Intracranial calcifications associated with factors related and unrelated to atherosclerosis in older people: A community dwelling cohort study.

The cause of intracranial calcification is not fully understood. The aim of the current study was to identify factors associated with intracranial calcification and to determine whether these factors differ in calcification of different sites. A total of 404 community-dwelling people aged 65 or older were included in the study. All subjects underwent brain computed tomography (CT), blood tests, and a Mini-Mental State Examination (MMSE). Intracranial calcifications were scored using CT. Stepwise regression analysis was performed to examine factors associated with intracranial calcification, with each calcification score used as a dependent variable. Independent variables included age, gender, hemoglobin A1c (HbA1c), dyslipidemia, estimated glomerular filtration rate (eGFR), blood pressure, body mass index (BMI), smoking, serum iron, ferritin, and intact parathyroid hormone (PTH). Stepwise regression analysis detected male gender as a predictor of pineal gland calcification and intact PTH as a predictor of basal ganglia calcification. Age and lifestyle diseases were identified as predictors of calcification of the falx cerebri, internal carotid arteries, and vertebral arteries. These results indicate that the mechanisms of calcifications of the pineal gland and basal ganglia might differ from that of artery calcification, and that causes of intracranial calcification might be classified using factors that are and are not related to atherosclerosis.

Development of a laparoscopic sigmoidectomy simulator: Sigmaster.

The sigmoid colon simulator was designed to accurately reproduce the anatomical layer structure and the arrangement of characteristic organs in each layer, and to have conductivity so that energy devices can be used. Dry polyester fibers were used to reproduce the layered structures, which included characteristic blood vessels, nerve sheaths, and intestinal tracts. The adhesive strength of the layers was controlled to allow realistic peeling techniques. The features of the Sigmaster are illustrated through a comparison of simulated sigmoidectomy using Sigmaster and actual surgery. We developed a laparoscopic sigmoidectomy simulator called Sigmaster. Sigmaster is a training device that closely reproduces the membrane structures of the human body and allows surgeons to experience the entire laparoscopic sigmoidectomy process.

Endothelial CLEC-1b plays a protective role against cancer hematogenous metastasis.

Metastasis, which is the spread of cancer cells into distant organs, is a critical determinant of prognosis in patients with cancer, and blood vessels are the major route for cancer cells to spread systemically. Extravasation is a critical process for the hematogenous metastasis; however, its underlying molecular mechanisms remain poorly understood. Here, we identified that senescent ECs highly express C-type lectin domain family 1 member B (CLEC-1b), and that endothelial CLEC-1b inhibits the hematogenous metastasis of a certain type of cancer. CLEC-1b expression was enhanced in ECs isolated from aged mice, senescent cultured human ECs, and ECs of aged human. CLEC-1b overexpression in ECs prevented the disruption of endothelial integrity, and inhibited the transendothelial migration of cancer cells expressing podoplanin (PDPN), a ligand for CLEC-1b. Notably, target activation of CLEC-1b in ECs decreased the hematogenous metastasis in the lungs by cancer cells expressing PDPN in mice. Our data reveal the protective role of endothelial CLEC-1b against cancer hematogenous metastasis. Considering the high CLEC-1b expression in senescent ECs, EC senescence may play a beneficial role with respect to the cancer hematogenous metastasis.

Laparoscopic total pelvic exenteration combined with transanal total mesorectal excision for locally advanced prostate cancer with rectal infiltration.

Introduction: Intensive treatment is typically considered for very high-risk patients with locally advanced prostate cancer and an expected survival time of 5 years or longer. Herein, we report a case of locally advanced prostate cancer with rectal infiltration treated with laparoscopic total pelvic exenteration combined with transanal total mesorectal excision. Case presentation: A 73-year-old man presented with a ring-shaped mass around the rectum. He was diagnosed with prostate cancer with rectal infiltration and underwent laparoscopic total pelvic exenteration combined with transanal total mesorectal excision following neoadjuvant androgen deprivation therapy. Twenty-two months postoperatively during ongoing androgen deprivation therapy, no biochemical recurrence was observed. Conclusion: To our knowledge, this is the first report of a laparoscopic total pelvic exenteration combined with transanal total mesorectal excision for prostate cancer with rectal infiltration. We believe this surgery may be considered a new option for high-risk prostate cancer patients with rectal infiltration.

Can the Single-stapling Technique Following Intersphincteric Resection with Transanal Total Mesorectal Excision Become the New Standard Anastomosis?

For transanal total mesorectal excision (TaTME), the indication for single-stapling technique (SST) has been expanded to include lower anastomosis, even in intersphincteric resection (ISR). We focused on the anastomotic techniques following ISR with TaTME and examined the feasibility and safety of the SST below the anorectal junction (ARJ). Data on postoperative anastomosis-related complications and anorectal function was evaluated in comparison to conventional manual hand-sewn coloanal anastomosis in ISR with TaTME. We examined patients with 3-6 cm tumors from the anal verge who underwent ISR with TaTME between January 2018 and March 2020, and whose anastomotic line was located below the ARJ. Postoperative short-term outcomes and anorectal functions were compared. We also analyzed the effects of various factors on major low anterior resection syndrome (LARS) using multivariate logistic regression analysis. In total, 87 patients-48 in the hand-sewn anastomosis group and 39 in the SST group-were included in this study. SST below the ARJ in ISR with TaTME did not exacerbate surgical outcomes, including anastomosis-related complications. The SST group had a significantly lower LARS score as compared to the hand-sewn anastomosis group, and the proportion of major LARS was significantly lower. Only hand-sewn anastomosis was identified as a statistically significant independent risk factor for major LARS. In TaTME, SST below the ARJ was safe and feasible and had a lower negative impact on postoperative anastomosis-related complications and anorectal function as compared to hand-sewn anastomosis. Thus, SST is a promising anastomotic option for patients with low-lying rectal tumors.

Transanal Total Mesorectal Excision for Rectal Cancer: Toward Standardization of the Surgical Technique.

Laparoscopic surgery is widely used for rectal cancer; however, this technique is challenging due to tapering of the mesorectum in the pelvis, and the forward angle of the distal rectum, which renders this part of the rectum less accessible from the abdominal cavity. Hence, concerns regarding its safety and curability have been raised, particularly for inadequate distal and circumferential resection margins. Recently, transanal total mesorectal excision (TaTME), which involves endoscopic total mesorectal excision (TME) retrogradely from the anal side, has attracted attention worldwide as a solution to these problems. TaTME is superior to the conventional laparoscopic approach for rectal cancer in terms of both oncological and functional preservations. However, a shallow learning curve caused by the unfamiliar anatomical view from the anal side can pose challenges. Therefore, an efficient educational system needs to be established. Randomized controlled trials comparing conventional laparoscopic TME with TaTME are ongoing to demonstrate the usefulness of TaTME. This article reviews changes in the surgical treatment of rectal cancer, with a focus on TaTME, and describes the indications, surgical techniques, and training curricula for TaTME.

A novel treatment based on powder jet deposition technique for dentin hypersensitivity: a randomized controlled trial.

BACKGROUND: This study aimed to evaluate the efficacy and safety of dentin hypersensitivity (DH) treatment using a newly developed device based on a powder jet deposition (PJD) technique that creates a hydroxyapatite (HAP) layer on the dentin surface, thereby alleviating the hypersensitivity. The effect of the PJD treatment was compared with that of conventional treatment using Teethmate Desensitizer (TMD; calcium-phosphate containing material with TTCP (Ca4(PO4)2O) and DCPA (CaHPO4)), which has been used clinically in Japan with well-confirmed effectiveness. MATERIALS AND METHODS: A randomized controlled trial was conducted including 35 patients who had symptoms of DH in two or more quadrants. Two test teeth were selected per patient (70 teeth in total) and randomly assigned to PJD or TMD treatment. The efficacy was evaluated using the improvement rate for air and scratch pain according to the scores obtained via visual analog scale 12 weeks after treatment. The safety assessment was performed focusing on gingival index (GI) and spontaneous pain. The t-test was used to analyze the non-inferiority of PJD treatment compared to TMD treatment. RESULTS: The improvement rate of air pain was 69.0% for PJD and 69.7% for TMD. The improvement rate of scratch pain was 80.8% for PJD and 81.7% for TMD. Non-inferiority with a margin of 10% was not observed for both air and scratch pain. No change was observed in GI from baseline and the improvement rate of spontaneous pain for PJD was higher than that for TMD. CONCLUSION: Non-inferiority of PJD to TMD treatment was not observed in this study; however, it was not statistically demonstrated, and the results were thus interpreted as inconclusive. PJD did improve the DH symptoms, as did TMD. PJD's therapeutic effect was most likely attributable to the deposition of a HAP layer on the tooth surface, which would alleviate hypersensitivity for at least 12 weeks without causing severe adverse events. TRIAL REGISTRATION: UMIN-CTR. ID: UMIN000025022. date: 02/12/2016.

Endoscopic Surgical Skill Qualification System: propensity-score matched cohort analysis of accredited supervisors in laparoscopic rectal cancer surgery.

BACKGROUND: The Endoscopic Surgical Skill Qualification System (ESSQS) in Japan evaluates the surgical skills required for laparoscopic surgery as an operator as well as a supervisor. This study aimed to demonstrate the benefits of an ESSQS-certified surgeon's participation in laparoscopic rectal resections as a supervisor (assistant or advisor). METHODS: We retrospectively reviewed laparoscopic resection results for cStage II and III rectal cancer performed at 56 Japanese hospitals between 2014 and 2016. We used propensity score matching to generate paired cohorts with or without an ESSQS-certified supervisor at a one-to-one ratio. The impact of ESSQS-certified supervisors' participation on short-term outcomes was assessed. In the matched cohort, multivariable logistic regression analysis and multivariable regression analysis of postoperative complication rate and intraoperative blood loss were performed to further mitigate the impact of pathological factors. RESULTS: Two groups (n = 399 each) with or without an ESSQS-certified supervisor were well matched by clinical factors. The group with an ESSQS-certified supervisor had lower blood loss (68 mL vs. 98 mL, P = 0.036) and a lower incidence of severe morbidities of Clavien-Dindo grade ≥IIIa (8.0% vs. 13.3%, P = 0.016). Multivariable logistic regression analysis and multivariable regression analysis confirmed that the attendance of ESSQS-certified supervisors reduced postoperative complication occurrence (adjusted odds ratio: 2.28, 95% confidence interval: 1.38 - 3.80, P = 0.001) and intraoperative blood loss (estimated difference: -15.7 mL, P = 0.016). CONCLUSION: This study demonstrated the educational benefits of ESSQS-certified supervisors, including assistants and advisors, evidenced by their superior short-term outcomes.

Toward the development of a training program that promotes a "social model of disability" for physical therapists: a discussion on experiential learning surrounding the use of "acceptance of disability" by physical therapists.

[Purpose] This study aimed to extract knowledge for the development of a training program for creating a social model of disability for physical therapists, focusing on the experiential learning of those physical therapists who did not use acceptance of disability according to their subjective judgment. [Participants and Methods] The study included 11 physical therapists who were interviewed about their use of acceptance of disability and the circumstances leading to its non-use. [Results] The study identified the past and current use of acceptance of disability, as well as cases and reasons for its discontinuation, along with changes in clinical content. [Conclusion] The study extracted knowledge for the development of training programs in line with the components of the experiential learning model.

Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.

Spermidine improves angiogenic capacity of senescent endothelial cells, and enhances ischemia-induced neovascularization in aged mice.

Aging is closely associated with the increased morbidity and mortality of ischemic cardiovascular disease, at least partially through impaired angiogenic capacity. Endothelial cells (ECs) play a crucial role in angiogenesis, and their angiogenic capacity declines during aging. Spermidine is a naturally occurring polyamine, and its dietary supplementation has exhibited distinct anti-aging and healthy lifespan-extending effects in various species such as yeast, worms, flies, and mice. Here, we explore the effects of spermidine supplementation on the age-related decline in angiogenesis both in vitro and in vivo. Intracellular polyamine contents were reduced in replicative senescent ECs, which were subsequently recovered by spermidine supplementation. Our findings reveal that spermidine supplementation improved the declined angiogenic capacity of senescent ECs, including migration and tube-formation, without affecting the senescence phenotypes. Mechanistically, spermidine enhanced both autophagy and mitophagy, and improved mitochondrial quality in senescent ECs. Ischemia-induced neovascularization was assessed using the hind-limb ischemia model in mice. Limb blood flow recovery and neovascularization in the ischemic muscle were considerably impaired in aged mice compared to young ones. Of note, dietary spermidine significantly enhanced ischemia-induced angiogenesis, and improved the blood flow recovery in the ischemic limb, especially in aged mice. Our results reveal novel proangiogenic functions of spermidine, suggesting its therapeutic potential against ischemic disease.

Short-term outcomes following intracorporeal vs. extracorporeal anastomosis after laparoscopic right and left-sided colectomy: a propensity score-matched study.

BACKGROUND: To compare the short-term outcomes of patients undergoing intracorporeal anastomosis (IA) during laparoscopic colectomy to those undergoing extracorporeal anastomosis (EA). METHODS AND MATERIALS: The study was a single-centre retrospective propensity score-matched analysis conducted. Consecutive patients who underwent elective laparoscopic colectomy without the double stapling technique between January 2018 and June 2021 were investigated. The main outcome was overall postoperative complications within 30 days after the procedure. The authors also performed a sub-analysis of the postoperative results of ileocolic anastomosis and colocolic anastomosis, respectively. RESULTS: A total of 283 patients were initially extracted; after propensity score matching, there were 113 patients in each of the IA and EA groups. There were no differences in patient characteristics between the two groups. The IA group had a significantly longer operative time than the EA group (208 vs. 183 min, P =0.001). The rate of overall postoperative complications was significantly lower in the IA group ( n =18, 15.9%) than in the EA group ( n =34, 30.1%; P =0.02), especially in colocolic anastomosis after left-sided colectomy (IA: 23.8% vs. EA: 59.1%; P =0.03). Postoperative inflammatory marker levels were significantly higher in the IA group on postoperative day 1 but not on postoperative day 7. There was no difference in the postoperative lengths of hospital stay between the two groups, and no deaths occurred. CONCLUSION: The data suggest that performing IA during laparoscopic colectomy can potentially reduce the risk of postoperative complications, especially in colocolic anastomosis after left-sided colectomy.

Single-center comparative study of short-term outcomes of transanal and laparoscopic total mesorectal excisions for low and middle rectal cancers.

BACKGROUND: Transanal total mesorectal excision is a promising surgical treatment for rectal cancer. However, evidence regarding the differences in outcomes between the transanal and laparoscopic total mesorectal excisions is scarce. We compared the short-term outcomes of transanal and laparoscopic total mesorectal excisions for low and middle rectal cancers. METHODS: This retrospective study included patients who underwent low anterior or intersphincteric resection for middle (5-10 cm) or low (< 5 cm) rectal cancer at the National Cancer Center Hospital East, Japan, from May 2013 to March 2020. Primary rectal adenocarcinoma was confirmed histologically. Circumferential resection margins (CRMs) of resected specimens were measured; margins ≤ 1 mm were considered positive. The operative time, blood loss, hospitalization length, postoperative readmission rate, and short-term treatment results were compared. RESULTS: Four hundred twenty-nine patients were divided into two mesorectal excision groups: transanal (n = 295) and laparoscopic (n = 134). Operative times were significantly shorter in the transanal group than in the laparoscopic group (p < 0.001). The pathological T stage and N status were not significantly different. The transanal group had significantly lower positive CRM rates (p = 0.04), and significantly lower incidence of the Clavien-Dindo grade III (p = 0.02) and IV (p = 0.03) complications. Both groups had distal margin positivity rates of 0%. CONCLUSIONS: Compared to laparoscopic, transanal total mesorectal excision for low and middle rectal cancers has lower incident postoperative complication and CRM-positivity rates, demonstrating the safety and usefulness of local curability for middle and low rectal cancers.

Global Medical Device Clinical Trials Involving Both the United States and Japan: Key Considerations for Development, Regulatory Approval, and Conduct.

As medical device development becomes increasingly global, the opportunities and potential advantages offered by international clinical trial and regulatory approval strategies are also growing. In particular, medical device clinical trials involving sites in both the United States and Japan and intended to support marketing in both countries may warrant particular consideration, given the similarities in their regulatory systems, patients and clinical practice patterns, and market sizes. Since 2003, the US-Japan Harmonization By Doing (HBD) initiative has been focused on identifying and addressing clinical and regulatory barriers to medical devices access in both countries via collaboration between governmental, academic, and industry stakeholders. Through the efforts of HBD participants, US-Japanese clinical trials have been conducted and the resulting data have supported regulatory approval for marketing in both countries. Based on these experiences, this paper outlines some of the key factors to consider when developing a global clinical trial involving US and Japanese participation. These considerations include the mechanisms for consultation with regulatory authorities on clinical trial strategies, the regulatory framework for clinical trial notification and approval, recruitment and conduct of clinical sites, and lessons learned from specific US-Japanese clinical trial experiences. The goal of this paper is to promote global access to promising medical technologies by assisting potential clinical trial sponsors in understanding when an international strategy may be appropriate and successful.

Two-team lateral lymph node dissection assisted by the transanal approach for locally advanced lower rectal cancer: comparison with the conventional transabdominal approach.

BACKGROUND: An optimal surgical approach to lateral lymph node dissection (LLND) remains controversial. With the recent popularity of transanal total mesorectal excision, a two-team procedure combining the transabdominal and transanal approaches was established as a novel approach to LLND. This study aimed to clarify the safety and feasibility of two-team LLND (2team-LLND) and compare its short-term outcomes with those of conventional transabdominal LLND (Conv-LLND). METHODS: Between April 2013 and March 2020, 463 patients diagnosed with primary locally advanced rectal cancer underwent a transanal total mesorectal excision; among them, 93 patients who underwent bilateral prophylactic LLND were included in this single-center, retrospective study. Among these patients, 50 and 43 patients underwent Conv-LLND (the Conv-LLND group) and 2team-LLND (the 2team-LLND group), respectively. The short-term outcomes, including the operation time, blood loss volume, number of complications, and number of harvested lymph nodes, were compared between the two groups. RESULTS: The intraoperative and postoperative complications in the 2team-LLND group were equivalent to those in the Conv-LLND group; furthermore, the incidence of postoperative urinary retention in the 2team-LLND group was acceptably low (9%). Compared with the Conv-LLND group, the 2team-LLND group had a significantly shorter operation time (P = 0.003), lower median blood loss (P = 0.02), and higher number of harvested lateral lymph nodes (P = 0.0005). CONCLUSION: The intraoperative and postoperative complications of 2team-LLND were comparable with those of Conv-LLND. Thus, 2team-LLND was safe and feasible for advanced lower rectal cancer. Moreover, it was superior to Conv-LLND in terms of the operation time, blood loss volume, and number of harvested lateral lymph nodes. Therefore, it can be a promising LLND approach.

Single-stapling technique versus hand-sewn anastomosis in inter-sphincteric resection with transanal total mesorectal excision (Super SST): protocol for a multicentre randomized clinical trial.

BACKGROUND: Currently, hand-sewn anastomosis is the standard procedure for inter-sphincteric resection (ISR); however, distal purse-string suturing during transanal total mesorectal excision (TaTME) has allowed a single-stapling technique (SST). Although it was originally intended for cases requiring anastomosis of 2 cm or more above the anorectal junction (ARJ), SST could be safely performed in ISR. The aim of this trial is to determine the superiority of SST over hand-sewn anastomosis in ISR with TaTME. METHODS: The Super SST trial is a multicentre randomized clinical trial comparing stapled and hand-sewn anastomoses in ISR with TaTME. The trial will recruit patients scheduled for TaTME with anastomosis below the ARJ, who will be allocated 1:1 to receive either hand-sewn or stapled anastomosis. The primary endpoint is anastomosis-related complications within 30 postoperative days. Secondary endpoints include all early and late complications, operating time, reoperation, mortality rate, length of postoperative hospital stay, readmission, incidence of anal pain and rectal mucosal prolapse, length of temporary stoma retention, the proportion of patients with a temporary stoma at 1 year after surgery, and anorectal function at 1 year after surgery. CONCLUSION: This trial will provide important clinical insights for new and promising anastomotic options for patients with very low rectal cancer. Registration number: UMIN000047818 (https://www.umin.ac.jp/ctr/index-j.htme).

Efficacy of transperineal minimally invasive surgery with laparoscopic abdominoperineal excision for lower rectal cancer.

PURPOSE: In abdominoperineal excision (APE), the advantages of the "down-to-up" approach are expected to be more obvious when performed as a two-team approach, including transperineal minimally invasive surgery (TpMIS). We investigated the efficacy of TpMIS with laparoscopic APE for lower rectal cancer. METHODS: Patients who underwent laparoscopic APE with (n = 20) or without (n = 30) TpMIS between December 2013 and April 2020 were retrospectively reviewed. Patient and tumor characteristics, intraoperative outcome, short-term outcome, and pathological findings were compared. Additional subgroup analyses were performed in technically challenging cases, including male patients, obese patients, and patients with tumors located at the anterior wall. RESULTS: There was no marked difference in the patient or tumor characteristics or short-term outcomes, including morbidity and mortality between the two groups. Pathological results were comparable, and the circumferential resection margin (CRM) positive rate was 10% in both groups. TpMIS achieved a significant reduction in operative time (p = 0.02). In a subgroup analysis, the amount of blood loss was also smaller in males (p = 0.02) and patients with a high BMI (> 25) (p = 0.005) than in others. CONCLUSION: Simultaneously performing TpMIS and laparoscopic APE is feasible owing to the favorable complication and CRM-positive rates. In terms of operative time and blood loss, TpMIS is expected to be advantageous in both easy and challenging cases.

Gliovascular interface abnormality in mice with endothelial cell senescence.

In the brain, neurons, glial cells, vascular endothelial cells (ECs), and mural cells form a functional structure referred to as the neurovascular unit (NVU). The functions of the NVU become impaired with aging. To gain insight into the mechanism underlying the aging-related changes in the NVU, we characterized in the present study the gliovascular interface in transgenic mice expressing a dominant-negative form of the telomeric repeat-binding factor 2 (TERF2) specifically in ECs using the Tie2 promoter. In these transgenic mice, senescence occurred in the cerebral ECs and was accompanied by upregulation of the mRNAs of proinflammatory cell adhesion molecules and cytokines. It is noteworthy that in the deep layers of the cerebral cortex, astrocytes exhibited an increase in the signals for S100ß as well as a decrease in the polarization of the water channel aquaporin-4 (AQP4) to the perivascular endfeet of the astrocytes. Mechanistically, the perivascular localization of dystroglycan and its ligand, laminin α2, was decreased, and their localization correlated well with the perivascular localization of AQP4, which supports the notion that their interaction regulates the perivascular localization of AQP4. The diminished perivascular localization of laminin α2 may be attributed to its proteolytic degradation by the matrix metalloproteinase-2 released by senescent ECs. Pericyte coverage was increased and negatively correlated with the decrease in the perivascular localization of AQP4. We propose that aging-related changes in ECs induce a mild morphological alteration of astrocytes and affect the localization of AQP4 at the gliovascular interface.