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Abstract Background The Great East Japan Earthquake and the subsequent Fukushima nuclear power plant accident in 2011 posed significant challenges to the educational sector, particularly affecting nursing students in the disaster area. However, to the best of our knowledge, there are no reports on the effects of the natural disaster coupled with the nuclear accident on the nursing students. Therefore, this study aimed to determine the impact of the Fukushima disasters on rate of academic failure events in nursing education. Methods A retrospective cohort approach was conducted, focusing on 677 students from Soma Nursing School admitted between 2001 and 2017. Four failure events—failure to pass the national examination, student retention, suspension, and withdrawal from school—were compared between three time periods: pre-disaster, early peri-disaster, and later peri-disaster. This analysis was followed by a questionnaire survey among the students and an interview with faculty members to gain further insights. Results Of the student cohort, 17% had at least one failure event. Students in the later peri-disaster phase faced an elevated failure rate at 29%. Variables such as being male, admission during later peri-disaster period, and local pre-admission residence played a significant role in these failure events in multivariate logistic regression analysis (adjusted odds ratio [95% confidence interval, p value]; 2.63 [1.49–4.64,

BackgroundPolicies, such as stay home, bubbling, and stay with your community, recommending that individuals reduce contact with diverse communities, including families and schools, have been introduced to mitigate the spread of the COVID-19 pandemic. However, these policies are violated if individuals from various communities gather, which is a latent risk in a real society where people move among various unreported communities. ObjectiveWe aimed to create a physical index to assess the possibility of contact between individuals from diverse communities, which serves as an indicator of the potential risk of SARS-CoV-2 spread when considered and combined with existing indices. MethodsMoving direction entropy (MDE), which quantifies the diversity of moving directions of individuals in each local region, is proposed as an index to evaluate a region’s risk of contact of individuals from diverse communities. MDE was computed for each inland municipality in Tokyo using mobility data collected from smartphones before and during the COVID-19 pandemic. To validate the hypothesis that the impact of intercommunity contact on infection expansion becomes larger for a virus with larger infectivity, we compared the correlations of the expansion of infectious diseases with indices, including MDE and the densities of supermarkets, restaurants, etc. In addition, we analyzed the temporal changes in MDE in municipalities. ResultsThis study had 4 important findings. First, the MDE values for local regions showed significant invariance between different periods according to the Spearman rank correlation coefficient (>0.9). Second, MDE was found to correlate with the rate of infection cases of COVID-19 among local populations in 53 inland regions (average of 0.76 during the period of expansion). The density of restaurants had a similar correlation with COVID-19. The correlation between MDE and the rate of infection was smaller for influenza than for COVID-19, and tended to be even smaller for sexually transmitted diseases (order of infectivity). These findings support the hypothesis. Third, the spread of COVID-19 was accelerated in regions with high-rank MDE values compared to those with high-rank restaurant densities during and after the period of the governmental declaration of emergency (P

IntroductionVaccination has been implemented as a useful measure to combat the COVID-19 pandemic. However, there is a tendency for individuals to avoid vaccination due to the possibility of adverse events, making it important to investigate the relationship between COVID-19 vaccines and their adverse events. This study explored longitudinal adverse event patterns and factors that influence adverse events following the second to fourth doses of the COVID-19 vaccine through a latent class analysis.MethodsParticipants were recruited from the Fukushima Prefecture and included individuals who had completed four doses of the COVID-19 mRNA vaccine. This study utilized data from questionnaire surveys and blood collection conducted between September 2021 and November 2022. In the questionnaire, factors such as sex, age, medical history, medication, type of vaccine administered, and adverse events following vaccination were recorded. Additionally, in the blood data, serological tests [IgG(S)] and cellular immune responses (T-spot) were measured. Descriptive statistics, latent class analysis, multivariable logistic regression, and multiple regression analyses were performed to identify the longitudinal adverse event patterns and influencing factors. By analyzing adverse events over time, we identified two distinct groups: those less prone to experiencing adverse events (Group 1) and those more susceptible (Group 2) to latent class analysis.ResultsA total of 1,175 participants were included after excluding those without any adverse events. The median age of the participants in Group 1 was 70 years, and in Group 2 it was 51 years. The proportion of female participants was 298 in Group 1 and 353 in Group 2. Patients in Group 2 were significantly younger (p

ObjectiveEvacuation, owing to a disaster, impacts various aspects of an individual's life, including health status. This study aimed to determine the prevalence of obesity among residents of Katsurao Village, Fukushima Prefecture, after the evacuation order due to the Fukushima nuclear disaster in 2011 was lifted in 2016 and to compare the prevalence of obesity by place of residence (inside or outside the village).MethodsThe number of examinees, sex, age, place of residence, body mass index (BMI), exercise habits, smoking habits, drinking habits, and dietary status were extracted from the results of health checkups since 2016. We compared the BMI of the indigenes of Katsurao Village by place of residence (inside or outside the village) over time.ResultsAlthough 7 years have passed since 2016, ~70% of the registered residents of Katsurao Village still live outside the village. The obesity rates have consistently been higher among people living outside the village compared to those inside, and the place of residence was the only factor significantly associated with obesity.ConclusionThe findings of this study suggest early intervention is necessary to prevent health risks associated with disaster evacuation if the evacuation period is prolonged.

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an "antibody score", which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

This study investigates the neutralizing activity against the XBB1.5 variant and the ancestral strain in a population post-bivalent vaccination using a pseudo virus assay validated with authentic virus assay. While bivalent booster vaccination and past infections enhanced neutralization against the XBB 1.5 strain, individuals with comorbidities showed reduced responses. The study suggests the need for continuous vaccine updates to address emerging SARS-CoV-2 variants and highlights the importance of monitoring real-world immune responses.

Background: Telemedicine with video communication has become commonly applied during and after the COVID-19 pandemic. While audio-only encounters are not allowed in Japan after August 2023. The Centers for Medicaid and Medicare Services (CMS) in the United States revised the telehealth policy to make the video visit standard. We present here a case with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and diagnosed her with the Herpes zoster at audio-only encounters followed by an in-person clinic visit. Case Presentation: A 31-year-old woman called our hospital for a complaint of right chest discomfort and a tingling sensation. The SARS-CoV-2 infection was confirmed on her with the polymerase chain reaction (PCR) test 4 days before the symptom onset. A telephone encounter was made for her since the video communication failed to be prepared. The attending physician made a diagnosis of herpes zoster based on her verbal explanation of symptoms and localized skin lesions. An anti-viral medication with amenamevir was given. The photos of skin lesions were sent 3 days after the audio visit, which was consistent with herpes zoster. The patient visited our outpatient clinic and was confirmed for herpes zoster serologically with positive antibodies of both varicella-zoster IgM and IgG. Conclusions: The audio-only visit could help diagnose herpes zoster if the follow-up examinations are performed adequately. Audio-only encounters preserve the flexibility of telemedicine when video communication cannot be prepared promptly.

ABSTRACTBackground Iron deficiency (ID) and iron deficiency anemia (IDA) are long-standing health problems in athletes, affecting both performance and health. ID prevalence in young athletes remains high and a matter of concern. ID and IDA can lead to fatigue, reduced endurance, and decreased oxygen transport, potentially compromising athletic performance. We hypothesized that ID would still be a major health concern in university athletes across sports clubs in Japan.Purpose The study aimed to investigate the prevalence of ID and IDA in athletes participating in Kendo, badminton, baseball, and handball at the University of Tsukuba (Tsukuba, Ibaraki Prefecture, Japan). The study also examined the correlation between hypoferritinemia and other variables, such as previous use of iron supplements, body mass index (BMI), energy intake, and years of athletics.Methods Between January and December 2019, 126 university athletes, consisting of 79 males and 47 females, underwent physical measurements and blood tests. The blood test included complete blood count, levels of serum ferritin, serum iron, and total iron-binding capacity. The anemia was defined in accordance with the WHO criteria. Daily energy and iron intake were estimated with the food frequency questionnaire in Japanese (FFQg). Thirty-four female athletes responded to a survey about their menstruation and low-dose estrogen-progestin (LEP) usage.Results While none of the athletes had anemia, 22 (47%) female athletes exhibited serum ferritin levels of 30 ng/mL or less, defining them as hypoferritinemia. The multivariate logistic regression model revealed that a shorter duration of the athletic experience (adjusted odd ratio [95% confidence interval]: 0.62 [0.43–0.90]), lower energy intake (0.994 [0.989–0.999]), and higher dietary iron intake (4.40 [1.12–17.26]) were associated with hypoferritinemia. Seventeen (50%) female athletes reported a decline in subjective performance during menstruation, albeit two took LEP regularly.Conclusions This study reveals that ID is a prevalent health concern among young female athletes across sports clubs. It underscores the need for their education on the importance of assessing ID status. Limitation includes the nature of single-site and observational study, the absence of hepcidin measurement, and an unspecified amount of exercise. Comprehensive investigations are needed to elucidate the causes and optimal treatments for ID in young athletes.

IntroductionFollowing the Great East Japan Earthquake, the living environment of socially isolated older adults has become a pressing concern. In response, Nagaya, a collective housing program, was established in Soma City, Fukushima, Japan to address social isolation among older adults and support their long-term health. This study aimed to identify characteristics of individuals in Nagaya and examine the sustainability of this initiative.MethodsWe conducted a retrospective analysis of residents who were relocated to Nagaya, emphasizing their characteristics, the continuity of their stay in Nagaya, and their care certification levels, using data up to December 31, 2022. We employed Kaplan–Meier curves to analyze the duration for which residents continued to reside in Nagaya and the time leading up to the requiring care-level certification.ResultsOf 65 people who moved to Nagaya after the disaster, 30 people (46.2%) continued to live there, 21 (32.3%) died during their stay, and 14 (21.5%) moved out. The overall duration of occupancy averaged 6.39 years (SD 3.83 years). The proportion of requiring care-level certification occurrences per person-year was 0.0577 for those without care certification and 0.3358 for those with requiring support level at the time of moving in.ConclusionIn summary, Nagaya-style communal housing may offer suitable living environments for older adults with diverse needs during disasters and serve as a valuable tool for developing public policies in aging societies.

Abstract The present study aimed to clarify the characteristics of young evacuees who had missed the Comprehensive Health Check of the Fukushima Health Management Survey (FHMS) after the Great East Japan Earthquake in 2011. The FHMS has been conducted as a prospective cohort study to evaluate the health status of evacuees annually after the great earthquake in 2011. This study focused on the annual participation rate in the Comprehensive Health Check of evacuees aged between 20 and 37 years in 2011 who evacuated due to the Fukushima Daiichi Nuclear Power Plant accident. The characteristics of subjects who did not participate after the second survey year were identified with a multivariate logistic regression model. The participation rate was estimated at 26.6% (9720 among 36,502 residents) and 15.6% (5691 residents) in 2011 and 2012, respectively. The logistic regression model revealed the following characteristics at baseline as independent predictors of non-participation after the second year of the survey: age ≤ 24 years (adjusted odds ratio 2.11, 95% CI 1.84–2.42), 25–29 years of age (1.28, 1.13–1.45), men (1.52, 1.38–1.69), evacuation outside the municipality but within Fukushima prefecture (1.54, 1.40–1.70), evacuation outside the Fukushima prefecture (1.40, 1.21–1.63), anemia (1.23, 1.06–1.43), smoking habit (1.34, 1.21–1.48), and drinking habit (1.20, 1.09–1.32). A medical history of heart disease showed opposite odds ratios, which indicate the association with continuous participation (0.43, 0.26–0.72, respectively). We observed deteriorated participation in the prospective study of the Comprehensive Health Check of the FHMS among evacuees of a younger age group, men, those evacuated outside their municipalities, and those with history of anemia, smoking and drinking habits. Hence, the cohort study may have missed certain population groups with worse health behaviors. Thus, it is necessary to consider various measures to increase the participation rate in the disaster cohort study to understand the long-term health effects of disasters on younger residents in evacuation zones.

Abstract To reveal waning humoral immunity after second dose BNT162b2 vaccinations in a rural Japanese community and determine factors affecting antibody titers. We aimed to report Immunoglobulin G (IgG) antibody against the SARS-CoV-2 spike (S1) protein levels and neutralizing activity in a large scale community based cohort. Methods: Participants in the observational cross-sectional study received a second dose of vaccination with BNT162b2 (Pfizer/BioNTech) and were not previously infected with COVID-19. Questionnaire-collected data on sex, age, adverse vaccine reactions, and medical history was obtained. Results: Data from 2496 participants revealed that older age groups reached a low antibody titer 90–120 days after the second vaccination. Neutralizing activity decreased with age; 35 (13.3%) of those aged ≥ 80 years had neutralizing activity under the cut-off value. Neutralizing activity > 179 days from the second vaccination was 11.6% compared to that at

The bivalent mRNA vaccine is recommended to address coronavirus disease variants, with additional doses suggested for high-risk groups. However, the effectiveness, optimal frequency, and number of doses remain uncertain. In this study, we examined the long-term cellular and humoral immune responses following the fifth administration of the mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients undergoing hemodialysis. To our knowledge, this is the first study to monitor long-term data on humoral and cellular immunity dynamics in high-risk populations after five doses of mRNA vaccination, including the bivalent mRNA vaccine. Whereas most patients maintained humoral immunity throughout the observation period, we observed reduced cellular immune reactivity as measured by the ancestral-strain-stimulated ELISpot assay in a subset of patients. Half of the individuals (50%; 14/28) maintained cellular immunity three months after the fifth dose, despite acquiring humoral immunity. The absence of a relationship between positive controls and T-Spot reactivity suggests that these immune alterations were specific to SARS-CoV-2. In multivariable analysis, participants aged ≥70 years showed a marginally significant lower likelihood of having reactive results. Notably, among the 14 individuals who received heterologous vaccines, 13 successfully acquired cellular immunity, supporting the effectiveness of this administration strategy. These findings provide valuable insights for future vaccination strategies in vulnerable populations. However, further research is needed to evaluate the involvement of immune tolerance and exhaustion through repeated vaccination to optimize immunization strategies.

Abstract Background Disaster relief operations involve a variety of components of healthcare efforts. The post-disaster recovery is a key component of hospital preparedness. This study aimed to investigate the role of hospital nurses in the disaster area and their challenges during the relief efforts after the Great East Japan Earthquake in 2011. Methods Semi-structured interviews were conducted with ten nurses who worked in a general public hospital before the Great East Japan Earthquake and were dispatched to the evacuation centers after the disaster. A qualitative approach with the thematic analysis method was employed. Three research queries (RQs) were prepared before the interview. Results The study participants played administrative roles as city employees in addition to performing nursing services as healthcare providers in evacuation centers. The first RQ on their challenges in evacuation centers gave us four themes: criticism by the evacuees, conflicts between multiple roles, difficulties in performing the first experience, and anxiety in working. The second RQ asking about motivation to accomplish disaster relief efforts raised three themes of carrying out the nursing role, acceptance by evacuees, and strengths of human connections. Two themes of awareness of disaster medicine and professional growth were raised from the third RQ of gains from the experiences in the evacuation centers. Conclusions The hospital nurses in the disaster area performed multiple roles in the relief efforts in the evacuation centers, which developed a psychological burden on them. A sense of competence supported the motivation to accomplish the disaster relief activities and professional growth as a specialist in disaster medicine. A study limitation is missing hospital nurses who resigned during the relief efforts. Further study is warranted to refine the disaster preparedness of hospital operations.

Abstract This study aimed to evaluate the sequential changes in the proportion of anemia among young women over eight years after the Great East Japan Earthquake in 2011 using a prospective study of the Fukushima Health Management Survey. This study focused on the women aged between 20 and 44 who lived in the evacuation area of the nuclear power plant accident. The yearly age-adjusted proportion of anemia was accessed with data between July 2011 and March 2019. A total of 9,198 women participated in the health checkup in 2011, albeit the participation was decreased to 1,241 in 2018. The age-adjusted proportion of anemia was 16.7% in 2012 and then declined after 2013 (p with Cochran-Armitage trend test = 0.03). The multivariate regression analysis identified

Objectives SARS-CoV-2 vaccination is a crucial intervention for infection control; however, the immune response to vaccination in dialysis patients has been reported to be moderate compared with healthy adults. There are few studies available on humoral response in immunised dialysis patients compared with well-matched control group, we conducted a prospective cohort study measuring SARS-CoV-2 antibody titres in Fukushima Prefecture, Japan since September 2021.Participants We compared the titres of both anti-SARS-CoV-2 S1 IgG and neutralising antibodies of 65 haemodialysis patients (dialysis group) with 500 residents in Soma, Fukushima (control group).Methods Coarsened exact matching was used to balance sex, age and days from the second dose between dialysis and control groups.Results Significant differences in the titres of anti-SARS-CoV-2 S1 IgG and neutralising antibodies were observed between the dialysis and control groups; anti-SARS-CoV-2 S1 IgG: 168.35 (4.48–1074.29) AU/mL and 269.81 (4.72–945.96) AU/mL in dialysis and control groups, p=0.02, neutralising antibodies: 35.77 (2.94–826.06) AU/mL and 62.22 (0.00–535.57) AU/mL, p=0.007, respectively).Conclusions We observed significantly reduced anti-SARS-CoV-2 S1 antibody and neutralising antibodies in haemodialysis patients compared with cohorts matched for duration after vaccination. Patients receiving haemodialysis should be carefully monitored for immunological responses to the vaccination and COVID-19 infection.

Booster vaccination reduces the incidence of severe cases and mortality related to COVID-19, with cellular immunity playing an important role. However, little is known about the proportion of the population that has achieved cellular immunity after booster vaccination. Thus, we conducted a Fukushima cohort database and assessed humoral and cellular immunity in 2526 residents and healthcare workers in Fukushima Prefecture in Japan through continuous blood collection every 3 months from September 2021. We identified the proportion of people with induced cellular immunity after booster vaccination using the T-SPOT.COVID test, and analyzed their background characteristics. Among 1089 participants, 64.3% (700/1089) had reactive cellular immunity after booster vaccination. Multivariable analysis revealed the following independent predictors of reactive cellular immunity: age < 40 years (adjusted odds ratio: 1.81; 95% confidence interval: 1.19–2.75; p-value: 0.005) and adverse reactions after vaccination (1.92, 1.19–3.09, 0.007). Notably, despite IgG(S) and neutralizing antibody titers of ≥500 AU/mL, 33.9% (349/1031) and 33.5% (341/1017) of participants, respectively, did not have reactive cellular immunity. In summary, this is the first study to evaluate cellular immunity at the population level after booster vaccination using the T-SPOT.COVID test, albeit with several limitations. Future studies will need to evaluate previously infected subjects and their T-cell subsets.

Abstract Aim To elucidate influence of a do‐not‐attempt‐resuscitation (DNAR) order on nurses’ perceptions of the medical procedures and nursing practices for non‐cancer older patients. Design A vignette‐based questionnaire study. Methods A questionnaire survey asking nurses their perceptions of clinical practices for the following three vignettes was performed in a community hospital in Japan (N = 120): the control vignettes with an older patient with repeated heart failure who was living alone and the other two with either an absence of relatives or a diagnosis of dementia. We also prepared additions to each vignette describing a DNAR order. Results Nurses’ perception on cardiopulmonary resuscitation, defibrillation, blood tests and intravenous nutrition showed statistically significant and minimally important declines after the DNAR order compared with before for all three vignettes (p

Background Anemia is a common health issue among adolescents. Anemic conditions could affect physical performance; however, the actual profiles of anemia in adolescent students in sports clubs have not been well documented. Methods We conducted a retrospective chart review of individuals aged 13–22 years who belonged to sports clubs in schools and visited an outpatient clinic between August 1, 2016, and August 31, 2020. The medical and laboratory records, including serum levels of ferritin, folate, vitamin B12, and creatinine kinase at their first visit were assessed. Results A total of 485 individuals (231 male (48%) and 254 female (52%) patients) were eligible for the study. The most common club activity was track and field (n = 171 (35%)). The overall prevalence of the World Health Organization-defined anemia was 16.5% (95% CI [13.1–20.4]; 9.0% [5.4–13.8] and 23.1% [17.8–29.2] in males and females, respectively) after excluding pre-treated individuals. Hypoferritinemia and elevation of serum creatinine kinase levels were identified as independent contributors to anemia in both sexes (odds ratios: 13.2 (95% CI [4.2–41.1]), p < 0.001 and 14.7 (95% CI [1.8–118.4]), p = 0.012, respectively for males; odds ratios: 6.6 (95% CI [1.3–13.9]), p < 0.001 and 2.7 (95% CI [1.4–5.5]), p = 0.004, respectively for females). Discussion Anemia is prevalent in both male and female adolescent students in sports clubs. Iron deficiency and excessive training indicated by elevated creatinine kinase levels may contribute to the risk of anemia. Physicians should assess the amount of exercise, and not merely iron storage, in clinical practice.

Anisakiasis is a parasitic disease caused by Anisakis simplex and has become an emerging zoonosis as preferences for eating raw or undercooked seafood have become more common. Few case reports of asymptomatic anisakiasis have been published to date. A 79-year-old asymptomatic man underwent esophagogastroduodenoscopy (EGD) for gastric cancer screening. The gastroenterologist diagnosed superficial gastritis without any malignant lesions but found an Anisakis larva while reviewing EGD images. The physician performed a second EGD and removed the larva. The patient reported that he ate the flatfish sashimi for dinner on the day before the first EGD. This case indicates the existence of asymptomatic gastric anisakiasis, indicating that anisakiasis incidence may have previously been underestimated.

Intensive vaccination is recommended for populations more vulnerable to COVID-19 infection, although data regarding the built of immunity after vaccination for dialysis patients are lacking. This prospective, observational cohort study of maintenance hemodialysis patients examined IgG antibody levels against the SARS-CoV-2 spike (S1) protein, neutralizing activity, and interferon gamma levels after the third dose of the BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine. Humoral immunity was repeatedly measured for up to two months. The study includes 58 patients on hemodialysis. Median neutralizing antibodies reached a maximum at 56 and 9 days after booster vaccination with BNT162b2 and mRNA-1273, respectively. The median IgG antibody titer reached a maximum of 3104.38 and 7209.13 AU/mL after 16 days of booster dose, and cellular immunity was positive in 61.9% and 100% of patients with BNT162b2 and mRNA-1273 vaccination, respectively. By repeating the measurements over a period of two months, we clarified the chronological aspects of the acquisition of humoral immunity in dialysis patients after a booster COVID-19 vaccination; most dialysis patients acquired not only humoral immunity, but also cellular immunity against SARS-CoV-2. Future research should investigate the continued long-term dynamics of antibody titers and cellular immunity after the third or further vaccinations, evaluating the need for additional vaccinations for hemodialysis patients.

Measuring long-term antibody titer kinetics and subsequent coronavirus disease 2019 (COVID-19) vaccinations are crucial for identifying vulnerable populations. Our aim was to determine the association between long-term antibody kinetics, including peak titers and factors, up to seven months post-second vaccination. A three-time antibody survey was conducted in 2021 among healthcare workers in Japan to investigate the changes in humoral immunity using chemiluminescence immunoassay. The study involved 205 participants who had received the second vaccine dose, completed the three-time survey, and were not infected with SARS-CoV-2. A latent growth curve model was used to identify factors affecting the peak titer and decreasing the antibody slope. Of the eligible participants, the mean titers of immunoglobulin G (IgG) against the spike (S) protein and the neutralizing activity 7 months after the second vaccination decreased to 154.3 (8.8% of the peak titer) and 62.1 AU/mL (9.5% of the peak titer), respectively. The IgG growth model showed that age significantly affected peak titers (p < 0.001); however, a significant difference was not found for the decreasing slope. Ultimately, aging adults had significantly low peak antibody titers; however, age was unrelated to the slope of log-transformed IgG against the S protein.

Vaccination is effective in preventing COVID-19-related hospitalization among all age groups, but there is limited evidence on the effectiveness of the booster of the SARS-CoV-2 vaccine among adolescents. We analyzed the data on the status of SARS-CoV-2 infection and their vaccination profiles in adolescents aged 13–18 years in Soma city (Fukushima, Japan) (n = 1835) from 14 May to 15 June 2022. The crude incidence rate and 95% confidence interval were calculated with the negative-binomial regression model after classifying the immunization status. The crude effectiveness of a booster administration to prevent infections was estimated as 86.4% (95% confidence interval: 57.2–95.7) when compared with the primary vaccination alone. The results of this study support that the community-based mass vaccination campaign of a booster dose among adolescents has additional protection from COVID-19 during the period of the B.1.1.529 (omicron) variant wave.

Background Iron deficiency is widely recognized as being the cause of anemia in athletes, although iron status in athletes of Kendo, a traditional Japanese martial art based on swordsmanship and practiced as an educational sport, has not been widely investigated. Methods We performed a health assessment on anemia and serum ferritin levels, along with nutrient intake evaluation, for Kendo practitioners in a university in Japan. Results A total of 56 Kendo practitioners (39 male and 17 female) aged between 18 and 23 years participated in the study. No individuals exhibited WHO-defined anemia (less than 13 or 12 g/dL of hemoglobin levels in male or female), while hypoferritinemia (less than 30 ng/mL) was found in seven (41%) females but not in males. Significantly higher body mass index was found in the female athletes with hypoferritinemia compared to females with normo-ferritinemia in sub-analysis (median [interquartile range]; 25.6 [24.2, 26.9] versus 22.6 [21.7, 24.1], respectively. p

This was a retrospective cohort study, which aimed to investigate the factors associated with hesitancy to receive a third dose of a coronavirus disease 2019 (COVID-19) vaccine. A paper-based questionnaire survey was administered to all participants. This study included participants who provided answers in the questionnaire about whether they had an intent to receive a third dose of a vaccine. Data on sex, age, area of residence, adverse reactions after the second vaccination, whether the third vaccination was desired, and reasons to accept or hesitate over the booster vaccination were retrieved. Among the 2439 participants, with a mean (±SD) age of 52.6 ± 18.9 years, and a median IgG-S antibody titer of 324.9 (AU/mL), 97.9% of participants indicated their intent to accept a third vaccination dose. The logistic regression revealed that participants of a younger age (OR = 0.98; 95% CI: 0.96–1.00) and with a higher antibody level (OR = 2.52; 95% CI: 1.27–4.99) were positively associated with hesitancy over the third vaccine. The efficacy of the COVID-19 vaccine and concerns about adverse reactions had a significant impact on behavior regarding the third vaccination. A rapid increase in the booster dose rate is needed to control the pandemic, and specific approaches should be taken with these groups that are likely to hesitate over the third vaccine, subsequently increasing booster contact rate.

Total pancreatectomy with islet autotransplantation (TPIAT) is a promising treatment for refractory chronic pancreatitis (CP). Pathological features of CP include progressive fibrosis in pancreas parenchyma, atrophy, and/or ductal occlusion. Complete acinar atrophy (CAA) caused by chronic fibrosis and necroinflammation results in exocrine sufficiency and may influence islet isolation characteristics during TPIAT. In this analysis of patients who underwent TPIAT at our center, we compared transplant outcomes among those with CAA ( n = 5) vs non-acinar atrophy (NAA; matching controls, n = 36). Data were analyzed using one-way analysis of variance with Bonferroni post hoc test or Student’s t test. Pancreas digestion was longer in CAA than in NAA cases (18.6 vs 14.6 min) despite a lower pancreas weight (55.2 vs 91.2 g). Obtained tissue volume was 1.0 ml in the CAA group and 12.1 ml in the NAA group. Both groups had similar islet viability (96%) and islet dose (CAA, 3,391 IEQ/kg; NAA, 4141.1 IEQ/kg). During islet infusion, serum cytokine (IL-6, IL-8, and MCP-1) levels and plasma hsa-miR-375 levels were lower in the CAA group than in the NAA group, but not significantly. Serum tumor necrosis factor α levels at 3 h after infusion were significantly higher in CAA group than in NAA group. After TPIAT, the metabolic outcomes of the CAA group were comparable with that of the NAA group. Narcotics usage decreased significantly over 24 months in both groups, with the CAA group reporting being pain free at 12 months. Complete atrophy of acinar cells of pancreas did not significantly impact islet yield or endocrine function after TPIAT.

Introduction: The primary care clinic plays a major role in triage for coronavirus disease 2019 (COVID-19), where seroprevalence in the setting of primary care clinic remains less clear. As a point-of-care immunodiagnostic test for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the serosurvey represents an alternative to the polymerase chain reaction (PCR) test to measure the magnitude of COVID-19 outbreak in the communities lacking sufficient diagnostic capability for PCR testing. Methods: We assessed seropositivity for the SARS-CoV-2 IgG between April 21 and May 20, 2020, at 2 primary care clinics in Tokyo, Japan. Results: The overall positive percentage of SARS-CoV-2 IgG was 3.83% (95% confidence interval [CI]: 2.76-5.16) for the entire cohort (n = 1071). The 23 special wards of central Tokyo exhibited a significantly higher prevalence compared with the other areas of Tokyo after classification by residence ( P = .02, 4.68% [3.08-6.79] vs 1.83 [0.68-3.95] in central and suburban Tokyo, respectively). In central Tokyo, the southern area showed the highest seroprevalence compared with the other areas (7.92% [3.48-15.01]), corresponding to the cumulative number of confirmed COVID-19 patients by PCR test reported by the Tokyo Metropolitan Government. Conclusion: The seroprevalence surveyed in this study was too low for herd immunity, suggesting the need for robust disease control and prevention. A regional-level approach, rather than state- or prefectural-level, could be of importance in ascertaining detailed profiles of the COVID-19 outbreak.

COVID-19 vaccines are the most critical measure for controlling the COVID-19 pandemic; however, we have little information on their complications. We experienced a case of a patient who developed hyperthyroidism complicated with atrial fibrillation and heart failure on the sixth day after the first dose of COVID-19 vaccination. This case report shows the importance of considering hyperthyroidism as a possible complication after COVID-19 vaccination.

Background The overall proportion of female physician is increasing worldwide. However, its ratio exhibits a substantial diversity among each member country of Organisation for Economic Co-operation and Development (OECD). This study aimed to reveal the social factors of countries associated with the percentage of female physicians. Methods We retrieved the percentage of female physicians and social characteristic which may affect the ratio of female physicians of 36 OECD countries in 2016 or nearest year from the World Bank Open Data. Multivariate regression analysis was performed after univariate evaluations with Spearman’s coefficient to explore correlation of social variables with the proportion of female physicians. Results The percentages of female adolescents who dropped out of school before lower secondary school, female population that attained or completed Master’s or equivalent degree, female labour force, and female academic staff in tertiary education showed statistically significant correlation with proportion of female physicians (Spearman coefficient = -0.527, 0.585, 0.501, and 0.499; P = .01, .001, .002, and .008). Female’s educational attainment at least Master’s or equivalent and that of female academic staff at tertiary education were selected after multivariate analysis. Conclusion Our study revealed the relationships between advanced education opportunity and female participation in academic positions with the percentage of female physicians. Our research is limited in the difficulty to evaluate physicians’ working hours in spite of its possible effect. Further studies with qualitative assessment are warranted to explore the detail reasons to cause gender gap in physician.

Selection of an optimal donor pancreas is the first key task for successful islet isolation. We conducted a retrospective multicenter study in 11 centers in North America to develop an islet donor scoring system using donor variables. The data set consisting of 1,056 deceased donors was used for development of a scoring system to predict islet isolation success (defined as postpurification islet yield >400,000 islet equivalents). With the aid of univariate logistic regression analyses, we developed the North American Islet Donor Score (NAIDS) ranging from 0 to 100 points. The c index in the development cohort was 0.73 (95% confidence interval 0.70–0.76). The success rate increased proportionally as the NAIDS increased, from 6.8% success in the NAIDS < 50 points to 53.7% success in the NAIDS ≥ 80 points. We further validated the NAIDS using a separate set of data consisting of 179 islet isolations. A comparable outcome of the NAIDS was observed in the validation cohort. The NAIDS may be a useful tool for donor pancreas selection in clinical practice. Apart from its utility in clinical decision making, the NAIDS may also be used in a research setting as a standardized measurement of pancreas quality.

A major problem after clinical autologous islet transplantation (AIT) is the difficulty in achieving insulin independence. To follow up on our demonstration in a murine model that high-mobility group box 1 (HMGB1) was released from islets and involved in early loss of transplanted islets, we tested the role of HMGB1 in clinical AIT. Serum HMGB1 levels from 15 AIT patients were significantly elevated during islet infusion (7.6 ± 1.2 ng/ml) and 24 h after infusion (8.0 ± 1.4 ng/ml) compared to admission levels (2.4 ± 0.6 ng/ml). The first elevation of HMGB1 was associated with islet damage, but the later elevation was not. The change in the HMGB1 level from admission to first peak (ΔHMGB1) was significantly higher in the AIT group (8.1 ± 1.1 ng/ml) than in the pancreatectomy-only control (2.2 ± 0.5 ng/ml) ( p < 0.05). Circulating serum levels of soluble receptor for advanced glycation end products (sRAGE) were also elevated during islet infusion. In vitro studies demonstrated that damaged human islets released HMGB1 but not sRAGE. In terms of outcomes, the insulin-free group showed significantly lower ΔHMGB1 (5.2 ± 0.6 ng/ml) and higher ΔsRAGE (2.3 ± 0.6 ng/ml) than the insulin-dependent group (10.6 ± 1.9 ng/ml and 0.7 ± 0.2 ng/ml, respectively). The ΔHMGB1 correlated with the number of white blood cell, IP-10, EGF, and eotaxin. In conclusion, serum HMGB1 was elevated in AIT and could be associated with inflammatory reactions that deteriorate islet engraftment. Therefore, anti-HMGB1 therapy might be a candidate for further improving the outcomes of clinical AIT.

Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation.

Islet transplantation is one of the most promising therapies for type 1 diabetes (T1D). A major issue in islet transplantation is the loss of graft function at late phase. Several studies suggested the involvement of islet-specific T-cells in such islet graft dysfunction. In this study, we investigated the breadth and type of glutamic acid decarboxylase 65 (GAD65)-specific T-cells in T1D patients after allogeneic islet transplantation. Peripheral blood mononuclear cells (PBMCs) were obtained from islet-transplanted T1D patients during insulin-independent period and cultured for 7 days with pools of GAD65 overlapping peptides in the presence of IL-2. Cytokine secretion profiles of peptide-reactive T-cells were analyzed after a short-term restimulation with the same peptides by a multiplex bead-based cytokine assay and by an intracytoplasmic cytokine detection assay. Robust GAD65-specific CD4 + and CD8 + T-cell responses were detected in patients who eventually developed chronic graft dysfunction. Multiple GAD65 peptides were found to induce specific T-cell responses in these patients, indicating that the repertoire of GAD65-specific T-cells was broad. Furthermore, GAD65-specific CD4 + T-cells were composed of heterogeneous populations, which differentially expressed cytokines including IFN-γ and type 2 cytokines, but not IL-10. In contrast, patients who showed only marginal GAD65-specific T-cell responses maintained substantially longer graft survival and insulin independence. In conclusion, our study suggests that the emergence of islet-specific T-cells precedes the development of chronic graft dysfunction in islet-transplanted patients. Thus, our observations support the hypothesis that these islet-specific T-cells contribute to the development of chronic islet graft dysfunction.

Establishing reliable islet potency assay is a critical and unmet issue for clinical islet transplantation. Recently, we reported that islets contained high levels of high mobility group box 1 (HMGB1) and damaged islets released HMGB1 in a mouse model. In this study, we hypothesized that the amount of released HMGB1 could reflect the degree of islet damage, and could predict the outcome of islet transplantation. Four groups of damaged mouse islets and three groups of damaged human islets were generated by hypoxic conditions. These islets were assessed by in vivo (transplantation) and in vitro (released HMGB1 levels, released C-peptide levels, PI staining, TUNEL staining, ATP/DNA, and glucose-stimulated insulin release test) assays. In addition, the ability of each assay to distinguish between noncured ( n = 13) and cured ( n = 7) mice was assessed. The curative rates of STZ-diabetic mice after receiving control, hypoxia-3h, hypoxia-6h, and hypoxia-24h mouse islets were 100%, 40%, 0%, and 0%, respectively. Only amounts of released HMGB1 and ratio of PI staining significant increased according to the degree of damages in both human and mouse islets. In terms of predictability of curing diabetic mice, amounts of released HMGB1 showed the best sensitivity (100%), specificity (100%), positive (100%), and negative predictive values (100%) among all the assays. The amount of released HMGB1 reflected the degree of islet damage and correlated with the outcome of islet transplantation in mice. Hence, released HMGB1 levels from islets should be a useful marker to evaluate the potency of isolated islets.

The major endpoints for clinical islet transplantation for type 1 diabetes are insulin independence and reduction of hypoglycemic episodes. Both endpoints are influenced by patients' and physicians' preferences regarding the use of exogenous insulin. Therefore, development of an objective endpoint for assessing clinical islet transplantation is desirable. HOMA-beta score is useful in assessing functional β-cell mass. However, this score uses blood insulin levels that are influenced by exogenous insulin injection and therefore is not suitable for patients who receive exogenous insulin. For assessing functional β-cell mass for type 1 diabetic patients after islet transplantation, we created the Secretory Unit of Islet Transplant Objects (SUITO) index using fasting C-peptide and fasting glucose. The formula of the SUITO index is fasting C-peptide (ng/ml)/[fasting blood glucose – 63 (mg/dl)] x 1500. We demonstrated that, within 1 month of islet transplantation, an average SUITO index of >26 was an excellent predictor of achieving insulin independence. In addition, daily SUITO index scores correlated with a reduction of insulin dose and adversely correlated with blood glucose levels during an intravenous glucose tolerance test. Other important endpoints, reduction of hypoglycemic episodes and quality of life, also correlated with the SUITO index. Thus, the SUITO index is excellent for assessing important endpoints (insulin independence, reduction of hypoglycemia, improved quality of life) after allogeneic islet transplantation.

One of the major issues in clinical islet transplantation is the poor efficacy of islet isolation. During pancreas preservation and islet isolation, islets suffer from hypoxia as islets are highly sensitive to hypoxic conditions. Cold preservation has been applied to minimize hypoxia-induced cell damage during organ preservation. However, the studies related to hypoxia-induced islet cell damage during islet isolation are limited. Recently, we demonstrated that mouse islets contain high levels of high-mobility group box 1 protein (HMGB1), and during proinflammatory cytokine-induced damage, islets release HMGB1 outside the cell. The released HMGB1 is involved in the initial events of early islet loss. In the present study, we hypothesize that low temperature conditions could prevent both hypoxia induced islet cell damage and HMGB1 release from islets in a mouse model. Isolated mouse islets underwent normoxic condition (95% air and 5% CO 2 ) at 37°C or hypoxic conditions (1% O 2 , 5% CO 2 , and 94% N 2 ) at 37°C (hypoxia-37°C islets), 22°C (hypoxia-22°C islets), or 4°C (hypoxia-4°C islets) for 12 h. In vitro and in vivo viability and functionality tests were performed. HMGB1, IL-6, G-CSF, KC, RANTES, MCP-1, and MIP-1 α levels in the medium were measured. Low temperature conditions substantially reduced hypoxia-induced necrosis ( p < 0.05) and apoptosis ( p < 0.05). In addition, low temperature islet culture significantly increased the insulin secretion from islets by high glucose stimulation ( p < 0.05). All of the recipient mice reversed diabetes after receiving the hypoxia-4°C islets but not after receipt of hypoxia-37°C or 22°C islets. The amounts of released HMGB1, IL-6, G-CSF, KC, RANTES, MCP-1, and MIP-1 α were significantly reduced in the hypoxia-4°C islets compared to those of the hypoxia-37°C islets ( p

Autologous islet transplantation after total pancreatectomy is an excellent treatment for painful chronic pancreatitis. Traditionally, islets have been isolated without purification; however, purification is applied when the tissue volume is large. Nevertheless, the impact of tissue volume and islet purification on clinical outcomes of autologous islet transplantation has not been well examined. We analyzed 27 cases of autologous islet transplantation performed from October 2006 to January 2011. After examining the relationship between tissue volume and portal pressure at various time points, we compared islet characteristics and clinical outcomes between cases with complications (complication group) and without (noncomplication group), as well as cases with purification (purification group) and without (nonpurification group). Tissue volume significantly correlated with maximum ( R = 0.61), final ( R = 0.53), and delta (i.e., difference between base and maximum; R = 0.71) portal pressure. The complication group had a significantly higher body mass index, tissue volume, islet yield, and portal pressure (maximum, final, delta), suggesting that complications were associated with high tissue volume and high portal pressure. Only one of four patients (25%) in the complication group became insulin free, whereas 11 of 23 patients (49%) in the noncomplication group became insulin free with smaller islet yields. The purification group had a higher islet yield and insulin independence rate but had similar final tissue volume, portal pressure, and complication rates compared with the nonpurification group. In conclusion, high tissue volume was associated with high portal pressure and complications in autologous islet transplantation. Islet purification effectively reduced tissue volume and had no negative impact on islet characteristics. Therefore, islet purification can reduce the risk of complications and may improve clinical outcome for autologous islet transplantation when tissue volume is large.

For clinical islet transplantation, isolated islets deteriorate rapidly in culture, although culturing islets prior to transplantation provides flexibility for evaluation of isolated islets and pretreatment of patients. In the present study, we compared human fresh islets to cultured islets with in vitro and in vivo assays. After culture for 24, 48, and 72 h, islet yield significantly decreased from 2,000 to 1,738 ± 26 (13% loss), 1,525 ± 30 (24% loss), or 1,298 ± 18 IEQ (35% loss), respectively. The ATP contents were significantly higher in the 6-h cultured group (near fresh group) than in 48-h culture groups. The stimulation index was relatively higher in the 6-h cultured group than in 48-h cultured group. Human islets with or without culture were transplanted into diabetic nude mice. The attainability of posttransplantation normoglycemia was significantly higher in fresh group than in the culture groups. Intraperitoneal glucose tolerance testing (IPGTT) showed that the blood glucose levels of mice transplanted with fresh islets were significantly lower than with cultured islets at 30, 60, 90, and 120 min after injection. These data suggest that human islet transplantation without culture could avoid the deterioration of islets during culture and improve the outcome of islet transplantation. Based on these data, we have transplanted fresh islets without culture for our current clinical islet transplantation protocol.

Islet transplantation is one of the most promising treatments for an unstable form of type 1 diabetes. However, islet transplantation still has some obstacles, such as low success rate of islet isolation, difficulty to obtain long-term insulin freedom, and adverse events related to transplant protocol. We describe the adverse events of current clinical islet transplantation at our institute in this report. Nine type 1 diabetic patients received 17 islet infusions from March 2005 to October 2008. The islet infusion procedure and immunosuppression regimen were based on a modified Edmonton protocol. Severe adverse events (SAEs) were defined as events that were more than grade 3 according to the Terminology Criteria for Adverse Events in Trials of Adult Pancreatic Islet Transplantation, version 4.1 (Collaborative Islet Transplant Registry, CITR). Sixteen events were reported as SAEs and among them 12 events were probably or definitely related to transplant protocols; all occurred within 1 year after infusion except for one. Five adverse events (31%) occurred within 10 days after transplantation and were related to infusion procedures. Seven events (44%) occurred after 50 days and were related to immunosuppressive therapy. SAEs related to the protocol included three events of elevated liver enzymes, two of hemorrhage into gall bladder or peritoneal cavity, two of neutropenia, two of infection, one of vomiting, one of diarrhea, and one of renal dysfunction. All events were grade 3, except for one case that was grade 4 of neutropenia. All SAEs resolved with no sequelae. Neoplasms and deaths were not observed in our study. The present study suggests need to improve both infusion procedure and immunosuppressive strategy from the view of preventing SAEs.

For islet transplantation, maintaining organ viability after pancreas procurement is critically important for optimal graft function and survival. We recently reported that islet yield was significantly higher in the modified ET-Kyoto (MK) solution, which includes a trypsin inhibitor (ulinastatin), compared with the UW solution, and that the advantages of MK solution are trypsin inhibition and less collagenase inhibition. In this study, we compared ulinastatin with other trypsin inhibitors, gabexate mesilate, and nafamostat mesilate, in preservation solution for islet isolation. Ulinastatin was easily dissolved in ET-Kyoto solution, while ET-Kyoto with gabexate mesilate and nafamostat mesilate became cloudy immediately after addition. Although there were no significant differences in islet yield among the three groups, viability was significantly higher for the MK group than for the GK group or the NK group. The stimulation index was significantly higher for the MK group than for the GK group. In summary, there are no other trypsin inhibitors that are more effective than ulinastatin. Based on these data, we now use ET-Kyoto solution with ulinastatin for clinical islet transplantation.

Porcine islets are considered to be a promising resource for xenotransplantation. However, it is difficult to isolate porcine islets because of the marked fragility and rapid dissociation. Endogenous trypsin is one of the main factors to damage islets during the isolation procedure. Recent studies have suggested that trypsin inhibitors during the preservation of pancreas or the collagenase digestion can improve the result of islet isolation. In this study, we examined whether a 1-antitrypsin (Aralast™), which inhibits several endogenous proteases and has immunomodulatory properties, can protect islets from the proteases and improve the results of porcine islet isolation. Twelve porcine pancreata were divided into three groups: without Aralast group (standard, n = 5), preserved with Aralast using the ductal injection (DI) method (DI, n = 3), and with Aralast using the DI method and in the collagenase solution (DI+C, n = 4). Efficacy of islet isolation was assessed by islet yields, purity, and viability. The trypsin activity of the preservation and the digestion solution during the isolation procedure was measured. During islet isolation, the trypsin activity in DI+C group was significantly inhibited compared to the standard group, whereas DI group showed less effect than DI+C group. The average of postpurification islet equivalents (IEQ) per pancreas weight in the DI+C group was significantly higher than the standard group (standard: 3516 ± 497 IEQ/g, DI: 4607 ± 1090 IEQ/g, DI+C: 7097 ± 995 IEQ/g; p = 0.017 between standard and DI+C). In the DI+C group, stimulation index was higher than in other groups, although there was no significant difference. The presence of Aralast in both DI solution and collagenase solution markedly inhibited trypsin activity during pancreas digestion procedure and improved the porcine islet isolation. Inhibition of trypsin activity by Aralast could improve porcine islet isolation.

Porcine islets are a promising resource for xenotransplantation. However, low efficacy of islet isolation because of their marked fragility remains a problem. Recently we found that the standard purification method using COBE 2991 cell processor (COBE) with Ficoll density gradient solution damaged islets mechanically by high shearing force. In this study, we evaluated our new purification method using large plastic bottles for the efficacy of islet purification. Ten porcine pancreata were used. The average warm ischemic time was over 40 min; therefore, these pancreata were considered to be in a marginal condition. After digestion, the digested tissue was divided into three groups. Each group was purified using either top loading method with bottle (top group) or bottom loading method with bottle (bottom group) or standard COBE method (COBE group). Islet yield per pancreas weight (IEQ/g) and the rate of postpurification recovery in the top group were significantly higher than the COBE group (top: 8060 ± 1652 IEQ/g, bottom: 4572 ± 614 IE/g, COBE: 3900 ± 734 IE/g. p < 0.02 in top vs. COBE; top percentage of recovery: 99.3 ± 12.3%, bottom: 62.6 ± 8.8%, COBE: 49.5 ± 6.7%, p < 0.02 in top vs. bottom and COBE). The average sizes of purified islets in the top and bottom groups were significantly larger than COBE group (Average diameter top: 156 ± 8 μm, bottom: 147 ± 6 μm, COBE: 119 ± 6 μm, p < 0.01 in top vs. COBE and in bottom vs. COBE), which indicated that bottle method can reduce shear force during purification. Our new purification using top loading bottle method enabled us to obtain a high yield of porcine islets from marginal pancreata.

Total or partial pancreatectomy followed by autologous islet transplantation is a therapeutic option for the treatment of refractory chronic pancreatitis (CP). Maximization of islet yields from fibrotic and inflamed organs is crucial for prevention of posttransplant diabetes. We adapted technical advancements developed for islet allotransplantation toward islet autotransplantation. Eight patients (two men, six women; ages 24–58 years) underwent total ( n = 7) or partial ( n = 1) pancreatectomy for the treatment of CP refractory to maximal medical management. Pancreata were preserved in UW solution (UW group) in initial three cases and the last five pancreata were preserved with pancreatic ductal injection followed by ET-Kyoto/oxygenated PFC solutions (DI+TLM group). Islets were isolated by modified Ricordi method and were purified only in one case. All islet infusions were performed under general anesthesia via direct vein injection into the portal venous system with pressure monitoring. Total islet yields (129,314 ± 51,627 vs. 572,841 ± 116,934 IEQ, p < 0.04), islet yield/pancreas weight (1,233 ± 359 vs. 6,848 ± 847 IEQ/g, p < 0.003), and islet yield/patient body weight (1,951 ± 762 vs. 7,305 ± 1,531 IEQ/kg, p < 0.05) were significantly higher in the DI+TLM group when compared to the UW group. Pellet size was also higher (5.3 ± 0.3 vs. 13.5 ± 3.4 ml) in the DI+TLM group, suggesting that this method of preservation effectively protected pancreatic tissue against autolysis. First month posttransplant basal C-peptide and the secretory unit of islet transplant objects (SUITO) index were also higher in the DI+TLM group when compared to the UW group (2.0 ± 0.3 vs. 1.4 ± 0.4 ng/ml and 42.6 ± 12.7 vs. 14.6 ± 5.6, respectively). There were no technical complications related to the infusion. Our results suggest that higher islet yields can be achieved even from chronically inflamed and fibrotic organs using DI+TLM. The techniques applied for islet isolations from normal pancreata are showing promise for fibrotic pancreata from CP patients.

For pancreatic islet transplantation, the most common method of islet purification is density gradient centrifugation because of the differences in density between islets and acinar tissue. The density of islets/acinar tissue depends on several conditions, such as osmolality of purification solution. In this study, we evaluated the osmolality of iodixanol-controlled density gradients (400, 450, and 500 mOsm/kg) on the islet purification step. The density of the purification solutions was controlled by changing the volumetric ratio of iodixanol and the purification solutions (iodixanol-Kyoto solutions; IK solutions). The osmolality of density gradients was controlled by addition of 10x Hanks balanced salt solution (HBSS) solution. Density of both islets and acinar tissue increased relative to increase of the osmolality of purification solutions. There were no significant differences among the three groups on islet yield after density-adjusted purification and the rate of postpurification recovery. In vitro and in vivo assays suggest that the quality of islets was similar among the three groups. Our data suggest that efficacy of purification and quality of isolated islets is similar when the osmolality of purification solutions is between 400 and 500 mOsm/kg and density adjustment is applied. Since the density of islet and acinar tissue is changed according to osmolality, the density adjustment is important when using several osmolality solutions.

One endpoint of clinical islet cell transplantation for type 1 diabetic patients is the elimination or reduction of hypoglycemia. We previously developed a simple tool to evaluate islet graft function: the secretory unit of islet transplant objects (SUITO) index. The aim of this study is to clarify the association between the SUITO index and hypoglycemic episodes. Data from 310 clinical evaluations of 11 islet recipients were included in this study. Fasting plasma C-peptide and glucose levels were measured at every evaluation. The SUITO index was calculated according to the following formula: 1500 × C-peptide level (ng/ml)/[blood glucose level (mg/dl) – 63]. The number of hypoglycemic events (

Poor efficacy is one of the issues for clinical islet transplantation. Recently, we demonstrated that pancreatic ductal preservation significantly improved the success rate of islet isolation; however, two transplants were necessary to achieve insulin independence. In this study, we introduced iodixanol-based purification, thymoglobulin induction, and double blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression to improve the efficacy of clinical islet transplantation. Nine clinical-grade human pancreata were procured. Pancreatic ductal preservation was performed using ET-Kyoto solution in all cases. When the isolated islets met the clinical criteria, they were transplanted. We utilized two methods of immunosuppression and anti-inflammation. The first protocol prescribed daclizumab for induction, then sirolimus and tacrolimus to maintain immunosuppression. The second protocol used thymoglobulin for induction and tacrolimus and mycophenolate mofetil to maintain immunosuppression. Eternacept and anakinra were administered as anti-inflammatory drugs. The total amount of insulin required, HbA1c, and the SUITO index were determined to analyze and compare the results of transplantation. All isolated islet preparations (9/9) met the criteria for clinical transplantation, and they were transplanted into six type 1 diabetic patients. All patients achieved insulin independence with normal HbA1c levels; however, the first protocol required two islet infusions ( N = 3) and the second protocol only required a single infusion ( N = 3). The average SUITO index, at 1 month after a single-donor islet transplantation, was significantly higher in the second protocol (49.6 ± 8.3 vs. 19.3 ± 6.3, p < 0.05). Pancreatic ductal preservation, iodixanol-based purification combined with thymoglobulin induction, and blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression dramatically improved the efficacy of clinical islet transplantations. This protocol enabled us to perform successful single-donor islet transplantations. Further large-scale studies are necessary to confirm these results and clarify the mechanism of each component.

Total pancreatectomy with autologous islet cell transplantation (TP with AIT) is an effective treatment for chronic pancreatitis patients with severe abdominal pain. Body mass index (BMI) of the pancreatic donor is proven to be a useful predictor for islet isolation and transplantation outcomes in allogenic islet transplantation. However, the association between BMI and islet isolation outcome and/or metabolism after AIT was previously unclear. Twelve patients who received TP with AIT at our hospital were included in this study. All pancreata were preserved with both pancreatic ductal injection and oxygen-charged static two-layer method using ET-Kyoto solution. The cohort was divided into two groups: low BMI group (BMI < 23 kg/m 2 , n = 5) and high BMI group (BMI ≥ 23, n = 7). The high BMI group had a significantly higher islet yield per gram than the low BMI group both in pancreas postdigestion and in final product (postdigestion: 7330 ± 539 vs. 3509 ± 563 IE/g; p < 0.001; final product: 6555 ± 585 vs. 3476 ± 546 IE/g; p = 0.004). For islet yield in final product per patient body weight, the high BMI group also had significantly higher islet yield than the low BMI group (7997 ± 779 vs. 4175 ± 750 IE/kg, p = 0.007). Insulin independence rate in the high BMI group (71%) was also higher than that low BMI group (40%), but it did not reach statistical significance. Pancreata from patients with higher BMI could obtain higher islet yield in the setting of autologous islet cell transplantation for chronic pancreatitis.

β-Cell replacement therapy via islet transplantation is an effective treatment for diabetes mellitus, but its widespread use is severely limited by the shortage of donor organs. Because pancreatic stem/progenitor cells are abundantly available in the pancreas of these patients and in donor organs, the cells could become a useful target for β-cell replacement therapy. We previously established a mouse pancreatic stem cell line without genetic manipulation. In this study, we used the techniques to identify and isolate human pancreatic stem/progenitor cells. The cells from a duct-rich population were cultured in 23 kinds of culture media, based on media for mouse pancreatic stem cells or for human embryonic stem cells. The cells in serum-free media formed “cobblestone” morphologies, similar to a mouse pancreatic stem cell line. On the other hand, the cells in serum-containing medium and the medium for human embryonic stem cells formed “fibroblast-like” morphologies. The cells divided actively until day 30, and the population doubling level (PDL) was 6–10. However, the cells stopped dividing after 30 days in any culture conditions. During the cultures, the nucleus/cytoplasm (N/C) ratio decreased, suggesting that the cells entered senescence. Exendin-4 treatment and transduction of PDX-1 and NeuroD proteins by protein transduction technology into the cells induced insulin and pancreas-related gene expression. Although the duplications of these cells were limited, this approach could provide a potential new source of insulin-producing cells for transplantation.

Inconsistent islet isolation is one of the issues of clinical islet transplantation. In the current study, we applied ductal injection to improve the consistency of islet isolation. Seven islet isolations were performed with the ductal injection of ET-Kyoto solution (DI group) and eight islet isolations were performed without the ductal injection (standard group) using brain-dead donor pancreata. Isolated islets were evaluated based on the Edmonton protocol for transplantation. The DI group had significantly higher islet yields (588,566 ± 64,319 vs. 354,836 ± 89,649 IE, p < 0.01) and viability (97.3 ± 1.2% vs. 92.6 ± 1.2%, p < 0.02) compared with the standard group. All seven isolated islet preparations in the DI group (100%), versus only three out of eight isolated islet preparations (38%) in the standard group met transplantation criteria. The islets from the DI group were transplanted into three type 1 diabetic patients and all three patients became insulin independent. Ductal injection significantly improved quantity and quality of isolated islets and resulted in high success rate of clinical islet transplantation. This simple modification will reduce the risk of failure of clinical islet isolation.

Total pancreatectomy with islet autotransplantation (TPIAT) is the treatment of choice to preserve pancreatic endocrine function, alleviate pain, and improve quality of life (QoL) when other strategies are ineffective for chronic pancreatitis (CP) patients. This study utilized pancreatic disease-specific surveys developed by the European Organisation for Research and Treatment of Cancer (EORTC) to conduct a comprehensive, single-center examination of a large cohort of patients to gain understanding of QoL post-TPIAT. Two validated QoL surveys of the EORTC--QLQ-C30 and QLQ-PAN26--were administered in a prospective cohort of CP patients during pre-and post-operative scheduled visits. A total of 116 patients responded to the preoperative survey and were included in this study. The global health scale of QLQ-C30 was significantly improved after TPIAT when compared to baseline with delta scores of 24.26, 20.54, and 26.7 at 1, 2, and 3 years post-TPIAT (p < 0.001). The EORTC-PAN26 revealed significant improvements in symptom scales for pancreatic pain, bloating, digestive symptoms, taste, indigestion, weight loss, body image, and future worries. The comprehensive surveys in such a large cohort expands the QoL criterion in CP patients and indicates significant improvement in QoL post-TPIAT, further validating TPIAT as a treatment option for refractory CP. [ABSTRACT FROM AUTHOR]