Toll-like receptors (TLRs) of the innate immune system are known targets for enhancing vaccine efficacy. We investigated whether imiquimod, a synthetic TLR7 agonist, can expedite the immune response ...against influenza virus infection when combined with influenza vaccine. BALB/c mice were immunized intraperitoneally with monovalent A(H1N1)pdm09 vaccine combined with imiquimod (VCI) prior to intranasal inoculation with a lethal dose of mouse-adapted A(H1N1)pdm09 virus. For mice immunized 3 days before infection, the survival rates were significantly higher in the VCI group (60%, mean survival timeMST, 11 days) than in the vaccine-alone (30%; MST, 8.8 days), imiquimod-alone (5%; MST, 8.4 days), and phosphate-buffered saline (PBS) (0%; MST, 6.2 days) groups (P < 0.01). In the VCI group, 45 and 35% of the mice survived even when they were infected 2 days or 1 day after immunization. Virus-specific serum IgM, IgG, and neutralizing antibodies appeared earlier with higher geometric mean titers in the VCI group than in the control groups. The pulmonary viral load was significantly lower at all time points postinfection in the VCI, vaccine-alone, and imiquimod-alone groups than in the PBS control group (P < 0.05). The protection induced by VCI was specific for A(H1N1)pdm09 virus but not for A(H5N1) virus. Since imiquimod combined with RNase-treated vaccine is as protective as imiquimod combined with untreated vaccine, mechanisms other than TLR7 may operate in expediting and augmenting immune protection. Moreover, increased gamma interferon mRNA expression and IgG isotype switching, which are markers of the Th1 response induced by imiquimod, were not apparent in our mouse model. The mechanisms of imiquimod-induced immune protection deserve further study.
Soluble angiotensin‐converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by blocking spike (S) proteins on virions from ...binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a “muco‐trapping” ACE2‐Fc conjugate, termed ACE2‐(G4S)6‐Fc, comprised of the extracellular segment of ACE2 (lacking the C‐terminal collectrin domain) that is linked to mucin‐binding IgG1‐Fc via an extended glycine‐serine flexible linker. ACE2‐(G4S)6‐Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2‐Fc decoys or similar truncated ACE2‐Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2‐(G4S)6‐Fc effectively trapped fluorescent SARS‐CoV‐2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2‐(G4S)6‐Fc in hamsters as late as 2 days postinfection provided a 10‐fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2‐(G4S)6‐Fc as an inhaled immunotherapy for COVID‐19, as well as other emerging viruses that bind ACE2 for cellular entry.
Highlights ► Dual vaccination of seasonal influenza and H1N1 2009 in institutionalized elderly. ► Functional status and comorbidity assessed to minimize healthy vaccine bias. ► Dual vaccination was ...better than vaccination of seasonal influenza alone. ► Reduce all cause mortality and hospitalization by dual vaccination.
To examine the real-world safety of adding bevacizumab to first-line irinotecan-based chemotherapy for patients with metastatic colorectal cancer (mCRC).
Patients diagnosed with CRC in three Canadian ...provinces (Ontario, Saskatchewan and British Columbia) who received publicly funded bevacizumab and/or irinotecan from 2000 to 2016 were identified from cancer registries. Propensity score 1:1 matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to contemporaneous and historical controls, adjusting for baseline demographic and clinical characteristics. Safety end points evaluated during first-line treatment plus 30 days included mortality within 30 days and all-cause-, chemotherapy- and bevacizumab-related hospitalisations. Chemotherapy- and bevacizumab-related visits were defined as hospitalisations for specific conditions commonly associated with chemotherapy (e.g. infections) or bevacizumab (e.g. arteriovenous thromboembolism) using most responsible diagnosis codes. In PSM and IPTW-weighted cohorts, we assessed event frequencies using odds ratios from logistic regressions and event rate ratios using negative binomial regression models. The results from each province and comparison were pooled using random-effects meta-analysis.
We identified 16 250 mCRC patients who received first-line irinotecan-based treatment. In PSM cohorts, bevacizumab was associated with fewer deaths within 30 days of treatment compared with contemporaneous (pooled odds ratio = 0.62; 95% confidence interval 0.50–0.75) and historical controls (pooled odds ratio = 0.73; 95% confidence interval 0.58–0.93). Hospitalisations were more frequent among patients treated with bevacizumab compared with historical controls but similar to contemporaneous controls. As patients receiving bevacizumab were exposed to a longer average treatment duration, across their full treatment duration, patients receiving bevacizumab had significantly lower rates of hospitalisations (contemporaneous pooled rate ratio = 0.56; 95% confidence interval 0.47–0.67; historical pooled rate ratio = 0.73; 95% confidence interval 0.56–0.95). Similar trends were observed for chemotherapy- and bevacizumab-related hospitalisations and in IPTW-weighted cohorts.
We did not observe any increase in rates of hospitalisation or death within 30 days of treatment among mCRC patients treated with bevacizumab plus chemotherapy versus chemotherapy alone; these findings should be interpreted with caution due to the risk of residual confounding.
•Bevacizumab with chemotherapy to treat metastatic colorectal cancer increased hospital visits during treatment compared with chemotherapy alone.•Patients receiving bevacizumab experienced lower rate of hospitalisation over longer treatment duration than chemotherapy alone.•No observed increase in deaths within 30 days of treatment suggests bevacizumab toxicity to be manageable in the real world.•Comparative real-world safety evaluation with population-based administrative data enables valuable ongoing pharmacovigilance.
We report on the effect of the nitrogen to rare earth (N2/RE) flux ratio on the structural, transport, and magnetic properties of samarium nitride (SmN) and dysprosium nitride (DyN) thin films. Both ...materials display a reduced lattice constant when the N2/RE flux ratio decreases, i.e., with increased nitrogen vacancies (VN) concentration. The films show several orders of magnitude increase in the electrical resistivity with increased N2/RE flux ratio. Finally, magnetic measurements on DyN films display a deviation from the free ion moment at low temperature, which is eased in more conductive films. This was interpreted as a further reduction in the quenching of the orbital angular momentum caused by the increased VN concentration. The Curie temperature was also found to increase with VN.
Although the majority of infections by the pandemic influenza H1N1 (2009) virus is mild, a higher mortality occurs in young adults with no risk factors for complications. Some of these severe cases ...were infected by the virus with an aspartate to glycine substitution at 225 position (D225G, H3 numbering) in the hemagglutinin (HA). Previous studies with the highly virulent 1918 pandemic H1N1 virus suggested that such substitution was associated with a dual binding specificity of the virus for both alpha2,3- and alpha2,6-linked sialic acid receptors on host cells. Thus, the D225G mutant may cause more severe disease with its increased predilection for the lower respiratory tract, where the alpha2,3 sialic acid receptor is more prevalent, but this hypothesis has not been investigated. We obtained a mutant virus after four sequential passages in lungs of BALB/c mice with a wild-type pandemic influenza A H1N1 (2009) virus. One plaque purified mutant virus had a single non-synonymous D225G mutation in the HA gene. This mutant was more lethal to chick embryo and produced a viral load of about two log higher than that of the wild-type parental virus during the first 24 h. A pathogenicity test showed that the 50% lethal dose in mice (LD50) was reduced from over 2 x 10(6) plaque-forming units (PFU) with the parental virus to just 150 PFU with the mutant virus. The survival of mice challenged with the mutant virus was significantly decreased when compared with the parental virus (P < 0.0001). Significantly higher viral titers and elevated proinflammatory cytokines in lung homogenates of mice infected with the mutant virus were found, which were compatible with severe histopathological changes of pneumonitis. The only consistent mutation in the genomes of viral clones obtained from dying mice was D225G substitution.
Aim
To examine the optimal range of International Normalized Ratio (INR) for Chinese patients receiving warfarin for moderate‐intensity anticoagulation.
Methods
This was a retrospective cohort study ...conducted at the ambulatory setting of a 1400‐bed public teaching hospital in Hong Kong. The INR measurements and occurrence of serious or life‐threatening haemorrhagic and thromboembolic events among patients newly started on warfarin from 1 January 1999 to 30 June 2001 for indications with target INR 2–3 were analysed. The INR‐specific incidence of bleeding and thromboembolism were calculated.
Results
A total of 491 patients were included, contributing to 453 patient‐years of observation period. Forty‐seven of the 491 patients experienced 25 haemorrhagic events (5.5 per 100 patient‐years) and 27 thromboembolic events (6.0 per 100 patient‐years). The percentage of patient‐time spent within therapeutic INR range (2–3), INR <2 and INR >3 were 50, 44 and 6%, respectively. The incidence of either haemorrhagic or thromboembolic events was lowest (≤4 events per 100 patient‐years) at INR values between 1.8 and 2.4.
Conclusions
An INR of 1.8–2.4 appeared to be associated with the lowest incidence rate of major bleeding or thromboembolic events in a cohort of Hong Kong Chinese patients receiving warfarin therapy for moderate‐intensity anticoagulation.
Currently, Coronavirus Disease 2019 (COVID-19)—a respiratory contagion spreading through expiratory droplets—has evolved into a global pandemic, severely impacting the public health. Importantly, the ...emerging of immune evasion SARS-CoV-2 variants and the limited effect of current antivirals against SARS-CoV-2 in clinical trials suggested that alternative strategies in addition to the conventional vaccines and antivirals are required to successfully control the COVID-19 pandemic. Here, we propose to use liquid-repellent coatings to prevent the spread of the disease in the absence of effective vaccines, antimicrobial agents, or therapeutics, wherein the deposition and penetration of pathogen droplets are prohibited. We use SARS-CoV-2 as a model pathogen and find that SARS-CoV-2 remnants are reduced by seven orders of magnitude on coated surfaces, yielding a repelling efficacy far outperforming the inactivation rate of disinfectants. The SARS-CoV-2 remnant scales exponentially with the liquid/solid adhesion, uncovering the mechanism and effective means for minimizing pathogen attachment. The antipathogen coating that both repels and inactivates pathogens is demonstrated by incorporating the super-liquid-repellent coating with antipathogen additives. Together with its versatility over a wide range of substrates and pathogens, the novel antipathogen coating is of considerable value for infection control in everyday life as well as during pandemics.
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Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed ...IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM.
The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling.
In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years.
The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.
Avian influenza virus H7N9 has jumped species barrier, causing sporadic human infections since 2013. We have previously isolated an H7N9 virus from a patient, and an H7N9 virus from a chicken in a ...live poultry market where the patient visited during the incubation period. These two viruses were genetically highly similar. This study sought to use a human bronchial epithelial cell line model to infer the virulence of these H7N9 viruses in humans.
Human bronchial epithelial cell line Calu-3 was infected with two H7N9 viruses (human H7N9-HU and chicken H7N9-CK), a human H5N1 virus and a human 2009 pandemic H1N1 virus. The infected cell lysate was collected at different time points post-infection for the determination of the levels of pro-inflammatory cytokines (tumor necrosis factor α TNF-α and interleukin 6 IL-6), anti-inflammatory cytokines (interleukin 10 IL-10 and transforming growth factor beta TGF-β), chemokines (interleukin 8 IL-8 and monocyte chemoattractant protein 1 MCP-1), and interferons (interferon β IFN-β and interferon lambda 1 IFNL1). The viral load in the cell lysate was also measured.
Comparison of the human and chicken H7N9 viruses showed that H7N9-HU induced significantly higher levels of TNF-α at 12 h post-infection, and significantly higher levels of IL-8 from 12 to 48 h post-infection than those of H7N9-CK. However, the level of IFNL1 was lower for H7N9-HU than that of H7N9-CK at 48 h post-infection (P < 0.001). H7N9-HU had significantly higher viral loads than H7N9-CK at 3 and 6 h post-infection. H5N1 induced significantly higher levels of TNF-α, IL-6, IL-8, IL-10 and MCP-1 than those of H7N9 viruses at 48 h post-infection. Conversely, H1N1 induced lower levels of TNF-α, IL-10, MCP-1, IFNL1 and IFN-β when compared with H7N9 viruses at the same time point.
H7N9-HU induced higher levels of pro-inflammatory IL-6 and IL-8 and exhibited a more rapid viral replication than H7N9-CK. However, the level of antiviral IFNL1 was lower for H7N9-HU than H7N9-CK. Our results suggest that the gained properties in modulating human innate immunity by H7N9-HU transformed it to be a more virulent virus in humans than H7N9-CK.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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