Factors impacting antibody kinetics, including fever and vaccination intervals, in SARS-CoV-2-naïve adults receiving the first four mRNA COVID-19 vaccine doses.

To evaluate the antibody response following the initial four doses of mRNA vaccines (BNT162b2 or mRNA-1273) in SARS-CoV-2-naïve healthy adults and investigate factors influencing antibody titer increases, this prospective cohort study was conducted in Japan from March 2021. The study included participants who received either the 1st and 2nd doses (n = 467), 3rd dose (n = 157), or 4th dose (n = 89). Blood samples were collected before and up to 6 months after each dose, and anti-receptor-binding domain antibody levels were measured. Multivariate analysis (usin multiple linear regression or linear mixed models) revealed several factors significantly associated with higher post-vaccination antibody levels, including mRNA-1273 vaccine (after the 1st and 2nd dose), male gender (after the 3rd and 4th doses), younger age (after the 1st and 2nd dose), non-smoking status (after the 2nd dose), non-use of immunosuppressive agents (after the 1st dose), higher pre-vaccination antibody titers (after the 2nd, 3rd, and 4th doses), and higher post-vaccination fever (after the 2nd and 4th doses). Furthermore, longer intervals since the last dose were significantly associated with higher antibody levels after the 3rd and 4th doses. These findings provide valuable insights for optimizing vaccination strategies.

Association between being at-risk of malnutrition and discontinued home medical care among older patients: a 1-year follow-up study.

BACKGROUND: Both malnutrition and at-risk of malnutrition are prevalent among older patients receiving home medical care. Discontinuation of home medical care usually occurs when an older patient is admitted to a hospital or nursing home or dies. This study aimed to assess prospective associations between nutritional status and discontinuation of home medical care in older patients. METHODS: Three hundred and thirty-three Japanese older patients receiving home-visit nursing care services were included in this study. Their nutritional status was assessed using the Mini Nutritional Assessment®-Short Form, and patients were classified into three groups (well-nourished, at-risk of malnutrition and malnourished). Outcomes were confirmed at the 1-year follow-up survey. Hazard ratios (HRs) and 95% confidence intervals (CIs) for discontinuation of home medical care based on nutritional status were calculated using a Cox proportional hazard model. Covariates included age, sex, living status, economic status, activities of daily living, comorbidities and dysphagia status. RESULTS: In total, 297 patients (median age: 84 years) were analysed. At baseline, 48.5% of the patients were at-risk of malnutrition and 18.9% were malnourished. During the observation period of 1 year, 27.6% patients discontinued their home medical care. In the adjusted model, the HR for discontinuation of home medical care among those at-risk of malnutrition was 2.44 (95% CI: 1.34-4.45) times than that of the well-nourished group, although the malnourished group was not significantly associated with discontinuation of home medical care (HR: 1.69, 95% CI: 0.77-3.72; referent: well-nourished). CONCLUSIONS: At-risk of malnutrition was associated with discontinuation of home medical care among older patients.

No association between inactivated influenza vaccination and influenza viral load at diagnosis among young Japanese children: An observational study of the 2013/2014 through 2017/2018 influenza seasons.

BACKGROUND: The association between inactivated influenza vaccination and viral load in young children remains unclear. METHODS: During the 2013/2014 to 2017/2018 influenza seasons in Japan, children under 6 years of age with pre-defined influenza-like illness and influenza-positive status by real-time RT-PCR were recruited at pediatric clinics for this observational study. Influenza viral load was measured for the most predominant subtype/lineage in each season. Using median dichotomized viral load as an outcome, a multilevel logistic regression model was applied to estimate the multivariable adjusted odds ratio (MOR) and 95% confidence interval (CI) for higher viral load. RESULTS: A total of 1,185 influenza-positive children were analyzed. The median log10 viral load copy number (copies per milliliter) was 5.5 (interquartile range, 4.6 to 6.1) and did not differ by vaccination status: 5.5 for unvaccinated, 5.7 for one dose, and 5.5 for two doses (p = 0.67). The MOR of vaccinated (one or two doses) versus unvaccinated children was 1.19 (95% CI: 0.86-1.64). Other factors showing significant associations with higher viral load were positive results for A(H1N1)pdm09 and A(H3N2) in comparison with B/Yamagata. The respective MORs were 3.25 (95% CI: 2.28-4.64) and 1.81 (95% CI: 1.32-2.49). Significantly elevated MORs against higher viral load were also observed for higher body temperature at influenza diagnosis and shorter duration from fever onset to specimen collection. CONCLUSION: No association was observed between inactivated-influenza vaccination and viral load at influenza-positive diagnosis. Influenza subtype/lineage, body temperature, and time elapsed since fever onset were significantly associated with viral load.

Immunogenicity and safety of influenza vaccine in patients with lung cancer receiving immune checkpoint inhibitors: A single-center prospective cohort study.

INTRODUCTION: Patients with lung cancer have a high risk of influenza complications. International guidelines recommend annual influenza vaccination for patients with cancer. Immune checkpoint inhibitors (ICIs) are progressively used to treat lung cancer. Data regarding immunogenicity and safety of influenza vaccine are limited in patients with lung cancer receiving ICIs; therefore, we conducted this single-center, prospective observational study in the Japanese population. METHODS: Patients with lung cancer receiving ICIs and influenza immunization were enrolled. Blood samples were collected from patients for serum antibody titer measurement pre- and 4 ± 1 weeks post-vaccination. The primary endpoint was seroprotection rate (sP) at 4 ± 1 weeks post-vaccination. The secondary endpoints were geometric mean titer (GMT), mean fold rise, seroresponse rate (sR), seroconversion rate (sC), and immune-related adverse events (irAEs), defined as adverse effects caused by ICI administration, 6 months post-vaccination. RESULTS: Influenza vaccination in the 23 patients included in the immunogenicity analyses significantly increased GMT for all strains, and sP, sR, and sC were 52%-91%, 26%-39%, and 26%-35%, respectively. In the 24 patients included in the safety analyses, 7 (29%) and 5 (21%) patients exhibited systemic and local reactions, respectively. Only one patient (4%) (hypothyroidism, grade 2) showed post-vaccination irAEs. CONCLUSIONS: Overall, influenza vaccination in patients with lung cancer receiving ICIs showed acceptable immunogenicity and safety, thus supporting annual influenza vaccination in this population.

Incidence and risk factors for norovirus-related diarrhea in Japanese geriatric intermediate care facilities: A prospective cohort study.

AIM: The risk of developing infectious diarrhea among elderly residents at Japanese geriatric intermediate care facilities is unclear. We investigated the incidence rate and risk factors of norovirus-related diarrhea at such facilities. METHODS: This prospective cohort study followed 1727 residents from November 2018 to April 2020 at 10 geriatric intermediate care facilities in Osaka, Japan regarding the occurrence of diarrhea. Resident data were collected from their medical records using structured forms at two to three of the following three time points: at recruitment, if they developed diarrhea, and when they left the facility. Residents who developed diarrhea were tested using rapid diagnostic tests for norovirus. Cox proportional hazard model was employed to hazard ratios (HRs) with 95% confidence intervals (CIs) to estimate the risk factors for norovirus-related diarrhea. RESULTS: During the study period, 74 residents developed diarrhea, 13 of whom were norovirus positive. The incidence rate of norovirus-related diarrhea was 10.11 per 1000 person-years (95% CI: 4.61-15.61). In terms of risk factors, people with care-needs level 3 were at a higher risk for developing norovirus-related diarrhea (adjusted HR [aHR] = 7.35, 95% CI: 1.45-37.30). Residents with hypertension (aHR = 3.41, 95% CI: 1.05-11.04) or stroke (aHR = 8.84, 95% CI: 2.46-31.83), and those who walked with canes (aHR = 16.68, 95% CI: 1.35-206.52) also had a significantly higher risk for norovirus-related diarrhea. CONCLUSIONS: Throughout the study period, the incidence of development of diarrhea was low. Care-needs level 3, stroke, hypertension and use of a cane were identified as risk factors for norovirus-related diarrhea in Japanese geriatric intermediate care facilities. Geriatr Gerontol Int 2023; 23: 179-187.

Smoking and drinking habits relating to development of ulcerative colitis in Japanese: A multicenter case-control study.

Background and Aim: The number of patients with ulcerative colitis (UC) has been increasing in Japan. To elucidate the risk factors for developing UC in Japan, a hospital-based case-control study was conducted. This study examined the association between smoking/drinking habits and UC onset in detail. Methods: Cases comprised 132 Japanese patients who had been newly diagnosed with UC between 2008 and 2014 at 38 collaborating hospitals in Japan, and controls comprised 167 patients without UC. Detailed data on smoking and drinking habits were collected using a self-administered questionnaire. Results: Ex-smokers showed an increasing odds ratio (OR) for UC development compared with never smokers (OR 2.42, 95% confidence interval 1.24-4.72). The ORs of ex-smokers were particularly high among subjects aged less than 40 years, subjects who had smoked more than 10 pack-years, and subjects who were within 13 years of quitting smoking. Regarding drinking habits, ex-drinkers also showed a more than twofold higher OR for UC compared to never drinkers. Ex-drinkers 40 years or older, ex-drinkers who had consumed more than 364 drink-years, and subjects who were less than 6 years after quitting drinking showed increased ORs for UC. Conclusion: These findings suggest the need for careful attention for UC onset among heavy smokers who quit smoking before 40 years of age and heavy drinkers who quit drinking at ≥40 years of age.

Antibody responses after BNT162b2 vaccination in Japanese geriatric intermediate care facilities.

Background: To evaluate antibody responses against the primary series of vaccination of severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2] vaccines in the staff and residents of Japanese geriatric intermediate care facilities. Methods: All subjects (159 staff and 96 residents) received two doses of the BNT162b2 mRNA vaccine 3 weeks apart. Baseline data of subject were collected using a structured form. Serum samples were collected three times: before vaccination, 3 weeks after the first dose, and 4 weeks after the second dose, and anti-receptor binding domain of the spike protein of SARS-CoV-2 [anti-RBD] IgG was measured using two immunoassays. Results: After the second dose, geometric mean titers [GMT] of anti-RBD with both the Abbott and Roche assay were significantly lower in residents than staff (2282 AU/mL vs. 8505 AU/mL, and 258 U/mL vs. 948 U/mL, respectively). Multivariate analysis of characteristics affecting antibody responses (≥1280 AU/mL for Abbott and > 210 U/mL for Roche) showed lower odds ratios [ORs] for older age (adjusted OR per 10 year increase [aOR] = 0.62, 95 % confidence interval [95 %CI]; 0.38-1.02), steroid usage (aOR = 0.09, 95 %CI; 0.01-0.60) and regular nonsteroidal anti-inflammatory drugs [NSAIDs] usage (aOR = 0.16, 95 %CI; 0.03-0.88). Conclusions: Elderly people and steroid and NSAID users had lower antibody responses following the second vaccine dose.

Survey of pediatricians concerning the human papillomavirus vaccine in Japan: Positive attitudes toward vaccination during the period of proactive recommendation being withheld.

In 2013, the human papillomavirus (HPV) vaccine was introduced as a national immunization program in Japan. However, because of a wide range of symptoms after vaccination, the Japanese Ministry of Health, Labor and Welfare decided to withhold proactive recommendations, a situation that has continued for more than eight years. During the withholding, absent any scientific or epidemiological evidence to support a relationship between HPV vaccines and symptoms, we surveyed pediatricians at Osaka Pediatric Association and analyzed the changing of attitudes in 2020 (n = 200) and 2021 (n = 190). A total of 44.5% respondents in 2020 and 67.9% in 2021 offered HPV vaccination to targets at the time the questionnaire was administered, indicating that the rate of pediatricians providing vaccines had increased significantly (p < .001). A total of 74.0% of respondents in 2020 and 77.9% in 2021 had a positive opinion of HPV vaccination (p = .369), and 64.3% in 2020 and 78.3% in 2021 were "not at all concerned or had almost no concern" about HPV vaccination (p = .002). These results suggest that, in general, most physicians who are primarily responsible for HPV vaccination in a given field had a positive attitude toward vaccination during the proactive recommendation having been withheld.

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against community-acquired pneumonia in older individuals after the introduction of childhood 13-valent pneumococcal conjugate vaccine: A multicenter hospital-based case-control study in Japan.

BACKGROUND: In the era of childhood pneumococcal conjugate vaccine (PCV) immunization, especially 13-valent pneumococcal conjugate vaccine (PCV13) immunization, serotype replacement of Streptococcus pneumoniae and herd immunity in adults have been reported worldwide. Therefore, continuous evaluation of the effectiveness of the pneumococcal vaccine in adults is crucial because vaccine effectiveness may change owing to these factors. The purpose of this study was to evaluate the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against all-cause pneumonia and pneumococcal pneumonia in older individuals with community-acquired pneumonia (CAP) after the introduction of childhood PCV13 in Japan, a topic that has remained largely unexplored. METHODS: We evaluated pneumococcal vaccine effectiveness in this multicenter, matched case-control study conducted in hospitals and clinics. Cases included patients (aged ≥ 65 years) newly diagnosed with CAP between October 2016 and September 2019. A maximum of five non-pneumonia control patients matched for sex, school grade, date of outpatient visit, and medical institution were selected for each case. Conditional logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of pneumococcal vaccines for the occurrence of all-cause CAP and pneumococcal CAP. RESULTS: The analysis included 740 individuals (142 patients and 598 controls). The median age of participants was 75 years (men: 54%). The adjusted OR for pneumococcal vaccination against all-cause CAP was 1.31 (95% CI: 0.84-2.06), while that for PPSV23 vaccination in the previous 5 years was 1.33 (95% CI: 0.85-2.09). The adjusted OR for PPSV23 vaccination in the previous 5 years against pneumococcal CAP was 0.93 (95% CI: 0.35-2.50). CONCLUSIONS: This study was unable to demonstrate the effectiveness of PPSV23 against all-cause and pneumococcal pneumonia after the introduction of childhood PCV13 in Japan. Nonetheless, additional studies are needed to validate these results.

Kinetics of anti-SARS-CoV-2 antibody titer in healthy adults up to 6 months after BNT162b2 vaccination measured by two immunoassays: A prospective cohort study in Japan.

BACKGROUND: Although several assays are used to measure anti-receptor-binding domain (RBD) antibodies induced after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination, the assays are not fully comparable in practice. This study evaluated the immunogenicity of the BNT162b2 mRNA vaccine in healthy adults using two immunoassays. METHODS: This prospective cohort study included SARS-CoV-2-naïve adults, predominantly healthcare workers, aged 20-64 years, who received two BNT162b2 vaccine doses between March and May 2021. Blood samples were collected before the first vaccination (S0), before the second vaccination (S1), 4 weeks after the second vaccination (S2), and 6 months after the second vaccination (S3). anti-RBD antibodies were measured using the Architect SARS-CoV-2 IgG II Quant (Abbott Laboratory) and Elecsys anti-SARS-CoV-2 S (Roche Diagnostics) assays. RESULTS: Among the 385 participants, the geometric mean antibody titers (GMTs) on the Architect assay (AU/mL) were 7.5, 693, 7007, and 1030 for S0, S1, S2, and S3, respectively. The corresponding GMTs on the Elecsys assay (U/mL) were 0.40, 24, 928, and 659, respectively. The GMT ratio (S3/S2) was 0.15 on the Architect and 0.71 on the Elecsys assay. The correlation between antibody titers measured with the two assays were strong at all time points after vaccination (Spearman's correlation coefficient: 0.74 to 0.86, P < 0.01 for all). GMT was significantly lower in the older age group after vaccination (P < 0.01), with no significant differences according to sex. Seroprotection (≥5458 AU/mL on the Architect assay and ≥ 753 U/mL on the Elecsys) at each time point was 0 %, 1 %, 67 %, and 1 % on the Architect assay and 0 %, 1 %, 62 %, and 43 % on the Elecsys, respectively. CONCLUSIONS: Two BNT162b2 vaccine doses resulted in adequate anti-RBD antibody response, which varied by age. As the two assays showed different kinetics, the results of single immunoassays should be interpreted with caution.

Annual trends in adverse events following mumps vaccination in Japan: A retrospective study.

BACKGROUND: In Japan, a monovalent mumps vaccine is provided on a voluntary basis. Due to public concerns over post-vaccination aseptic meningitis, the vaccination coverage is not high enough. The present study investigated the incidence of adverse events, including aseptic meningitis, after Torii strain-derived mumps vaccination. METHODS: This retrospective, observational study used data collected by a vaccine manufacturer regarding adverse events following mumps vaccinations at medical institutions between 1992 and 2018. In addition, the number of Torii strain-derived mumps vaccines shipped each year was obtained. The incidence (per 100,000 doses) and 95% confidence intervals (CIs) were calculated for all adverse events and each adverse event, categorized as aseptic meningitis, encephalitis, mumps, mumps complications, and others. RESULTS: During the study period, 8,262,121 mumps vaccine doses were shipped, and 688 subjects reported adverse events. The incidence for all adverse events (per 100,000 doses) was 8.33, and the incidence was 4.19 for aseptic meningitis, 0.33 for encephalitis, 0.80 for mumps, 0.25 for mumps complications, and 3.78 for others. The incidence of aseptic meningitis (per 100,000 doses) was 7.90 (95% CI: 5.61-10.18) between 1998 and 2000 but declined by half, to 3.91 (2.46-5.36), between 2001 and 2003. The most recent incidence (per 100,000 doses) of aseptic meningitis, for the period 2016 to 2018, was 2.78 (1.94-3.62). CONCLUSION: The incidence of post-vaccination aseptic meningitis has declined significantly since 2001, and the incidence has remained stable at fewer than 3 cases per 100,000 doses since 2010. Multiple factors might have contributed to the decline in aseptic meningitis incidence, including (i) lowered misclassification of aseptic meningitis resulting from echovirus infection; (ii) changes in the vaccine manufacturing process in 2000; and (iii) publication in 2008 of the recommendation for vaccination of children at 1 year of age.

Influence of Prior Influenza Vaccination on Current Influenza Vaccine Effectiveness in Children Aged 1 to 5 Years.

BACKGROUND: Although annual influenza vaccination is an important strategy used to prevent influenza-related morbidity and mortality, some studies have reported the negative influence of prior vaccination on vaccine effectiveness (VE) for current seasons. Currently, the influence of prior vaccination is not conclusive, especially in children. METHODS: We evaluated the association between current-season VE and prior season vaccination using a test-negative design in children aged 1-5 years presenting at nine outpatient clinics in Japan during the 2016/17 and 2017/18 influenza seasons. Children with influenza-like illness were enrolled prospectively and tested for influenza using real-time RT-PCR. Their recent vaccination history was categorized into six groups according to current vaccination doses (0/1/2) and prior vaccination status (unvaccinated = 0 doses/vaccinated = 1 dose or 2 doses): (1) 0 doses in the current season and unvaccinated in prior seasons (reference group); (2) 0 doses in the current season and vaccinated in a prior season; (3) 1 dose in the current season and unvaccinated in a prior season; (4) 1 dose in the current season and vaccinated in a prior season; (5) 2 doses in the current season and unvaccinated in a prior season, and (6) 2 doses in the current season and vaccinated in a prior season. RESULTS: A total of 799 cases and 1196 controls were analyzed. The median age of the subjects was 3 years, and the proportion of males was 54%. Overall, the vaccination rates (any vaccination in the current season) in the cases and controls were 36% and 53%, respectively. The VEs of the groups were: (2) 29% (95% confidence interval: -25% to 59%); (3) 53% (6% to 76%); (4) 70% (45% to 83%); (5) 56% (32% to 72%), and (6) 61% (42% to 73%). The one- and two-dose VEs of the current season were significant regardless of prior vaccination status. The results did not differ when stratified by influenza subtype/lineage. CONCLUSION: Prior vaccination did not attenuate the current-season VE in children aged 1 to 5 years, supporting the annual vaccination strategy.

Association between coffee and green tea intake and pneumonia among the Japanese elderly: a case-control study.

A large prospective cohort study in the United States examined the association between coffee intake and overall and cause-specific mortality and showed a inverse association between pneumonia and influenza deaths and coffee intake. In Japan, the mortality rate of pneumonia in elderly people is high, and its prevention is an important issue. The present study investigated the association between coffee and green tea intake and pneumonia among the elderly. The design was a hospital-based case control study. The cases were patients over 65 years old newly diagnosed as pneumonia. As a control, patients with the same sex and age (range of 5 years) who visited the same medical institution around the same time (within 2 months after examination of the case) for a disease other than pneumonia were selected. There were two controls per case. Odds ratio (OR) and 95% confidence interval (CI) for pneumonia of coffee and green tea intake during the past month were calculated using a conditional logistic regression model. A total of 199 cases and 374 controls were enrolled. When compared to those who do not drink coffee, the OR for pneumonia of those who drink less than one cup of coffee per day was 0.69 (95% CI 0.39-1.21), OR of those who drink one cup was 0.67 (0.38-1.18), and OR of those who drink two or more cups was 0.50 (0.28-0.88) (Trend p = 0.024). No association was found between pneumonia and green tea consumption. This study suggested a preventive association between coffee intake over 2 cups per day and pneumonia in the elderly.

Prognostic significance of cribriform adenocarcinoma of the lung: validation analysis of 1,057 Japanese patients with resected lung adenocarcinoma and a review of the literature.

BACKGROUND: Cribriform-predominant adenocarcinoma of the lung (Cribri-ADC) is a recently described tumor growth pattern. However, its prognostic impact has not been clearly determined. We analyzed the data of a series of 1,057 Japanese patients with resected lung adenocarcinoma to identify the clinical significance of Cribri-ADC. METHODS: Cribriform pattern (Cribri-p) is defined as invasive back-to-back fused tumor glands with poorly formed glandular spaces or invasive tumor nests comprising tumors cells that produced glandular lumina. We investigated the correlations of Cribri-p and Cribri-ADC with clinicopathological factors as well as disease-free survival (DFS) and overall survival (OS). RESULTS: Cribri-p was present in 217 patients (20.5%) and Cribri-ADC was determined in 25 patients (2.4%). Cribri-p was associated with larger tumor size, pleural invasion, vascular invasion, lymphatic invasion, and spreading through air spaces (STAS) (all, P<0.0001). Cribri-ADC was associated with younger age (P=0.019), vascular invasion (P=0.0025), STAS (P<0.0001), and ALK rearrangement (P=0.012). The DFS curve of patients with Cribri-ADC was identical to that of patients with solid adenocarcinoma; however, the OS curve was located between that of patients with papillary and acinar adenocarcinoma. Of the 10 patients who had tumor recurrences, eight had EGFR mutations or ALK rearrangement, six of whom achieved relatively long survival (median, 64.6, range, 37.4-113 months) following treatment with tyrosine kinase inhibitors (TKIs). In multivariate analysis, Cribri-ADC was not an independent prognostic factor of either recurrence or death. CONCLUSIONS: Cribri-ADC is associated with a higher risk of recurrence; however, most patients can be successfully treated with TKIs.

Association of Dietary Fatty Acid Intake With the Development of Ulcerative Colitis: A Multicenter Case-Control Study in Japan.

BACKGROUND: Dietary fatty acids can affect chronic intestinal inflammation and have been reported to be associated with the development of ulcerative colitis (UC), mainly in Europe and the United States. The association of dietary intake of fatty acids and the risk for UC was investigated in Japan, where dietary habits lead to lower meat and higher fish consumption than in Western countries. METHODS: A multicenter case-control study of 83 newly diagnosed patients with UC and 128 age- and sex-matched control patients in the hospital was conducted from 2008 to 2014. Dietary fatty acid intake in the preceding 1 month and 1 year were examined using a self-administered diet history questionnaire that was developed for Japanese people. RESULTS: About 92% of patients had experienced the first symptoms of UC within the preceding 11 months. Regarding dietary habits in the preceding year, the risk for UC was significantly decreased in patients who consumed n-6/n-3 polyunsaturated fatty acids at a ratio of ≥5.2 (odds ratio [OR] = 0.26; 95% confidence interval [CI], 0.10-0.68). Conversely, an increased risk for UC was observed in the highest tertiles of consumption of docosahexaenoic acid (OR = 7.22; 95% CI, 2.09-24.95), eicosapentaenoic acid (OR = 6.91; 95% CI, 1.88-25.44), and docosapentaenoic acid (OR = 4.83; 95% CI, 1.56-14.95). CONCLUSIONS: The ratio of n-6/n-3 polyunsaturated fatty acid intake was associated with a decreased risk for UC development. However, high intakes of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid may increase the risk for UC development.

Lifestyles Associated with Prognosis After Eradication of Hepatitis C Virus: A Prospective Cohort Study in Japan.

BACKGROUND: Hepatocellular carcinoma develops in some patients with hepatitis C virus (HCV), even after achieving sustained virological response (SVR). AIMS: We examined factors associated with liver disease progression in a prospective cohort study of SVR patients. METHODS: Participants were patients who had visited a hospital for clinical follow-up of chronic HCV infection in 2005 and had reached SVR as a result of subsequent antiviral treatment. Baseline information including lifestyle and dietary habits before SVR was collected in 2005 using self-administered questionnaires, and clinical information before SVR was collected from medical records in 2005. Study outcome was liver disease progression such as liver cirrhosis, hepatocellular carcinoma, and/or liver disease-related death after SVR. Proportional hazard models were employed to calculate hazard ratios (HRs) and 95% confidence intervals for each variable. RESULTS: Of 180 SVR patients, 27 patients (15%) showed liver disease progression after SVR: 26 (14%) were diagnosed with liver cirrhosis, two (1%) with hepatocellular carcinoma, and/or one (0.6%) with liver-disease-related death. Besides older age at SVR (HR = 11.9, P < 0.01) and aspartate aminotransferase-to-platelet ratio index score ≥ 1.0 before SVR (HR = 2.63, P = 0.03), alcohol drinkers before SVR (HR = 2.82, P = 0.06) were suggested to be associated with liver disease progression after SVR, whereas higher consumption of vitamin B12 before SVR showed a decreased HR for liver disease progression (HR = 0.41, P = 0.09). CONCLUSIONS: Alcohol drinking might be associated with liver disease progression, whereas vitamin B12 intake might have protective effects against liver disease progression after eradication of HCV. Further studies are needed to confirm these findings.

Large nest micropapillary pattern of lung adenocarcinoma has poorer prognosis than typical floret pattern: analysis of 1,062 resected tumors.

BACKGROUND: A micropapillary pattern (MP-p) is related to poor prognosis in patients with lung adenocarcinoma (L-ADC). In 2015, the WHO defined the MP-p as "papillary tufts forming florets that lack fibrovascular cores and may appear detached from alveolar walls"; however, the sizes of tumor clusters in air space were not mentioned in this classification. METHODS: We evaluated the MP-p dividing the cluster sizes in the air space by reviewing 1,062 cases of resected L-ADCs. We classified MP-p into two types according to cluster size as follows: typical floret MP-p, tumors with small-to-medium-sized clusters (1-20 tumor cells); and large nest MP-p, tumors with large-sized clusters (>20 tumor cells, large nest). We then recorded the frequency of each type and investigated the association between the MP-p type and clinicopathological factors. RESULTS: Twenty-nine percent of L-ADCs (n=308) were MP-p-positive. Typical floret MP-p and large nest MP-p were observed in 244 tumors (22.9%) and 64 tumors (6.0%), respectively. Only 7 additional micropapillary ADCs were detected when we reclassified ADCs in addition to large nest MP-p. Tumors with large nest MP-p showed the highest frequency of node metastasis and worse prognosis compared to those with typical floret MP-p and absent (P<0.001). In multivariate analysis, patients with L-ADC with typical floret MP-p and large nest MP-p showed a higher recurrence rate [hazard ratio (HR): 1.762 (type 1 vs. absent), HR: 2.450 (type 2 vs. absent)]. CONCLUSIONS: Large nest MP-p should be included in the original MP-p and recorded separately.

Discohesive growth pattern (Disco-p) as an unfavorable prognostic factor in lung adenocarcinoma: an analysis of 1062 Japanese patients with resected lung adenocarcinoma.

Discohesive growth pattern (Disco-p) is often observed in lung adenocarcinoma (ADC) and mimics tumor budding (TB), stromal invasive-type micropapillary pattern (SMPP), and complex glandular pattern. However, the clinical impact of Disco-p in lung ADC has not been well studied. To investigate the prognostic significance of Disco-p, we analyzed 1062 Japanese patients with resected lung ADC. Disco-p was defined as an invasive growth pattern composed of single tumor cells, or trabeculae or small nests of tumor cells associated with desmoplastic fibrous stroma. We recorded the percentage of Disco-p in 5% increments independent of the major histologic pattern and investigated its correlation with different clinicopathological factors. We also analyzed the overall survival (OS) and disease-free survival (DFS). Disco-p was observed in 203 tumors (19.1%). Disco-p was significantly associated with male sex, smoking, lymph node metastasis, large tumor size, high TNM stage, lymphovascular and pleural invasion, spread through air spaces, and TB (all, p < 0.001). Of the total cases, only eight cases exhibited a dubious pattern between SMPP and Disco-p. Disco-p was also associated with wild-type EGFR (p < 0.001) and ALK fusion (p = 0.008). Patients harboring tumors with Disco-p had significantly worse prognoses (OS and DFS (both, p < 0.001)) compared with those without Disco-p. On multivariate analysis, Disco-p was an independent prognostic factor of worse OS (hazard ratio (HR), 2.572; 95% confidence interval (CI), 1.789-3.680; p < 0.001), and DFS (HR, 3.413; 95% CI, 2.482-4.683; p < 0.001), whereas TB was not an independent unfavorable prognostic factor. Disco-p was an independent unfavorable prognostic factor in patients with resected lung ADC, although a careful evaluation is necessary to distinguish it from similar patterns. We proposed that Disco-p should be recognized as a new invasive pattern and accurately recorded for the better management of patients with lung ADCs.

Safety of influenza vaccination on adverse birth outcomes among pregnant women: A prospective cohort study in Japan.

BACKGROUND: Pregnant women are in the highest priority group for receiving influenza vaccination. However, they may be reluctant to receive the vaccination due to concerns about the influence of vaccination on the fetuses. METHODS: This prospective cohort study of 10 330 pregnant women examined the safety of influenza vaccination in terms of adverse birth outcomes. Influenza vaccination during pregnancy was determined from questionnaires before and after the 2013/2014 influenza season. All subjects were followed until the end of their pregnancy. Adverse birth outcomes, including miscarriage, stillbirth, preterm birth, low birth weight, and malformation, were assessed by obstetrician reports. RESULTS: Adverse birth outcomes were reported for 641 (10%) of the 6387 unvaccinated pregnant women and 356 (9%) of the 3943 vaccinated pregnant women. Even after adjusting for potential confounders, vaccination during pregnancy showed no association with the risk of adverse birth outcomes (odds ratio 0.90, 95% confidence interval 0.76-1.07). Vaccination during the first or second trimester displayed no association with adverse birth outcomes, whereas vaccination during the third trimester was associated with a decreased risk of adverse birth outcomes (odds ratio 0.70, 95% confidence interval 0.51-0.98). CONCLUSIONS: Influenza vaccination during pregnancy did not increase the risk of adverse birth outcomes, regardless of the trimester in which vaccination was performed, when compared to unvaccinated pregnant women.

Aberrant endosperm formation caused by reduced production of major allergen proteins in a rice flo2 mutant that confers low-protein accumulation in grains.

Rice flo2 mutation produces grains showing a reduced amount of storage proteins. Using Nipponbare and the flo2 mutant, we created rice transformants that showed defective production of major allergen proteins RA14 and RA33 (14-16 kDa and 33 kDa allergen proteins, respectively) by RNAi introduction. The knock-down transformant generated using Nipponbare showed greatly reduced accumulation of both allergen proteins, normal growth, and production of a sufficient amount of normal-shaped seeds. F1 seeds were obtained by crossing between the transformants containing RNAi genes to RA14 and RA33, and showed decreased accumulation of both proteins. However, a peculiar phenotype was observed in the flo2 transformants that lacked accumulation of RA14 or RA33. They showed significantly reduced fertility. A wrinkled grain feature was found on the transformant lacking accumulation of RA14. F1 seeds obtained by crossing these transformants showed significantly lower fertility. F2 seeds showed decreases in both allergen proteins but morphological abnormality with small and severely wrinkled features. These results indicated that it is hard to obtain any transformant lacking accumulation of these allergen proteins using the flo2 mutant, whereas a knock-down transformant of both allergen protein genes was obtained when a wild-type Nipponbare was used as a host. These facts strongly suggest that RA14 and RA33 have some roles in rice seeds.