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Summary: Background & Aims: The prevalence of artificially administered nutrition and hydration (AANH) in different age groups among patients with advanced cancer remains unknown. The present study investigated the current utilization of AANH according to age groups in palliative care units. Methods: This was a secondary analysis of a prospective cohort study. We obtained information on primary nutritional administration routes during the first week of admission and data on the averaged calorie sufficiency rate or total calorie intake on the 7th day of admission. Patients were divided into five age groups (18–39, 40–59, 60–74, 75–89, and 90- years). Among patients receiving AANH, the proportions of higher-calorie AANH were compared between the five age groups. Results: A total of 1453 patients were included. The proportion of patients categorized as receiving nutrition and hydration via the parenteral route was the highest in the 18–39 and 40–59 groups (52.4 and 41.1%, respectively). Among patients receiving AANH (n = 534), the proportions of patients categorized into the

Parenteral morphine is widely used for dyspnea of imminently dying cancer patients (terminal dyspnea). However, the efficacy of other opioids such as oxycodone remains largely unknown.To explore the efficacy of parenteral oxycodone vs. morphine by continuous infusion over 24 hours in cancer patients with terminal dyspnea.This was a pre-planned subgroup analysis of a multicenter prospective observational study. Inclusion criteria were advanced cancer patients admitted to palliative care units, Eastern Cooperative Oncology Group performance status = 3-4, and a dyspnea intensity ≥2 on the Integrated Palliative care Outcome Scale (IPOS) for which oxycodone or morphine was initiated by continuous infusion. We measured dyspnea IPOS scores over 24 hours.We analyzed 164 patients who received oxycodone (n = 26) and morphine (n = 138) for dyspnea (median survival = 5 days). The mean age was 70 years, 58 patients (35%) had lung cancer, and 97 (59%) had lung metastases. Complete case analysis revealed that mean dyspnea IPOS scores decreased from 3.0 (standard deviation = 0.7) to 1.5 (0.7) in the oxycodone group (difference in means = 1.5; P 0.001), and from 2.9 (0.7) to 1.6 (1.0) in the morphine group (difference in means = 1.3; P 0.001). No significant between-group differences existed in the IPOS scores at 24 hours (P = 0.753). Adverse events were seen in no and 5 patients in the oxycodone and morphine groups, respectively.Parenteral oxycodone may be equally effective and safe as morphine in the treatment of terminal dyspnea in cancer patients. Future randomized controlled trials should confirm the efficacy and safety of opioids other than morphine for terminal dyspnea.

Background/Objectives Recent studies have revealed thiamine deficiency (TD) as a cause of delirium in cancer patients. However, the extent to which Wernicke encephalopathy is present and in what patients is not well understood. Subjects/Methods In this retrospective descriptive study, we investigated referred cancer patients who were diagnosed with delirium by a psycho-oncologist to clarify the proportion of TD, the therapeutic effect of thiamine administration, and the factors involved in its onset. Results Among 71 patients diagnosed with delirium by a psycho-oncologist, TD was found in 45% of the patients. Intravenous administration of thiamine led to a recovery in about 60% of these patients. We explored the factors associated with TD using a multivariable regression model with a Markov chain Monte Carlo imputation procedure. We found an association between TD and chemotherapy (adjusted odds ratio, 1.98 [95% confidence interval, 1.04–3.77]); however, there were no significant associations between TD and the other factors we considered. Conclusions TD is not particularly rare in delirium patients undergoing psychiatric consultation. The delirium was resolved in more than half of these patients by intravenous administration of thiamine. Oncologists should consider TD as a cause of delirium in cancer patients. Further prospective study is needed to clarify the relationship between TD and delirium in cancer patients.

A phase 3 study was conducted to verify the efficacy and safety of 5% sofpironium bromide (BBI‐4000) gel (hereinafter referred to as sofpironium) administrated for 6 weeks in Japanese patients with primary axillary hyperhidrosis. The primary efficacy end‐point was the proportion of patients who satisfied both criteria of a Hyperhidrosis Disease Severity Score (HDSS) of 1 or 2 at the end of 6‐week treatment and a 50% or more reduction in total gravimetric weight of sweat at the end of treatment relative to baseline. A total of 281 patients were randomized to receive 5% sofpironium (141 patients) or vehicle (140 patients), and all patients were included in the full analysis set (FAS). In the FAS, 70.1% of patients were female, and the median age was 35.0 years. The proportion of patients who achieved the primary efficacy end‐point was 53.9% in the sofpironium group and 36.4% in the vehicle group, with a statistically significant difference of 17.5% (95% confidence interval, 6.02–28.93) between these two groups (P = 0.003). The incidence of adverse events was 44.0% in the sofpironium group and 30.7% in the vehicle group, and the incidence of adverse drug reactions was 16.3% in the sofpironium group and 5.0% in the vehicle group. Reported adverse events were generally mild or moderate in severity. In the sofpironium group, common events (incidence, ≥5%) were nasopharyngitis (14.2%) and dermatitis/erythema at the application site (8.5%/5.7%), with no serious adverse events reported. This study demonstrated the efficacy and safety of 5% sofpironium.

ObjectiveCognitive dysfunction has a negative effect on cancer treatment; however, in a cancer setting, specific treatments can restore cognitive function. Such conditions are known as reversible dementia, with one of these being vitamin B12 (VB12) deficiency. However, there have been no reports of VB12 deficiency identified by preoperative evaluation in cancer patients.MethodWe studied a patient who was referred to the Department of Psycho-oncology on suspicion of cognitive decline prior to lung cancer surgery. Preoperative evaluation revealed VB12 deficiency.ResultsThe patient was an 82-year-old woman diagnosed with lung cancer. She also presented with cognitive decline and, therefore, was referred to the Department of Psycho-oncology for preoperative evaluation. The patient scored 19 points on a Mini-Mental State Examination (MMSE), which is indicative of cognitive decline. As the onset of symptoms occurred several months previously and they were subacute, the possibility of reversible dementia was considered. Extensive examination revealed VB12 deficiency, and VB12 replacement therapy normalized the MMSE score to 25 points before surgery.Significance of the resultsWhen cognitive decline is observed in cancer patients, it is necessary to actively evaluate the serum levels of some B vitamins, including VB12.

ObjectiveIt is well known that the burden on the families of cancer patient extends across many aspects, but there have been no reports of family members developing delirium due to the burden of caring for a cancer patient.MethodsWe reported a caregiver who developed Wernicke encephalopathy (WE) while caring for a family member with advanced cancer.ResultsThe subject was a 71-year-old woman who had been caring for her husband, diagnosed with gastric cancer and liver metastases, for 5 months. She visited the “caregivers’ clinic” after referral by an oncologist who was worried about a deterioration in her mental condition that had appeared several weeks previously. The woman had a history of diabetes mellitus. Some giddiness was observed and, based on her inability to answer questions, her level of consciousness was checked and some disorientation was observed. She was diagnosed with delirium. A blood sample was collected to investigate the cause of the delirium, but the test data showed no hypoglycemia. Her appetite had declined since her husband was diagnosed with cancer. Thiamine deficiency was suspected as thiamine stores in the body are depleted within about 18 days and her loss of appetite had continued for 5 months. On intravenous injection of 100 mg of thiamine, her consciousness level was returned to normal in 1 h. A diagnosis of WE was supported by the patient's abnormally low serum thiamine level.Significance of the resultsThe family members of cancer patients may develop a loss of appetite due to the burden of caring, resulting in WE. When providing care for signs of distress in family members, it is necessary to pay attention not only to the psychological aspects but also to their level of consciousness and physical aspects, particularly the possibility of serious illness resulting from reduced nutritional status.

Despite the fact that both thiamine deficiency (TD) and Wernicke encephalopathy (WE) have been observed to some degree in cancer patients, such cases of TD and/or WE reported to date have all been diagnosed after the initiation of treatment. We here report a case of TD that presented without the commonly accepted triad of WE symptoms based on a total nutritional evaluation prior to the onset of treatment for cancer. The patient was a 71-year-old man with esophageal cancer who was referred to the oncology outpatient clinic for evaluation to determine the treatment plan. Although he did not present with delirium, cerebellar signs, or ocular symptoms, TD was suspected based on a reduction in appetite lasting 2 months as thiamine stores in the body are depleted in as few as 18 days. Blood findings showed a marked decline in serum thiamine level supported, which the diagnosis of TD. This case revealed the existence of a cancer patient with subclinical TD prior to the onset of treatment for cancer. Due to the fact that TD can occur without the characteristic symptoms as in this case, we believe it is important that total nutritional evaluation of cancer patients always be considered.

Although there have been recent reports of nonalcoholic thiamine deficiency (TD), no association has been reported between the exacerbation of the psychiatric symptoms of Alzheimer's disease patient and TD. An 89‐year‐old woman with dementia visited our hospital because of acute deterioration in behavioral and psychological symptoms of dementia (BPSD). Her medical history revealed a decrease in oral food intake lasting more than 2 weeks, so that TD was suspected and abnormal behavior improved significantly after thiamine administration. Thiamine deficiency should be suspected in patients with dementia who demonstrate acute deterioration in BPSD possibly related to poor oral food intake.

Land abandonment, e.g. agricultural land abandonment, can result in various social and ecological impacts. It would thus be helpful if the extent and spatial pattern of future land abandonment could be projected. However, the trajectory of future land abandonment generally depends on various factors, including biophysical conditions and future changes in socioeconomic indicators in the area. In this study, we developed a general framework for a scenario-based land abandonment projection, featuring a coupled regional economic and spatially explicit land change modeling approach. We applied this framework in selected municipalities in Fukushima Prefecture, Japan, under two socioeconomic development scenarios (2014-2050): low population and economic growth (LL scenario) and high population and economic growth (HH scenario). The case study results, which are also visualized through a set of hot spot maps, revealed that agricultural land abandonment would be more intense under the HH scenario due to the much higher future decline in farmer population driven by the shift in people's employment and main source of livelihood. Under the LL scenario, residential and urban land abandonment would be more profound because of the much higher future decline in total population. In general, our results provide insights into some plausible future socioeconomic changes, their interplay and their consequent land abandonment in the case study area, which would be useful in the context of forward-looking adaptive development planning. The proposed framework can be applied to other case study areas.

Rurioctocog alfa (recombinant Factor VIII: AdvateⓇ) is available for the control of bleeding in patients with hemophilia A in Japan. To evaluate the immunogenicity, safety, and efficacy of prophylactic and on-demand use of rurioctocog alfa, postmarketing surveillance was conducted on 114 previously untreated Japanese patients aged 0–82 years with ≤ 3 exposure days under the conditions of routine clinical practice. A post-hoc comparison of mean annualized bleeding rates between patients in the regular prophylaxis group (7.4 bleeds/year) and in the on-demand treatment group (15.7 bleeds/year) using a negative binomial model found a statistically significant difference (P = 0.0164) in the subset of patients with severe hemophilia A. Favorable prophylactic and on-demand hemostatic efficacy (“excellent” or “good”) was shown in 71.4–88.5% across all treatment regimens. A total of 31 events of adverse drug reactions were reported. Of 114 patients, 21 (18.4%) developed de novo FVIII inhibitor; of these, 17 occurred within 50 exposures. One death was reported. A family history of positive inhibitors was significantly associated with inhibitor development (Fisher exact P value = 0.0004); no other risk factors were identified. Rurioctocog alfa was found to be well-tolerated and effective in previously untreated Japanese patients with hemophilia A in this postmarketing surveillance of routine clinical practice.

BackgroundIn recent years, the use of both molecular targeting agents (MTAs) and immune-checkpoint inhibitors (ICIs) tend to occupy important positions in systemic anticancer therapy (SACT). The objective of this study is to describe the predictors of SACT include both MTAs and ICIs near the end of life (EOL) and the effect on EOL care in patients with advanced cancer.MethodsWe analyzed all patients who died of advanced cancer from August 2016 to August 2019, and we analyzed the survival time of patients who underwent anticancer agents excluded due to the loss of information about the last administration of SACT. The primary endpoint of this study was to identify predictors during the last administration of SACT near EOL.ResultsIn a multivariate analysis, the Eastern Cooperative Oncology Group performance status (ECOG-PS) (ORs 33.781) was significantly related factors within 14 days of death from the last administration of SACT. Age (ORs 0.412), ECOG-PS (ORs 11.533), primary cancer site of upper GI cancers (ORs 2.205), the number of comorbidities (ORs 0.207), MTAs (ORs 3.139), and ICIs (ORs 3.592) were significantly related factors within 30 days of death. The median survival time (MST) of patients with PS 3–4 was 29 days, while that of patients with both PS 0–2 was 76 days. The prevalence rate of delirium with MTAs was 17.5%, which was significantly lower than that of patients without it (31.8%). The prevalence rate of the mean dose of opioids in patients with ICIs was 97.9 mg/day, which was significantly higher than that of patients without it (44.9 mg/day).ConclusionsAge, ECOG-PS, primary cancer site, the number of comorbidities, MTAs, and ICIs use were significant associated with SACT near EOL. Information on these factors may aid clinical decision making in referral to palliative care institutes.

Some genetic and treatment-related factors are risk factors for inhibitor development in patients with hemophilia A (PwHA). However, the genotype distribution of the factor VIII gene (F8) and genetic impact on inhibitor development in Japanese PwHA remain unknown. In 2007, the Japan Hemophilia Inhibitor Study 2 (J-HIS2) was organized to establish a nationwide registry system for hemophiliacs and to elucidate risk factors for inhibitor development, designed for prospective investigation following a retrospective study (J-HIS1) which had already finished. Patients, newly diagnosed after January 2007, were enrolled in J-HIS2 and followed up for inhibitor development and clinical environments since 2008 onward. In the present study, F8 genotypes of PwHA were investigated in the patients recruited from the J-HIS2 cohort as well as those with inhibitor from the J-HIS1 cohort. F8 variants identified in 59 PwHA with inhibitor in J-HIS1 were: 20 intron-22 inversions, 5 intron-1 inversions, 9 large deletions, 4 nonsense, 8 missense, 11 small in/del, and 2 splice-site variants. F8 variants identified in 267 (67 with inhibitor) PwHA in J-HIS2 were: 76(28) intron–22 inversions, 3(2) intron–1 inversion, 1(0) duplication, 8(5) large deletions, 21(7) nonsense, 109(7) missense, 40(11) small in/del, and 9(7) splice-site variants. Forty variants were novel. The cumulative inhibitor incidence rate in the severe group with null changes was 42.4% (95% confidence interval [CI]: 33.7–50.8), higher than that with nonnull changes (15.6% [95%CI: 6.8–27.8]), in J-HIS2. Relative risk for inhibitor development of null changes was 2.89. The spectrum of F8 genotype and genetic impact on inhibitor development in Japanese PwHA were consistent with the previous reports.

Introduction We investigated whether disruption of the inferior longitudinal fasciculus and inferior fronto‐occipital fasciculus are associated with visual hallucinations in Parkinson's disease (PD). Methods Sixty consecutive right‐handed patients with PD with and without visual hallucinations were enrolled in this cross‐sectional study. Diffusion tensor imaging was acquired by 3.0 T magnetic resonance imaging. We measured fractional anisotropy and mean diffusivity of the bilateral inferior longitudinal fasciculus and inferior fronto‐occipital fasciculus using diffusion tensor tractography analysis software. Results Seventeen patients with PD had visual hallucinations; these patients tended to have lower fractional anisotropy and higher mean diffusivity values in all fasciculi than did patients without visual hallucinations. A univariate logistic analysis showed that the presence of visual hallucinations was significantly associated with lower fractional anisotropy and higher mean diffusivity of the left inferior longitudinal fasciculus, and lower Mini‐Mental State Examination (MMSE) scores. A multivariable logistic analysis adjusted by MMSE scores and disease duration showed a significant association between the presence of visual hallucinations and fractional anisotropy and mean diffusivity values of the left inferior longitudinal fasciculus. Conclusions Our results suggest that disruption of left inferior longitudinal fasciculus integrity is associated with visual hallucinations in patients with PD, independent of cognitive impairment and disease duration., We investigated whether disruption of the inferior longitudinal fasciculus is associated with visual hallucinations in Parkinson's disease (PD) used by diffusion tensor imaging. A multivariable logistic analysis adjusted by MMSE scores showed a significant association between the presence of visual hallucinations and fractional anisotropy and mean diffusivity values of the left inferior longitudinal fasciculus. Our results suggest that disruption of left inferior longitudinal fasciculus integrity is associated with visual hallucinations in patients with PD, independent of cognitive impairment.

We describe a proposed cascode GaN device configuration that allows stable operation during zero voltage switching (ZVS) turn-on transition and suppresses non-ZVS losses. We verified that application of our proposed device to an LLC resonant converter resulted in stable operation. In our device configuration, a GaN high-electron-mobility transistor (HEMT) gate is directly driven by a commercial Si MOSFET driver via a charge pump circuit. This allows the slew rate (dv/dt) to be controlled by an external gate resistance. In addition, we demonstrate that the 650-V normally-on GaN HEMT used in our proposed device configuration has highly reliable characteristics. The predicted lifetime for a 0.1% failure rate under actual bias conditions (Vds = 500 V at (150°C)) exceeds 1000 years (8.76 $\times $ 106)hr).

Background: We report a case in which a family member caring for her mother with dementia developed Wernicke encephalopathy, which is a neuropsychiatric disorder caused by acute/subacute thiamine deficiency, during the course of care. Case presentation: A 63-year-old woman consulted our psychiatric outpatient clinic complaining of difficulty in providing care. She had started caring for her mother with dementia 6 months previously, during which time she began to feel tired. In addition, a loss of appetite had appeared 2 months prior to her visit, and this had decreased to about 30% of normal from 10 days previously. Neurologically, she experienced mild unsteadiness, but she was fully conscious and had no ocular symptoms. Based on the fact that the store of thiamine in the body is exhausted in about 18 days, the possibility of thiamine deficiency was considered, and her unsteadiness disappeared after an intravenous injection of thiamine. Test results showed her serum thiamine level to be abnormally low, and the patient was diagnosed with Wernicke encephalopathy. Conclusions: The burden of caring for a dementia patient may affect the nutritional status of the family caregiver. Thiamine deficiency should be one of the items considered as a nutritional issue in such caregivers.

The benefits of artificial nutrition and hydration in patients with advanced cancer remain unknown. Therefore, we conducted a prospective study to evaluate effects of enteral nutrition (EN) and parenteral nutrition and hydration (PNH) on survival in palliative care units.This study involved a secondary analysis of a multicenter cohort study. Data of primary nutritional administration routes during the first week after admission (oral intake, enteral tube feeding, parenteral nutrition, parenteral hydration, poor oral intake) were obtained. Data of averaged calorie sufficiency rate/total calorie intake [high (75% ≤ or 750 kcal/day ≤), moderate (50-75% or 500-750 kcal/day), low (25-50% or 250-500 kcal/day), very low (25% or250 kcal/day)] were also obtained. After investigating the implementation of artificial nutrition and hydration, participants were divided into three groups according to the nutritional administration route and calorie sufficiency rate/total calorie intake: EN, PNH, and control. We conducted time-to-event analyses using the Kaplan-Meier method, log-rank test, and univariate and multivariate Cox regression analyses.Patients were divided into the EN group (n = 730), PNH group (n = 190), and control group (n = 533). Differences in survival rates among the three groups were significant (Log-rank P 0.001). Median survival times were 43.0 (95% CI 40-46), 33.0 (95% CI 29-37), and 15.0 (95% CI 14-16) days, respectively (P 0.001). In the multivariate-adjusted model, a significantly lower risk of mortality was observed in Cox's proportional hazard model in the EN group and PNH groups (HR 0.43 [95% CI 0.37-0.49], P 0.001; and HR 0.52 [95% CI 0.44-0.62], P 0.001, respectively) than in the control group.This study indicated the clinical benefits of EN and PNH for patients with advanced cancer. Nevertheless, managing symptoms to improve oral intake is essential before initiation of PNH, because EN was superior to PNH.

One-way carsharing systems are expected to support users' mobility in cities including multimodal trips where carsharing and public transport are combined. Station-based carsharing enables users to travel to parking places near the public transportation stations and provide a means of access and egress. As a result, it is hoped that carsharing might even rise the modal share of public transportation. When setting up the carsharing station network from a transport social welfare perspective, we suggest that therefore the improvement in gained accessibility in the network should be considered. We discuss this with the example of the “Harmonious Mobility” carsharing scheme in Toyota City, Japan; one of a few one-way carsharing schemes in Japan. We use metaheuristics to determine the optimal vehicle locations and discuss the resulting potential impact on accessibility from specific points in the network, the network as whole as well as the potential of multimodal trips.

Clinical efficacy of aggressive end-of-life (EOL) chemotherapy remains unclear. Medical records of patients with advanced cancer between August 2011 and August 2016 were retrospectively analyzed. The primary endpoint was to identify prognostic factors at the last administration of chemotherapy. The secondary endpoint was to analyze the relationship between EOL symptoms and EOL treatment details. Among 300 evaluated patients, the number of patients who died within 14 and 30 days from the last administration of chemotherapy were 16 (5.3%) and 50 (16.7%), respectively. Multivariate analysis revealed that ECOG-PS (OR 3.698, p

Objectives To investigate the usefulness of S-1 plus cisplatin alternating with S-1 plus docetaxel as first-line treatment in patients with advanced gastric cancer, we conducted a phase I/II study to determine the maximum tolerated dose and recommended dose, and evaluate efficacy and toxicity. Materials and methods Patients with histologically confirmed unresectable and recurrent gastric cancer were enrolled in this study. Cisplatin was administered on day 1 and the dose escalated by 10 mg/m from a starting dose of 40 mg/m in the phase I part. S-1 was given orally at 80 mg/m on days 1 to 14 and docetaxel at 40 mg/m on day 22 in combination with S-1 80 mg/m on days 22 to 35. The treatment was repeated every 6 weeks. The primary endpoint of the phase II analysis was the response rate. Results Nine patients entered the phase I and 24 the phase II part. Because 50% of patients (3/6) developed dose-limiting toxicities in the phase I part, the maximum tolerated dose of cisplatin was presumed to be 50 mg/m. Therefore, the estimated recommended dose of cisplatin was 40 mg/m; 27 patients received that dose. The response rate was 59.3% (95% confidence interval, 40.8-77.8) and the median follow-up 26.2 months. The median progression-free survival was 7.9 months and the median overall survival 18.6 months. The most common grade 3/4 toxicities were neutropenia (59.3%), leucopenia (37.0%), and anemia (29.6%). These toxicities were tolerable and manageable. Conclusion This alternating treatment seems to have promising activity with tolerable toxicities in the first-line treatment of patients with advanced gastric cancer.

Bleeding and obstruction are common localized symptoms in patients with unresectable gastric cancer. Although there are several reports about surgical and endoscopic therapies for gastric cancer, there are few regarding palliative radiation therapy. We retrospectively analyzed data for 23 gastric cancer patients who underwent palliative radiation between April 2006 and March 2014, with either localized bleeding (n = 18) or upper gastric obstruction (n = 10). The median (range) total dose and fraction (Fr) of radiotherapy (RT) were 42 (18–60) Gy and 20 (9–30) Fr, respectively. The response rates were 88.8% (bleeding) and 80% (obstruction). The median event-free survival times of the bleeding and obstruction groups from the start of radiation were 103 and 104 days, respectively. Adverse events with RT and chemo-radiotherapy (CRT) were grade 2 nausea (n = 4) and grade 2 esophagitis (n = 3) and grade 2 neutropenia (n = 3). In univariate analysis, the antrum as the gastric primary site (p = 0.063) and peritoneal metastasis (p = 0.054) occurred more frequently in the non-responders (n = 4) than the responders (n = 19).

A 36-year-old man with a history of irradiation for acute lymphoblastic leukemia developed headache with cortical dysfunction lasting for 4 weeks. The clinical features were consistent with stroke-like migraine attacks after radiation therapy (SMART) syndrome. Six months later, he developed cerebral infarction due to occlusions of the left anterior and middle cerebral arteries. This is the first case report describing SMART syndrome followed by severe cerebral infarction. Although an association between the two episodes was not assumed, this case indicates that protective therapies against infarction might need to be considered for patients with SMART syndrome.

Rurioctocog alfa (recombinant factor VIII: Advate®) is available for the control of bleeding among patients with hemophilia A in Japan. To evaluate the perioperative safety and hemostatic efficacy of Advate®, a postmarketing surveillance was conducted in Japanese patients undergoing surgery in a real-world setting. A total of 74 surgical procedures performed in 58 subjects aged 0–75 years, including three females, were studied. A hemostatic efficacy rating of “excellent” or “good” was reported in 73/74 surgical procedures (98.6%). Perioperative bleeding was successfully controlled by Advate® in five subjects with positive FVIII inhibitors (2.4-9.1 BU/mL). Advate® was administered at higher initial bolus doses (114-385 IU/kg) and at higher rates by subsequent initial continuous infusion (8.3-15 IU/kg/hour) in the five subjects with inhibitor than in the subjects without inhibitor (n = 47; mean initial bolus dose: 53.4 IU/kg; subsequent mean initial continuous infusion: 3.8 IU/kg/h). Adverse drug reactions were reported in 7/74 (9.5%) procedures, two of which were the development of de novo FVIII inhibitors. Overall, the perioperative use of Advate® in a real-world setting was found to be safe and effective among Japanese patients with hemophilia A.

A 79-year-old woman with a history of Guillain-Barré syndrome (GBS) developed somnolence and tetraparesis after pneumonia. Based on clinical and laboratory findings, she was diagnosed with complications of acute inflammatory demyelinating polyneuropathy (AIDP) and acute disseminated encephalomyelitis (ADEM). Anti-galactocerebroside (Gal-C) IgG antibodies were detected in her serum. Cases of recurrent GBS in patients who are positive for this antibody are extremely rare. The anti-Gal-C IgG antibodies likely played an important role in the pathogenesis of the AIDP and ADEM.

A 63-year-old man developed vomiting, paraparesis, dysuria, bulbar palsy, and orthostatic hypotension over a period of 5 months. Neuroradiological examinations showed a swollen lower brainstem with a dural arteriovenous fistula at the craniocervical junction (DAVF-CCJ). A steroid was administered intravenously in the hospital to relieve brainstem edema. A few hours later, however, the patient developed acute tetraparesis with respiratory failure. Recently, there have been several reports describing the acute worsening of paraparesis in patients with a spinal dural arteriovenous fistula after steroid treatment. In addition to these reports, the present case suggests the risk of administering steroids to patients with DAVF-CCJ, especially those with brainstem dysfunction.

Background: Tumor fever and infection are common febrile etiologies among advanced cancer patients. To date, only few studies have been conducted to differentiate between tumor fever and infections. Objective: This study aimed to identify discriminating factors that provide rapid results and are feasible and minimally invasive for discriminating between tumor fever and infection in advanced cancer patients. Methods: This is a retrospective cohort study. Advanced cancer patients with clinically diagnosed tumor fever or infection, who received medical treatment from palliative care specialists in 10 nationwide Japanese hospitals, were consecutively identified during August 2012 and November 2014. The symptoms, physical findings, blood test results at baseline and during fever, imaging findings, and sociodemographic factors of these patients were retrospectively extracted. Results: Thirty-three patients with tumor fever and 72 patients with infection were identified. Their mean age was 68.8 years, 68 (64.8%) were men, and the median palliative performance status (PPS) was 50. Statistically significant factors predicting tumor fever by logistic regression analysis were as follows: deterioration of PPS (odds ratio, 0.078), shaking chills during fever (0.067), and change from baseline data of neutrophil/lymphocyte ratio of ≥5 (0.14). Conclusions: Shaking chills during fever, and changes from baseline of performance status and white blood cell differentiation can be useful to differentiate between tumor fever and infection among advanced cancer patients. Further confirmatory studies are needed.

e24061 Background: Advanced cancer patients complain of highly distressing symptom at the end-of-life, and important reasons for palliative intervention to relive symptoms. Methods: We analyzed 1282 patients who died of advanced cancer from August 2011 to August 2019 retrospectively. We divided into patients who complain of symptom include fatigue, dyspnea, nausea and vomiting, and cancer pain, or didn’t for 3 days prior to death, and analyzed predictors by multiple logistics method. The primary endpoint of this study was to identify frequency and predictors of end-of-life symptoms in advanced cancer patients. Results: As a background, the median age is 73 years old, 690 males, 592 females, 227 gastroesophageal cancers, 250 biliary pancreatic cancers, 54 hepatocellular carcinomas, 189 colorectal cancer, 251 lung cancers, 71 breast cancers, 58 urological malignancies, 60 gynecological malignancies, 47 head and neck cancer, 31 hematological malignancies, and 22 sarcomas. Number of patients who complained of dyspnea, fatigue, nausea and vomiting, and cancer pain were 235 (18.3%), 318 (24.8%), 81 (6.3%), and 322 (25.1%) at the end-of-life. In a multivariate analysis, peritoneal metastasis (ORs 1.812), with mental (ORs 0.549), palliative referral (ORs 0.680), Eastern Cancer Organization Group Performance Status (ECOG-PS) (OR0.679) and consciousness level (ORs 0.610) was independent predictors in patients with fatigue at the end-of-life. Chest cancer (Odds Ratio 2.635), lung (ORs 2.159), brain (ORs 0.431) and peritoneal metastasis (ORs 0.602), with mental (ORs 0.429), respiratory (ORs 1.960) and metabolic disorder (ORs 0.520), palliative referral (ORs 0.645) and consciousness level (ORs 0.468) was independent predictors in patients with dyspnea. Lung metastasis (ORs 0.480, peritoneal metastasis (ORs 1.812), with anti-cancer therapy (OR 2.244) and consciousness level (ORs 0.610) was independent predictors in patients with nausea and vomiting. Brain metastasis (ORs 0.435, liver metastasis (ORs 1.374), and consciousness level (ORs 0.599) was independent predictors in patients with cancer pain. Conclusions: We reported frequency and independent predictors of end-of-life symptoms in advanced cancer patients. Information on these predictors be useful to explaining about their end-of-life in advance.

The idea that noncrop habitat enhances pest control and represents a win–win opportunity to conserve biodiversity and bolster yields has emerged as an agroecological paradigm. However, while noncrop habitat in landscapes surrounding farms sometimes benefits pest predators, natural enemy responses remain heterogeneous across studies and effects on pests are inconclusive. The observed heterogeneity in species responses to noncrop habitat may be biological in origin or could result from variation in how habitat and biocontrol are measured. Here, we use a pest-control database encompassing 132 studies and 6,759 sites worldwide to model natural enemy and pest abundances, predation rates, and crop damage as a function of landscape composition. Our results showed that although landscape composition explained significant variation within studies, pest and enemy abundances, predation rates, crop damage, and yields each exhibited different responses across studies, sometimes increasing and sometimes decreasing in landscapes with more noncrop habitat but overall showing no consistent trend. Thus, models that used landscape-composition variables to predict pest-control dynamics demonstrated little potential to explain variation across studies, though prediction did improve when comparing studies with similar crop and landscape features. Overall, our work shows that surrounding noncrop habitat does not consistently improve pest management, meaning habitat conservation may bolster production in some systems and depress yields in others. Future efforts to develop tools that inform farmers when habitat conservation truly represents a win–win would benefit from increased understanding of how landscape effects are modulated by local farm management and the biology of pests and their enemies., This work was supported through the National Socio-Environmental Synthesis Center (SESYNC) National Science Foundation Award DBI-1052875 for the project “Evidence and Decision-Support Tools for Controlling Agricultural Pests with Conservation Interventions” organized by D.S.K. and R.C.-K

The International Immune Tolerance Induction (I-ITI) Study in hemophilia A patients with inhibitors included 16 Japanese patients among a total of 115 test subjects. The results within this group of Japanese patients were 11 cases of I-ITI off-study, three cases of I-ITI on-study, and two cases of tolerance on prophylaxis. There was no significant difference in success rate between the low-dose and high-dose groups (Study I). Successively, independent follow-up survey in Japan was conducted in 14 cases, with consent (Study II). Ten cases were off-study at the end of the I-ITI Study. Of these 10 cases, seven of seven successful cases remained clinical successes at the end of the follow-up study, one partial success became a full success while a second relapsed, and one failure was subsequently evaluated as a partial success. Four cases that were on-study at the end of I-ITI Study were classified as three successes and one failure at the end of the follow-up study. As a result, the status at the end of follow-up study was: 11 ITI successes (78.6 %); one partial success; one failure; and one relapse. Thus, the ITI follow-up study was helpful in providing a long-term prognostic determination of inhibitors.

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Background We aimed to develop an adaptable prognosis prediction model that could be applied at any time point during the treatment course for patients with cancer receiving chemotherapy, by applying time-series real-world big data. Methods Between April 2004 and September 2014, 4,997 patients with cancer who had received systemic chemotherapy were registered in a prospective cohort database at the Kyoto University Hospital. Of these, 2,693 patients with a death record were eligible for inclusion and divided into training (n = 1,341) and test (n = 1,352) cohorts. In total, 3,471,521 laboratory data at 115,738 time points, representing 40 laboratory items [e.g., white blood cell counts and albumin (Alb) levels] that were monitored for 1 year before the death event were applied for constructing prognosis prediction models. All possible prediction models comprising three different items from 40 laboratory items (40C3 = 9,880) were generated in the training cohort, and the model selection was performed in the test cohort. The fitness of the selected models was externally validated in the validation cohort from three independent settings. Results A prognosis prediction model utilizing Alb, lactate dehydrogenase, and neutrophils was selected based on a strong ability to predict death events within 1–6 months and a set of six prediction models corresponding to 1,2, 3, 4, 5, and 6 months was developed. The area under the curve (AUC) ranged from 0.852 for the 1 month model to 0.713 for the 6 month model. External validation supported the performance of these models. Conclusion By applying time-series real-world big data, we successfully developed a set of six adaptable prognosis prediction models for patients with cancer receiving chemotherapy.

SummaryBackground We previously reported that a humanized anti-factor IXa/X bispecific antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive hemostatic activity against bleeding in an animal model of acquired hemophilia A. After further molecular engineering of hBS23, we recently identified an improved humanized bispecific antibody, ACE910, for clinical investigation. Objectives To elucidate the in vivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use. Methods A non-human primate model of acquired hemophilia A was established by injecting anti-primate FVIII neutralizing antibody. When bleeds emerged following an artificial bleed-inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2 days. Bleeding symptoms were monitored for 3 days. A pharmacokinetic study and multiple-dosing simulations of ACE910 were also performed. Results A single bolus of 1 or 3 mg kg−1 ACE910 showed hemostatic activity comparable to that of 10 U kg−1 (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half-life (3 weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once-weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis. Conclusions ACE910 may offer an alternative on-demand treatment option for patients with hemophilia A, as well as user-friendly and aggressive routine supplementation.

The spatial prioritization of biodiversity restoration sites on a national scale lags behind that of protected areas. We present a simple framework for spatial restoration prioritization using complementarity analysis based on the differences between past and present species distributions and restoration feasibility. In the framework, sites that were not only diverse or unique in the past (high restoration potential), but also have high restoration feasibility (e.g. low anthropogenic pressures) are ranked higher. We applied the framework to endangered bird species that breed in Japan for which distribution data were available from nationwide distribution censuses conducted in 1978 and 1998. The data were compiled in a 20-km grid resolution across Japan. We incorporated the degree of urbanization and number of farmers as a cost to optimize the sets of cells with regard to restoration feasibility. We successfully identified candidate sets of restoration cells, in which at most six can be allocated for each species under the constraint that the total area selected does not exceed 15% of the degraded cells. At most, 11 cells were allocated for each species under the constraint that restoration cells were within 15% of all ecosystem types. Comparison with the distribution of existing nature restoration sites revealed that only 9.3 or 9.7% (depended on the constraint) of high-priority cells overlapped cells including existing restoration sites. Our framework provides an objective, efficient method to obtain a testable plan for biodiversity restoration, which might contribute to the attainment of the 2020 target set by the Convention on Biological Diversity.

e23011 Background: Prognosis of end-of-life characteristics, which are indicators of palliative care, especially in elderly cancer patients, remains unclear. Methods: We retrospectively analyzed 510 patients who died of advanced cancer at our hospital from August 2011 to August 2016. The patients were divided into two groups: elderly patients (over 80 years old, N = 140) and non-elderly patients (under 80 years old, N = 370). The number of patients (306 male and 204 female) with gastro-esophageal, biliary-pancreatic, colorectal, lung, breast, urological, gynecological, hepatocellular, and other cancers were 114, 98, 82, 84, 25, 36, 20 and 51, respectively. The primary endpoint of the study was to analyze the relationship of end-of-life symptoms, treatment, and chemotherapy with age. The secondary endpoint was to identify the prognostic factors in elderly patients with advanced cancer at the end-of-life. Results: ECOG Performance Status of 0.1 was recorded for 12 patients and 2-4 for 498 patients. The prevalence rate of cancer pain in elderly patients was 19.3%, which was significantly lower than that in non-elderly patients (31.4%). Fatigue in elderly patients was 27.9%, which was significantly lower than that in non-elderly patients (37.6%). Continuous deep sedation usage in elderly patients was 12.9%, which was significantly lower than that in non-elderly patients (28.9%). The mean opioid dose in elderly patients was 23.3mg/day, which was significantly lower than that that in non-elderly patients (43.8mg/day). The rate of more than one line of chemotherapy for elderly patients was 44.4%, which was lower than that for non-elderly patients (65.4%). The rate of use of more than one type of cytotoxic agent in the last regimen for elderly patients was 13.3%, which was lower than that for non-elderly patients (30.8%). Consciousness level was recognized as a significant prognostic factor (HR 1.714, p = 0.048) using multivariate analysis of prognosis in elderly patients at the end-of-life. Conclusions: End-of-life symptoms and the intensity of end-of-life treatment, including chemotherapy, were lesser in elderly patients as compared to non-elderly patients. Consciousness level was a significant prognostic factor in elderly patients at the end-of-life.

In the present study, a tandem-bicycle ergometer was developed, because it is believed that such an ergometer can be used to eliminate differences in signaling between single- and tandem-exercise in cardiorespiratory responses, and is able to quantify interdependence in one load. It is necessary to verify whether cardiorespiratory responses to submaximal exercise are the same between single and tandem-bicycle ergometers. Accordingly, we compared cardiorespiratory variables during exercise in three conditions: 1) with a general bicycle single saddle using a general bicycle ergometer, 2) with a tandem bicycle front saddle using a tandem ergometer, and 3) with a tandem bicycle rear saddle using a tandem ergometer. Eleven healthy males participated in this study. The subjects exercised for 15 min at three intensities (1.5, 2.0 and 2.5 kp) in each condition. The pedaling rate was constantly kept at 60 rpm. Heart rate (HR), oxygen uptake (VO2), and the rating of perceived exertion (RPE) were measured during the last minute of each intensity. There were no significant differences in the variables HR, VO2, and RPE at each load among the three conditions. The ranges of coefficient of variation (CV) values were 3.0 - 4.8%: HR and 4.2 - 5.1%: VO2. It was reported that between-day CV for HR and VO2 during treadmill running was 1.0 - 10.7% and 1.9 - 11.6%. Given these CV values of present and previous studies, it can be seen that physiological response is stable during developed tandem-bicycle ergometer exercise. These results suggest that cardiorespiratory responses to exercise are at comparable levels between a normal bicycle ergometer and the newly developed tandem-bicycle ergometer.

We describe the results of immunological studies, reaction kinetics and epitope localization of six inhibitor antibodies to factor IX (FIX) developed in severe haemophilia B patients. Three of the six patients had suffered recent anaphylactoid reactions to FIX concentrates, two others had in the past and one had none. All six inhibitors rapidly inactivated FIX activity in vitro, and the prominent immunoglobulin (IgG) subclass of the antibody was IgG4 when analysed with ELISA. Interestingly, we found an additional IgG1 component in the antibody samples from the patients who had recently experienced anaphylactoid reactions to FIX. When analysed with Western blotting in these three patients, the IgG4 antibody bound with enhanced affinity to the heavy chain or the light chain of FIX, and in two of the three the IgG1 antibody also bound strongly to the FIX heavy chain. The results suggest that the heavy chain of FIX might play a more significant role than the light chain in the pathogenesis of anaphylactoid reactions in haemophilia B patients with FIX inhibitors.

In Japan, a rapid pace of aging coupled with the lower birth rates causes the decrease of the population especially in rural area, which leads to the problems with the delivery of healthcare services. We investigated the relationship between the geographical accessibility (time and distance) and the utilization rate of outpatient services in the elderly by major disease groups in Tokushima prefecture, Japan. Distances and driving times to the nearest facilities from residential sites in major disease categories were measured by using geographic information system. Utilization data was obtained from the claim data. In diseases of the musculoskeletal system and connective tissue (M00-M99), diseases of the digestive system (K00-K93), endocrine, nutritional and metabolic diseases (E00-E90), diseases of the eye and adnexa (H00-H59) and diseases of the respiratory system (J00-J99), there were moderate negative correlations (around –0.4 to –0.6) both in distance and time. Distance and time to the nearest facilities were important factors for the utilization of outpatient services of major disease categories in Japanese elderly. Comprehensive approach which include socio- economic factors is needed to mitigate access problems in aging Japanese society.

We evaluated the psychological distress using a scale of the K6, the 6-item scale of psychological distress on public health nurse in Kagawa prefecture, Japan. We send the questionnaire to all public health nurses (n = 419) in Kagawa prefecture. Then, a total of 256 public health nurses (1 man and 255 women), had completely answered the questionnaires, were analyzed in a cross-sectional investigation study. The association between psychological distress and considerable factors were evaluated by using the K6, with psychological distress defined as 13 or more points out of a total of 24 points. A total of 15 public health nurses (5.9%) were defined as psychological distress. Clear relationships between the K6 score and age, experience duration as public health nurse were not noted. The K6 score in subjects with anxiety of preventing suicide was significantly higher than that without. In addition, the K6 score in subjects who feel their own mental status was excellent was also lower than that in subjects without that. In conclusion, some factors might be associated with psychological distress, as assessed by the K6, in public health nurse in Kagawa prefecture, Japan.

We evaluated whole body reaction time and one leg with eye closed balance in elderly Japanese. A total of 2059 elderly Japanese (730 men and 1329 women), aged 60 - 79 years, were enrolled in the cross-sectional investigation study. Anthropometric parameters, whole body reaction time and one leg with eye closed balance were measured. Whole body reaction time was significantly higher and one leg with eye closed balance was significantly lower in 70’s than those in 60’s in both sexes. Two hundred twenty seven men (31.1%) and 533 women (40.1%) were having no medications. In men, whole body reaction time was significantly higher and one leg with eye closed balance was significantly lower in subjects with medications than those in subjects without in 60’s. However, significant differences of whole body reaction time and one leg with eye closed balance between subjects with and without medications in men with 70’s and women with 60’s and 70’s were not noted. This standard mean value may provide a useful reference database for evaluating whole body reaction time and one leg with eye closed balance in Japanese elderly subjects.

Only a limited number of case reports documenting the off-label use of recombinant factor VIIa (rFVIIa) in Japanese patients with postpartum haemorrhage (PPH) have been published. Data on Japanese cases with severe PPH in which rFVIIa was administered were collected. Data of obstetric haemorrhage patients treated with rFVIIa between 2005 and 2010 were retrospectively collected throughout Japan. The data included patients' background information, blood product requirements, dose/timing of rFVIIa, and adverse effects. Treating clinicians subjectively assessed the effect of rFVIIa on bleeding at each administration using four categories: "Stopped", "Decreased", "Unchanged", and "Increased". A total of 25 women received rFVIIa for the treatment of obstetric haemorrhage in 18 institutions. After the final administration, bleeding was "stopped" in 16 patients (64%), "decreased" in eight patients (32%), and "unchanged" in one patient (4%). A significant reduction in blood product requirement was observed following the first rFVIIa administration. Hysterectomy was required in two patients (15.4%) after rFVIIa administration. Four asymptomatic thrombotic events were reported in three patients. These results suggest that rFVIIa can be a beneficial therapeutic option that can reduce blood loss and prevent hysterectomy in Japanese patients with massive obstetric bleeding.