Measurements of submicron aerosol chemical composition were made over the central Arctic Ocean from 5 August to 8 September 2008 as a part of the Arctic Summer Cloud Ocean Study (ASCOS) using an ...aerosol mass spectrometer (AMS). The median levels of sulphate and organics for the entire study were 0.051 and 0.055 μ g m−3, respectively. Positive matrix factorisation was performed on the entire mass spectral time series and this enabled marine biogenic and continental sources of particles to be separated. These factors accounted for 33% and 36% of the sampled ambient aerosol mass, respectively, and they were both predominantly composed of sulphate, with 47% of the sulphate apportioned to marine biogenic sources and 48% to continental sources, by mass. Within the marine biogenic factor, the ratio of methane sulphonate to sulphate was 0.25 ± 0.02, consistent with values reported in the literature. The organic component of the continental factor was more oxidised than that of the marine biogenic factor, suggesting that it had a longer photochemical lifetime than the organics in the marine biogenic factor. The remaining ambient aerosol mass was apportioned to an organic-rich factor that could have arisen from a combination of marine and continental sources. In particular, given that the factor does not correlate with common tracers of continental influence, we cannot rule out that the organic factor arises from a primary marine source.
AbstractSeveral state departments of transportation (state DOTs) have encountered significant challenges to accurately estimate costs of their highway projects. It is not uncommon that states’ DOT ...estimates (owner’s estimates) are significantly different from contractors’ submitted bids. This is a critical problem for state highway agencies that strive to develop more accurate cost estimates, deliver projects within the budget, and optimize constrained funds for their highway programs. This inaccuracy problem is a temporal issue since the engineer’s estimate is developed ahead of time before the project is advertised and bids are received. The question that transportation agencies are interested in finding an answer to is: are there any significant risk factors in the construction market indicating to the increased likelihood of the deviation between owner’s estimate and the submitted low bid? In this research, a temporal perspective is selected to answer this question through identifying risk factors affecting the accuracy of the owner’s estimate. The ratio of low bid to owner’s estimate is examined using time-series analysis. The objectives of this research are to (1) examine several variables representing local highway construction market, overall construction market, macroeconomic conditions, and energy market, to identify the leading indicators of ratio of low bid to owner’s estimate; and (2) use the identified leading indicators to develop an appropriate time-series model to forecast the ratio of low bid to owner’s estimate. Four variables are identified as the major leading indicators: (1) number of projects awarded in the same month at the state level; (2) average number of bidders last month; (3) producer price index for steel mill products (PPISM); and (4) construction cost index (CCI). Several seasonal autoregressive integrated moving average with explanatory variable (ARIMAX) models are developed that are capable of forecasting the ratio of low bid to owner’s estimate with a high accuracy. This research contributes to the state of knowledge of analyzing the difference between owner’s estimate and low bid through: (1) identification of leading indicators of ratio of low bid to owner’s estimate that convey the extent of risk and uncertainty associated with construction projects at the cost estimation phase; and (2) development of appropriate multivariate time-series models (i.e., ARIMAX models) to predict the ratio of low bid to owner’s estimate. It is anticipated that the results will help cost estimating professionals in transportation agencies better understand the variability between their estimates and submitted bids by highway contractors, and thus, prepare more accurate cost estimates and develop appropriate risk management strategies for enhanced decision-making.
The thermal conductivity of phase change material (PCM) significantly affects the thermal performance of latent heat thermal energy storage (LHTES) system, which is attractive for energy conservation ...and waste heat utilization. Metal foam can be applied to enhance the low thermal conductivity of pure PCM. In the present study, copper foam and nickel foam with various porosities and pore sizes were impregnated with pure paraffin with vacuum assistance. A steady-state test system which considered the thermal contact resistance (TCR) between the specimen and adjacent surfaces was constructed to measure the effective thermal conductivities of the composite PCMs. The thermal conductivities were also theoretically calculated based on the correlations and models from the literature. The results showed that the thermal conductivities measured with steady-state method showed good agreement with the theoretical predictions, and the thermal conductivities of the composite PCMs were drastically enhanced, e.g., the thermal conductivities of the paraffin/copper foam composite PCMs fabricated by the copper foams with the porosities of 96.95%, 92.31%, 88.89% and pore size of 25 PPI were about thirteen, thirty-one, forty-four times larger than that of pure paraffin, respectively. The ratios of TCR to the total thermal resistances of the composite PCMs with the thickness of about 20.0 mm were in the ranges of 15.0–50.0%.
•Paraffin/metal foam composite PCMs were prepared with vacuum impregnation.•Thermal conductivities of the composite PCMs were measured.•Thermal contact resistance was measured.•Experimental results showed good agreement with theoretical predictions.
Two patients, one with transfusion-dependent β-thalassemia and the other with sickle cell disease, received autologous CD34+ cells edited with CRISPR-Cas9 targeting of
BCL11A
. Their clinical course ...over the following 16 to 18 months supports further experimental testing of CRISPR-Cas9 gene editing to treat these diseases.
Summary Background China has achieved Millennium Development Goal 4 to reduce under-5 mortality rate by two-thirds between 1990 and 2015. In this study, we estimated the national and subnational ...levels and causes of child mortality in China annually from 1996 to 2015 to draw implications for achievement of the SDGs for China and other low-income and middle-income countries. Methods In this systematic analysis, we adjusted empirical data on levels and causes of child mortality collected in the China Maternal and Child Health Surveillance System to generate representative estimates at the national and subnational levels. In adjusting the data, we considered the sampling design and probability, applied smoothing techniques to produce stable trends, fitted livebirth and age-specific death estimates to natvional estimates produced by the UN for international comparison, and partitioned national estimates of infrequent causes produced by independent sources to the subnational level. Findings Between 1996 and 2015, the under-5 mortality rate in China declined from 50·8 per 1000 livebirths to 10·7 per 1000 livebirths, at an average annual rate of reduction of 8·2%. However, 181 600 children still died before their fifth birthday, with 93 400 (51·5%) deaths occurring in neonates. Great inequity exists in child mortality across regions and in urban versus rural areas. The leading causes of under-5 mortality in 2015 were congenital abnormalities (35 700 deaths, 95% uncertainty range UR 28 400–45 200), preterm birth complications (30 900 deaths, 24 200–40 800), and injuries (26 600 deaths, 21 000–33 400). Pneumonia contributed to a higher proportion of deaths in the western region of China than in the eastern and central regions, and injury was a main cause of death in rural areas. Variations in cause-of-death composition by age were also examined. The contribution of preterm birth complications to mortality decreased after the neonatal period; congenital abnormalities remained an important cause of mortality throughout infancy, whereas the contribution of injuries to mortality increased after the first year of life. Interpretation China has achieved a rapid reduction in child mortality in 1996–2015. The decline has been widespread across regions, urban and rural areas, age groups, and cause-of-death categories, but great disparities remain. The western region and rural areas and especially western rural areas should receive most attention in improving child survival through enhanced policy and programmes in the Sustainable Development Goals era. Continued investment is crucial in primary and secondary prevention of deaths due to congenital abnormalities, preterm birth complications, and injuries nationally, and of deaths due to pneumonia in western rural areas. The study also has implications for improving child survival and civil registration and vital statistics in other low-income and middle-income countries. Funding Bill & Melinda Gates Foundation.
Summary
Background
Dupilumab (monoclonal antibody inhibiting IL‐4/IL‐13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate‐to‐severe atopic ...dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16‐week, randomised, placebo‐controlled phase III trial in adolescents (NCT03054428).
Objectives
To characterize the pharmacokinetics of dupilumab, and long‐term safety and efficacy in adolescents.
Methods
This was a global, multicentre, phase IIa, open‐label, ascending‐dose, sequential cohort study with a phase III open‐label extension (OLE) in adolescents with moderate‐to‐severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg−1 or 4 mg kg−1) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8‐week safety follow‐up. Patients then enrolled in the OLE, continuing 2 mg kg−1 or 4 mg kg−1 dupilumab weekly. Primary end points were dupilumab concentration–time profile and incidence of treatment‐emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI).
Results
Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target‐mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L−1 and 161 ± 60 mg L−1 for 2 mg kg−1 and 4 mg kg−1, respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% 2 mg kg−1, 47% 4 mg kg−1) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 mean ± SD reduction −34% ± 20% (2 mg kg−1) and −51% ± 29% (4 mg kg−1). With continuing treatment, EASI scores improved further week 52: −85% ± 12% (2 mg kg−1) and −84% ± 20% (4 mg kg−1).
Conclusions
In adolescents with moderate‐to‐severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52‐week safety and efficacy data support long‐term use of dupilumab in this patient population.
What's already known about this topic?
Adolescents with moderate‐to‐severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options.
Dupilumab (monoclonal antibody against interleukin‐4 receptor α) is approved for the treatment of adolescents with moderate‐to‐severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union).
A 16‐week, randomized, placebo‐controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile.
What does this study add?
These studies demonstrate the long‐term safety and efficacy of dupilumab in adolescents with moderate‐to‐severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16‐week dupilumab phase III trial.
The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16‐week phase III monotherapy trial.
Linked Comment: Sibbald. Br J Dermatol 2020; 182:12–13.
Plain language summary available online
Multidrug resistance (MDR) is usually correlated with the poor prognosis of gastric cancer. In this study, we revealed a total of 11 microRNAs (miRNA) that regulated MDR of gastric cancer via ...high-throughput functional screening, and miR-508-5p reversed MDR most efficiently among these candidate miRNAs. The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3'-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1. These findings suggest that a miR-508-5p/ZNRD1/ABCB1 regulatory loop has a critical role in MDR in gastric cancer. In addition, miR-508-5p could be used as a prognostic factor for overall survival in gastric cancer. These data reveal an important role for miR-508-5p in the regulation of MDR in gastric cancer, and suggest the potential application of miR-508-5p in drug resistance prediction and treatment.
An epidemic of severe acute respiratory syndrome (SARS) has been associated with an outbreak of atypical pneumonia originating in Guangdong Province, People's Republic of China. We aimed to identify ...the causative agent in the Guangdong outbreak and describe the emergence and spread of the disease within the province.
We analysed epidemiological information and collected serum and nasopharyngeal aspirates from patients with SARS in Guangdong in mid-February, 2003. We did virus isolation, serological tests, and molecular assays to identify the causative agent.
SARS had been circulating in other cities of Guangdong Province for about 2 months before causing a major outbreak in Guangzhou, the province's capital. A novel coronavirus, SARS coronavirus (CoV), was isolated from specimens from three patients with SARS. Viral antigens were also directly detected in nasopharyngeal aspirates from these patients. 48 of 55 (87%) patients had antibodies to SARS CoV in their convalescent sera. Genetic analysis showed that the SARS CoV isolates from Guangzhou shared the same origin with those in other countries, and had a phylogenetic pathway that matched the spread of SARS to the other parts of the world.
SARS CoV is the infectious agent responsible for the epidemic outbreak of SARS in Guangdong. The virus isolated from patients in Guangdong is the prototype of the SARS CoV in other regions and countries.
High energy particles introduce severe radiation damage in metallic materials, such as Ag. Here we report on the study on twin boundary (TB) affected zone in irradiated nanotwinned Ag wherein time ...accumulative defect density and defect diffusivity are substantially different from those in twin interior. In situ studies also reveal surprising resilience and self-healing of TBs in response to radiation. This study provides further support for the design of radiation-tolerant nanotwinned metallic materials.
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