Evaluation of vaccine allergy safety track program to assess potential COVID-19 vaccine allergy: a cost-effectiveness analysis.

BACKGROUND: Concerns about new COVID-19 vaccines played a key role in vaccine hesitancy and hampered population uptake. Hong Kong initiated a Vaccine Allergy Safety Track (VAS-Track) program to assess potential COVID-19 vaccine-associated allergies. A 'Hub-and-Spoke' model of predominately non-specialists supported by the allergist hub was established to meet overwhelming demand despite limited specialists. OBJECTIVE: To assess the cost-effectiveness of VAS-Track as a pre- and post-vaccination assessment service for individuals potentially at high risk of COVID-19 vaccine-related allergy. METHODS: An individual-level decision-analytical model was constructed using data from VAS-Track participants supplemented by published estimates. Analyses were from a health service provider perspective over 12 months. We calculated the incremental cost-effectiveness ratio (ICER) to estimate the cost per quality-adjusted life years (QALYs) gained. Willingness-to-pay threshold was based on local GDP per capita (US$ 49,590). Sensitivity analyses examined robustness of findings. RESULTS: Cost-effectiveness varied widely across age groups. VAS-Track was cost-saving for older adults (dominant strategy for age ≥ 50) compared with standard practice across a range of sensitivity analyses. VAS-Track was not cost-effective for younger groups (age 18-49: ICER: US$ 410,914/QALY for pre-vaccination and US$ 213,786/QALY for post-vaccination assessments). Infection rate, cost of treating severe infection, and vaccination rate were most influential on cost-effectiveness estimates. CONCLUSION: VAS-Track was cost-effective both as a pre- and post-vaccination assessment service for adults over 50. The 'Hub-and-Spoke' model using non-specialists with limited allergy specialist resources to provide vaccine allergy assessment services would provide high economic value compared with usual care for adults aged 50 and over.

OTUD1 Deficiency Alleviates LPS-Induced Acute Lung Injury in Mice by Reducing Inflammatory Response.

The ovarian tumor (OTU) family consists of deubiquitinating enzymes thought to play a crucial role in immunity. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) pose substantial clinical challenges due to severe respiratory complications and high mortality resulting from uncontrolled inflammation. Despite this, no study has explored the potential link between the OTU family and ALI/ARDS. Using publicly available high-throughput data, 14 OTUs were screened in a simulating bacteria- or LPS-induced ALI model. Subsequently, gene knockout mice and transcriptome sequencing were employed to explore the roles and mechanisms of the selected OTUs in ALI. Our screen identified OTUD1 in the OTU family as a deubiquitinase highly related to ALI. In the LPS-induced ALI model, deficiency of OTUD1 significantly ameliorated pulmonary edema, reduced permeability damage, and decreased lung immunocyte infiltration. Furthermore, RNA-seq analysis revealed that OTUD1 deficiency inhibited key pathways, including the IFN-γ/STAT1 and TNF-α/NF-κB axes, ultimately mitigating the severity of immune responses in ALI. In summary, our study highlights OTUD1 as a critical immunomodulatory factor in acute inflammation. These findings suggest that targeting OTUD1 could hold promise for the development of novel treatments against ALI/ARDS.

Extended Paid Maternity Leave Associated With Improved Maternal Mental Health In Hong Kong.

In July 2020, Hong Kong extended statutory paid maternity leave from ten weeks to fourteen weeks to align with International Labour Organization standards. We used the policy enactment as an observational natural experiment to assess the mental health implications of this policy change on probable postnatal depression (Edinburgh Postnatal Depression Scores of 10 or higher) and postpartum emotional well-being. Using an opportunistic observational study design, we recruited 1,414 survey respondents with births before (August 1-December 10, 2020) and after (December 11, 2020-July 18, 2022) policy implementation. Participants had a mean age of thirty-two, were majority primiparous, and were mostly working in skilled occupations. Our results show that the policy was associated with a 22 percent decrease in mothers experiencing postnatal depressive symptoms and a 33 percent decrease in postpartum emotional well-being interference. Even this modest change in policy, an additional four weeks of paid leave, was associated with significant mental health benefits. Policy makers should consider extending paid maternity leave to international norms to improve mental health among working mothers and to support workforce retention.

Geniposide effectively safeguards HT22 cells against Aß-induced damage by activating mitophagy via the PINK1/Parkin signaling pathway.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the significant involvement of amyloid-beta (Aß) peptide in its pathogenesis. Geniposide, derived from the versatile medicinal of Gardenia jasminoides, is one of the active compounds studied extensively. The objective was to explore the impact of geniposide on Aß25-35-induced damage in HT22 cells, specifically focusing on its modulation of PINK1/Parkin-mediated mitophagy. In our investigation, geniposide exhibited remarkable restorative effects by enhancing cell viability and preserving the mitochondrial membrane potential. Moreover, it effectively reduced and mitigated the oxidative stress and apoptosis rates induced by Aß25-35. Notably, geniposide exhibited the capacity to enhance autophagic flux, upregulate LC3II and Beclin-1 expression, and downregulate the expression of p62. Furthermore, geniposide positively influenced the expression of PINK1 and Parkin proteins, with molecular docking substantiating a strong interaction between geniposide and PINK1/Parkin proteins. Intriguingly, the beneficial outcomes of geniposide on alleviating the pronounced apoptosis rates, the overproduction of reactive oxygen species, and diminished the PINK1 and Parkin expression induced by Aß25-35 were compromised by the mitophagy inhibitor cyclosporine A (CsA). Collectively, these findings suggested that geniposide potentially shields HT22 cells against neurodegenerative damage triggered by Aß25-35 through the activation of mitophagy. The insights contribute valuable references to the defensive consequences against neurological damage of geniposide, thereby highlighting its potential as a therapeutic intervention in AD.

Compound c17 alleviates inflammatory cardiomyopathy in streptozotocin-induced diabetic mice by targeting MyD88.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus and is associated with increased morbidity and mortality due to cardiac dysfunction. Chronic inflammation plays a significant role in the development of DCM, making it a promising target for novel pharmacological strategies. Our previous study has synthesized a novel compound, c17, which exhibited strong anti-inflammatory activity by specifically targeting to myeloid differentiation primary response 88 (MyD88). In this study, we evaluated the therapeutic effect of c17 in DCM. METHODS: The small molecular selective MyD88 inhibitor, c17, was used to evaluate the effect of MyD88 on DCM in both high concentration of glucose- and palmitic acid-stimulated macrophages and streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice. RESULTS: The treatment of c17 in T1DM mice resulted in improved heart function and reduced cardiac hypertrophy, inflammation and fibrogenesis. RNA sequencing analysis of the heart tissues revealed that c17 effectively suppressed the inflammatory response by regulating the MyD88-dependent pathway. Co-immunoprecipitation experiments further confirmed that c17 disrupted the interaction between MyD88 and Toll-like receptor 4 (TLR4), consequently inhibiting downstream NF-κB activation. In vitro studies demonstrated that c17 exhibited similar anti-inflammatory activity by targeting MyD88 in macrophages, which are the primary regulators of cardiac inflammation. Furthermore, conditioned medium derived from c17-treated macrophages showed reduced capacity to induce hypertrophy, pro-fibrotic reactions, and secondary inflammation in cardiomyocytes. CONCLUSIONS: In conclusion, the small-molecule MyD88 inhibitor, c17, effectively combated the inflammatory DCM, therefore could be a potential candidate for the treatment of this disease.

Potential health and economic impact associated with achieving risk factor control in Chinese adults with diabetes: a microsimulation modelling study.

Background: The prevalence of diabetes has risen sharply in China. Improving modifiable risk factors such as glycaemia and blood pressure could substantially reduce disease burden and treatment costs to achieve a healthier China by 2030. Methods: We used a nationally representative population-based survey of adults with diabetes in 31 provinces in mainland China to assess the prevalence of risk factor control. We adopted a microsimulation approach to estimate the impact of improved control of blood pressure and glycaemia on mortality, quality-adjusted life-years (QALYs), and healthcare cost. We applied the validated CHIME diabetes outcomes model over a 10-year time horizon. Baseline scenario of status quo was evaluated against alternative strategies based on World Health Organization and Chinese Diabetes Society guidelines. Findings: Among 24,319 survey participants with diabetes (age 30-70), 69.1% (95% CI: 67.7-70.5) achieved optimal diabetes control (HbA1c <7% [53 mmol/mol]), 27.7% [26.1-29.3] achieved blood pressure control (<130/80 mmHg) and 20.1% (18.6-21.6) achieved both targets. Achieving 70% control rate for people with diabetes could reduce deaths before age 70 by 7.1% (5.7-8.7), reduce medical costs by 14.9% (12.3-18.0), and gain 50.4 QALYs (44.8-56.0) per 1000 people over 10 years compared to the baseline status quo. The largest health gains were for strategies including strict blood pressure control of 130/80 mmHg, particularly in rural areas. Interpretation: Based on a nationally representative survey, few adults with diabetes in China achieved optimal control of glycaemia and blood pressure. Substantial health gains and economic savings are potentially achievable with better risk factor control especially in rural settings. Funding: Chinese Central Government, Research Grants Council of the Hong Kong Special Administrative Region, China [27112518].

COVID-19 Vaccine Allergy Safety Track (VAS-Track) pathway: real-world outcomes on vaccination rates and antibody protection.

BACKGROUND: Misdiagnosed vaccine-related "allergies" lead to unnecessary vaccine deferrals and incomplete vaccinations, leaving patients unprotected against COVID-19. To overcome limitations and queues for Allergist assessment, the "VAS-Track" pathway was developed to evaluate patients via a multi-disciplinary triage model including nurses, non-specialists, and Allergists. OBJECTIVE: We assessed the effectiveness and safety of VAS-Track and evaluate its real-world impact in terms of vaccination rates and COVID-19 protection. METHODS: Patients referred to VAS-Track between September 2021 and March 2022 were recruited. Subgroup analysis was performed with prospective pre- and post-clinic antibody levels. RESULTS: Nurse-assisted screening identified 10,412 (76%) referrals as inappropriate. 369 patients were assessed by VAS-Track. Overall, 100% of patients were recommended to complete vaccination and 332 (90%) completed their primary series. No patients reported any significant allergic reactions following subsequent vaccination. Vaccination completion rates between patients seen by non-specialists and additional Allergist review were similar (90% vs. 89%, p = 0.617). Vaccination rates were higher among patients with prior history of immediate-type reactions (odds ratio: 2.43, p = 0.025). Subgroup analysis revealed that only 20% (56/284) of patients had seropositive COVID-19 neutralizing antibody levels (≥ 15 AU/mL) prior to VAS-Track, which increased to 92% after vaccine completion (pre-clinic antibody level 6.0 ± 13.5 AU/mL vs. post-clinic antibody level 778.8 ± 337.4 AU/mL, p > 0.001). CONCLUSIONS: A multi-disciplinary allergy team was able to streamline our COVID-19 VAS services, enabling almost all patients to complete their primary series, significantly boosting antibody levels and real-world COVID-19 protection. We propose similar multidisciplinary models to be further utilized, especially in the settings with limited allergy services.

The Role of the Allergist in Coronavirus Disease 2019 Vaccine Allergy Safety: A Pilot Study on a "Hub-and-Spoke" Model for Population-Wide Allergy Service.

BACKGROUND: Hong Kong started its coronavirus disease 2019 (COVID-19) vaccination program in February 2021. A territory-wide Vaccine Allergy Safety (VAS) clinic was set up to assess individuals deemed at "higher risk" of COVID-19 vaccine-associated allergies. A novel "hub-and-spoke" model was piloted to tackle the overwhelming demand of services by allowing nonallergists to conduct assessment. OBJECTIVE: To evaluate the outcomes of the VAS hub-and-spoke model for allergy assessment. METHODS: Records of patients attending the VAS hub-and-spoke Clinics between March and August 2021 were reviewed (n = 2725). We studied the overall results between the Hub (allergist led) and Spoke (nonallergist led) Clinics. The Hub and the Hong Kong West Cluster Spoke Clinic were selected for subgroup analysis as they saw the largest number of patients (n = 1411). RESULTS: A total of 2725 patients were assessed under the VAS hub-and-spoke model. Overall, 2324 patients (85.3%) were recommended to proceed with vaccination. Allergists recommended significantly more patients for vaccination than nonallergists (odds ratio = 21.58; P < .001). Subgroup analysis revealed that 881 of 1055 (83.5%) patients received their first dose of COVID-19 vaccination safely after assessment. Among those recommended vaccination, more patients assessed by allergists received their first dose of vaccination (odds ratio = 4.18; P < .001). CONCLUSION: The hub-and-spoke model has proven to be successful for the vaccination campaign. This study has illustrated the crucial role of allergists in countering vaccine hesitancy. Results from the study revealed considerable differences in outcomes between allergist-led and nonallergist-led clinics. Precise reasons for these differences warrant further evaluation. We are hopeful that the hub-and-spoke model can be similarly adapted for other allergist-integrative services in the future.

Diterpenoid Lactones with Anti-Inflammatory Effects from the Aerial Parts of Andrographis paniculata.

Andrographis paniculata (AP) has been widely used in China for centuries to treat various diseases, and especially to treat inflammation. Diterpenoid lactones are the main anti-inflammatory components of AP. However, systematic chemical composition and biological activities, as well as key pharmacophores, of these diterpenoid lactones from AP have not yet been clearly understood. In this study, 17 diterpenoid lactones, including 2 new compounds, were identified by spectroscopic methods, and most of them attenuated the generation of TNF-α and IL-6 in LPS-induced RAW 274.7 cells examined by ELISA. Pharmacophores of diterpenoid lactones responsible for the anti-inflammatory activities were revealed based on the quantitative structure-activity relationship (QSAR) models. Moreover, new compounds (AP-1 and AP-4) exerted anti-inflammatory activity in LPS microinjection-induced zebrafish, which might be correlated with the inhibition of the translocation of NF-κB p65 from cytoplasm to nucleus. Our study provides guidelines for future structure modification and rational drug design of diterpenoid lactones with anti-inflammatory properties in medical chemistry.

3-Dehydroandrographolide protects against lipopolysaccharide-induced inflammation through the cholinergic anti-inflammatory pathway.

Acute lung injury (ALI) is a deadly disease without effective chemotherapy, so far. Traditional Chinese medicine andrographis herba is frequently used in the treatment of respiratory diseases. In searching for natural anti-ALI components from andrographis herba, the activities of 3-dehydroandrographolide (3-DA), a new natural andrographolide product from andrographis herba were evaluated. In this study, murine macrophage RAW 264.7 cells and BALB/c mice were treated with LPS (lipopolysaccharide, 100 ng/ml in vitro; 3 mg/kg, intratracheal) to establish inflammation models. 3-DA attenuated the release of pro-inflammatory cytokines IL-6 and TNF-α, inhibited the degradation and phosphorylation of IκBα, and suppressed the nuclear translocation of NF-κB p65 as well as the phosphorylation of Akt at Ser473 in LPS-stimulated RAW 264.7 macrophage cells. Furthermore, 3-DA increased α7nAchR expression level and bound with α7nAchR. More importantly, the anti-inflammatory effects of 3-DA were counteracted in the presence of α7nAchR siRNA or methyllycaconitine (MLA, a α7nAchR specific inhibitor), suggesting that α7nAchR is a potential target in the anti-inflammatory effects of 3-DA. Besides, 3-DA significantly inhibited inflammation in LPS-induced ALI mice, which was associated with the decrease of lung water content and inflammatory cytokines, the inhibition of neutrophil and macrophage infiltration, and activation of the NF-κB/Akt signaling pathway. Moreover, these protective effects were attenuated by the treatment of MLA. Taken together, 3-DA alleviates LPS-induced inflammation via the cholinergic anti-inflammatory pathway in vitro and in vivo. These findings provide a rationale for the role of the cholinergic anti-inflammatory pathway in inflammation and the promising clinical application of 3-DA to treat ALI.

Ffuzz: Towards full system high coverage fuzz testing on binary executables.

Bugs and vulnerabilities in binary executables threaten cyber security. Current discovery methods, like fuzz testing, symbolic execution and manual analysis, both have advantages and disadvantages when exercising the deeper code area in binary executables to find more bugs. In this paper, we designed and implemented a hybrid automatic bug finding tool-Ffuzz-on top of fuzz testing and selective symbolic execution. It targets full system software stack testing including both the user space and kernel space. Combining these two mainstream techniques enables us to achieve higher coverage and avoid getting stuck both in fuzz testing and symbolic execution. We also proposed two key optimizations to improve the efficiency of full system testing. We evaluated the efficiency and effectiveness of our method on real-world binary software and 844 memory corruption vulnerable programs in the Juliet test suite. The results show that Ffuzz can discover software bugs in the full system software stack effectively and efficiently.

[Pathomorphologic study of the fibrous cap and fatty core of coronary arthrosclerotic plaque in sudden coronary death].

OBJECTIVE: The differences in the thickness of fibrous cap and the percentage of fatty core of the coronary atherosclerotic plaques between sudden coronary death (SCD) group and the control group were investigated. METHODS: Sixty-four autopsy cases were divided into SCD and control groups. Samples were taken from the most severely damaged portions of the coronary atherosclerotic plaques, sectioned, stained with HE, and the percentage of examined by light microscopy for morphologic changes and structural alternations. Image analysis system was adopted to compare the thickness of fibrous cap and percentage of fatty core in the whole plaque between the two groups, and allthe data were analyzed and calculated with SPSS 11.5 statistic software. RESULTS: There were 15 grade III and 21 grade IV atherosclerotic cases found in the SCD group, while there were 16 and 12 found in the control group, respectively. Although no significant differences on the severity of atherosclerosis were found between the two groups (P > 0.05), there were significant differences on the thickness of the fibrous cap and the percentage of fatty core found between the two groups (P < 0.01). CONCLUSION: Our study indicates that there are significant differences in the thickness of fibrous cap and the percentage of fatty core in atherosclerosis plaques between the SCD group and the control group. These observed differences may be helpful for morphological diagnosis of SCD.