An Integrated Nanoplatform via Dual Channel Excitation for Both Precise Fluorescence Imaging and Photodynamic Therapy of Orthotopic Breast Tumor in NIR-II Region.

Although research on photodynamic therapy (PDT) of malignant tumor has made considerable progress in recent years, it is a remaining challenge to extend PDT to the second near-infrared window (NIR-II) along with real-time and accurate NIR-II fluorescence imaging to determine drug enrichment status and achieve high treatment efficacy. In this work, lanthanide nanoparticles (Ln NPs)-based nanoplatform (LCR) equipped with photosensitizer Chlorin e6 (Ce6) and targeting molecular NH2-PEG1000-cRGDfK are developed, which can achieve NIR-II photodynamic therapy (PDT) and NIR-II fluorescence imaging by dual channel excitation. Under 808 nm excitation, Nd3+ in the outer layer can absorb the energy and transfer inward to emit strong NIR-II emissions (1064 and 1525 nm). Due to the low background noise of NIR-II light and the targeting effect of NH2-PEG1000-cRGDfK, LCR can recognize tiny tumor tissue (≈3 mm) and monitor drug distribution in vivo. Under 1530 nm excitation, internal Er3+ can be self-sensitized, generating intense upconversion emission (662 nm) that can effectively activate Ce6 for in vivo PDT due to the deep tissue penetration of NIR-II light. This study provides a paradigm of theranostic nanoplatform for both real-time fluorescence imaging and PDT of orthotopic breast tumor in NIR-II window.

Comprehensive analysis of hepatitis B virus infections in blood donors in southern China that are surface antigen positive but nucleic acid testing negative.

BACKGROUND: Hepatitis B virus (HBV) infection is one of the major concerns for the safety of blood transfusion in high-prevalent countries such as in China. Prior studies outside of China have shown hepatitis B surface antigen (HBsAg) false-reactive rate of 0.02% to 0.04%. Similarly, false-negative HBsAg and HBV DNA results may occur in infected donors. Our study analyzed HBsAg enzyme-linked immunosorbent assay (ELISA)-reactive but NAT-negative donations in Shenzhen Blood Center, China. STUDY DESIGN AND METHODS: HBsAg ELISA-positive/NAT-negative plasma samples identified from screening 101,025 donations during 2017-2018 were analyzed by molecular and serologic tests including neutralization, chemiluminescence immunoassays, and various HBV DNA amplification assays. Molecular characterizations of HBsAg-positive/NAT-negative samples were determined by quantitative polymerase chain reaction (qPCR) and nested PCR amplification of the basic core and precore promotor regions (295 base pairs) and HBsAg (S) region (496 base pairs). RESULTS: Screening of 101,025 eligible blood donations identified 157 (0.16%, 95% confidence interval, 0.13%-0.18%) HBsAg ELISA-positive/NAT-negative plasma samples; of those, 71 (45.2%) were HBsAg confirmed positive by further HBsAg testing and DNA positive by molecular tests with increased sensitivity. Of the 71, all but one was antibody to hepatitis B core antigen reactive without antibody to hepatitis B surface antigen, yielding one recent (window-period) HBV infection. Of the remaining donations, 80 (51%) were not considered as HBV-infected donors, and 6 (3.8%) were interpreted as indeterminate since HBsAg results were discordant with unconfirmed HBV DNA results. In the 71 confirmed positives, HBsAg levels ranged from 0.05 to 400 IU/mL and HBV DNA from 6 to 2654 IU/mL; however, the correlation between the two was weak (R2 = 0.24). CONCLUSION: Fewer than half of HBsAg ELISA-positive/NAT-negative samples were confirmed as HBsAg positive. Our study demonstrates that in highly HBV-endemic countries, assays with high sensitivity and specificity may be required.

Evidence on COVID-19 Mortality and Disparities Using a Novel Measure, COVID excess mortality percentage: Evidence from Indiana, Wisconsin, and Illinois.

COVID-19 mortality rates increase rapidly with age, are higher among men than women, and vary across racial/ethnic groups, but this is also true for other natural causes of death. Prior research on COVID-19 mortality rates and racial/ethnic disparities in those rates has not considered to what extent disparities reflect COVID-19-specific factors, versus preexisting health differences. This study examines both questions. We study the COVID-19-related increase in mortality risk and racial/ethnic disparities in COVID-19 mortality, and how both vary with age, gender, and time period. We use a novel measure validated in prior work, the COVID Excess Mortality Percentage (CEMP), defined as the COVID-19 mortality rate (Covid-MR), divided by the non-COVID natural mortality rate during the same time period (non-Covid NMR), converted to a percentage. The CEMP denominator uses Non-COVID NMR to adjust COVID-19 mortality risk for underlying population health. The CEMP measure generates insights which differ from those using two common measures-the COVID-MR and the all-cause excess mortality rate. By studying both CEMP and COVID-MRMR, we can separate the effects of background health from Covid-specific factors affecting COVID-19 mortality. We study how CEMP and COVID-MR vary by age, gender, race/ethnicity, and time period, using data on all adult decedents from natural causes in Indiana and Wisconsin over April 2020-June 2022 and Illinois over April 2020-December 2021. CEMP levels for racial and ethnic minority groups can be very high relative to White levels, especially for Hispanics in 2020 and the first-half of 2021. For example, during 2020, CEMP for Hispanics aged 18-59 was 68.9% versus 7.2% for non-Hispanic Whites; a ratio of 9.57:1. CEMP disparities are substantial but less extreme for other demographic groups. Disparities were generally lower after age 60 and declined over our sample period. Differences in socio-economic status and education explain only a small part of these disparities.

A pH-Responsive Charge-Convertible Drug Delivery Nanocarrier for Precise Starvation and Chemo Synergistic Oncotherapy.

A pH-responsive charge-convertible drug delivery nanocarrier (MSN-TPZ-GOx@ZnO@PAH-PEG-DMMA, abbreviated as MTGZ@PPD) was prepared, which could specifically release hypoxia-activated chemotherapeutic Tirapazamine (TPZ) and glucose oxidase (GOx) in the tumor site for precise starvation and chemo synergistic oncotherapy. Acid-responsive Schiff base structure modified mesoporous silica nanoparticles (MSN) co-load with GOx and TPZ, then link with ZnO quantum dots (QDs). PAH-PEG-DMMA (PPD) polymer makes MTGZ@PPD with biocompatibility and charge-convertible feature. MTGZ@PPD is negatively charged at physiological pH, and the charge reversal of PPD and acidolysis of the Schiff base structure under the acidic tumor microenvironment (TME) induce a positively charged surface, which could potentiate the cell internalization. ZnO QDs could decompose at acidic TME, achieving controllable drug release. GOx could starve the tumor cells and enhance hypoxia level, thus initiates the activation of TPZ to realize synergistic starvation therapy and chemotherapy. This intelligent MTGZ@PPD has shown great potential for starvation and chemo synergistic oncotherapy.

Understanding COVID-19 Vaccine Effectiveness against Death Using a Novel Measure: COVID Excess Mortality Percentage.

COVID-19 vaccines have saved millions of lives; however, understanding the long-term effectiveness of these vaccines is imperative to developing recommendations for booster doses and other precautions. Comparisons of mortality rates between more and less vaccinated groups may be misleading due to selection bias, as these groups may differ in underlying health status. We studied all adult deaths during the period of 1 April 2021-30 June 2022 in Milwaukee County, Wisconsin, linked to vaccination records, and we used mortality from other natural causes to proxy for underlying health. We report relative COVID-19 mortality risk (RMR) for those vaccinated with two and three doses versus the unvaccinated, using a novel outcome measure that controls for selection effects. This measure, COVID Excess Mortality Percentage (CEMP), uses the non-COVID natural mortality rate (Non-COVID-NMR) as a measure of population risk of COVID mortality without vaccination. We validate this measure during the pre-vaccine period (Pearson correlation coefficient = 0.97) and demonstrate that selection effects are large, with non-COVID-NMRs for two-dose vaccinees often less than half those for the unvaccinated, and non-COVID NMRs often still lower for three-dose (booster) recipients. Progressive waning of two-dose effectiveness is observed, with an RMR of 10.6% for two-dose vaccinees aged 60+ versus the unvaccinated during April-June 2021, rising steadily to 36.2% during the Omicron period (January-June, 2022). A booster dose reduced RMR to 9.5% and 10.8% for ages 60+ during the two periods when boosters were available (October-December, 2021; January-June, 2022). Boosters thus provide important additional protection against mortality.

Selection Effects and COVID-19 Mortality Risk after Pfizer vs. Moderna Vaccination: Evidence from Linked Mortality and Vaccination Records.

Prior research generally finds that the Pfizer-BioNTech (BNT162b2) and Moderna (mRNA1273) COVID-19 vaccines provide similar protection against mortality, sometimes with a Moderna advantage due to slower waning. However, most comparisons do not address selection effects for those who are vaccinated and with which vaccine. We report evidence on large selection effects, and use a novel method to control for these effects. Instead of directly studying COVID-19 mortality, we study the COVID-19 excess mortality percentage (CEMP), defined as the COVID-19 deaths divided by non-COVID-19 natural deaths for the same population, converted to a percentage. The CEMP measure uses non-COVID-19 natural deaths to proxy for population health and control for selection effects. We report the relative mortality risk (RMR) for each vaccine relative to the unvaccinated population and to the other vaccine, using linked mortality and vaccination records for all adults in Milwaukee County, Wisconsin, from 1 April 2021 through 30 June 2022. For two-dose vaccinees aged 60+, RMRs for Pfizer vaccinees were consistently over twice those for Moderna, and averaged 248% of Moderna (95% CI = 175%,353%). In the Omicron period, Pfizer RMR was 57% versus 23% for Moderna. Both vaccines demonstrated waning of two-dose effectiveness over time, especially for ages 60+. For booster recipients, the Pfizer-Moderna gap is much smaller and statistically insignificant. A possible explanation for the Moderna advantage for older persons is the higher Moderna dose of 100 µg, versus 30 µg for Pfizer. Younger persons (aged 18-59) were well-protected against death by two doses of either vaccine, and highly protected by three doses (no deaths among over 100,000 vaccinees). These results support the importance of a booster dose for ages 60+, especially for Pfizer recipients. They suggest, but do not prove, that a larger vaccine dose may be appropriate for older persons than for younger persons.

Economic impact payment, human mobility and COVID-19 mitigation in the USA.

This paper studies the effect of the economic impact payment (EIP) on individual contributions to COVID-19 mitigation efforts in the USA, where the mitigation efforts are measured by the reduction of daily human mobility. I empirically estimate the effect of the EIP in April 2020 and use cellphone GPS data of 45 million smartphone devices as a proxy for human mobility across 216,069 Census Block Groups. The results show that when receiving the EIP, households significantly increased "Median Home Dwell Time" by an average of 3-5% (about 26-45 min). The paper highlights this unintended effect of the EIP, namely, that in addition to providing economic assistance, the EIP also helped increase individual contributions to mitigation efforts that slowed COVID-19 virus transmission in early 2020. Supplementary Information: The online version supplementary material available at 10.1007/s00181-021-02117-0.

Resveratrol activates CD8+ T cells through IL-18 bystander activation in lung adenocarcinoma.

Resveratrol, a natural product, has demonstrated anti-tumor effects in various kinds of tumor types, including colon, breast, and pancreatic cancers. Most research has focused on the inhibitory effects of resveratrol on tumor cells themselves rather than resveratrol's effects on tumor immunology. In this study, we found that resveratrol inhibited the growth of lung adenocarcinoma in a subcutaneous tumor model by using the ß-cyclodextrin-resveratrol inclusion complex. After resveratrol treatment, the proportion of M2-like tumor-associated macrophages (TAMs) was reduced and tumor-infiltrating CD8T cells showed significantly increased activation. The results of co-culture and antibody neutralization experiments suggested that macrophage-derived IL-18 may be a key cytokine in the resveratrol anti-tumor effect of CD8T cell activation. The results of this study demonstrate a novel view of the mechanisms of resveratrol tumor suppression. This natural product could reprogram TAMs and CD8T effector cells for tumor treatment.

Understanding COVID-19 Vaccine Effectiveness Against Death Using a Novel Measure: COVID Excess Mortality Percentage.

COVID-19 vaccines have saved millions of lives and prevented countless adverse patient disease outcomes. Understanding the long-term effectiveness of these vaccines is imperative to developing recommendations for precautions and booster doses. Comparisons between more and less vaccinated groups may be misleading due to selection bias, as these groups may differ in underlying health status and thus risk of adverse COVID-19 outcomes. We study all adult deaths over April 1, 2021-June 30, 2022 in Milwaukee County, Wisconsin, linked to vaccination records, use mortality from other natural causes to proxy for underlying health, and report relative COVID-19 mortality risk (RMR) for vaccinees versus the unvaccinated, using a novel outcome measure that controls for selection effects. This measure, COVID Excess Mortality Percentage (CEMP) uses the non-COVID natural mortality rate (Non-Covid-NMR) as a measure of population risk of COVID mortality without vaccination. We validate this measure during the pre-vaccine period (r = 0.97) and demonstrate that selection effects are large, with Non-Covid-NMRs for two-dose vaccinees less than half those for the unvaccinated, and Non-COVID NMRs still lower for three dose (booster) recipients. Progressive waning of two-dose effectiveness is observed, with relative mortality risk (RMR) for two-dose vaccinees aged 60 + versus the unvaccinated of 11% during April-June 2021, rising steadily to 36% during the Omicron period (January-June, 2022). Notably, a booster dose reduced RMR to 10-11% for ages 60+. Boosters thus provide important additional protection against mortality.

The Effect of the COVID-19 Pandemic on the Elderly: Population Fatality Rates, COVID Mortality Percentage, and Life Expectancy Loss.

The COVID-19 pandemic has disproportionately affected the elderly. This Article provides a detailed analysis of those effects, drawing primarily on individual-level mortality data covering almost three million persons aged 65+ in three Midwest states (Indiana, Illinois, and Wisconsin). We report sometimes surprising findings on population fatality rates ("PFR"), the ratio of COVID to non-COVID deaths, reported as a percentage, which we call the "Covid Mortality Percentage," and mean life expectancy loss ("LEL"). We examine how these COVID-19 outcomes vary with age, gender, race/ethnicity, socio-economic status, and time period during the pandemic. For all persons in the three Midwest areas, COVID PFR through year-end 2021 was 0.22%, mean years of life lost ("YLL") was 13.0 years, the COVID Mortality Percentage was 12.4%, and LEL was 0.028 years (eleven days). In contrast, for the elderly, PFR was 1.03%; YLL was 8.8 years, the COVID Mortality Percentage was 13.2%, and LEL was 0.091 years (thirty-four days). Controlling for gender, PFR and LEL were substantially higher for Blacks and Hispanics than for Whites at all ages. Racial/ethnic disparities for the elderly were large early in the pandemic but diminished later. Although COVID-19 mortality was much higher for the elderly, the COVID Mortality Percentage over the full pandemic period was only modestly higher for the elderly, at 13.2%, than for non-elderly adults aged 25-64, at 11.1%. Indeed, in 2021, this ratio was lower for the elderly than for the middle-aged, reflecting higher elderly vaccination rates.

Environmental justice and the COVID-19 pandemic: Evidence from New York State.

The decline in human mobility and socioeconomic activities during the COVID-19 pandemic has been accompanied by reports of significant improvements in air quality. We evaluate whether there was a uniform improvement in air quality across neighborhoods, with a special attention on differences by race. We focus on the COVID-19 lockdown in New York State, an early epicenter of the pandemic in the United States. Using a triple difference-in-differences model, we find that, despite the seasonal decline in particulate matter pollution starting late March (concurrent with the lockdown period), the lockdown narrowed the disparity in air quality between census tracts with high and low shares of non-white population in rural New York, whereas the racial gap in air quality remained unchanged in urban New York.

Identification of Potential Biomarkers From Hepatocellular Carcinoma With MT1 Deletion.

Background: Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Metallothioneins (MTs) are metal-binding proteins involved in multiple biological processes such as metal homeostasis and detoxification, as well as in oncogenesis. Copy number variation (CNV) plays a vital role in pathogenesis and carcinogenesis. Nevertheless, there is no study on the role of MT1 CNV in HCC. Methods: Array-based Comparative Genomic Hybridization (aCGH) analysis was performed to obtain the CNV data of 79 Guangxi HCC patients. The prognostic effect of MT1-deletion was analyzed by univariate and multivariate Cox regression analysis. The differentially expressed genes (DEGs) were screened based on The Gene Expression Omnibus database (GEO) and the Liver Hepatocellular Carcinoma of The Cancer Genome Atlas (TCGA-LIHC). Then function and pathway enrichment analysis, protein-protein interaction (PPI) and hub gene selection were applied on the DEGs. Lastly, the hub genes were validated by immunohistochemistry, tissue expression and prognostic analysis. Results: The MT1-deletion was demonstrated to affect the prognosis of HCC and can act as an independent prognostic factor. 147 common DEGs were screened. The most significant cluster of DEGs identified by Molecular Complex Detection (MCODE) indicated that the expression of four MT1s were down-regulated. MT1X and other five hub genes (TTK, BUB1, CYP3A4, NR1I2, CYP8B1) were associated with the prognosis of HCC. TTK, could affect the prognosis of HCC with MT1-deletion and non-deletion. NR1I2, CYP8B1, and BUB1 were associated with the prognosis of HCC with MT1-deletion. Conclusions: In the current study, we demonstrated that MT1-deletion can be an independent prognostic factor in HCC. We identified TTK, BUB1, NR1I2, CYP8B1 by processing microarray data, for the first time revealed the underlying function of MT1 deletion in HCC, MT1-deletion may influence the gene expression in HCC, which may be the potential biomarkers for HCC with MT1 deletion.

Synergistic Chemo-Photothermal Antibacterial Effects of Polyelectrolyte-Functionalized Gold Nanomaterials.

With the increasing threat of bacterial infection to human health, the development of different antimicrobial agents is essential. Therefore, based on the photothermal conversion properties of gold nanomaterials, the polyelectrolyte (PE)-coated gold nanorods (GNR@PE) and gold nanostars (GNS@PE) are designed and synthesized. Consequently, the chemo-photothermal synergistic antibacterial effect is achieved. GNR@PE effectively eliminates the high toxicity of cetyltrimethylammonium bromide (CTAB), and both GNR@PE and GNS@PE have good biocompatibility and stability. Because of the cation coating, GNR@PE and GNS@PE show high localized surface charge, which causes strong affinity to bacteria and destruction of bacterial cell walls and cell membranes. They have good chemical antibacterial effects, and the chemical antibacterial rates are above 50%. Under the irradiation of an 808 nm laser, for Gram-negative bacteria and Gram-positive bacteria, GNR@PE (50.00 µg/mL) and GNS@PE (55.00 µg/mL) can kill more than 99% of bacteria through chemo-photothermal effects. GNR@PE and GNS@PE can help eliminate inflammation caused by infection and promote wound healing in the mice model and have few side effects on the organs of mice.