Efficacy of autologous platelet-rich plasma gel in patients with hard-to-heal diabetic foot ulcers: a multicentre study in Japan.

OBJECTIVE: To evaluate the healing outcome of a platelet-rich plasma (PRP) gel prepared using TKKT01 (a wound care device to prepare the PRP gel) in patients with hard-to-heal diabetic foot ulcers (DFUs) and who showed an inadequate response to ≥4 weeks of standard of care (SoC). METHOD: This open-label, single-arm, multicentre study was conducted in 15 centres in Japan. Eligible patients received PRP gel treatment twice a week for eight weeks, followed by a final evaluation after the completion of week 8 (day 57). The primary endpoint was the percentage of patients who achieved ≥50% reduction in wound radius at the final evaluation (achievement criterion, ≥60% of patients). Secondary endpoints included: wound area and volume reduction rates; time to possible wound closure by secondary intention; time to possible wound closure using a relatively simple procedure (e.g., skin graft and suture); and safety at the final evaluation. RESULTS: A total of 54 patients were included in the full analysis set, with 47 patients included in the per protocol set; the primary endpoint was met in 38/47 (80.9%) (95% confidence interval: 66.7-90.9%) patients who achieved ≥50% wound radius reduction at the final evaluation. High rates of wound area (72.8%) and volume (92.7%) reduction were observed at the final evaluation. The median time to possible wound closure by secondary intention and by use of a relatively simple procedure was 57 and 43 days, respectively. Complete wound closure at the final evaluation was achieved in 27 (57.4%) patients. No safety concerns were raised. CONCLUSION: In this study, the efficacy and safety of PRP gel treatment with TKKT01 in patients with hard-to-heal DFUs in Japan were confirmed by our findings. DECLARATION OF INTEREST: This study was funded by Rohto Pharmaceutical Co., Ltd., Japan. NO has been paid a consulting fee by Rohto Pharmaceutical Co., Ltd. KH is the Chief Medical Officer of Rohto Pharmaceutical. Co., Ltd. The other authors have no conflict of interest to declare.

Site-specific dose conversion factors for radon progeny based on ambient aerosol characteristics in an outdoor environment and a tourist cave.

Site-specific Dose Conversion Factors (DCFs) for radon progeny were estimated based on the aerosol measurement results in an outdoor environment and a tourist cave. The Activity Median Diameter (AMD) and unattached fraction were measured and used to calculate the effective dose per unit intake of radon progeny. The AMDs in the outdoor environment was in the range of 0.24-0.71 µm with the unattached fraction of 0.17. In the tourist cave, two peaks were found in the aerosol size distribution at nucleation and accumulation modes and the unattached fraction was measured to be 0.69 with a range of 0.36-0.85. The DCFs at the outdoor environment did not differ from those from the publication of the International Commission on Radiological Protection; however, the DCF in the tourist cave was significantly higher due to the discrepancy in the unattached fraction and the aerosol size distribution. It was found that these two factors would significantly affect the DCF so that we should be aware of it.

Effect of Early Rehabilitation on Walking Independence and Health-Related Quality of Life in Patients With Chronic Foot Wounds: A Multicenter Randomized Clinical Trial.

Rehabilitation is usually provided to patients with chronic foot wounds (CFWs) after surgery. This study aimed to assess whether early postoperative rehabilitation could maintain walking independence in hospitalized patients with CFWs. This single-blind, randomized clinical trial was performed between September 10, 2018 and March 2019, involving 60 patients who underwent both surgical procedures and rehabilitation. Participants were randomly allocated into the early rehabilitation (EG, n = 30) or the control (CG, n = 30) groups. EG received early rehabilitation immediately after surgery, while CG received late rehabilitation after wound closure. Both groups received rehabilitation sessions 5 times per week until discharge. The primary outcome was walking independence, measured via Functional Independence Measure (FIM)-gait scores. Secondary outcomes included health-related quality of life (HRQoL) using EuroQol 5 dimensions 5-level (EQ-5D-5L) and the presence of rehabilitation-related adverse events, including dehiscence of wounds and falls. Differences in intervention timing effects were analyzed using nonparametric split-plot factorial design analysis, including Fisher's exact test, Mann-Whitney U test, and Wilcoxon signed-rank test (P < .05). Out of the 60 participants, 53 patients completed the discharge follow up. Three participants (10.0%) from the EG and 4 (13.3%) from the CG dropped out due to postoperative complications unrelated to rehabilitation intervention. No rehabilitation-related adverse events were found. Participants in the EG maintained greater FIM-gait scores during hospitalization than the CG (difference, -1; P = .0001), with a difference of 0 (P = .109) at discharge. EQ-5D-5L significantly improved in both groups (EG: difference, 0.13 [P = .014], CG: difference, 0.17 [P = .0074]). The EG intervention was associated more with maintaining walking independence at discharge than CG intervention. Postoperative rehabilitation improved HRQoL without adverse events, indicating that clinicians should recommend early rehabilitation for patients with CFW to enhance walking independence.

A novel low-density lipoprotein/fibrinogen apheresis method for chronic limb-threatening ischemia in patients with poor options for revascularization: A multicenter, single-arm clinical trial.

INTRODUCTION: Low-density lipoprotein (LDL) apheresis is a treatment option for patients with unhealed chronic limb-threatening ischemia (CLTI) after revascularization. The newly developed AS-25 is a direct hemoperfusion-type apheresis device that differs from conventional LDL apheresis therapy and is designed to specifically adsorb both LDL-C and fibrinogen. We evaluate the efficacy and safety of AS-25. METHODS: This study included 61 patients whose ulcers failed to heal after revascularization or were ineligible for revascularization. Of these, 50 were undergoing hemodialysis. The primary endpoint was the healing rate of a target lesion of interest (ulcer), using historical data as control. RESULTS: The ulcer healing rate of 45.9% was significantly higher than the historical data. No significant safety concerns were observed. CONCLUSIONS: AS-25 was effective in healing ulcers and preventing major amputation even in CLTI refractory patients on hemodialysis, thus showing potential clinical applicability and high significance. CLINICAL TRIAL REGISTRATION: UMIN study ID UMIN000020336.

Effect of Partial Foot Amputation Level on Gait Independence in Patients With Chronic Lower Extremity Wounds: A Retrospective Analysis of a Japanese Multicenter Database.

Partial foot amputation (PFA) is generally planned to minimize the amputation level; nonetheless, the effect of PFA levels on gait independence in amputees remains unclear. This study aimed to investigate the impact of PFA levels of the forefoot on gait independence in patients with chronic lower extremity (LE) wounds. This multicenter retrospective cohort study included 232 hospitalized Japanese patients treated and rehabilitated for chronic LE wounds. A multivariate analysis based on PFA levels was conducted for gait independence at discharge, with age and comorbidities as independent variables. Patients with Lisfranc amputation had significantly less independent gait than patients with more distal amputation and those without amputation (<22% vs >40%; P = .027; Fisher's exact test). Logistic regression analysis revealed that Lisfranc amputation (odds ratio [OR]: 0.257, P = .047), age (OR: 0.559, P = .043), and chronic limb-threatening ischemia (OR: 0.450, P = .010) were independent factors associated with gait independence. Additionally, the regression model confirmed discrimination performance using the C index (0.691, P < .001) with receiver operating characteristic analysis. In patients with chronic LE wounds undergoing PFA, Lisfranc amputation was negatively associated with gait independence.

Changes in physical function and ambulatory state after Achilles tendon lengthening for diabetic foot ulcers.

[Purpose] The recurrence rate of diabetic foot ulcers is high and is related to kinematic factors. Achilles tendon lengthening has been shown to reduce the recurrence rate of foot ulcers by increasing the range of motion in the ankle joint and decreasing the plantar load. However, there are few reports on the effects of Achilles tendon lengthening in Japanese patients, but the results are yet to be clarified. This study aims to investigate the effects of Achilles tendon lengthening on physical function and ambulatory state in patients with diabetic foot ulcers. [Participants and Methods] This study initially included 10 patients with diabetic ulcers who had undergone Achilles tendon lengthening between April 2013 and March 2020. We retrospectively evaluated the factors available from the medical records. [Results] The dorsiflexion range of motion in the ankle joint increased by 10.5 degrees on average after surgery, while the plantar load decreased by 19.1 percent, while gait speed and stride length remained unchanged. [Conclusion] Achilles tendon lengthening for diabetic foot ulcers increased the range of motion in the ankle joint and decreased the plantar load without changing the ambulatory state.

Efficacy of Belt Electrode Skeletal Muscle Electrical Stimulation in the Postoperative Rest Period in Patients with Diabetes who Have Undergone minor Amputations: A Randomized Controlled Trial.

This study aimed to investigate whether belt electrode skeletal muscle electrical stimulation (B-SES) would improve postoperative lower limb function and walking ability in patients with diabetes who have undergone minor amputations. Diabetic patients who had undergone minor amputations were assigned randomly to a B-SES or control group. The B-SES group underwent conventional physical therapy for 20 min and B-SES for 20 min. The control group underwent only the 20-min conventional physical therapy. In both groups, rehabilitation was introduced by the physical therapists for 14 days from postoperative day 1. The outcome measures were range of motion in the ankle joint, knee extension muscle strength, ambulation status, and quality of life score. All these were evaluated before the intervention and 2 and 4 weeks after the intervention. From the 84 patients initially assessed, 32 were assigned to either the B-SES (N = 16) or control (N = 16) group. Preoperatively, there were no significant differences in all endpoints. The B-SES group showed significant improvement in the ankle dorsiflexion angle at 2 weeks postoperatively and knee joint extension strength at 4 weeks postoperatively. Postoperative B-SES with standard physical therapy might improve the range of motion of dorsiflexion of the ankle joint and extensor strength of the knee joint in patients with diabetes who have undergone minor amputations. B-SES is a useful tool to improve postoperative physical function in diabetic patients who have undergone minor amputations. A multicenter study is needed to determine the effective B-SES combined with regular physiotherapy for minor amputation.

Comprehensive exposure assessments from the viewpoint of health in a unique high natural background radiation area, Mamuju, Indonesia.

Mamuju is one of the regions in Indonesia which retains natural conditions but has relatively high exposure to natural radiation. The goals of the present study were to characterize exposure of the entire Mamuju region as a high natural background radiation area (HNBRA) and to assess the existing exposure as a means for radiation protection of the public and the environment. A cross-sectional study method was used with cluster sampling areas by measuring all parameters that contribute to external and internal radiation exposures. It was determined that Mamuju was a unique HNBRA with the annual effective dose between 17 and 115 mSv, with an average of 32 mSv. The lifetime cumulative dose calculation suggested that Mamuju residents could receive as much as 2.2 Sv on average which is much higher than the average dose of atomic bomb survivors for which risks of cancer and non-cancer diseases are demonstrated. The study results are new scientific data allowing better understanding of health effects related to chronic low-dose-rate radiation exposure and they can be used as the main input in a future epidemiology study.

Re-amputation in patients with diabetes-related minor amputations who underwent physical therapy during their hospitalization.

BACKGROUND: Diabetes-related foot lesions are a major cause of non-traumatic lower limb amputations and are associated with a high re-amputation rate. Lesions can cause hindrance in activities of daily living, reduce physical function, and lower a patient's quality of life. Physical therapy is necessary to prevent these limitations. Thus far, there has been limited investigation into the re-amputation rate in patients who have undergone physical therapy. This study aimed to elucidate modifiable risk factors for re-amputation in patients with minor amputations who were treated with physical therapy during their hospitalization. METHODS: This was a retrospective cohort study of 245 consecutive hospitalized patients who presented to our Wound Care Center between January 2015 and February 2018 and received physical therapy after a minor amputation. Participants were identified from admission records to surgical and physical therapy units stored in the electronic medical records. We examined re-amputations that occurred in the ipsilateral lower extremity during the 1-year post-discharge outpatient period. The maximum follow-up period was set at 1 year. We used Cox proportional hazards analysis to examine factors affecting the risk of re-amputation. RESULTS: Of the 129 patients enrolled, 42 patients (32.5%) underwent re-amputations during an average observation period of 6.2 months (range, 2.1 to 10.9 months). The factors associated with re-amputation were a requirement for hemodialysis, ankle dorsiflexion angle, and the Functional Independence Measure (FIM) ambulation score. CONCLUSIONS: In diabetes patients with minor amputations, a requirement for hemodialysis, ankle dorsiflexion angle, and the FIM ambulation score were shown to be modifiable risk factors for re-amputation. This emphasizes that maintaining vascular endothelial function through lower limb muscle exercises for hemodialysis, improving ankle mobility, and relieving plantar pressure during walking are necessary to reduce the risk of re-amputation. Patients with these risk factors should be encouraged to participate in physical therapy.

Temporal and Spatial Variation of Radon Concentrations in Environmental Water from Okinawa Island, Southwestern Part of Japan.

In this study, to get a better understanding in characterizing groundwater and ensure its effective management, the radon concentrations in water samples were measured through Ryukyu limestone in southern Okinawa Island, Japan. Water samples were collected from a limestone cave (Gyokusendo cave, dropping water) and two springs (Ukinju and Komesu, spring water), and the radon concentrations were measured by liquid scintillation counters. The radon concentrations in the samples from the Gyokusendo cave, and Ukinju and Komesu springs were 10 ± 1.3 Bq L-1, 3.2 ± 1.0 Bq L-1, and 3.1 ± 1.1 Bq L-1, respectively. The radon concentrations showed a gradually increasing trend from summer to autumn and decreased during winter. The variation of radon concentrations in the dripping water sample from the Gyokusendo cave showed a lagged response to precipitation changes by approximately 2-3 months. The estimated radon concentrations in the dripping water sample were calculated with the measured radon concentrations from the dripping water obtained during the study period. Based on our results, groundwater in the Gyokusendo cave system was estimated to percolate through the Ryukyu limestone in 7-10 days, and the residence time of groundwater in the soil above Gyokusendo cave was estimated to be approximately 50-80 days. This work makes a valuable contribution to the understanding of groundwater processes in limestone aquifers, which is essential for ensuring groundwater sustainability.

A unique high natural background radiation area - Dose assessment and perspectives.

The biological effects of low dose-rate radiation exposures on humans remains unknown. In fact, the Japanese nation still struggles with this issue after the Fukushima Dai-ichi Nuclear Power Plant accident. Recently, we have found a unique area in Indonesia where naturally high radiation levels are present, resulting in chronic low dose-rate radiation exposures. We aimed to estimate the comprehensive dose due to internal and external exposures at the particularly high natural radiation area, and to discuss the enhancement mechanism of radon. A car-borne survey was conducted to estimate the external doses from terrestrial radiation. Indoor radon measurements were made in 47 dwellings over three to five months, covering the two typical seasons, to estimate the internal doses. Atmospheric radon gases were simultaneously collected at several heights to evaluate the vertical distribution. The absorbed dose rates in air in the study area vary widely between 50 nGy h-1 and 1109 nGy h-1. Indoor radon concentrations ranged from 124 Bq m-3 to 1015 Bq m-3. That is, the indoor radon concentrations measured exceed the reference levels of 100 Bq m-3 recommended by the World Health Organization. Furthermore, the outdoor radon concentrations measured were comparable to the high indoor radon concentrations. The annual effective dose due to external and internal exposures in the study area was estimated to be 27 mSv using the median values. It was found that many residents are receiving radiation exposure from natural radionuclides over the dose limit for occupational exposure to radiation workers. This enhanced outdoor radon concentration might be as a result of the stable atmospheric conditions generated at an exceptionally low altitude. Our findings suggest that this area provides a unique opportunity to conduct an epidemiological study related to health effects due to chronic low dose-rate radiation exposure.

Japanese population dose from natural radiation.

The radiation doses from natural radiation sources in Japan are reviewed using the latest knowledge. The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) and the Nuclear Safety Research Association report the annual effective doses from cosmic rays, terrestrial radiation, inhalation, and ingestion as natural sources. In this paper, the total annual effective dose from cosmic-ray exposure is evaluated as 0.29 mSv. The arithmetic mean of the annual effective dose from external exposure to terrestrial radiation is 0.33 mSv for the Japanese population using the data of nationwide surveys by the National Institute of Radiological Sciences. Previously in Japan, although three different groups have conducted nationwide indoor radon surveys using passive-type radon monitors, to date only the Japan Chemical Analysis Center (JCAC) has performed a nationwide radon survey using a unified method for radon measurements conducted indoor, outdoor, and in the workplace. Consequently, the JCAC results are used for the annual effective dose from radon and that for radon inhalation is estimated as 0.50 mSv using a current dose conversion factor. In this paper, UNSCEAR values are used for the mean indoor and outdoor thoron-progeny concentrations, and the annual effective dose from thoron is reported as 0.09 mSv. Thus, the annual effective dose from radon and thoron inhalation is 0.59 mSv. From a JCAC large-scale survey of foodstuffs, the committed effective dose from the main radionuclides in dietary intake is 0.99 mSv. Finally, the Japanese population dose from natural radiation is given as 2.2 mSv, which is similar to the reported global average of 2.4 mSv.

Simultaneous measurements of radon and thoron exhalation rates and comparison with values calculated by UNSCEAR equation.

We simultaneously measured radon and thoron exhalation rates in areas of weathered acid rocks in Japan to investigate the relationship between them and between measured and calculated radon exhalation rates. To calculate the radon exhalation rate, we used an equation proposed by UNSCEAR. Our analysis showed that both the radon and thoron exhalation rates measured at one location in a natural environment fluctuated widely, even within one day. We found a strong correlation between the radon and thoron exhalation rates. The measured radon exhalation rates tended to be lower than the calculated values: the mean ratio of the measured exhalation rate to the calculated rate was 0.65. We concluded that the UNSCEAR equation is applicable under a controlled environment (temperature, humidity, etc.), but not where there are artificial underground structures that may influence the transportation of radon in soil.

Mitigation of the effective dose of radon decay products through the use of an air cleaner in a dwelling in Okinawa, Japan.

Field measurements were conducted to assess the effects of an air cleaner on radon mitigation in a dwelling with a high radon concentration in Okinawa, Japan. The measurements included indoor radon concentration, individual radon progeny concentration, equilibrium equivalent concentration of radon (EECRn), unattached fraction, and size distribution of aerosol-attached radon progeny. These measurements were conducted in a 74 m(3) room with/without the use of an air cleaner. The results showed that the mean radon concentration during the measurement was quite high (301 Bq m(-3)). The operation of air cleaner decreased the radon progeny activity concentration, EECRn and equilibrium factor by 33%, 57% and 71%, respectively, whereas the unattached fraction increased by 174%. In addition, the activity concentration of attached radon progeny in the accumulation mode (50-2000 nm) was obviously deceased by 42%, when the air cleaner was operated. According to dosimetric calculations, the operation of air cleaner reduced the effective dose due to radon progeny by about 50%.

Topographic study on nerve-associated lymphatic vessels in the murine craniofacial region by immunohistochemistry and electron microscopy.

The distribution and fine structure of lymphatic vessels associated with nerves was studied by immunohistochemistry in the murine craniofacial region. The tissue sections and blocks were immunostained for LYVE-1, protein gene product 9.5, CD34 and aquaporin-1 to demonstrate the lymphatic vessels, nerves, blood vessels and water channel protein, respectively. Transmission electron microscopic examination was also performed to investigate the relationship between the lymphatics and nerves. In the nasal area, the lymphatics were found in dura mater on the cribriform plate and beneath the nasal mucosa, this supposedly supplying the cerebrospinal fluid drainage route along the olfactory nerves. The proximal portions of the cranial nerves were equipped with the lymphatics in the epineurium. In the distal portions of the nerves, the lymphatics were distributed in close proximity of the perineural sheath, and thus might contribute to maintenance of microenvironment suitable for the nerves by an absorptive activity of the lymphatic endothelial cells. The present findings suggest that the lymphatic system associated with the cranial nerves provides the pathway for transport of cerebrospinal fluid, tissue fluid, and free cells involved in immune response and tumor metastasis in the craniofacial region.

Radon-thoron discriminative measurements in Gansu Province, China, and their implication for dose estimates.

Indoor radon measurements were carried out in cave dwellings of the Chinese loess plateau in Gansu province, where previously the Laboratory of Industrial Hygiene (LIH), China, and the U.S. National Cancer Institute (NCI) had conducted an international collaborative epidemiological study. The LIH-NCI study showed an increased lung cancer risk due to high residential radon levels, and estimated the excess odds ratio at 100 Bq/m3 to be 0.19 (Wang et al., 2002). The present study used two types of newly developed passive monitors: One is a discriminative monitor for radon and thoron; the other is a selective monitor for thoron decay products. The arithmetic mean concentrations of indoor radon and thoron were 91 and 351 Bq/m3, respectively. As reported by our previous study in Shanxi and Shaanxi provinces (Tokonami et al., 2004), the presence of high thoron concentration was confirmed and thoron was predominant over radon in the cave dwellings. However, the mean equilibrium equivalent thoron concentration (EETC) was found to be much lower than expected when assuming the equilibrium factor of 0.1 provided by the UNSCEAR (2000) report. The effective dose by radon and thoron decay products was estimated to be 3.08 mSv/yr. It was significantly lower than the dose of 8.22 mSv/yr estimated from the measurements that did not take into consideration any discrimination between radon and thoron. Excess relative risk of lung cancer per sievert may be much higher than the risk estimated from the LIH-NCI study, considering that discriminative measurements were not used in their study.

Radon and thoron exposures for cave residents in Shanxi and Shaanxi provinces.

Measurements of natural radiation were carried out in cave dwellings distributed in the Chinese loess plateau. Those dwellings are located in Shanxi and Shaanxi provinces. Radon and thoron gas concentrations were measured using a passive integrating radon-thoron discriminative detector. Concentrations of thoron decay products were estimated from measurements of their deposition rates. A detector was placed at the center of each dwelling for 6 months and replaced with a fresh one for another 6 months. Measurements were conducted in 202 dwellings from August 2001 through August 2002. A short-term measurement was conducted during the observation period. In addition, gamma-ray dose rates were measured both indoors and outdoors with an electronic pocket dosimeter. Radioactivities in soil were determined by gamma-ray spectrometry with a pure germanium detector. Among 193 dwellings, indoor radon concentrations ranged from 19 to 195 Bq m(-3) with a geometric mean (GM) of 57 Bq m(-3), indoor thoron concentrations ranged from 10 to 865 Bq m(-3) with a GM of 153 Bq m(-3), and indoor equilibrium equivalent thoron concentrations ranged from 0.3 to 4.9 Bq m(-3) with a GM of 1.6 Bq m(-3). Arithmetic means of the gamma-ray dose rates were estimated to be 140 nGy h(-1) indoors and 110 nGy h(-1) outdoors. The present study revealed that the presence of thoron is not negligible for accurate radon measurements and thus that special attention should be paid to thoron and its decay products for dose assessment in such an environment. More systematic studies are necessary for a better understanding of thoron and its decay products.