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Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
In this brief report, computed tomography perfusion (CTP) thresholds predicting follow-up infarction in patients presenting <3 hours from stroke onset and achieving ultra-early reperfusion (<45 minutes from CTP) are reported. CTP thresholds that predict follow-up infarction vary based on time to reperfusion: Tmax >20 to 23 seconds and cerebral blood flow <5 to 7 ml/min−1/(100 g)−1 or relative cerebral blood flow <0.14 to 0.20 optimally predicted the final infarct. These thresholds are stricter than published thresholds.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
OBJECTIVES/SPECIFIC AIMS: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of ~16 months. Novel methods to improve local control are needed. Nab-paclitaxel (abraxane) has shown efficacy in pancreatic cancer and is FDA approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced disease. METHODS/STUDY POPULATION: We performed a phase 1 study using a 3+3 dose-escalation strategy to determine the safety and tolerability of dose escalated nab-paclitaxel with fractionated radiotherapy for patients with unresectable or borderline resectable pancreatic cancer. Following induction chemotherapy with 2 cycles of nab-paclitaxel and gemcitabine, patients were treated with weekly nab-paclitaxel and daily radiotherapy to a dose of 52.5 Gy in 25 fractions. Final dose-limiting toxicity (DLT) determination was performed at day 65 after the start of radiotherapy. RESULTS/ANTICIPATED RESULTS: Nine patients received nab-paclitaxel at a dose level of either 100 mg/m2 (n=3) or 125 mg/m2 (n=6). One DLT (grade 3 neuropathy) was observed in a patient who received 125 mg/m2 of nab-paclitaxel. Other grade 3 toxicities included fatigue (11%), anemia (11%), and neutropenia (11%). No grade 4 toxicities were observed. With a median follow-up of 8 months (range 5–28 months), median survival was 19 months and median progression-free survival was 10 months. Following chemoradiation, 3 patients underwent surgical resection, all with negative margins and limited tumor viability. Of the 3 patients, 2 initially had borderline resectable tumors and 1 had an unresectable tumor. Tumor (SMAD-4, Caveolin-1) and peripheral (circulating tumor cells and microvesicles) biomarkers were collected and are being analyzed. DISCUSSION/SIGNIFICANCE OF IMPACT: The combination of fractionated radiation and weekly nab-paclitaxel was safe and well tolerated. This regimen represents a potentially promising therapy for patients with unresectable and borderline resectable pancreatic cancer and warrants further investigation.
Belle Époque Belgium recorded an unprecedented trade boom. Exploiting a new granular trade dataset, we find that the number of products delivered abroad and destinations serviced more than doubled in less than 40 years. To explain this remarkable achievement, we study the relationship between trade costs and the intensive and extensive margins of trade. The establishment of a foreign diplomatic network that lowered beachhead costs and enabled the entry of new products was an essential fact of the trade boom. Interestingly, the expansion in trade in certain sectors did not translate into faster productivity growth. We offer some explanations.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
This paper will discuss the structure-property model developed that correlates the tensile modulus to the elastic properties and angular distribution of constituent graphitic layers for carbon fiber derived from a polyethylene precursor. In addition, a high-temperature fiber tensile device was built to enable heating of carbon fiber bundles at a variable rate from 25 °C to greater than ∼2300 °C, while simultaneously applying a tensile stress. This capability combined with synchrotron wide-angle x-ray diffraction (WAXD), enabled observation in situ and in real time of the microstructural transformation from different carbon fiber precursors to high-modulus carbon fiber. Experiments conducted using PAN- and PE-derived fiber precursors reveal stark differences in their carbonization and high-temperature graphitization behavior.
Through undulator sources at 3rd generation synchrotrons, highly coherent X-rays with sufficient flux are nowadays routinely available, which allow carrying over photon correlation spectroscopy (PCS) from visible light to the X-ray regime. X-ray photon correlation spectroscopy (XPCS) is based on the auto-correlation of X-ray speckle patterns during the temporal evolution of a material and provides access both to equilibrium and non-equilibrium properties of materials at the Angstrom scale. Owing to technical limitations (detector readout), XPCS has typically been used for the detection of slow dynamics on the scale of seconds. The variety of scattering geometries employed in conventional X-ray analysis can be combined with XPCS. In this work, we report on bulk diffraction (XRD) used to study the prototypical shape memory alloy Ni63Al37 undergoing a structural, diffusionless (martensitic) transformation. Two-time correlation functions reveal non-equilibrium dynamics superimposed with microstructural avalanches.
Long term stability of mixed perovskite compounds is one of the important concerns for prolonged viability and economical use of perovskite based solar cells. Degradation in perovskite films mainly occurs due to exposure to moisture. Hence, a controlled atmospheric condition and lower humidity is preferred for device fabrication and use. Many different strategies such as use of thin and wide band gap semiconductor layer, improvement in pour filling of metal oxide film, and utilization of AgTFSI have been attempted to improve device stability. However, for long term durability, there is an urgent need to increase stability of parent perovskite layer, apart from use of protective layers. In this study we examined water resistant additive, structural modifications, and stoichiometric modification for enhanced film durability. These strategies and preliminary results are discussed in this report.
Does excluding food and energy prices from the Consumer Price Index (CPI) produce a measure that better captures permanent price changes? To examine this question, we decompose CPI inflation and “core” inflation into their permanent and transitory components, using a correlated unobserved-components model. The stationarity of inflation may be time-varying, so we examine the performance of the core measure of inflation separately for periods in which inflation is I(1) and I(0). For a period in which inflation appears to be I(1), we find that core inflation and the permanent component of overall inflation are closely related, but there are some caveats. For a period in which inflation appears to be I(0), we decompose the core and overall price levels and find that the permanent component of the core CPI is much more volatile than the actual core series and that the core excludes volatile permanent shocks to the overall price level.
The contamination of water by a large variety of molecules is a major environmental issue that will require the use of efficient and versatile materials to purify hydrological systems from source to point-of-use. The present study describes the aqueous-phase adsorption of heavy metal ions and multiple organic compounds at environmentally relevant concentrations onto graphene-single-walled carbon nanotube free-standing hybrid papers. Optical absorption spectroscopy results clearly showed that the hybrid nanocomposites exhibit superior adsorption properties compared to activated carbon, the most widely used adsorbent to date.
To explore the perceptions of educators from the Western Cape Province about the feasibility of implementing South African food-based dietary guidelines (FBDG) in the national curriculum of primary schools.
Combined quantitative and qualitative methods. We report on the quantitative component.
Twelve public primary schools of different socio-economic status in three education districts of the Western Cape: Metro Central, Metro East and Cape Winelands.
Educators (n 256) participated in the self-completed questionnaire survey.
Educators assessed that FBDG were appropriate to South African schoolchildren (94%), could be used as an education tool (97%) and fill gaps in the current curriculum about healthy dietary habits (91%). Besides Life Orientation, FBDG could be taught in other learning areas from grades 3 to 7 (9–13 years old). Important barriers to implementing FBDG in the curriculum were educators’ workload (61%), insufficient time (46%), learners’ disadvantaged background (43%) and educators’ lack of knowledge (33%). Other approaches to teach children about FBDG included linking these to the National School Nutrition Programme (82%), school tuck shops (79%), parent meetings (75%), school nutrition policy (73%) and school assembly (57%). Educators in high-income schools perceived that learners’ lifestyle was significantly worse (P < 0·001) and that tuck shops and the school assembly were the best means to teach pupils about FBDG (P < 0·001 and P < 0·05).
Implementing FBDG in the national school curriculum is seen as important together with optimizing the school physical environment. Key factors required for successful implementation in the curriculum are sufficient educational materials, adequate time allocation and appropriate educator training.