Association between administration or recommendation of the human papillomavirus vaccine and primary care physicians' knowledge about vaccination during proactive recommendation suspension: a nationwide cross-sectional study in Japan.

OBJECTIVE: The Japanese government suspended the proactive recommendation of the human papillomavirus vaccine (HPVv) in 2013, and the vaccination rate of HPVv declined to <1% during 2014-2015. Previous studies have shown that the recommendation by a physician affects a recipient's decision to receive a vaccine, and physicians' accurate knowledge about vaccination is important to increase vaccine administration. This study aimed to evaluate the association between physicians' knowledge of vaccination and the administration or recommendation of HPVv by primary care physicians (PCPs) in the absence of proactive recommendations from the Japanese government. DESIGN: Cross-sectional study analysed data obtained through a web-based, self-administered questionnaire survey. SETTING: The questionnaire was distributed to Japan Primary Care Association (JPCA) members. PARTICIPANTS: JPCA members who were physicians and on the official JPCA mailing list (n=5395) were included. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary and secondary outcomes were the administration and recommendation of HPVv, respectively, by PCPs. The association between PCPs' knowledge regarding vaccination and each outcome was determined based on their background and vaccination quiz scores and a logistic regression analysis to estimate the adjusted ORs (AORs). RESULTS: We received responses from 1084 PCPs and included 981 of them in the analysis. PCPs with a higher score on the vaccination quiz were significantly more likely to administer the HPVv for routine and voluntary vaccination (AOR 2.28, 95% CI 1.58 to 3.28; AOR 2.71, 95% CI 1.81 to 4.04, respectively) and recommend the HPVv for routine and voluntary vaccination than PCPs with a lower score (AOR 2.17, 95% CI 1.62 to 2.92; AOR 1.88, 95% CI 1.32 to 2.67, respectively). CONCLUSIONS: These results suggest that providing accurate knowledge regarding vaccination to PCPs may improve their administration and recommendation of HPVv, even in the absence of active government recommendations.

Factors associated between behavior of administrating or recommending mumps vaccine and primary care physicians' knowledge about vaccination: A nationwide cross-sectional study in Japan.

BACKGROUND: In Japan, the mumps-containing vaccine was withdrawn from routine vaccination in 1993, and it became a voluntary vaccination. This study aimed to evaluate the association between the physicians' knowledge about vaccinations and the administration or recommendation of the mumps vaccine. METHODS: We conducted a nationwide cross-sectional study targeting primary care physicians (PCPs) in Japan. We used a web-based self-administered questionnaire by Preventive Medicine and Health Promotion Committee Vaccine Team, the Japan Primary Care Association (JPCA), from March to June in 2019. The outcome of the study was the association between PCPs' knowledge about vaccine and the administration or recommendation of mumps vaccine. We obtained the information on background, subsidies of mumps vaccination for children from the local government, and vaccination quiz scores. We performed logistic regression analysis to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 10,470 PCPs in JPCA, 5075 were excluded. We received responses from 1084 PCPs (20.1%) and enrolled 981 participants in the analysis. PCPs with a higher score on the vaccination quizzes were significantly more likely to administrate the mumps vaccine for adults (adjusted odds ratio [AOR] 1.93, 95% CI 1.45-2.59, p < 0.001) and recommend mumps vaccine to adults than PCPs with a lower score (AOR 1.78, 95% CI 1.33-2.40, p < 0.001). CONCLUSIONS: We revealed an association between the administration or recommendation of mumps vaccine and PCPs' better vaccination knowledge.

Biphasic regulation of levofloxacin on lipopolysaccharide-induced IL-1beta production.

Fluoroquinolones have been known to exert modulatory activity on immune responses to microbial infection. However, the mechanism of this immunomodulation has not been well elucidated. In this study, we investigated the effect of levofloxacin on lipopolysaccharide (LPS)-induced production of interleukin-1beta (IL-1beta) in RAW264.7 cells. We showed that LPS-stimulated release of pre-synthesized IL-1beta was promoted by levofloxacin, in part via the p38 mitogen-activated protein kinase (MAPK) pathway. On the other hand, newly synthesized IL-1beta production was inhibited by levofloxacin. This immunoregulatory function of levofloxacin in the later phase as well as promotion of pre-synthesized IL-1beta release by levofloxacin in the early phase might be advantageous in the host defense to microbial pathogens.

Involvement of IRAK-M in peptidoglycan-induced tolerance in macrophages.

The molecular mechanisms by which pathogen-associated molecular patterns recognized by TLR2, such as peptidoglycan (PGN), induce homotolerance are largely unknown. It was recently reported that IRAK-M negatively regulates TLR signaling. In this study, we elucidate the molecular mechanisms of tolerance induced by PGN, with a focus on the role of IRAK-M. We demonstrate that pretreatment of macrophage RAW264.7 cells with a high concentration (30 microg/ml) of PGN for 16 h effectively induces tolerance against following stimulation with 30 microg/ml of PGN; while pretreatment with a low concentration (1 microg/ml) of PGN does not. IRAK-M is induced in cells treated with the high concentration of PGN 4-24 h after PGN stimulation, but not in cells treated with the low concentration of PGN up to 24 h after stimulation. Phosphorylation of MAPKs and IkappaBalpha is inhibited after the second PGN stimulation in tolerant cells. Kinase activity of IRAK-1 and association between IRAK-1 and MyD88 are also suppressed in PGN-induced tolerant cells. Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates the production of TNF-alpha after PGN restimulation. These results suggest that induction of IRAK-M and inhibition of kinase activity of IRAK-1 are crucial to PGN-induced tolerance in macrophages.

Raf1 plays a pivotal role in lipopolysaccharide-induced activation of dendritic cells.

Activation of extracellular-regulated kinases 1/2 (ERK) is involved in lipopolysaccharide (LPS)-induced cellular responses such as the increased production of proinflammatory cytokines. However, mitogen-activated protein kinases (MAPKs) such as p38 are also activated by LPS and have been postulated to be important in the control of these end points. Therefore, establishing the relative contribution of MAPKs in each cell type is important, as is elucidating the molecular mechanisms by which these MAPKs are activated in LPS-induced signaling cascades. We demonstrated in DC2.4 dendritic cells that ERK regulates tyrosine phosphorylation of phosphatidyl-inositol-3-kinase (PI3-K) and the production of TNF-alpha. We also demonstrated that Raf1 is phosphorylated and involved in the production of TNF-alpha and tyrosine phosphorylation of PI3-K via ERK. Raf1 also regulates the activation of NF-kappaB. We propose that Raf1 plays a pivotal role in LPS-induced activation of the dendritic cells.

Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages.

The mechanisms by which lipopolysaccharide (LPS) is recognized, and how such recognition leads to innate immune responses, are poorly understood. Stimulation with LPS induces the activation of a variety of proteins, including mitogen-activated protein kinases (MAPKs) and NF-kappaB. Activation of protein tyrosine kinases (PTKs) is also necessary for a number of biological responses to LPS. We used a murine macrophage-like cell line, RAW264.7, to demonstrate that Janus kinase (JAK)2 is tyrosine phosphorylated immediately after LPS stimulation. Anti-Toll-like receptor (TLR)4 neutralization antibody inhibits the phosphorylation of JAK2 and the c-Jun NH2-terminal protein kinase (JNK). Both the JAK inhibitor AG490 and the kinase-deficient JAK2 protein reduce the phosphorylation of JNK and phosphatidylinositol 3-kinase (PI3K) via LPS stimulation. Pharmacological inhibition of the kinase activity of PI3K with LY-294002 decreases the phosphorylation of JNK. Finally, we show that JAK2 is involved in the production of IL-1beta and IL-6. PI3K and JNK are also important for the production of IL-1beta. These results suggest that LPS induces tyrosine phosphorylation of JAK2 via TLR4 and that JAK2 regulates phosphorylation of JNK mainly through activation of PI3K. Phosphorylation of JAK2 via LPS stimulation is important for the production of IL-1beta via the PI3K/JNK cascade. Thus JAK2 plays a pivotal role in LPS-induced signaling in macrophages.