Current patterns of care and outcomes for dermatofibrosarcoma protuberans: An international multi-institutional collaborative.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma with an infiltrative growth pattern that makes it challenging to clear margins. High quality data regarding DFSP natural history, management, and outcomes are limited. METHODS: Data were retrospectively collected for adult DFSP patients who underwent resection at 10 institutions in eight countries. Demographics, tumor characteristics, treatment strategies, and outcomes were analyzed. RESULTS: Analysis included 347 patients consisting of young (median, 42 years), White (76.2%), males (54.2%) with truncal lesions (57.3%). The majority (76.8%) were symptomatic at presentation. Preoperative imaging was used in 55.9% of cases. Diagnosis was established with excisional biopsy in 50.9% versus incisional biopsy in 25.0% of cases. Despite planned margins of >1.0 cm in 67.4% of cases, only 69.0% of patients achieved R0 resection. Twenty-two percent of patients underwent at least one re-excision. R0 resection was achieved at a second procedure in 80.2% and a third procedure in 86.2%. Ultimately, R0 resection was feasible in 89.5% of all patients. Fibrosarcomatous transformation (FST) was observed in 12.6%. In total, 6.6% (N = 23) recurred (17 local, six distant). Of the six distant recurrences, 50.0% had FST. With a median follow-up of 47.0 months, disease-specific survival rate was 98.8%. In multivariable analysis, R0 margins at index resection were associated with wider circumferential margins and non-FST histology. CONCLUSIONS: In this international, multicenter collaborative, DFSP practice patterns were heterogeneous but achieved favorable recurrence rates and survival. Multiple excisions to clear margins remain commonplace and can inform future efforts to optimize margin selection.

Infection of surgery for bone and soft tissue sarcoma with biological reconstruction: Data from the Japanese nationwide bone tumor registry.

BACKGROUND: Although biological reconstruction (such as recycled autograft, vascularized autograft, allograft, or bone transport) is possible for bone defects after malignant bone or soft tissue tumor resection, a high incidence of postoperative complications, including infection, poses a problem. The difficulty in accumulating cases has resulted in a lack of reliable etiological information, such as the incidence and risk factors of postoperative infections. METHODS: We conducted a retrospective study on the nationwide registry data. The primary endpoint was the need for additional surgical intervention for infection control. The overall incidence of postoperative infection and the related risk factors were analyzed. RESULTS: We included 707 malignant bone and soft tissue tumors with biological reconstruction, including recycled autograft, vascularized autograft, allograft, bone transport, and combinations of these. The incidence of postoperative infection was 10.8%. Patients reconstructed by pedicled autograft showed a higher incidence of infection, while cases involving the combination of recycled and pedicled autograft or allograft showed a lower incidence. Independent risk factors for infection included age over 17, tumor diameter over 10 cm, the tumor located on the trunk or being high grade, reconstruction by pedicled autograft, and delayed wound healing. CONCLUSION: Infection incidence was comparable to those in previous reports. Several conventional and novel risk factors were extracted by administering nationwide registry data. Data from the nationwide registry was informative for analyzing the incidence of postoperative infection in biological reconstruction with malignant bone and soft tissue tumor resection.

Japan-Multimodal Intervention Trial for the Prevention of Dementia: A randomized controlled trial.

INTRODUCTION: We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI). METHODS: Participants aged 65-85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months. RESULTS: Of 531 participants, 406 completed the trial. The between-group difference in composite score changes was 0.047 (95% CI: -0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels. DISCUSSION: The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required. HIGHLIGHTS: This trial evaluated the efficacy of multidomain intervention in individuals with MCI. The trial did not show a significant difference in preplanned cognitive outcomes. Interventions had positive effects on a wide range of secondary health outcomes. Those with adequate adherence or high risk of dementia benefited from interventions.

FOUR-WEEK ORAL ADMINISTRATION OF BALOXAVIR MARBOXIL AS AN ANTI-INFLUENZA VIRUS DRUG SHOWS NO TOXICITY IN CHICKENS.

High pathogenicity avian influenza is an acute zoonotic disease with high mortality in birds caused by a high pathogenicity avian influenza virus (HPAIV). Recently, HPAIV has rapidly spread worldwide and has killed many wild birds, including endangered species. Baloxavir marboxil (BXM), an anti-influenza agent used for humans, was reported to reduce mortality and virus secretion from HPAIV-infected chickens (Gallus domesticus, order Galliformes) at a dosage of ≥2.5 mg/kg when administered simultaneously with viral challenge. Application of this treatment to endangered birds requires further information on potential avian-specific toxicity caused by repeated exposure to BXM over the long term. To obtain information of potential avian-specific toxicity, a 4-wk oral repeated-dose study of BXM was conducted in chickens (n = 6 or 7 per group), which are commonly used as laboratory avian species. The study was conducted in reference to the human pharmaceutical guidelines for nonclinical repeated-dose drug toxicity studies to evaluate systemic toxicity and exposure. No adverse changes were observed in any organs examined, and dose proportional increases in systemic exposure to active pharmaceutical ingredients were noted from 12.5 to 62.5 mg/kg per day. BXM showed no toxicity to chickens at doses of up to 62.5 mg/kg per day, at which systemic exposure was approximately 71 times higher than systemic exposure at 2.5 mg/kg, the reported efficacious dosage amount, in HPAIV-infected chickens. These results also suggest that BXM could be considered safe for treating HPAIV-infected endangered birds due to its high safety margin compared with the efficacy dose. The data in this study could contribute to the preservation of endangered birds by using BXM as a means of protecting biodiversity.

[Generational differences in lifestyle changes among outpatients with cardiovascular disease during the coronavirus disease pandemic].

AIM: The coronavirus disease (COVID-19) pandemic has caused significant disruptions in various aspects of daily life. The Japanese Government declared a state of emergency in April 2020, which resulted in reduced physical activity. This study investigated the impact of these lifestyle changes by generation among outpatients with cardiovascular disease (CVD). METHODS: In autumn 2020, we conducted a questionnaire survey of 1,156 CVD outpatients who visited the Department of Cardiology at our institution. The survey collected data on physical activities and changes in daily behaviors over the course of the COVID-19 pandemic. Participants were classified into 3 age groups: middle-aged (n=114, ≤64 years old), semi-old (n=330, aged 65-74 years old), and old (n=712, ≥75 years old). The number of steps per day and sedentary time per day were compared between autumn 2019 and 2020, over the course of the pandemic. RESULTS: In autumn 2020, the number of steps per day was significantly decreased and sedentary time significantly increased in all age groups compared to the pre-pandemic levels. However, there were no significant differences in the extent of changes in steps per day or sedentary time over the study period across all age groups. Regarding changes in daily behaviors, only the old-age group reported a decline in volunteering and reduced utilization of daycare services. CONCLUSIONS: The COVID-19 pandemic has resulted in changes in daily activities and lifestyles across all age groups. Because lifestyle patterns differ across generations, it may be necessary to implement age-specific interventions and procedures.

Cancer may accelerate locomotive syndrome and deteriorate quality of life: a single-centre cross-sectional study of locomotive syndrome in cancer patients.

BACKGROUND: Thanks to recent advancement in cancer treatment, an increasing number of cancer patients are expected to live longer with cancer. The ambulatory ability is essential for cancer patients to spend their own independent lives, but locomotive syndrome (LS), a condition of reduced mobility due to impairment of locomotive organs, in cancer patients has been seldom examined. METHODS: This was a single-institutional cross-sectional study. Cancer patients receiving cancer therapy between April 2020 and March 2021 were asked to participate. LS was classified as stage 0-3, and compared with their performance status (PS). Physical component summary (PCS) and mental component summary (MCS) were calculated from the results of Short Form-8. Logistic regression analysis was performed to identify risk factors for LS stage 3. RESULTS: One hundred and seventy-six cancer patients were included. The rate of LS was 96.0%. That of LS stage 3 was 40.9% and as high as 29.7% even if limited to those with PS 0. The mean PCS and MCS were both inferior to the national averages. PCS decreased as the LS stage advanced. Old age and underweight were revealed as independent risk factors for LS stage 3. CONCLUSIONS: The ratio of LS in cancer patients was extremely high, and the LS stage correlated with physical QOL. Even those with PS 0 can have severe LS; thus, LS can be a sensitive detector of physical disability of cancer patients than PS. The improvement of LS can be a key to the preservation of their ADL and QOL.

Vegetable and Fruit Intake Frequency and Mortality in Patients With and Without Chronic Kidney Disease: A Hospital-Based Cohort Study.

OBJECTIVE: Patients with advanced chronic kidney disease (CKD) are generally discouraged from consuming high amounts of vegetables and fruits given the potential risk of hyperkalemia. In the general population, however, lower vegetable and fruit intake is associated with higher mortality. This Japanese hospital-based prospective cohort study including non-CKD and CKD participants examined whether the frequency of vegetable and fruit intake is associated with mortality, and whether the presence of CKD modifies this association. METHODS: Participants were 2,006 patients who visited the outpatient department of a general hospital between June 2008 and December 2016 (55% men; mean age, 69 years). Among these participants, 902 (45%) and 131 (7%) were non-dialysis-dependent patients with CKD and hemodialysis patients, respectively. The frequency of vegetable and fruit intake was determined by a self-report questionnaire using an ordinal scale, "never or rarely," "sometimes," and "every day." Multivariable Cox proportional hazards analysis was conducted, adjusting for potential confounders. RESULTS: Vegetable and fruit intake frequency decreased with worsening CKD stage (P for trend < .001). Baseline serum potassium levels stratified by CKD stage were similar across the three vegetable and fruit intake frequency groups. During a median follow-up of 5.7 years, 561 participants died (47.1/1,000 person-years). Adjusted hazard ratios relative to the "every day" group were 1.25 (95% confidence interval, 1.04-1.52) and 1.60 (95% confidence interval, 1.23-2.08) for the "sometimes" and "never or rarely" groups, respectively, after adjusting for demographic factors, comorbidities, and CKD status. When stratified by CKD status, a similar, albeit non-significant, dose-dependent relationship was observed between vegetable and fruit intake frequency and all-cause mortality irrespective of CKD status, with no effect modification by CKD status (Pinteraction = .69). CONCLUSION: A lower frequency of vegetable and fruit intake is significantly associated with a higher risk of death regardless of CKD status.

Incidence and risk of infection in malignant soft tissue tumor resection: Data from the nationwide soft tissue tumor registry.

BACKGROUND: Postoperative infection is a devastating complication in limb salvage surgery for malignant soft tissue tumors. The low absolute case numbers of these rare cancers represent a bottleneck for data collection and analysis. The administration of nationwide registry data is a practical option for the accumulation of cases. METHODS: Data on malignant soft tissue tumor resection were extracted from the Bone and Soft Tissue Tumor Registry in Japan. The incidence of postoperative infection and its risk factors were analyzed. RESULTS: A total of 14,460 cases were included. The incidence of infection was 2.6%. Significant risks for infection were male sex, lower extremity or trunk location, tumor diameter of over 10 cm, trans-compartmental invasion, high grade, autologous bone graft, myocutaneous flap, vascular reconstruction, reconstruction by prosthesis, postoperative radiotherapy, and delayed wound healing. CONCLUSIONS: The incidence was lower than those in the previous studies, perhaps because of less frequent radiotherapy application. Some of the significant risk factors represented local invasiveness of the tumor, suggesting the importance of the preservation of soft tissue for infection prevention. The administration of nationwide registry data was informative for the analysis of infection in malignant soft tissue tumor resection.

Incidence and risk of surgical site infection/periprosthetic joint infection in tumor endoprosthesis-data from the nationwide bone tumor registry in Japan.

BACKGROUND: Surgical site infection (SSI)/periprosthetic joint infection (PJI) is a devastating complication in limb salvage surgery with endoprosthesis reconstruction for malignant bone tumors. The main bottleneck for data collection and analysis for the status of SSI/PJI in tumor endoprosthesis is the low absolute case numbers of this rare cancer. The accumulation of many cases is possible by administrating nationwide registry data. METHODS: The data on malignant bone tumor resection with tumor endoprosthesis reconstruction were extracted from the Bone and Soft Tissue Tumor Registry in Japan. The primary endpoint was defined as the need for additional surgical intervention for infection control. The incidence of postoperative infection and its risk factors were analyzed. RESULTS: A total of 1342 cases were included. The incidence of SSI/PJI was 8.2%. The incidence of SSI/PJI in the proximal femur, distal femur, proximal tibia, and pelvis were 4.9%, 7.4%, 12.6%, and 41.2%, respectively. Location in the pelvis or proximal tibia, tumor grade, indication of myocutaneous flaps, and delayed wound healing proved to be independent risks for SSI/PJI, whereas age, sex, previous surgery, tumor size, surgical margin, application of chemotherapy and radiotherapy were not significant. CONCLUSIONS: The incidence was equal to those in previous studies. The result reconfirmed the high incidence of SSI/PJI in pelvis and proximal tibia cases and cases with delayed wound healing. Novel risk factors such as tumor grade and application of myocutaneous flaps were marked. The administration of nationwide registry data was informative for the analysis of SSI/PJI in tumor endoprosthesis.

[Orthopaedic Management of Bone Metastasis].

Thanks to advancement in cancer therapy, an increasing number of cancer patients are expected to live longer with cancer in Japan. Activities of daily living(ADL)and quality of life(QOL)of cancer patients has become much more important than ever. Because a decline in mobility negatively affects ADL and QOL, the management of locomotive organs of cancer patients is crucial. In 2018, the Japanese Orthopaedic Association decided their annual activity theme as"locomotive syndrome in cancer patients", with the concept of preventing and improving locomotive syndrome for longer and healthier life of cancer patients. Bone metastasis, as a major cause of locomotive syndrome in cancer patients, needs to be evaluated and managed properly for better ADL and QOL of cancer patients. Pathological fractures, spinal instability, and spinal injury cause not only severe pain and massive functional impairment of patients but increased nursing care burden. To resolve these problems, surgery plays a major role. Possible surgical procedures include internal fixation, curettage, cementation, and arthroplasty for the long bones, whereas percutaneous vertebroplasty, decompression, posterior/anterior spinal fusion, and total en bloc spondylectomy for the spine. Less invasive surgical procedure tends to be chosen for a patient with poorer prognosis. The main purpose of bone metastasis surgery is to maintain ADL and QOL of cancer patients hopefully during the remaining survival time; therefore, estimated survival should be considered when determining the surgical strategy. In addition, case-by- case careful peri-operative management is required because cancer therapy can vary widely in patient age, cancer type, and tumor stage. To accommodate the variety of orthopaedic surgeries to the diversity of cancer therapy, the corporation between oncologists and orthopaedic surgeons is indispensable.

Baloxavir treatment of ferrets infected with influenza A(H1N1)pdm09 virus reduces onward transmission.

Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community.

Polypharmacy, chronic kidney disease, and incident fragility fracture: a prospective cohort study.

INTRODUCTION: Polypharmacy is associated with an increased risk of fracture in aging populations, but no study has accounted for the impact of kidney function on this association. This study aimed to examine the association between polypharmacy and incident fragility fracture based on chronic kidney disease (CKD) status. MATERIALS AND METHODS: Participants were 2023 patients (55% men; mean age, 69 years) of Sado General Hospital enrolled in the Project in Sado for Total Health (PROST) between June 2008 and December 2016. Among these, 65%, 28%, and 7% had non-CKD, non-dialysis-dependent CKD, and dialysis-dependent CKD, respectively. Multivariable Cox proportional hazards analysis was conducted with adjustments for potential confounders. RESULTS: Prevalences of polypharmacy (≥ 5 medications) and hyperpolypharmacy (≥ 10 medications) among participants were 43% and 9% for non-CKD, 62% and 23% for non-dialysis-dependent CKD, and 85% and 34% for dialysis-dependent CKD, respectively. During a median follow-up of 5.6 years, 256 fractures occurred. More medications were associated with a higher risk of fractures. Specifically, compared to participants without polypharmacy, adjusted hazard ratios were 1.32 (95% CI 0.96-1.79) and 1.99 (1.35-2.92) for those with polypharmacy and hyperpolypharmacy, respectively, after adjusting for osteoporosis risk factors, CKD status, and comorbidities. No effect modification by CKD status was observed (interaction P = 0.51). Population-attributable fractions of hyperpolypharmacy for fracture were 9.9% in the total cohort and 42.1% in dialysis-dependent CKD patients. CONCLUSION: Hyperpolypharmacy is associated with an increased risk of fragility fracture regardless of CKD status, and has a strong impact on incident fragility fractures in dialysis-dependent CKD patients.

A randomized phase III trial of denosumab before curettage for giant cell tumor of bone. JCOG1610.

OBJECTIVES: The aim of JCOG1610 (randomized controlled phase III trial) was to confirm the superiority of preoperative denosumab to curettage with adjuvant local therapy for patients with giant cell tumor of bone without possible post-operative large bone defect. METHODS: The primary endpoint was relapse-free survival and the total sample size was set at 106 patients. Patient accrual began in October 2017. However, the accrual was terminated in December 2020 due to a recommendation from the Data and Safety Monitoring Committee because of poor patient accrual. Now, we report the descriptive results obtained in this study. RESULTS: A total of 18 patients had been registered from 13 Japanese institutions at the time of termination on December 2020. Eleven patients were assigned to Arm A (curettage and adjuvant local therapy) and 7 to Arm B (preoperative denosumab, curettage and adjuvant local therapy). Median follow-up period was 1.6 (range: 0.5-2.8) years. Protocol treatment was completed in all but one patient in Arm A who had a pathological fracture before surgery. All patients in Arm B were treated with five courses of preoperative denosumab. Relapse-free survival proportions in Arm A and B were 90.0% (95% confidence interval: 47.3-98.5) and 100% (100-100) at 1 year, and 60.0% (19.0-85.5) and 62.5% (14.2-89.3) at 2 years, respectively [hazard ratio (95% confidence interval): 1.51 (0.24-9.41)]. CONCLUSION: In terms of relapse-free survival, the superiority of preoperative denosumab was not observed in patients with giant cell tumor of bone without possible post-operative large bone defect.

Detection of Decarboxylated Amino Acids after in Vitro Protease Digestion of the Hydrophilic Fraction of Crude Drug Extracts.

Many constituents of crude drugs in Japanese Kampo formulas are thought to function as pro-drugs, whose pharmacological activity is manifested after oral administration. Proteins and peptides in crude drugs may be digested and metabolized in the digestive tract and liver. However, few studies have reported the pharmacological activity of peptides in crude drugs. Here, we applied an analysis using LC-tandem mass spectrometry (LC-MS/MS) to identify the compounds derived from six crude drugs that are assumed to have anti-inflammatory effects. To simulate in vivo protease digestion, each water-soluble fraction of the crude drug extracts was treated with proteases, including endoproteinases and exopeptidases. Amines in the resultant digests were modified by 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate and analyzed using LC-MS/MS, which demonstrated the presence of four decarboxylated amino acids (primary amines). In the digest of the hydrophilic fraction of the fruit of Ziziphus jujuba Miller var. inermis Rehder (Taiso), isobutylamine, isoamylamine, and 2-methylbutylamine were identified, which may be derived from valinyl, leucinyl, and isoleucinyl residues, respectively. Additionally, tyramine possibly derived from tyrosyl residues was identified in the digests of all the crude drugs. In primary cultured rat hepatocytes treated with interleukin-1ß, all these decarboxylated amino acids suppressed the production of nitric oxide, a proinflammatory mediator. Our approach, i.e., in vitro protease digestion and LC-MS/MS analysis, suggests that decarboxylated amino acids may be formed in vivo from peptides and may be responsible for the anti-inflammatory effect of crude drugs included in Kampo medicine.

Stroke incidence and chronic kidney disease: A hospital-based prospective cohort study.

AIM: This prospective cohort study aimed to (i) examine stroke incidence and stroke subtypes by chronic kidney disease (CKD) stage, (ii) examine whether CKD patients with or without proteinuria have a high risk of stroke independent of traditional cardiovascular risk factors, and (iii) determine precise estimates of stroke risk by CKD stage while accounting for competing mortality risk. METHODS: Participants were 2023 patients enrolled in the Project in Sado for Total Health between June 2008 and December 2016 (55% men; mean age, 69 years), of whom 52% had CKD (stage 1-2, 10%; G3a, 48%; G3b, 17%; G4-5, 11% and G5D, 14%). RESULTS: During a median follow-up of 5.7 years, 157 participants developed stroke and 448 died without developing stroke. Most stroke cases were ischaemic among non-dialysis-dependent CKD participants, but the relative frequency of ischaemic stroke was near that of intracerebral haemorrhage among dialysis-dependent CKD participants. After adjustment, stage 1-2 (hazard ratio [HR], 2.97; 95% confidence interval [CI], 1.60-5.51) and stage G3-5 participants with proteinuria (HR, 2.50; 95% CI, 1.56-4.02), but not stage G3-5 participants without proteinuria (HR, 0.64; 95% CI, 0.38-1.08), had a higher stroke risk compared to non-CKD participants. In competing risk analyses, the association was attenuated but remained significant. CONCLUSION: Although the distribution of stroke subtypes differed, CKD participants with proteinuria and those with CKD stage 5D had a 2- and 4-times higher risk of stroke, respectively, than that of non-CKD participants, after accounting for competing mortality risk and traditional risk factors.

A rise-assisting robot extends life space and improves facial expressions of nursing home residents.

BACKGROUND: The introduction of nursing care-support devices using robotic technology is expected to reduce the task burden in long-term care facilities. OBJECTIVE: To investigate the use of the rise-assisting robot, Resyone, in extending and improving the life space of nursing home residents with severe care needs. METHODS: We performed a feasibility study in which Resyone was used to facilitate visits to additional sites in and around the nursing home as part of the care package of three residents. Two weeks before and four weeks after implementation of the new arrangements, the 30 caregivers involved were asked to record transfer times and destinations, while also checking the residents' facial expressions. RESULTS: Before implementation, participants had limited life spaces, but afterwards they regularly visited additional destinations including the garden, home entrance and corridors, which previously they had not visited frequently. The residents' facial expressions became more positive and less negative. This study demonstrates that Resyone can enrich care activities in severely disabled individuals. CONCLUSION: These findings suggest that the sustainable use of Resyone would improve the quality of care at care facilities. Moreover, the extension of otherwise limited life space has the potential to improve care receivers' quality of life. TRIAL REGISTRATION: UMIN Clinical Trials Registry No. UMIN000039204 (20/01/2020); retrospectively registered; interventional study; parallel, non-randomized, single blinded. URL of trial registry records: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000044709 .

Exercise Capacity and Frailty Are Associated with Cerebral White Matter Hyperintensity in Older Adults with Cardiovascular Disease.

Cerebral white matter hyperintensity (WMH) is highly prevalent among older adults. There is little information about the relationship among WMH extent, frailty status, and exercise capacity in older adults with cardiovascular disease (CVD). We assessed the association of WMH with frailty and exercise capacity in CVD patients.Seventy-eight stable older adults with CVD were evaluated for WMH, the Kihon Checklist (KCL), short physical performance battery score (SPPB), and cardiopulmonary exercise testing. WMH volume was quantified on brain magnetic resonance imaging. Patients were classified into 3 groups (using tertiles of 0.52% and 1.05%) according to WMH as a percentage of intracranial volume (ICV), and their KCL scores and exercise capacities were compared. The 3 WMH/ICV groups were mild (n = 26, 0.26% ± 0.14% of intracranial volume), moderate (n = 26, 0.70% ± 0.15%), and severe (n = 26, 1.75% ± 0.67%). Peak VO2 was 15.2 ± 3.7 mL kg-1 minute-1 (mild group), 12.9 ± 3.5 mL kg-1 min-1 (moderate), and 11.4 ± 2.3 mL kg-1 minute-1 (severe) (mild versus moderate, P = 0.049; mild versus severe, P = 0.001). Multivariate regression analysis showed significant associations of severe WMH/ICV with peak VO2 and SPPB. Cerebral WMH was strongly negatively associated with SPPB and peak VO2. WMH volume may be related to exercise capacity and frailty in stable older adult patients with CVD.

Ageing impairs restoration of endometrial blood flow impedance after laparoscopic myomectomy in infertile women with uterine fibroids.

The aim of this study was to evaluate temporal changes in endometrial blood flow after laparoscopic myomectomy (LM). Nineteen infertile women with uterine fibroids who underwent LM were included. The uterine radial artery resistance index (RA-RI) and recovery index were measured before and at 1 week and 3 months after LM. The median RA-RI at 1 week but not 3 months after LM was significantly higher than before. The median recovery indexes at 1 week and 3 months after LM were 14.3% and 1.3%, respectively. Although there was no significant correlation between the patient's age and recovery index at 1 week (r = 0.28, p = .24) after LM, a moderately significant correlation was observed at 3 months (r = 0.54, p = .002). In conclusion, the endometrial blood flow after LM changed over time, and recovery of blood flow was negatively correlated with patient age.IMPACT STATEMENTWhat is already known on this subject? Uterine blood flow is important for wound healing after myomectomy, but no studies have evaluated endometrial blood flow after myomectomy.What do the results of this study add? The endometrial blood flow impedance of RA-RI increased after LM and returned to before surgery at 3 months postoperatively. RA-RI recovery index negatively correlated with patient age.What are the implications of these findings for clinical practice and/or further research? The changes in endometrial blood flow impedance after myomectomy suggest that endometrial blood flow may be involved in wound healing at the enucleation site. The impairment of endometrial blood flow recovery after myomectomy due to increased age may provide a rationale for individualised wound healing after myomectomy. The measurement of endometrial blood flow may be useful in personalising the assessment of the waiting period for pregnancy after myomectomy.

Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection.

BACKGROUND: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. OBJECTIVES: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. METHODS: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. RESULTS: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. CONCLUSIONS: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

A novel approach to the selection of an appropriate pacing position for optimal cardiac resynchronization therapy using CT coronary venography and myocardial perfusion imaging: FIVE STaR method (fusion image using CT coronary venography and perfusion SPECT applied for cardiac resynchronization therapy).

BACKGROUND: Nearly one-third of patients with advanced heart failure (HF) do not benefit from cardiac resynchronization therapy (CRT). We developed a novel approach for optimizing CRT via a simultaneous assessment of the myocardial viability and an appropriate lead position using a fusion technique with CT coronary venography and myocardial perfusion imaging. METHODS AND RESULTS: The myocardial viability and coronary venous anatomy were evaluated by resting Tc-99m-tetrofosmin myocardial perfusion imaging (MPI) and contrast CT venography, respectively. Using fusion images reconstructed by MPI and CT coronary venography, the pacing site and lead length were determined for appropriate CRT device implantations in 4 HF patients. The efficacy of this method was estimated by the symptomatic and echocardiographic functional parameters. In all patients, fusion images using MPI and CT coronary venograms were successfully reconstructed without any misregistration and contributed to an effective CRT. Before the surgery, this method enabled the operators to precisely identify the optimal indwelling site, which exhibited myocardial viability and had a lead length necessary for an appropriate device implantation. CONCLUSIONS: The fusion image technique using myocardial perfusion imaging and CT coronary venography is clinically feasible and promising for CRT optimization and enhancing the patient safety in patients with advanced HF.