New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF

Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4–VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4–VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.

Promising gas therapies for severe COVID-19.

The novel coronavirus disease 2019 (COVID-19) pandemic is a worldwide catastrophe, thoroughly challenging the healthcare systems. A growing number of victims suffer from a remarkable acute respiratory distress syndrome (ARDS) that necessitates admission to the intensive care unit (ICU), but there are no satisfactory treatments. Various gas therapies including nitric oxide, ozone, hyperbaric oxygen, hydrogen, and heliox have been employed in the fight against the pandemic and have improved clinical outcomes. However, the potential roles of these gases in COVID-19 treatment need to be verified in well-designed randomized controlled trials. This paper reviews advances in gaseous therapy of COVID-19.

New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF.

Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4-VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4-VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.

Targeting integrin pathways: mechanisms and advances in therapy.

Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

Risk tradeoffs between nitrogen dioxide and ozone pollution during the COVID-19 lockdowns in the Greater Bay area of China.

Photochemical regime for ozone (O3) formation is complicated in the sense that reducing emission of nitrogen oxides (NOx) may increase O3 concentration. The lockdown due to COVID-19 pandemic affords a unique opportunity to use real observations to explore the O3 formation regime and the effectiveness of NOx emission control strategies. In this study, observations from ground networks during the lockdowns were used to assess spatial disparity of the Ratio of Ozone Formation (ROF) for nitrogen dioxide (NO2) reduction in the Greater Bay Area (GBA) of China. The health risk model from Air Quality Health Index (AQHI) system in Hong Kong was adopted to evaluate the risk tradeoffs between NO2 and O3. Results show that the levels of O3 increase and NO2 reduction were comparable due to high ROF values in urban areas of central GBA. The ozone reactivity to NO2 reduction gradually declined outwards from central GBA. Despite the O3 increases, the NOx emission controls reduced the Integrated Health Risk (IHR) of NO2 and O3 in most regions of the GBA. When risk coefficients from the AQHI in Canada or the global review were adopted in the risk analyses, the results are extremely encouraging because the controls of NOx emission reduced the IHR of NO2 and O3 almost everywhere in the GBA. Our results underscore the importance of using a risk-based method to assess the effectiveness of emission control measures and the overall health benefit from NOx emission controls in the GBA.

Superoxide Dismutase Prevents SARS-CoV-2-Induced Plasma Cell Apoptosis and Stabilizes Specific Antibody Induction.

The infection of coronavirus disease (COVID-19) seriously threatens human life. It is urgent to generate effective and safe specific antibodies (Abs) against the pathogenic elements of COVID-19. Mice were immunized with SARS-CoV-2 spike protein antigens: S ectodomain-1 (CoV, in short) mixed in Alum adjuvant for 2 times and boosted with CoV weekly for 6 times. A portion of mice were treated with Maotai liquor (MTL, in short) or/and heat stress (HS) together with CoV boosting. We observed that the anti-CoV Ab was successfully induced in mice that received the CoV/Alum immunization for 2 times. However, upon boosting with CoV, the CoV Ab production diminished progressively; spleen CoV Ab-producing plasma cell counts reduced, in which substantial CoV-specific Ab-producing plasma cells (sPC) were apoptotic. Apparent oxidative stress signs were observed in sPCs; the results were reproduced by exposing sPCs to CoV in the culture. The presence of MTL or/and HS prevented the CoV-induced oxidative stress in sPCs and promoted and stabilized the CoV Ab production in mice in re-exposure to CoV. In summary, CoV/Alum immunization can successfully induce CoV Ab production in mice that declines upon reexposure to CoV. Concurrent administration of MTL/HS stabilizes and promotes the CoV Ab production in mice.

Physical distancing implementation, ambient temperature and Covid-19 containment: An observational study in the United States.

Governments may relax physical distancing interventions for coronavirus disease 2019 (Covid-19) containment in warm seasons/areas to prevent economic contractions. However, it is not clear whether higher temperature may offset the transmission risk posed by this relaxation. This study aims to investigate the associations of the effective reproductive number (Rt) of Covid-19 with ambient temperature and the implementation of physical distancing interventions in the United States (US). This study included 50 states and one territory of the US with 4,532,650 confirmed cases between 29 January and 31 July 2020. We used an interrupted time-series model with a state-level random intercept for data analysis. An interaction term of 'physical distancing×temperature' was included to examine their interactions. Stratified analyses by temperature and physical distancing implementation were also performed to analyse the modifying effects. The overall median (interquartile range) Rt was 1.2 (1.0-2.3). The implementation of physical distancing was associated with a 12% decrease in the risk of Rt (relative risk [RR]: 0.88, 95% confident interval [CI]: 0.86-0.89), and each 5 °C increase in temperature was associated with a 2% decrease (RR: 0.98, 95%CI: 0.97-0.98). We observed a statistically significant interaction between temperature and physical distancing implementation, but all the RRs were small (close to one). The containing effects of high temperature were attenuated by 5.1% when physical distancing was implemented. The association of COVID-19 Rt with physical distancing implementation was more stable (0.88 vs. 0.89 in days when temperature was low and high, respectively). Increased temperature did not offset the risk of Covid-19 Rt posed by the relaxation of physical distancing implementation. Our study does not recommend relaxing the implementation of physical distancing interventions in warm seasons/areas.

An improved decomposition method to differentiate meteorological and anthropogenic effects on air pollution: A national study in China during the COVID-19 lockdown period.

Although the effects of meteorological factors on severe air pollution have been extensively investigated, quantitative decomposition of the contributions of meteorology and anthropogenic factors remains a big challenge. The novel coronavirus disease 2019 (COVID-19) pandemic affords a unique opportunity to test decomposition method. Based on a wind decomposition method, this study outlined an improved method to differentiate complex meteorological and anthropogenic effects. The improved method was then applied to investigate the cause of unanticipated haze pollution in China during the COVID-19 lockdown period. Results from the wind decomposition method show that weakened winds increased PM2.5 concentrations in the Beijing-Tianjin area and northeastern China (e.g., by 3.19 µg/m3 in Beijing). Using the improved decomposition method, we found that the combined meteorological effect (e.g., drastically elevated humidity levels and weakened airflow) substantially increased PM2.5 concentrations in northern China: the most substantial increases were in the Beijing-Tianjin-Hebei region (e.g., by 26.79 µg/m3 in Beijing). On excluding the meteorological effects, PM2.5 concentrations substantially decreased across China (e.g., by 21.84 µg/m3 in Beijing), evidencing that the strict restrictions on human activities indeed decreased PM2.5 concentrations. The unfavorable meteorological conditions, however, overwhelmed the beneficial effects of emission reduction, causing the severe haze pollution. These results indicate that the integrated meteorological effects should be considered to differentiate the meteorological and anthropogenic effects on severe air pollution.

Effectiveness of non-pharmaceutical interventions on COVID-19 transmission in 190 countries from 23 January to 13 April 2020.

BACKGROUND: To evaluate and compare the effectiveness of four types of non-pharmaceutical interventions (NPIs) to contain the time-varying effective reproduction number (Rt) of coronavirus disease-2019 (COVID-19). METHODS: This study included 1,908,197 confirmed COVID-19 cases from 190 countries between 23 January and 13 April 2020. The implemented NPIs were categorised into four types: mandatory face mask in public, isolation or quarantine, social distancing and traffic restriction (referred to as mandatory mask, quarantine, distancing and traffic hereafter, respectively). RESULTS: The implementations of mandatory mask, quarantine, distancing and traffic were associated with changes (95% confidence interval, CI) of -15.14% (from -21.79% to -7.93%), -11.40% (from -13.66% to -9.07%), -42.94% (from -44.24% to -41.60%) and -9.26% (from -11.46% to -7.01%) in the Rt of COVID-19 when compared with those without the implementation of the corresponding measures. Distancing and the simultaneous implementation of two or more types of NPIs seemed to be associated with a greater decrease in the Rt of COVID-19. CONCLUSION: Our study indicates that NPIs can significantly contain the COVID-19 pandemic. Distancing and the simultaneous implementation of two or more NPIs should be the strategic priorities for containing COVID-19.

Meteorological factors and COVID-19 incidence in 190 countries: An observational study.

Novel corona virus disease 2019 (COVID-19), which first emerged in December 2019, has become a pandemic. This study aimed to investigate the associations between meteorological factors and COVID-19 incidence and mortality worldwide. This study included 1,908,197 confirmed cases of and 119,257 deaths from COVID-19 from 190 countries between 23 January and 13 April, 2020. We used a distributed lag non-linear model with city-/country-level random intercept to investigate the associations between COVID19 incidence and daily temperature, relative humidity, and wind speed. A series of confounders were considered in the analysis including demographics, socioeconomics, geographic locations, and political strategies. Sensitivity analyses were performed to examine the robustness of the associations. The COVID-19 incidence showed a stronger association with temperature than with relative humidity or wind speed. An inverse association was identified between the COVID-19 incidence and temperature. The corresponding 14-day cumulative relative risk was 1.28 [95% confidence interval (CI), 1.20-1.36] at 5 °C, and 0.75 (95% CI, 0.65-0.86) at 22 °C with reference to the risk at 11 °C. An inverse J-shaped association was observed between relative humidity and the COVID-19 incidence, with the highest risk at 72%. A higher wind speed was associated with a generally lower incidence of COVID-19, although the associations were weak. Sensitivity analyses generally yielded similar results. The COVID-19 incidence decreased with the increase of temperature. Our study suggests that the spread of COVID-19 may slow during summer but may increase during winter.

A mechanism-based parameterisation scheme to investigate the association between transmission rate of COVID-19 and meteorological factors on plains in China.

The novel coronavirus disease 2019 (COVID-19), which first emerged in Hubei province, China, has become a pandemic. However, data regarding the effects of meteorological factors on its transmission are limited and inconsistent. A mechanism-based parameterisation scheme was developed to investigate the association between the scaled transmission rate (STR) of COVID-19 and the meteorological parameters in 20 provinces/municipalities located on the plains in China. We obtained information on the scale of population migrated from Wuhan, the world epicentre of the COVID-19 outbreak, into the study provinces/municipalities using mobile-phone positioning system and big data techniques. The highest STRs were found in densely populated metropolitan areas and in cold provinces located in north-eastern China. Population density had a non-linear relationship with disease spread (linearity index, 0.9). Among various meteorological factors, only temperature was significantly associated with the STR after controlling for the effect of population density. A negative and exponential relationship was identified between the transmission rate and the temperature (correlation coefficient, -0.56; 99% confidence level). The STR increased substantially as the temperature in north-eastern China decreased below 0 °C (the STR ranged from 3.5 to 12.3 when the temperature was between -9.41 °C and -13.87 °C), whilst the STR showed less temperature dependence in the study areas with temperate weather conditions (the STR was 1.21 ± 0.57 when the temperature was above 0 °C). Therefore, a higher population density was linearly whereas a lower temperature (<0 °C) was exponentially associated with an increased transmission rate of COVID-19. These findings suggest that the mitigation of COVID-19 spread in densely populated and/or cold regions will be a great challenge.