Venous Screening Activities at the Site of Hokkaido East Iburi Earthquake: Report from the Result of Venous Screening in Preventive Awareness Activities.

After previous earthquakes, high prevalence of cardiovascular diseases including venous thromboembolism (VTE) has been reported. We performed venous screening at the site of Hokkaido East Iburi Earthquake which happened at 6th September 2018. VTE screening using ultrasound sonography was performed for total 7 days at Atsuma town, Mukawa town and Abira town (total 9 shelters). Deep vein thrombosis (DVT) was found in 19 of 195 evacuees (9.7%), including 8 fresh thrombus cases (4.1%). On multivariable analysis of evacuees and shelter environment factors, systolic blood pressure, use of cardboard bed and toilet environment were significant predictor of DVT. Introduction and setting-up of cardboard beds were found as an important shelter environment factor. (This is secondary publication from Jpn J Phlebol 2021; 32(1): 5-10.).

[Comparison and clarification of public health and public health nursing competencies: A report of the Committee on Public Health Nursing (2017-2018)].

Objectives　The Committee on Public Health Nursing (2017-2018) of the Japanese Society of Public Health aimed to elucidate the competencies of public health and public health nursing to provide basic materials for public health, public health nursing education, practice, and research.Methods　We studied the core competencies of public health professionals and public health nursing in the United States and examined similarities to and differences from those in Japan.Results　The United States and Japan shared similar public health and public health nursing competencies in that they targeted populations, identified health problems, and clarified health challenges for effective actions. However, differences were noted in the understanding of target groups, perspectives for identifying health problems and overcoming health challenges, and conceptualization of individuals in populations. In public health, the target population practiced clear boundaries, such as residing in certain geographical areas and ethnic groups, among others. In health challenges, the top-down approach was employed to resolve health problems in certain populations. The individual was recognized as a part of a population composed of a certain group. In public health nursing, target population (e.g., from individuals/families to groups/communities/social groups) were understood in a continuous and multilayered manner. Individual/family health problems were associated with the characteristics of groups, communities, and social groups that encompass the continuum. Moreover, health challenges were addressed in a manner oriented toward the transformation of social groups as a whole. Public health nursing competencies in both countries, which share many similarities, were developed to achieve the objectives of public health. In the United States, the competencies and skills considered necessary, such as analytical/assessment and cultural competency skills, were clearly expressed and constructed in line with the core competencies of public health professionals. However, in Japan, skills and abilities necessary as competencies in public health nursing mentioned above were not specified.Conclusion　Elucidating the core competencies of public health professionals in Japan is essential to develop human resources that can contribute to effective practices in public health and public health nursing. Toward this end, skills and abilities necessary as competencies in public health nursing in Japan, which were not previously verbalized, should be described in detail.

Reduced pain sensitivity of episodic pain syndrome model mice carrying a Nav1.9 mutation by ANP-230, a novel sodium channel blocker.

The sodium channel Nav1.9 is expressed in the sensory neurons of small diameter dorsal root ganglia that transmit pain signals, and gain-of-function Nav1.9 mutations have been associated with both painful and painless disorders. We initially determined that some Nav1.9 mutations are responsible for familial episodic pain syndrome observed in the Japanese population. We therefore generated model mice harboring one of the more painful Japanese mutations, R222S, and determined that dorsal root ganglia hyperexcitability was the cause of the associated pain. ANP-230 is a novel non-opioid drug with strong inhibitory effects on Nav1.7, 1.8 and 1.9, and is currently under clinical trials for patients suffering from familial episodic pain syndrome. However, little is known about its mechanism of action and effects on pain sensitivity. In this study, we therefore investigated the inhibitory effects of ANP-230 on the hypersensitivity of Nav1.9 p.R222S mutant model mouse to pain. In behavioral tests, ANP-230 reduced the pain response of the mice, particularly to heat or mechanical stimuli, in a concentration- and time-dependent manner. Furthermore, ANP-230 suppressed the repetitive firing of dorsal root ganglion neurons of these mutant mice. Our results clearly demonstrate that ANP-230 is an effective analgesic for familial episodic pain syndrome resulting from DRG neuron hyperexcitability, and that such analgesic effects are likely to be of clinical significance.

Suppression of RNF213, a susceptibility gene for moyamoya disease, inhibits endoplasmic reticulum stress through SEL1L upregulation.

RNF213, a susceptibility gene for moyamoya disease, is associated with stress responses to various stressors. We previously reported that Rnf213 knockout (KO) mitigated endoplasmic reticulum (ER) stress-induced diabetes in the Akita mouse model of diabetes. However, the role of RNF213 in ER stress regulation remains unknown. In the present study, RNF213 knockdown significantly inhibited the upregulation of ER stress markers (CHOP and spliced XBP1) by chemical ER stress-inducers in HeLa cells. Levels of SEL1L, a critical molecule in ER-associated degradation (ERAD), were increased by RNF213 knockdown, and SEL1L knockdown prevented the inhibitory effect of RNF213 suppression on ER stress in HeLa cells, indicating SEL1L involvement in this inhibition of ER stress. SEL1L upregulation was also confirmed in pancreatic islets of Rnf213 KO/Akita mice and in Rnf213 KO mouse embryonic fibroblasts. Additionally, RNF213 suppression increased levels of HRD1, which forms a complex with SEL1L to degrade misfolded protein in cells under ER stress. In conclusion, we demonstrate that RNF213 depletion inhibits ER stress possibly through elevation of the SEL1L-HRD1 complex, thereby promoting ERAD in vitro and in vivo.

The Environment Encouraging COVID-19 Response at Public Health Centers and Future Challenges in Japan.

The coronavirus disease 2019 (COVID-19) pandemic has triggered the implementation of public health measures globally. The health department of local governments has played a critical role in confronting COVID-19. In Japan, public health centers (PHCs) are focal points for COVID-19 response. Understanding the response to COVID-19 in local areas is critical to ensure adequate preparation for future emergencies. Therefore, the purpose of this study is to clarify how the COVID-19 operations by PHCs in Japan were managed and facilitated at the beginning of the infection spread, and their future challenges. We designed a case study that included two PHCs with a population of approximately 400,000 in Japan. Semi-structured focus group interviews with public health nurses from these two PHCs were conducted in September and October 2020. The data were analyzed using chronological time-series analysis. The switch to crisis response was encouraged by the business continuity plan. Their operations for the prevention of COVID-19 in the community were facilitated by the existing network. Further, strengthening the knowledge and skill regarding infectious disease control and management skills during infectious disease-related health emergencies were recommended. It is important to ensure that the environment facilitates emergency response and that people-and-community-centered health promotion activities are conducted, during an emergency situation, with more innovative action and leadership.

Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1.

BACKGROUND: Brachydactyly type A1 (BDA1) is an autosomal dominant disorder characterized by uniform shortening of the middle phalanges in all digits. It is associated with variants in the Indian Hedgehog (IHH) gene, which plays a key role in endochondral ossification. To date, heterozygous pathogenic IHH variants involving several codons, which are restricted to a specific region of the N-terminal active fragment of IHH, have been reported. The purpose of this study was to identify the pathogenic variant in a Japanese family with BDA1 and to evaluate its pathogenesis with regard to previous reports. METHODS: The proband, a 9-year-old boy, his siblings, and his father had shortened digits and a short stature of variable severity. Based on physical examinations, radiographic findings and family history, they were diagnosed with BDA1. This family is the first case of an isolated malformation in Japan. Sanger sequencing of IHH was performed on these individuals and on the proband's unaffected mother. The significance of the variants was assessed using three-dimensional analysis methods. RESULTS: Sanger sequencing showed a novel IHH heterozygous variant, NM_002181.4:c.544_549delTCAAAG(p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del].. These two residues are located outside the cluster region considered a hotspot of pathogenic variants. Three-dimensional modelling showed that S182 and K183 are located on the same surface as other residues associated with BDA1. Analysis of residue interactions across the interface between IHH and its interacting receptor protein revealed the presence of hydrogen bonds between them. CONCLUSIONS: We report a novel variant, NM_002181.4:c.544_549delTCAAAG (p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del] in a Japanese family with BDA1. Indeed, neither variations in codons 182 or 183 nor with such two-amino-acid deletions in IHH have been reported previously. Although these two residues are located outside the cluster region considered a hotspot of pathogenic variants, we speculate that this variant causes BDA1 through impaired interactions between IHH and target receptor proteins in the same manner as other pathogenic variants located in the cluster region. This report expands the genetic spectrum of BDA1.

E44Q mutation in NaV1.7 in a patient with infantile paroxysmal knee pain: electrophysiological analysis of voltage-dependent sodium current.

Gain-of-function mutations in voltage-gated sodium channels (NaV1.7, NaV1.8, and NaV1.9) are known causes of inherited pain disorders. Identification and functional assessment of new NaV1.7 mutations could help elucidate the phenotypic spectrum of NaV1.7 channelopathies. We identified a novel NaV1.7 mutation (E44Q in exon 2) that substitutes a glutamic acid residue for glutamine in the cytoplasmic N-terminus of NaV1.7 in a patient with paroxysmal pain attacks during childhood and his family who experienced similar pain episodes. To study the sodium channel's function, we performed electrophysiological recordings. Voltage-clamp recordings revealed that the mutation increased the amplitude of the non-inactivating component of the sodium current, which might facilitate channel opening. These data demonstrate that E44Q is a gain-of-function mutation in NaV1.7, which is consistent with our patient's pain phenotype.

Culturally sensitive disaster nursing by Public health nurses in Japan.

OBJECTIVE: To clarify culturally sensitive disaster nursing by public health nurses (PHNs) in Japan, an island nation located on the Pacific Rim, with regard to PHNs' intentions and comforting supports for affected people. DESIGN: Qualitative descriptive study. SAMPLE: Participants were 17 local PHNs and 13 affected people in nine disaster-affected municipalities throughout Japan. MEASUREMENTS: Semi-structured interviews were conducted between October 2018 and July 2019. Two types of categories were qualitatively created: categories for PHNs' culturally sensitive disaster nursing actions, including their intentions; and categories for comforting supports that PHNs provided for affected people through the four phases of disaster. The relationship between these two types of categories was determined. Cultural factors were extracted from the culturally sensitive disaster nursing actions of PHNs and categorized. RESULTS: Regarding intentions, in the acute phase, PHNs utilized culture. In the sub-acute phase, they utilized, acted based on, followed, thought of, and balanced cultural knowledge. In the mid-term-phase, they utilized, thought of, followed, and balanced with local culture. In the long-term phase, they merged, thought of, balanced, utilized, and followed local cultural practices. The actions associated with these intentions corresponded to comforting supports for affected people. Cultural factors, such as transportation style, were obtained in each phase. CONCLUSION: To enhance the resilience of a community affected by disaster, PHNs should focus on maximizing, preserving, and accommodating culture to maintain familiar life patterns when people's circumstances are totally disrupted by powerful forces of nature.

A Case of Isolated Infragenicular Arterial Lesions Successfully Treated with Open Endarterectomy.

A 68-year-old man with a history of superior mesenteric arterial thromboembolism due to chronic atrial fibrillation had experienced intermittent claudication (IC) of his left leg for 3 years. Computed tomography angiography showed focal occlusive lesions in the left distal popliteal artery and proximal segments of the infrapopliteal arteries. Endarterectomy was performed for these localized arterial lesions, and a drastic symptomatic improvement of IC after revascularization was achieved. The endarterectomized segments remained patent for 4 years after the surgery. Endarterectomy could be a useful alternative to bypass surgery and endovascular therapy for the treatment of localized infragenicular arterial lesions.

Mechanical allodynia triggered by cold exposure in mice with the Scn11a p.R222S mutation: a novel model of drug therapy for neuropathic pain related to NaV1.9.

Mutations within the SCN11A gene which encodes the voltage-gated sodium channel NaV1.9 mainly expressed in small fiber sensory neurons have been associated with neuropathic disorders; however, suitable medications have not been fully investigated. To develop drug therapies against NaV1.9-related neuropathic pain, we aimed to establish a novel model using mice carrying the Scn11a p.R222S mutation initially identified in patients with familial episodic limb pain that is characterized by paroxysmal pain induced by fatigue or bad weather conditions. We investigated the influence of cold exposure (4 °C, overnight) on the behavioral and biochemical phenotypes of Scn11a p.R222S mutant (R222S) and wild type C57BL/6N (WT) mice. We also tested the effects of acetaminophen (125, 250 mg/kg, perorally, p.o.) and traditional Japanese medicine, goshajinkigan (0.5 or 1.0 g/kg, p.o.), which are analgesic drugs prescribed to patients with neuropathic pain, in this model of cold-induced mechanical allodynia in R222S mice.Cold-exposed R222S mice exhibited enhanced mechanical allodynia and thermal hypersensitivity compared with WT mice. The decrease of the mechanical withdrawal threshold in R222S mice was reversible 24 h after housing at room temperature. There was no significant change in the levels of interleukin-1ß, interleukin-6, tumor necrosis factor-α, or interferon-γ in the plasma or spinal cords of WT and R222S mice after cold exposure. Both acetaminophen (250 mg/kg) and goshajinkigan (1.0 g/kg) significantly attenuated mechanical allodynia in R222S mice. The model of cold-induced mechanical allodynia in mice with the Scn11a p.R222S mutation is novel and useful for evaluating analgesic drugs for intractable neuropathies related to NaV1.9.

Competency framework, methods, evaluation, and outcomes of natural disaster preparedness and response training: a scoping review protocol.

OBJECTIVE: This systematic scoping review aims to clarify and map the range of natural disaster preparedness and response training for public health personnel around the world. INTRODUCTION: Various preparedness and response training courses, exercises, and drills for public health professionals have been developed for natural disasters. Most of these focus on developing competency. However, there is no overview of the frameworks, methods, evaluation, and outcomes of these disaster preparedness and response training courses, exercises, and drills. INCLUSION CRITERIA: This review will consider all studies that focus on the framework, evaluation, and outcome of training in natural disaster preparedness for public health personnel. METHODS: The databases and sources to be searched will include MEDLINE (PubMed), CINAHL with Full Text Plus, Academic Search Premier, APA PsycINFO, and Ichushi-Web. Searches for gray literature will be conducted using websites that discuss, introduce, or provide competence-based disaster preparedness and response training. These websites will mainly be for public organizations or universities with a focus on public health. The review will consider studies published in both English and Japanese. Retrieval of full-text studies and data extraction will be performed independently by two reviewers. The findings will be summarized in tabular form and accompanied by narrative text.

Graft flow predictive equation in distal bypass grafting for critical limb ischemia.

OBJECTIVE: Graft flow (GF) seems to be an important prognostic predictor in distal bypass for critical limb ischemia, but previous studies have failed to clarify the association between GF and the graft prognosis. GF differs significantly among grafts, and each graft seems to have an optimal GF depending on various factors. We hypothesized that comparison between the measured GF (mGF) and optimal estimated GF (eGF) would be important in predicting graft prognosis. Herein, we aimed to develop a GF predictive equation by assessing GF determinants and to validate the equation against a clinical dataset. METHODS: A total of 198 distal bypasses with vein grafts for critical limb ischemia from 2011 to 2016 were enrolled. Of these grafts, 135 normal grafts without any abnormalities on early postoperative ultrasound examination were used to develop and validate the equation. Various anatomic and patient-related factors were analyzed to detect GF determinants with stepwise selection, and the GF predictive equation was developed with multiple linear regression analysis. After developing the equation, all 198 grafts were categorized into two groups according to the equation developed based on data from the 135 normal grafts as follows: optimal flow grafts (OFGs), in which mGF > eGF - 14.6, and suboptimal flow grafts (SFGs), in which mGF < eGF - 14.6. The cutoff value of 14.6 was determined using receiver operating characteristic curves to detect graft abnormalities. By comparing OFGs and SFGs, the efficacy of the equation in predicting bypass abnormalities and graft prognosis was assessed. RESULTS: The GF determinants were runoff, hemodialysis (HD), diabetes mellitus (DM), and graft quality (GQ). The predictive equation was estimated as follows: GF(ml/min)=(32.9×run-off)+(9.9×GQ)-(13.0×DM)-(35.1×HD)+12.1 (R2 = 0.71, coefficient: runoff and GQ, 3 [good], 2 [fair], 1 [poor]; DM and HD, 1 [yes], 0 [no]). In the efficacy assessment of the equation, SFGs showed a significantly higher rate of bypass abnormalities (64.0% vs 12.2%; P < .0001), graft intermediate stenosis (10.7% vs 1.6%; P = .0071), graft critical stenosis (28.0% vs 3.2%; P < .0001), and early graft occlusion (17.3% vs 4.3%; P = .0037) than OFGs and were associated with a higher rate of revision surgery within 2 years after surgery (50.7% vs 34.2%; P = .026). SFGs also showed significantly lower primary patency rates (P < .0001) and secondary patency rates (P = .0005). CONCLUSIONS: GF was well-estimated with runoff, GQ, and the presence of DM and HD. A comparison between mGF and eGF, calculated with the equation, will help to detect bypass abnormalities and determine the necessity of additional intraoperative procedures and, thus, achieve optimal outcomes.

Distal Bypass Grafting Using the Basilic-Cephalic Loop Vein for Chronic Limb-Threatening Ischemia under Peripheral Nerve Blockades in a Patient with Severely-Reduced Heart Function and End-Stage Renal Disease.

A 51-year-old man with severe comorbidities required redo revascularization due to left chronic limb-threatening ischemia caused by a previous vein graft occlusion. The saphenous veins were not available due to previous surgeries. Femoro-posterior tibial artery bypass surgery was successfully performed using the basilic-cephalic loop vein under peripheral nerve blockades. This anesthesia allowed a series of surgical revascularizations without general anesthesia, and the postoperative courses were uneventful. The patient survived for 4 years with ambulatory status. In conclusion, loop graft can be an alternative single vein material for distal bypass when no saphenous veins are available.

Familial episodic limb pain in kindreds with novel Nav1.9 mutations.

We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as"". In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p.V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p.F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6-8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input-current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.

Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice.

Ring finger 213 ( RNF213) is a susceptibility gene for moyamoya disease (MMD), a progressive cerebrovascular disease. Recent studies suggest that RNF213 plays an important role not only in MMD, but also in extracranial vascular diseases, such as pulmonary hypertension (PH). In this study, we undertook genetic screening of RNF213 in patients with PH and performed functional analysis of an RNF213 variant using mouse models. Direct sequencing of the exons in the C-terminal region of RNF213, where MMD-associated mutations are highly clustered, and of the entire coding exons of BMPR2 and CAV1, the causative genes for PH, was performed in 27 Japanese patients with PH. Two MMD-associated rare variants (p.R4810K and p.A4399T) in RNF213 were identified in two patients, three BMPR2 mutations (p.Q92H, p.L198Rfs*4, and p.S930X) were found in three patients, whereas no CAV1 mutations were identified. To test the effect of the RNF213 variants on PH, vascular endothelial cell (EC)-specific Rnf213 mutant transgenic mice were exposed to hypoxia. Overexpression of the EC-specific Rnf213 mutant, but neither Rnf213 ablation nor EC-specific wild-type Rnf213 overexpression, aggravated the hypoxia-induced PH phenotype (high right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels). Under hypoxia, electron microscopy showed unique EC detachment in pulmonary vessels, and western blots demonstrated a significant reduction in caveolin-1 (encoded by CAV1), a key molecule involved in EC functions, in lungs of EC-specific Rnf213 mutant transgenic mice, suggestive of EC dysfunction. RNF213 appears to be a genetic risk factor for PH and could play a role in systemic vasculopathy.

Successful limb salvage through staged bypass combined with free gracilis muscle transfer for critical limb ischemia with osteomyelitis after failed endovascular therapy.

BACKGROUND: Critical limb ischemia with osteomyelitis is so difficult to treat that even appropriate revascularization and wound therapy cannot achieve limb salvage because of uncontrollable infection. It is still difficult to judge the possibility of limb salvage before revascularization. CASE PRESENTATION: A 73-year-old male complained of a small ulcer on his left toe, which was treated with multiple endovascular therapy. After failed endovascular therapy, he suffered extensive tissue loss with tibial osteomyelitis. We carried out staged surgery that was composed of dual bypass to the sural artery and posterior tibial artery. After intensive debridement and wound care, insertion of a subsequent free gracilis muscle flap to cover the exposed tibial bone was performed, achieving functional limb salvage. CONCLUSION: Even in the threatened limb with extensive tissue loss and osteomyelitis, intensive and multidisciplinary treatment with staged revascularization, muscle transfer, and appropriate wound care achieved functional limb salvage.

Dysregulation of RNF213 promotes cerebral hypoperfusion.

RNF213 is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of RNF213 in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on Rnf213 knockout (KO) and vascular endothelial cell-specific Rnf213 mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin-labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%; p = 0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%; p = 0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of RNF213 in the maintenance of CBF.