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Abstract Background Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy. Case presentation A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient’s heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient’s heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment. Conclusions Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.

Abstract Nanobubbles of gas remain dissolved in water for longer periods than ordinary bubbles, and exhibit unique physicochemical and biological properties. As a result, nanobubble water (NBW) is finding widespread use many applications, such as cleaning in the industry and purification of lake water. The ozone NBW (O3-NBW), in particular, has been used in clinical dentistry; however, it has several disadvantages, including the instability of ozone, which is spontaneously converted to molecular oxygen (O3 to O2), and its broad range of antibacterial activity, which can disrupt the oral microbiota. Therefore, the use of NBW in dental medicine requires greater evaluation. Here, we examined the effects of oxygen and hypochlorite NBW (O2-NBW and HOCl-NBW, respectively) on the microbiota in human saliva in 16 male patients (35–75 years old; median: 53.5 years) using multiple assays, including next generation sequencing analysis. 16S rRNA gene sequencing revealed no significant changes in both alpha-diversity and beta-diversity. Principal Coordinate Analysis (PCoA) revealed two subclusters in both unweighted and weighted UniFrac distances. Overall, the results revealed that HOCl-NBW exposure of saliva may lead to inhibition or delay in oral biofilm formation while maintaining the balance of the oral microbiome. These results can lead to the development of a novel type of mouthrinse for prevention of oral infectious diseases.

Abstract Periplasmic solute-binding proteins (SBPs) specific for chitooligosaccharides, (GlcNAc)n (n = 2, 3, 4, 5 and 6), are involved in the uptake of chitinous nutrients and the negative control of chitin signal transduction in Vibrios. Most translocation processes by SBPs across the inner membrane have been explained thus far by two-domain open/closed mechanism. Here we propose three-domain mechanism of the (GlcNAc)n translocation based on experiments using a recombinant VcCBP, SBP specific for (GlcNAc)n from Vibrio cholerae. X-ray crystal structures of unliganded or (GlcNAc)3-liganded VcCBP solved at 1.2–1.6 Å revealed three distinct domains, the Upper1, Upper2 and Lower domains for this protein. Molecular dynamics simulation indicated that the motions of the three domains are independent and that in the (GlcNAc)3-liganded state the Upper2/Lower interface fluctuated more intensively, compared to the Upper1/Lower interface. The Upper1/Lower interface bound two GlcNAc residues tightly, while the Upper2/Lower interface appeared to loosen and release the bound sugar molecule. The three-domain mechanism proposed here was fully supported by binding data obtained by thermal unfolding experiments and ITC, and may be applicable to other translocation systems involving SBPs belonging to the same cluster.

The relationship between solar-wind conditions and substorm activity is modelled with an approach based on an echo state network. Substorms are a fundamental physical phenomenon in the magnetosphere–ionosphere system, but the deterministic prediction of substorm onset is very difficult because the physical processes that underlie substorm occurrences are complex. To model the relationship between substorm activity and solar-wind conditions, we treat substorm onset as a stochastic phenomenon and represent the stochastic occurrences of substorms with a non-stationary Poisson process. The occurrence rate of substorms is then described with an echo state network model. We apply this approach to two kinds of substorm onset proxies. One is a sequence of substorm onsets identified from auroral electrojet intensity, and the other is onset events identified from activity of Pi2 pulsations, which are irregular geomagnetic oscillations often associated with substorm onsets. We then analyse the response of substorm activity to solar-wind conditions by feeding synthetic solar-wind data into the echo state network. The results indicate that the effect of the solar-wind speed is important, especially for Pi2 substorms. A Pi2 pulsation can often occur even if the interplanetary magnetic field (IMF) is northward, while the activity of auroral electrojets is depressed during northward IMF conditions. We also observe spiky enhancements in the occurrence rate of substorms when the solar-wind density abruptly increases, which might suggest an external triggering due to a sudden impulse of solar-wind dynamic pressure. It seems that northward turning of the IMF also contributes to substorm occurrences, though the effect is likely to be minor.

Abstract Background Simulation-based education and peer-assisted learning (PAL) are both known as useful educational methods. Previous research has reported that combining these two methods are effective for training medical residents in short-term evaluation. This study was aimed to evaluate the middle- to long-term effects of simulation-based education combined with PAL on the performance of medical residents during emergency department duties. Methods This study was designed as a case-control study and conducted over three years at Okayama University Hospital in Japan. Postgraduate-year-one medical residents were assigned to three groups: a simulation group that received simulation-based education, a lecture group that received traditional lecture-based education, and a control group that received no such prior trainings. Prior training in emergency department duties using PAL was performed as an educational intervention for the simulation and lecture groups during the clinical orientation period. The residents’ medical knowledge was assessed by written examinations before and after the orientation. The performance of residents during their emergency department duties was assessed by self-evaluation questionnaires and objective-assessment checklists, following up with the residents for three months after the orientation period and collecting data on their 1st, 2nd, and 3rd emergency department duties. All the datasets collected were statistically analyzed and compared by their mean values among the three groups. Results A total of 75 residents were included in the comparative study: 27 in the simulation group, 24 in the lecture group, and 24 in the control group. The simulation and lecture groups obtained significantly higher written examination scores than the control group. From the self-evaluation questionnaires, the simulation group reported significantly higher satisfaction in their prior training than the lecture group. No significant differences were found in the emergency department performance of the residents among the three groups. However, when evaluating the improvement rate of performance over time, all three groups showed improvement in the subjective evaluation, and only the simulation and lecture groups showed improvement in the objective evaluation. Conclusion Simulation-based education combined with PAL is effective in improving the knowledge and satisfaction of medical residents, suggesting the possibility of improving work performance during their emergency department duties.

Abstract Background Photodynamic therapy (PDT) using photosensitisers is a minimally invasive treatment for malignant tumours. However, ideal photosensitisers are not yet established. Recently, we developed a new photosensitiser, glucose‐conjugated chlorin e6 (G‐Ce6). Objectives To evaluate the clinical efficacy of vascular‐targeted PDT (VTP), a type of PDT utilising a short drug‐light interval, using G‐Ce6 to treat spontaneously occurring tumours in dogs. Methods Five dogs with spontaneously occurring tumours (malignant melanoma: three; haemangiopericytoma: two; and squamous cell carcinoma: one) were subjected to VTP. These dogs were intravenously injected with G‐Ce6 at doses of 1–3 mg/kg 5 min before laser irradiation. Tumours were superficially or interstitially irradiated using a 677‐nm diode laser. Results Repeated VTP decreased tumour size, yielding complete remission in three dogs. Complications such as oedema surrounding normal tissues and fistulae were observed, and the oedema was self‐limiting. The fistula was cured by debriding the necrotic tissues formed after VTP. Conclusions Our findings demonstrate that VTP using G‐Ce6 had antitumour effects in dogs with spontaneously occurring tumours.

Abstract Background Perioperative greater trochanteric fracture following total hip arthroplasty (THA) using the anterolateral approach is a recognized perioperative complication. There was no previous study to determine the relationship between bone mineral density (BMD) and three-dimensional greater trochanter morphology for perioperative greater trochanter fractures. The purpose of this study is to identify the influence of greater trochanteric bone density and three-dimensional morphology on perioperative greater trochanteric fracture following THA using the anterolateral approach. Methods We investigated 209 hips done primary THA using the anterolateral approach and preoperative BMD test for the proximal femoral bone with a minimum of 6 months follow-up. We picked up all patients who had perioperative greater trochanteric fractures. Multivariate analysis was done in order to investigate the influence of the greater trochanter young adult mean (YAM) and three-dimensional morphology on perioperative greater trochanteric fractures. Results There were 10 joints (10/209, 4.8%) with perioperative greater trochanteric fractures. Osteosynthesis was required only in one joint (1/209, 0.5%) because the bone fragments were significantly displaced proximally by the gluteus medius. Multivariate analysis showed the combination of Type B femoral shape (in cases where the top of the great trochanter was inside the longitudinal central axis of the planned femoral stem in computed tomography (CT)- based three-dimensional templating) and a YAM of

Abstract Risk factors of severe coronavirus disease 2019 (COVID-19) have been previously reported; however, histological risk factors have not been defined thus far. The aim of this study was to clarify subclinical hidden interstitial lung disease (ILD) as a risk factor of severe pneumonia associated with COVID-19. We carefully examined autopsied lungs and chest computed tomography scanning (CT) images from patients with COVID-19 for interstitial lesions and then analyzed their relationship with disease severity. Among the autopsy series, subclinical ILD was found in 13/27 cases (48%) in the COVID-19 group, and in contrast, 8/65 (12%) in the control autopsy group (p = 0.0006; Fisher’s exact test). We reviewed CT images from the COVID-19 autopsy cases and verified that subclinical ILD was histologically detectable in the CT images. Then, we retrospectively examined CT images from another series of COVID-19 cases in the Yokohama, Japan area between February–August 2020 for interstitial lesions and analyzed the relationship to the severity of COVID-19 pneumonia. Interstitial lesion was more frequently found in the group with the moderate II/severe disease than in the moderate I/mild disease (severity was evaluated according to the COVID-19 severity classification system of the Ministry of Health, Labor, and Welfare [Japan]) (moderate II/severe, 11/15, 73.3% versus moderate I/mild, 108/245, 44.1%; Fisher exact test, p = 0.0333). In conclusion, it was suggested that subclinical ILD could be an important risk factor for severe COVID-19 pneumonia. A benefit of these findings could be the development of a risk assessment system using high resolution CT images for fatal COVID-19 pneumonia.

Abstract Background Physician shortage and maldistribution is an urgent health policy issue requiring resolution. Determination of factors associated with regional retention and development of effective policy interventions will help to solve this issue. The purpose of the present study was to identify factors associated with regional retention and discuss their policy implications. Methods We conducted a cross-sectional online survey from February to March of 2022 for graduates from regional quotas (special quotas for medical schools to select students engaged in community medicine) and Jichi Medical University (JMU) and students at 10 medical schools including JMU. Completed surveys were obtained from 375 graduates and 1153 students. Questions included intention to continue to work in their home prefecture in the future, as well as background information and potential factors associated with regional retention. In the analyses, regional quotas and JMU were referred to as community medicine-oriented programs and schools (CMPS). We performed logistic regression analyses to identify factors associated with regional retention. Results Among the students, scholarship-bonded obligatory service, satisfaction with current life, intention to belong to ikyoku (a traditional physician allocation/training system in Japanese medical schools), and interest in general practice/family medicine were significantly positively associated with regional retention. Among the graduates, satisfaction with training environment, intention to belong to ikyoku, and recommending their program to high school students were significantly positively associated with regional retention. For students of CMPS, satisfaction with the career development program was positively associated with future regional retention. For graduates, this association was observed only in the crude analysis. Conclusions In addition to known factors such as interest in general practice/family medicine, intention to belong to ikyoku had a substantial impact on regional retention. The present results suggest that the career support system represented by ikyoku as well as a career development program are of potential importance for increasing regional retention through the mechanisms of a sense of belonging and a life-long education system. These findings provide useful information for the development of further policy interventions that interweave traditional and new systems to maximize their effectiveness.

Abstract Background Adult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This disease is characterized by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet morphology. Methods We measured the number, maximum diameter, total area, and circularity (representing how closely islets resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5) using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed the interobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists. Results There was no significant difference in the number, maximum diameter, or total area of islets between the two groups, even after correcting for these parameters per unit area. However, the number of islets with low circularity (

Abstract Background This study aimed to identify patients with upper urinary tract urothelial carcinoma (UTUC) having potential Lynch syndrome (pLS) by immunohistochemistry (IHC) of DNA mismatch repair gene-related proteins (MMRPs) and Amsterdam criteria II and explore their clinical characteristics. Methods We retrospectively collected the clinical data of 150 consecutive patients with UTUC who underwent surgical resection at our institution between February 2012 and December 2020, and immunohistochemistry (IHC) of four MMRPs (MLH1, MSH2, MSH6, and PMS2) on all UTUC specimens was performed. Patients who tested positive for Amsterdam criteria (AMS) II and/or IHC screening were classified as having pLS and others as non-pLS, and their characteristics were explored. Results In this study, 5 (3%) and 6 (4%) patients were positive for AMS II and IHC screening, respectively. Two patient were positive for both AMS II and IHC screening, resulting in 9 (6%) patients with pLS. The pLS group was predominantly female (67% vs. 36%; p = 0.0093) and had more right-sided tumors (100% vs. 43%; p = 0.0009) than the non-pLS group. Of the 6 patients who were positive for IHC screening, 4 showed a combined loss of MSH2/MSH6 (n = 3) and MLH1/PMS2 (n = 1). Other two patients showed single loss of MSH6 and PSM2. Conclusions AMS II and IHC screening identified pLS in 6% of patients with UTUC. The IHC screening-positive group tends to have relatively high rate of combined loss, but some patients have single loss. AMS II may overlook patients with LS, and a universal screening may be required for patients with UTUC as well as those with colorectal and endometrial cancer.

Purpose: Neurogenic erectile dysfunction (ED) is a common side effect of radical prostatectomy (RP) because of cavernous nerve damage. In these patients, the production of nitric oxide (NO), which is important for erection, is decreased in the corpus cavernosum. Therefore, NO donors are useful for post-RP ED. However, short half-life and systemic side effects are problems of NO application in ED therapy. To avert these problems, we developed a red-light controllable NO releaser, NORD-1. This study aimed to investigate the effect of NORD-1 and red-light irradiation on neurogenic ED using a rat model of bilateral cavernous nerve injury (BCNI). Materials and Methods: BCNI and sham operations were conducted on 8-week-old rats. After 4 weeks, erectile function was evaluated using changes in intracavernous pressure (ICP) during electrostimulation of the cavernous nerve. ICP was measured under three conditions; without NORD-1 and red-light irradiation, with NORD-1 and without red-light irradiation, and with NORD-1 and red-light irradiation. SiR650 which absorbs red-light but does not release NO was used for the negative control. After the experiment, localization of NORD-1 was observed using a microscope. Results: Erectile function in a BCNI rat model was significantly decreased compared to sham-operated rats (p