water availability (through water addition) on the vital rates of seedlings of three species (Viola elatior Fries, Viola pumila Chaix and Viola stagnina Kit.) were analysed in dry, mesic and wet grasslands. Water addition and grassland type had the largest effects on survival (accounting for 41 and 24% of total variation, respectively) across species. Height growth rate was positively affected by grassland type (19%) and water addition (12%) and varied among species (8%), while leaf accumulation rates and reproduction were affected by grassland type and clipping. The data suggested facilitative effects of the canopy on seedling survival in the dry grassland. This study presents evidence that environmental conditions and biotic interactions may have differential effects on seedling survival, growth and reproduction. The findings highlight the complex interplay between spatial and temporal environmental variation and biotic interactions in structuring plant communities.


Use of club drugs by HIV-seropositive and HIV-seronegative gay and bisexual men.
Club drugs such as methylenedioxymethamphetamine (MDMA, ecstasy), gamma hydroxybutyrate (GHB), and ketamine are among the fastest-growing drugs of abuse in the United States. Reports have shown that some gay and bisexual men are likely to engage in club-drug use in a myriad of venues. This is concerning given that the use of club drugs has been linked to high-risk sexual behaviors. Further, the use of club drugs by HIV-seropositive individuals may have detrimental outcomes on disease progression by either influencing adherence, resulting in drug-drug interactions with antiretrovirals, or potentially compounding immune suppression. Clinicians caring for HIV-seropositive and -seronegative individuals should be aware of the clinical effects and management guidelines associated with these chemicals. This article reviews the available literature with regard to the use of club drugs by HIV-seropositive and -seronegative gay and bisexual men. Although club-drug use may be associated with many risk behaviors for HIV infection, this review focuses on risk behavior among gay and bisexual men since this is the group for which the most data have been reported. The clinical effects and management guidelines associated with these agents are described, and the potential detrimental effects of these substances on HIV disease are discussed.


Puzzles, challenges, and information reservoir of SARS-CoV-2 quasispecies.
Upon the emergence of SARS-CoV-2 in the human population, it was conjectured that for this coronavirus the dynamic intra-host heterogeneity typical of RNA viruses would be toned down. Nothing of this sort is observed. Here we review the main observations on the complexity and diverse composition of SARS-CoV-2 mutant spectra sampled from infected patients, within the framework of quasispecies dynamics. The analyses suggest that the information provided by myriads of genomic sequences within infected individuals may have a predictive value of the genomic sequences that acquire epidemiological relevance. Possibilities to reconcile the presence of broad mutant spectra in the large RNA coronavirus genome with its encoding a 3' to 5' exonuclease proofreading-repair activity are considered. Indeterminations in the behavior of individual viral genomes provide a benefit for the survival of the ensemble. We propose that this concept falls in the domain of "stochastic thinking," a notion that applies also to cellular processes, as a means for biological systems to face unexpected needs.


Active site topology of artificial peroxidase-like hemoproteins based on antibodies constructed from a specifically designed ortho-carboxy-substituted tetraarylporphyrin.
The topology of the binding site has been studied for two monoclonal antibodies 13G10 and 14H7, elicited against iron(III)-alpha,alpha,alpha,beta-meso-tetrakis(ortho-carboxyphenyl)porph yrin [alpha,alpha,alpha, beta-Fe[(o-COOHPh)4-porphyrin]], and which exhibit in the presence of this alpha,alpha,alpha, beta-Fe[(o-COOHPh)4-porphyrin] cofactor a peroxidase activity. A comparison of the dissociation constants of the complexes of 13G10 and 14H7 with various tetra-aryl-substituted porphyrin has shown that: (a) the central iron(III) atom of alpha,alpha,alpha,beta-Fe[(o-COOHPh)4-porphyrin] is not recognized by either of the two antibodies; and (b) the ortho-carboxylate substituents of the meso-phenyl rings of alpha,alpha,alpha, beta-Fe[(o-COOHPh)4-porphyrin] are essential for the recognition of the porphyrin by 13G10 and 14H7. Measurement of the dissociation constants for the complexes of 13G10 and 14H7 with the four atropoisomers of (o-COOHPh)4-porphyrinH2 as well as mono- and di-ortho-carboxyphenyl-substituted porphyrins suggests that the three carboxylates in the alpha, alpha, beta position are recognized by both 13G10 and 14H7 with the two in the alpha, beta positions more strongly bound to the antibody protein. Accordingly, the topology of the active site of 13G10 and 14H7 has roughly two-thirds of the alpha,alpha,alpha,beta-Fe[(o-COOHPh)4-porphyrin] cofactor inserted into the binding site of the antibodies, with one of the aryl ring remaining outside. Three of the carboxylates are bound to the protein but no amino acid residue acts as an axial ligand to the iron atom. Chemical modification of lysine, histidine, tryptophan and arginine residues has shown that only modification of arginine residues causes a decrease in both the binding of alpha,alpha,alpha, beta-Fe[(o-COOHPh)4-porphyrin] and the peroxidase activity of both antibodies. Consequently, at least one of the carboxylates of the hapten is bound to an arginine residue and no amino acids such as lysine, histidine or tryptophan participate in the catalysis of the heterolytic cleavage of the O-O bond of H2O2. In addition, the amino acid sequence of both antibodies not only reveals the presence of arginine residues, which could be those involved in the binding of the carboxylates of the hapten, but also the presence of several amino acids in the complementary determining regions which could bind other carboxylates through a network of H bonds.


A large-scale immuno-epidemiological simulation of influenza A epidemics.
Agent based models (ABM) are useful to explore population-level scenarios of disease spread and containment, but typically characterize infected individuals using simplified models of infection and symptoms dynamics. Adding more realistic models of individual infections and symptoms may help to create more realistic population level epidemic dynamics. Using an equation-based, host-level mathematical model of influenza A virus infection, we develop a function that expresses the dependence of infectivity and symptoms of an infected individual on initial viral load, age, and viral strain phenotype. We incorporate this response function in a population-scale agent-based model of influenza A epidemic to create a hybrid multiscale modeling framework that reflects both population dynamics and individualized host response to infection. At the host level, we estimate parameter ranges using experimental data of H1N1 viral titers and symptoms measured in humans. By linearization of symptoms responses of the host-level model we obtain a map of the parameters of the model that characterizes clinical phenotypes of influenza infection and immune response variability over the population. At the population-level model, we analyze the effect of individualizing viral response in agent-based model by simulating epidemics across Allegheny County, Pennsylvania under both age-specific and age-independent severity assumptions. We present a framework for multi-scale simulations of influenza epidemics that enables the study of population-level effects of individual differences in infections and symptoms, with minimal additional computational cost compared to the existing population-level simulations.


Successful treatment of AIDS-related pulmonary Kaposi's sarcoma with liposomal daunorubicin.
We report a 35 year old male, human immunodeficiency virus (HIV)-infected patient with acquired immune deficiency syndrome (AIDS), who presented with rapidly progressive pulmonary Kaposi's sarcoma. The tumour regressed with treatment with liposomal daunorubicin and remained in partial remission until the patient died 12 months later from complications of HIV infection. Liposomal daunorubicin may be a safe and effective alternative to the treatment protocols in current use for pulmonary Kaposi's sarcoma.


A Serum Protein Biomarker Panel Improves Outcome Prediction in Human Traumatic Brain Injury.
Brain-enriched protein biomarkers of tissue fate are being introduced clinically to aid in traumatic brain injury (TBI) management. The aim of this study was to determine how concentrations of six different protein biomarkers, measured in samples collected during the first weeks after TBI, relate to injury severity and outcome. We included neurocritical care TBI patients that were prospectively enrolled from 2007 to 2013, all having one to three blood samples drawn during the first 2 weeks. The biomarkers analyzed were S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), tau, and neurofilament-light (NF-L). Glasgow Outcome Score (GOS) was assessed at 12 months. In total, 172 patients were included. All serum markers were associated with injury severity as classified on computed tomography scans at admission. Almost all biomarkers outperformed other known outcome predictors with higher levels the first 5 days, correlating with unfavorable outcomes, and UCH-L1 (0.260, pseduo-R2) displaying the best discrimination in univariate analyses. After adjusting for acknowledged TBI outcome predictors, GFAP and NF-L added most independent information to predict favorable/unfavorable GOS, improving the model from 0.38 to 0.51 pseudo-R2. A correlation matrix indicated substantial covariance, with the strongest correlation between UCH-L1, GFAP, and tau (r = 0.827-0.880). Additionally, the principal component analysis exhibited clustering of UCH-L1 and tau, as well as GFAP, S100B, and NSE, which was separate from NF-L. In summary, a panel of several different protein biomarkers, all associated with injury severity, with different cellular origin and temporal trajectories, improve outcome prediction models.


Vascular access for haemodialysis.
In a fifteen month period (August 1987 to November 1988) forty patients requiring haemodialysis had 83 angioaccess procedures performed. Arteriovenous (AV) shunts and arteriovenous fistulae were the commonest procedures, comprising 56 (67%) and 20 (24%) of the patients respectively. Subclavian catheters and artificial grafts were used less frequently. Nephrologists and senior house officers attached to the Renal Unit were responsible for fashioning A-V shunts and inserting subclavian catheters while the A-V fistulae were fashioned by the urologists and vascular surgeons. The commonest complication of A-V shunts were clotting, occurring in 31 (55.4%) followed by bleeding in 14 (25%). Eight (32%) of the A-V fistulae never functioned from the beginning. It is noted that we are still very dependent on A-V shunts for vascular access in end stage renal disease (ESRF) patients and this is associated with an unacceptable level of complications. This dependency on A-V shunts in ESRD patients should be stopped or phased out. A-V fistulae should be used more frequently. Their constructions should be well thought out, executed and supervised by the few surgeons who are versed in them together with their follow-ups.


Structural formation and charge storage mechanisms for intercalated two-dimensional carbides MXenes.
Although many studies have been focused on the characterization of MXenes, surface structures and formation mechanisms in terms of their experimental processes still remain controversial. Herein, we systematically investigated the structures formed from MX intercalated with different atoms from group IA to VIIA (A = H, Li, Na, K, Mg, Al, Si, P, O, S, F, and Cl) at different sites. An effective procedure based on first-principles calculations was developed to reveal the formation mechanisms of MAX, MXA2, MXTx, and MXTxAx' structures. The competition and matching mechanisms were introduced to determine the formation probabilities of the MAX phase. The transformation processes from MAX to MXA2 have been correlated with the energies and configurations of the transformed MX and the chemical potential of the A atom in terms of the experimental processes. The structure of MXTx obtained using different methods has been formulated as a function of the experimental conditions and the c lattice parameter. The experimental results can be well explained based on these results. As a representative, it was proved that the capacity of Ti3C2TxAx' (A = Li) depends on the c lattice parameter and the calculated allowable value can range from 130.3 mA h g-1 (Ti3C2F2Li) to 536.8 mA h g-1 (Ti3C2O2Li4). A higher value can be expected if the sample with a suitable c-axis value can be obtained. Energy storage mechanism should be classified into a double-layer capacitance process in the Ti3C2F2 units and a redox storage mechanism in the Ti3C2O2 units. The procedure can be employed to optimize the structures and compositions of the MXenes.


Improved outcome in adult B-cell acute lymphoblastic leukemia.
A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult multicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with > 25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65 y) with only 9% adolescents (15 to 20 y), but 28% elderly patients (50 to 65 y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2 for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2 (24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2 for 5 days, an increase of IdM to high-dose, 1,500 mg/m2 (HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (> 2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P = .04), and the overall survival rates from 0% to 49% and 51% (P = .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P = .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or > 50,000/microL, LFS 71% versus 29% (P = .003) and hemoglobin value > or < 8 g/dL, LFS 67% versus 27% (P = .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (> 50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.


A Protocol for the secure linking of registries for HPV surveillance.
In order to monitor the effectiveness of HPV vaccination in Canada the linkage of multiple data registries may be required. These registries may not always be managed by the same organization and, furthermore, privacy legislation or practices may restrict any data linkages of records that can actually be done among registries. The objective of this study was to develop a secure protocol for linking data from different registries and to allow on-going monitoring of HPV vaccine effectiveness. A secure linking protocol, using commutative hash functions and secure multi-party computation techniques was developed. This protocol allows for the exact matching of records among registries and the computation of statistics on the linked data while meeting five practical requirements to ensure patient confidentiality and privacy. The statistics considered were: odds ratio and its confidence interval, chi-square test, and relative risk and its confidence interval. Additional statistics on contingency tables, such as other measures of association, can be added using the same principles presented. The computation time performance of this protocol was evaluated. The protocol has acceptable computation time and scales linearly with the size of the data set and the size of the contingency table. The worse case computation time for up to 100,000 patients returned by each query and a 16 cell contingency table is less than 4 hours for basic statistics, and the best case is under 3 hours. A computationally practical protocol for the secure linking of data from multiple registries has been demonstrated in the context of HPV vaccine initiative impact assessment. The basic protocol can be generalized to the surveillance of other conditions, diseases, or vaccination programs.


Activity-dependent enhancement of synaptic transmission in hippocampal slices treated with the phosphatase inhibitor calyculin A.
The role of protein phosphatases in regulating synaptic transmission in the CA1 region of the hippocampus was examined using slices pretreated with calyculin A, a specific inhibitor of protein phosphatases 1 and 2A. Stimulation of afferents at 1 Hz (but not 0.1 Hz) for periods of 5-10 min caused a long-lasting enhancement of synaptic transmission. The increase in synaptic responses was not due to a change in fiber excitability, as there was a shift to the left in the input-output curve following the synaptic enhancement. The enhancement was observed only in the input that received the 1 Hz stimulation and not in an independent control pathway, indicating that the increase in synaptic strength is input specific and limited to repetitively activated synapses. Applying 1 Hz stimulation when synaptic transmission was blocked by replacing extracellular Ca2+ with Mg2+ prevented or significantly reduced any change in synaptic efficacy after reperfusion with normal Ca(2+)-containing medium. In contrast, 1 Hz stimulation given when synaptic transmission was blocked by non-NMDA and NMDA glutamate receptor antagonists still caused a synaptic enhancement following washout of the antagonists. The enhancement of synaptic transmission also was not blocked by loading CA1 cells with the calcium chelator BAPTA. Thus, influx of Ca2+ into presynaptic elements is required for the synaptic enhancement elicited by 1 Hz stimulation in calyculin A-treated hippocampal slices. Consistent with the activation of processes that cause an increase in transmitter release, the magnitude of paired-pulse facilitation decreased following the synaptic enhancement, and the NMDA receptor-mediated component of the synaptic response was increased by 1 Hz stimulation. These results suggest that when protein phosphatases are inhibited by calyculin A, prolonged periods of 1 Hz stimulation lead to activation of presynaptic Ca(2+)-dependent protein kinases, resulting in a persistent increase in evoked transmitter release. They also indicate that the activity of presynaptic protein phosphatases is critically important for limiting increases in synaptic strength following repetitive afferent activity.


Randomized controlled trial of a prenatal and postnatal lactation consultant intervention on infant health care use.
To determine whether infants of women randomized to a prenatal and postpartum lactation support intervention incur fewer otitis media-, respiratory tract-, or gastrointestinal-related visits than controls. Randomized, unmasked controlled trial recruiting women from prenatal care settings. Breastfeeding sensitive (BFS) illness visits for otitis media or respiratory tract or gastrointestinal complaints were obtained up to 12 months. Two urban community health centers. Analytic sample of 338 low-income, primarily Hispanic and/or black mother-infant dyads (n = 163 for the intervention group and n = 175 for the control group). Study lactation consultants attempted 2 prenatal meetings, 1 postpartum hospital and/or home visit, and telephone calls as needed. Controls received the standard of care. Combined outpatient and emergency department visits with illness and BFS illness diagnoses. There was a significant interaction between treatment and Medicaid; among those not receiving Medicaid, the number of otitis media visits was higher among controls (P</=.03). Visits for any illness and BFS, gastrointestinal, or respiratory tract illnesses did not differ by treatment group. Intervention group infants received more breast milk than controls, but exclusive breastfeeding rates remained low and did not differ between groups at any point. Only the number of otitis media visits was reduced, in a subset of the intervention group. The intervention did not reduce visits for respiratory tract or gastrointestinal illness. Limited intervention contact and low exclusive breastfeeding rates may have attenuated intervention effects. Future interventions designed to yield markedly increased breastfeeding rates may show greater effects in low-income multiethnic samples. Health coverage for visits may moderate intervention effects.


Farmer suicides: a qualitative study from Australia.
Farmers in Australia, in general, have poorer health outcomes, including higher rates of suicide. To investigate risk and protective factors and attitudes towards suicide and help-seeking among farmers living and working in New South Wales and Queensland in Australia. A qualitative study in which three farming sites were selected in each state to represent an area with a suicide rate equal to, below and above the state average. Focus groups were conducted with men and women separately. Focus groups involved 30 men and 33 women. Inductive thematic analysis showed three broad themes characterized responses: environment and society; community and relationships; and individual factors. There was considerable overlap and dynamic interaction between themes. A combination of individual factors, as well as social and environmental stressors, was described as most likely to increase risk of suicide death and reduce help-seeking. The vast majority of known farmer suicides described involved men and many of the issues discussed pertained specifically to male farmers. Participants found suicide as an act complex, intertwined with many factors, and hard to fathom. A common belief was that an individual must feel a complete lack of hope and perceive their situation vastly differently from others to contemplate suicide. Future suicide prevention efforts for farmers should take a biopsycho-ecological approach. Physical, psychological and cultural isolation could be addressed with education and training programmes and public campaigns. These could also improve people's ability to recognize possible suicidality.


The role of obesity and its bioclinical correlates in the progression of chronic kidney disease.
In spite of a progressive fall in the incidence of traditional risk factors of cardiovascular morbidity (cigarette smoking, high blood pressure, and hyperlipidemia), there is an upward trend in the prevalence of obesity and chronic kidney disease (CKD). Furthermore, there is a strong correlation between body mass indices and the relative risk of progression of CKD. The close biophysiological interaction between obesity and CKD is evident by a similar occurrence of comorbidities including insulin resistance, hyperlipidermia, endothelial dysfunction, and sleep disorders. Truncal obesity is a primary component of metabolic syndrome; unlike peripheral fat, the visceral adipocytes are more resistant to insulin. In addition, lipolysis results in a release of free fatty acid and TG, whereas hypertriglycedemia is potentiated by uremic activation of fatty acid synthase. Hypertriglycedemia and low HDL cholesterol increase the relative risk of progression of CKD. Furthermore, endothelial inflammation and premature atherosclerosis are promoted by hyperhomocysteinemia and oxidation of LDL, both of which are commonly observed in CKD and obesity. Predominance of oxidative stress in both obesity and azotemia stimulate synthesis of angiotensin II, which in turn increases TGF-B and plasminogen activator inhibitor-1, thereby propagating glomerular fibrosis. Furthermore, local synthesis of angiotensinogen by adipocytes, leptin activation of sympathetic nervous system, and hyperinsulinemia contribute to the development of hypertension in obesity and CKD. In addition, increased renal tubular expression of Na-K-ATPase and a blunted response to natiuretic hormones in obesity promote salt and water retention. Glomerular hyperfiltration from systemic volume load and hypertension results in mesangial cellular proliferation and progressive renal fibrosis. In addition, maternal nutritional deprivation increases the incidence of obesity, hypertension, and diabetes in adulthood. Reduced fetal protein synthesis contributes to oxidative glomerular injury and impairment of renal morphogenesis. Thus, kidneys are poorly equipped to handle physiologic stress that may result from the rapid body growth and programmed metabolic dysfunction later in life. Finally, in order to minimize morbidity of obesity-related kidney disease, preventive strategy must include optimal maternal health care, promotion of healthy nutrition and routine physical exercise, and early detection of CKD.


Distribution of variable vs fixed costs of hospital care.
Most strategies proposed to control the rising cost of health care are aimed at reducing medical resource consumption rates. These approaches may be limited in effectiveness because of the relatively low variable cost of medical care. Variable costs (for medication and supplies) are saved if a facility does not provide a service while fixed costs (for salaried labor, buildings, and equipment) are not saved over the short term when a health care facility reduces service. To determine the relative variable and fixed costs of inpatient and outpatient care for a large urban public teaching hospital. Cost analysis. A large urban public teaching hospital. All expenditures for the institution during 1993 and for each service were categorized as either variable or fixed. Fixed costs included capital expenditures, employee salaries and benefits, building maintenance, and utilities. Variable costs included health care worker supplies, patient care supplies, diagnostic and therapeutic supplies, and medications. In 1993, the hospital had nearly 114000 emergency department visits, 40000 hospital admissions, 240000 inpatient days, and more than 500000 outpatient clinic visits. The total budget for 1993 was $429.2 million, of which $360.3 million (84%) was fixed and $68.8 million (16%) was variable. Overall, 31.5% of total costs were for support expenses such as utilities, employee benefits, and housekeeping salaries, and 52.4% included direct costs of salary for service center personnel who provide services to individual patients. The majority of cost in providing hospital service is related to buildings, equipment, salaried labor, and overhead, which are fixed over the short term. The high fixed costs emphasize the importance of adjusting fixed costs to patient consumption to maintain efficiency.


The psychosocial effects of torture, mass human rights violations, and refugee trauma: toward an integrated conceptual framework.
Torture is a complex trauma that often occurs within the context of widespread persecution and human rights violations. In addition, the nature of modern warfare is such that whole populations are at risk of suffering extensive trauma, injustices, loss, and displacement. Refugees, in particular, experience sequential stresses that may compound each other over prolonged periods of time. The present overview examines whether contemporary notions of trauma, and especially a focus on the category of posttraumatic stress disorder (PTSD), are adequate in assessing the multiple effects of such experiences. Recent studies are reviewed to indicate the strengths and limitations of current research approaches. Rates of PTSD in such studies have varied with relatively low rates being found in recent epidemiologic studies undertaken on refugee populations. It is suggested that a focus on intervening psychosocial adaptive systems may assist in delineating more clearly the pathways that determine whether traumatized persons achieve psychosocial restitution or are at risk of ongoing psychiatric disability. A model is proposed which suggests that torture and related abuses may challenge five core adaptive systems subserving the functions of "safety," "attachment," "justice," "identity-role," and "existential-meaning." It is argued that a clearer delineation of such adaptive systems may provide a point of convergence that may link research endeavors more closely to the subjective experience of survivors and to the types of clinical interventions offered by trauma treatment services.


A novel interferon-gamma regulated human melanoma-associated antigen, gp33-38, defined by monoclonal antibody Me14-D12. II. Molecular cloning of a genomic probe.
The human Me14-D12 antigen is a cell surface glycoprotein regulated by interferon-gamma (IFN-gamma) on tumor cell lines of neuroectodermal origin. It consists of two non-convalently linked subunits with apparent mol. wt sizes of 33,000 and 38,000. Here we describe the molecular cloning of a genomic probe for the Me14-D12 gene using the gene transfer approach. Mouse Ltk- cells were stably cotransfected with human genomic DNA and the Herpes Simplex virus thymidine kinase (TK) gene. Primary and secondary transfectants expressing the Me14-D12 antigen were isolated after selection in HAT medium by repeated sorting on a fluorescence activated cell sorter (FACS). A recombinant phage harboring a 14.3 kb insert of human DNA was isolated from a genomic library made from a positive secondary transfectant cell line. A specific probe derived from the phage DNA insert allowed the identification of two mRNAs of 3.5 kb and 2.2 kb in primary and secondary L cell transfectants, as well as in human melanoma cell lines expressing the Me14-D12 antigen. The regulation of Me14-D12 antigen by INF-gamma was retained in the L cell transfectants and could be detected both at the level of protein and mRNA expression.


Nationwide Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS).
To evaluate the safety and efficacy of brachytherapy with permanent iodine-125 seed implantation (PI) for prostate cancer. The nationwide Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS) has continued since July 2005. This manuscript presents the rationale, J-POPS study design, and the characteristics of initial participants enrolled in this study from July 2005 to June 2007. All participants were treated with PI in accordance with the American Brachytherapy Society recommendations. The primary outcome measure was biochemical progression-free survival. Progression-free survival, overall survival, cause-specific survival, longitudinal changes in health-related quality of life, disease-specific quality of life, the International Prostate Symptom Score, and the incidence of adverse events were also investigated as secondary outcome measurements. Overall, 6,927 patients were enrolled by the end of 2010, that is approximately 40 % of all cases treated around the country. During the first 2 years, 2,354 participants were enrolled and 2,339 were actually treated with PI. The age range of participants was 45 to 89 years (median 69 years) and their risk classifications were 1,037 (44.3 %) at low risk, 1,126 (48.1 %) at intermediate risk, and 134 (5.7 %) at high risk, in addition to 16 participants whose classification was unknown. Of all patients, 76.6 % were treated with PI without external beam radiation therapy and 49.3 % received neoadjuvant hormone therapy. The J-POPS, a nationwide prospective cohort study that enrolled approximately 40 % of all PI cases in Japan, will provide highly reliable evidence, including outcomes and quality of life, after long-term follow-up.


A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival.
The extent of tumor resection that should be undertaken in patients with glioblastoma multiforme (GBM) remains controversial. The purpose of this study was to identify significant independent predictors of survival in these patients and to determine whether the extent of resection was associated with increased survival time. The authors retrospectively analyzed 416 consecutive patients with histologically proven GBM who underwent tumor resection at the authors' institution between June 1993 and June 1999. Volumetric data and other tumor characteristics identified on magnetic resonance (MR) imaging were collected prospectively. Five independent predictors of survival were identified: age, Karnofsky Performance Scale (KPS) score, extent of resection, and the degree of necrosis and enhancement on preoperative MR imaging studies. A significant survival advantage was associated with resection of 98% or more of the tumor volume (median survival 13 months, 95% confidence interval [CI] 11.4-14.6 months), compared with 8.8 months (95% CI 7.4-10.2 months; p < 0.0001) for resections of less than 98%. Using an outcome scale ranging from 0 to 5 based on age, KPS score, and tumor necrosis on MR imaging, we observed significantly longer survival in patients with lower scores (1-3) who underwent aggressive resections, and a trend toward slightly longer survival was found in patients with higher scores (4-5). Gross-total tumor resection is associated with longer survival in patients with GBM, especially when other predictive variables are favorable.


A Planar Microfluidic Mixer Based on Logarithmic Spirals.
A passive, planar micromixer design based on logarithmic spirals is presented. The device was fabricated using polydimethylsiloxane soft photolithography techniques, and mixing performance was characterized via numerical simulation and fluorescent microscopy. Mixing efficiency initially declined as Reynolds number increased, and this trend continued until a Reynolds number of 15 where a minimum was reached at 53%. Mixing efficiency then began to increase reaching a maximum mixing efficiency of 86% at Re = 67. Three-dimensional simulations of fluid mixing in this design were compared to other planar geometries such as the Archimedes spiral and Meandering-S mixers. The implementation of logarithmic curvature offers several unique advantages that enhance mixing, namely a variable cross-sectional area and a logarithmically varying radius of curvature that creates 3-D Dean vortices. These flow phenomena were observed in simulations with multilayered fluid folding and validated with confocal microscopy. This design provides improved mixing performance over a broader range of Reynolds numbers than other reported planar mixers, all while avoiding external force fields, more complicated fabrication processes, and the introduction of flow obstructions or cavities that may unintentionally affect sensitive or particulate-containing samples. Due to the planar design requiring only single-step lithographic features, this compact geometry could be easily implemented into existing micro-total analysis systems requiring effective rapid mixing.


Endovascular treatment of intracranial microarteriovenous malformations.
Microarteriovenous malformations (micro-AVMs) are an uncommon subgroup of brain AVMs defined by a nidus measuring < 1 cm in diameter. The clinical features, angiographic characteristics, and outcomes in patients with micro-AVMs who had been treated endovascularly after presenting with hemorrhage were reviewed to identify common features affecting prognosis. Between 1997 and 2006, 25 patients (12 females and 13 males) with 26 micro-AVMs were treated. Twenty-four patients presented with intracerebral hematoma and 1 with subarachnoid hemorrhage only. All patients underwent CT on admission, diagnostic cerebral angiography, and 1 session of endovascular treatment during the acute phase. Procedure-related complications occurred in 3 patients (12%), which caused temporary hemiparesis in 1 (4%) and no clinical sequelae in 2 patients (8%). Complete nidus obliteration was achieved at the end of the embolization in 22 (84.6%) of 26 lesions. Two recurrences were evident on follow-up angiography 6 months postembolization, resulting in a complete obliteration rate of 77% (20 of 26 lesions) after a single treatment. Late angiography was performed in 12 patients, and no further recurrences were identified. Immediate complete obliteration of a micro-AVM with a high permanent cure and low morbidity rates was accomplished using endovascular treatment. Early embolization after bleeding should be considered as an alternative to resection.


The genetics and genomics of the drought response in Populus.
The genetic nature of tree adaptation to drought stress was examined by utilizing variation in the drought response of a full-sib second generation (F(2)) mapping population from a cross between Populus trichocarpa (93-968) and P. deltoides Bart (ILL-129) and known to be highly divergent for a vast range of phenotypic traits. We combined phenotyping, quantitative trait loci (QTL) analysis and microarray experiments to demonstrate that 'genetical genomics' can be used to provide information on adaptation at the species level. The grandparents and F(2) population were subjected to soil drying, and contrasting responses to drought across genotypes, including leaf coloration, expansion and abscission, were observed, and QTL for these traits mapped. A subset of extreme genotypes exhibiting extreme sensitivity and insensitivity to drought on the basis of leaf abscission were defined, and microarray experiments conducted on these genotypes and the grandparent species. The extreme genotype groups induced a different set of genes: 215 and 125 genes differed in their expression response between groups in control and drought, respectively, suggesting species adaptation at the gene expression level. Co-location of differentially expressed genes with drought-specific and drought-responsive QTLs was examined, and these may represent candidate genes contributing to the variation in drought response.


The merits of unconscious thought in creativity.
Research has yielded weak empirical support for the idea that creative solutions may be discovered through unconscious thought, despite anecdotes to this effect. To understand this gap, we examined the effect of unconscious thought on two outcomes of a remote-association test (RAT): implicit accessibility and conscious reporting of answers. In Experiment 1, which used very difficult RAT items, a short period of unconscious thought (i.e., participants were distracted while holding the goal of solving the RAT items) increased the accessibility of RAT answers, but did not increase the number of correct answers compared with an equal duration of conscious thought or mere distraction. In Experiment 2, which used moderately difficult RAT items, unconscious thought led to a similar level of accessibility, but fewer correct answers, compared with conscious thought. These findings confirm and extend unconscious-thought theory by demonstrating that processes that increase the mental activation of correct solutions do not necessarily lead them into consciousness.


Regionalization versus competition in complex cancer surgery.
The empirical association between high hospital procedure volume and lower mortality rates has led to recommendations for the regionalization of complex surgical procedures. While regionalization may improve outcomes, it also reduces market competition, which has been found to lower prices and improve health care quality. This study estimates the potential net benefits of regionalizing the Whipple surgery for pancreatic cancer patients. We confirm that increased hospital volume and surgeon volume are associated with lower inpatient mortality rates. We then predict the price and outcome consequences of concentrating Whipple surgery at hospitals that perform at least two, four, and six procedures respectively per year. Our consumer surplus calculations suggest that regionalization can increase consumer surplus, but potential price increases extract over half of the value of reduced deaths from regionalization. We reach three conclusions. First, regionalization can increase consumer surplus, but the benefits may be substantially less than implied by examining only the outcome side of the equation. Second, modest changes in outcomes due to regionalization may lead to decreases in consumer surplus. Third, before any regionalization policy is implemented, a deep and precise understanding of the nature of both outcome/volume and price/competition relationships is needed.


Conservative and liberal attitudes drive polarized neural responses to political content.
People tend to interpret political information in a manner that confirms their prior beliefs, a cognitive bias that contributes to rising political polarization. In this study, we combined functional magnetic resonance imaging with semantic content analyses to investigate the neural mechanisms that underlie the biased processing of real-world political content. We scanned American participants with conservative-leaning or liberal-leaning immigration attitudes while they watched news clips, campaign ads, and public speeches related to immigration policy. We searched for evidence of "neural polarization": activity in the brain that diverges between people who hold liberal versus conservative political attitudes. Neural polarization was observed in the dorsomedial prefrontal cortex (DMPFC), a brain region associated with the interpretation of narrative content. Neural polarization in the DMPFC intensified during moments in the videos that included risk-related and moral-emotional language, highlighting content features most likely to drive divergent interpretations between conservatives and liberals. Finally, participants whose DMPFC activity closely matched that of the average conservative or the average liberal participant were more likely to change their attitudes in the direction of that group's position. Our work introduces a multimethod approach to study the neural basis of political cognition in naturalistic settings. Using this approach, we characterize how political attitudes biased information processing in the brain, the language most likely to drive polarized neural responses, and the consequences of biased processing for attitude change. Together, these results shed light on the psychological and neural underpinnings of how identical information is interpreted differently by conservatives and liberals.


Evaluation of an automated, homogeneous enzyme immunoassay for serum thyroxine measurement in dog and cat serum.
A homogenous enzyme immunoassay (EIA) for measurement of serum thyroxine (T4) concentration was evaluated for use with canine and feline serum. The EIA method was linear from 0 to 150 nmol T4/L for human serum, 0 to 94 nmol T4/L for feline serum and 10 to 60 nmol T4/L for canine serum. Intra- and interassay precision studies yielded coefficients of variation </= 8% using single point measurements. Method comparison studies gave close agreement between radioimmunoassay (RIA) and EIA results. Correlation coefficients (r values) were 0.88 and 0.97 for canine and feline samples respectively, after application of species-specific factors to correct the calibrator values assigned for human serum samples. The EIA showed no interference from hemolysis at hemoglobin concentrations </= 20 g/L or from moderate lipemia. Highly lipemic specimens could be tested after centrifugation to clarify the sample. The EIA showed less interference from autoantibodies to T4 than the RIA method. The EIA method allows automation of T4 testing in a veterinary hospital or laboratory, and can be integrated with the routine clinical chemistry panel.


A multi centre randomized open label trial of chloroquine for the treatment of adults with SARS-CoV-2 infection in Vietnam.
Background: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. There is currently no vaccine to prevent COVID-19 or therapeutic agent to treat COVID-19. This clinical trial is designed to evaluate chloroquine as a potential therapeutic for the treatment of hospitalised people with COVID-19. We hypothesise that chloroquine slows viral replication in patients with COVID-19, attenuating the infection, and resulting in more rapid decline of viral load in throat/nose swabs. This viral attenuation should be associated with improved patient outcomes. Method: The study will start with a 10-patient prospective observational pilot study following the same entry and exclusion criteria as for the randomized trial and undergoing the same procedures. The main study is an open label, randomised, controlled trial with two parallel arms of standard of care (control arm) versus standard of care with 10 days of chloroquine (intervention arm) with a loading dose over the first 24 hours, followed by 300mg base orally once daily for nine days. The study will recruit patients in three sites in Ho Chi Minh City, Vietnam: the Hospital for Tropical Diseases, the Cu Chi Field Hospital, and the Can Gio COVID hospital. The primary endpoint is the time to viral clearance from throat/nose swab, defined as the time following randomization until the midpoint between the last positive and the first of the negative throat/nose swabs. Viral presence will be determined using RT-PCR to detect SARS-CoV-2 RNA. Discussion: The results of the study will add to the evidence-based guidelines for management of COVID-19. Given the enormous experience of its use in malaria chemoprophylaxis, excellent safety and tolerability profile, and its very low cost, if proved effective then chloroquine would be a readily deployable and affordable treatment for patients with COVID-19. Trial registration: Clinicaltrials.gov NCT04328493 31/03/2020.