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Depression and dementia, in particular Alzheimer's disease (AD), are critically important issues in the mental health of old age. Both conditions apparently reduce quality of life and increase the impairment of activities of daily living for elderly persons. AD usually shows poor prognosis owing to progressive neuronal degeneration, while depression is basically reversible. However, depressive symptoms are common in AD and occur in approximately 20-30% of patients with AD. Epidemiological studies have shown a possible pathological association between depression and AD. Some longitudinal studies have reported that depression is a prodromal sign or might be both a prodromal symptom of AD and a risk factor. Other studies have suggested that depressive symptoms appear to coincide with or follow the onset of AD rather than precede it. However, it still remains controversial whether depressive symptoms represent a risk factor for AD, whether they are an early symptom of neurodegeneration, or whether they are a reaction to early cognitive deficits. A better understanding of the link between AD and depression might have important clinical and research implications. This review provides an overview of current knowledge regarding a relation between depression and AD and also proposes a research and clinical perspective on depression in AD.

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.

Background Screening tests reveal the early signs of cognitive decline, enabling better self-care and preparation for the future. We developed and evaluated the accuracy of a rapid (20 s) and easy-to-use tool called ONSEI, assessing the cognitive decline equivalent to dementia in actual clinical practice by correlating clinical diagnoses with the ONSEI classification. Methods In this retrospective observational study, data were collected from individuals who visited three neurosurgical clinics in neighboring prefectures of Tokyo, Japan. ONSEI analysis was performed using a smartphone or tablet. The tool adopts a machine-learning algorithm using the speaker's age, time-orientation task score, and acoustic features of spoken responses to that task. Significant differences in accuracy, sensitivity, and specificity were evaluated by Fisher's exact test. Results The overall classification accuracy of ONSEI was 98.1% (p<0.001). The sensitivity and specificity were 97.3% (p<0.001) and 98.5% (p<0.001), respectively. The proportion of correct classifications was consistent across different age groups. Conclusion ONSEI showed high classification accuracy for dementia in cognitively normal individuals in actual clinical practice, regardless of the facility at which the tests were conducted or the age of the participants. Thus, ONSEI can be useful for dementia screening and self-care.

We conducted a phase II study to evaluate the efficacy and safety of chemoradiotherapy concurrent with S‐1 plus cisplatin in patients with unresectable locally advanced squamous cell carcinoma of the head and neck. Chemotherapy consisted of S‐1 twice daily on days 1–14 at 60 mg/m2/day and cisplatin at 20 mg/m2/day on days 8–11, repeated twice at a 5‐week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently starting on day 1. For patients achieving an objective response after chemoradiotherapy, two additional cycles of chemotherapy were administered. Of the 45 enrolled patients, the percentage of clinical complete remission, the primary endpoint, was 64.4% (8 complete response, 21 good partial response) on central review. After a median follow‐up of 3.52 years, 3‐year local progression‐free survival was 62.2%, with 3‐year progression‐free survival of 60.0%, 3‐year overall survival of 64.4%, and 3‐year time to treatment failure of 48.9%. Grade 3 or 4 toxicity included pharyngeal mucositis (46.7%), oral mucositis (44.4%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%), and febrile neutropenia (4.4%). No treatment‐related deaths were observed. This combination showed promising efficacy with acceptable toxicities. Based on previous our phase I study (Tahara M et al., Cancer Science 2011; 102: 419–424), we conducted a phase II study to evaluate the efficacy and safety of concurrent chemoradiotherapy with S‐1 plus cisplatin for patients with unresectable locally advanced squamous cell carcinoma of the head and neck. Results of this phase II study showed that this combination resulted in promising efficacy with acceptable toxicities.

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

The Developing Countries’ Vaccine Manufacturers Network, joined by global health organizations, held its 20th meeting celebrating two decades of vaccine innovations for global public good. Health leaders from industry, academia and global health organizations reviewed efforts to accelerate innovation, improve access to vaccines, overcome inequalities and strengthen technological and public-health management capabilities. Discussion topics included World Health Organization’s immunization strategy, Pan American Health Organization’s system-strengthening efforts, Gavi’s evaluation of vaccine coverage in middle income countries and developments on public-market intelligence. Health market trends, delivery gaps, integration of system-wide needs, costs and benefits, and implications for stakeholder decision-making were areas of focus. Novel thinking was discussed on integration of policy, financing, regulatory pathways and alignment of innovation priorities to improve efficiency in vaccine development pathways. The Vaccine Innovation Prioritization Strategy collaboration presented nine global innovation priorities, and many other partners and members presented updates on their priorities. Novel technologies and platforms, such as RNA-based vaccines, adenoviral vectors, bioconjugation, blow-fill-seal and two-dimensional barcodes, provided opportunities to accelerate vaccine innovations. Challenges in planning and operations at global level included those in health security, polio eradication, re-emergence of diseases, disparities between forecasts and orders and heterogeneous regulatory requirements. Manufacturers were urged to accelerate innovation and prequalification of high-impact vaccines, such as pneumococcal, human papillomavirus and rotavirus vaccines, to strengthen immunization globally.

Symptomatic anti-Alzheimer's disease (AD) drugs have been commonly used for the treatment of AD. Knowing the natural courses of patients with AD on placebo is highly relevant for clinicians to understand their efficacy and for investigators to design clinical studies. The data on rating scales for dementia such as Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Severe Impairment Battery were extracted from eight previous Japanese Phase II and III studies. Natural courses of Japanese AD patients in placebo groups were evaluated and statistically analyzed in a pooled and retrospective fashion. Decreases in ADAS-cog and Severe Impairment Battery was larger at week 22 or 24 than at week 12. Scores of ADAS-cog appeared to deteriorate faster in moderate AD than in mild AD. The present data will provide clinicians following up patients with AD with helpful information on how to manage AD patients and investigators with instruction for clinical study design.

Background: Alzheimer's drugs are believed to have limited availability and to be unaffordable in low- and middle-income countries compared to high-income countries. The price, availability and affordability of Alzheimer's drugs have not been reported before. Methods: During 2007 an international survey was conducted in 21 countries in six continents (Argentina, Australia, Brazil, the Dominican Republic, France, India, Japan, Macedonia, Mexico, New Zealand, Nigeria, the Philippines, Portugal, Serbia, South Korea, Switzerland, Taiwan, Thailand, Uganda, the U.K. and the U.S.A.). Prices of Alzheimer's drugs were compared using the affordability index (the total number of units purchasable with one's daily income) derived from purchasing power parity (PPP) converted prices as well as raw prices. Results: Donepezil is available in all 21 countries, whereas the newer drugs are less available. A 5 mg tablet of branded originator donepezil costs just US$0.26 in India and US$0.31 in Mexico, whereas it costs US$6.64 in the U.S.A. Pricing conditions of rivastigmine, galantamine and memantine appear to be similar to that of donepezil. The cheapest branded originators are from India and Mexico. However, in terms of PPP, Alzheimer's drugs in other low- and middle-income countries are much more expensive than in high-income countries. Most people in low- and middle-income countries cannot afford Alzheimer's drugs. Conclusions: Alzheimer's drugs, albeit available, are often unaffordable for those who need them most. It is hoped that equitable differential pricing will be applied to Alzheimer's drugs.

Background/Aims: We examined the effect of aging on cognitive function at the limit of human life expectancy by characterizing state of cognition in centenarians without clinical cognitive impairment. Methods: Participants were 68 centenarians without cognitive impairment (Clinical Dementia Rating (CDR) 0), 96 controls 60 to 74 years old, and 46 controls 75 to 89 years old. We visited the places where centenarians were living and administered the Mini-Mental State Examination (MMSE) individually. Control subjects came to the assembly hall within their dwelling area, to be administered the MMSE. Results: Mean total scores of centenarians (22.3) were lower than for either 60–74 (27.2) or 75–89 (26.2). Comparison of scores in each of five cognitive domains measured by MMSE showed a significant age-group effect upon orientation, memory, and attention. Centenarians’ scores were lower than for younger groups in every domain except for the language and praxis, concentration, and for repetition. Conclusion: The centenarians’ scores in memory and orientation declined as in earlier studies of normal aging. Centenarians’ scores for attention and concentration differed from those in previous studies. The present result suggests that even primary memory is influenced by advanced age in centenarians, while ability to store information declines, ability to process is maintained.

Background/Aims: The 7-Minute Screen (7MS) is a screening battery to identify individuals with a high probability of Alzheimer’s disease (AD). The 7MS consists of four subtests (Temporal Orientation, Enhanced Cued Recall, Clock Drawing, and Verbal Fluency), each measuring a different aspect of cognition. The present study is designed to examine the predictive validity of the 7MS to distinguish between patients with early-stage AD and healthy control subjects. Methods: Sixty-three patients who were diagnosed as having probable or possible AD and 91 community-dwelling elderly individuals of comparable age, sex distribution, and education were administered the 7MS (paper-and-pencil version) and other screening batteries. All patients were rated Clinical Dementia Rating (CDR) 0.5–1, categorized as early-stage AD, and all participants obtained a score of less than 6 for the Geriatric Depression Scale (15-item version). Results: Mean scores for patients and controls on all the four subtests were significantly different. When using the total score of the 7MS, which was calculated by the original logistic regression formula based on all of the four subtests, the sensitivity for early-stage AD was 90.5% with a specificity of 92.3%. Correlation analysis indicated high concurrent validity between the 7MS and existing standard cognitive screening batteries (e.g., MMSE, HDS-R). In correlation analysis and multiple regression analysis, demographic effects (age, sex, and education) were not significantly associated with the total score of the 7MS in controls. Conclusions: The results showed that the 7MS had a high level of sensitivity and specificity. We also found that the 7MS was not affected by demographic characteristics. These findings demonstrated that the 7MS is a useful screening tool for discriminating patients with early-stage AD from intact individuals.