Tokyo Women's Medical University Research Articles

Persistently low tricuspid annular plane systolic excursion and its prognosis in Japanese hospitalized patients with heart failure with reduced ejection fraction.

In patients with heart failure (HF) with reduced left ventricular ejection fraction (HFrEF), low tricuspid annular plane systolic excursion (TAPSE) on echocardiography is associated with poor prognosis. The significance of TAPSE changes post-HF treatment among HFrEF patients remains unclear. We evaluated the factors associated with persistently low TAPSE and its prognostic impact in Japanese hospitalized patients with HFrEF. We prospectively examined 260 HFrEF patients from the prospective observational HIJ-HF III study of HF patients hospitalized at Tokyo Women's Medical University between 2015 and 2019. Persistently low TAPSE was defined as TAPSE < 17mm on both pre- and 1-year post-discharge echocardiography. The primary endpoint of the study was all-cause mortality or re-hospitalization due to HF. Prognosis and characteristics were compared between patients with and without persistently low TAPSE. Using characteristics and echocardiography data, factors associated with persistently low TAPSE were assessed using logistic regression analysis. We identified the prognostic impact of persistently low TAPSE in HFrEF patients using Cox proportional hazards models. Seventy-eight (30%) of the 260 patients had persistently low TAPSE. They had higher New York Heart Association functional class; lower baseline TAPSE and left ventricular ejection fraction; and fewer angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Significant factors associated with persistently low TAPSE included higher brain natriuretic peptide level at 1year after discharge, lower baseline levels of TAPSE and septal s'. Over a follow-up period of 32months (range 12-69months) after the 1-year echocardiography, the rate of the primary endpoint was significantly higher among patients with persistently low TAPSE than that among others (n = 31 (40%) vs. n = 39 (21%), respectively, log-rank p < 0.001). Cox multivariate analysis revealed that persistently low TAPSE was independently associated with adverse events (Hazard ratio, 1.975; 95% confidence interval 1.183-3.295; p = 0.009). Exactly 30% of hospitalized patients with HFrEF had low TAPSE both pre- and 1-year post-discharge. Persistently low TAPSE had independent predictive value of prognosis in these patients.

Outcomes of kidney transplantation in recipients with SARS-cov-2 infection: a 282-case single-center experience in Japan.

The coronavirus disease 2019, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has become a global epidemic. There are concerns regarding the severity of SARS-CoV-2 infections in kidney transplant (KTx) recipients. However, there is limited data on how the epidemic has affected the treatment and prognosis of these patients. Therefore, we aimed to report the changes in the treatment and outcomes of KTx recipients infected with SARS-CoV-2 during each wave at our institution. A total of 282 KTx recipients who were infected with SARS-CoV-2 during the study period were followed up at Tokyo Women's Medical University between March 2020 and August 2022. We investigated the outcomes and treatments of infected KTx recipients. Nineteen (6.7%) patients showed severe outcomes, including eight SARS-CoV-2 infection-related deaths. Risk factors associated with severe outcomes included underlying conditions, such as diabetes mellitus, heart disease, and liver disease (odds ratios, 2.09, 2.88, and 5.52, respectively). Treatment strategies changed throughout the epidemic in response to changes in the SARS-CoV-2 variants. Antiviral drugs were gradually administered as soon as they were approved for use. Treatment strategies for KTx recipients were gradually established over the course of the epidemic. Although the proportion of infected KTx recipients decreased compared to that of the general population throughout the epidemic, many patients still followed a severe course.

Small vessel disease burden predicts incident stroke and all-cause death, but not acute coronary event.

Total small vessel disease (SVD) score is used to measure the burden of SVD by incorporating four established neuroimaging markers; white matter hyperintensity, lacune, cerebral microbleed, and enlarged perivascular space, ranging from 0 to 4. Whether total SVD scores predict all vascular outcomes remains unclear. This study aimed to clarify the predictive value of the total SVD score for incident stroke, mortality, and acute coronary syndrome in independent outpatients with vascular risk factors. We derived data from The Tokyo Women's Medical University Cerebrovascular Disease registry, a prospective observational registry in which 1011 patients with evidence of cerebral vessel disease on magnetic resonance imaging were enrolled. They were followed up until March 2023. The primary outcomes were stroke, all-cause death, and acute coronary syndrome (ACS). After excluding those with a modified Rankin scale score >1, Mini-mental State Examination score <24, and missing T2* images, 692 patients were included. During a median follow-up period of 4.6 years, stroke, ACS, and all-cause death occurred in 52, 24, and 45 patients, respectively. In multivariate analysis, the total SVD score was independently associated with stroke, and all-cause death but not with acute coronary syndrome. Both cutoff values of the total SVD score for stroke, and all-cause death were 1. In conclusion, the total SVD score could predict stroke and mortality but not acute coronary syndrome. Our results suggest intensive management of patients with a total SVD score ≥1 to prevent stroke and all-cause death. Patients with higher total SVD scores were significantly more likely to have a stroke (A; P = 0.012) than those with lower total SVD scores. However, no association was observed between total SVD scores and acute coronary syndrome (B, P = 0.604). For incident stroke, total SVD scores of 1 and 2 were the cutoff levels.

Impact of the State of Emergency Declaration for Severe Acute Respiratory Syndrome Coronavirus-2 Pandemic Suppression on Individuals with Type 1 Diabetes Mellitus.

Objective To examine the impact of lifestyle changes caused by the first emergency declaration issued in 2020 on glycemic control and body weight changes in Japanese individuals with type 1 diabetes mellitus. Methods This study included Japanese individuals with type 1 diabetes mellitus who visited Tokyo Women's Medical University Hospital between January 2019 and September 2020 (n=278). Seasonal changes in glycated hemoglobin (HbA1c) levels and the body mass index (BMI) were compared. A self-administered questionnaire regarding changes in treatment, diet, exercise, sleep, and telecommuting was used to assess lifestyle changes. Results Although HbA1c levels decreased from winter to summer in 2019 and 2020, the annual change was slightly but significantly greater in 2020 than in 2019. Seasonal changes in the BMI between 2019 and 2020 were also significantly different. An increase in the daily insulin dose, overall blood glucose level, diurnal change in blood glucose level, and food intake were significantly associated with increased HbA1c levels. Furthermore, HbA1c levels decreased with increasing moderate physical activity and sleep duration. The change in the BMI increased with increasing insulin dose, overall high blood glucose levels, and food intake. However, an increase in moderate physical activity was associated with a decrease in the BMI. HbA1c levels were significantly lower after the first emergency declaration in individuals with type 1 diabetes mellitus than that before the emergency declaration, even after accounting for seasonal variations. Conclusion Decreased HbA1c levels were associated with a decreased food intake, increased moderate exercise, and increased sleep duration during the state of emergency. The BMI remained relatively unchanged.

Expansion of HLA-DR Positive Peripheral Helper T and Naive B Cells in Anticitrullinated Protein Antibody-Positive Individuals At Risk for Rheumatoid Arthritis.

To investigate immune dysregulation in the peripheral blood that contributes to the pre-rheumatoid arthritis (RA) stage of RA development in anticitrullinated protein antibody (ACPA)+ individuals. Using 37 markers by mass cytometry, we investigated peripheral blood mononuclear cells (PBMCs) from ACPA+ at-risk individuals, ACPA+ early untreated patients with RA, and ACPA- controls in the Tokyo Women's Medical University cohort (n = 17 in each group). Computational algorithms, FlowSOM and Optimized t-Distributed Stochastic Neighbor Embedding, were employed to explore specific immunologic differences between study groups. These findings were further evaluated, and longitudinal changes were explored, using flow cytometry and PBMCs from the US-based Targeting Immune Responses for Prevention of RA cohort that included 11 ACPA+ individuals who later developed RA (pre-RA), of which 9 had post-RA diagnosis PBMCs (post-RA), and 11 ACPA- controls. HLA-DR+ peripheral helper T (Tph) cells, activated regulatory T cells, PD-1hi CD8+ T cells, and CXCR5-CD11c-CD38+ naive B cells were significantly expanded in PBMCs from at-risk individuals and patients with early RA from the Tokyo Women's Medical University cohort. Expansion of HLA-DR+ Tph cells and CXCR5-CD11c-CD38+ naive B cells was likewise found in both pre-RA and post-RA time points in the Targeting Immune Responses for Prevention of RA cohort. The expansion of HLA-DR+ Tph cells and CXCR5-CD11c-CD38+ naive B cells in ACPA+ individuals, including those who developed inflammatory arthritis and classified RA, supports a key role of these cells in transition from pre-RA to classified RA. These findings may identify a new mechanistic target for treatment and prevention in RA.

Misalignment of center of foveal avascular zone and center of photoreceptors in eyes with history of retinopathy of prematurity

To determine the relationship between the center of the foveal avascular zone (FAZ) and the center of the foveal photoreceptors in eyes with a history of retinopathy of prematurity (ROP). To accomplish this, we reviewed the medical records of patients with ROP who were examined at the ROP Clinic of the Tokyo Women's Medical University Hospital. We studied 43 eyes of 23 children with ROP and 67 eyes of 36 control children without any fundus abnormalities. The optical coherence tomography angiographic (OCTA) en face images were used to measure the size and location of the foveal avascular zone (FAZ), and cross-sectional OCT images to measure the central retinal thickness (CRT). Our results showed that the size of the FAZ was significantly smaller in the ROP group (0.200 ± 0.142 mm2) than in the control group (0.319 ± 0.085 mm2; P < 0.01). The CRT was significantly thicker in the ROP group (228 ± 30 µm) than in the control group (189 ± 13 µm; P < 0.01). The mean length of the foveal bulge was not significantly different between the two groups. The actual distance of the misalignment between the center of the FAZ and the center of the photoreceptors was significantly greater in the ROP group (50.4 ± 29.5 µm) than in the control group (39.6 ± 21.9 µm; P = 0.001). The correlations between the actual distance of misalignment and the size of the FAZ, CRT, and length of the foveal bulge in both groups were not significant. Despite the significant misalignment in eyes with a history of ROP, the center of the foveal photoreceptors was consistently located within the narrow FAZ which indicates that the development of the FAZ and photoreceptor formation are interrelated.

Reconsideration of Surgical Indication for Prolactin-producing Pituitary Tumor Focusing on Visual Impairment.

Prolactin-producing pituitary tumor (PRLoma) is the most prevalent functional pituitary tumor. If the tumor becomes large, vision can be impaired. In contrast to other pituitary tumors, cabergoline (CAB) is extremely effective for PRLoma and has become the first-line treatment. In this study, we examined our experience with the pharmacological and surgical management of PRLomas with visual impairment (VI) to determine whether VI could be a surgical indication. Further, we discussed the function of surgery in situations where the gold standard of PRLoma treatment was CAB administration. Of the 159 patients with PRLomas (age, 13-77 [mean = 36.3] years; men, 29; women, 130) at Tokyo Women's Medical University Hospital from 2009 to 2021, 18 (age, 15-67 [mean = 35.8] years; men, 12; woman, 6) had VI (subjectively, 12; objectively, 6). They started CAB treatment immediately (maximum dose: 0.5 to 6 mg/week; average: 2.17 mg/week). VI improved in 16 patients (88.9%) but did not improve in 2 (11.1%) requiring surgeries. One of the two patients had a parenchymal tumor resistant to CAB, and the other had a cystic tumor due to intratumoral bleeding. Consequently, CAB is the first-line treatment for PRLomas with VI because of its significantly high rate of improvement. However, close and rigorous surveillance is necessary for cases resistant to CAB, and the correct decision is required regarding surgical interventions at proper timing and appropriate surgical approaches considering the purpose of surgery.

Association of elevated serum carbohydrate antigen 19-9 levels with extensive interstitial lung disease in patients with systemic sclerosis: A cross-sectional study.

To assess the usefulness of carbohydrate antigen 19-9 (CA19-9) as a biomarker for systemic sclerosis-associated interstitial lung disease (SSc-ILD), using serum samples and clinical parameters of patients with SSc. Patients with SSc admitted to Tokyo Women's Medical University Hospital between 2010 and 2021 and those who underwent chest computed tomography (CT) were included. Patients were diagnosed with ILD based on chest CT findings, and SSc-ILD was categorized as either a limited or extensive disease based on chest CT and pulmonary function test findings. Serum CA19-9 levels were measured in 56 patients with SSc and in 32 healthy individuals. Additionally, we evaluated the difference in serum CA19-9 levels between the groups, the correlation with ILD area and pulmonary function, and discriminative performance to diagnose extensive ILD. Of the 56 patients with SSc, 40 (71.4%) had ILD, and 17 (30.4%) were classified as having extensive disease. Serum CA19-9 levels were significantly elevated in patients with extensive disease compared to those with limited disease (median [interquartile range]: 25.7 U/mL [10.1-50.8] vs. 8.8 U/mL [4.5-17.6], p = .02) and correlated with ILD area (r = .30, p = .02). There was no significant correlation between serum CA19-9 level and pulmonary function. The cutoff of CA19-9 for the diagnosis of the extensive disease was determined to be 19.8 U/mL, with a sensitivity of 64% and specificity of 82% and an area under the curve of 0.74 (95% confidence interval 0.58-0.90). The serum CA19-9 level may be a useful marker for identifying patients with SSc-ILD with extensive disease.

Predictive factors and oncological outcomes of pathological T3a upstaging in patients with clinical T1 renal cell carcinoma undergoing partial nephrectomy.

To investigate predictive factors and oncological outcomes of pathological T3a upstaging in renal cell carcinoma patients who were initially diagnosed as clinical T1 and treated with partial nephrectomy. The clinical records and survival data of 1617 patients, who had undergone partial nephrectomy for clinical T1 renal cell carcinoma at Tokyo Women's Medical University, Tokyo, Japan between January 2011 and December 2020, were analyzed retrospectively. Of 1617 clinical T1 renal cell carcinoma patients who underwent partial nephrectomy, 28 (1.73%) had pathological T3a upstaging. In the multivariable analysis for pathological T3a upstaging using logistic regression models, male sex and clinical T1b were significant factors associated with pathological T3a upstaging (male sex: odds ratio=5.07, 95% confidence interval: 1.18-21.8, clinical T1b: odds ratio=8.36, 95% confidence interval: 3.56-19.6). The Kaplan-Meier method of the recurrence-free survival showed shorter recurrence-free survival in patients with pathological T3a upstaging than in those with pathological T1 (P<0.0001). In the multivariable analysis using Cox proportional hazards regression models, pathological T3a upstaging was no longer significantly associated with recurrence-free survival after adjustment for other pathological factors (hazard ratio=1.59, 95% confidence interval: 0.58-4.36). In a sensitivity analysis that analyzed its components individually instead of whole pathological T3a, neither perinephric fat invasion, sinus fat invasion, nor renal vein invasion was associated with recurrence-free survival. Male sex and clinical T1b were significant predictors for pathological T3a upstaging after partial nephrectomy in clinical T1 renal cell carcinoma patients. Although patients with pathological T3a upstaging had worse recurrence-free survival compared with those without upstaging, multivariable analyses revealed that pathological T3a upstaging was not an independent predictor for poor recurrence-free survival.

Association of the Stanford Integrated Psychosocial Assessment for Transplant and 1-Year Outcome of Living Kidney Transplantation in Japan

Since most kidney transplantations in Japan are performed on the basis of living donors, after-transplant outcomes should achieve optimum results, overcoming participants' possible reduced adherence. This study investigated the association between the Japanese version of the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT-J) and outcomes, one year after the patient's living kidney transplant (LKT). The prospective cohort study was undertaken at Tokyo Women's Medical University Hospital from January 2020 to July 2021, with a one-year follow-up period. The SIPAT-J assesses 18 psychosocial risk factors: (A) Patient's Readiness Level and Illness Management (SIPAT A), (B) Social Support System Level of Readiness (SIPAT B), (C) Psychological Stability and Psychopathology (SIPAT C), and (D) Lifestyle and Effect of Substance Use (SIPAT D). The evaluators, a psychiatrist and three clinical psychologists, conducted an independent, blinded application of the SIPAT-J using participants' medical records. The study focused on physical composite outcomes, psychiatric outcomes, and non-adherent behaviors. The participants were 173 LKT recipients (median age (IQR) 51 (38-59)); 67.1% were male, and 67.1% were employed. The median (IQR) SIPAT scores were SIPAT A [7 (5-9)], SIPAT B [7 (5-9)], SIPAT C [2 (0-4)], SIPAT D [3 (3-4)], and SIPAT total [20 (16-23)]. The physical composite outcome was 25 (14.5%), psychiatric outcome 9 (5.2%), and non-adherent behavior 17 (9.8%). SIPAT C (odds ratio [OR]=1.34, 95% confidence interval [Cl]=1.06-1.72, p=0.02) was significantly associated with the psychiatric outcome. SIPAT B (OR=1.49, 95% Cl=1.12-1.98, p=0.01) and SIPAT total (OR=1.13, 95% Cl=1.03-1.24, p=0.01) were significantly associated with non-adherent behaviors. There was no significant association between the SIPAT and physical composite outcomes. This study is the first to examine the association between SIPAT and physical and psychiatric outcomes one year after LKT, controlling for follow-up periods and factors other than SIPAT. Comprehensive psychosocial assessment before LKT and early identification of factors that may negatively affect transplant success can allow targeted interventions to be implemented and increase the likelihood of favorable recipient outcomes.

A fact-finding survey on pre-ulcerative lesions of foot in patients with diabetes: analysis using the Diabetes Study from the Center of Tokyo Women's Medical University 2018 (DIACET 2018).

We aimed to identify the frequency and risk factors of pre-ulcerative lesions of foot in Japanese individuals with diabetes. This was a single-center cross-sectional observational study. We conducted a questionnaire survey of 5029 individuals with diabetes (mean age 63years; 2185 women; 1015 individuals with type 1 diabetes and 4014 individuals with type 2 diabetes) who (a) participated in the Diabetes Study from the Center of Tokyo Women's Medical University: DIACET 2018, and (b) responded to the presence of pre-ulcerative lesions of foot. A pre-ulcerative lesions of foot was defined as a calluses, ingrown nails, or symptoms of fungal infection. The associations between pre-ulcerative lesions of foot and commonly available clinical information were examined using the logistic regression analysis. 412 of 1015 (40.6%) individuals with type 1 diabetes and 1585 of 4014 (39.5%) individuals with type 2 diabetes reported having any type of pre-ulcerative lesions of foot. The frequency of calluses, ingrown nails, and symptoms of fungal infection, respectively, were 16.8%, 15.8%, and 21.9% in type 1 diabetes and 10.5%, 18.5%, and 24.7% in type 2 diabetes. In the separate analysis by type of diabetes, common risk factors found to be significantly correlated with pre-ulcerative lesions of foot were female gender, numbness in the feet and foot deformation. Proactive foot screening by health care professionals was considered important, especially in individuals with type 1 and type 2 diabetes with advanced complications and foot deformation. The online version contains supplementary material available at 10.1007/s13340-023-00649-7.

Experiences of dialogue in advance care planning educational programs.

Advance care planning (ACP) is a process in which adults engage in an ongoing dialogue about future medical treatment and care. Though ACP is recommended to improve the quality of end-of-life care, the details of the dialogue experience in ACP are unknown. To explore participants' experiences of dialogue in an ACP educational program that encouraged them to discuss the value of a way of life. This qualitative descriptive study used the focus group interview method. Data were analyzed using qualitative content analysis. A dialogue-based ACP educational program was conducted in four regions in Japan for local citizens to discuss the value of their way of life. A total of 66 individuals (mean age = 55.5 ± 17.2years; 50 women and 16 men) participated in focus group interviews. This study was approved by the Ethical Review Committee of Tokyo Women's Medical University (no. 4723) and Kyoto University (no. R2099). Five main themes were extracted: discussing one's thoughts with others in a considerate manner, reflecting on one's way of life through others, feeling a sense of connection with others through storytelling, realizing the difficulties of talking about "what if" topics, and turning one's eyes toward the future through the dialogue. These themes were interrelated and illustrated the complexity of the experience of discussing values. The results suggest that dialogue in ACP is useful in clarifying values. They also indicated the need for dealing with the ethical challenges of discussing value and the importance of caring for the interlocutor to have a safe dialogue. In the ACP process, safety in dialogue may improve readiness in ACP, and health practitioners who support ACP need to address the ethical challenges entailing dialogue about values.

#4635 CIRCULATING NEPHRIN AUTOANTIBODIES IN PATIENTS WITH POST-TRANSPLANT RECURRENCE OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Abstract Background and Aims Post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) is a major challenge in the field of nephrology and kidney transplantation. Primary FSGS is thought to be caused by circulating factors (CFs) that injure podocytes, but these factors remain unknown despite intensive efforts to identify them. Recently, one post-transplant recurrent FSGS patient with pretransplant nephrin autoantibodies was reported (Watts AJB et al, JASN 33:238, 2022). Furthermore, we reported very early post-transplant recurrence changes of podocytes and possible roles of circulating nephrin autoantibodies in a patient with FSGS recurrence (Hattori M et al, AJT 22:2478, 2022). To confirm these preliminary results, we examined the autoantibodies to nephrin and the punctate deposition of IgG colocalized with nephrin using stocked plasma samples and grafted kidney biopsy specimens of the patients with FSGS recurrence. Method This study was approved by the local Ethics Committee of Tokyo Women's Medical University (approval no. 2021-0184). The clinical and research activities reported here are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism”. From 1989 to 2022, a total of 78 patients with FSGS underwent kidney transplantation in our institution, and 16 patients experienced post-transplant recurrence of FSGS. Since the stoked plasma samples were available in 14 out of 16 patients, these 14 patients were included in this study. All 14 patients showed immediate post-transplant recurrence and had no pathogenic variants in FSGS-related genes including NPHS1. Circulating anti-nephrin autoantibodies were measured using the ELISA methods based on the Watts's report with one modification, that is, recombinant extracellular domain of human nephrin was obtained commercially (R&amp;D systems, USA). To validate the ELISA system, circulating anti-nephrin autoantibodies were also measured in 9 genetic FSGS patients, 13 membranous nephropathy (MN) patients, 4 lupus nephritis (LN) patients, and 13 healthy controls. Dual immunofluorescence (IF) staining of nephrin and IgG and image acquisition using the two-dimensional structured illumination microscopy mode with a Nikon microscope were performed as previously reported (Hattori M et al, AJT 22:2478, 2022). Results The cut-off level of anti-nephrin antibody calculated from the results of a total 30 cases including 13 MN patients, 4 LN patients, and 13 healthy controls using Frey's formula (J Immunol Method, 1998) was 172.2 U/mL All 14 recurrent patients enrolled in this study had higher titter than the cut-off level and the mean ± SD of the anti-nephrin antibody level in these patients was 939.9 ± 261.8 U/mL. In contrast, the mean anti-nephrin antibody level in patients with genetic FSGS was 98.6 ± 77.3 U/mL, which was comparable with healthy controls. The IF staining of graft biopsy specimens showed punctate depositions of IgG colocalized with nephrin in all 14 recurrent patients. Conclusion The autoantibodies to nephrin in plasma samples and the punctate deposition of IgG colocalized with nephrin in grafted kidney biopsy specimens were observed in all 14 patients with post-transplant recurrent FSGS. Further studies in larger numbers of patients as well as in patients of other ethnicities are clearly required to confirm this surprising result; however, circulating nephrin autoantibodies could be a possible candidate for CFs in the pathogenesis of recurrent FSGS.

#3627 PHOSPHATIDYLSERINE EXPOSURE AND SHORTENED LIFE SPAN OF ERYTHROCYTES IN RENAL ANEMIA

Abstract Background and Aims The lifespan of erythrocytes in patients with renal anemia is shortened (∼70 days) compared to that of healthy erythrocytes (120 days), but the pathological mechanisms and causes are unclear. Senescent erythrocytes express phosphatidylserine (PS) on their outer membrane, which is a signal for being removed by macrophages. The PS localization in the cellular membrane is mainly regulated by two transporters: flippases and scramblases. Flippases, type Ⅳ P-type ATPases (P4-ATPases), maintain PS localization in the inner leaflet by transporting PS from the outer leaflet of the cell membrane. When scramblases are activated, they facilitate equal distribution of phospholipids between the inner and outer lipid bilayers, resulting in the exposure of PS on the outer leaflet. Recently, we have revealed that reduced flippase activity contributes to PS exposure in healthy senescent erythrocytes [1]. In this study, we examined the percentage of PS-exposed cells and the transporter activity in erythrocytes from renal anemia to elucidate the mechanism of the shortened lifespan. Method This study was approved by the Ethics Committee of Tokyo Women's Medical University (#3835, #4822R2). Erythrocytes from the renal anemic patients undergoing maintenance hemodialysis were separated with the centrifugation using Percoll-density gradient according to our previous report. Resultant heavy and light fractions were used as senescent and young erythrocytes, respectively. We analyzed the percentage of PS-exposed cells (n = 12), flippase/scramblase activities (n = 7), and the factors involved in those enzymatic activities such as intracellular K+ (n = 10) and ATP concentration (n = 9). We also measured protein 4.1a/b and HbA1c as an index of erythrocytes’ age. Results The cells from renal anemia were separated to heavy (senescent) and light (young) fractions, which was similar to the distributions previously performed on healthy erythrocytes. The PS-exposed erythrocytes in the heavy fraction were slightly more than those of the light fraction (p &amp;lt; 0.01, Wilcoxon test), and the flippase activity of the heavy fraction decreased more than that of the light fraction (p &amp;lt; 0.01, paired t-test). Intracellular K+ concentration decreased in the heavy fraction more than in the light fraction similar to the healthy senescent erythrocytes, but there was no statistical difference in the intracellular ATP concentration between the heavy and light fractions. The measurement of protein 4.1a/b and HbA1c in these fractions is still in progress. Conclusion Similar to healthy erythrocytes, reduced flippase activity contributes to PS exposure in senescent erythrocytes of renal anemia, maybe due to the decreased intracellular K+ concentration. This may occur in an earlier stage of senescence than the healthy ones, which may explain the mechanism of the shortened life span.

New Scale Predicting Distant Recurrence in Locally Advanced Lower Rectal Cancer Patients After Neoadjuvant Chemoradiotherapy.

Neoadjuvant chemoradiotherapy (nCRT) for locally advanced lower rectal cancer (LALRC) is effective in preventing locoregional recurrence; however, it is less effective for preventing distant recurrence. This study aimed to evaluate a new scale for predicting distant recurrence before administering nCRT. Sixty-three patients underwent nCRT for LALRC between 2009 and 2016 at the Tokyo Women's Medical University. Of these, 51 consecutive patients who underwent curative surgery were enrolled in this study. Patients with ≥cT3 status or cN-positive LALRC were classified into three groups before nCRT based on the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR): high-risk, NLR ≥3.2 and LMR <5.0; intermediate-risk, NLR <3.2 and LMR ≥5.0 or NLR ≥3.2 and LMR <5.0; and low-risk, NLR <3.2 and LMR ≥5.0. Independent risk factors associated with distant relapse-free survival were analysed using the Cox proportional hazards model. Relapse-free survival from distant metastasis was evaluated using the log-rank test. Patient characteristics and tumour-associated factors were not significantly different between the groups. Distant recurrence in the high-, intermediate-, and low-risk groups was 61.5%, 42.9%, and 20.8% (p=0.046), respectively. In the multivariate analysis, the new scale was an independent risk factor for distant relapse-free survival (high-risk vs. low-risk groups, p=0.004 and intermediate-risk vs. low-risk groups, p=0.055). The 3-year distant relapse-free survival rate in the high-, intermediate-, and low-risk groups was 38.5%, 56.3%, and 81.7% (p=0.028), respectively. A new scale combining the pre-nCRT NLR and LMR was independently associated with distant relapse-free survival. The new scale for LALRC may aid selection for total neoadjuvant chemotherapy.

Association between total cerebral small vessel disease score and cognitive function in patients with vascular risk factors.

Hypertension is the most important risk factor for cerebral small vessel disease (SVD). In this cross-sectional study, we tested the independent association of cerebral SVD burden with global cognitive function and each cognitive domain in patients with vascular risk factors. The Tokyo Women's Medical University Cerebral Vessel Disease (TWMU CVD) registry is an ongoing prospective, observational registry in which patients with any evidence of CVD in magnetic resonance imaging (MRI) and at least one vascular risk factor were consecutively enrolled. For SVD-related findings, we evaluated white matter hyperintensity, lacunar infarction, cerebral microbleeds, enlarged perivascular space, and medial temporal atrophy. We used the total SVD score as the SVD burden. They underwent the Mini-mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) global cognitive tests, and each cognitive domain was evaluated. After excluding patients without MRI T2* images and those with MMSE score <24, we analyzed 648 patients. The total SVD score was significantly associated with MMSE and MoCA-J scores. After adjustment for age, sex, education, risk factors, and medial temporal atrophy, the association between the total SVD score and MoCA-J score remained significant. The total SVD score was independently associated with attention. In conclusion, the total SVD score, cerebral SVD burden, was independently association with global cognitive function and attention. A strategy to reduce SVD burden will have the potential to prevent cognitive decline. A total of 648 patients with any evidence of cerebral small vessel disease (SVD) in MRI and at least one vascular risk factor underwent Mini-mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) global cognitive tests. The total SVD scores count the presence of each SVD-related findings (white matter hyperintensity, Lacunar infarction, cerebral microbleeds and enlarged perivascular space), ranging from 0 to 4, as the SVD burden. Total SVD scores were significantly associated with MoCA-J scores (r = -0.203, P < 0.001). After adjustment for age, sex, education, risk factors, and medial temporal atrophy, the association between the total SVD score and global cognitive scores remained significant.

Introduction of Medical Physics Course at Tokyo Women's Medical University

Introduction of Medical Physics Course at Tokyo Women's Medical University

Stratification of Destination Therapy Candidates by J-HeartMate Risk Score Among Elderly Non-Responders to Cardiac Resynchronization Therapy

Background: For elderly patients with refractory heart failure (HF), destination therapy (DT) with a continuous-flow left ventricular assist device (LVAD) is a possible treatment. The aim of DT is for long-term, satisfying quality of life on LVAD support. Previously, elderly non-responders to cardiac resynchronization therapy (CRT) were primarily destined for palliative care, but DT has been available in Japan since April 30, 2021. This study investigated the prognosis of elderly CRT non-responders and assessed the feasibility of DT in these patients based on the J-HeartMate Risk Score (J-HMRS).Methods and Results: Of the 559 patients who underwent CRT at Tokyo Women’s Medical University between 2000 and 2018, 198 were aged 65–75 years. Among these, 76 were identified as non-responders based on echocardiographic data, and were included in this study. We calculated patients’ J-HMRS and investigated associations between the J-HMRS and cardiac events after CRT. Patients were divided into 3 groups according to the J-HMRS: low (n=23), medium (n=29), and high (n=24) risk. Patients in the low-risk group experienced as many HF rehospitalizations and ventricular arrhythmia events as those in the other groups. However, survival analysis revealed that, after CRT, survival was higher for patients in the low- compared with high-risk group (P=0.04).Conclusions: The J-HMRS classified 30% of elderly CRT non-responders as low risk and as suitable candidates for DT in Japan.

Kampo medicine for women's health care “1st International Symposium on Kampo Medicine”

Traditional & Kampo MedicineVolume 9, Issue 2 p. 123-124 LETTER TO THE EDITOR Kampo medicine for women's health care “1st International Symposium on Kampo Medicine” Yu Jing, Yu Jing Kampo Medicine Pharmacology Research Laboratory, Graduate School of Pharmaceutical Sciences, Yokohama University of Pharmacy, Kanagawa, JapanSearch for more papers by this authorMotoko Fukuzawa, Motoko Fukuzawa Omotesando Fukuzawa Clinic, Tokyo, JapanSearch for more papers by this authorYasumasa Sato, Yasumasa Sato Department of Obstetrics and Gynecology, Kampo Medicines, Gifu Prefectural General Medical Center, Gifu, JapanSearch for more papers by this authorYoko Kimura, Corresponding Author Yoko Kimura kimura.yoko@twmu.ac.jp Institute of Oriental Medicine, Tokyo Women's Medical University, Tokyo, Japan Correspondence Yoko Kimura, Institute of Oriental Medicine, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan. Email: kimura.yoko@twmu.ac.jpSearch for more papers by this author Yu Jing, Yu Jing Kampo Medicine Pharmacology Research Laboratory, Graduate School of Pharmaceutical Sciences, Yokohama University of Pharmacy, Kanagawa, JapanSearch for more papers by this authorMotoko Fukuzawa, Motoko Fukuzawa Omotesando Fukuzawa Clinic, Tokyo, JapanSearch for more papers by this authorYasumasa Sato, Yasumasa Sato Department of Obstetrics and Gynecology, Kampo Medicines, Gifu Prefectural General Medical Center, Gifu, JapanSearch for more papers by this authorYoko Kimura, Corresponding Author Yoko Kimura kimura.yoko@twmu.ac.jp Institute of Oriental Medicine, Tokyo Women's Medical University, Tokyo, Japan Correspondence Yoko Kimura, Institute of Oriental Medicine, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan. Email: kimura.yoko@twmu.ac.jpSearch for more papers by this author First published: 11 August 2022 https://doi.org/10.1002/tkm2.1326Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume9, Issue2August 2022Pages 123-124 RelatedInformation

Population Pharmacokinetic Model of Amiodarone and N-Desethylamiodarone Focusing on Glucocorticoid and Inflammation.

Some population pharmacokinetic models for amiodarone (AMD) did not incorporate N-desethylamiodarone (DEA) concentration. Glucocorticoids activate CYP3A4 activity, metabolizing AMD. In contrast, CYP3A4 activity may decrease under inflammation conditions. However, direct evidence for the role of glucocorticoid or inflammation on the pharmacokinetics of AMD and DEA is lacking. The pilot study aimed to address this gap using a population pharmacokinetic analysis of AMD and DEA. A retrospective cohort observational study in adult patients who underwent AMD treatment with trough concentration measurement was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to March 2019. Both structural models of AMD and DEA applied 1-compartment models, which included significant covariates using a stepwise forward selection and backward elimination method. The eligible 81 patients (C-reactive protein level: 0.26 [interquartile range; 0.09-1.92] mg/dL) had a total of 408 trough concentrations for both AMD and DEA. The median trough concentrations were 0.49 [0.31-0.81] µg/mL for AMD and 0.43 [0.28-0.71] µg/mL for DEA during a median follow-up period of 446 [147-1059] d. Three patients received low-dose oral glucocorticoid. The final model identified that AMD clearance was 7.9 L/h, and the apparent DEA clearance was 10.3 L/h. Co-administered glucocorticoids lowered apparent DEA clearance by 35%. These results indicate that co-administered glucocorticoids may increase DEA concentrations in patients without severe inflammation.