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Koichiro Watanabe,1 Shinji Fujimoto,2 Tatsuro Marumoto,2 Tadayuki Kitagawa,3 Kazuyuki Ishida,3 Tadashi Nakajima,2 Yoshiya Moriguchi,4 Keita Fujikawa,2 Takeshi Inoue5 1Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan; 2Japan Medical Office, Takeda Pharmaceutical Co., Ltd, Tokyo, Japan; 3Takeda Development Center – Japan, Takeda Pharmaceutical Co., Ltd, Osaka, Japan; 4Medical Affairs, Lundbeck Japan K.K., Tokyo, Japan; 5Department of Psychiatry, Tokyo Medical University, Tokyo, JapanCorrespondence: Koichiro Watanabe, Department of Neuropsychiatry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan, Tel +81-422-47-5511, Fax +81-422-45-4697, Email koichiro@tke.att.ne.jpAim: Anhedonia in major depressive disorder may be resistant to first-line antidepressants. We examined the effect of vortioxetine, a multimodal antidepressant, on anhedonia-like symptoms in Japanese patients with major depressive disorder.Methods: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent major depressive disorder and a Montgomery–Åsberg Depression Rating Scale (MADRS) total score of at least 26. The primary outcome was the mean change from baseline to week 8 in anhedonia-like symptoms as measured by MADRS anhedonia factor score, composed of: Q1, apparent sadness; Q2, reported sadness; Q6, concentration; Q7, lassitude; and Q8, inability to feel. Mean change in MADRS total score and anhedonia factor score were compared among treatment groups, with data categorized by median baseline anhedonia factor score (0– 17 or ≥ 18).Results: Data were available for 489 patients. The least-squares mean difference in MADRS anhedonia factor score change from baseline to week 8 versus placebo was − 1.34 for vortioxetine 10 mg (P = 0.0300) and − 1.77 for vortioxetine 20 mg (P = 0.0044). The least-squares mean difference between vortioxetine and placebo in MADRS total score change from baseline to week 8 was − 3.11 (10 mg dose) and − 3.37 (20 mg dose) for patients with a higher baseline anhedonia factor score (≥ 18), and − 2.08 (10 mg) and − 2.61 (20 mg) for patients with a lower baseline score (0– 17).Conclusion: This post hoc analysis suggests that vortioxetine may have therapeutic potential in patients with anhedonia-like symptoms of major depressive disorder. ClinicalTrials.gov identifier for primary study: NCT02389816.Keywords: anhedonia, antidepressant, Japanese, major depressive disorder, vortioxetine

Takeshi Inoue,1 Shinji Fujimoto,2 Tatsuro Marumoto,2 Tadayuki Kitagawa,3 Kazuyuki Ishida,3 Tadashi Nakajima,2 Yoshiya Moriguchi,4 Keita Fujikawa,2 Koichiro Watanabe5 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Japan Medical Office, Takeda Pharmaceutical Co., Ltd, Tokyo, Japan; 3Takeda Development Center – Japan, Takeda Pharmaceutical Co., Ltd, Osaka, Japan; 4Medical Affairs, Lundbeck Japan K.K., Tokyo, Japan; 5Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6‐7‐1 Nishishinjuku, Shinjuku‐ku, Tokyo, 160‐0023, JapanTel +81-3-3342-6111 (ext. 5754)Fax +81-3-3340-4499Email tinoue@tokyo-med.ac.jpAim: Several weeks of treatment with an antidepressive agent may be required before efficacy is demonstrated in patients with major depressive disorder. This study investigated the predictive value of early partial improvement with vortioxetine for treatment response and remission.Methods: This was a post hoc analysis of an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent major depressive disorder and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of at least 26. The key outcomes were the predictive value of early partial improvement (reduction in MADRS total score of ≥ 20% from baseline to week 2) with vortioxetine for MADRS response (≥ 50% decrease in score from baseline) and remission (decrease in score to ≤ 10) at week 8.Results: Relevant data were available for 478 patients; 62/158 patients receiving placebo, 71/162 receiving vortioxetine 10 mg, and 66/158 receiving vortioxetine 20 mg were early improvers. Early improvers receiving vortioxetine (10 mg or 20 mg) were more likely than non-early improvers to achieve a week 8 response (71.2– 73.2% vs 29.7– 38.0%) or remission (50.7– 51.5% vs 17.4– 18.7%). Positive predictive values for response and remission with vortioxetine were ∼ 70% and ∼ 50%, respectively; negative predictive values were ∼ 70% and ∼ 80%, respectively.Conclusion: Improvement with vortioxetine may be predicted by early partial improvement in MADRS score. Some patients may benefit from longer-term treatment even without early improvement, another finding that may aid clinical decision-making. ClinicalTrials.gov registration for primary study: NCT02389816.Keywords: antidepressant, Japanese, major depressive disorder, vortioxetine

Takeshi Inoue,1 Shinji Fujimoto,2 Tatsuro Marumoto,2 Tadayuki Kitagawa,3 Kazuyuki Ishida,3 Tadashi Nakajima,2 Yoshiya Moriguchi,4 Keita Fujikawa,2 Koichiro Watanabe5 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Japan Medical Office, Takeda Pharmaceutical Co., Ltd, Tokyo, Japan; 3Takeda Development Center – Japan, Takeda Pharmaceutical Co., Ltd, Osaka, Japan; 4Medical Affairs, Lundbeck Japan K.K., Tokyo, Japan; 5Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, JapanCorrespondence: Takeshi InoueDepartment of Psychiatry, Tokyo Medical University, 6‐7‐1 Nishishinjuku, Shinjuku‐ku, Tokyo, 160‐0023, JapanTel +81-3-3342-6111 (ext. 5754)Fax +81-3-3340-4499Email tinoue@tokyo-med.ac.jpAim: Antidepressants, including selective serotonin reuptake inhibitors, often elicit a poor response in patients with major depressive disorder (MDD) with significant anxiety symptoms. This study investigated the effects of the multimodal antidepressant vortioxetine in patients with MDD and associated anxiety.Methods: This was a post hoc analysis of data from an 8-week, randomized, double-blind, placebo-controlled, Phase 3 study of vortioxetine (10 mg or 20 mg) in Japanese patients aged 20– 75 years with recurrent MDD and a Montgomery–Åsberg Depression Rating Scale (MADRS) score of at least 26. Changes from baseline to week 8 in MADRS total score and Hamilton Depression Rating Scale (HAM-D) anxiety/somatization factor score were assessed in patients with anxious depression (HAM-D anxiety/somatization factor score ≥ 7) and without anxious depression.Results: Data were available for 489 patients. In patients with anxious depression, the least-squares (LS) mean difference (95% confidence interval [CI]) versus placebo in change in MADRS total score was − 3.44 (− 6.10, − 0.77) for vortioxetine 10 mg and − 4.51 (− 7.15, − 1.87) for vortioxetine 20 mg. In patients with non-anxious depression, the LS mean difference (95% CI) versus placebo was − 1.81 (− 4.71, 1.09) and − 1.05 (− 4.00, 1.90) for vortioxetine 10 mg and 20 mg, respectively. Changes from baseline in HAM-D anxiety/somatization factor score were greater in patients treated with vortioxetine 10 mg or 20 mg than in those treated with placebo.Conclusion: Vortioxetine may be effective for patients with anxiety symptoms in MDD. Further research is warranted to investigate these effects in a real-world clinical setting.Clinical Trials Registration: ClinicalTrials.gov identifier for primary study: NCT02389816.Keywords: antidepressant, anxiety, major depressive disorder, serotonin reuptake inhibitor and modulator (S-RIM), vortioxetine

Masushi Kohta,1 Takehiko Ohura,2 Katsuyuki Okada,3 Yoshinori Nakamura,4 Eiko Kumagai,5 Hitomi Kataoka,6 Tomomi Kitagawa,7 Yuki Kameda,8 Toshihiro Kitte9 1Medical Engineering Laboratory, ALCARE Co. Ltd., Tokyo, Japan; 2Pressure Ulcers and Wound Healing Research Center, Sapporo, Japan; 3Department of Dermatology, Kiryu Kosei General Hospital, Kiryu, Japan; 4Department of Medical Home Healthcare Center, Tenri Hospital Shirakawa Branch, Tenri, Japan; 5Murata Day Surgery & WOC Clinic, Sendai, Japan; 6Department of Nursing, Yamagata University, Yamagata, Japan; 7Department of Nursing, Hikone Municipal Hospital, Hikone, Japan; 8Wound Care Marketing Division, ALCARE Co Ltd., Tokyo, Japan; 9Department of Health Care Policy, Shiga Government Office, Otsu, JapanCorrespondence: Masushi KohtaMedical Engineering Laboratory, ALCARE Co., Ltd., 1-21-10 Kyojima, Sumida-ku, Tokyo 131-0046, JapanTel +81-3-3611-1101Fax +81-3-3613-6894Email mkouta@alcare.co.jpPurpose: The Pressure Injury Primary Risk Assessment Scale for Home Care (PPRA-Home) was developed to predict pressure injury risk in geriatric individuals requiring long-term care in home settings. This study aimed to compare the convergent validity of the PPRA-Home to that of the two other standardized pressure injury prevention scales: the Braden and Ohura-Hotta (OH) scales.Methods: A multicenter, cross-sectional study was conducted with 34 home-based geriatric support service providers located in five Japanese districts. The study included 69 participants (30 had a pressure injury and 39 did not) who were at classified at care levels of 1 through 5 under Japan’s long-term care insurance system. Care managers served as assessors for the PPRA-Home, while physicians or certified expert nurses served as assessors for the Braden and OH scales. Convergent validity was investigated by examining correlation coefficients between total scores on the PPRA-Home and the other two scales. Receiver operating curve analysis was used to quantify each scale’s accuracy for the two groups: those with and without a pressure injury.Results: The PPRA-Home was found to be negatively correlated with the Braden scale (r=− 0.79, p< 0.05), and positively correlated with the OH scale (r=0.58, p< 0.05). The area under the curve (AUC) for the PPRA-Home, Braden scale, and OH scale were 0.737, 0.814, and 0.794, respectively. A PPRA-Home cutoff score of 4 had a sensitivity of 63.3% and specificity of 81.6%.Conclusion: The AUC for the PPRA-Home as scored by care managers was similar to those of the Braden and OH scales as scored by physicians or expert nurses. More research on the PPRA-Home’s content and predictive validity is required.Keywords: pressure ulcer, risk assessment, geriatrics, wound care

Katsunori Yogo,1 Masaki Misawa,2 Morihito Shimizu,2 Hidetoshi Shimizu,3 Tomoki Kitagawa,3 Ryoichi Hirayama,4 Hiromichi Ishiyama,5 Takako Furukawa,1 Hiroshi Yasuda6 1Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; 2Health and Medical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki, Japan; 3Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan; 4National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba-shi, Chiba, Japan; 5Graduate School of Medical Science, Kitasato University, Sagamihara, Kanagawa, Japan; 6Department of Radiation Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, JapanCorrespondence: Katsunori YogoNagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-Ku, Nagoya, Aichi 461-8673, JapanTel +81 52 719 1103Fax +81 52 719 3172Email yogo@met.nagoya-u.ac.jpPurpose: Gold nanoparticles (AuNPs) are candidate radiosensitizers for medium-energy photon treatment, such as γ-ray radiation in high-dose-rate (HDR) brachytherapy. However, high AuNP concentrations are required for sufficient dose enhancement for clinical applications. Here, we investigated the effect of positively (+) charged AuNP radiosensitization of plasmid DNA damage induced by 192Ir γ-rays, and compared it with that of negatively (−) charged AuNPs.Methods: We observed DNA breaks and reactive oxygen species (ROS) generation in the presence of AuNPs at low concentrations. pBR322 plasmid DNA exposed to 64 ng/mL AuNPs was irradiated with 192Ir γ-rays via HDR brachytherapy. DNA breaks were detected by observing the changes in the form of the plasmid and quantified by agarose gel electrophoresis. The ROS generated by the AuNPs were measured with the fluorescent probe sensitive to ROS. The effects of positively (+) and negatively (−) charged AuNPs were compared to study the effect of surface charge on dose enhancement.Results: +AuNPs at lower concentrations promoted a comparable level of radiosensitization by producing both single-stranded breaks (SSBs) and double-stranded breaks (DSBs) than those used in cell assays and Monte Carlo simulation experiments. The dose enhancement factor (DEF) for +AuNPs was 1.3 ± 0.2 for SSBs and 1.5 ± 0.4 for DSBs. The ability of +AuNPs to augment plasmid DNA damage is due to enhanced ROS generation. While −AuNPs generated similar ROS levels, they did not cause significant DNA damage. Thus, dose enhancement using low concentrations of +AuNPs presumably occurred via DNA binding or increasing local +AuNP concentration around the DNA.Conclusion: +AuNPs at low concentrations displayed stronger radiosensitization compared to −AuNPs. Combining +AuNPs with 192Ir γ-rays in HDR brachytherapy is a candidate method for improving clinical outcomes. Future development of cancer cell-specific +AuNPs would allow their wider application for HDR brachytherapy.Keywords: gold nanoparticles, high-dose-rate brachytherapy, DNA damage, radiosensitization, 192Ir γ-rays, positively charged nanoparticles

Carcinogenesis and cancer progression, driven by mutations in oncogenes and tumor-suppressor genes, result in biological differences between normal and cancer cells in various cellular processes. Specific genes and signaling molecules involved in such cellular processes may be potential therapeutic targets of agents that specifically interact with the key factors in cancer cells. Increased glucose uptake is fundamental to many solid tumors and well associated with increases in glycolysis and the overexpression of glucose transporters (GLUTs) such as GLUT1 and GLUT3 at the plasma membrane. Here, we used cell-based screening to identify glycogen synthase kinase-3β (GSK-3β) inhibitors that selectively target GLUT3-expressing tumorigenic HeLa cell hybrids as compared with non-tumorigenic hybrids that express GLUT1 alone. The GSK-3 inhibitors as well as GSK-3β RNAi suppressed GLUT3 expression at the level of transcription, leading to apoptosis. This suppression was associated with NF-κB in a p53-independent manner. Furthermore, GSK-3 inhibitors exhibited a synergistic effect with anticancer agents such as adriamycin and camptothecin in GULT3-overexpressing colon cancer cells, but little effect in non-producing A431 cells. These results suggest a potential use of GSK-3 inhibitors to selectively kill cancer cells that overexpress GLUT3.

Kenichi Hirashima,1,2 Yumi Higuchi,1 Masakazu Imaoka,1 Emiko Todo,1 Tomomi Kitagawa,1 Tetsuya Ueda11Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Habikino Campus, Habikino City, Osaka, Japan; 2Faculty of Health and Welfare, Department of Physical Therapy, Tokushima Bunri University, Nishihamaboji, Yamashiro Town, Tokushima City, Tokushima, Japan Aim: Dual-task methods, in which walking is the primary task, are not sufficient for accurately screening for the risk of falls among healthy older adults. Therefore, the goal of this research was to investigate whether using a dual-task method over an extended walking distance can predict falls among community-dwelling older adults.Methods: We enrolled independent community-dwelling adults aged ≥65 years. Physical performance, cognitive function, psychological function, and a dual-task test were assessed at baseline. Our dual-task test required the subjects to walk 60 m while stepping over lines. The intervals between the lines ranged from 50–100 cm and were unequal. Falls and fall-related injuries were measured over a 12-month follow-up period using monthly postal surveys. Results: Ninety-two of 118 subjects (mean age, 75.4±5.5 years) completed the 12-month follow-up. Sixteen (17.4%) of fallers had injurious falls or fell more than or equal to two times. There were no significant differences between the fallers and non-fallers, except in age and in the number of missteps during the dual-task test when walking ≥40 m. The Kaplan–Meier analysis revealed that those who had more than one misstep while walking ≥40 m had a significantly higher incidence of injurious or multiple falls than those who had no missteps.Conclusion: Our findings suggest that the dual-task method with an extended walking distance may be able to predict falls among community-dwelling older adults. Keywords: cohort study, community-dwelling older adults, dual-task, falls