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.

A complex form of hereditary spastic paraplegia harboring a novel variant, p.W1515*, in the SPG11 gene.

Individuals with hereditary spastic paraplegia (HSP) are known to present with a variety of symptoms, including intellectual disability, cognitive decline, parkinsonism, and epilepsy. We report here our experience of treating a family with consanguinity, including three patients with HSP-related symptoms. We performed whole-exome sequencing and identified a novel pathogenic nonsense variant, c.4544G > A, p.W1515*, in the SPG11 gene. Proband and her affected sister showed the same course of gait disturbance due to spastic paraplegia from childhood and progressive cognitive decline from early adulthood. Brain MRI depicted a thinning of the corpus callosum, severe atrophic changes in the frontotemporal lobes, and ears of the lynx sign. Patients with SPG11 variants clinically present with distinctive symptoms.

Long-Term Maintenance of Golimumab Effectiveness for Injection Spacing in Rheumatoid Arthritis Patients with Low Disease Activity Who Previously Received Other TNF Inhibitors: Minimum 2-year Data From an Observational Study.

BACKGROUND: Golimumab (GLM) has been reported to have lower immunogenicity than do other TNF inhibitors used for treating rheumatoid arthritis (RA). We previously found a prolonged effect of and improvement similar to that associated with infliximab (IFX) after switching to subcutaneous GLM (GLM-SC) for control of RA activity or adverse events. Thus, this study aimed to evaluate the continued maintenance of treatment efficacy and safety for > 2 years by switching to GLM-SC in RA patients with low disease activity or in remission after previous treatment with another tumor necrosis factor (TNF) inhibitor. METHODS: Thirty-two patients treated with etanercept or infliximab were switched to GLM-SC and maintained low disease activity. The patients were divided into two groups (GLMq4w and GLMq8w) through discussion with each patient, considering their general condition and convenience. The groups included patients with low disease activity or in remission who switched to 50-mg GLM therapy at 4-week and 8-week intervals, respectively. RESULTS: The mean DAS28-ESR and DAS-CRP values in the GLMq4w group (17 patients) and GLMq8w group (15 patients) were maintained from baseline throughout the 104-week treatment period. Two patients from the GLMq4w group showed disease flaring to moderate disease activity. No serious adverse events occurred, and the treatment continuation rate at 104 weeks was 100% in both groups. After > 2 years of treatment, three patients in the GLMq8w group and one patient in the GLMq4w group discontinued GLM treatment due to relapse or complications. The 5-year survival rates were 88.2% and 75.5% in the GLMq4w and GLMq8w groups, respectively. The average treatment duration was 5.0 (2.0-7.5) years. CONCLUSION: Administration of GLM-SC at 4-week and 8-week intervals after switching from TNF inhibitors showed sustained long-term efficacy and acceptable safety in RA patients with low disease activity.

[A Case of Castleman's Disease with Lymphadenopathy during the Treatment of Gastric Cancer].

We report a patient who had Castleman's disease with lymphadenopathy during the treatment of gastric cancer. In May 2017, a 63-year-old man underwent gastrointestinal endoscopy, which revealed a tumor on the posterior wall of the lower part of the stomach. Based on a biopsy, he was diagnosed with suspected adenocarcinoma, Group 4. In June 2017, he visited our hospital, and endoscopic submucosal dissection(ESD)was performed. The pathological diagnosis of the resected specimens was L, Less, 20×10 mm, Type 0-Ⅱc, tub1, pT1a(M), UL(-), ly(-), v(-), pHM0, pVM0, pStage ⅠA. He was referred to our department for the treatment of abdominal lymphadenopathy. His lymphadenopathy was localized in the gastric lesser curvature as an enlarged lymph node 15mm in size, based on the findings of contrast-enhanced CT. On FDG- PET/CT, we found a slight accumulation of SUVmax 2.4 in the early phase in the same lymph node. We could not confirm a diagnosis, and we performed laparoscopic dissection of the lymph node for diagnosis and treatment. The size of the specimen was 14×14mm, surface was smooth, and lymph node was elastic and soft. We found lymphoid follicles with atrophic germinal center using HE staining. We also found increased hyperplastic blood vessels around the germinal center, and he was diagnosed with hypervascular Castleman's disease.

Maintenance of efficacy and safety with subcutaneous golimumab in rheumatoid arthritis patients with low disease activity who previously received TNF inhibitors.

The study was conducted to evaluate continued maintenance of the efficacy and safety of therapy by switching to subcutaneous golimumab (GLM-SC) in rheumatoid arthritis patients with low disease activity or remission who previously received a tumor necrosis factor (TNF) inhibitor. Thirty patients who had been treated with etanercept or infliximab were switched to GLM-SC in maintaining disease activity at a low level. The patients were divided into two groups through discussion with each patient, considering general condition and convenience: the low disease activity (LDA) group and the LDAq8w group, which included patients with low disease activity or remission who switched to 50 mg GLM therapy at 4- and 8-week intervals, respectively. The effects of the TNF inhibitors to GLM-SC switch were evaluated at 12, 24, and 52 weeks after switching. The mean DAS28-ESR and DAS-CRP values in the LDA groups (16 patients) and LDAq8w groups (14 patients) were maintained from baseline throughout the 52-week treatment period. DAS28-ESR remission (93.8 and 92.3%) rates were also maintained through week 52 from the baseline remission rate (75.0 and 78.6%) in the LDA and LDAq8w groups, respectively. Thus, both GLM-SC treatment regimens were effective in maintaining the clinical response achieved with LDA secondary to TNF inhibitors. No serious adverse events occurred, and the continuation rate at 52 weeks was 100% in both groups. Therapeutic efficacy is adequately maintained in most patients switching from TNF inhibitor to GLM-SC (50 mg/4-8 weeks). Patients receiving TNF inhibitor can seamlessly switch to GLM-SC without serious safety concerns.

Efficacy of Switching from Infliximab to Subcutaneous Golimumab in Patients with Rheumatoid Arthritis to Control Disease Activity or Adverse Events.

BACKGROUND: Some rheumatoid arthritis (RA) patients initially respond to treatment with infliximab (IFX), but subsequently their responsiveness decreases. OBJECTIVES: Our objective was to evaluate the efficacy and safety of switching from IFX to subcutaneous golimumab (GLM-SC) in RA patients. METHODS: Thirty-three patients who had been treated for a mean 4.4 years with IFX (3-6 mg/kg/8 weeks) were switched to GLM-SC to control disease activity or adverse events. The patients with low disease activity (LDA) or remission were divided into two groups: the LDA group and the LDA every 8 weeks (q8w) group, which included patients with LDA or remission who switched to GLM therapy with 50 mg at 4- and 8-week intervals, respectively. The moderate disease activity (MDA) group included patients with MDA who switched to GLM therapy with 50 mg at 4-week intervals. Effects of the IFX to GLM-SC switch were evaluated at weeks 12, 24, and 52 after switching. RESULTS: The mean disease activity score 28-ESR and -C-reactive protein values in the LDA and LDAq8w groups were maintained from baseline throughout the 52-week treatment period. The mean disease activity score 28 values at 12, 24, and 52 weeks in the MDA group were improved significantly compared with baseline. Treatment discontinuations due to adverse events occurred in one patient in the MDA group, and no serious adverse events occurred during the observation period in the LDA group or the LDAq8w group. The GLM continuation rates at 52 weeks were 100% in the LDA and LDAq8w groups and 83.3% in the MDA group. Thus, GLM-SC treatment regimens were effective in controlling disease activity and improving the clinical response related to adverse events caused by IFX. CONCLUSION: The clinical efficacy of GLM-SC was sustained or improved in patients who switched from IFX without serious safety concerns.

Clinical outcome in patients with rheumatoid arthritis switched to tocilizumab after etanercept or infliximab failure.

The present study retrospectively assessed the efficacy of tocilizumab in patients with rheumatoid arthritis (RA) who failed to respond to treatment with etanercept or infliximab. A retrospective study of 33 RA patients who did not respond to etanercept or infliximab was conducted. Responses of subjects switching from etanercept to tocilizumab (n = 17) were compared with those switching from infliximab to tocilizumab (n = 16). Treatment with disease-modifying antirheumatic drugs before the switch, especially methotrexate (MTX), was maintained. Disease activity was assessed by the Disease Activity Score 28-C Reactive Protein (DAS28-CRP), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Patients who switched from etanercept were significantly less likely to have used MTX and were significantly older than patients who switched from infliximab. In both groups, there was a significant reduction from baseline in DAS28-CRP, SDAI, and CDAI values at 24 weeks with no significant differences between groups. However, at week 52, DAS28-CRP, SDAI, and CDAI values in the group switched from etanercept were significantly worse than those in the group switched from infliximab. All patients switched from infliximab were using MTX. In the evaluation between patients who switched from etanercept monotherapy, etanercept plus MTX, and infliximab plus MTX, a significant improvement from baseline was seen in DAS28-CRP, SDAI, and CDAI for all patients at 24 weeks with no significant differences between groups. Disease activity was maintained at 52 weeks in the group that switched from etanercept plus MTX and infliximab plus MTX. However, the efficacy of tocilizumab was decreased in the group that switched from etanercept monotherapy. Switching from etanercept plus MTX or from infliximab plus MTX to tocilizumab plus MTX improved response to therapy, but switching from etanercept monotherapy to tocilizumab monotherapy did not improve response to therapy.

Repeat etanercept administration restores clinical response of patients with rheumatoid arthritis.

We determined whether repeated treatment with the tumor necrosis factor-α (TNF-α) antagonist etanercept can be effective after an initial clinical response to this drug is lost. We describe three female patients with active, refractory rheumatoid arthritis who were administered with a second course of etanercept after eventually becoming refractory to a first course. Disease activity was high in all three patients before initial etanercept therapy, and each of them had clinically responded by 24 weeks. However, the initial clinical effect was lost between 1.5 and 3.5 years thereafter, and tocilizumab was administered, but the effect was lost again between 3 and 18 months later. Two patients did not respond to subsequent treatment with adalimumab and infliximab. Etanercept administered once again reduced disease activity in all three patients, none of whom developed any acute side effects. Etanercept re-administration significantly improved clinical disease activity and inflammatory parameters in three patients with RA who were refractory to biological anti-TNF agents.

Which subgroup of rheumatoid arthritis patients benefits from switching to tocilizumab versus etanercept after previous infliximab failure? A retrospective study.

A retrospective study of 39 rheumatoid arthritis (RA) patients with an inadequate response to infliximab was conducted. The responses of subjects switching from infliximab to tocilizumab (n = 23) were compared to those of subjects switching to etanercept (n = 16). Disease activity was assessed by the Disease Activity Score 28-CRP ([C-reactive protein] DAS28-CRP), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Twenty-two patients completed 48 weeks of tocilizumab treatment, and 15 patients completed 48 weeks of etanercept treatment. In both treatment groups, 1 patient each discontinued treatment because of lack of efficacy. No serious adverse events occurred during the study, and no patients in either group withdrew due to adverse events. At week 48, there was a significant reduction from baseline in DAS28-CRP, SDAI, and CDAI values after switching to either tocilizumab or etanercept, and there was no significant difference in efficacy, as measured by the DAS28-CRP, SDAI, and CDAI, between the two treatment groups (p = 0.12, 0.76, and 0.86, respectively). These results suggest that safety and tolerability were similar for both treatments. A switch from infliximab to either tocilizumab or etanercept in patients with RA who have not responded to infliximab is a feasible, well-tolerated treatment option.

A proteomic approach for comprehensively screening substrates of protein kinases such as Rho-kinase.

BACKGROUND: Protein kinases are major components of signal transduction pathways in multiple cellular processes. Kinases directly interact with and phosphorylate downstream substrates, thus modulating their functions. Despite the importance of identifying substrates in order to more fully understand the signaling network of respective kinases, efficient methods to search for substrates remain poorly explored. METHODOLOGY/PRINCIPAL FINDINGS: We combined mass spectrometry and affinity column chromatography of the catalytic domain of protein kinases to screen potential substrates. Using the active catalytic fragment of Rho-kinase/ROCK/ROK as the model bait, we obtained about 300 interacting proteins from the rat brain cytosol fraction, which included the proteins previously reported as Rho-kinase substrates. Several novel interacting proteins, including doublecortin, were phosphorylated by Rho-kinase both in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: This method would enable identification of novel specific substrates for kinases such as Rho-kinase with high sensitivity.