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Abstract Background Despite the increasing global demand, few medical students aspire to become generalists. To address this shortage, we investigated medical students' impressions of generalists in Japan. Methods This cross‐sectional study used a web‐based questionnaire from a previous study. The participants chose the impression of a generalist from four categories based on the previous report: family physician, hospital family physician, hospitalist, and general internal medicine. Results Medical students' impressions were as follows: family physicians (32%), hospitalists (28%), general internal medicine staff (20%), and hospital family physicians (18%). Students considered reasonable working hours, research opportunities, a clinical clerkship in generalist medicine, and information from university faculty as essential for making career choices. Conclusions The study demonstrated that the number of Japanese medical students who considered generalists to be family physicians/hospital family physicians and the number of those who considered generalists to be hospitalists/general internal medicine were almost equal. To increase the number of medical students who consider and choose to become generalists, understanding their impressions of generalist practice and their needs regarding work settings in that role is crucial.

Abstract Background Postpartum mental health care is a public health priority requiring interprofessional and interorganizational collaboration. Primary care physicians (PCPs) have the potential to play an essential role in facilitating access to health care and providing comprehensive and coordinated care for postpartum mental health problems. In Japan, however, there are no previous studies on the extent to which PCPs are involved in postpartum mental health care. Therefore, this study aimed to investigate the practices and experiences of Japanese PCPs in providing such care. Methods This study presents a subset of the findings from a cross‐sectional study using an online questionnaire on postpartum care among Japanese PCPs. We employed descriptive analysis to examine their practices and experiences in providing general and postpartum mental health care. Results We received 339 valid responses from 5811 PCPs. The median proportion of the outpatients with mental health problems that PCPs regularly saw was 15%. Approximately two out of three PCPs (68.7%) reported routinely performing screening for depression and anxiety. Seventy‐six percent of PCPs had the opportunity to provide care for postpartum women. Approximately one in two PCPs (47.8%) had managed cases of postpartum mental health problems and collaborated with various professionals and resources to provide care. Conclusions The majority of Japanese PCP participants in the study provide mental health care and have managed cases of postpartum mental health problems, collaborating with various health professionals.

Abstract Background Living in rural areas is a major contributor of health inequity. Tackling health inequity is important for primary care physicians. Therefore, it is important to compare the quality of primary care between rural and urban areas. To the best of our knowledge, this is the first study to examine the association between rurality and patient experience (PX) in Japan using validated measures. Methods This cross-sectional study was conducted using online surveys. Participants were selected using a stratified random sample based on sex and age. The Japanese version of the Person-Centered Primary Care Measure (PCPCM) was used as an indicator of PX. We used the Rurality Index for Japan (RIJ) to measure rurality. Furthermore, we used multivariate linear regression analysis to examine the relationship between the RIJ and PCPCM after adjusting for confounders. Results Of the 1112 eligible participants, 800 responded to the survey (response rate:71.9%). The mean PCPCM scores were 2.46 (standard deviation: 0.73) and median RIJ was 15 (interquartile range: 6–33). The crude and adjusted coefficients of rurality were − 0.02 (− 0.006–0.001, p = 0.114) and − 0.02 (− 0.005–0.001), respectively, demonstrating that rurality was not significantly associated with the total PCPCM score. Subgroup analyses were similar to the main analyses. Conclusion We found that PX in primary care did not differ by rurality in the general Japanese population.

Abstract Background Scope of practice (SoP) is an important factor for primary care physicians (PCPs). One of the strong determinants of SoP is rurality. Although Japan has several rural areas, the SoP in rural areas and the effect of rurality on SoP have not been investigated. This study aimed to describe SoP in Japanese primary care settings and examine the association between rurality and SoP. Methods This cross-sectional study included PCPs in Japan. The participants were randomly sampled from the mailing list of the Japan Primary Care Association. The Scope of Practice Inventory (SPI) and Scope of Practice for Primary Care (SP4PC) were used as indicators of SoP. The Rurality Index for Japan (RIJ) was used for rurality. This study compared the number of items of SPI (total score, inpatient care, urgent care and ambulatory care) and SP4PC experienced by > 80% of all PCPs in the most urban (RIJ:1–10) and rural areas (RIJ: 91–100). A multivariable linear regression analysis was also performed to examine the relationship between the RIJ and SPI/SP4PC. Results Of 1,000 potential participants, 299 physicians responded to the survey (response rate: 29.9%). PCPs in the most rural areas experienced a greater number of items in the inpatientl/urgent care domains of the SPI and SP4PC than those in the most urban areas. The RIJ was the only common factor for a broader SoP in both the SPI and SP4C models. The coefficients of SoP were 0.09 (95% confidence interval: 0.03–0.16) in the SPI model and 0.017 (0.005–0.03) in the SP4PC model. Conclusion Rurality was considerably associated with SoP. The findings of this study will be helpful in understanding the SoP on rural and urban areas.

Abstract Background Preconception care is not widespread in Japan and there is a pressing need to improve the practice. The present study assessed the knowledge and behavior of preconception care among women to seek effective intervention. Our research questions were: 1) How much do women know about preconception care? 2) How much are they practicing preconception care and what are the information sources of their behavior? 3) Do the women's preconception care behavior associated with accurate knowledge? Methods The research was conducted in a rural town in central Japan. Using an exploratory sequential mixed methods design, we undertook interviews, developed a survey based on the qualitative results, and then conducted a survey. The interviews explored how preconception care was perceived and practiced in women of childbearing age. The survey was designed to investigate the knowledge of preconception care among women with and without pregnancy experience, their practice behavior of preconception care, and whether the behavior is associated with knowledge. Results The participants were 13 for the interview and 232 for the survey. They had limited access to preconception care recommendations and advice for specific actions was given by obstetricians and gynecologists after pregnancy. There was a large gap in knowledge about preconception care between parous and nulliparous women, especially about the need for folic acid supplementation. Practices that were manageable in their daily lives, such as cessation of smoking and alcohol, diet, and weight management, were considered common sense. In contrast, recommended practices that require medical attention, such as screening for sexually transmitted diseases and cervical cancer, tended to be less accurately known and practiced. Participants' sources of information about preconception care were the Internet, family and friends and mass media. Conclusion In rural Japan, women of childbearing age lack knowledge about preconception care, especially before their first pregnancy. Primary care providers should try outreach to schools and women’s groups in the community, promote information sharing among family and close friends, and utilize information technology to enhance the knowledge and practice of preconception care.

Abstract Background Guidelines worldwide recommend that physicians should not treat their family members. However, studies in the U.S. have shown that approximately 74–83% of physicians have experience of treating family members. Primary care physicians were more likely to have such experiences than other specialists. In Japan, physicians do not have any guidelines regarding treating family members, and little is known about the experiences of primary care physicians. Therefore, we investigated the experience of treating family members or relatives among primary care physicians in Japan. Methods This cross-sectional study used an online questionnaire. We recruited 2,000 physicians who were members of the Japan Primary Care Association using random sampling. Data were collected from February 10 to March 10, 2021. We compare the experiences of treating family members between clinic-based doctors and hospital-based doctors using the chi-square test. We performed logistic regression analysis to adjust for gender, age, presence of a doctor in family, and physician’s geographic location (rural or not rural). Results A total of 466 physicians (response rate = 23.3%) completed the survey. Of the sample, 79.8% had experience of treating family members or relatives. In the univariate analysis, being a clinic-based physician was associated with experience in treating family members compared to hospital-based physicians (87.6% vs. 74.9%, p = 0.001). Multivariable analysis showed that being a clinic-based physician (odds ratio 2.30, 95% confidence interval 1.31–4.04) and age of 45–64 years (odds ratio 2.93, 95% confidence interval 1.74–4.93) were significantly related to experience treating family. Gender and geographic location were not statistically significant factors. Conclusions A high percentage of Japanese primary care physicians, especially those who worked in clinics, reported experience treating family members or relatives. These findings will serve as basic data for future studies regarding the care of families and relatives of physicians in Japan.

Abstract Background Many women face a variety of barriers to seeing obstetricians and gynecologists (OB/GYNs). Primary care physicians (PCPs) in Japan are not well equipped to address and adequately handle women’s health issues. Hence, opportunities for women to consult PCPs about women’s health issues are often limited during busy outpatient encounters. It is essential to explore PCP’s roles in women’s health care by examining women’s health needs in a primary care setting. The aim of the study is to describe the prevalence and distribution of women’s health issues and help-seeking intentions among women visiting a primary care clinic. Methods This was a cross-sectional study using a questionnaire. We included women aged 20–60 years who visited a primary care clinic for any reason. The questionnaire comprised a list of women’s health issues, the General Help Seeking Questionnaire to assess help-seeking intentions, and participants’ demographics including their reasons for visiting and regularity of OB/GYN visits. Results We distributed the questionnaire to 294 women and analyzed 260 valid responses. The average age of the respondents was 40.5 years old, and they had an average of 5.2 clinic visits a year. Approximately half of them (50.4%) visited for their own care. One hundred thirty-nine (53.9%) reported at least one women’s health issue, and 73.9% of them had no regular visit to an OB/GYN. The major concerns of women’s health issues included gynecological cancer screenings and menstrual problems. The distribution of help-seeking intentions for each source of care appeared to be classified into three patterns. One fifth of the women indicated high help-seeking intentions for PCPs, and a greater number of women expressed higher help-seeking intentions for PCPs when they did not regularly see an OB/GYN. Conclusions A significant number of women who visited a primary care clinic had a specific concern about women’s health issues, and a majority of them had not regularly visited their OB/GYN. PCPs may have an important role in providing an opportunity for women to discuss their concerns about women’s health issues as part of comprehensive care during a daily clinical encounter.

Objectives Diagnostic delay in cancer is a challenge in primary care. Although screening tests are effective in diagnosing some cancers such as breast, colorectal and cervical cancers, symptom-based cancer diagnosis is often difficult due to its low incidence in primary care and the influence of patient anxiety, doctor–patient relationship and psychosocial context. A general practitioner’s gut feeling for cancer may play a role in the early diagnosis of cancer in primary care where diagnostic resources are limited. The aim of this study is to summarise existing evidence about the test accuracy of gut feeling (index test) in symptomatic adult patients presenting to general practice, compared with multidisciplinary team-confirmed diagnosis of cancer (reference standard).Design Diagnostic accuracy review following Cochrane methods was performed.Data sources MEDLINE, EMBASE, Cochrane Library, the Database of Abstracts of Reviews of Effects and Medion databases.Eligibility criteria Cross-sectional, cohort and randomised studies of test accuracy that compared gut feeling (index test) with an appropriate cancer diagnosis (reference standard). No language or publication status restrictions were applied. We included all studies published before 25 March 2022.Data extraction and synthesis Methodological quality was appraised, using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria. Meta-analysis with hierarchical summary receiver operating characteristic (HSROC) models was used.Results Of 1286 potentially relevant studies identified, six met the inclusion criteria. For two of the six studies, data could not be extracted despite contacting authors. No studies satisfied all QUADAS-2 criteria. After meta-analysis of data from the remaining studies, the summary point of HSROC had a sensitivity of 0.40 (95% CI: 0.28, 0.53) and a specificity of 0.85 (95% CI: 0.75, 0.92).Conclusions Gut feeling for cancer when used in symptomatic adult patients in general practice has a relatively low sensitivity and high specificity. When the prevalence of cancer in the symptomatic population presenting in general practice exceeds 1.15%, the performance of gut feeling reaches the National Institute for Health and Care Excellence 3% positive predictive value threshold for action, which recommends urgent access to specialist care and further investigations. The findings support the continued and expanded use of gut feeling items in referral pathways.

Objectives Rural–urban healthcare disparities exist globally. Various countries have used a rurality index for evaluating the disparities. Although Japan has many remote islands and rural areas, no rurality index exists. This study aimed to develop and validate a Rurality Index for Japan (RIJ) for healthcare research.Design We employed a modified Delphi method to determine the factors of the RIJ and assessed the validity. The study developed an Expert Panel including healthcare professionals and a patient who had expertise in rural healthcare.Setting The panel members were recruited from across Japan including remote islands, mountain areas and heavy snow areas. The panel recruited survey participants whom the panel considered to have expertise.Participants The initial survey recruited 100 people, including rural healthcare providers, local government staff and residents.Primary outcome measures Factors to include in the RIJ were identified by the Expert Panel and survey participants. We also conducted an exploratory factor analysis on the selected factors to determine the factor structure. Convergent validity was examined by calculating the correlation between the index for physician distribution and the RIJ. Criterion-related validity was assessed by calculating the correlation with average life expectancy.Results The response rate of the final survey round was 84.8%. From the Delphi surveys, four factors were selected for the RIJ: population density, direct distance to the nearest hospital, remote islands and whether weather influences access to the nearest hospital. We employed the factor loadings as the weight of each factor. The average RIJ of every zip code was 50.5. The correlation coefficient with the index for physician distribution was −0.45 (p

ObjectiveDespite extensive vaccination campaigns to combat the coronavirus disease (COVID-19) pandemic, variants of concern, particularly the Omicron variant (B.1.1.529 or BA.1), may escape the antibodies elicited by vaccination against SARS-CoV-2. Therefore, this study aimed to evaluate 50% neutralizing activity (NT50) against SARS-CoV-2 D614G, Delta, Omicron BA.1, and Omicron BA.2 and to develop prediction models to predict the risk of infection in a general population in Japan.MethodsWe used a random 10% of samples from 1,277 participants in a population-based cross-sectional survey conducted in January and February 2022 in Yokohama City, the most populous municipality in Japan. We measured NT50 against D614G as a reference and three variants (Delta, Omicron BA.1, and BA.2) and immunoglobulin G against SARS-CoV-2 spike protein (SP-IgG).ResultsAmong 123 participants aged 20–74, 93% had received two doses of SARS-CoV-2 vaccine. The geometric means (95% confidence intervals) of NT50 were 65.5 (51.8–82.8) for D614G, 34.3 (27.1–43.4) for Delta, 14.9 (12.2–18.0) for Omicron BA.1, and 12.9 (11.3–14.7) for Omicron BA.2. The prediction model with SP-IgG titers for Omicron BA.1 performed better than the model for Omicron BA.2 (bias-corrected R2 with bootstrapping: 0.721 vs. 0.588). The models also performed better for BA.1 than for BA.2 (R2 = 0.850 vs. 0.150) in a validation study with 20 independent samples.ConclusionIn a general Japanese population with 93% of the population vaccinated with two doses of SARS-CoV-2 vaccine, neutralizing activity against Omicron BA.1 and BA.2 were substantially lower than those against D614G or the Delta variant. The prediction models for Omicron BA.1 and BA.2 showed moderate predictive ability and the model for BA.1 performed well in validation data.

Vaccine rollouts have been underway to combat the COVID-19 pandemic globally. Based on ongoing interviews with ten primary care physicians ‘in the field’, this paper elucidates how in practice the vaccinations were carried out in Japan in 2021 from a cultural anthropological perspective. We examine what the primary care physicians did to prepare for the rollouts, what problems they faced, and how they responded to these problems. Large-scale vaccination projects are supposed to proceed smoothly and quickly, or to have what Anna Tsing calls ‘scalability’. In practice, however, they required a variety of tasks for coordination, information sharing, and promotion. Despite feeling stressed by the lack of information and exhausted by the work overload, the primary care physicians carried out the vaccinations as an important service to their patients and communities. The findings of this paper will provide valuable materials for improving future vaccine rollouts.

BackgroundDespite the broad global use of antibiotics, there is no established definition of early antibiotic treatment failure (EATF) to aid clinical evaluation of treatment, which leads to inconsistent assessments of drug effectiveness.AimThis scoping review aims to identify common components of EATF definitions by synthesizing studies mentioning EATF and its relevant thesaurus matches.DesignScoping review.MethodsThis scoping review was conducted following the PRISMA Scoping review guidelines. A systematic literature search was conducted using MEDLINE (PubMed), CENTRAL, CINAHL, and Web of Science, as well as a manual Google search. Search terms were EATF and its thesaurus matches. After removing duplications, candidate studies were screened by title and abstract prior to full text searches, and quality analysis was performed on eligible studies using the Critical Appraisal Skills Programme. From each eligible study, the timing of evaluation, basic components, and detailed information for each definition of EATF were collected. The components of each definition for EATF were then summarized and counted, and finally the most common essential components were identified.ResultsOur systematic literature search found 2,472 candidate studies. After title and abstract screening, full text search and quality assessment, 61 studies, including 56 original studies and five reviews, were eligible for our analysis. Of these 56 original studies, 43 mentioned the timing of EATF evaluation 72 hours after the start of treatment with antibiotics. From these 43 studies, the most common indicators of EATF were extracted, among which a set of essential components for a definition of EATF were identified: mortality, vital signs, fever, symptoms, and additional treatment.ConclusionsOur scoping review uncovered five essential factors for EATF. Further study is needed to evaluate the validity of our findings.

Abstract Background Within the vague system of primary care and COVID‐19 infection control in Japan, we explored how primary care (PC) physicians exhibited adaptive performance in their institutions and communities to cope with the COVID‐19 pandemic from January to May 2020. Methods Narrative analysis conducted by a team of medical professionals and anthropologists. We purposefully selected 10 PC physicians in community‐based hospitals and clinics and conducted a total of 17 individual and group interviews. The verbatim transcript data were analyzed using the conceptual framework of adaptive performance. Results We identified three “phases” of the time period (January–May 2020). In Phase 1, PC physicians initially perceived the disease as a problem unrelated to them. In Phase 2, the Diamond Princess outbreak triggered adaptive performance of the physicians, who began to deal with medical issues related to COVID‐19 by using social networking services and applying the collected information to their organization and/or communities. Following this, in Phase 3, the PC physicians’ adaptive performance in their own communities and institutions emerged in the face of the pandemic. Reflecting their sensitivity to local context, the PC physicians were seen to exhibit adaptive performance through dealing with context‐dependent problems and relationships. Conclusions PC physicians exhibited adaptive performance in the course of coping with the realities of COVID‐19 in shifting phases and in differing localities in the early stages of the pandemic. The trajectories of adaptive performance in later stages of the pandemic remain to be seen.

Objectives SARS-CoV-2 infection (COVID-19) has affected tertiary medical institutions and primary care. Admission for ambulatory care sensitive conditions (ACSCs) is an important indicator of primary care quality. However, no nationwide study, especially in Asia, has examined the association between admissions for ACSCs and local surges in COVID-19. This study aimed to examine how the number of admissions for ACSCs has changed in Japan between the areas with higher and lower rates of COVID-19 infection.Design This was a retrospective two-stage cross-sectional study. We employed a difference-in-difference design to compare the number of hospital admissions for ACSCs between the areas with higher and lower rates of COVID-19 infection in Japan.Setting The study used a nationwide database in Japan.Participants All patients were aged 20 years and above and were admitted due to ACSCs during the study period between March and September 2019 (before the pandemic) and between March and September 2020 (during the pandemic).Results The total number of ACSC admissions was 464 560 (276 530 in 2019 and 188 030 in 2020). The change in the number of admissions for ACSCs per 100 000 was not statistically significant between the areas with higher and lower rates of COVID-19 infection: 7.50 (95% CI −87.02 to 102.01). In addition, in acute, chronic and preventable ACSCs, the number of admissions per 100 000 individuals did not change significantly.Conclusion Although admissions for ACSCs decreased during the COVID-19 pandemic, there was no significant change between the areas with higher and lower rates of COVID-19 infection. This implies that the COVID-19 pandemic affected the areas with higher infection rates and the areas with lower rates.

This is a short communication to reflect on experiences at North American Primary Care Research Group (NAPCRG) conference from the perspective of Asian family physicians. They feel that NAPCRG can play an important role to level up the skills and talents in countries with less-established primary care research capacity and capability. NAPCRG should not be restricted to networking functions for only North America, Europe and Oceania but should include Asia, South America and Africa. These international academic networks will strengthen primary care research in the world.

Abstract Background The number of women with congenital heart disease (CHD) who are of childbearing age is increasing due to advancements in medical management. Nonetheless, data on the outcomes of delivery in women with CHD remain limited. Therefore, we conducted a retrospective cohort study using a nationwide database of deliveries by women with CHD. Methods Deliveries by women with CHD discharged from acute-care hospitals between April 2017 and March 2018 were identified based on the Diagnosis Procedure Combination database which covers almost all acute-care hospitals in Japan. By using this database, we tried to include relatively high-risk deliveries by women with CHD. Subjects were divided into three groups according to the underlying disease complexity: simple, moderate, and great complexity. The clinical characteristics and incidence of peripartum cardiovascular events were compared among the three groups. Results A total of 249 deliveries from 107 hospitals were included. The largest facility had 29 deliveries per year. Given the uncertainty of underlying cardiac anomalies, 48 women were excluded, and the remaining 201 women (median age, 32 years) were analyzed. In-hospital maternal death, use of extracorporeal membrane oxygenation, intra-aortic balloon pump, pacemaker, and direct current cardioversion were not observed. Nine patients (4.5%) required intravenous diuretic administration. However, the difference in the frequency of diuretic use was not significant among the three groups (simple, 1.9%; moderate, 7.2%; great, 6.9%; P = 0.204). One participant required valve replacement surgery at 22 days after a successful cesarean section. As the disease complexity increased, deliveries occurred more frequently at university hospitals (simple, 41.7%; moderate, 52.2%; great, 72.4%; P = 0.013) and the length of hospitalization was significantly longer, with median durations of 9.0 (interquartile range [IQR] 7.0–11.0) days, 10.0 (IQR 8.0–24.0) days, and 11.0 (IQR 8.0–36.0) days in the simple, moderate, and great complexity groups, respectively (P = 0.002). Conclusions Appropriate patient selection and management by specialized tertiary institutions may contribute to positive outcomes in pregnancies in women with CHD.

Objectives Continuity of care is a core dimension of primary care, and better continuity is associated with better patient outcomes. Therefore, care fragmentation can be an indicator to assess the quality of primary care, especially in countries without formal gatekeeping system, such as Japan. Thus, this study aimed to describe care fragmentation among older adults in an ageing city in Japan.Design Cross-sectional study.Setting The most populated basic municipality in Japan.Participants Older adults aged 75 years and older.Interventions This study used a health claims database, including older adults who visited medical facilities at least four times a year in an urban city in Japan. The Fragmentation of Care Index (FCI) was used as an indicator of fragmentation. The FCI was developed from the Continuity of Care Index and is based on the total number of visits, different institutions visited and proportion of visits to each institution. We employed Tobit regression analysis to examine the association between the FCI and age, sex, type of insurance and most frequently visited facility.Results The total number of participants was 413 600. The median age of the study population was 81 years, and 41.6% were men. The study population visited an average of 3.42 clinics/hospitals, and the maximum number of visited institutions was 20. The proportion of patients with FCI >0 was 85.0%, with a mean of 0.583. Multivariable analysis showed that patients receiving public assistance had a lower FCI compared with patients not receiving public assistance, with a coefficient of 0.137.Conclusions To our knowledge, this is the first study to demonstrate care fragmentation in Japan. Over 80% of the participants visited two or more medical facilities, and their mean FCI was 0.583. The FCI could be a basic indicator for assessing the quality of primary care.

A patient in Japan with coronavirus disease and hypervirulent Klebsiella pneumoniae K2 sequence type 86 infection died of respiratory failure. Bacterial and fungal co-infections caused by region-endemic pathogens, including hypervirulent K. pneumoniae in eastern Asia, should be included in the differential diagnosis of coronavirus disease patients with acutely deteriorating condition.

Abstract Background Rural-urban health care disparities are an important topic in health services research. Hence, developing valid and reliable tools to measure rurality is needed to support high quality research. However, Japan, has no index to measure rurality for health care research. In this study, we conducted a systematic scoping review to identify the important factors and methodological approaches to consider in a rurality index to inform the development of a rurality index for Japan. Methods For our review, we searched six bibliographic databases (MEDLINE, PubMed, CINAHIL, ERIC, Web of Science and the Grey Literature Report) and official websites of national governments such as Government and Legislative Libraries Online Publications Portal (GALLOP), from 1 January 1989 to 31 December 2018. We extracted relevant variables used in the development of rurality indices, the formulas used to calculate indices, and any measures for reliability and validity of these indices. Results We identified 17 rurality indices from 7 countries. These indices were primarily developed to assess access to health care or to determine eligibility for incentives for health care providers. Frequently used factors in these indices included population size/density and travel distance/time to emergency care or referral centre. Many indices did not report reliability or validity measures. Conclusions While the concept of rurality and concerns about barriers to access to care for rural residents is shared by many countries, the operationalization of rurality is highly context-specific, with few universal measures or approaches to constructing a rurality index. The results will be helpful in the development of a rurality index in Japan and in other countries.

Abstract Active microfluidics for the applications to cellular deformability measurements is an emerging research field ranging from engineering to medicine. Here, we review conventional and microfluidic methods, and introduce an on-chip cell manipulation system with the design principle of fast and fine cell manipulation inside a microchannel. In the latter part of the review, we focus on the results of red blood cell (RBC) deformability measurements as one of the most frequently studied non-adherent cells by on-chip methods. The relationship between mechanical properties and biological structures/features, as well as medical/diagnostic applications, are also discussed.

Single-cell manipulation in microfluidic channels at the micrometer scale has recently become common. However, the current mainstream method using a syringe pump and a piezoelectric actuator is not suitable for long-term experiments. Some methods incorporate a pump mechanism into a microfluidic channel, but they are not suitable for mass production owing to their complex structures. Here, we propose a sidewall-driven micropump integrated into a microfluidic device as well as a method for reducing the pulsation of flow. This sidewall-driven micropump consists of small chambers lined up on both sides along the main flow path, with a wall separating the flow path and each chamber being deformed by air pressure. The chambers are pressurized to make the peristaltic motion of the wall possible, which generates flow in the main flow path. This pump can be created in a single layer, which allows a simplified structure to be achieved, although pulsation can occur when the pump is used alone. We created two types of chips with two micropumps placed in the flow path and attempted to reduce pulsation by driving them in different phases. The proposed dually driven micropump reduced pulsation when compared with the single pump. This device enables precise particle control and is expected to contribute to less costly and easier cell manipulation experiments.

Abstract Japan's health system is well known for achieving one of the world's highest life expectancy with universal health coverage. However, the country now faces challenges of a rapidly aging population and changes in patterns and burden of disease. Primary care is an important component of a well‐functioning health system. In Japan, primary care services are provided in both the community and hospital settings. The distinction between primary and secondary care may not always be clear. This review is based on the framework from the 2015 WHO publication on primary care systems in Europe. Our aim is to describe the journey of primary care in Japan, with its past, present, and future as a valuable addition to the academic English literature. We also hope that this article would inspire readers outside of Japan who might face similar issues in their respective countries.

Background: Expert generalist practice (EGP) is increasingly being viewed as the defining expertise of generalist care. In Japan, several prominent family doctors consider it important and relevant in the Japanese context. However, no study has examined Japanese family doctor educators’ perceptions of EGP. Aim: To explore Japanese family doctor educators’ perceptions of EGP. Design & setting: A qualitative study among family doctor educators in Japan. Method: Focus group interviews were conducted using a semi-structured interview guide following a short lecture on EGP. A qualitative description method was adopted and the framework method was used to conduct thematic analysis. Results: Participants were 18 family medicine doctor educators, including 11 directors and six associate directors of family medicine training programmes. The results suggested that the concept of EGP was important and applicable to primary care in Japan. Participants’ perceptions on EGP pertained to the following four areas: impact of EGP, triggers for EGP, enablers for EGP, and educational strategies for EGP. Conclusion: The concept of EGP may be useful in clinical practice in Japan, especially in complex patient care. A clearer framework for or description of EGP, and of non-traditional methods, such as ascetic practice and awareness of the self, were proposed as possible educational strategies.

Colorectal anastomotic leakage is one of the most feared and fatal complications of colorectal surgery. To date, no external coating material that can prevent anastomotic leakage has been developed. As myoblasts possess anti-inflammatory capacity and improve wound healing, we developed a multilayered human skeletal muscle myoblast (HSMM) sheet by periodic exposure to supraphysiological hydrostatic pressure during repeated cell seeding. We assessed whether the application of an HSMM sheet can promote the healing process after colonic anastomosis. Partial colectomy and insufficient suturing were employed to create a high-risk colo-colonic anastomosis model in 60 nude rats. Rats were divided into a control group ( n = 30) and an HSMM sheet group ( n = 30). Macroscopic findings, anastomotic bursting pressure, and histology at the colonic anastomotic site were evaluated on postoperative day (POD) 3, 5, 7, 14, and 28. The application of an HSMM sheet significantly suppressed abscess formation at the anastomotic site compared to the control group on POD3 and 5. The anastomotic bursting pressure in the HSMM sheet group was higher than that in the control group on POD3 and 5. Inflammatory cell infiltration in the HSMM sheet group was significantly suppressed compared to that in the control group throughout the time course. Collagen deposition in the HSMM sheet group on POD3 was significantly abundant compared to that in the control group. Regeneration of the mucosa at the colonic anastomotic site was promoted in the HSMM sheet group compared to that in the control group on POD14 and 28. Immunohistochemical analysis demonstrated that surviving cells in the HSMM sheet gradually decreased with postoperative time and none were detected on POD14. These results suggest that the application of a multilayered HSMM sheet may prevent postoperative colonic anastomotic leakage.

There is urgent demand for biologically compatible vascular grafts for both adult and pediatric patients. The utility of conventional nonbiodegradable materials is limited because of their thrombogenicity and inability to grow, while autologous vascular grafts involve considerable disadvantages, including the invasive procedures required to obtain these healthy vessels from patients and insufficient availability in patients with systemic atherosclerosis. All of these issues could be overcome by tissue-engineered vascular grafts (TEVGs). A large body of evidence has recently emerged in support of TEVG technologies, introducing diverse cell sources (e.g., somatic cells and stem cells) and novel fabrication methods (e.g., scaffold-guided and self-assembled approaches). Before TEVG can be applied in a clinical setting, however, several aspects of the technology must be improved, such as the feasibility of obtaining cells, their biocompatibility and mechanical properties, and the time needed for fabrication, while the safety of supplemented materials, the patency and nonthrombogenicity of TEVGs, their growth potential, and the long-term influence of implanted TEVGs in the body must be assessed. Although recent advances in TEVG fabrication have yielded promising results, more research is needed to achieve the most feasible methods for generating optimal TEVGs. This article reviews multiple aspects of TEVG fabrication, including mechanical requirements, extracellular matrix components, cell sources, and tissue engineering approaches. The potential of periodic hydrostatic pressurization in the production of scaffold-free TEVGs with optimal elasticity and stiffness is also discussed. In the future, the integration of multiple technologies is expected to enable improved TEVG performance.

Objectives Although frequent emergency department (ED) use is a global issue, little research has been conducted in a country like Japan where universal health insurance is available. The study aims to (1) document the proportion of ED visits that are by frequent users and (2) describe the differences in characteristics of frequent ED users and other ED users including expenditures between a secondary and a tertiary hospital.Design A prevalence study for a period of 1 year.Setting A secondary hospital and a tertiary hospital in central Japan.Participants All patients who presented to the EDs.Primary outcome measures We defined frequent ED user as a patient who visited the ED≥5 times/year. The main outcome measures were the proportion of frequent ED users among all ED users and the proportion of healthcare expenditures by the frequent ED users among all ED expenditures.Results Of 25 231 ED visits over 1 year, 134 frequent ED users accounted for 1043 visits—0.66% of all ED users, comprised 4.1% of all ED visits, and accounted for 1.9% of total healthcare expenditures. Median ED visits per one frequent ED user was 7.9. At the patient level, after adjusting for age, gender and receiving public assistance, older age (OR 1.01, 95% CI: 1.00 to 1.02) and receiving public assistance (OR 7.19, 95% CI 2.87 to 18.07) had an association with frequent ED visits. At the visit-level analysis, evaluation by internal medicine (OR 1.27, 95% CI 1.02 to 1.57), psychiatry (OR 124.69, 95% CI 85.89 to 181.01) and obstetrics/gynaecology (OR 2.77, 95% CI 2.09 to 3.67) were associated with frequent ED visits.Conclusion The proportion of frequent ED users, of total visits, and of expenditures attributable to them—while still in the low end of the distribution of published ranges—are lower in this study from Japan than in reports from many other countries.

This paper discusses the modeling and analysis of a high-speed adjustable grasping robot controlled by a pneumatic actuator. The robot is composed of two grippers, two wires for connecting a pneumatic cylinder and an arm with gripper joints with a spring as well as two stoppers for controlling the gripper stopping point with a brake. By supplying pressurized air into the pneumatic cylinder, the two grippers move forward together with the arm and capture the object by adjusting the air pressure in the cylinder. After capturing the target object, the system can release the object by changing the pressure air in the air cylinder using another port. By considering the state equation of the air, we obtain a dynamic model of the robot, including the actuator. Through numerical simulation, we show that the simulation results can explain the experimental results from the developed robot system. Through our experiments, we confirm that the developed high-speed grasping robot can grasp continuously moving objects with a gap of ±15 mm at 300 mm/s.

Abstract Background Maintaining a maternity care system is one of the biggest issues in Japan due to the decreasing number of obstetricians, especially in remote areas and islands. The aim of this qualitative study was to explore the challenges in women’s health and maternity care in remote areas and islands for primary care physicians and obstetricians in order to provide an insight necessary to develop a better health care system. Methods We conducted semi-structured interviews with 13 primary care physicians and 4 obstetricians practicing maternity care at clinics/hospitals in remote areas and islands across Japan. Interview data were analyzed, using the modified Grounded Theory Approach, to elucidate the challenges primary care physicians faced in their practice. Results Primary care physicians who engaged in maternity care recognized the following challenges: low awareness of primary care, lack of training opportunities, unclear goal of the training, lack of certification system, lack of consultation system, and lack of obstetricians to offer support. These six challenges along with the specialty’s factors such as sudden changes of patients’ condition were considered to result to the provider’s hesitation and anxiety to engage in the practice. Conclusions This study found six environmental/systemic factors and three specialty’s factors as the main challenges for primary care physicians in providing maternity care in remote areas and islands for primary care physicians in Japan. Increasing the awareness of primary care and developing a maternity care training program to certify primary care physicians may enable more primary care physicians to engage in and provide women’s health and maternity care in remote areas and islands.

Abstract Background The Japanese health care system has yet to establish structured training for primary care physicians; therefore, physicians who received an internal medicine based training program continue to play a principal role in the primary care setting. To promote the development of a more efficient primary health care system, the assessment of its current status in regard to the spectrum of patients’ reasons for encounters (RFEs) and health problems is an important step. Recognizing the proportions of patients’ RFEs and health problems, which are not generally covered by an internist, can provide valuable information to promote the development of a primary care physician-centered system. Methods We conducted a systematic review in which we searched six databases (PubMed, the Cochrane Library, Google Scholar, Ichushi-Web, JDreamIII and CiNii) for observational studies in Japan coded by International Classification of Health Problems in Primary Care (ICHPPC) and International Classification of Primary Care (ICPC) up to March 2015. We employed population density as index of accessibility. We calculated Spearman’s rank correlation coefficient to examine the correlation between the proportion of “non-internal medicine-related” RFEs and health problems in each study area in consideration of the population density. Results We found 17 studies with diverse designs and settings. Among these studies, “non-internal medicine-related” RFEs, which was not thought to be covered by internists, ranged from about 4% to 40%. In addition, “non-internal medicine-related” health problems ranged from about 10% to 40%. However, no significant correlation was found between population density and the proportion of “non-internal medicine-related” RFEs and health problems. Conclusions This is the first systematic review on RFEs and health problems coded by ICHPPC and ICPC undertaken to reveal the diversity of health problems in Japanese primary care. These results suggest that primary care physicians in some rural areas of Japan need to be able to deal with “non-internal-medicine-related” RFEs and health problems, and that curriculum including practical non-internal medicine-related training is likely to be important.

Abstract Background Daptomycin has been reported to cause artificial prolongation of prothrombin time (PT) by interacting with some test reagents of PT. This prolongation was particularly prominent with high concentrations of daptomycin in vitro. However, whether this prolongation is important in clinical settings and the optimal timing to assess PT remain unclear. Methods A prospective clinical study was conducted with patients who received daptomycin for confirmed or suspected drug-resistant, gram-positive bacterial infection at a university hospital in Japan. PT at the peak and trough of daptomycin was tested using nine PT reagents. Linear regression analyses were used to examine the difference in daptomycin concentration and the relative change of PT-international normalized ratios (PT-INR). Results Thirty-five patients received daptomycin (6 mg/kg). The mean ± standard deviation of the trough and peak concentrations of daptomycin were 13.5 ± 6.3 and 55.1 ± 16.9 μg/mL, respectively. Twelve patients (34%) received warfarin. With five PT reagents, a significant proportion of participants experienced prolongation of PT-INR at the daptomycin peak concentration compared to the PT-INR at the trough, although the mean relative change was less than 10%. None of the participants clinically showed any signs of bleeding. A linear, dose-dependent prolongation of PT was observed for one reagent [unadjusted coefficient β 3.1 × 10−3/μg/mL; 95% confidence interval (CI) 2.3 × 10−5–6.3 × 10−3; p = 0.048]. When patients were stratified based on warfarin use, this significant linear relationship was observed in warfarin users for two PT reagents (adjusted coefficient β, 6.4 × 10−3/μg/mL; 95% CI 3.5 × 10−3–9.3 × 10−3; p

Abstract Shortage of autologous blood vessel sources and disadvantages of synthetic grafts have increased interest in the development of tissue-engineered vascular grafts. However, tunica media, which comprises layered elastic laminae, largely determines arterial elasticity, and is difficult to synthesize. Here, we describe a method for fabrication of arterial grafts with elastic layer structure from cultured human vascular SMCs by periodic exposure to extremely high hydrostatic pressure (HP) during repeated cell seeding. Repeated slow cycles (0.002 Hz) between 110 and 180 kPa increased stress-fiber polymerization and fibronectin fibrillogenesis on SMCs, which is required for elastic fiber formation. To fabricate arterial grafts, seeding of rat vascular SMCs and exposure to the periodic HP were repeated alternatively ten times. The obtained medial grafts were highly elastic and tensile rupture strength was 1451 ± 159 mmHg, in which elastic fibers were abundantly formed. The patch medial grafts were sutured at the rat aorta and found to be completely patent and endothelialized after 2.5 months, although tubular medial constructs implanted in rats as interpositional aortic grafts withstood arterial blood pressure only in early acute phase. This novel organized self-assembly method would enable mass production of scaffold-free arterial grafts in vitro and have potential therapeutic applications for cardiovascular diseases.

Cycle-to-cycle variation (CCV) of in-cylinder flow occurs in internal combustion engines. It is necessary to analyze CCV of flow to separate averaged-flow (as low frequency / low wave number) from turbulence (as high frequency / high wave number), because an averaged flow varies from cycle to cycle. Two averaging methods are used for the extraction of mean component from instantaneous flow. One is temporal-averaging method, the other is spatial-averaging method. In the temporal -averaging method, a fluctuation of flow is captured at fixed point in Eulerian, turbulence is regarded as the high frequency component, and it is removed by a low pass filtering. In the spatial-averaging method, the turbulence in spatial arrangement of flow velocity is directly averaged by using vortex scale as a threshold (e.g. Moving-averaging filter and Gaussian-averaging filter). However, the temporal-averaging and the spatial-averaging have completely different characteristics. Therefore, it is necessary to clarify the difference of filtering characteristics in each averaging filter. In this study, comparisons of averaged flow patterns of temporal-average and spatial-average are carried out. Moreover, variable sized spatial filter which is based on Taylor's frozen-turbulence hypothesis is proposed. As a result, variable sized filtering is found close to the filter characteristic of the time average method.

In this paper, we propose an on-chip micromixer driven by an elastic wall with a virtual actuator. The on-chip micro mixer is composed of a circular chamber surrounded by a ring-shaped channel under isolation with an elastic wall. When vibrational pressure is put on the driving channel by an actuator, the volume of the circular chamber changes through the deformation of the elastic wall, as if there exists a virtual actuator near the wall. As a result, the liquid in the circular chamber is pushed out and pulled through the neck channel. This action creates a swirling flow in the circular chamber while maintaining isolation from the driving channel. Through experiments, we confirmed the swirling flow under an isolated environment using an air-based valve. The advantage of this approach is that the micromixer can be designed with a single layer having a simple mechanism.

In this paper, a high-speed on-chip mixer using two effects is proposed, i.e., push/pull inequality and wettability. Push/pull inequality and wettability are effective for generating a rotational fluid motion in the chamber and for enhancing the rotational speed by reducing the viscous loss between the liquid and channel wall, respectively. An on-chip mixer is composed of three components, a microfluidic channel for making the main fluid flow, a circular chamber connected to the channel for generating a rotational flow, and an actuator connected at the end of the channel allowing a push/pull motion to be applied to the liquid in the main channel. The flow patterns in the chamber under push/pull motions are nonreversible for each motion and, as a result, produce one-directional torque to the fluid in the circular chamber. This nonreversible motion is called push/pull inequality and eventually creates a swirling flow in the chamber. Using hydrophilic treatments, we executed the experiment with a straight channel and a circular chamber to clarify the mixing characteristics at different flow speeds. According to the results, it is confirmed that the swirling velocity under appropriately tuned wettability is 100 times faster than that without tuning.

We propose a method to characterize the mechanical properties of cells using a robot-integrated microfluidic chip (robochip) and microscopy. The microfluidic chip is designed to apply the specified deformations to a single detached cell using an on-chip actuator probe. The reaction force is simultaneously measured using an on-chip force sensor composed of a hollow folded beam and probe structure. In order to measure the cellular characteristics in further detail, a sub-pixel level of resolution of probe position is required. Therefore, we utilize the phase detection of moiré fringe. Using this method, the experimental resolution of the probe position reaches 42 nm. This is approximately ten times smaller than the optical wavelength, which is the limit of sharp imaging with a microscope. Calibration of the force sensor is also important in accurately measuring cellular reaction forces. We calibrated the spring constant from the frequency response, by the proposed sensing method of the probe position. As a representative of mechanical characteristics, we measured the elastic modulus of Madin-Darby Cannie Kidney (MDCK) cells. In spite of the rigid spring constant, the resolution and sensitivity were twice that achieved in our previous study. Unique cellular characteristics can be elucidated by the improvements in sensing resolution and accuracy.

The dispersion of cell deformability mapping is affected not only by the resolution of the sensing system, but also by cell deformability itself. In order to extract the pure deformability characteristics of cells, it is necessary to improve the resolution of cell actuation in the sensing system, particularly in the case of active sensing, where an actuator is essential. This paper proposes a novel concept, a “flow reduction mechanism”, where a flow is generated by a macroactuator placed outside of a microfluidic chip. The flow can be drastically reduced at the cell manipulation point in a microchannel due to the elasticity embedded into the fluid circuit of the microfluidic system. The great advantage of this approach is that we can easily construct a high resolution cell manipulation system by combining a macro-scale actuator and a macro-scale position sensor, even though the resolution of the actuator is larger than the desired resolution for cell manipulation. Focusing on this characteristic, we successfully achieved the cell positioning based on a visual feedback control with a resolution of 240 nm, corresponding to one pixel of the vision system. We show that the utilization of this positioning system contributes to reducing the dispersion coming from the positioning resolution in the cell deformability mapping.

The deformability of a red blood cell (RBC) is one of the most important biological parameters affecting blood flow, both in large arteries and in the microcirculation, and hence it can be used to quantify the cell state. Despite numerous studies on the mechanical properties of RBCs, including cell rigidity, much is still unknown about the relationship between deformability and the configuration of flowing cells, especially in a confined rectangular channel. Recent computer simulation techniques have successfully been used to investigate the detailed behavior of RBCs in a channel, but the dynamics of a translating RBC in a narrow rectangular microchannel have not yet been fully understood. In this study, we numerically investigated the behavior of RBCs flowing at different velocities in a narrow rectangular microchannel that mimicked a microfluidic device. The problem is characterized by the capillary number C a , which is the ratio between the fluid viscous force and the membrane elastic force. We found that confined RBCs in a narrow rectangular microchannel maintained a nearly unchanged biconcave shape at low C a , then assumed an asymmetrical slipper shape at moderate C a , and finally attained a symmetrical parachute shape at high C a . Once a RBC deformed into one of these shapes, it was maintained as the final stable configurations. Since the slipper shape was only found at moderate C a , measuring configurations of flowing cells will be helpful to quantify the cell state.

This paper proposes a microfluidic device which can perform simultaneous observation on cell growth with and without applying periodic hydrostatic pressure (Yokoyama et al. Sci. Rep. 2017, 7, 427). The device is called on-chip cell incubator. It is known that culture with periodic hydrostatic pressure benefits the elasticity of a cultured cell sheet based on the results in previous studies, but how the cells respond to such a stimulus during the culture is not yet clear. In this work, we focused on cell behavior under periodic hydrostatic pressure from the moment of cell seeding. The key advantage of the proposed device is that we can compare the results with and without periodic hydrostatic pressure while all other conditions were kept the same. According to the results, we found that cell sizes under periodic hydrostatic pressure increase faster than those under atmospheric pressure, and furthermore, a frequency-dependent fluctuation of cell size was found using Fourier analysis.

In cell culture, the pH of the culture medium is one of the most important conditions. However, the culture medium may have non-uniform pH distribution due to activities of cells and changes in the environment. Although it is possible to measure the pH distribution with an existing pH meter using distributed electrodes, the method involves direct contact with the medium and would greatly increase the risk of contamination. Here in this paper, we propose a computed tomography (CT) scan for measuring pH distribution using the color change of phenol red with a light-emitting diode (LED) light source. Using the principle of CT scan, we can measure pH distribution without contacting culture medium, and thus, decrease the risk of contamination. We have developed the device with a LED, an array of photo receivers and a rotation mechanism. The system is firstly calibrated with different shapes of wooden objects that do not pass light, we succeeded in obtaining their 3D topographies. The system was also used for measuring a culture medium with two different pH values, it was possible to obtain a pH distribution that clearly shows the boundary.

To achieve fast and accurate cell manipulation in a microfluidic channel, it is essential to know the true nature of its input-output relationship. This paper aims to reveal the transfer function of such a micro manipulation controlled by a macro actuator. Both a theoretical model and experimental results for the manipulation are presented. A second-order transfer function is derived based on the proposed model, where the polydimethylsiloxane (PDMS) deformation plays an important role in the manipulation. Experiments are conducted with input frequencies up to 300 Hz. An interesting observation from the experimental results is that the frequency responses of the transfer function behave just like a first-order integration operator in the system. The role of PDMS deformation for the transfer function is discussed based on the experimentally-determined parameters and the proposed model.

PURPOSE: To evaluate the displacement of the central ocular surface during non-contact tonometry with and without soft contact lenses and determine the factors associated with the displacement of the central ocular surface and intraocular pressure (IOP) reading changes caused by wearing soft contact lenses (CLs). METHODS: One eye each in 21 subjects was studied. The cornea was photographed using a high-speed camera at 5,000 frames/sec during non-contact tonometry without contact lenses (NCL), with -5.0 diopters (D), -0.5 D and +5.0 D CL. The displacement of the ocular surface and the factors affecting displacement at the IOP reading and maximum displacement time were investigated. RESULTS: The IOP readings while wearing +5 D CL were significantly higher than those obtained while wearing -5 D CL. The ocular surface displacement between +5 D CL and other groups were significantly different. A significant positive correlation was found between the ocular surface displacement of subjects at the IOP reading time and the IOP obtained with the non-contact tonometer. A significant negative correlation was found between the ocular surface curvature and the IOP obtained using the non-contact tonometer. The radius of curvature of the ocular surface affected the displacement during the IOP reading and maximum displacement time. CONCLUSIONS: Our results indicate that soft contact lens use changes the ocular surface behavior and IOP readings during non-contact tonometry. The radius of curvature of the eye affects the ocular surface displacement and IOP readings in this situation.

In this paper, we focus on the mechanical characterization of co-cultured spheroids of human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSC) (HUVEC/MSC spheroids). HUVEC/MSC spheroids aggregate during culture, thereby decreasing in size. Since this size decrease can be caused by the contractility generated by the actomyosin of MSCs, which are intracellular frames, we can expect that there is a temporal transition for the mechanical characteristics, such as stiffness, during culture. To measure the mechanical characteristics, we use a microfluidic chip that is integrated with force sensor probes. We show the details of the measurement configuration and the results of mechanical characterization of the HUVEC/MSC spheroids. To evaluate the stiffness of the spheroids, we introduce the stiffness index, which essentially shows a spring constant per unit size of the spheroid at a certain time during measurement. From the measurement results, we confirmed that the stiffness index firstly increased during the days of culture, although after four days of culture, the stiffness index decreased. We confirmed that the proposed system can measure the stiffness of HUVEC/MSC spheroids.

BACKGROUND: Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process. METHODS AND RESULTS: An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension. CONCLUSION: Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

An on-chip deformability checker is proposed to improve the velocity–deformation correlation for red blood cell (RBC) evaluation. RBC deformability has been found related to human diseases, and can be evaluated based on RBC velocity through a microfluidic constriction as in conventional approaches. The correlation between transit velocity and amount of deformation provides statistical information of RBC deformability. However, such correlations are usually only moderate, or even weak, in practical evaluations due to limited range of RBC deformation. To solve this issue, we implemented three constrictions of different width in the proposed checker, so that three different deformation regions can be applied to RBCs. By considering cell responses from the three regions as a whole, we practically extend the range of cell deformation in the evaluation, and could resolve the issue about the limited range of RBC deformation. RBCs from five volunteer subjects were tested using the proposed checker. The results show that the correlation between cell deformation and transit velocity is significantly improved by the proposed deformability checker. The absolute values of the correlation coefficients are increased from an average of 0.54 to 0.92. The effects of cell size, shape and orientation to the evaluation are discussed according to the experimental results. The proposed checker is expected to be useful for RBC evaluation in medical practices.

This paper proposes a gravity-based system capable of generating high-resolution pressure for precise cell manipulation or evaluation in a microfluidic channel. While the pressure resolution of conventional pumps for microfluidic applications is usually about hundreds of pascals as the resolution of their feedback sensors, precise cell manipulation at the pascal level cannot be done. The proposed system successfully achieves a resolution of 100 millipascals using water head pressure with an in-phase noise cancelation mechanism. The in-phase mechanism aims to suppress the noises from ambient vibrations to the system. The proposed pressure system is tested with a microfluidic platform for pressure validation. The experimental results show that the in-phase mechanism effectively reduces the pressure turbulence, and the pressure-driven cell movement matches the theoretical simulations. Preliminary experiments on deformability evaluation with red blood cells under incremental pressures of one pascal are successfully performed. Different deformation patterns are observed from cell to cell under precise pressure control.

Preoperative examination for abdominal aortic aneurysms (AAAs) occasionally reveals an abnormal decrease in coagulation factors and thrombocytopenia, fulfilling the criteria for disseminated intravascular coagulation (DIC). Treatment of the underlying disorder is indispensable for alleviating DIC. We report an uncommon case of a patient with AAA and DIC who showed prolonged thrombocytopenia despite successful treatment of AAA and temporary recovery of coagulation factors. A 70-year-old man presented with AAA and shaggy aorta accompanied by DIC and underwent aneurysmectomy. Combined preoperative use of nafamostat mesilate and recombinant human soluble thrombomodulin was effective in controlling DIC. Although recovery of coagulation factors was observed after surgery, the thrombocytopenia continued throughout the postoperative course and was refractory to platelet transfusion. Because HPA antibody and PA-IgG were present, a trial administration of γ-globulin was performed; this resulted in rapid improvement of thrombocytopenia. Although DIC recurred again 2 weeks thereafter, coagulation factors subsequently recovered without any medication.

This study aims at examining various discourse functions of the Japanese averbal sentence formed by the sequence . Previous studies have characterized this construction in terms of three aspects : i) expression of a directly perceived event as forming a semantic unit with no distinction between subject and predicate ; ii) anchoring of the event in the moment of perception ; iii) introduction of a new utterance level. From this perspective, the Japanese averbal sentence has been compared with a type of averbal sentence in French, like “Le lavabo qui déborde !”. On the other hand, based on examples taken from newspapers, and former works about averbal sentences in other languages, this study claims that, besides the first type extensively discussed, other three types should be distinguished : i) one which expresses a situation as forming a semantic unit and introduces a displaced utterance level, but with no anchoring in the utterance moment. This type establishes various discourse relations, like Background, Elaboration, Contrast with surrounding sentences ; ii) one which introduces a new utterance level, but does not focus on any unitary event, but to make a prominent topic or a spatial or temporal frame of the referent of the noun phrase ; iii) one which shares no characteristics of the first type and is specialized in focusing on a discourse topic whose scope amounts to the whole text.