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Overlapping and distinct neural networks supporting novel word learning in bilinguals and monolinguals
No full textThis study investigated how bilingual experience alters neural mechanisms supporting novel word learning. We hypothesised that novel words elicit increased semantic activation in the larger bilingual lexicon, potentially stimulating stronger memory integration than in monolinguals. English monolinguals and Spanish–English bilinguals were trained on two sets of written Swahili–English word pairs, one set on each of two consecutive days, and performed a recognition task in the MRI-scanner. Lexical integration was measured through visual primed lexical decision. Surprisingly, no group difference emerged in explicit word memory, and priming occurred only in the monolingual group. This difference in lexical integration may indicate an increased need for slow neocortical interleaving of old and new information in the denser bilingual lexicon. The fMRI data were consistent with increased use of cognitive control networks in monolinguals and of articulatory motor processes in bilinguals, providing further evidence for experience-induced neural changes: monolinguals and bilinguals reached largely comparable behavioural performance levels in novel word learning, but did so by recruiting partially overlapping but non-identical neural systems to acquire novel words
Slip-rate on the Main Köpetdag (Kopeh Dagh) strike-slip fault, Turkmenistan, and the active tectonics of the South Caspian
No full textWe provide the first measurement of strike-slip and shortening rates across the 200-kmlong right-lateral strike-slip Main Köpetdag† Fault (MKDF) in Turkmenistan. Strike-slip and shortening components are accommodated on parallel structures separated by ~10 km. Using Infra-red-stimulated luminescence and reconstruction of offset alluvial fans we find a right lateral rate of 9.1 ± 1.3 mm/yr averaged over 100 ± 5 ka, and a shortening rate of only ~0.3 mm/yr averaged over 35 ± 4 ka across the frontal thrust, though additional shortening is likely to be accommodated locally by folding and faulting, and regionally within the eastern Caspian lowlands to its south. The MKDF is estimated to have ~35 km of cumulative right-lateral slip which, if these geological measurements are correct, would accumulate in only 3-5 Ma at the rate we have determined, suggesting that the present tectonic configuration started within that time period. We use the MKDF slip-rate to form a velocity triangle, from which we estimate the Iran South Caspian and Eurasia-South Caspian shortening rates, and show that the South Caspian Basin moves at 10.4 +/- 1.1 mm/yr in direction 333⁰ +/- 5 relative to Eurasia and at 4.8 +/- 0.8 mm/yr in direction 236⁰ +/- 14 relative to Iran. In contrast to both the eastern Köpetdag and the Caspian lowlands the MKDF has little recent or historical seismicity. The rapid slip-rate estimated here suggests that it is a zone of high earthquake hazard
Advances in microfluidic in vitro systems for neurological disease modeling
No full textNeurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure-prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro-engineer cell-scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to "Organ-on-chip" models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and "Organ-on-chip" systems have enabled new understanding of metabolic coupling and blood-brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro-pathophysiological systems, moving from "Organ-on-chip" to "Disease-on-chip." This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases
Variation in referral rates to emergency departments and inpatient services from a GP Out Of Hours service and the potential impact of alternative staffing models
No full textIntroduction: Out of hours (OOH) primary care is a critical component of the acute care system overnight
and at weekends. Referrals from OOH services to hospital will add to the burden on hospital assessment in the Emergency Department (ED) and on call specialties.
Methods: We studied the variation in referral rates (to the emergency department and direct specialty
admission) of individual clinicians working in the Oxfordshire, UK OOH service covering a population of 600,000 people. We calculated the referral probability for each clinician over
a 13 month period of practice (1.12.14 – 31.12.2015), stratifying by clinician factors and location and timing of assessment. We used Simul8 software to determine the range of hospital referrals potentially due to variation in clinician referral propensity.
Results: Among the 119,835 contacts with the service, 5,261 (4.4%) were sent directly to the ED and
3,474 (3.7%) were admitted directly to specialties. More referrals were made to ED by primary care physicians if they didn’t work in the local practices (5.5% vs 3.5% P = 0.011).
For clinicians with >1000 consultations, percentage of patients referred varied from 1% to 21% of consultations. Simulations where propensity to refer was made less extreme showed
a difference in maximum referrals of 50 patients each week.
Conclusions: There is substantial variation in clinician referral rates from out of hours primary care to the acute hospital setting. The number of patients referred could be influenced by this variation in clinician behaviour. Referral propensity should be studied including casemix adjustment to determine if interventions targeting such behaviour are effective
A high-dose 24-hour tranexamic acid infusion for the treatment of significant gastrointestinal bleeding: HALT-IT RCT
No full textBackground
Tranexamic acid reduces blood loss in surgery and the risk of death in trauma patients. Meta-analyses of small trials suggest that tranexamic acid decreases the number of deaths from gastrointestinal bleeding, but these meta-analyses are prone to selection bias.
Objective
The trial provides reliable evidence of the effect of tranexamic acid on mortality, rebleeding and complications in significant acute gastrointestinal bleeding.
Design
A multicentre, randomised, placebo-controlled trial and economic analysis. Patients were assigned by selecting one treatment pack from a box of eight, which were identical apart from the pack number. Patients, caregivers and outcome assessors were masked to allocation. The main analyses were by intention to treat.
Setting
The setting was 164 hospitals in 15 countries, co-ordinated from the London School of Hygiene & Tropical Medicine.
Participants
Adults with significant upper or lower gastrointestinal bleeding (n = 12,009) were eligible if the responsible clinician was substantially uncertain about whether or not to use tranexamic acid. The clinical diagnosis of significant bleeding implied a risk of bleeding to death, including hypotension, tachycardia or signs of shock, or urgent transfusion, endoscopy or surgery.
Intervention
Tranexamic acid (a 1-g loading dose over 10 minutes, then a 3-g maintenance dose over 24 hours) or matching placebo.
Main outcome measures
The primary outcome was death due to bleeding within 5 days of randomisation. Secondary outcomes were all-cause and cause-specific mortality; rebleeding; need for endoscopy, surgery or radiological intervention; blood product transfusion; complications; disability; and days spent in intensive care or a high-dependency unit.
Results
A total of 12,009 patients were allocated to receive tranexamic acid (n = 5994, 49.9%) or the matching placebo (n = 6015, 50.1%), of whom 11,952 (99.5%) received the first dose. Death due to bleeding within 5 days of randomisation occurred in 222 (3.7%) patients in the tranexamic acid group and in 226 (3.8%) patients in the placebo group (risk ratio 0.99, 95% confidence interval 0.82 to 1.18). Thromboembolic events occurred in 86 (1.4%) patients in the tranexamic acid group and 72 (1.2%) patients in the placebo group (risk ratio 1.20, 95% confidence interval 0.88 to 1.64). The risk of arterial thromboembolic events (myocardial infarction or stroke) was similar in both groups (0.7% in the tranexamic acid group vs. 0.8% in the placebo group; risk ratio 0.92, 95% confidence interval 0.60 to 1.39), but the risk of venous thromboembolic events (deep-vein thrombosis or pulmonary embolism) was higher in tranexamic acid-treated patients than in placebo-treated patients (0.8% vs. 0.4%; risk ratio 1.85, 95% confidence interval 1.15 to 2.98). Seizures occurred in 38 patients who received tranexamic acid and in 22 patients who received placebo (0.6% vs. 0.4%, respectively; risk ratio 1.73, 95% confidence interval 1.03 to 2.93). In the base-case economic analysis, tranexamic acid was not cost-effective and resulted in slightly poorer health outcomes than no tranexamic acid.
Conclusions
Tranexamic acid did not reduce death from gastrointestinal bleeding and, although inexpensive, it is not cost-effective in adults with acute gastrointestinal bleeding.
Future work
These results caution against a uniform approach to the management of patients with major haemorrhage and highlight the need for randomised trials targeted at specific pathophysiological processes.
Limitations
Although this is one of the largest randomised trials in gastrointestinal bleeding, we cannot rule out a modest increase or decrease in death due to bleeding with tranexamic acid.
Trial registration
Current Controlled Trials ISRCTN11225767, ClinicalTrials.gov NCT01658124 and EudraCT 2012-003192-19.
Funding
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 58. See the NIHR Journals Library website for further project information
Knowledge from probability
No full textWe give a probabilistic analysis of inductive knowledge and belief and explore its predictions concerning knowledge about the future, about laws of nature, and about the values of inexactly measured quantities. The analysis combines a theory of knowledge and belief formulated in terms of relations of comparative normality with a probabilistic reduction of those relations. It predicts that only highly probable propositions are believed, and that many widely held principles of belief-revision fail
Finding signs of life on Earth-like planets: high-resolution transmission spectra of Earth through time around FGKM stars
No full textThousands of transiting exoplanets have already been detected orbiting a wide range of host stars, including the first planets that could potentially be similar to Earth. The upcoming Extremely Large Telescopes and the James Webb Space Telescope will enable the first searches for signatures of life in transiting exoplanet atmospheres. Here, we quantify the strength of spectral features in transit that could indicate a biosphere similar to the modern Earth on exoplanets orbiting a wide grid of host stars (F0 to M8) with effective temperatures between 2500 and 7000 K: transit depths vary between about 6000 ppm (M8 host) to 30 ppm (F0 host) due to the different sizes of the host stars. CO2 possess the strongest spectral features in transit between 0.4 and 20 μm. The atmospheric biosignature pairs O2+CH4 and O3+CH4—which identify Earth as a living planet—are most prominent for Sun-like and cooler host stars in transit spectra of modern Earth analogs. Assessing biosignatures and water on such planets orbiting hotter stars than the Sun will be extremely challenging even for high-resolution observations. All high-resolution transit spectra and model profiles are available online: they provide a tool for observers to prioritize exoplanets for transmission spectroscopy, test atmospheric retrieval algorithms, and optimize observing strategies to find life in the cosmos. In the search for life in the cosmos, transiting planets provide the first opportunity to discover whether or not we are alone, with this database as one of the keys to optimize the search strategies
Genetic architectures of proximal and distal colorectal cancer are partly distinct
No full textObjective: an understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.
Design: to identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48,214 CRC cases and 64,159 controls of European ancestry. We characterized effect heterogeneity at CRC risk loci using multinomial modeling.
Results: We identified 13 loci that reached genome-wide significance (P<5×10-8) and that were not reported by previous GWAS for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.
Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumor
Disseminating public health messages about second-hand smoking through mosque congregations in Bangladesh
No full textMaking flowers speak: Petrarch and idiorrhythmy
No full textThis article brings Petrarch’s (1304–74) lyric poetry into dialogue with Barthes’s
notion of “idiorrythmie” (idiorrhythmy) as outlined in his lecture course Comment vivre
ensemble (How to Live Together). It explores both the idiorrhythmic aspects of Petrarchan desire
and the traits of lyric utterance through which they are expressed, with a focus on canzone 126 of
Petrarch’s Rerum vulgarium fragmenta (Fragments of Vernacular Things). The article begins
with a study of Barthes’s exposition of idiorrhythmy: its medieval origins in the monastic
communities of Mount Athos and the productively unstable and improvised character of the
“living together,” and apart, that it implies. Most significant for the analysis that follows is
idiorrhythmy’s relationship to eros, Barthes’s idea that idiorrhythmy preserves a space for the
body’s desires in opening to interruptions, deviations, and digressions. The remainder of the
article offers a close reading of Petrarch’s Rvf 126, focusing on one image in the poem that, like
Barthes’s idiorrhythmy, is rooted in fantasy and embraces errancy: the image of a flower that
turning and falling around the poet’s beloved seems to speak of love