Time-series transcriptome analysis of peripheral blood mononuclear cells obtained from individuals who received the SARS-CoV-2 mRNA vaccine.

Messenger ribonucleic acid (mRNA) vaccination against coronavirus disease 2019 (COVID-19) is an effective prevention strategy, despite a limited understanding of the molecular mechanisms underlying the host immune system and individual heterogeneity of the variable effects of mRNA vaccination. We assessed the time-series changes in the comprehensive gene expression profiles of 200 vaccinated healthcare workers by performing bulk transcriptome and bioinformatics analyses, including dimensionality reduction utilizing the uniform manifold approximation and projection (UMAP) technique. For these analyses, blood samples, including peripheral blood mononuclear cells (PBMCs), were collected from 214 vaccine recipients before vaccination (T1) and on Days 22 (T2, after second dose), 90, 180 (T3, before a booster dose), and 360 (T4, after a booster dose) after receiving the first dose of BNT162b2 vaccine (UMIN000043851). UMAP successfully visualized the main cluster of gene expression at each time point in PBMC samples (T1-T4). Through differentially expressed gene (DEG) analysis, we identified genes that showed fluctuating expression levels and gradual increases in expression levels from T1 to T4, as well as genes with increased expression levels at T4 alone. We also succeeded in dividing these cases into five types based on the changes in gene expression levels. High-throughput and temporal bulk RNA-based transcriptome analysis is a useful approach for inclusive, diverse, and cost-effective large-scale clinical studies.

Awareness, Attitudes, and Concerns Regarding Heated Tobacco Products Among Physicians in Japan.

BACKGROUND: New tobacco products, particularly heated tobacco products (HTPs), have been introduced across several international markets as alternatives to combustible products, such as cigarettes. However, there are limited studies on physicians' perceptions of HTPs. This study analyzes the awareness of HTPs among physicians and assesses their concerns and attitudes toward patients using HTPs. METHODS: A self-administered questionnaire was sent to a sample of 7,500 member physicians (6,000 male and 1,500 female) from the Japan Medical Association (JMA). The smoking status of physicians was categorized as never smokers, ever HTP smokers, current HTP smokers, and ever and current smokers of other products. Physicians' awareness and attitudes toward patients using HTPs were analyzed using descriptive statistics. The correlation between the outcomes was examined using logistic regression models, whereas physicians' concerns about HTPs were analyzed using descriptive statistics. RESULTS: Data were obtained from 5,492 physicians (21.9% women; aged 60.4; standard deviation, 12.1 years) with a response rate of 74.6%. Overall, 76.7% of the physicians had awareness of HTP, and about half of whom asked patients about using HTPs. Physicians who took longer to discuss cessation were more likely to discourage patient use. Smoking status was associated with discouraging HTP use in patients. Physicians who had experience with HTP use were primarily concerned about the products' long-term safety and less about product regulation. CONCLUSION: Japanese physicians do not have sufficient information and knowledge about HTPs. Therefore, evidence-based guidelines are required to support physicians in advising patients against HTP use.

Heterogeneity assessment of vaccine-induced effects using point-of-care surrogate neutralization test for severe acute respiratory syndrome coronavirus 2.

INTRODUCTION: Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic even after vaccination. We aimed to identify immunological heterogeneity over time in vaccinated healthcare workers using neutralization antibodies and neutralizing activity tests. METHODS: Serum samples were collected from 214 healthcare workers before vaccination (pre) and on days 22, 90, and 180 after receiving the first dose of BNT162b2 vaccine (day 0). Neutralization antibody (NAb, SARS-CoV-2 S-RBD IgM/IgG) titers and two kinds of surrogate virus neutralization tests (sVNTs) were analyzed (UMIN000043851). RESULTS: The NAb (SARS-CoV-2 S-RBD IgG) titer peaked on day 90 after vaccination (30,808.0 µg/ml ± 35,211; p < 0.0001) and declined on day 180 (11,678.0 µg/ml ± 33,770.0; p < 0.0001). The neutralizing activity also peaked on day 90 and declined with larger individual differences than those of IgG titer on day 180 (88.9% ± 15.0%, 64.8% ± 23.7%, p < 0.0001). We also found that the results of POCT-sVNT (immunochromatography) were highly correlated with those of conventional sVNT (ELISA). CONCLUSIONS: Neutralizing activity is the gold standard for vaccine efficacy evaluation. Our results using conventional sVNT showed large individual differences in neutralizing activity reduction on day 180 (64.8% ± 23.7%), suggesting an association with the difference in vaccine efficacy. POCT-sVNT is rapid and user-friendly; it might be used for triage in homes, isolation facilities, and event venues without restrictions on the medical testing environment.

Effectiveness and Safety of Rivaroxaban by General Practitioners　- A Multicenter, Prospective Study in Japanese Patients With Non-Valvular Atrial Fibrillation (GENERAL).

BACKGROUND: Direct oral anticoagulants have become a standard therapy for non-valvular atrial fibrillation (NVAF). However, little is known about their effectiveness/safety when prescribed by general practitioners to treat high-risk populations such as the elderly, those who are frail or have cognitive dysfunction.Methods and Results:In this multicenter, prospective study, a total of 5,717 NVAF patients (mean age 73.9 years) receiving rivaroxaban were registered by general practitioners, with a maximum 3-year follow up (mean 2.0±0.5 years). The primary endpoint was a composite of stroke and systemic embolism (SE). The annual incidence (per 100 person-years) of stroke/SE was 1.23% and for major bleeding, it was 0.63%. Multivariate analyses identified age ≥75 years (hazard ratio [HR]; 2.67, P<0.001) and history of ischemic stroke (HR; 1.89, P=0.005) as significant risk factors of stroke/SE, with history of major bleeding (HR; 14.9, P<0.001) and warfarin use (HR; 2.15, P=0.002) as risk factors for major bleeding events. Neither cognitive dysfunction, defined by the receipt of anti-dementia medications, nor frailty, evaluated by the classification of the Japanese Long-term Care Insurance system, correlated with stroke/SE or major bleeding events. CONCLUSIONS: The low incidence of adverse events, including stroke/SE and bleeding, in patients prescribed rivaroxaban by general practitioners supports its use as a safe and efficacious treatment in the standard clinical care of high-risk patient populations.

Evaluation of a new point-of-care quantitative reverse transcription polymerase chain test for detecting severe acute respiratory syndrome coronavirus 2.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is rapidly spreading worldwide, and the resultant disease, coronavirus disease (COVID-19), has become a global pandemic. Although there are multiple methods for detecting SARS-CoV-2, there are some issues with such tests, including long processing time, expense, low sensitivity, complexity, risk of contamination, and user friendly. This study evaluated the reproducibility and usability of a new point-of-care test (POCT) using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) for detecting SARS-CoV-2. METHODS: Samples from 96 patients with suspected SARS-CoV-2 infection were assessed using the real-time qRT-PCR-based POCT and the conventional real-time qRT-PCR method based on the Japanese National Institute of Infectious Diseases guidelines (registration number: jRCT1032200025). RESULTS: The real-time qRT-PCR-based POCT had a positive agreement rate of 90.0% (18/20), a negative agreement rate of 100% (76/76), and a total agreement rate of 97.9% (94/96), and the significantly high score of questionnaire survey (total score p < 0.0001). In the two cases in which real-time qRT-PCR-based POCT results did not match conventional real-time qRT-PCR test results, the SARS-CoV-2 RNA copy numbers were 8.0 copies per test in one case and below the detection limit in the other case when quantified using conventional real-time qRT-PCR. All patients could be triaged within 1 day using the real-time qRT-PCR-based POCT without invalid reports. CONCLUSIONS: The real-time qRT-PCR-based POCT not only had high reproducibility and useability but also allowed rapid patient triage. Therefore, it may be helpful in clinical settings.

Validity of salt intake assessment system based on a 24-h dietary recall method using a touch panel computer.

BACKGROUND: An electronic system for salt intake assessment using a 24-h dietary recall method has been developed in Japan. We evaluated the validity of this salt intake system for assessing salt intake. METHODS: We prospectively obtained data on estimated salt intake using 24-hour urinary sodium excretion (24-hUNaCl) and salt intake by the salt intake assessment system from 203 consecutive outpatients with essential hypertension (age: 67.8 ± 10.7 years; 53.7% men). RESULTS: Mean values were 9.7 ± 2.9 g/day for 24-hUNaCl and 9.1 ± 2.9 g/day for the salt intake assessment system before corrections. The salt intake estimated by the present system was significantly correlated with 24-hUNaCl (r = 0.66, p < 0.0001). After corrections for habitual use of discretionary seasonings, habitual intake of salty foods, and physical activity, correlation coefficients between salt intake and 24-hUNaCl increased from 0.60 to 0.66 in men <65 years, from 0.80 to 0.81 in men ≥ 65 years, from 0.64 to 0.75 in women <65 years, and from 0.52 to 0.59 in women ≥ 65 years. After further correction for regional differences in average salt intake, the correlation coefficient reached 0.72 in all patients. CONCLUSION: After correction for dietary habits, lifestyle factors, and differences in average salt intake by region, this system may be a useful tool in Japan to encourage salt restriction in the clinical treatment of hypertension and improve public health in terms of salt restriction overall.

Observational study of frailty in older Japanese patients with non-valvular atrial fibrillation receiving anticoagulation therapy.

The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants to such patients because of possible harm. The effects of frailty on anticoagulant therapy in older Japanese patients with nonvalvular atrial fibrillation (NVAF) are unclear. Herein, we prescribed rivaroxaban to Japanese patients with NVAF and monitored for a mean of 2.0 years. The primary endpoint was stroke or systemic embolism. The secondary endpoints were all-cause or cardiovascular death, composite endpoint, and major or non-major bleeding. Frailty was assessed using the Japanese long-term care insurance system. A multiple imputation technique was used for missing data. The propensity score (PS) was obtained to estimate the treatment effect of frailty and was used to create two PS-matched groups. Overall, 5717 older patients had NVAF (mean age: 73.9 years), 485 (8.5%) were classified as frail. After PS matching, background characteristics were well-balanced between the groups. Rivaroxaban dosages were 10 and 15 mg/day for approximately 80% and the remaining patients, respectively. Frailty was not associated with the primary endpoint or secondary endpoints. In conclusion, frailty does not affect the effectiveness or safety of rivaroxaban anticoagulant therapy in older Japanese patients with NVAF.Trial registration: UMIN000019135, NCT02633982.

Pretreatment body mass index affects achievement of target blood pressure with sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease.

Sodium-glucose cotransporter 2 inhibitor (SGLT2-I) shows excellent antihypertensive effects in addition to its hypoglycemic effects. However, whether body mass index (BMI) affects the antihypertensive effect of SGLT2-I remains unknown. We investigated the impact of baseline BMI on the achievement of target blood pressure (BP) with SGLT2-I treatment in Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We retrospectively evaluated 447 Japanese patients with T2DM and CKD treated with SGLT2-I for at least 1 year. The primary outcome was achieving the target BP (<130/80 mmHg) after SGLT2-I treatment. Patients were divided into two groups according to a baseline BMI of 29.1 determined by receiver operating characteristic analysis and analyzed in a cohort model with propensity score matching. In each group, 130 patients were compared by propensity score matching. The target BP achievement rate was significantly higher in the BMI < 29.1 group than in the BMI ≥ 29.1 group (34% and 21%, respectively, p = 0.03). The odds ratio for achieving the target BP in the BMI ≥ 29.1 group was 0.50 (95% confidence interval, 0.28-0.90, p = 0.02). The BMI < 29.1 group had significantly lower systolic and diastolic BPs after SGLT2-I treatment than the BMI ≥ 29.1 group. Only the BMI < 29.1 group was showed a significant decrease in the logarithmic albumin-to-creatinine ratio from baseline after SGLT2-I treatment. In patients with T2DM and CKD, baseline BMI was associated with the antihypertensive effects of SGLT2-I. Patients in the lower baseline BMI group were more likely to achieve the target BP after SGLT2-I treatment. Pretreatment BMI affects the antihypertensice effect of SGLT2 inhibirors in patients with T2DM and CKD.

Clinical characteristics and outcomes of Japanese atrial fibrillation patients with poor medication adherence: A sub-analysis of the GENERAL study.

BACKGROUND: Oral anticoagulation therapy is essential for preventing stroke in patients with atrial fibrillation (AF). However, poor anticoagulant adherence may hamper medication safety and effective prevention of stroke. METHODS: GENERAL is a prospective cohort study of AF patients taking rivaroxaban prescribed by general practitioners in Japan. In this study, anticoagulant adherence was calculated as the proportion of days covered (PDC), and patients were retrospectively divided into two groups: good adherence (PDC ≥80 %) and poor adherence (<80 %). RESULTS: Of 5680 patients in the GENERAL study, the poor adherence group consisted of 223 patients (3.9 %). Baseline clinical characteristics were almost comparable regarding age (PDC ≥80 % vs. <80 %: 73.9 vs. 74.0 years, p = 0.92) and sex (male 64.6 % vs. 66.8 %, p = 0.52). The PDC <80 % group more often had various co-morbidities, and had significantly higher CHADS2 (2.14 vs. 2.28, p = 0.04) and CHA2DS2-VASc scores (3.12 vs. 3.31, p = 0.045). There was no significant difference in HAS-BLED score (1.41 vs. 1.47, p = 0.39). During 2-year follow-up, the incidences of stroke or systemic embolism (1.14 vs. 3.56 % per patient-year, p < 0.01), major bleeding (0.59 vs. 1.78 % per patient-year, p < 0.01), and net clinical outcome (the composite of stroke, systemic embolism, major bleeding, or death) (3.49 vs. 7.78 % per patient-year, p < 0.01) were significantly higher in the poor adherence group; however, there was no significant difference in all-cause (1.89 vs. 2.73 % per patient-year, p = 0.23) and cardiovascular mortality (0.86 vs. 1.49 % per patient-year, p = 0.18). Multivariate analysis revealed that the poor adherence group was independently associated with stroke or systemic embolism (adjusted hazard ratio 3.12, 95 % confidence interval 1.79-5.47), major bleeding (2.87, 1.31-6.34), and net clinical outcome, (2.02, 1.39-2.93), but not with all-cause (1.18, 0.64-2.17) or cardiovascular death (1.39, 0.60-2.93). CONCLUSIONS: Poor anticoagulant adherence, as measured by PDC <80 %, was associated with higher incidence of stroke or systemic embolism and major bleeding in the GENERAL study.

Long-term outcome and risk factors associated with events in patients with atrial fibrillation treated with oral anticoagulants: The ASSAF-K registry.

BACKGROUND: Oral anticoagulant therapy for atrial fibrillation (AF) has changed dramatically. Direct oral anticoagulant (DOAC) therapy is administered by general practitioners and specialists. However, the beneficial long-term effects and safety of DOACs have not been well investigated in real-world clinical practice. METHODS: The ASSAF-K (a study of the safety and efficacy of OAC therapy in the treatment of AF in Kanagawa), a prospective, multi-center, observational study, was conducted to clarify patient characteristics, status of OAC treatment, long-term outcomes, and adverse events, including cerebrovascular disease, bleeding, and death. RESULTS: A total of 4014 patients were enrolled (hospital: 2500 cases; clinic: 1514 cases). The number of patients in the final dataset was 3367 (mean age, 72.6 ±â€¯10.0 years; males, 66.3 %). CHA2DS2-VASc and HAS-BLED scores were 3.0 ±â€¯1.6 and 2.2 ±â€¯1.0, respectively. The risk factors of the primary composite outcome (all-cause death, serious bleeding events, cerebral hemorrhage, and stroke) were higher age, lower body mass index, lower diastolic blood pressure, lower creatine clearance, history of heart failure, history of stroke, and medication of anti-platelet agents. The event-free rates of the primary composite outcome with DOACs, warfarin, and without OACs were 92.7 %, 88.0 %, and 87.4 %, respectively. The event rate of DOACs was significantly lower than that of warfarin [HR 0.63 (95 % CI 0.48-0.81)], and similar results were observed after adjustment for AF stroke risk score [HR 0.70 (95 % CI 0.54-0.90)]. Serious bleeding events tended to occur less frequently with DOACs compared with warfarin [unadjusted HR 0.53 (95 % CI 0.31-0.91), adjusted HR 0.61 (95 % CI 0.33-1.11)]. CONCLUSIONS: This multi-center registry demonstrated the long-term outcome in patients with AF treated with and without OACs and suggests that DOAC therapy is safe and beneficial in hospitals and clinics.

The concomitant use of sodium-glucose co-transporter 2 inhibitors improved the renal outcome of Japanese patients with type 2 diabetes treated with glucagon-like peptide 1 receptor agonists.

Aims: This study aimed to clarify the renal influence of glucagon-like peptide 1 receptor agonists (GLP1Ras) with or without sodium-glucose co-transporter 2 inhibitors (SGLT2is) on Japanese patients with type 2 diabetes mellitus (T2DM). Methods: We retrospectively extracted 547 patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. The progression of albuminuria status and/or a ≥ 15% decrease in the estimated glomerular filtration rate (eGFR) per year was set as the renal composite outcome. Propensity score matching was performed to compare GLP1Ra-treated patients with and without SGLT2i. Results: After matching, 186 patients in each group were compared. There was no significant difference of the incidence of the renal composite outcomes (17% vs. 20%, P = 0.50); however, the annual decrease in the eGFR was significantly smaller and the decrease in the urine albumin-to-creatinine ratio was larger in GLP1Ra-treated patients with the concomitant use of SGLT2is than in those without it (-1.1 ±â€…5.0 vs. -2.8 ±â€…5.1 mL/min/1.73 m2, P = 0.001; and -0.08 ±â€…0.61 vs. 0.05 ±â€…0.52, P = 0.03, respectively). Conclusion: The concomitant use of SGLT2i with GLP1Ra improved the annual decrease in the eGFR and the urine albumin-to-creatinine ratio in Japanese patients with T2DM.

Polypharmacy influences the renal composite outcome in patients treated with sodium-glucose cotransporter 2 inhibitors.

Polypharmacy is a serious concern in general practice, especially among elder patients; however, the evidence showing significantly poor renal outcomes is not sufficient. This survey was performed to evaluate the effect of polypharmacy on the incidence of the renal composite outcome among a sample of patients with sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment. We assessed 624 Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease who received SGLT2i treatment for greater than 1 year. The patients were classified as those with concomitant treatment, that was limited to the medications for hypertension, T2DM, and dyslipidemia, with greater than or equal to seven medications (n = 110) and those with less than seven medications (n = 514). Evaluation of the renal composite outcome was performed by propensity score matching and stratification into quintiles. A subgroup analysis of patients of greater than or equal to 62 years of age and less than 62 years of age was also performed. The incidence of the renal composite outcome was larger in patients with greater than or equal to seven medications than in those with less than seven medications in the propensity score-matched cohort model (6% vs. 17%, respectively, p = 0.007) and also in the quintile-stratified analysis (odds ratio [OR], 2.23, 95% confidence interval [CI, 1.21-4.12, p = 0.01). The quintile-stratified analysis of patients of less than 62 years of age-but not those of greater than or equal to 62 years of age-also showed a significant difference (OR, 3.29, 95% CI, 1.41-7.69, p = 0.006). Polypharmacy appears to be associated to the incidence of the renal composite outcome, especially in young patients.

The Proportion of Long-term Response to Anti-N IgG Antibody after 12 Months for COVID-19 Subclinical Infections and a Longitudinal Survey for COVID-19 Subclinical Infections in 2021.

Objective To examine the continuation of antibody prevalence status after 12 months and background factors in antibody-positive subjects following asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We initially determined the SARS-CoV-2 anti-nucleocapsid protein immunoglobulin G (anti-N IgG) antibody prevalence in 1,603 patients, doctors, and nurses at 65 medical institutions in Kanagawa Prefecture, Japan. We then obtained consent from 33 of the 39 subjects who tested positive and performed follow-up for 12 months. Results Follow-up for up to 12 months showed that a long-term response of the anti-N IgG antibody could be detected in 6 of the 33 participants (18.2%). The proportions with hypertension, using an angiotensin-receptor blocker, and without a drinking habit were higher among the participants with a long-term anti-N IgG antibody response for up to 12 months than among those without a long-term antibody response. Conclusions The proportion of individuals with subclinical COVID-19 who continuously had a positive result for the anti-N IgG antibody at 12 months was low.

Blood pressure after treatment with sodium-glucose cotransporter 2 inhibitors influences renal composite outcome: Analysis using propensity score-matched models.

AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcome in patients with type 2 diabetes mellitus, but the mechanism is not fully understood. The aim of this retrospective study was to assess the association of achieved blood pressure with renal outcomes in Japanese type 2 diabetes mellitus patients with chronic kidney disease. MATERIALS AND METHODS: We assessed 624 Japanese type 2 diabetes mellitus patients with chronic kidney disease taking SGLT2i for >1 year. The patients were classified as those with post-treatment mean arterial pressure (MAP) of ≥92 mmHg (n = 344) and those with MAP of <92 mmHg (n = 280) for propensity score matching (1:1 nearest neighbor match with 0.04 of caliper value and no replacement). The end-point was a composite of progression of albuminuria or a decrease in the estimated glomerular filtration rate by ≥15% per year. RESULTS: By propensity score matching, a matched cohort model was constructed, including 201 patients in each group. The incidence of renal composite outcome was significantly lower among patients with MAP of <92 mmHg than among patients with MAP of ≥92 mmHg (n = 11 [6%] vs n = 26 [13%], respectively, P = 0.001). The change in estimated glomerular filtration rate was similar in the two groups; however, the change in the albumin-to-creatinine ratio was significantly larger in patients with MAP of <92 mmHg. CONCLUSIONS: In Japanese type 2 diabetes mellitus patients with chronic kidney disease, blood pressure after SGLT2i administration influences the renal composite outcome. Blood pressure management is important, even during treatment with SGLT2i.

Retrospective Analysis of the Renoprotective Effects of Long-Term Use of Six Types of Sodium-Glucose Cotransporter 2 Inhibitors in Japanese Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.

Aim: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) provide renal protection in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to elucidate the renal effects of long-term use of six types of SGLT2is in Japanese patients with T2DM and chronic kidney disease (CKD). Materials and Methods: The Kanagawa Physicians Association maintains a registry of patients who visit their 31 clinics. We retrieved clinical data of patients with T2DM and CKD who were prescribed with SGLT2is for >1 year. Results: A total of 763 patients with a median treatment duration of 33 months were included. The logarithmic value of urine albumin-creatinine ratio (LNACR) decreased significantly from 1.60 ± 0.65 to 1.51 ± 0.67. The multiple linear regression analysis revealed that the LNACR at the initiation of treatment, change in (Δ) diastolic blood pressure, and Δ hemoglobin A1c were independently correlated with ΔLNACR (P < 0.001). The decrease in the LNACR was significantly smaller in the patients with estimated glomerular filtration rate (eGFR) [mL/(min ·1.73 m2)] of <60 (P < 0.05). The eGFR decreased from 77.4 ± 22.3 to 72.7 ± 22.5 mL/(min ·1.73 m2) (P < 0.001). The multiple linear regression analysis showed that the LNACR at the initiation of treatment, Δbody weight at the previous survey, ΔeGFR at the previous survey, and the eGFR at the initiation of treatment correlated independently with ΔeGFR during the maintenance period (P < 0.001). Greater changes in the eGFR during the maintenance period were observed in the patients with macroalbuminuria or eGFR of <60 (P < 0.01). Conclusions: The study confirmed that the long-term use of six types of SGLT2i improved the albumin-creatinine ratio (ACR), although the eGFR gradually decreased during the treatment. The change in the ACR was significantly smaller in the patients with eGFR of <60 mL/(min ·1.73 m2) than in those with eGFR of >60 mL/(min ·1.73 m2). However, this was a retrospective observational study; further studies are needed to formulate final conclusions.

[How have we understood and responded clinically to pandemic H1N1 2009?].

Pandemic H1N1 2009 (pdmH1) has a broad clinical spectrum. Although many cases are mild, its pathogenesis is not necessarily low as it often causes serious respiratory disorder in children, and thus early treatment is necessary. As the positive rate as determined by rapid diagnostic kit is low, and false negative results can occur when the test is conducted too early following symptomatic onset, patients suspected of pdmH1 influenza warrant initiation of treatment even before establishment of a definite diagnosis. For therapeutic drugs, oseltamivir, zanamivir, and peramivir can be similarly efficacious, but intravenous administration is required in patients suffering symptoms of respiratory disorder and/or vomiting. As for the infectiousness, based on higher household transmission from parents to children in comparison to seasonal influenza A (FluA), as well as a high prevalence among primary school children, pdmH1 appears more likely to affect children, especially school children. In addition, since pdmH1 has a long incubation period, which can facilitate latent viral transmission, wearing a mask is useful during the epidemic period. A judgment of recovery should be carefully made especially in children, because the virus remains for a long time even after resolution of fever.

Study design of GENERAL (general practitioners and embolism prevention in NVAF patients treated with rivaroxaban: Real-life evidence): A multicenter prospective cohort study in primary care physicians to investigate the effectiveness and safety of rivaroxaban in Japanese patients with NVAF.

BACKGROUND: Rivaroxaban, a direct oral anticoagulant (DOAC), has become available for stroke prevention in patients with non-valular atrial fibrillation (NVAF). However, little is known about its effectiveness and safety when prescribed by general practitioners in real-life settings. METHODS: GENERAL is a multicenter, prospective, non-interventional observational study of patients receiving rivaroxaban for NVAF in daily clinical practice prescribed specifically by general practitioners. The target number of participating medical institutions is 500-700 clinics with fewer than 20 beds and the target number of participants is 5000. The baseline clinical data, including antidementia medication and frailty, and follow-up data including concomitant treatment and outcomes until September 2018 (maximum three years) will be collected. The primary efficacy endpoints will be stroke and/or systemic embolism and the secondary endpoints will be major bleeding meeting the ISTH guidelines, non-major and clinically relevant bleeding, onset of symptomatic stroke (ischemic/hemorrhagic), systemic embolism, deep vein thrombosis/pulmonary thromboembolism, myocardial infarction and/or cardiovascular death, and systemic embolism. Based on the provided information, the event assessment committee will investigate the endpoint-related events. The annual incidence and predictive factors for primary/secondary endpoint will be investigated based on underlying disease, age, renal function, and CHADS2, CHA2DS2-VASC, and HAS-BLED scores using Cox regression. We will also compare the incidence of the primary/secondary endpoint between the present study, EXPAND study, and FUSHIMI AF registry study. RESULTS: The results of this study are currently under investigation. CONCLUSION: This study will provide important information regarding the effectiveness and safety of rivaroxaban treatment in Japanese patients with NVAF among general practitioners.

Rationale and design of ASSAF-K (A study of the safety and efficacy of anticoagulant therapy in the treatment of atrial fibrillation in Kanagawa).

BACKGROUND: Atrial fibrillation (AF) is one of the most prevalent cardiac arrhythmias associated with substantially increased risks of ischemic stroke and thromboembolism. Oral anticoagulants (OACs) are the cornerstone of AF management and effectively prevent AF-related stroke. As new non-vitamin K antagonist OACs (NOACs) have become available, the landscape of stroke prevention in AF has changed. However, there are considerable gaps between daily clinical practice and current guideline-based recommendations for anticoagulant therapy in Japan. Consequently, little is known about the real-world setting and the current use of NOACs, especially by practitioners in Japan. METHODS: We conducted a prospective, observational study in 3847 patients with AF who were enrolled in clinics and hospitals located in Kanagawa Prefecture from September 2013 through March 2015. The participating centers included practitioners (small clinics), medium-sized hospitals, and university hospitals. The primary endpoints were epidemiologic characteristics, status of treatment with anticoagulants and antiplatelet agents, outcomes, and adverse events, including cerebrovascular disease, bleeding, and death. RESULTS: The mean CHADS2 score was 1.81±1.27, the mean CHADS2-Vasc score was 3.02±1.58, and the mean HAS-BLED score was 2.23±1.06, respectively. The usage rate of warfarin was 44.2% overall, and the usage rate of NOACs was 33.5%. CONCLUSIONS: The results of the study are expected to serve as the basis for providing clinical practice guidance to healthcare institutions in Japan, with the ultimate goals of better characterizing the appropriate use of OACs and providing clinical decision support to physicians to facilitate the design of appropriate therapeutic strategies and the selection of anticoagulants for the management of AF.