Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons.

BACKGROUND: Many pregnant persons in the United States are receiving messenger RNA (mRNA) coronavirus disease 2019 (Covid-19) vaccines, but data are limited on their safety in pregnancy. METHODS: From December 14, 2020, to February 28, 2021, we used data from the "v-safe after vaccination health checker" surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) to characterize the initial safety of mRNA Covid-19 vaccines in pregnant persons. RESULTS: A total of 35,691 v-safe participants 16 to 54 years of age identified as pregnant. Injection-site pain was reported more frequently among pregnant persons than among nonpregnant women, whereas headache, myalgia, chills, and fever were reported less frequently. Among 3958 participants enrolled in the v-safe pregnancy registry, 827 had a completed pregnancy, of which 115 (13.9%) resulted in a pregnancy loss and 712 (86.1%) resulted in a live birth (mostly among participants with vaccination in the third trimester). Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported. Although not directly comparable, calculated proportions of adverse pregnancy and neonatal outcomes in persons vaccinated against Covid-19 who had a completed pregnancy were similar to incidences reported in studies involving pregnant women that were conducted before the Covid-19 pandemic. Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases). CONCLUSIONS: Preliminary findings did not show obvious safety signals among pregnant persons who received mRNA Covid-19 vaccines. However, more longitudinal follow-up, including follow-up of large numbers of women vaccinated earlier in pregnancy, is necessary to inform maternal, pregnancy, and infant outcomes.

JYNNEOS vaccine safety surveillance during the 2022 mpox outbreak using the Vaccine Adverse Event Reporting System (VAERS) and v-safe, United States, 2022-2023.

BACKGROUND: In response to the 2022 mpox outbreak in the United States, people with higher potential for exposure to mpox were recommended to receive two doses of the JYNNEOS vaccine. Vaccine safety was monitored using two complementary systems. METHODS: The Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system that accepts reports of adverse events following vaccination. VAERS is capable of rapidly identifying rare adverse events and unusual reporting patterns. Medical records were requested and reviewed for adverse events of special interest, including myocarditis. Adverse event reporting rates were calculated as the number of verified adverse event cases divided by the number of JYNNEOS doses administered. V-safe for mpox was a voluntary smartphone-based vaccine safety surveillance system that sent enrolled persons text messages linked to health surveys asking about reactions and health impact events occurring after vaccination. RESULTS: There were 1,207,056 JYNNEOS doses administered in the United States. VAERS received 1,927 reports for JYNNEOS. The myocarditis reporting rate per million doses was 2.69 after dose 1 and 8.64 after dose 2. V-safe had 213 participants complete at least one health survey. Rates of injection site and systemic reactions were similar in the first week following dose 1 and dose 2. CONCLUSIONS: JYNNEOS vaccine safety surveillance findings from VAERS and v-safe did not identify any unexpected safety concerns. The VAERS reporting rate for myocarditis was similar to previously published population background rates.

Postmarketing Safety Surveillance of a Hexavalent Vaccine in the Vaccine Adverse Event Reporting System.

We assessed the safety of hexavalent vaccine diphtheria and tetanus toxoids and acellular pertussis, inactivated poliovirus, hepatitis b, and haemophilus influenzae b conjugate vaccine in the Vaccine Adverse Event Reporting System. Five hundred-one reports of adverse events (AEs) were identified; 21 (4.2%) were serious. Most frequently reported AEs were fever (10.2%) and injection site erythema (5.4%). AEs reported were consistent with findings from prelicensure studies.

Safety Monitoring of Bivalent COVID-19 mRNA Vaccine Booster Doses Among Children Aged 5-11 Years - United States, October 12-January 1, 2023.

On October 12, 2022, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for bivalent (mRNA encoding the spike protein from the SARS-CoV-2 ancestral strain and BA.4/BA.5 Omicron variants) formulations of Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines for use as a single booster dose ≥2 months after completion of primary series or monovalent booster vaccination for children aged 5-11 years (Pfizer-BioNTech) and 6-17 years (Moderna); on December 8, 2022, FDA amended the EUAs to include children aged ≥6 months (1,2). The Advisory Committee on Immunization Practices (ACIP) recommends that all persons aged ≥6 months receive an age-appropriate bivalent mRNA booster dose (3). The safety of bivalent mRNA booster doses among persons aged ≥12 years has previously been described (4). To characterize the safety of bivalent mRNA booster doses among children aged 5-11 years after receipt of bivalent Pfizer-BioNTech and Moderna booster doses, CDC reviewed adverse events and health impacts reported to v-safe,* a voluntary, smartphone-based U.S. safety surveillance system established by CDC to monitor adverse events after COVID-19 vaccination, and to the Vaccine Adverse Event Reporting System (VAERS), a U.S. passive vaccine safety surveillance system co-managed by CDC and FDA† (5). During October 12-January 1, 2023, a total of 861,251 children aged 5-11 years received a bivalent Pfizer-BioNTech booster, and 92,108 children aged 6-11 years received a bivalent Moderna booster.§ Among 3,259 children aged 5-11 years registered in v-safe who received a bivalent booster dose, local (68.7%) and systemic reactions (49.5%) were commonly reported in the week after vaccination. Approximately 99.8% of reports to VAERS for children aged 5-11 years after bivalent booster vaccination were nonserious. There were no reports of myocarditis or death after bivalent booster vaccination. Eighty-four percent of VAERS reports were related to vaccination errors, 90.5% of which did not list an adverse health event. Local and systemic reactions reported after receipt of a bivalent booster dose are consistent with those reported after a monovalent booster dose; serious adverse events are rare. Vaccine providers should provide this information when counseling parents or guardians about bivalent booster vaccination. Preliminary safety findings from the first 11 weeks of bivalent booster vaccination among children aged 5-11 years are reassuring. Compared with the low risk of serious health effects after mRNA COVID-19 vaccination, the health effects of SARS-CoV-2 infection include death and serious long-term sequalae (6). ACIP recommends that all persons aged ≥6 months receive an age-appropriate bivalent mRNA booster dose ≥2 months after completion of a COVID-19 primary series or receipt of a monovalent booster dose.¶.

Safety Monitoring of mRNA COVID-19 Vaccine Third Doses Among Children Aged 6 Months-5 Years - United States, June 17, 2022-May 7, 2023.

As of May 7, 2023, CDC's Advisory Committee on Immunization Practices (ACIP) recommends that all children aged 6 months-5 years receive at least 1 age-appropriate bivalent mRNA COVID-19 vaccine dose. Depending on their COVID-19 vaccination history and history of immunocompromise, these children might also need additional doses* (1-3). Initial vaccine safety findings after primary series vaccination among children aged 6 months-5 years showed that transient local and systemic reactions were common whereas serious adverse events were rare (4). To characterize the safety of a third mRNA COVID-19 vaccine dose among children aged 6 months-5 years, CDC reviewed adverse events and health surveys reported to v-safe, a voluntary smartphone-based U.S. safety surveillance system established by CDC to monitor health after COVID-19 vaccination (https://vsafe.cdc.gov/en/) and the Vaccine Adverse Event Reporting System (VAERS), a U.S. passive vaccine safety surveillance system co-managed by CDC and the Food and Drug Administration (FDA) (https://vaers.hhs.gov/) (5). During June 17, 2022-May 7, 2023, approximately 495,576 children aged 6 months-4 years received a third dose (monovalent or bivalent) of Pfizer-BioNTech vaccine and 63,919 children aged 6 months-5 years received a third dose of Moderna vaccine.† A third mRNA COVID-19 vaccination was recorded for 2,969 children in v-safe; approximately 37.7% had no reported reactions, and among those for whom reactions were reported, most reactions were mild and transient. VAERS received 536 reports after a third dose of mRNA COVID-19 vaccine for children in these age groups; 98.5% of reports were nonserious and most (78.4%) were classified as a vaccination error.§ No new safety concerns were identified. Preliminary safety findings after a third dose of COVID-19 vaccine for children aged 6 months-5 years are similar to those after other doses. Health care providers can counsel parents and guardians of young children that most reactions reported after vaccination with Pfizer-BioNTech or Moderna vaccine were mild and transient and that serious adverse events are rare.

A nomogram prediction of outcome in patients with COVID-19 based on individual characteristics incorporating immune response-related indicators.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) has quickly become a global threat to public health, and it is difficult to predict severe patients and their prognosis. Here, we intended developing effective models for the late identification of patients at disease progression and outcome. METHODS: A total of 197 patients were included with a 20-day median follow-up time. We first developed a nomogram for disease severity discrimination, then created a prognostic nomogram for severe patients. RESULTS: In total, 40.6% of patients were severe and 59.4% were non-severe. The multivariate logistic analysis indicated that IgG, neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase, platelet, albumin, and blood urea nitrogen were significant factors associated with the severity of COVID-19. Using immune response phenotyping based on NLR and IgG level, the logistic model showed patients with the NLRhi IgGhi phenotype are most likely to have severe disease, especially compared to those with the NLRlo IgGlo phenotype. The C-indices of the two discriminative nomograms were 0.86 and 0.87, respectively, which indicated sufficient discriminative power. As for predicting clinical outcomes for severe patients, IgG, NLR, age, lactate dehydrogenase, platelet, monocytes, and procalcitonin were significant predictors. The prognosis of severe patients with the NLRhi IgGhi phenotype was significantly worse than the NLRlo IgGhi group. The two prognostic nomograms also showed good performance in estimating the risk of progression. CONCLUSIONS: The present nomogram models are useful to identify COVID-19 patients with disease progression based on individual characteristics and immune response-related indicators. Patients at high risk for severe illness and poor outcomes from COVID-19 should be managed with intensive supportive care and appropriate therapeutic strategies.

Safety Monitoring of Bivalent COVID-19 mRNA Vaccine Booster Doses Among Persons Aged ≥12 Years - United States, August 31-October 23, 2022.

On August 31, 2022, the Food and Drug Administration (FDA) authorized bivalent formulations of BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines; these vaccines include mRNA encoding the spike protein from the original (ancestral) strain of SARS-CoV-2 (the virus that causes COVID-19) and from the B.1.1.529 (Omicron) variants BA.4 and BA.5 (BA.4/BA.5). These bivalent mRNA vaccines were authorized for use as a single booster dose ≥2 months after completion of primary series or monovalent booster vaccination; Pfizer-BioNTech bivalent booster was authorized for persons aged ≥12 years and Moderna for adults aged ≥18 years.*,† On September 1, 2022, the Advisory Committee on Immunization Practices (ACIP) recommended that all persons aged ≥12 years receive an age-appropriate bivalent mRNA booster dose.§ To characterize the safety of bivalent mRNA booster doses, CDC reviewed adverse events and health impacts reported after receipt of bivalent Pfizer-BioNTech and Moderna booster doses during August 31-October 23, 2022, to v-safe,¶ a voluntary smartphone-based U.S. safety surveillance system established by CDC to monitor adverse events after COVID-19 vaccination, and the Vaccine Adverse Event Reporting System (VAERS),** a U.S. passive vaccine safety surveillance system managed by CDC and FDA (1). During August 31-October 23, 2022, approximately 14.4 million persons aged ≥12 years received a bivalent Pfizer-BioNTech booster dose, and 8.2 million adults aged ≥18 years received a bivalent Moderna booster dose.†† Among the 211,959 registrants aged ≥12 years who reported receiving a bivalent booster dose to v-safe, injection site and systemic reactions were frequently reported in the week after vaccination (60.8% and 54.8%, respectively); fewer than 1% of v-safe registrants reported receiving medical care. VAERS received 5,542 reports of adverse events after bivalent booster vaccination among persons aged ≥12 years; 95.5% of reports were nonserious and 4.5% were serious events. Health care providers and patients can be reassured that adverse events reported after a bivalent booster dose are consistent with those reported after monovalent doses. Health impacts after COVID-19 vaccination are less frequent and less severe than those associated with COVID-19 illness (2).

COVID-19 Vaccine Safety in Children Aged 5-11 Years - United States, November 3-December 19, 2021.

On October 29, 2021, the Food and Drug Administration (FDA) amended the Emergency Use Authorization (EUA) for Pfizer-BioNTech COVID-19 (BNT162b2) mRNA vaccine to expand its use to children aged 5-11 years, administered as 2 doses (10 µg, 0.2mL each) 3 weeks apart (1). As of December 19, 2021, only the Pfizer-BioNTech COVID-19 vaccine is authorized for administration to children aged 5-17 years (2,3). In preauthorization clinical trials, Pfizer-BioNTech COVID-19 vaccine was administered to 3,109 children aged 5-11 years; most adverse events were mild to moderate, and no serious adverse events related to vaccination were reported (4). To further characterize safety of the vaccine in children aged 5-11 years, CDC reviewed adverse events after receipt of Pfizer-BioNTech COVID-19 vaccine reported to the Vaccine Adverse Event Reporting System (VAERS), a passive vaccine safety surveillance system co-managed by CDC and FDA, and adverse events and health impact assessments reported to v-safe, a voluntary smartphone-based safety surveillance system for adverse events after COVID-19 vaccination,* during November 3-December 19, 2021. Approximately 8.7 million doses of Pfizer-BioNTech COVID-19 vaccine were administered to children aged 5-11 years† during this period; VAERS received 4,249 reports of adverse events after vaccination with Pfizer-BioNTech COVID-19 vaccine in this age group, 4,149 (97.6%) of which were not serious. Approximately 42,504 children aged 5-11 years were enrolled in v-safe after vaccination with Pfizer-BioNTech COVID-19 vaccine; after dose 2, a total of 17,180 (57.5%) local and 12,223 systemic (40.9%) reactions (including injection-site pain, fatigue, or headache) were reported. The preliminary safety findings are similar to those from preauthorization clinical trials (4,5). The Advisory Committee on Immunization Practices (ACIP) recommends the Pfizer-BioNTech COVID-19 vaccine for children aged 5-11 years for the prevention of COVID-19 (6). Parents and guardians of children aged 5-11 years vaccinated with Pfizer-BioNTech COVID-19 vaccine should be advised that local and systemic reactions are expected after vaccination. Vaccination is the most effective way to prevent COVID-19. CDC and FDA will continue to monitor vaccine safety and will provide updates as needed to guide COVID-19 vaccination recommendations.

Safety Monitoring of the Janssen (Johnson & Johnson) COVID-19 Vaccine - United States, March-April 2021.

On February 27, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Janssen (Ad.26.COV2.S) COVID-19 vaccine (Janssen Biotech, Inc., a Janssen Pharmaceutical company, Johnson & Johnson) (1). The Janssen COVID-19 vaccine, the third COVID-19 vaccine authorized for use in the United States, uses a replication-incompetent human adenoviral type 26 vector platform* (2) and is administered as a single intramuscular dose, whereas the first two authorized vaccines use an mRNA platform and require 2 doses. On February 28, 2021, the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for use of Janssen COVID-19 vaccine among persons aged ≥18 years (3). During April 13-23, CDC and FDA recommended a pause in use of Janssen vaccine after reports of six cases of cerebral venous sinus thrombosis (CVST) with thrombocytopenia (platelet count <150,000/µL of blood) among Janssen vaccine recipients (4). Similar thrombotic events, primarily among women aged <60 years, have been described in Europe after receipt of the AstraZeneca COVID-19 vaccine, which uses a replication-incompetent chimpanzee adenoviral vector (5-7). The U.S. CVST cases that prompted the pause in Janssen vaccination, as well as subsequently detected CVST cases, are described elsewhere (8). This report summarizes adverse events among Janssen vaccine recipients, including non-CVST cases of thrombosis with thrombocytopenia syndrome (TTS), reported to the Vaccine Adverse Events Reporting System (VAERS), a passive surveillance system, and through v-safe, an active monitoring system. As of April 21, 2021, 7.98 million doses of the Janssen COVID-19 vaccine had been administered. Among 13,725 VAERS reports reviewed, 97% were classified as nonserious and 3% as serious,† including three reports among women of cases of thrombosis in large arteries or veins accompanied by thrombocytopenia during the second week after vaccination. These three cases and the previously detected CVST cases are consistent with 17 cases of TTS,§ a newly defined condition. Approximately 338,700 Janssen COVID-19 vaccine recipients completed at least one v-safe survey during the week after vaccination; 76% reported a systemic reaction, 61% reported a local reaction, and 34% reported a health impact.¶ Fatigue and pain were commonly reported symptoms in both VAERS and v-safe. The overall safety profile is consistent with preauthorization clinical trials data. Prompt review of U.S. vaccine safety data detected three additional cases of non-CVST TTS, in addition to the previously recognized CVST cases that initiated the pause in use of the Janssen COVID-19 vaccine. Ongoing monitoring of adverse events after COVID-19 vaccination, including vaccination with the Janssen single-dose vaccine, is essential for evaluating the risks and benefits of each vaccine.

First Month of COVID-19 Vaccine Safety Monitoring - United States, December 14, 2020-January 13, 2021.

Two coronavirus disease 2019 (COVID-19) vaccines are currently authorized for use in the United States. The Food and Drug Administration (FDA) issued Emergency Use Authorization (EUA) for the Pfizer-BioNTech COVID-19 vaccine on December 11, 2020, and for the Moderna COVID-19 vaccine on December 18, 2020; each is administered as a 2-dose series. The Advisory Committee on Immunization Practices issued interim recommendations for Pfizer-BioNTech and Moderna COVID-19 vaccines on December 12, 2020 (1), and December 19, 2020 (2), respectively; initial doses were recommended for health care personnel and long-term care facility (LTCF) residents (3). Safety monitoring for these vaccines has been the most intense and comprehensive in U.S. history, using the Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting system, and v-safe,* an active surveillance system, during the initial implementation phases of the COVID-19 national vaccination program (4). CDC conducted descriptive analyses of safety data from the first month of vaccination (December 14, 2020-January 13, 2021). During this period, 13,794,904 vaccine doses were administered, and VAERS received and processed† 6,994 reports of adverse events after vaccination, including 6,354 (90.8%) that were classified as nonserious and 640 (9.2%) as serious.§ The symptoms most frequently reported to VAERS were headache (22.4%), fatigue (16.5%), and dizziness (16.5%). A total of 113 deaths were reported to VAERS, including 78 (65%) among LTCF residents; available information from death certificates, autopsy reports, medical records, and clinical descriptions from VAERS reports and health care providers did not suggest any causal relationship between COVID-19 vaccination and death. Rare cases of anaphylaxis after receipt of both vaccines were reported (4.5 reported cases per million doses administered). Among persons who received Pfizer-BioNTech vaccine, reactions reported to the v-safe system were more frequent after receipt of the second dose than after the first. The initial postauthorization safety profiles of the two COVID-19 vaccines in current use did not indicate evidence of unexpected serious adverse events. These data provide reassurance and helpful information regarding what health care providers and vaccine recipients might expect after vaccination.

Oxygen-substituted borophene as a potential anode material for Li/Na-ion batteries: a first principles study.

Two-dimensional graphene-like hexagonal borophene sheets (HBSs) have a thermodynamically unsteady configuration since boron has one electron less than the carbon in graphene. To overcome this problem, we proposed a novel 2D graphene-like HBS oxide (h-B3O) in theory, which is designed by substituting partial boron atoms in a HBS with oxygen atoms. Molecular dynamics simulations indicate that h-B3O has good thermal stability. Besides, we also explored the potential of h-B3O monolayers as anodes for Li-ion batteries (LIBs) and Na-ion batteries (NIBs) by using first-principles calculations. The results indicated that the h-B3O monolayer has high adsorption energies (-2.33/-1.70 eV for Li/Na), low diffusion barriers (0.67/0.42 eV for Li/Na) and suitable average open-circuit voltages (0.36/0.32 V for LIBs/NIBs). Particularly, h-B3O has a large theoretical specific capacity of 1161 mA h g-1 for LIBs. Thus, benefiting from these characteristics, the h-B3O monolayer is considered as a promising candidate for an anode material for LIBs/NIBs.

LDH, CRP and ALB predict nucleic acid turn negative within 14 days in symptomatic patients with COVID-19.

AIMS: To search for biochemical indicators that can identify symptomatic patients with COVID-19 whose nucleic acid could turn negative within 14 days, and assess the prognostic value of these biochemical indicators in patients with COVID-19. PATIENTS AND METHODS: We collected the clinical data of patients with COVID-19 admitted to our hospital, by using logistic regression analysis and AUC curves, explored the relationship between biochemical indicators and nucleic acid positive duration, the severity of COVID-19, and hospital stay respectively. RESULTS: A total of two hundred and thirty-three patients with COVID-19 were enrolled in the study. We found patients whose nucleic acid turned negative within 14 days had lower LDH, CRP and higher ALB (P < 0.05). ROC curve results indicated that lower LDH, TP, CRP and higher ALB predicted the nucleic acid of patients turned negative within 14 days with statistical significance(P < 0.05), AST, LDH, CRP and PCT predicted the severe COVID-19 with statistical significance, and CRP predicted hospital stay >31days with statistical significance (P < 0.05). After verification, the probability of nucleic acid turning negative within 14 days in patients with low LDH (<256 U/L), CRP (<44.5 mg/L) and high ALB (>35.8 g/L) was about 4 times higher than that in patients with high LDH, CRP and low ALB (P < 0.05). CONCLUSIONS: LDH, CRP and ALB are useful prognostic marker for predicting nucleic acid turn negative within 14 days in symptomatic patients with COVID-19.

Prognostic Value of C-Reactive Protein in Patients With Coronavirus 2019.

BACKGROUND: An elevated serum C-reactive protein (CRP) level was observed in most patients with coronavirus disease 2019 (COVID-19). METHODS: Data for COVID-19 patients with clinical outcome in a designated hospital in Wuhan, China, were retrospectively collected and analyzed from 30 January 2020 to 20 February 2020. The prognostic value of admission CRP was evaluated in patients with COVID-19. RESULTS: Of 298 patients enrolled, 84 died and 214 recovered. Most nonsurvivors were male, older, or with chronic diseases. Compared with survivors, nonsurvivors showed significantly elevated white blood cell and neutrophil counts, neutrophil to lymphocyte ratio (NLR), systemic immune inflammation index (defined by platelet count multiplied by NLR), CRP, procalcitonin, and D-dimer and showed decreased red blood cell, lymphocyte, and platelet counts. Age, neutrophil count, platelet count, and CRP were identified as independent predictors of adverse outcome. The area under the receiver operating characteristic (ROC) curve (AUC) of CRP (0.896) was significantly higher than that of age (0.833), neutrophil count (0.820), and platelet count (0.678) in outcome prediction (all P < .05). With a cutoff value of 41.4, CRP exhibited sensitivity of 90.5%, specificity of 77.6%, positive predictive value of 61.3%, and negative predictive value of 95.4%. CRP was also an independent discriminator of severe/critical illness on admission with an AUC (0.783) comparable to age (0.828) and neutrophil count (0.729) (both P > .05). CONCLUSIONS: In patients with COVID-19, admission CRP correlated with disease severity and tended to be a good predictor of adverse outcome.

Current status of the clinical use of PD-1/PD-L1 inhibitors: a questionnaire survey of oncologists in China.

BACKGROUND: The purpose of the present study was to obtain information on the use of PD-1/PD-L1 inhibitors by oncologists in China through a national questionnaire survey. METHODS: Between the 7th and 25th of July in 2019, a questionnaire designed by the Chinese Society of Clinical Oncology Immuno-Oncology (CSCO IO) Committee on the current status of the use of PD-1/PD-L1 inhibitors was distributed online and offline to cancer-related medical departments in thirty different provinces and autonomous regions of China. The national questionnaire consisted of three sections as follows: general information, current status of the application of PD-1/PD-L1 inhibitors in the clinic, and oncologists' concerns regarding utilization. RESULTS: The valid response rate of the current status survey was 76.3%. The proportion of senior doctors (physician-in-charge or a more superior position for more than 3 years) among the respondents was relatively high (67.0% in 588). Of the respondents, 59.2% had prescribed PD-1/PD-L1 inhibitors during clinical treatment, and the most frequent reason for not prescribing these inhibitors was the choice "do not understand the mechanism and the efficacy of PD-1/PD-L1 inhibitors". In addition, 77.9% of the prescribers used the medications in an off-label situation, and the most important motivation for this use was the fact that "there were indications abroad but not domestically". In addition, 77.9% of the prescribers believed that "immunotherapy-related adverse effects could be controlled or intervened through follow-up management". The prescribers were mostly concerned about "how to identify pseudoprogression and hyperprogression" and "immunity-related adverse effects management". CONCLUSION: The present study highlights the current status of PD-1/PD-L1 inhibitors in China. Increasing numbers of medical oncologists are interested in PD-1/PD-L1 inhibitors, and they are in need of immunotherapy education.

Therapeutic effects of saponin components on porcine reproductive and respiratory syndrome virus-infected piglets.

The present study aimed to evaluate the potential therapeutic effects of Anemoside B4 (AB4), Panax notoginseng saponins (PNS), Notoginsenoside R1 (SR1), Saikosaponin A (SSA) and Saikosaponin D (SSD) on piglets infected with porcine reproductive and respiratory syndrome virus (PRRSV). A total of 132 completely healthy piglets were randomly divided into 22 groups consisting of six animals each. Control piglets were intramuscularly injected with 2 ml of PRRSV (NJGC strain) solution containing 106  TCID50  virus/ml. For low-, middle- and high-dose saponin treatment groups, the piglets were initially administrated with the same volume of PRRSV solution, followed by intraperitoneal injection with AB4, PNS, SR1, SSA or SSD at 1, 5 or 10 mg/kg b.w. on day 3. The piglets in drug control group were intraperitoneally injected with 10 mg/kg b.w. of each saponin without prior PRRS challenge, while those in blank control group were injected with the same amount of normal saline. The results indicated that all the five saponin components could decrease the incidence and severity of PRRSV-induced immunopathological damages, including the elevated body temperature, weight loss, anaemia and internal inflammation. Moreover, the saponin components could enhance protein absorption and immune responses. Taken together, this study reveals that the saponin components are effective against PRRSV infection and strengthen the immune system and thus may serve as potential antiviral therapeutic agents.

Cigarette Smoke Induces Human Airway Epithelial Senescence via Growth Differentiation Factor 15 Production.

Cigarette smoke (CS)-induced airway epithelial senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), although the underlying mechanisms remain largely unknown. Growth differentiation factor (GDF) 15 is increased in airway epithelium of smokers with COPD and CS-exposed human airway epithelial cells, but its role in CS-induced airway epithelial senescence is unclear. In this study, we first analyzed expression of GDF15 and cellular senescence markers in airway epithelial cells of current smokers and nonsmokers. Second, we determined the role of GDF15 in CS-induced airway epithelial senescence by using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9 genome editing approach. Finally, we examined whether exogenous GDF15 protein promoted airway epithelial senescence through the activin receptor-like kinase 1/Smad1 pathway. GDF15 up-regulation was found in parallel with increased cellular senescence markers, p21, p16, and high-mobility group box 1 in airway epithelial cells of current smokers compared with nonsmokers. Moreover, CS extract induced cellular senescence in cultured human airway epithelial cells, represented by induced senescence-associated ß-galactosidase activity, inhibited cell proliferation, increased p21 expression, and increased release of high-mobility group box 1 and IL-6. Disruption of GDF15 significantly inhibited CS extract-induced airway epithelial senescence. Lastly, GDF15 protein bound to the activin receptor-like kinase 1 receptor and promoted airway epithelial senescence via activation of the Smad1 pathway. Our findings highlight an important contribution of GDF15 in promoting airway epithelial senescence upon CS exposure. Senescent airway epithelial cells that chronically accumulate in CS-exposed lungs could contribute substantially to chronic airway inflammation in COPD development and progression.

HER2 expression in primary gastric cancers and paired synchronous lymph node and liver metastases. A possible road to target HER2 with radionuclides.

Resistance has been reported to human epidermal growth factor receptor 2 (HER2)-targeted therapy with the tyrosine kinase inhibitor lapatinib and the antibody trastuzumab in metastatic gastric cancer. An alternative or complement might be to target the extracellular domain of HER2 with therapy-effective radionuclides. The fraction of patients with HER2 expression in primary tumors and major metastatic sites, e.g., lymph nodes and liver, was analyzed to evaluate the potential for such therapy. Samples from primary tumors and lymph node and liver metastases were taken from each patient within a few hours, and to our knowledge, such sampling is unique. The number of analyzed cases was therefore limited, since patients that had received preoperative radiotherapy, chemotherapy, or HER2-targeted therapy were excluded. From a large number of considered patients, only 29 could be included for HER2 analysis. Intracellular mutations were not analyzed since they are assumed to have no or minor effect on the extracellular binding of molecules that deliver radionuclides. HER2 was positive in nearly 52 % of the primary tumors, and these expressed HER2 in corresponding lymph node and liver metastases in 93 and 100 % of the cases, respectively. Similar values for primary tumors and also good concordance with metastases have been indicated in the literature. Thus, relevant radionuclides and targeting molecules for nuclear medicine-based noninvasive, whole-body receptor analysis, dose planning, and therapy can be applied for many patients; see "Discussion" Hopefully, more patients can then be treated with curative instead of palliative intention.

VISA is required for B cell expression of TLR7.

B cells play a critical role in the initialization and development of the systemic lupus erythematosus that is dependent on the expression of the endosomal ssRNA receptor TLR7. Previous studies have established that B cell expression of TLR7 is controlled by the type I IFN secreted by plasmacytoid dendritic cells. In this article, we report that VISA, also known as MAVS, IPS-1, and CardIf, essential for RIG-I/MDA5-mediated signaling following sensing of cytosolic RNA, regulate B cell expression of TLR7 and CD23. We found that B cells from a VISA(-/-) mouse express reduced TLR7 but normal basal levels of type I IFN. We also show that although IFN-ß and TLR7 agonists synergize to promote TLR7 expression in VISA(-/-) B cells, they do not fully complement the defect seen in VISA(-/-) cells. Cell transfer experiments revealed that the observed effects of VISA(-/-) are B cell intrinsic. The reduced TLR7 expression in B cells is correlated with impaired TLR7 agonist-induced upregulation of activation markers CD69 and CD86, cell proliferation, production of IFN-α, TNF, and IL-12, and NF-κB activation. Finally, studies indicate that genetic background may influence the observed phenotype of our VISA(-/-) mice, because VISA(-/-) B cells differ in CD23 and TLR7 expression when on C57BL/6 versus 129Sv-C57BL/6 background. Thus, our findings suggest an unexpected link between VISA-mediated cytosolic RLR signaling and autoimmunity.