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The 13th Symposium on Polar Science/Ordinary sessions [OM] Polar meteorology and glaciology, Wed. 16 Nov.

The aim of this study was to clarify the roles of the cerebellum and basal ganglia for temporal integration. We studied 39 patients with spinocerebellar ataxia (SCA), comprising SCA6, SCA31, Machado–Joseph disease (MJD, also called SCA3), and multiple system atrophy (MSA). Thirteen normal subjects participated as controls. Participants were instructed to tap on a button in synchrony with isochronous tones. We analyzed the inter-tap interval (ITI), synchronizing tapping error (STE), negative asynchrony, and proportion of delayed tapping as indicators of tapping performance. The ITI coefficient of variation was increased only in MSA patients. The standard variation of STE was larger in SCA patients than in normal subjects, especially for MSA. Negative asynchrony, which is a tendency to tap the button before the tones, was prominent in SCA6 and MSA patients, with possible basal ganglia involvement. SCA31 patients exhibited normal to supranormal performance in terms of variability STE, which was surprising. In conclusion, cerebellar patients generally showed greater STE variability, except for SCA31. The pace of tapping was affected in patients with possible basal ganglia pathology. Our results suggest that interaction between the cerebellum and the basal ganglia is essential for temporal processing. The cerebellum and basal ganglia together with their interaction regulates synchronized tapping, resulting in distinct tapping patterns among different SCA subtypes.

Background/Aims Filgotinib (FIL), an oral Janus kinase 1 preferential inhibitor, has demonstrated safety and efficacy as treatment for signs and symptoms of RA, and it is approved in Japan and Europe for treatment of RA. Patient characteristics can influence response to RA treatment; this post hoc analysis was performed to determine whether age, body weight (BW), and body mass index (BMI) influenced efficacy. Methods Patients from FINCH 1 (F1, n = 1755, inadequate response to methotrexate [MTX-IR]; NCT02889796) or FINCH 3 (F3, n = 1249, MTX-naïve; NCT02886728) were included for analysis of clinical response at week 12 (F1 primary endpoint) or 24 (F3 primary endpoint). Patients were stratified by age ( Results FIL200+MTX in MTX-IR patients demonstrated greater efficacy vs placebo+MTX regardless of age, BW, and BMI (Table 1). Apart from the ≥65-year-old subgroup, in which there was no clear pattern, FIL200+MTX in MTX-naïve patients demonstrated greater efficacy vs MTX across subgroups (Table 1). Rates of treatment-emergent adverse events (TEAEs) were greater in the ≥65-year-old subgroup vs the Conclusion This exploratory analysis showed FIL200+MTX was efficacious regardless of subgroup characteristics defined by age, BW, or BMI. Most comparisons of FIL200+MTX vs MTX and vs placebo+MTX favored FIL200+MTX. Disclosure Y. Tanaka: Consultancies; Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK, and AbbVie. Member of speakers’ bureau; Daiichi-Sankyo; Eli Lilly; Novartis; YL Biologics; Bristol-Myers; Eisai; Chugai; AbbVie; Astellas; Pfizer; Sanofi; Asahi-Kasei; GSK; Mitsubishi-Tanabe; Gilead Sciences, Inc.; and Janssen. Grants/research support; AbbVie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, and Daiichi-Sankyo. J. Curtis: Grants/research support; from AbbVie, Amgen, BMS, Corrona, Eli Lilly, Janssen, Myriad, Pfizer, Regeneron, Roche, and UCB. S. Wassenberg: Consultancies; AbbVie; Amgen; BMS; Gilead Sciences, Inc.; Eli Lilly; Hexal; MSD; Nichi-Iko; Pfizer; and Sanofi. P. Kiely: Member of speakers’ bureau; Novartis, Lilly, Galapagos, Sobi, Abbvie. L. Ye: Shareholder/stock ownership; Employee and shareholder of Gilead Sciences, Inc. Z. Yin: Shareholder/stock ownership; Employee and shareholder of Gilead Sciences, Inc. B. Downie: Shareholder/stock ownership; Employee and shareholder of Gilead Sciences, Inc. H. Enomoto: Shareholder/stock ownership; former employee/shareholder of Gilead Sciences, Inc. S. Strengholt: Shareholder/stock ownership; shareholder of and employee of Galapagos BV. A. Akhdar: Shareholder/stock ownership; shareholder of and employee of Galapagos BV. C. Watson: Shareholder/stock ownership; shareholder of and employee of Galapagos BV. T. Atsumi: Honoraria; Gilead Sciences, Inc.; Mitsubishi Tanabe; Chugai; Astellas Pharma; Takeda; Pfizer; AbbVie: Eisai; Daiichi Sankyo Co. Ltd.; BMS; UCB Japan Co. Ltd.; Eli Lilly, Otsuka Pharmaceutical Co. Alexion Inc.

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

Purpose To assess comorbidity burden and pain-management patterns among working-aged patients with knee osteoarthritis only (KOA/O) and patients with knee osteoarthritis plus osteoarthritis at another site (KOA/+) in Japan. Patients and methods Retrospective claims data analysis was conducted using the Japan Medical Data Center database. Working-aged adults (aged 40 to 71 years) with 5 years of follow-up and diagnosed with knee osteoarthritis (KOA) between January 1, 2011, and December 31, 2012, were evaluated. The first claim with a KOA diagnosis defined the index date. Patients were divided into two mutually exclusive cohorts: KOA/O and KOA/+. Longitudinal pain-management patterns during each year of follow-up were analyzed. Results A total of 2542 patients met study criteria: 1575 KOA/O and 967 KOA/+. Mean age and number of comorbidities were higher among the KOA/+ versus KOA/O cohort. Pharmaceutical treatment was received by 91.5% of patients in the KOA/+ compared with 85.1% of patients in the KOA/O cohort during the first year of follow-up. The most common pharmacological treatment received during the first year of follow-up was either topical or oral nonsteroidal anti-inflammatory drugs for both cohorts. During each year of follow-up, the KOA/+ cohort had greater proportion of patients with at least one health-care encounter (ie, hospital admissions, outpatient and pharmacy visits) and higher direct medical costs compared with the KOA/O cohort. Conclusion This study demonstrates that a greater proportion of the working population with KOA/+ received pain-related treatment compared with patients with KOA/O. Further studies are necessary to evaluate appropriate pain management for both KOA only and KOA with other sites.

Kisspeptin neurons, i.e. KNDy neurons, in the arcuate nucleus (ARC) coexpress neurokinin B and dynorphin and regulate gonadotropin-releasing hormone/luteinizing hormone (LH) pulses. Because it remains unclear whether these neurons are associated with reproductive dysfunction in diabetic females, we examined the expression of KNDy neurons detected by histochemistry in streptozotocin (STZ)-induced diabetic female rats 8 weeks after STZ injection. We also evaluated relevant metabolic parameters – glucose, 3-hydroxybutyrate, and non-esterified fatty acids – as indicators of diabetes progression. Severe diabetes with hyperglycemia and severe ketosis suppressed the mRNA expression of KNDy neurons, resulting in low plasma LH levels and persistent diestrus. In moderate diabetes with hyperglycemia and moderate ketosis, kisspeptin-immunoreactive cells and plasma LH levels were decreased, while the mRNA expression of KNDy neurons remained unchanged. Mild diabetes with hyperglycemia and slight ketosis did not affect KNDy neurons and plasma LH levels. The number of KNDy cells was strongly and negatively correlated with plasma 3-hydroxybutyrate levels. The vaginal smear analysis showed unclear proestrus in diabetic rats 3–5 days after STZ injection, and the mRNA expression of kisspeptin in the ARC was decreased 2 weeks after STZ injection in severely diabetic rats. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV), which induce an LH surge, were unaffected at 2 and 8 weeks after STZ injection regardless of the diabetes severity. These results suggest that diabetes mellitus progression in females may negatively affect ARC kisspeptin neurons but not AVPV kisspeptin neurons, implicating a potential role of ARC kisspeptin neurons in menstrual disorder and infertility.

The 12th Symposium on Polar Science, 15–18 Nov. 2021, National Institute of Polar Research (NIPR) Research Organization of Information and Systems (ROIS)

The objective of the present analysis was to determine whether changes in Brief Pain Inventory (BPI) average pain scores by patient global impression of improvement (PGI‐I) category and the cut‐off for clinically important difference (CID) were different between Asian and Caucasian patients with chronic pain due to osteoarthritis. This analysis used data from 3 (Caucasian) and 2 (Asian) randomized, placebo‐controlled, 10‐ to 14‐week duloxetine studies for the treatment of patients ≥40 years of age with osteoarthritis pain. The receiver operating characteristic (ROC) analysis was used to characterize the association between changes in BPI average pain scores and PGI‐I levels at study endpoint. The CID was characterized by PGI‐I, and the cut‐off point for CID in BPI average pain scores was determined by the intersection of a 45‐degree tangent line with each ROC curve. Data from 668 Asian and 868 Caucasian patients were available for analysis. Baseline BPI average pain ratings including worst and least pain were comparable between Asians and Caucasians. Ratings for percentage change from baseline to endpoint for BPI average pain scores in Asian patients and Caucasian patients were similar across the 7 PGI‐I categories, regardless of age, gender, study, and treatment. The ROC analysis results of cut‐off points in BPI average pain scores demonstrated the raw change cut‐off was −3.0, and percentage change cut‐off was −40% for both Asian and Caucasian patients. Overall, the present analysis concludes changes in BPI average pain scores by PGI‐I category and the cut‐off for CID were similar for Asian and Caucasian patients with chronic pain due to osteoarthritis.

The purpose of the study involves measuring the threshold for electric currents (i.e., current perception threshold or CPT) under several stimulating current frequencies. Specifically, current perception threshold (CPT) was measured in 53 healthy volunteers between the ages of 21 and 67. The stimulation currents were applied on the right index finger with stimulus frequencies in the range of 50 Hz - 300 kHz. The method of limits and method of constant stimuli were combined to measure the CPT. In a manner consistent with the findings obtained by previous studies, the results indicated that CPT was higher in men than in women and in older individuals than in young subjects. Bioelectromagnetics. 9999:XX-XX, 2019. © 2019 Bioelectromagnetics Society.

The posterior parietal cortex (PPC) features close anatomical and functional relationships with the prefrontal cortex. However, the necessity of the PPC in executive functions has been questioned. The present study used the stop-signal task to examine response inhibition, an executive function that inhibits prepotent response tendency. The brain activity and resting-state functional connectivity were measured to analyze a parcellation-based network that was aimed at identifying a candidate PPC region essential for response inhibition in humans. The intraparietal sulcus (IPS) was activated during response inhibition and connected with the inferior frontal cortex and the presupplementary motor area, the two frontal regions known to be necessary for response inhibition. Next, transcranial magnetic stimulation (TMS) was used to test the essential role of the IPS region for response inhibition. TMS over the IPS region prolonged the stop-signal reaction time (SSRT), the standard behavioral index used to evaluate stopping performance, when stimulation was applied 30–0 ms before stopping. On the contrary, stimulation over the temporoparietal junction region, an area activated during response inhibition but lacking connectivity with the two frontal regions, did not show changes in SSRT. These results indicate that the IPS identified using the parcellation-based network plays an essential role in executive functions. SIGNIFICANCE STATEMENT Based on the previous neuropsychological studies reporting no impairment in executive functions after lesions in the posterior parietal cortex (PPC), the necessity of PPC in executive functions has been questioned. Here, contrary to the long-lasting view, by using recently developed analysis in functional MRI (“parcellation-based network analysis”), we identified the intraparietal sulcus (IPS) region in the PPC as essential for response inhibition: one executive function to stop actions that are inaccurate in a given context. The necessity of IPS for response inhibition was further tested by an interventional technique of transcranial magnetic stimulation. Stimulation to the IPS disrupted the performance of stopping. Our findings suggest that the IPS plays essential roles in executive functions.

Large basilar trunk aneurysm caused by bilateral occlusion of the proximal common carotid artery is rare. We treated one case with vertebral V3 portion-radial artery-distal common carotid artery (V3-RA-dCCA) bypass. Basilar trunk aneurysm and bilateral occlusion of the proximal CCA were found incidentally in a 70-year-old woman. During the next 5 years, the aneurysm gradually enlarged to 12 mm, and blood flow of the anterior circulation was supplied through the posterior communicating artery. V3-RA-dCCA bypass was performed to reduce the stress of blood flow and prevent aneurysm growth and rupture. After exposing the neck portion, forearm of RA, and V3 portion of the vertebral artery, we created a space just below the sternocleidomastoid muscle to bypass the RA. We flushed the RA with albumin to stiffen the artery and temporarily clamped the bilateral sides of the RA to prevent twisting. We anastomosed the V3 and RA with a 9–0 thread and temporarily clamped the V3. After flushing the RA with albumin to prevent twisting, we clamped the external and internal carotid arteries, opened the dCCA with a vascular punch to prevent arterial dissection, and anastomosed the RA to the dCCA. The patency of the bypass was confirmed with Doppler and indocyanine green video angiography. The postoperative course was uneventful, bypass patency was good, and the aneurysm did not expand further. V3-RA-dCCA bypass may be an effective and low-risk treatment for large basilar trunk aneurysms with bilateral occlusion of the proximal common carotid artery.

Shridhar D. Jawak, Bo N. Andersen, Veijo Pohjola, Øystein Godøy, Kim Holmén, Agnar Sivertsen, Richard Hann, Hans Tømmervik, Andreas Kääb, Małgorzata Błaszczyk, Roberto Salzano, Bartłomiej Luks, Kjell Arild Høgda, Rune Storvold, Lennart Nilsen, Rosamaria Salvatori, Kottekkatu Padinchati Krishnan, Sourav Chatterjee, Dag A. Lorentzen, Rasmus Erlandsson, Tom Rune Lauknes, Eirik Malnes, Stein Rune Karlsen, Hiroyuki Enomoto, Ann Mari Fjæraa, Jie Zhang, Sabine Marty, Knut Ove Nygård, Heikki Lihavainen, Svalbard Integrated Arctic Earth Observing System (SIOS) is an international partnership of research institutions studying the environment and climate in and around Svalbard. SIOS is developing an efficient observing system, where researchers share technology, experience, and data, work together to close knowledge gaps, and decrease the environmental footprint of science. SIOS maintains and facilitates various scientific activities such as the State of the Environmental Science in Svalbard (SESS) report, international access to research infrastructure in Svalbard, Earth observation and remote sensing services, training courses for the Arctic science community, and open access to data. This perspective paper highlights the activities of SIOS Knowledge Centre, the central hub of SIOS, and the SIOS Remote Sensing Working Group (RSWG) in response to the unprecedented situation imposed by the global pandemic coronavirus (SARS-CoV-2) disease 2019 (COVID-19). The pandemic has affected Svalbard research in several ways. When Norway declared a nationwide lockdown to decrease the rate of spread of the COVID-19 in the community, even more strict measures were taken to protect the Svalbard community from the potential spread of the disease. Due to the lockdown, travel restrictions, and quarantine regulations declared by many nations, most physical meetings, training courses, conferences, and workshops worldwide were cancelled by the first week of March 2020. The resumption of physical scientific meetings is still uncertain in the foreseeable future. Additionally, field campaigns to polar regions, including Svalbard, were and remain severely affected. In response to this changing situation, SIOS initiated several operational activities suitable to mitigate the new challenges resulting from the pandemic. This article provides an extensive overview of SIOS’s Earth observation (EO), remote sensing (RS) and other operational activities strengthened and developed in response to COVID-19 to support the Svalbard scientific community in times of cancelled/postponed field campaigns in Svalbard. These include (1) an initiative to patch up field data (in situ) with RS observations, (2) a logistics sharing notice board for effective coordinating field activities in the pandemic times, (3) a monthly webinar series and panel discussion on EO talks, (4) an online conference on EO and RS, (5) the SIOS’s special issue in the Remote Sensing (MDPI) journal, (6) the conversion of a terrestrial remote sensing training course into an online edition, and (7) the announcement of opportunity (AO) in airborne remote sensing for filling the data gaps using aerial imagery and hyperspectral data. As SIOS is a consortium of 24 research institutions from 9 nations, this paper also presents an extensive overview of the activities from a few research institutes in pandemic times and highlights our upcoming activities for the next year 2021. Finally, we provide a critical perspective on our overall response, possible broader impacts, relevance to other observing systems, and future directions. We hope that our practical services, experiences, and activities implemented in these difficult times will motivate other similar monitoring programs and observing systems when responding to future challenging situations. With a broad scientific audience in mind, we present our perspective paper on activities in Svalbard as a case study.

Objective Assess long-term comorbidity burden and pain management patterns among working-age patients with knee osteoarthritis (KOA) only without low back pain (LBP) (KOA-noLBP) and patients with KOA plus LBP (KOA+LBP) in Japan. Methods Retrospective claims data analyses were conducted on data from the Japan Medical Data Center (JMDC) database. Adult patients (≥40 years) with a diagnosis of knee osteoarthritis (KOA) (January 1, 2011–December 31, 2012) and 5 years of follow-up were evaluated. The first claim with a KOA diagnosis defined the index date. Longitudinal pain management patterns were assessed in both cohorts. Results Overall, 1,828 patients met study criteria (717 with KOA-noLBP; 1,111 with KOA+LBP). The mean age of patients with KOA-noLBP was 52.1 years, and that of patients with KOA+LBP was 53.1 years, with more females in the KOA+LBP cohort (49.4% vs. 55.0%). Regardless of cohort, >90% of patients received pharmacological intervention during the 5-year follow-up period. The most common regimen first received was either topical or oral nonsteroidal anti-inflammatory drugs. A higher mean number of pharmaceutical treatments were received by patients in the KOA+LBP cohort (3.6) than by patients in the KOA-noLBP cohort (2.7) during the follow-up period. Regardless of cohort, most of the direct medical cost was derived from medication. Conclusion This study demonstrates that a greater proportion of the JMDC population of working individuals with KOA were comorbid with LBP and received pain-related treatment in the long-term perspective relative to patients with KOA without LBP. Appropriate pain management for both KOA and LBP would be key for effective resource utilization in an aging society facing socioeconomic burdens

The 11th Symposium on Polar Science/Special session: [S] Accelerating Arctic research: Recent progress and future prospect of Arctic research, Tue. 1 Dec.

The 11th Symposium on Polar Science/Special session: [S] Accelerating Arctic research: Recent progress and future prospect of Arctic research, Tue. 1 Dec.

The 11th Symposium on Polar Science/Ordinary sessions: [OM] Polar Meteorology and Glaciology, Poster presentations, Mon. 16 Nov. - Fri. 18 Dec.

Hiroyuki Enomoto, 1 Shinji Fujikoshi, 2 Kei Ogawa, 1 Toshinaga Tsuji, 3 Sakae Tanaka 4 1Medicines Development Unit Japan, Eli Lilly Japan K.K., Tokyo 107-0052, Japan; 2Medicines Development Unit Japan, Eli Lilly Japan K.K., Kobe 651-0086, Japan; 3Medical Affairs Department, Shionogi & Co., Ltd., Shibata, Osaka 530-0012, Japan; 4Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, JapanCorrespondence: Hiroyuki EnomotoMedicines Development Unit Japan, Eli Lilly Japan K.K., 4-15-1-13F, Akasaka, Minato-Ku, Tokyo 107-0052, JapanTel +81 3 5574 9143Fax +81 3 5574 9979Email enomoto_hiroyuki@lilly.comPurpose: This post hoc analysis of a Japanese phase 3 randomized study (ClinicalTrials.gov identifier: NCT02248480) investigated relationships between changes in pain severity and changes in health-related quality of life (HRQoL) in duloxetine-treated patients with knee osteoarthritis (OA).Patients and Methods: Patients with knee OA and Brief Pain Inventory (BPI) average pain score ≥ 4 received duloxetine 60 mg/day or placebo for 14 weeks. Spearman rank correlation coefficients were calculated for change in pain severity, as assessed by the BPI, and change in HRQoL, as assessed by the items of the (i) 36-item Short-Form Health Survey (SF-36; a generic measure of HRQoL) and (ii) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; an OA-specific measure of HRQoL).Results: After 14 weeks of treatment, there was a significantly greater improvement (p< 0.001) for duloxetine (n=177) vs placebo (n=176) in BPI average pain severity score and significantly greater improvements (p< 0.01) for duloxetine vs placebo for 5 of the 8 SF-36 domains (including the Role-Physical, Bodily Pain, and Physical Functioning domains) and all 24 individual WOMAC items. The correlation between BPI change from baseline and SF-36 item change from baseline was statistically significant (p< 0.05) for 2 of the 8 SF-36 items (Bodily Pain, Physical Functioning) in duloxetine-treated patients. The correlation between BPI change from baseline and WOMAC item change from baseline was statistically significant for 22 of the 24 WOMAC items in duloxetine-treated patients.Conclusion: This post hoc analysis suggested that the pain reduction observed in duloxetine-treated patients with knee OA was associated with improvements in OA-specific aspects of HRQoL, ie, pain and physical functioning.Keywords: 36-item Short-form Health Survey, Brief Pain Inventory, placebo effect, Western Ontario and McMaster Universities Osteoarthritis Index

A previously conducted placebo-controlled, randomized, phase 3 study of 353 Japanese patients with knee osteoarthritis (OA) showed significant improvements for duloxetine vs placebo in pain and health-related quality of life (HRQoL) (ClinicalTrials.gov Identifier: NCT02248480). Reported here are post hoc subgroup analyses evaluating the efficacy of duloxetine according to the pattern of prior nonsteroidal anti-inflammatory drug (NSAID) use.Patients with knee OA pain received once-daily duloxetine or placebo for 14 weeks. Pain was evaluated using the Brief Pain Inventory (BPI) and HRQoL was evaluated using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Patients were divided into four subgroups based on their prior NSAID use: (i) no prior NSAID use; (ii) low-frequency NSAID use (14 days/month); (iii) high-frequency transdermal NSAID use (transdermal NSAIDs only; ≥14 days/month for the 3 months before study entry); and (iv) high-frequency other NSAID use (eg, oral NSAIDs only, both oral and transdermal NSAIDs; ≥14 days/month for the 3 months before study entry).In each of the four prior NSAID use subgroups, there were greater reductions in BPI average pain severity score for duloxetine vs placebo at all timepoints during the 14-week treatment period; the treatment*prior NSAID use interaction was not statistically significant. In each subgroup, the proportion of patients achieving a ≥50% reduction in BPI average pain severity score was higher for duloxetine vs placebo. In each subgroup, there were greater reductions in WOMAC total score for duloxetine vs placebo at all timepoints; the treatment*prior NSAID use interaction was not statistically significant. In each subgroup, there were greater reductions at Week 14 in WOMAC pain, stiffness, physical function, and total scores for duloxetine vs placebo.Duloxetine was consistently effective with respect to pain relief and HRQoL in Japanese patients with knee OA pain, regardless of the pattern of prior NSAID use.

Kaname Ueda,1 Nao Sasaki,2 Amir Goren,3 Shawna R Calhoun,4 Katsuhiro Shinjo,5 Hiroyuki Enomoto,5 Takeshi Muneta6 1Health Outcomes/Health Technology Assessment/Real World Evidence, Eli Lilly Japan, Kobe, Japan; 2Bio-Medicines, Medicines Development Unit, Eli Lilly Japan, Kobe, Japan; 3Health Outcomes, Kantar Health, New York, NY, USA; 4Health Outcomes, Kantar Health, Horsham, PA, USA; 5Bio-Medicines, Medicines Development Unit, Eli Lilly Japan, Tokyo, Japan; 6Department of Orthopaedic Surgery, National Disaster Medical Center, Tokyo, Japan Purpose: Patient satisfaction is an important outcome in successful osteoarthritis (OA) treatment. The aim of this study was to evaluate treatment satisfaction for medication (TSM) in people with knee OA (KOA), identify the factors predictive of treatment satisfaction, and describe the burden of illness.Patients and methods: This cross-sectional, patient-reported study used an Internet-based survey and analyzed responses of respondents with KOA (N=400) on characteristics including pain sites and levels (including pain ratings using the Numerical Rating Scale and Short-Form McGill Pain Questionnaire), treatment satisfaction (Global, Effectiveness, and Convenience scores) based on the Treatment Satisfaction Questionnaire for Medication (TSQM-9), and quality of life (QoL; based on the Arthritis Impact Measurement Scale 2-Short Form). Respondents with only KOA (n=237) were compared with those having KOA and additional painful sites (KOA+; n=163). Factors predicting TSM were identified using multivariable linear regression analyses.Results: Respondents with KOA were more likely to report intermittent pain for 3 months or more compared with those with KOA+ (58.6% vs 48.5%, respectively; P=0.044), while those with KOA+ were more likely to report consistent pain for 3 months or more (P=0.022). Respondents with KOA+ also had more difficulty due to their knee pain while sleeping (P=0.022) and resting (P=0.015). Reported TSM did not differ significantly across KOA vs KOA+ groups, with both groups reporting low satisfaction; all domains of QoL were worse for those with KOA+. Knee pain reduction by medication predicted higher satisfaction across domains, while lower pre-medication pain and post-medication pain matching expectations predicted higher TSQM-9 Global and Effectiveness scores.Conclusion: Medication treatment satisfaction rates were low among Japanese respondents with KOA. Given that lower pain, greater pain reduction post-medication, and meeting pain management expectations were predictive of higher satisfaction, treatment strategies that can better address pain may prove beneficial for overall patient satisfaction. Keywords: quality of life, AIMS2-SF, SF-MPQ, TSQM-9, knee osteoarthritis

Yuji Uchio,1 Hiroyuki Enomoto,2 Levent Alev,2 Yuki Kato,3 Hiroyuki Ishihara,3 Toshinaga Tsuji,4 Toshimitsu Ochiai,5 Shinichi Konno6 1Department of Orthopaedic Surgery, Shimane University School of Medicine, Shimane, Japan; 2Bio-Medicine, Medicines Development Unit, Eli Lilly Japan K.K., Kobe, Japan; 3Clinical Development Department, Shionogi & Co., Ltd., Osaka, Japan; 4Medical Affairs Department, Shionogi & Co., Ltd., Osaka, Japan; 5Biostatistics Department, Shionogi & Co., Ltd., Osaka, Japan; 6Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan Purpose: To examine the efficacy and safety of duloxetine in Japanese patients with knee pain due to osteoarthritis. Patients and methods: Patients were randomized to receive duloxetine 60 mg/day or placebo for 14 weeks in a double-blind manner (ClinicalTrials.gov Identifier: NCT02248480). The primary efficacy endpoint was mean change in Brief Pain Inventory pain severity (BPI-Severity) average pain. Secondary endpoints included improvement in other BPI-Severity scales, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, health-related quality of life (HRQoL) scales, range of motion of the knee joint, safety and tolerability, and structural changes on X-ray images. Results: Of the 354 randomized patients, 161 in the duloxetine group and 162 in the placebo group completed the study. BPI-Severity average pain improved significantly with duloxetine vs. placebo (−2.57 vs. −1.80; adjusted mean difference: −0.77; 95% CI: −1.11 to −0.43; P

The Altai Mountains contain 1281 glaciers covering an area of 1191 km2. These glaciers have undergone significant changes in glacial length and area over the past decade. However, mass changes of these glaciers and their impacts remain poorly understood. Here we present surface mass balances of all glaciers in the region for the period 1990–2011, using a glacier mass-balance model forced by the outputs of a regional climate model. Our results indicate that the mean specific mass balance for the whole region is about −0.69 m w.e. yr−1 over the entire period, and about 81.3% of these glaciers experience negative net mass balance. We detect an accelerated wastage of these glaciers in recent years, and marked differences in mass change and its sensitivity to climate change for different regions and size classes. In particular, higher mass loss and temperature sensitivity are observed for glaciers smaller than 0.5 km2. In addition to temperature rise, a decrease in precipitation in the western part of the region and an increase in precipitation in the eastern part likely contribute to significant sub-region differences in mass loss. With significant glacier wastage, the contribution of all glaciers to regional water resources and sea-level change becomes larger than before, but may not be a potential threat to human populations through impacts on water availability.

The Japan Fracture Observational Study (JFOS), a prospective observational study, investigated the real-world effectiveness of daily teriparatide to reduce clinical fracture risk in osteoporotic patients.In routine clinical practice, Japanese patients initiated on teriparatide 20 μg/day by subcutaneous injection were enrolled. The primary end-point was the rate of clinical fractures at 6-month intervals over 24 months. Bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, and health-related quality-of-life (HRQoL) information was collected.Of 1,996 patients at baseline, 90.1% were female, and mean age was 76.9 years. Teriparatide persistence at 12 and 24 months was 68.0% and 51.6%, respectively. Compared to the first 6-month treatment interval, the odds ratio of fractures decreased by 56.4% during 6-12 months, 51.6% during 12-18 months, and 58.8% during 18-24 months (all p .01). After 24 months, BMD increased by 17.2% (lumbar spine) and 7.9% (total hip). After 6 months, P1NP levels increased by 259.3%. A reduction in back pain (100 mm visual analog scale) of 16.1 mm at 3 months was maintained through 24 months. HRQoL (pain, daily living activities, general health) improved by ≥10% at each post-baseline time point. Of 279 (14.6%) patients with ≥1 adverse event (AE), 71 (3.7%) experienced ≥1 drug-related AE (investigator assessed), including nausea (0.7%), dizziness (0.4%), and decreased appetite (0.3%). Osteosarcoma was not reported; there were no new safety signals.JFOS demonstrated effectiveness of teriparatide 20 μg/day to reduce the risk of clinical fractures in Japanese patients in a real-world setting.

The reduction of plasticity with age has been shown by many previous papers in animal experiments. This issue can be studied in humans because several non-invasive brain stimulation techniques induce synaptic plasticity in the human brain. We investigated the influence of individuals' age on the responder rate of the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS). The participants were 107 healthy volunteers: 53 older participants (Mean ± SD 65.0 ± 1.5 years) and 54 younger participants (37.2 ± 8.7). The quadripulse stimulation with 5-ms inter-pulse interval (QPS5) was applied over the primary motor cortex (M1). We measured motor evoked potentials (MEPs) before QPS, and at five time points after QPS for up to 25 min. In each participant, average MEP amplitude (size) ratios were quantified. We first classified participants as responders and non-responders simply by comparing the size ratio with 1.0 for consistency with previous studies, then as "significant responders", "non-responders", and "opposite responders" for more detailed analysis by comparing the size ratio with the mean and standard deviation of the MEP size ratios of the sham condition. The degree of LTP-like effects induced by QPS5 was significantly smaller in the older group compared to the younger group. Also, the rates of responders and significant responders were lower in the older group (58 and 47%, respectively) compared to the younger group (80 and 76%, respectively). The age of the participants significantly affected the LTP-like effect induced by QPS5, which suggests that brain plasticity decreases with age.

This study presents a 64-year (1951–2014) reconstruction of the surface mass balance of Glacier No. 31, located in the Suntar-Khayata Range of the eastern Siberia, where the ablation zone is characterized by the extensive dark ice surface. We use a temperature index-based glacier mass-balance model, which computes all major components of glacier mass budget and is forced by daily air temperature and precipitation from a nearby meteorological station. The glacier shows a mean annual mass balance of–0.35 m w.e.a–1 during the past 64 years, with an acceleration of–0.50 m w.e. a–1 during the recent years. A cumulative mass loss of the glacier is ~22.3 m w.e. over the study period, about 56% of which is observed during 1991–2014. In addition to the contribution of temperature rise and precipitation decrease to recent mass loss of the glacier, an experimental analysis, in which the clean and dark ice surfaces are respectively assumed to cover the entire ablation zone, indicates that dark ice surface, caused by insoluble impurities consisting of mineral dusts, cryoconite granules, and ice algae, plays a crucial role in the changing mass balance through enhancing melt rates in the ablation zone of the glacier.

A long-term Northern Hemisphere (NH) daily 5-km snow cover extent (SCE) product (JASMES) was developed by the application of a consistent objective snow cover mapping algorithm to data from historical optical sensors on polar orbiting satellites from 1978 to 2015. A conventional decision tree algorithm with multiple threshold tests was employed to analyze radiances for the five spectral bands available across the full analysis period. The accuracies of the analyzed SCE maps were evaluated against in-situ snow data measured at ground stations along with the SCE maps from the National Oceanic and Atmospheric Administration Climate Data Record (NOAA-CDR) product. The evaluation showed the JASMES product to have a more temporally stable producer's accuracy (PA; 1–omission error) than NOAA, which is a key factor in the analysis of long-term SCE trends. Comparison of seasonal NH SCE trends from the two products showed NOAA to have opposite trends to those of JASMES in the fall and winter seasons, and to have overestimated SCE decreasing trends in the spring and summer. These tendencies are consistent with the increasing spatial and temporal resolutions of information over time, which were used in generating the NOAA snow analysis. An estimation of unbiased SCEs based on the accuracies of SCE maps also endorses the long-term trends of the JASMES product. The JASMES NH seasonal SCE exhibited negative slopes in all seasons but was only statistically significant in the summer (JJA) and fall (SON). Delayed snow cover onset was observed to be the main driver of decreasing annual snow duration (SCD) trends. The spatial pattern of annual SCD trends exhibited noticeable asymmetry between continents, with the largest significant decreases observed over western Eurasia with relatively few statistically significant decreases over North America.

Purpose To assess comorbidity burden and pain-management patterns among working-aged patients with knee osteoarthritis only (KOA/O) and patients with knee osteoarthritis plus osteoarthritis at another site (KOA/+) in Japan. Patients and Methods Retrospective claims data analysis was conducted using the Japan Medical Data Center database. Working-aged adults (aged 40 to 71 years) with 5 years of follow-up and diagnosed with knee osteoarthritis (KOA) between January 1, 2011, and December 31, 2012, were evaluated. The first claim with a KOA diagnosis defined the index date. Patients were divided into two mutually exclusive cohorts: KOA/O and KOA/+. Longitudinal pain-management patterns during each year of follow-up were analyzed. Results A total of 2542 patients met study criteria: 1575 KOA/O and 967 KOA/+. Mean age and number of comorbidities were higher among the KOA/+ versus KOA/O cohort. Pharmaceutical treatment was received by 91.5% of patients in the KOA/+ compared with 85.1% of patients in the KOA/O cohort during the first year of follow-up. The most common pharmacological treatment received during the first year of follow-up was either topical or oral nonsteroidal anti-inflammatory drugs for both cohorts. During each year of follow-up, the KOA/+ cohort had greater proportion of patients with at least one health-care encounter (ie, hospital admissions, outpatient and pharmacy visits) and higher direct medical costs compared with the KOA/O cohort. Conclusion This study demonstrates that a greater proportion of the working population with KOA/+ received pain-related treatment compared with patients with KOA/O. Further studies are necessary to evaluate appropriate pain management for both KOA only and KOA with other sites.

The Tenth Symposium on Polar Science/Ordinary sessions: [OM] Polar Meteorology and Glaciology, Wed. 4 Dec. / 2F Auditorium, National Institute of Polar Research

Mobile phones are indispensable for daily life, and the adverse effects of the electromagnetic field (EMF) emitted by mobile phones have been a great concern. We studied the effects of long-term evolution (LTE) -like EMF for 30 min on an awake electroencephalogram (EEG). Thirty-eight healthy volunteers, aged 20-36 years old, participated in this study. The maximum local SAR (specific absorption rate) averaged over 10-g mass was 2.0 W/kg. The EEG was recorded before and after real or sham exposures. The effects of exposure conditions (real or sham) and the recording time (before, during, and after exposure) on each EEG power spectrum of θ, α, and β frequency ranges were analyzed. The θ and α band waves were enhanced after both exposure conditions. These results may be explained by the participants' drowsiness during the EEG recording in both exposures. We conclude that an LTE-like exposure for 30 min in this study showed no detectable harmful effects on awake EEGs in healthy humans.

After experiencing upper respiratory-tract symptoms, a 41-year-old woman developed encephalitis with consciousness disturbance and respiratory failure. She had external ophthalmoplegia and facial diplegia. Magnetic resonance imaging revealed a brainstem lesion with spared longitudinal pontine bundles. Abnormal findings of the brainstem auditory-evoked potentials and blink reflex supported brainstem damage. The patient was positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. Repeated immunological treatments improved her symptoms, but severe orthostatic hypotension emerged. A head-up tilt test revealed no arginine vasopressin response to hypotension. The atypical symptoms of this case highlighted that the brainstem is one of the pivotal regions in anti-NMDAR encephalitis.

The phase 3 teriparatide Fracture Prevention Trial showed significant reductions in vertebral (VF) and nonvertebral (NVF) fractures; however, patient exposure was insufficient for full analysis of low-incidence fractures, including hip. We assessed fracture results in pooled data from four prospective, observational teriparatide studies. Ambulatory women and men with osteoporosis received subcutaneous teriparatide 20 µg/day for up to 24 months per routine clinical practice. Fracture rates were compared between 6-month periods, using 0 to 6 months of treatment as the reference period. Analyses used a piecewise exponential model for first fracture. Hip, NVF, clinical VF (CVF), any clinical, and wrist fractures were assessed. For 8828 patients analyzed, mean age was 71 years; mean (SD) treatment duration was 17.4 (8.6) months. The rate of hip fracture decreased significantly for the > 12 to 18-month (- 47.7%) and > 18-month periods (-85.2%) versus the first 6 months of therapy, and for the > 18 versus the > 6 to 12-month period. NVF, CVF, and all clinical fractures were all significantly decreased in each post-reference period, with maximum decreases (> 18-month period) of 52.7%, 69.4%, and 61.2%, respectively, versus 0 to 6 months. No significant reduction was seen for rates of wrist fracture. Teriparatide treatment was associated with statistically significant decreases in hip fracture rate, particularly for > 18 months of treatment, and in NVF, CVF, and all clinical fracture rate in real-world patients. These results should be interpreted in the context of the non-controlled design of the source studies.

This research note describes how the Japanese five-year Arctic research program “Arctic Challenge for Sustainability (ArCS)” was implemented, focusing on its activities that supported the research, with a brief introduction of the background of Japan’s Arctic research. There were two shifts in the style of Japan’s Arctic research during the last 10–15 years: from small research projects by individual scientists to a large national program, and from a purely scientific program to a comprehensive Arctic research program. Governmental policy played a crucial role in these shifts. As a national program, ArCS was required to expand Japanese Arctic research capabilities, and to deliver research results to multiple stakeholders. It was to meet these requirements that several supporting activities were included in addition to the research itself: establishing research and observation platforms, sending young researchers to overseas institutions, sending experts to the Arctic Council working groups, and enhancing outreach activities targeting both the general public in Japan and the international Arctic research community. Objectives, design, and outcomes of these supporting activities are described respectively.

Atsushi Nishikawa,1 Fumito Yoshiki,2 Masanori Taketsuna,2 Kenta Kajimoto,2 Hiroyuki Enomoto2 1Global Patient Safety Japan, Quality and Patient Safety, Eli Lilly Japan K.K., 2Medicines Development Unit Japan, Eli Lilly Japan K.K., Kobe, Japan Abstract: Teriparatide (recombinant 1–34 N-terminal sequence of human parathyroid hormone) for the treatment of osteoporosis should be prescribed with caution in patients with severe stages of chronic kidney disease (CKD). However, in clinical settings, physicians and surgeons who treat such patients have few available options. We sought to further explore the safety and effectiveness of teriparatide for the treatment of osteoporosis in Japanese patients with severe stages of CKD. This was a post hoc analysis of a postmarketing surveillance study that included patients with osteoporosis at high risk of fracture and stage 4 or 5 CKD. Patients received subcutaneous teriparatide 20 µg daily for up to 24months. Safety profiles were assessed by physician-reported adverse drug reactions (ADRs). Effectiveness was assessed by measuring bone formation (via procollagen type 1 N-terminal propeptide [P1NP]), bone mineral density (BMD), and the incidence of clinical vertebral or nonvertebral fragility fractures. A total of 33 patients with severe stages of CKD (stage 4, n=30; stage 5, n=3) were included. All patients were female, and 81.8% had a history of previous fracture. No serious ADRs were recorded; a total of 4 ADRs were recorded for 4 of 33 patients. Increases in BMD and P1NP levels were observed both overall and in most individual patients. New fractures occurred in 1 patient with stage 5 CKD, but not in patients with stage 4 CKD. In this post hoc analysis conducted in Japan, teriparatide appeared to be effective for the treatment of osteoporosis in elderly female patients with severe stages of CKD, and no new safety concerns were observed. Keywords: bone mineral density, chronic kidney disease, fragility fracture, parathyroid hormone, teriparatide, safety&nbsp

Background Responses to plasticity-inducing brain stimulation protocols are highly variable. However, no data are available concerning the variability of responses to quadripulse stimulation (QPS). Objective We assessed the QPS parameters of motor cortical plasticity induction in a systematic manner, and later investigated the variability of QPS using optimal parameters. Methods First, two different interburst intervals (IBI) with the same total number of pulses were compared. Next we investigated three different IBIs with a different total number of pulses but with same duration of intervention. We also compared the after-effects of monophasic and biphasic QPS. Finally, variability of QPS was tested in 35 healthy subjects. Twenty motor evoked potentials (MEPs) were measured every 5–10 min for up to one hour after intervention. Results QPS at an IBI of 5 s produced MEPs changes that are dependent on the interstimulus interval of the four magnetic pulses, consistent with previous reports. Unexpectedly, QPS at an IBI of 2.5 s did not induce any plasticity, even with the same total number of pulses, that is, 1440. QPS at an IBI of 7.5 s produced a variable response but was likely to be comparable to conventional QPS. Biphasic QPS had shorter lasting after-effects compared with monophasic QPS. Finally, the after-effects of QPS were relatively consistent across subjects: more than 80% of subjects responded as expected in the excitatory QPS at an IBI of 5 s. Conclusions The IBI, total duration of the procedure and pulse waveform strongly affected the magnitude or duration of the plasticity induced by QPS. In this cohort, 80% of subjects responded to excitatory QPS as expected.

The rapid Arctic warming has been reported. Winter to spring shift of cryosphere is the key variables to be monitored related to warming mechanism. Satellite remote sensing is effective for observing cryospheric change from winter to spring. Although microwave observations with a frequency of 19 and 37 GHz have conventionally been used for the observation of snow covered areas, this study investigated use of the low-frequency 6 GHz band. To acquire information on the winter‒spring transition of ground conditions in Alaska, flight observations of a forest, wetland and lake were performed using an airborne microwave radiometer. Infrared observation measures surface warming and low frequency microwave can observe inside of snow cover. This combination expands the information on spring snow conditions with warming and melting. The TB from the ground displayed little regional variation in the cold period. The variation increased when the spring snow melting season began. Surface temperature increased during the spring warming period, however, the ground below the snow cover remained cold. Flight and satellite microwave observations provided us with the monitoring capability for the spring warming over Alaska, and illustrate the early warming of lowland and late warming in the mountain areas around Fairbanks. Although inside of snow are still cold in the mountain area, significant warming in the forest, and warming in accelerating at wetland and lake in the low land

Snow and ice algal communities were investigated on four glaciers in the Suntar-Khayata Mountain Range in eastern Siberia in Russia over three melting seasons from 2012 to 2014. Two taxa of green algae and five taxa of cyanobacteria were observed on the glaciers. The algal community was dominated by green algae: Ancylonema nordenskioldii in the lower bare ice area and Chloromonas sp. in the upper snow area. The total algal bio-volume showed altitudinal variation, ranging from 0.03 to 4.0 mL m−2, and was greatest in the middle of the glaciers. The altitudinal variations in the algal community were similar on all studied glaciers, suggesting that they are typical in this region. Observations over the three years revealed that there was no significant change in the community structure, but a significant change in the total biomass. Since the mean summer air temperature was significantly higher in 2012 when algal biomass was greater, the difference in algal biomass among the years is probably due to the duration of surface melting. The community structure on the studied glaciers is similar to those on glaciers in Arctic and sub-Arctic regions.

Exosomes are small extracellular vesicles secreted by variety of cell types such as neurons, astrocytes, and oligodendrocytes. It is suggested that exosomes play essential role in the maintenance of the neuronal functions and also in the clearance of amyloid-β (Aβ) from the brain. Aβ is well known to cause neuronal cell death, whereas little is known about its effect on astrocytes. In this study, we examined the effect of Aβ on release of exosomes from astrocytes in culture. We analyzed release of exosomes and apoE, both of which are known to remove/clear Aβ from the brain, in the culture medium of astrocytes. We found that exosome and apoE-HDL were successfully separated by density gradient ultracentrifugation demonstrated by distribution of their specific markers, flotillin and HSP90, and cholesterol, and morphological analysis using electron microscopy. Exosome release was significantly reduced by Aβ1-42 treatment in cultured astrocytes accompanied by an increased JNK phosphorylation. Whereas, apoE-HDL release remained unchanged. A JNK inhibitor restored the decreased levels of exosome release induced by Aβ treatment to levels similar to those of control, suggesting that Aβ1-42 inhibits exosome release via stimulation of JNK signal pathway. Because exosomes are shown to remove Aβ in the brain, our findings suggest that increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway.