OBJECTIVE To provide practical basis and policy recommendations for improving the pharmacovigilance （PV） system construction in medical institutions across China. METHODS A questionnaire survey was conducted using a mixed sampling strategy of “online random sampling+offline supplementary sampling” to distribute questionnaires among pharmaceutical professionals in tertiary medical institutions nationwide. The questionnaire covered aspects such as the construction of PV systems， job position settings， information system support， operational practices， and multi-stakeholder collaboration. The data were analyzed using descriptive methods and SPSS 20.0 statistical software. RESULTS A total of 70 valid questionnaires were collected from 66 medical institutions， primarily Class A tertiary hospitals. The survey found that 90.00% had designated PV personnel and 74.29% routinely conducted PV activities. However， there were notable disparities in resource allocation and information system capacity， with less than 50% of the institutions conducting post-marketing drug re-evaluation. PV activities were primarily focused on the collection and reporting of adverse drug reactions， with limited capabilities in signal detection and risk assessment. CONCLUSIONS Among the surveyed tertiary hospitals， PV systems have begun to take shape. However， challenges persist in terms of system establishment， resource allocation， risk assessment， and inter-organizational coordination. Policy efforts should focus on strengthening regulatory frameworks， improving information sharing mechanisms， enhancing professional training， and strengthening collaboration between hospitals and market authorization holders to ensure the effective implementation of PV in medical institutions.

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG^@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Objective: To explore the use of personal audio devices and hearing impairment among high school students, so as to provide reference for the development of adolescent hearing health work. Methods: The simple random sampling method was used to collect research data relating to 1 768 high school students. The situation of personal audio players, headphone and hearing damage were investigated by using a self designed questionnaire, so as to identify the related factors of hearing impairment which were analyzed statistically by multivariate Logistic regression. Results: The use rate of PAP and earphones was 98.64% and 94.12 %, respectively, and the use rate of female students(99.68%, 96.42%) was higher than that of male students(97.43%, 91.43 %)( χ 2=16.69, 19.79, P <0.01). Hearing impairment accounted for 13.35%. The Logistic regression analysis showed that PAP service years ( OR =1.59, P <0.05) were related to hearing impairment. Gender ( OR =0.60), in ear earphones ( OR =1.38), earplug earphones ( OR =1.37), and quiet use >1 h ( OR =1.50) were independently influenced with symptoms of hearing impairment during/after earphone use( P <0.05). Conclusion High usage rates of personal audio equipment among high school students lead to hearing impairment and related symptoms. Non essential use should be reduced.

Due to the insufficient long-term protection and significant efficacy reduction to new variants of current COVID-19 vaccines, the epidemic prevention and control are still challenging. Here, we employ a capsid and antigen structure engineering (CASE) strategy to manufacture an adeno-associated viral serotype 6-based vaccine (S663V-RBD), which expresses trimeric receptor binding domain (RBD) of spike protein fused with a biological adjuvant RS09. Impressively, the engineered S663V-RBD could rapidly induce a satisfactory RBD-specific IgG titer within 2 weeks and maintain the titer for more than 4 months. Compared to the licensed BBIBP-CorV (Sinopharm, China), a single-dose S663V-RBD induced more endurable and robust immune responses in mice and elicited superior neutralizing antibodies against three typical SARS-CoV-2 pseudoviruses including wild type, C.37 (Lambda) and B.1.617.2 (Delta). More interestingly, the intramuscular injection of S663V-RBD could overcome pre-existing immunity against the capsid. Given its effectiveness, the CASE-based S663V-RBD may provide a new solution for the current and next pandemic.

The rise of nanotechnology has opened new horizons for cancer immunotherapy. However, most nanovaccines fabricated with nanomaterials suffer from carrier-related concerns, including low drug loading capacity, unpredictable metabolism, and potential systemic toxicity, which bring obstacles for their clinical translation. Herein, we developed an antigen self-assembled nanovaccine, which was resulted from a simple acryloyl modification of the antigen to induce self-assembly. Furthermore, a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid (Zol) were integrated or absorbed onto the nanoparticles (denoted as MEAO-Z) to intensify the immune response. The synthesized nanovaccine with a diameter of around 70 nm showed successful lymph node transportation, high dendritic cell internalization, promoted costimulatory molecule expression, and preferable antigen cross-presentation. In virtue of the above superiorities, MEAO-Z induced remarkably higher titers of serum antibody, stronger cytotoxic T lymphocyte immune responses and IFN-γ secretion than free antigen and adjuvants. In vivo, MEAO-Z significantly suppressed EG7-OVA tumor growth and prolonged the survival time of tumor-bearing mice. These results indicated the translation promise of our self-assembled nanovaccine for immune potentiation and cancer immunotherapy.

Objectives:To investigate the clinical and genetic features of young Chinese patients with myeloproliferative neoplasms (MPN) .Methods:In this cross-sectional study, anonymous questionnaires were distributed to patients with MPN patients nationwide. The respondents were divided into 3 groups based on their age at diagnosis: young (≤40 years) , middle-aged (41-60 years) , and elderly (>60 years) . We compared the clinical and genetic characteristics of three groups of MPN patients.Results:1727 assessable questionnaires were collected. There were 453 (26.2%) young respondents with MPNs, including 274 with essential thrombocythemia (ET) , 80 with polycythemia vera (PV) , and 99 with myelofibrosis. Among the young group, 178 (39.3%) were male, and the median age was 31 (18-40) years. In comparison to middle-aged and elderly respondents, young respondents with MPN were more likely to present with a higher proportion of unmarried status (all P<0.001) , a higher education level (all P<0.001) , less comorbidity (ies) , fewer medications (all P<0.001) , and low-risk stratification (all P<0.001) . Younger respondents experienced headache (ET, P<0.001; PV, P=0.007; MF, P=0.001) at diagnosis, had splenomegaly at diagnosis (PV, P<0.001) , and survey (ET, P=0.052; PV, P=0.063) . Younger respondents had fewer thrombotic events at diagnosis (ET, P<0.001; PV, P=0.011) and during the survey (ET, P<0.001; PV, P=0.003) . JAK2 mutations were found in fewer young people (ET, P<0.001; PV, P<0.001; MF, P=0.013) ; however, CALR mutations were found in more young people (ET, P<0.001; MF, P=0.015) . Furthermore, mutations in non-driver genes (ET, P=0.042; PV, P=0.043; MF, P=0.004) and high-molecular risk mutations (ET, P=0.024; PV, P=0.023; MF, P=0.001) were found in fewer young respondents. Conclusion:Compared with middle-aged and elderly patients, young patients with MPN had unique clinical and genetic characteristics.

Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.

Objective:To investigate the risk factors of postoperative hypoxemia in patients admitted to intensive care unit (ICU) for resuscitation.Methods:Clinical data of 220 postoperative patients admitted to the ICU for resuscitation in Shandong Provincial Hospital Affiliated to Shandong University from June to August 2020 were collected and retrospectively analyzed. According to their oxygenation index within 30 minutes after admission to ICU, they were divided into hypoxemia group (oxygenation index≤ 300 mmHg, 1 mmHg≈0.133 kPa) and non-hypoxemia group (oxygenation index > 300 mmHg). Baseline data and perioperative indicators were compared between the two groups, and risk factors for early postoperative hypoxemia were analyzed. The improvement of oxygenation index of patients with hypoxemia in next morning after admission to ICU was observed, and the factors related to the improvement of hypoxemia were analyzed.Results:The incidence of hypoxemia was 36.8% (81/220) in the cohort. The majority cases of hypoxemia were from general surgery department, accounting for 42.0% (34/81). The incidence rate of hypoxemia from orthopaedic was the highest at 53.3% (16/30). Univariate analysis showed that body mass index (BMI), intraoperative hypoxemia, minimally invasive surgery were all risk factors of postoperative hypoxemia (test values were -2.566, 12.352 and 0.033; P values were 0.010, 0.000 and 0.019, respectively). Multivariate analysis showed that intraoperative hypoxemia and BMI were independent risk factors for postoperative hypoxemia [intraoperative hypoxemia: odds ratio ( OR) = 3.602, 95% confidence interval (95% CI) was 1.143-3.817, P = 0.001; BMI: OR = 1.119, 95% CI was 1.026-1.208, P = 0.036]. The improvement rate of hypoxemia next morning after admission to ICU was 63.0% (51/81). Pulmonary dysfunction was the independent risk factor for the improvement of hypoxemia ( OR = 0.200, 95% CI was 0.052-0.763, P = 0.019). Conclusions:Hypoxemia might occur early after surgery. Intraoperative hypoxemia and BMI were independent risk factors for postoperative hypoxemia.

Objective:To investigate the effect of transurethral plasma enucleation of prostate with bladder neck and prostatic apex urethral mucosa preservation on the incidence of retrograde ejaculation after surgery.Methods:The clinical data of 77 patients with benign prostatic hyperplasia (BPH) admitted to Jinhua people's Hospital from January 2018 to June 2020 were retrospectively analyzed. The ages of the two groups [(62.06±2.01)years old and (62.36 ± 2.12)years old] were comparable. There were no significant differences between the groups( P>0.05) in term of the prostate volume (72.91±17.57) ml vs. (68.07±17.28)ml, Q max [(7.33±2.02)ml/s vs. (7.79±2.09)ml/s)], and IPSS (25.51±5.66) vs.(25.17±4.90). The conventional operation group was treated with " trefoil" enucleation of prostate. The modified operation group underwent the following three improved techniques. Firstly, the anterior mucosa of the verumontanum was cut 1.5 cm away from the medial surface of the verumontanum to prevent the external sphincter injury. Secondly, part of the prostate tissue was retained by exceeding the verumontanum when cutting off the bilateral lobes. Thirdly, the middle lobe of the prostate was bluntly stripped to the bladder neck with the sheath of the electroscope in order to protect the transverse muscle fibers as well as the integrity of the bladder neck. The outcome and the ejaculation function of the two groups were analyzed. Results:There was no significant difference in operation time [(66.74±9.29)min vs. (71.29±15.32) min], catheter indwelling duration [(5.31±0.76)d vs.(5.00±1.06)d], and hospital stay [(7.57±0.88) d vs. (7.17±1.45)d] between the two groups ( P>0.05) after more than 6 months of follow-up. According to IIEF score, mild erectile dysfunction occurred in both groups, with the incidence rate of 20.7%(6/29) and 13.5%(5/37) respectively, and there was no significant difference between the two groups ( P>0.05). The postoperative maximum urinary flow rate (Q max) [(23.51±4.25) ml/s vs.(24.05±3.81)ml/s] and IPSS score (6.46±2.72 vs. 6.55±2.99) was significantly different from that before the operation ( P<0.05). However, there was no significant difference between the two groups ( P>0.05). The incidence of retrograde ejaculation in conventional operation group and modified operation group was 23/35(65.7%) and 13/42(31.0%), and the difference was statistically significant ( P<0.05). Immediate urinary continence were 24/35(68.6%) and 36/42(85.7%) in the conventional operation group and the modified operation group respectively, and there was no significant difference between the two groups( P>0.05). After 6 months of follow-up, urinary continence in both groups was 100.0%. Conclusions:Transurethral plasmakinetic enucleation of the prostate with the preservation of bladder neck and urethral mucosa of prostate apex is the same effective as conventional operation in the treatment of benign prostatic hyperplasia, but the incidence of retrograde ejaculation after operation is significantly reduced, which is suitable for those patients who desire to retain their ejaculation function.