Temporal virtual reality-guided, dual-task, trunk balance training in a sitting position improves persistent postural-perceptual dizziness: proof of concept.

BACKGROUND: Persistent postural-perceptual dizziness (PPPD) is a newly defined disorder characterized by functional dizziness. Due to its recent discovery, definitive treatment for PPPD has not been established; therefore, this study aimed to assess the effectiveness of virtual reality (VR)-guided, dual-task, trunk balance training for the management of PPPD using the mediVR KAGURA system. METHODS: We analyzed data of patients who presented with PPPD from January 1, 2021, to February 28, 2021. The VR group included patients who underwent mediVR KAGURA-guided training for 100 tasks (10 min). Patients with PPPD who received standard treatment and rehabilitation were assigned to the control group. Equilibrium tests were performed at baseline and immediately after mediVR KAGURA-guided training to examine its effectiveness in improving static and dynamic balance. Additionally, clinical questionnaires related to balance disorders were administered at baseline and 1 week after mediVR KAGURA-guided training to examine its effects on balance-related symptoms. The primary outcome was improvements in static and dynamic balance and Niigata PPPD Questionnaire (NPQ) scores. RESULTS: VR-guided training using mediVR KAGURA improved objective outcomes, including static and dynamic postural stability, after a single 10-min training session. Additionally, mediVR KAGURA-guided training improved scores on the Hospital Anxiety and Depression Scale and NPQ 1 week after the 10-min training session. CONCLUSION: VR-guided training using mediVR KAGURA represents a viable method for managing balancing ability, anxiety, and symptoms in patients with PPPD. Such training provides a safe and cost-effective solution for PPPD management. Further studies are required to evaluate the clinical efficacy of this strategy. TRIAL REGISTRATION: Institutional Ethics Committee of Kitano Hospital, approval number: 1911003. Registered 18 December 2019, https://kitano.bvits.com/rinri/publish_document.aspx?ID=426 .

Factors associated with preferred place of death among older adults: a qualitative interview study in Tama City, Tokyo, Japan.

OBJECTIVES: To analyse the cognitive processes involved in the decision-making of older adults who are not in the end-of-life stage regarding the selection of a preferred place of death. DESIGN: A qualitative cross-sectional study based on semistructured in-depth interviews. The interview scripts were sectioned by context, then summarised, conceptualised and categorised. Post-categorisation, the relationships between the conceptual factors were examined. SETTING: Tama City, Tokyo, Japan, from November 2015 to March 2016. PARTICIPANTS: 20 long-term care users and their families or care providers were interviewed about their preferred places of death and the factors behind their decisions. RESULTS: Three categories based on the preferred place of end-of-life care and death were extracted from the interview transcripts: (A) discouraging the decision of a preferred place of death, (B) enhancing the desire for home death and (C) enhancing the desire for a hospital/long-term care facility death. Category A consists of concerns about the caregiver's health, anxiety about solitary death, and constraints of and concerns about the household budget. Both categories B and C consist of subcategories of reinforcing and inhibiting factors of whether to desire a home death or a hospital/long-term care facility death. If their previous experiences with care at home, a hospital or a care facility were positive, they preferred the death in the same setting. If those experiences were negative, they tend to avoid the death in the same setting. CONCLUSIONS: One's mindset and decision regarding a preferred place of death include the consideration of economic factors, concerns for caregivers, and experiences of care at home or in a hospital/long-term care facility. Furthermore, health professionals need to be aware of the ambivalence of senior citizens to support their end-of-life decisions.

A questionnaire study of support for adult survivors of childhood cancer.

BACKGROUND: Childhood cancer survivors (CCSs) entering adulthood experience different problems, including late therapy-related complications. Long-term follow up (LTFU) is important for early intervention and psychosocial support for CCSs with late complications but it is frequently discontinued. This study aimed (i) to identify clearly the factors responsible for LTFU discontinuation, and (ii) to define the support needs of CCSs. METHODS: From July, 2017 to March, 2019 we conducted a questionnaire survey of 121 CCSs aged ≥ 18 years at the time of the survey to investigate people who have experienced childhood cancer and identify their support needs. This was conducted in cooperation with patient associations throughout Japan. The LTFU levels were determined by CCSs themselves based on their treatment history. Long-term follow-up rates and LTFU discontinuation factors were assessed using the Kaplan-Meier method and the Cox proportional-hazards model. RESULTS: Late complications were the most common problem encountered by CCSs (80%). The most common support need was "explanation of late complications by a physician," reported by 86.9% of respondents. The rate of LTFU continuation decreased over time. The LTFU was discontinued both for physicians' reasons (35.6%) and patients' reasons (64.4%). Not knowing the extent or level of one's LTFU was reported to be an independent factor (P < 0.05) preventing LTFU continuation. As necessary support to continue LTFU, 67.9% of respondents stated the need for "explanation of LTFU by a doctor" and 60.7% stated "convenience of outpatient visit". CONCLUSIONS: Childhood cancer survivors require support, especially for late complications. It is necessary to continue LTFU, raising LTFU awareness among physicians and CCSs.

Population-based survey regarding factors contributing to expectation for death at home.

BACKGROUND: In 2015 in Japan 12.7% of people die at home. Since the government has no policy to increase the number of hospital beds, at-home deaths should inevitably increase in the near future. Previous researches regarding expected place of death have focused on end-of-life patients. The aim of this study is to clarify the percentage and factors of senior people who expect at-home deaths whether they are end-of-life or not. METHODS: Using cross-sectional questionnaire survey data which had been taken by a research group with the support from Tama City Medical Association (Tokyo) in 2014, univariable and multivariable logistic regression analyses were conducted to identify associations among factors. The dependent variable was the expected site of death and other factors were set as independent variables. RESULTS: Of 1781 respondents, 46.5% expected at-home deaths. Data from 1133 people were analyzed and 46.5% of those wanted at-home deaths. Factors significantly associated with expectation of at-home death were men, stand-alone houses for dwelling, expectation to continue life in Tama city, twosome life with the spouse, healthiness, and economic challenge. CONCLUSION: Percentage of those who expected at-home deaths was much higher than the latest percentage of at-home deaths. Some factors associated with expectation of at-home deaths in this study have never been discussed.

Japanese childhood cancer survivors' readiness for care as adults: a cross-sectional survey using the Transition Scales.

BACKGROUND: Childhood cancer survivors' (CCSs') readiness for adult care has not been evaluated in Japan. We conducted a survey to examine transition barriers and facilitators in CCSs and compared the results with those of CCSs in Canada. METHODS: Participants were selected from the Heart Link mutual-aid health insurance membership directory and the Millefeuille Childhood Cancer Frontiers. We conducted a cross-sectional survey (self-report questionnaire) via mail, using the Transition Scales. RESULTS: In total, 268 questionnaires were collected by January 2016 (response rate, 42.5%). After confirming the reliability and validity of the Transition Scales, we analyzed 242 questionnaires. After excluding questionnaires for CCSs younger than 15 or older than 26 years, we compared scales scores between Japanese and Canadian CCSs. Relative to that of Japanese CCSs, Canadian CCSs showed greater cancer-related worry for 4 items (P < .001) and preference for self-management in 3 items (P < .001). Japanese CCSs showed greater preference for self-management, relative to that of Canadian CCSs, in 5 items (P < .001). In the expectation scale, Japanese CCSs showed lower levels of expectation concerning adult care in 6 of 12 items (P < .001). Relative to that of Canadian CCSs, a significantly higher number of Japanese CCSs preferred to visit the same doctor for long-term care as adults (P < .001). CONCLUSIONS: The results confirmed the reliability and validity of the Transition Scales and showed that Japanese CCSs expressed fewer cancer concerns, but a higher number of Japanese CCSs preferred to visit the same doctor for long-term care as adults.

Factors associated with the specific worries of childhood cancer survivors: Cross-sectional survey in Japan.

BACKGROUND: Previous research has shown that adult childhood cancer survivors (CCS) have many worries. We re-analyzed the employment data in order to identify these worries and their associated factors. METHODS: The participants were selected from the membership directory of Heart Link mutual-aid health insurance, and recruited by the CCS Network. We conducted a cross-sectional survey (a self-rated questionnaire on employment) via post or email with a link to an Internet website. We investigated the association between CCS factors and the specific worries. The adjusted odds ratios (OR) for the associated factors with a specific worry were estimated on logistic regression analysis. RESULTS: A total of 240 questionnaires were collected by November 2012. One questionnaire was excluded because the answers were not provided by the CCS him/herself. The most common worries were health-related problems (50%) and employment issues (40%), which were followed by his/her personality and life (23%) and self-appearance (20%). Fifty (21%) out of 239 CCS answered no specific worry. The common consistent factor associated with worries was the presence of late effects. Of note was that the CCS worries were not associated with age at diagnosis or follow up, gender, educational achievement or marriage. The worry about employment issues was associated with economic status, disability qualification, and employment status. CONCLUSIONS: The CCS worries were strongly affected by the presence of late effects. No significant association was noted between CCS worries and gender, age at diagnosis or follow up, or educational achievements. Economic status and disability qualification were associated with some worries.

Recent employment trend of childhood cancer survivors in Japan: a cross-sectional survey.

BACKGROUND: Previous research has shown that some adult childhood cancer survivors (CCSs) have experienced employment difficulties. However, the actual employment status of CCSs in Japan has not been studied. PARTICIPANTS AND METHODS: The participants were selected from the membership directory of Heart Link mutual-aid health insurance and recruited by the Childhood Cancer Patients' Network. We conducted a cross-sectional survey (a self-rated questionnaire on employment) via postal mail or an email communication with a link to an Internet website. We explored the association between the characteristics of CCSs who require disability qualification and having experienced unemployment. The adjusted odds ratios (ORs) for the factors with an outcome of interest were estimated with logistic regression analysis. RESULTS: In total, 44 CCSs indicated that they had a disability qualification. The significant independent factors related to needing a disability qualification were late effects [OR 12.3; 95 % confidence interval (CI) 3.37-45.2], brain tumors (OR 9.55; 95 % CI 1.90-48.0), and being a high school graduate (OR 9.86; CI 2.67-36.4). The unemployment rate was 15.9 % among CCSs, excluding homemakers and students. Approximately 70 % of unemployed CCSs had some late effects; independent factors related to unemployment were late effects (OR 6.22; 95 % CI 1.80-21.40), dropping out of school (OR 8.46; 95 % CI 1.66-43.10), and brain tumors (OR 2.73; 95 % CI 0.83-8.96). Most unemployed CCSs were likely to seek work, despite their health problems. CONCLUSIONS: The unemployment rate is not high in Japan, but some CCSs need extended disability qualification. The independent factors related to unemployment were late effects and dropping out of school.

Combination effect between bortezomib and tumor necrosis factor alpha on gefitinib-resistant non-small cell lung cancer cell lines.

Tumor cells that have acquired resistance to gefitinib may complicate the future treatment of patients with non-small cell lung cancer (NSCLC). To investigate the mechanisms of acquired resistance, an acquired gefitinib-resistant cell line, PC-9/ZD2001, has been established using a gefitinib-sensitive NSCLC cell line, PC-9. PC-9/ZD2001 showed collateral sensitivity to tumor necrosis factor (TNF)-alpha. Bortezomib is a proteasome inhibitor and enhances TNF-alpha-induced cell death. These observations suggest that the combination of bortezomib and TNF-alpha might have effects against gefitinib-resistant cells. To verify this hypothesis, a combination effect between these drugs was examined using MTT assay and immunoblotting. This combination showed synergistic cytotoxic effect in NSCLC cell lines with either acquired or intrinsic gefitinib resistance. However, this combination effect was not observed in gefitinib-sensitive cells. On the other hand, bortezomib inhibited TNF-alpha-induced IkappaB degradation in all cell lines. From these observations, it is concluded that the combination of bortezomib and TNF-alpha could be used to overcome gefitinib-resistance.

Mutant epidermal growth factor receptor undergoes less protein degradation due to diminished binding to c-Cbl.

Gefitinib (Iressa) sensitivity in non-small cell lung cancer (NSCLC) is associated with activating mutations in epidermal growth factor receptor (EGFR). It was reported that autophosphorylation of the mutant EGFR is prolonged compared with wild-type EGFR. To explore the mechanism of sustained autophosphorylation, the mutant and wild-type EGFR degradation activities were examined in NSCLC cell lines. EGFR degradation activity was measured by 125I-EGF. The degradation rate of EGFR was lower in the PC-9 NSCLC cell line, which expressed 15-bp deletion mutant EGFR, compared with that in the PC-14 NSCLC (wild-type EGFR). To clarify the mechanism, the stable transfected cell lines, 293_pEGFR and 293_pdelta15, expressing wild-type and mutant EGFR, respectively, were used. In 293_pdelta15, EGFR degradation and binding of c-Cbl ubiquitin ligase to this receptor were reduced compared with 293_pEGFR. Based on these results, we conclude that the mutant EGFR underwent less protein degradation due to diminished binding to c-Cbl.

Surface structure and its dynamic rearrangements of the KcsA potassium channel upon gating and tetrabutylammonium blocking.

KcsA is the first potassium channel for which the molecular structure was revealed. However, the high resolution structural information is limited to the transmembrane domain, and the dynamic picture of the full KcsA channel remains unsolved. We have developed a new approach to investigate the surface structure of proteins, and we applied this method to investigate the full length of the KcsA channel. Single-cysteine substitution was introduced into 25 sites, and specific reaction of these mutated channels to a bare surface of a flat gold plate was evaluated by surface plasmon resonance measurements. The surface plasmon resonance signals revealed the highest exposure for the mutant of the C-terminal end. When the gate of the KcsA channel is kept closed at pH 7.5, the extent of exposure showed periodic patterns for the consecutive sites located in the cytoplasmic (CP) and N-terminal domain. This suggests that these stretches take the alpha-helical structure. When the channel was actively gated at pH 4.0, many sites in the CP domain became exposed. Compared with the rigid structure in pH 7.5, these results indicate that the CP domain became loosely packed upon active gating. The C-terminal end of the M2 helix is a moving part of the gate, and it is exposed to the outer surface slightly at pH 4.0. By adding a channel blocker, tetrabutylammonium, the gate is further exposed. This suggests that in the active gating tetrabutylammonium keeps the gate open rather than being trapped in the central cavity.

Enhancement of sensitivity to tumor necrosis factor alpha in non-small cell lung cancer cells with acquired resistance to gefitinib.

Tumor cells that have acquired resistance to gefitinib through continuous drug administration may complicate future treatment. To investigate the mechanisms of acquired resistance, we established PC-9/ZD2001, a non-small-cell lung cancer cell line resistant to gefitinib, by continuous exposure of the parental cell line PC-9 to gefitinib. After 6 months of culture in gefitinib-free conditions, PC-9/ZD2001 cells reacquired sensitivity to gefitinib and were established as a revertant cell line, PC-9/ZD2001R. PC-9/ZD2001 cells showed collateral sensitivity to several anticancer drugs (vinorelbine, paclitaxel, camptothecin, and 5-fluorouracil) and to tumor necrosis factor alpha (TNF-alpha). Compared with PC-9 cells, PC-9/ZD2001 cells were 67-fold more sensitive to TNF-alpha and PC-9/ZD2001R cells were 1.3-fold more sensitive. Therefore, collateral sensitivity to TNF-alpha was correlated with gefitinib resistance. PC-9/ZD2001 cells expressed a lower level of epidermal growth factor receptor (EGFR) than did PC-9 cells; this down-regulation was partially reversed in PC-9/ZD2001R cells. TNF-alpha-induced autophosphorylation of EGFR (cross-talk signaling) was detected in all three cell lines. However, TNF-alpha-induced Akt phosphorylation and IkappaB degradation were observed much less often in PC-9/ZD2001 cells than in PC-9 cells or PC-9/ZD2001R cells. Expression of the inhibitor of apoptosis proteins c-IAP1 and c-IAP2 was induced by TNF-alpha in PC-9 and PC-9/ZD2001R cells but not in PC-9/ZD2001 cells. This weak effect of EGFR on Akt pathway might contribute to the TNF-alpha sensitivity of PC-9/ZD2001 cells. These results suggest that therapy with TNF-alpha would be effective in some cases of non-small-cell lung cancer that have acquired resistance to gefitinib.

Doublet regimen of cisplatin plus docetaxel for second-line chemotherapy after prior therapy with cisplatin plus irinotecan for non-small cell lung cancer: a phase II study.

BACKGROUND: To evaluate the safety and efficacy of second-line chemotherapy with docetaxel and cisplatin for non-small cell lung cancer (NSCLC), we performed a phase II study. METHODS: The subjects were 25 patients with NSCLC, 75 years or younger, without organ dysfunction (performance status [PS], 0 to 2) in whom treatment with cisplatin and irinotecan had been ineffective or had been followed by recurrence or relapse. Four weeks or more after the end of the previous therapy, 60 mg/m2 of cisplatin and 60 mg/m2 of docetaxel were administered at intervals of 3 weeks. RESULTS: Observed toxicities of grade 3 or 4 included anemia (24% of patients), leukocytopenia (48%), neutropenia (76%), thrombocytopenia (4%), hepatic dysfunction (8%), and electrolyte abnormalities (4%). However, no severe nonhematologic adverse reactions occurred. The overall response rate was 32% (95% confidence interval, 13.7-50.3). The median time to disease progression was 98 days, and the median survival time was 257 days. CONCLUSION: Our results suggest that cisplatin and docetaxel can be used as second-line chemotherapy against NSCLC. But further, comparative, study of this combination should be performed in patients with good PS and organ function who have responded to prior platinum-based chemotherapy.