The SARS-CoV-2 pandemic poses the greatest global public health challenge in a century. Neutralizing antibody is a correlate of protection and data on kinetics of virus neutralizing antibody ...responses are needed. We tested 293 sera from an observational cohort of 195 reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infections collected from 0 to 209 days after onset of symptoms. Of 115 sera collected ≥61 days after onset of illness tested using plaque reduction neutralization (PRNT) assays, 99.1% remained seropositive for both 90% (PRNT
) and 50% (PRNT
) neutralization endpoints. We estimate that it takes at least 372, 416 and 133 days for PRNT
titres to drop to the detection limit of a titre of 1:10 for severe, mild and asymptomatic patients, respectively. At day 90 after onset of symptoms (or initial RT-PCR detection in asymptomatic infections), it took 69, 87 and 31 days for PRNT
antibody titres to decrease by half (T
) in severe, mild and asymptomatic infections, respectively. Patients with severe disease had higher peak PRNT
and PRNT
antibody titres than patients with mild or asymptomatic infections. Age did not appear to compromise antibody responses, even after accounting for severity. We conclude that SARS-CoV-2 infection elicits robust neutralizing antibody titres in most individuals.
•A variety of MEK inhibitors have been tested as a single agent in clinical trials and shown to be limited to certain types of cancers.•Side effects from MEK inhibition can be significant but are ...more tolerable than effects from conventional cancer therapies.•Novel mechanisms of adaptive resistance to MEK inhibitor have been discovered in different cancers.•Combination clinical trials are being developed to overcome MEK inhibitor resistance.
The mitogen-activated protein kinase (MAPK) pathway plays a vital role in cellular processes such as gene expression, cell proliferation, cell survival, and apoptosis. Also known as the RAS-RAF-MEK-ERK pathway, the MAPK pathway has been implicated in approximately one-third of all cancers. Mutations in RAS or RAF genes such as KRAS and BRAF are common, and these mutations typically promote malignancies by over-activating MEK and ERK downstream, which drives sustained cell proliferation and uninhibited cell growth. Development of drugs targeting this pathway has been a research area of great interest, especially drugs targeting the inhibition of MEK. In vitro and clinical studies have shown promise for certain MEK inhibitors (MEKi) , and MEKi have become the first treatment option for certain cancers. Despite promising results, not all patients have a response to MEKi, and mechanisms of resistance typically arise in patients who do have a positive initial response. This paper summarizes recent developments regarding MEKi, the mechanisms of adaptive resistance to MEKi, and the potential solutions to the issue of adaptive MEKi resistance.
With the rapid growth of perishable food e-commerce businesses, there is a definite need for logistics services providers to manage parcel shipments with multi-temperature requirements. E-commerce ...characteristics, including time-critical delivery, fragmented orders, and high product variety, should be further considered to extend the ontology of multi-temperature joint distribution. However, traditional delivery route planning is insufficient because it merely minimises the cost of travelling between customer locations. Factors related to food quality and arrival time windows should also be considered. In addition, handling dynamic incident management, such as violations of handling requirements during delivery, is lacking. This leads to the likelihood of food deteriorating before it reaches the consumers, thereby impacting customer satisfaction. This paper proposes an Internet of Things-based multi-temperature delivery planning system (IoT-MTDPS), embedding a two-phase multi-objective genetic algorithm optimiser (2PMGAO). The formulation of delivery routing mainly considers product-dependent multi-temperature characteristics, service level, transportation cost, and number of trucks. Once there are unexpected incidents which are detected by Internet of Things technologies, 2PMGAO can optimise the membership functions of fuzzy logic for re-routing the e-commerce delivery plan. With using IoT-MTDPS, the capability of handling e-commerce orders is enhanced, while customer satisfaction can be maintained at a designated level.
To describe the infection control preparedness measures undertaken for coronavirus disease (COVID-19) due to SARS-CoV-2 (previously known as 2019 novel coronavirus) in the first 42 days after ...announcement of a cluster of pneumonia in China, on December 31, 2019 (day 1) in Hong Kong.
A bundled approach of active and enhanced laboratory surveillance, early airborne infection isolation, rapid molecular diagnostic testing, and contact tracing for healthcare workers (HCWs) with unprotected exposure in the hospitals was implemented. Epidemiological characteristics of confirmed cases, environmental samples, and air samples were collected and analyzed.
From day 1 to day 42, 42 of 1,275 patients (3.3%) fulfilling active (n = 29) and enhanced laboratory surveillance (n = 13) were confirmed to have the SARS-CoV-2 infection. The number of locally acquired case significantly increased from 1 of 13 confirmed cases (7.7%, day 22 to day 32) to 27 of 29 confirmed cases (93.1%, day 33 to day 42; P < .001). Among them, 28 patients (66.6%) came from 8 family clusters. Of 413 HCWs caring for these confirmed cases, 11 (2.7%) had unprotected exposure requiring quarantine for 14 days. None of these was infected, and nosocomial transmission of SARS-CoV-2 was not observed. Environmental surveillance was performed in the room of a patient with viral load of 3.3 × 106 copies/mL (pooled nasopharyngeal and throat swabs) and 5.9 × 106 copies/mL (saliva), respectively. SARS-CoV-2 was identified in 1 of 13 environmental samples (7.7%) but not in 8 air samples collected at a distance of 10 cm from the patient's chin with or without wearing a surgical mask.
Appropriate hospital infection control measures was able to prevent nosocomial transmission of SARS-CoV-2.
Abstract
SARS-CoV-2 infection of children leads to a mild illness and the immunological differences with adults are unclear. Here, we report SARS-CoV-2 specific T cell responses in infected adults ...and children and find that the acute and memory CD4
+
T cell responses to structural SARS-CoV-2 proteins increase with age, whereas CD8
+
T cell responses increase with time post-infection. Infected children have lower CD4
+
and CD8
+
T cell responses to SARS-CoV-2 structural and ORF1ab proteins when compared with infected adults, comparable T cell polyfunctionality and reduced CD4
+
T cell effector memory. Compared with adults, children have lower levels of antibodies to β-coronaviruses, indicating differing baseline immunity. Total T follicular helper responses are increased, whilst monocyte numbers are reduced, indicating rapid adaptive co-ordination of the T and B cell responses and differing levels of inflammation. Therefore, reduced prior β-coronavirus immunity and reduced T cell activation in children might drive milder COVID-19 pathogenesis.
The presence of plastic waste with a diameter of less than 5mm (“microplastics”) in marine environments has prompted increasing concern in recent years, both locally and globally. We conducted ...seasonal surveys of microplastic pollution in the surface waters and sediments from Deep Bay, Tolo Harbor, Tsing Yi, and Victoria Harbor in Hong Kong between June 2015 and March 2016. The average concentrations of microplastics in local coastal waters and sediments respectively ranged from 51 to 27,909particles per 100m3 and 49 to 279particles per kilogram. Microplastics of different shapes (mainly fragments, lines, fibers, and pellets) were identified as polypropylene, low-density polyethylene, high-density polyethylene, a blend of polypropylene and ethylene propylene, and styrene acrylonitrile by means of Attenuated Total Reflectance - Fourier Transform Infrared Spectroscopy. This is the first comprehensive study to assess the spatial and temporal variations of microplastic pollution in Hong Kong coastal regions.
•The severity of marine microplastic pollution in Hong Kong is moderate.•Microplastics found are less dense plastics including PP, PE, PP+EPDM and SAN.•Temporal and spatial variations of microplastics in surface water were observed.•Victoria Harbour was the most polluted coastal region (27,909±7407particles/100m3).
Modern consumption patterns lead to massive waste, which poses challenges in storage and highlights the urgent need for more sustainable product development. Customer feedback on products plays a ...crucial role in product design, yet previous studies overlooked these invaluable insights. In response, this study introduces a novel systematic methodology that integrates the strengths of text mining, Quality Function Deployment (QFD), and the Theory of Inventive Problem Solving (TRIZ). Text mining techniques are utilized to extract customer requirements from online platforms, while QFD is used to translate these requirements into technical specifications. By integrating the contradiction matrix from TRIZ theory with the triptych, technical conflicts are resolved. The design process for next-generation smart glasses is employed as an illustrative case to validate the proposed integrated innovation design approach. Analytical outcomes suggest that the introduced methodology can effectively address sustainable product design challenges and sets the stage for future advancements in smart glasses.
The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far ...were co-organised together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop US-FDA joined as co-sponsor – to support global harmonisation of regulatory recommendations for bioequivalence (BE) assessment.
At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main conclusions were drawn:
(1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a majority of the workshop participants were in favour of a more frequent application of such approaches. The regulatory conditions relevant in this context need further concretisation and harmonisation between the regions. Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE development programmes.
(2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously, BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions. Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in fed state.
(3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e.g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and, despite significant progress already achieved during previous years, more research is needed before they may be fully accepted for regulatory purposes.
(4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure into BE assessment with more restrictive criteria and the importance of comparison of the product-related within-subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were presented and discussed but need further consideration before harmonisation can be achieved.
The highly interactive meeting and extensive exchange between regulators and scientists from industry and academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation.
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The light output produced by light ions ( Z≤4) in CsI(Tl) crystals is studied over a wide range of detected energies (E≤300MeV). Energy-light calibration data sets are obtained with the 10 cm ...crystals in the recently upgraded High-Resolution Array (HiRA10). We use proton recoil data from 40,48Ca + CH2 at 28 MeV/u, 56.6 MeV/u, 39 MeV/u and 139.8 MeV/u and data from a dedicated experiment with direct low-energy beams. We also use the punch through points of p, d, and t particles from 40,48Ca + 58,64Ni, 112,124Sn collisions reactions at 139.8 MeV/u. Non-linearities, arising in particular from Tl doping and light collection effects in the CsI crystals, are found to significantly affect the light output and therefore the calibration of the detector response for light charged particles, especially the hydrogen isotopes. A new empirical parametrization of the hydrogen light output, L(E,Z=1,A), is proposed to account for the observed effects. Results are found to be consistent for all 48 CsI(Tl) crystals in a cluster of 12 HiRA10 telescopes.
The antibody response magnitude and kinetics may impact clinical severity, serological diagnosis and long-term protection of COVID-19, which may play a role in why children experience lower ...morbidity. We therefore tested samples from 122 children in Hong Kong with symptomatic (n = 78) and asymptomatic (n = 44) SARS-CoV-2 infections up to 200 days post infection, relative to 71 infected adults (symptomatic n = 61, and asymptomatic n = 10), and negative controls (n = 48). We assessed serum IgG antibodies to a 14-wide antigen panel of structural and accessory proteins by Luciferase Immuno-Precipitation System (LIPS) assay and circulating cytokines. Infected children have lower levels of Spike, Membrane, ORF3a, ORF7a, ORF7b antibodies, comparable ORF8 and elevated E-specific antibodies than adults. Combination of two unique antibody targets, ORF3d and ORF8, can accurately discriminate SARS-CoV-2 infection in children. Principal component analysis reveals distinct pediatric serological signatures, and the highest contribution to variance from adults are antibody responses to non-structural proteins ORF3d, NSP1, ORF3a and ORF8. From a diverse panel of cytokines that can modulate immune priming and relative inflammation, IL-8, MCP-1 and IL-6 correlate with the magnitude of pediatric antibody specificity and severity. Antibodies to SARS-CoV-2 internal proteins may become an important sero surveillance tool of infection with the roll-out of vaccines in the pediatric population.
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