Comprehensive Glycomic and Glycoproteomic Analyses of Human Programmed Cell Death Protein 1 Extracellular Domain.

Human programmed cell death protein 1 (hPD-1) is an essential receptor in the immune checkpoint pathway. It has played an important role in cancer therapy. However, not all patients respond positively to the PD-1 antibody treatment, and the underlying mechanism remains unknown. PD-1 is a transmembrane glycoprotein, and its extracellular domain (ECD) is reported to be responsible for interactions and signal transduction. This domain contains 4 N-glycosylation sites and 25 potential O-glycosylation sites, which implicates the importance of glycosylation. The structure of hPD-1 has been intensively studied, but the glycosylation of this protein, especially the glycan on each glycosylation site, has not been comprehensively illustrated. In this study, hPD-1 ECD expressed by human embryonic kidney 293 (HEK 293) and Chinese hamster ovary (CHO) cells was analyzed; not only N- and O-glycosylation sites but also the glycans on these sites were comprehensively analyzed using mass spectrometry. In addition, hPD-1 ECD binding to different anti-hPD-1 antibodies was tested, and N-glycans were found functioned differently. All of this glycan information will be beneficial for future PD-1 studies.

Breast Cancer Screening During the COVID-19 Pandemic in the United States: Results From Real-World Health Records Data.

PURPOSE: The COVID-19 pandemic abruptly interrupted breast cancer screening, an essential preventive service in primary care. We aimed to evaluate the pandemic's impact on overall and follow-up breast cancer screening using real-world health records data. METHODS: We retrospectively analyzed a cohort of women eligible for breast cancer screening through the study period from January 1, 2017 to February 28, 2022 using TriNetX Research Network data. We examined the temporal trend of monthly screening volume throughout the study period and compared the rate of adherence to follow-up screening within 24 months after the previous screening when the follow-up screening was due in the pre-COVID period vs the COVID period. To account for multiple screenings in the longitudinal data, we applied a logistic regression model using generalized estimating equations with adjustment for individual-level covariates. RESULTS: Among 1,186,669 screening-eligible women, the monthly screening volume temporarily decreased by 80.6% from February to April 2020 and then rebounded to close to pre-COVID levels by June 2020. Yet, the follow-up screening rate decreased from 78.9% (95% CI, 78.8%-79.0%) in the pre-COVID period to 77.7% (95% CI, 77.6%-77.8%) in the COVID period. Multivariate regression analysis also showed a lower adherence to follow-up screening during the COVID period (odds ratio = 0.86; 0.86-0.87) and a greater pandemic impact among women aged 65 years and older and women of non-Hispanic "other" race (Asian, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander). CONCLUSIONS: The COVID-19 pandemic had a transient negative effect on breast cancer screening overall and a prolonged negative effect on follow-up screening. It also exacerbated gaps in adherence to follow-up screening, especially among certain vulnerable groups, requiring innovative strategies to address potential health disparities in primary care.

Design, synthesis, and biological evaluation of novel 8-substituted quercetin derivatives targeting the ß­catenin/B-cell lymphoma 9 interaction.

The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for aberrantly active Wnt/ß-catenin signaling which actively participates in initiating and progressing of many cancers. Herein, we discovered novel 8-substituted quercetin derivatives with potential inhibitory activities targeting ß-catenin/BCL9 PPI. Among all the derivatives, compound B4 displayed the most promising PPI inhibitory activity with an IC50 value of 2.25 µM in a competitive fluorescence polarization assay and a KD value of 1.44 µM for the ß-catenin protein. Furthermore, B4 selectively inhibited the growth of colorectal cancer (CRC) cells, suppressed the transactivation of Wnt signaling, and downregulated the expression of oncogenic Wnt target gene. Especially, B4 showed potent anti-CRC activity in vivo with the tumor growth inhibition (TGI) of 75.99 % and regulated the tumor immune microenvironment.

Role of electroanatomical mapping-guided superior vena cava isolation in paroxysmal atrial fibrillation patients without provoked superior vena cava triggers: a randomized controlled study.

AIMS: Data about whether empirical superior vena cava (SVC) isolation (SVCI) improves the success rate of paroxysmal atrial fibrillation (PAF) are conflicting. This study sought to first investigate the characteristics of SVC-triggered atrial fibrillation and secondly investigate the impact of electroanatomical mapping-guided SVCI, in addition to circumferential pulmonary vein isolation (CPVI), on the outcome of PAF ablation in the absence of provoked SVC triggers. METHODS AND RESULTS: A total of 130 patients undergoing PAF ablation underwent electrophysiological studies before ablation. In patients for whom SVC triggers were identified, SVCI was performed in addition to CPVI. Patients without provoked SVC triggers were randomized in a 1:1 ratio to CPVI plus SVCI or CPVI only. The primary endpoint was freedom from any documented atrial tachyarrhythmias lasting over 30 s after a 3-month blanking period without anti-arrhythmic drugs at 12 months after ablation. Superior vena cava triggers were identified in 30 (23.1%) patients with PAF. At 12 months, 93.3% of those with provoked SVC triggers who underwent CPVI plus SVCI were free from atrial tachyarrhythmias. In patients without provoked SVC triggers, SVCI, in addition to CPVI, did not increase freedom from atrial tachyarrhythmias (87.9 vs. 79.6%, log-rank P = 0.28). CONCLUSION: Electroanatomical mapping-guided SVCI, in addition to CPVI, did not increase the success rate of PAF ablation in patients who had no identifiable SVC triggers. REGISTRATION: ChineseClinicalTrials.gov: ChiCTR2000034532.

Catheter ablation versus antiarrhythmic drug therapy for sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy.

BACKGROUND: Ventricular tachycardia (VT) is the primary cause of sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). However, the strategy for VT treatment in HCM patients remains unclear. This study is aimed to compare the effectiveness of catheter ablation versus antiarrhythmic drug (AAD) therapy for sustained VT in patients with HCM. METHODS: A total of 28 HCM patients with sustained VT at 4 different centers between December 2012 and December 2021 were enrolled. Twelve underwent catheter ablation (ablation group) and sixteen received AAD therapy (AAD group). The primary outcome was VT recurrence during follow-up. RESULTS: Baseline characteristics were comparable between two groups. After a mean follow-up of 31.4 ± 17.5 months, the primary outcome occurred in 35.7% of the ablation group and 90.6% of the AAD group (hazard ratio [HR], 0.29 [95%CI, 0.10-0.89]; P = 0.021). No differences in hospital admission due to cardiovascular cause (25.0% vs. 71.0%; P = 0.138) and cardiovascular cause-related mortality/heart transplantation (9.1% vs. 50.6%; P = 0.551) were observed. However, there was a significant reduction in the composite endpoint of VT recurrence, hospital admission due to cardiovascular cause, cardiovascular cause-related mortality, or heart transplantation in ablation group as compared to that of AAD group (42.9% vs. 93.7%; HR, 0.34 [95% CI, 0.12-0.95]; P = 0.029). CONCLUSIONS: In HCM patients with sustained VT, catheter ablation reduced the VT recurrence, and the composite endpoint of VT recurrence, hospital admission due to cardiovascular cause, cardiovascular cause-related mortality, or heart transplantation as compared to AAD.

The impact of health insurance on hypertension care: a household fixed effects study in India.

INTRODUCTION: Hypertension is highly prevalent in India, but the proportion of patients achieving blood pressure control remains low. Efforts have been made to expand health insurance coverage nationwide with the aim of improving overall healthcare access. It is critical to understand the role of health insurance coverage in improving hypertension care. METHODS: We used secondary data from the nationally representative sample of adults aged 15-49 years from the 2015-2016 National Family Health Survey (NFHS) in India. We defined the hypertension care cascade as four successive steps of (1) screened, (2) diagnosed, (3) treated, and (4) controlled, and operationalized these variables using blood pressure measurements and self-reports. We employed household fixed effect models that conceptually matched people with and without insurance within the household, to estimate the impact of insurance coverage on the likelihood of reaching each care cascade step, while controlling for a wide range of additional individual-level variables. RESULTS: In all 130,151 included individuals with hypertension, 20.4% reported having health insurance. For the insured hypertensive population, 79.8% (95% Confidence Interval: 79.3%-80.3%) were screened, 49.6% (49.0%-50.2%) diagnosed, 14.3% (13.9%-14.7%) treated, and 7.9% (7.6%-8.2%) controlled, marginally higher than the percentages for the uninsured 79.8% (79.5%-80.0%), 48.2% (47.9%-48.6%), 13.3% (13.1%-13.5%), and 7.5% (7.4%-7.7%) for each cascade step, respectively. From the household fixed effects model, health insurance did not show significant impact on the hypertension care cascade, with the estimated relative risks of health insurance 0.97 (0.93-1.02), 0.97 (0.91-1.03), 0.95 (0.77-1.30), and 0.97 (0.65-1.10) for each cascade step, respectively. We further performed stratified analyses by sociodemographic and behavioral risk factors and a sensitivity analysis with district fixed effects, all of which yielded results that confirmed the robustness of our main findings. CONCLUSIONS: Health insurance did not show significant impact on improving hypertension care cascade among young and middle-aged adults with hypertension in India. Innovative strategies for overcoming practical barriers to healthcare services in addition to improving financial access are needed to address the large unmet need for hypertension care.

Knowledge and trust of mothers regarding childhood vaccination in Rwanda.

INTRODUCTION: Knowledge and trust are some of the contributing factors to vaccine acceptance(VA) and Vaccine hesitancy (VH) is one of the top threats to global health. A significant drop in childhood vaccination has been observed in recent years. One important reason that influences mothers' choice to either postpone or avoid children's vaccinations is knowledge and trust in childhood vaccines. This study aimed to assess mothers' knowledge and trust on vaccination of their children, and to examine the association between vaccination knowledge and selected socio-demographic factors. METHODS: A cross-sectional survey was conducted from January 2022 to March 2022 to assess the knowledge and trust of mothers regarding childhood vaccination. Data was collected with self-administered questionnaires. Multivariable logistic regression analysis was employed to assess factors associated with childhood vaccine knowledge and trust. RESULTS: Of the 2,126 Rwandan parents who participated in the study, the proportions with good knowledge of - and good trust in childhood vaccination were 95.5% and 91.4%, respectively. The popular sources of information about childhood vaccination were health care professionals (91.8%) and mass media (28.9%). Multinomial logistic regression analysis showed that good knowledge of - and trust in childhood vaccination were associated with the relationship with child(ren), education, occupation, and monthly income. The Multinomial logistic regression also revealed that the determinants of good knowledge of - and trust in childhood vaccination were; caregiver (p = 4.0 × 10-4, adjusted Odds Ratio (aOR); 1.7, 95%C.I; 1.3 - 2.3), no formal educational status (p = 3.3 × 10-2, aOR; 1.7, 95%C.I; 1.0 - 3.0), the unemployed occupational status (p = 2.4 × 10-2, aOR; 1.2, 95%C.I; 1.0 - 1.4), and persons on more than $401 per month (p = 2.0 × 10-4, aOR; 3.5, 95%C.I; 1.8 - 6.8). CONCLUSION: The majority of parents in Rwanda had both good knowledge of-and good trust regarding childhood vaccination. Public health strategies to promote vaccination, education programmes as well as improved communication tools between health care professionals/traditional leaders/religious leaders and parents need to be considered to achieve favourable vaccination attitudes and practices for all parents in Rwanda.

Care settings of transient ischemic attack in the United States: A cohort study from the TriNetX health research network.

BACKGROUND: Evaluation and hospitalization rates after a transient ischemic attack (TIA)-like presentation vary widely in clinical practice. This study aimed to examine variations in care settings at initial TIA diagnosis in the United States. METHODS: We retrospectively analyzed an adult cohort with a first TIA principal diagnosis between January 1, 2015, and December 31, 2019, from TriNetX Diamond Network. Care settings at TIA diagnosis were defined as hospital care (including inpatient services and observation unit care without admission) and outpatient care (including any outpatient or emergency department visits). We estimated the distribution of care settings at TIA diagnosis and examined the associations of the hospital care setting with baseline age, sex, race, ethnicity, region, and stroke history. RESULTS: Among the 554,315 included patients, 38.8% received hospital care at their initial TIA diagnosis. A higher percentage of hospital care was observed in the age group of 50-64 years (40.3%), Black (46.0%), Hispanic (41.2%), South (40.9%), and Midwest (43.0%) Regions, and with a history of stroke (39.6%). Multivariable logistic regression consistently showed patients who were aged 50-64 years (Odds Ratio=1.09, 95% CI: [1.07, 1.11]), Black (1.28, [1.24, 1.32]), Hispanic (1.13, [1.09, 1.18]), from South (1.20, [1.18, 1.22]) and Midwest Region (1.33, [1.30, 1.35]), and had a history of stroke (1.02, [1.00, 1.04]) to more likely receive hospital care. CONCLUSIONS: Although there are TIA care disparities based on demographics, most patients with initial TIA received acute care in outpatient settings. It is imperative to ensure primary providers can risk-stratify TIA patients and provide rapid and proper management.

Cost-effectiveness of screening for chronic kidney disease using a cumulative eGFR-based statistic.

OBJECTIVES: Routine screening for chronic kidney disease (CKD) could enable timely interventions to slow down disease progression, but currently there are no clinical guidelines for screening. We aim to evaluate the cost-effectiveness of screening for CKD using a novel analytical tool based on a cumulative sum statistic of estimated glomerular filtration rate (CUSUMGFR). METHODS: We developed a microsimulation model that captured CKD disease progression, major complications, patients' awareness, and treatment adherence for a nationally representative synthetic cohort of age ≥ 30 years in the United States. In addition to the status quo with no screening, we considered four CUSUMGFR-based universal screening policies by frequency (annual or biennial) and starting age (30 or 60 years), and two targeted annual screening policies for patients with hypertension and diabetes, respectively. For each policy, we evaluated the total discounted disability-adjusted life years (DALYs) and direct health costs over a lifetime horizon and estimated the incremental cost-effectiveness ratio (ICER). We further performed one-way and probabilistic sensitivity analyses to assess the impact of parameter uncertainty. RESULTS: Compared with the status quo, all the CUSUMGFR-based screening policies were cost-effective under the willingness-to-pay (WTP) range of $50,000 -$100,000, with the estimated incremental cost-effectiveness ratios (ICERs) ranging from $15,614/DALYs averted to $54,373/DALYs averted. Universal annual screening with starting age of 30 was the non-dominated policy on the cost-effectiveness frontier under the WTP of approximately $25,000. Adding more recent treatment option of sodium-glucose cotransporter-2 (SGLT2) inhibitors to the treatment regimen was found to be cost-saving. Among the most influential model parameters, variation in the CKD progression rate, adherence, and testing cost resulted in the highest variability in model outcomes. CONCLUSIONS: CUSUMGFR-based screening policies for CKD are highly cost-effective in identifying patients at risk of end stage kidney disease in early stages of CKD. Given its simple requirement of a basic blood test, the CUSUMGFR-based screening can be easily incorporated into clinical workflow for disease monitoring and prevention.

Impact of inter-lesion distance and first-pass isolation on outcomes of pulmonary venous isolation for paroxysmal atrial fibrillation.

BACKGROUND: Contiguity of ablation lesions is a critical determinant of success for paroxysmal atrial fibrillation (PAF) ablation. Evidence supports maintaining an inter-lesional distance (ILD) ≤ 6 mm during pulmonary venous isolation (PVI). Meanwhile, first-pass isolation (FPI) on PVI outcome in follow-up was not deeply studied. The impact of ILD and FPI on PAF ablation outcomes was investigated. METHODS: Consecutive PAF patients who underwent first-time antral PVI were recruited. Coordinates of ablation points were extracted from the electro-anatomical mapping system and analyzed using custom-developed software to determine the ILD. A gap is defined as ILD greater than 6 mm. FPI was defined as the achievement of PVI by encircling the ipsilateral veins while simultaneously recording their electrical activity using a multipolar catheter. The primary endpoint was freedom from documented atrial arrhythmias including AF, atrial tachycardia (AT), or atrial flutter (AFL) lasting longer than 30 s during follow-up. RESULTS: A total of 105 patients underwent first-time antral PVI. During 13.3 ± 0.6 months of follow-up, atrial arrhythmias recurrence was noted in 22.9% of the patients. Atrial arrhythmia recurrence was significantly higher in patients with more gaps (> 2) (37.0% versus 11.9%, P < 0.01), and the number of gaps was an independent predictor of AF/AT/AFL recurrence. (Hazard ratio [HR] 1.20, 95% CI 1.03-1.40, P = 0.02). The group with FPI for at least one ipsilateral pair of PVs exhibited a decreased number of gaps (2.0 versus 7.0, P < 0.01) and demonstrated a significant correlation with a reduction of recurrence (HR 0.26, 95% CI 0.09-0.71, P = 0.01). Among 16 patients who underwent repeat ablation, the number of gaps during the index PVI was associated with PV reconnection (PVR) (P < 0.01). CONCLUSIONS: Gaps created during PVI are a modifiable determinant of AF/AT/AFL recurrence, and avoidance of gaps is crucial to improve clinical outcomes of PAF ablation. In addition, FPI exhibited a strong predictive capability for clinical success in patients with PAF.

A machine learning approach to differentiate wide QRS tachycardia: distinguishing ventricular tachycardia from supraventricular tachycardia.

BACKGROUND: Differential diagnosis of wide QRS tachycardia (WQCT) has been a challenging issue. Published algorithms to distinguish ventricular tachycardia (VT) and supraventricular tachycardia (SVT) have limited diagnostic capabilities. METHODS: A total of 278 patients with WQCT from January 2010 to March 2022 were enrolled. The electrophysiological study confirmed SVT in 154 patients and VT in 65 ones. Two hundred nineteen WQCT 12-lead ECGs were randomly divided into development cohort (n = 165) and testing cohort (n = 54) data sets. The development cohort was split into a training group (n = 115) and an internal validation group (n = 50). Forty ECG features extracted from the 219 WQCT ECGs are fed into 9 iteratively trained ML algorithms. This novel ML algorithm was also compared with four published algorithms. RESULTS: In the development cohort, the Gradient Boosting Machine (GBM) model displayed the maximum area under curve (AUC) (0.91, 95% confidence interval (CI) 0.81-1.00). In the testing cohort, the GBM model had a higher AUC of 0.97 compared to 4 validated ECG algorithms, namely, Brugada (0.68), avR (0.62), RWPTII (0.72), and LLA algorithms (0.70). Accuracy, sensitivity, specificity, negative predictive value, and positive predictive value of the GBM model were 0.94, 0.97, 0.90, 0.94, and 0.95, respectively. CONCLUSIONS: A GBM ML model contributes to distinguishing SVT from VT based on surface ECG features. In addition, we were able to identify important indicators for distinguishing WQCT.

Phosphorylation of Mad1 at serine 18 by Mps1 is required for the full virulence of rice blast fungus, Magnaporthe oryzae.

The spindle assembly checkpoint (SAC) proteins are conserved among eukaryotes safeguarding chromosome segregation fidelity during mitosis. However, their biological functions in plant-pathogenic fungi remain largely unknown. In this study, we found that the SAC protein MoMad1 in rice blast fungus (Magnaporthe oryzae) localizes on the nuclear envelope and is dispensable for M. oryzae vegetative growth and tolerance to microtubule depolymerizing agent treatment. MoMad1 plays an important role in M. oryzae infection-related development and pathogenicity. The monopolar spindle 1 homologue in M. oryzae (MoMps1) interacts with MoMad1 through its N-terminal domain and phosphorylates MoMad1 at Ser-18, which is conserved within the extended N termini of Mad1s from fungal plant pathogens. This phosphorylation is required for maintaining MoMad1 protein abundance and M. oryzae full virulence. Similar to the deletion of MoMad1, treatment with Mps1-IN-1 (an Mps1 inhibitor) caused compromised appressorium formation and decreased M. oryzae virulence, and these defects were dependent on its attenuating MoMad1 Ser-18 phosphorylation. Therefore, our study indicates the function of Mad1 in rice blast fungal pathogenicity and sheds light on the potential of blocking Mad1 phosphorylation by Mps1 to control crop fungal diseases.

Cost-effectiveness of population-based screening for chronic obstructive pulmonary disease in China: a simulation modeling study.

Background: China has the highest disease burden of chronic obstructive pulmonary disease (COPD) in the world; however, the diagnosis rate remains low. Screening for COPD in the population may improve early diagnosis and long-term health outcomes for patients with COPD. In this study, we aimed to evaluate the cost-effectiveness of population-based COPD screening policies in China. Methods: We developed a microsimulation model that simulated incidence, natural history, and clinical management of COPD over a lifetime horizon among the general population aged 35-80 years in China. We evaluated population-based screening policies with different screening methods (one-step with COPD Screening Questionnaire or two-step with additional portable spirometer test) and frequencies (one-time or every 1-10 years). We calculated the incremental cost-effectiveness ratio (ICER) of the screening policies compared with the status quo (without screening) and identified the most cost-effective screening policy. Scenario and sensitivity analyses were performed to assess the impact of key parameters and the robustness of model results. Findings: Compared with the status quo, all population-based COPD screening policies were cost-effective with estimated ICERs ranging between $8034 and $13,209 per quality-adjusted-life-year (QALY), all under the willingness-to-pay value of $38,441/QALY (three times China's gross domestic product per capita). A total of 0.39%-8.10% of COPD-related deaths and 0.58%-2.70% of COPD exacerbations were projected to be averted by COPD screening. Among all screening policies, annual two-step screening was the most cost-effective. Improving the linkage from screening to diagnosis and treatment could further increase population health benefits and the cost-effectiveness of COPD screening. Interpretation: Population-based screening for COPD could be cost-effective in China. Offering public programs for COPD screening similar to existing preventive health services for other chronic diseases could be a promising strategy to improve population health outcomes and mitigate the disease burden of COPD in China. Funding: Alexander von Humboldt Foundation, National Natural Science Foundation of China, CAMS Innovation Fund for Medical Science, Chinese Academy of Engineering project, and Horizon Europe.

The care cascade of chronic obstructive pulmonary disease in China: a cross-sectional study of individual-level data at enrolment into the national 'Happy Breathing' Programme.

Background: Understanding the chronic obstructive pulmonary disease (COPD) care cascade is crucial for identifying where and when to intervene to improve COPD outcomes. We aimed to determine the proportion of patients with COPD seeking care in China's health system who are lost at each stage of the COPD care cascade and how the patterns of loss vary across geographical regions and population groups. Methods: From November 3, 2018, to April 22, 2021, we used individual-level patient data from the national Chinese 'Happy Breathing' Programme, which aims to identify patients with COPD and provide appropriate care. COPD was defined as a post-bronchodilator ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) <0.70. We calculated the proportions of individuals who, at enrolment into the 'Happy Breathing' Programme, (i) had ever undergone a pulmonary function test, (ii) had been diagnosed with COPD in the past, (iii) were currently on treatment for COPD, and (iv) had achieved control of their COPD. We examined the association between reaching each stage of the care cascade and individual patient characteristics as well as regional-level economic development and available resources in the health system using multilevel regression. Findings: Among the 29,201 patients with COPD in the 'Happy Breathing' Programme, 41.0% (95% confidence interval [CI]: 40.4-41.6%) had ever been tested for COPD, 17.6% (95% CI: 17.1-18.0%) had previously been diagnosed with COPD, 8.5% (95% CI: 8.2-8.8%) were currently on treatment for COPD, 4.6% (95% CI: 4.3-4.8%) of patients had mild or no exacerbations in the prior year, and 3.9% (95% CI: 3.7-4.2%) of patients had suffered no exacerbations in the prior year. On average, patients living in the cities of Beijing, Wuhan, and Yinchuan had progressed further along the COPD care cascade than patients living in Daqing and Luoyang. Using multilevel regression, we found that young age, rural residence, and low regional per-capita GDP were significantly associated with larger losses at each stage of the COPD care cascade. Interpretation: Substantial proportions of patients with COPD are lost at each stage of the COPD care cascade in the Chinese health system. The largest losses occur during the initial stages of the cascade, when diagnosis first occurs. New policies and interventions are required to boost COPD care, especially screening and diagnosis, in the Chinese health system to reduce this large disease burden. Funding: This work was supported by Major Programme of National Natural Science Foundation of China (82090011), CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-049), and Horizon Europe (HORIZON-MSCA-2021-SE-01; project number 101086139-PoPMeD-SuSDeV). TB was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt professorship award.

COVID-19 antibody responses in individuals with natural immunity and with vaccination-induced immunity: a systematic review and meta-analysis.

BACKGROUND: The COVID-19 pandemic has caused a large mortality and morbidity burden globally. For individuals, a strong immune response is the most effective means to block SARS-CoV-2 infection. To inform clinical case management of COVID-19, development of improved vaccines, and public health policy, a better understanding of antibody response dynamics and duration following SARS-CoV-2 infection and after vaccination is imperatively needed. METHODS: We systematically analyzed antibody response rates in naturally infected COVID-19 patients and vaccinated individuals. Specifically, we searched all published and pre-published literature between 1 December 2019 and 31 July 2023 using MeSH terms and "all field" terms comprising "COVID-19" or "SARS-CoV-2," and "antibody response" or "immunity response" or "humoral immune." We included experimental and observational studies that provided antibody positivity rates following natural COVID-19 infection or vaccination. A total of 44 studies reporting antibody positivity rate changes over time were included. RESULTS: The meta-analysis showed that within the first week after COVID-19 symptom onset/diagnosis or vaccination, antibody response rates in vaccinated individuals were lower than those in infected patients (p < 0.01), but no significant difference was observed from the second week to the sixth month. IgG, IgA, and IgM positivity rates increased during the first 3 weeks; thereafter, IgG positivity rates were maintained at a relatively high level, while the IgM seroconversion rate dropped. CONCLUSIONS: Antibody production following vaccination might not occur as quickly or strongly as after natural infection, and the IgM antibody response was less persistent than the IgG response.

Nrf2 activation by neferine mitigates microglial neuroinflammation after subarachnoid hemorrhage through inhibiting TAK1-NF-κB signaling.

Oxidative stress and neuroinflammation are two major causes leading to early brain injury after subarachnoid hemorrhage (SAH). Nuclear factor E2-related factor 2 (Nrf2) is a critical transcription factor that contributes to antioxidant responses. Additionally, Nrf2 could inhibit transforming growth factor beta-activated kinase 1 (TAK1), which plays a vital role in microglial activation-mediated neuroinflammation. Neferine (NE) exhibits considerable protective effects in diverse disease models. However, the detailed effect and mechanism of NE on SAH remain unknown. Our data showed that NE treatment significantly reduced behavior and cognitive impairment, and brain edema in the early period after SAH. In addition, NE mitigated SAH-induced oxidative damage, neuroinflammation, and neural death. Moreover, NE inhibited M1 microglial polarization and enhanced M2 phenotype microglia both in vivo and in vitro. Further investigations revealed that NE enhanced the Nrf2-antioxidant response element (ARE) signaling pathway and suppressed TAK1-NF-κB signaling. In contrast, depletion of Nrf2 by ML385 suppressed Nrf2-ARE signaling, induced TAK1-NF-κB activation, and further promoted M1 microglial polarization. Additionally, ML385 abated the neuroprotective effects of NE against SAH. Notably, LPS also aggravated TAK1-NF-κB activation and reversed the beneficial effects of NE after SAH. In summary, NE provides protection after SAH by inhibiting oxidative stress and modulating microglial polarization through Nrf2 activation and TAK1-NF-κB suppression.

Preferences regarding COVID-19 vaccination among 12,000 adults in China: A cross-sectional discrete choice experiment.

Understanding public preferences concerning vaccination is critical to inform pandemic response strategies. To investigate Chinese adults' preferences regarding COVID-19 vaccine attributes, we conducted a cross-sectional online survey in 12,000 Chinese adults in June-July, 2021. Participants were requested to answer a series of discrete choice questions related to hypothetical COVID-19 vaccines. Using mixed logit models, our analysis revealed that participants had a higher preference for COVID-19 vaccines with longer duration of protection (coefficient: 1.272, 95% confidence interval [1.016 to 1.529]) and higher efficacy (coefficient: 1.063, [0.840, 1.287]). Conversely, participants demonstrated a lower preference associated with higher risk of rare but serious side-effects (coefficient: -1.158, [-1.359, -0.958]), oral administration (coefficient: -0.211, [-0.377, -0.046]), more doses (coefficient: -0.148, [-0.296, 0.000]) and imported origin (coefficient: -0.653, [-0.864, -0.443]). Moreover, preferences were heterogeneous by individual factors: highly educated participants were more sensitive to the negative vaccine attributes including price (coefficient -0.312, [-0.370, -0.253]) and imported vaccine (coefficient -0.941, [-1.186, -0.697]); there was also substantial heterogeneity in vaccine preferences with respect to age group, marital status, work status, income, chronic diagnosis history, COVID-19 vaccination history and geographic regions. As the first study of examining the public preferences for COVID-19 vaccine in China with a large nationwide sample of 12,000 adults, our results indicate that future vaccine should pose lower risk, possess longer protection period, have higher efficacy, be domestically produced, and have lower costs to increase the COVID-19 vaccination coverage. Our current study findings from this study provide insights and recommendations for not only COVID-19 vaccine design but also vaccine attribute preferences to increase vaccine uptake in potential future pandemics.

Portable spirometer-based pulmonary function test willingness in China: A nationwide cross-sectional study from the "Happy Breathing Program".

BACKGROUND: Understanding willingness to undergo pulmonary function tests (PFTs) and the factors associated with poor uptake of PFTs is crucial for improving early detection and treatment of chronic obstructive pulmonary disease (COPD). This study aimed to understand willingness to undergo PFTs among high-risk populations and identify any barriers that may contribute to low uptake of PFTs. METHODS: We collected data from participants in the "Happy Breathing Program" in China. Participants who did not follow physicians' recommendations to undergo PFTs were invited to complete a survey regarding their willingness to undergo PFTs and their reasons for not undergoing PFTs. We estimated the proportion of participants who were willing to undergo PFTs and examined the various reasons for participants to not undergo PFTs. We conducted univariable and multivariable logistic regressions to analyze the impact of individual-level factors on willingness to undergo PFTs. RESULTS: A total of 8475 participants who had completed the survey on willingness to undergo PFTs were included in this study. Out of these participants, 7660 (90.4%) were willing to undergo PFTs. Among those who were willing to undergo PFTs but actually did not, the main reasons for not doing so were geographical inaccessibility ( n  = 3304, 43.1%) and a lack of trust in primary healthcare institutions ( n  = 2809, 36.7%). Among the 815 participants who were unwilling to undergo PFTs, over half ( n  = 447, 54.8%) believed that they did not have health problems and would only consider PFTs when they felt unwell. In the multivariable regression, individuals who were ≤54 years old, residing in rural townships, with a secondary educational level, with medical reimbursement, still working, with occupational exposure to dust, and aware of the abbreviation "COPD" were more willing to undergo PFTs. CONCLUSIONS: Willingness to undergo PFTs was high among high-risk populations. Policymakers may consider implementing strategies such as providing financial incentives, promoting education, and establishing community-based programs to enhance the utilization of PFTs.