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Advance care planning is considered an important issue in end-of-life care for older adults. The ongoing COVID-19 pandemic has interrupted the healthcare system and end-of-life care tremendously. This review aimed to explore available articles on advance care planning amid the pandemic and analyze qualitatively. PubMed and Google Scholar were searched on February 2021 using the relevant keywords. Retrieved articles were screened applying inclusion criteria. Any article describing advance care planning during the COVID-19 era was included. A qualitative content analysis was conducted. In total, 20 articles incorporating 5542 participants from five countries were included. Among the articles, eight were primary studies and the rest were perspective papers or secondary analysis. From the qualitative content analysis six major themes emerged namely palliative care, lack of coordination among acute care, hospital palliative care, and long-term care, community-based advance care planning, real-time dissemination of scientific information on the regional pandemic situation, online system and legislation. The COVID-19 pandemic had decreased the uptake of advance care planning. Findings of the review suggested simplification of the procedure regarding advance care planning, implementation of community-based advance care planning and utilization of online resources to enhance the process. Geriatr Gerontol Int 2021; 21: 779-787.

A conceptual framework for advance care planning is lacking in societies like Japan's valuing family-centered decision-making.A consensus definition of advance care planning with action guideline adapted to Japanese society.We conducted a multidisciplinary modified Delphi study 2020-2022. Thirty physicians, 10 healthcare and bioethics researchers, six nurses, three patient care managers, three medical social workers, three law experts, and a chaplain evaluated, in 7 rounds (including two web-based surveys where the consensus level was defined as ratings by ≥70% of panelists of 7-9 on a nine-point Likert scale), brief sentences delineating the definition, scope, subjects, and action guideline for advance care planning in Japan.The resulting 29-item set attained the target consensus level, with 72%-96% of item ratings 7-9. Advance care planning was defined as "an individual's thinking about and discussing with their family and other people close to them, with the support as necessary of healthcare providers who have established a trusting relationship with them, preparations for the future, including the way of life and medical treatment and care that they wish to have in the future." This definition/action guideline specifically included support for individuals hesitant to express opinions to develop and express preparations for the future.Adaptation of advance care planning to Japanese culture by consciously enhancing and supporting individuals' autonomous decision-making may facilitate its spread and establishment in Japan and other societies with family-centered decision-making cultures.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity worldwide. Patients with severe COPD often fail to receive adequate palliative care and are subject to undesired hospital transfers and cardiopulmonary resuscitation. Although promoting advance care planning (ACP) in the community can help ensure the optimal delivery of palliative care for patients with COPD, the key challenges to routinely implementing ACP are not known. The aim of this study was to identify the perception of healthcare professionals with regard to ACP for adults living with severe COPD and the challenges to facilitating ACP. A multicenter qualitative study design was used. In-depth semistructured interviews were held involving 38 healthcare professionals from 19 institutions in Japan. Text data were analyzed by content analysis. Five main themes capturing the challenges to routine implementation of ACP were identified: daily decision-making; sense of ethical decision-making; in-depth interviewing skills; collaborative information sharing among team members; and knowledge dissemination regarding ACP. The model demonstrates the complexity inherent in ACP facilitation for community-dwelling adults with severe COPD, with all the elements required for successful ACP implementation. We recommend an approach that recognizes the importance of stakeholder education, particularly educating professionals to develop the knowledge, attitudes, and skills required for ACP facilitation: in-depth interviewing, collaborative information sharing, and ethical analysis, focusing on decision-making concerning everyday life support.

Objective: This study aimed to explore the predictors of morphine efficacy in the alleviation of dyspnea in COPD. Background: Dyspnea is prevalent in patients with chronic obstructive pulmonary disease (COPD) and often persists despite conventional treatment. Methods: A secondary analysis of a multi-institutional prospective before-after study was conducted focusing on morphine use for alleviating dyspnea in COPD patients. Subjects included COPD patients with dyspnea at seven hospitals in Japan. Patients received 12 mg/day of oral morphine (or 8 mg/day if they had low body weight or renal impairment). Univariate and multivariate logistic regression analyses were performed with numerical rating scale (NRS) score of the current dyspnea intensity in the evening of day 0, Eastern Cooperative Oncology Group Performance Status (ECOG PS; ≤2 or ≥3), age, and partial arterial pressure of carbon dioxide (PaCO2) as independent factors; an improvement of ≥1 in the evening NRS score of dyspnea from day 0 to 2 was the dependent factor. Results: Thirty-five patients were enrolled in this study between October 2014 and January 2018. Excluding one patient who did not receive the treatment, data from 34 patients were analyzed. In the multivariate analysis, lower PaCO2 was significantly associated with morphine efficacy for alleviating dyspnea (odds ratio [OR] 0.862, 95% confidence interval [CI] 0.747-0.994), whereas the NRS of dyspnea intensity on day 0 (OR 1.426, 95% CI 0.836-2.433), ECOG PS (OR 4.561, 95% CI 0.477-43.565), and patients' age (OR 0.986, 95% CI 0.874-1.114) were not. Discussion: Morphine can potentially alleviate dyspnea in COPD patients with lower PaCO2. Trial registration: UMIN000015288 (http://www.umin.ac.jp/ctr/index.htm).

(1) Background: While advance care planning (ACP) provides healthcare professionals with valuable tools to meet patients’ needs in a person-centered manner, several potential ethical challenges are inherent to the process. However, recent studies have largely focused on ACP practicalities such as implementation, execution, and completion rather than on the ethical challenges that clinicians routinely encounter in ACP practices. (2) Research question/aim/objectives: This study aimed to identify tips for clinicians managing ethical challenges in ACP practices. (3) Methods: It performed a brief search for all Japanese published books pertaining to ACP practice available as of January 2021 using the keywords “advance care planning (ACP)” and “autonomy” and analyze the content of nine practical ACP textbooks for clinicians. (4) Results: Two major themes capturing the essential recommendations for managing ethical challenges in ACP were ultimately identified, namely interprofessional ethics and informed consent. (5) Conclusion: The findings suggested tips for managing ethical challenges in ACP: refer to ethical frameworks for interprofessional collaboration and ethical decision making, assess decision-making capacity of family substitute decision makers and one’s eligibility for the role, understand the standard process of informed consent and how to handle situations when the patient are not well informed about the diagnosis and prognosis of non-cancer illness.

The Japan Geriatrics Society has so far announced "The Japan Geriatrics Society Position Statement 2012" and "Guidelines for the Decision-Making Processes in Medical and Long-Term Care for the Elderly - Focusing on the Use of Artificial Hydration and Nutrition" related to end-of-life care for older adults. In 2018, the Ministry of Health, Labor and Welfare revised the "Guidelines for the Decision-Making Processes in Medical and Long-Term Care in the End of Life," recommending the practice of advance care planning (ACP). This was the first time when the Japanese government publicized its stance on ACP. Immediately after the government's announcement, the Japan Medical Association announced its committee report, "The Super-aged Society and the End-of-life Care," which also recommended the practice of ACP. The guidelines were published when the society was experiencing substantial changes related to geriatric care in Japan, and required timely and ethically appropriate decision-making processes. However, because ACP is a concept imported from English-speaking countries, some Japanese people could find it difficult to understand the role and methodology of ACP because of differences in culture and the medical/long-term care system. Therefore, the Japan Geriatrics Society has decided to publish the "Recommendations for the Promotion of Advance Care Planning" for medical and long-term care professionals nationwide with the aim of using the recommendations on a daily basis. The society recognizes ACP as indispensable to improve end-of-life care for individuals, particularly for older adults. We anticipate that the recommendations will provide practical guidance for those strenuously working toward this goal. Geriatr Gerontol Int 2020; 20: 1024-1028..

Background: Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare intractable cardiovascular disorder (Orphanet ORPHAcode: 565612) in which defective intracellular lipolysis results in heart failure and coronary artery disease. Myocardial scintigraphy with (123)I-β-methyl-p-iodophenylpentadecanoic acid (BMIPP) is useful to evaluate myocardial TG metabolism; its washout rate (WR) reflects myocardial lipolysis. This study reports the effects of CNT-01 (tricaprin), a developing orphan drug to facilitate lipolysis, on BMIPP-WR in patients with TGCV. Methods: An investigator-initiated, multicenter, randomized, double-blind exploratory, trial (Phase IIa) was conducted (UMIN000035403). Seventeen patients with idiopathic TGCV were orally administered 1.5 g/day of CNT-01 or placebo for 8 weeks. Endpoints included delta BMIPP-WR and clinical parameters such as 6-minwalk distance and TGCV severity score. Results: During the protocol, delta BMIPP-WRs were −0.26±3.28 and 7.08±3.28% (95% confidence intervals, −7.36 to 6.84 and −0.01 to 14.18) in the placebo and CNT-01 groups, respectively. The baseline-adjusted difference of delta BMIPP-WR between the two groups was significant (p=0.035) after one patient was excluded from the placebo group because of pseudonormalization of BMIPP-WR related to coronary bypass graft stenosis. Clinical parameters did not show significant changes. Conclusions: This study proved the mechanism of CNT-01 to improve myocardial lipolysis in TGCV, as demonstrated by BMIPP scintigraphy.

Health care professionals working with older people living alone with chronic obstructive pulmonary disease (COPD) to complete advance care planning (ACP) often encounter the double burden of social isolation and acute exacerbations in this planning. The study explored clinicians' perceptions regarding factors influencing the completion of ACP for older people with COPD living alone. Individual interviews were conducted with 18 health care professionals using the video meeting platform in 2020. A semi-structured interview guide included: (a) behavior and lifestyle related to decision-making, (b) desired place to die, and (c) facilitators and barriers to autonomy in patients with severe COPD who live alone. Five main themes were identified: information sharing among team members, patient readiness, desired place of death, economic constraints, and care at the time of and after death. Partly due to the heterogeneity and complexity of clinical courses and treatment responses of COPD, a wide range of social issues of a person's life were related to practicality in the completion of ACP for older people with COPD living alone. Social work knowledge and skills such as in-depth interviewing, outreach finance and welfare support, and holistic perspective play an essential role in completing ACP for COPD patients living alone.

AIM An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome. METHODS A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and

Since the end of 2019, a life-threatening infectious disease (coronavirus disease 2019: COVID-19) has spread globally, and numerous victims have been reported. In particular, older persons tend to suffer more severely when infected with a novel coronavirus (SARS-CoV-2) and have higher case mortality rates; additionally, outbreaks frequently occur in hospitals and long-term care facilities where most of the residents are older persons. Unfortunately, it has been stated that the COVID-19 pandemic has caused a medical collapse in some countries, resulting in the depletion of medical resources, such as ventilators, and triage based on chronological age. Furthermore, as some COVID-19 cases show a rapid deterioration of clinical symptoms and accordingly, the medical and long-term care staff cannot always confirm the patient's values and wishes in time, we are very concerned as to whether older patients are receiving the medical and long-term care services that they wish for. It was once again recognized that it is vital to implement advance care planning as early as possible before suffering from COVID-19. To this end, in August 2020, the Japan Geriatrics Society announced ethical recommendations for medical and long-term care for older persons and emphasized the importance of conducting advance care planning at earlier stages. Geriatr Gerontol Int 2020; 20: 1112-1119.

Objectives To describe the implementation and 1-year results of a value-based bariatric surgery program in Brazil. Methods The study was conducted at a private hospital in Sao Paulo, Brazil (Hospital Alemao Oswaldo Cruz). A value-based healthcare program was implemented by designing an episode of care for eligible patients and developing a bundled payment model in which a single payment was made for the bariatric surgery covering the preoperative workup and ending 30 days after discharge. Assessment of outcomes included complication rate, hospital length of stay, intensive care admissions, reoperations, readmissions, and visits to the emergency department in the 30-day postoperative period. The results were compared with real-world evidence retrieved from a Brazilian private insurance database containing information on bariatric procedures performed in similar institutions (benchmark group). Results Eighty-three patients were enrolled in the value-based healthcare program (80.7% women; 18.0% with type 2 diabetes mellitus; 31.0% with high blood pressure). The mean age was 40.9 years, and body mass index was 42.1 kg/m2. The outcomes recorded in the benchmark group versus the value-based healthcare group involved complication rate, 2.6% versus 1.4% (P = 0.69); length of stay, 2.5 versus 2.0 days (P = 0.0001); intensive care admissions, 4.0% versus 1.2% (P = 0.31); emergency care visits, 15.0% versus 6.0% (P = 0.04); and readmissions, 2.3% versus 0 (P = 0.35), with an estimated cost reduction of 7.1%. Conclusions These initial results showed favorable surgical and 30-day outcomes, demonstrating the benefits of a value-based approach for the surgical management of obesity and its comorbidities.

Objectives To systematically review the economic evaluations of 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults aged ≥60 years to inform the development of local studies through the discussion of parameters and assumptions that influence the results of the analyses. Methods We searched the MEDLINE, Excerpta Medica, Cochrane Library, Latin-American and Caribbean Health Sciences Literature (LILACS), Brazilian Regional Library of Medicine, National Health Service Economic Evaluation, and Centre for Reviews and Dissemination—as well as the Scopus citation index and the Web of Science for full economic evaluations of PPV23 published up to March 2016. Two independent reviewers screened the articles for relevance and extracted the data. Main study characteristics and methods (clinical and epidemiological data, cost and incremental cost-effectiveness ratios (ICERs) were extracted and compared. Costs were updated to 2016 international dollars. Results Twenty-seven studies published from 1980 to 2016 were reviewed. Most studies were conducted in Europe and the USA; three studies were conducted in Latin America (Brazil, 2; Colombia, 1). In addition to the scenario comparing the vaccination with the PPV23 to non-vaccination, three studies also compared PPV23 to pneumococcal conjugate 13-valent vaccine (PCV13). All studies used static models. Most used a lifetime (44.4%) or 5–6 year’s time horizon (33.3%). Only three studies considered herd protection from children immunization with PCV13 in the model. Most studies considered PPV23 cost-effective (less than US$50,000 per LYG or QALY) and sometimes cost-saving (results ranging from cost-saving to US$84,636/QALY). The estimates of disease burden, the efficacy/effectiveness of PPV23, and the effects of herd protection from childhood immunization had most influence on the results. Conclusions Well-designed cost-effectiveness studies of PPV23 that represent the current epidemiological scenario and reduce uncertainty related to efficacy/effectiveness are extremely relevant to informing the decision-making process.

Recently, we have developed a novel granulation technology to manufacture hollow spherical granules (HSGs) for controlled-release formulations; however, the mechanism of the granulation is still unclear. The aim of this study is to determine the mechanism of the formation of the HSGs using a high shear granulator. Samples of granulated material were collected at various times during granulation and were investigated using scanning electron microscope and X-ray computed tomography. It was observed that the granulation proceeded by drug layering to the polymer, followed by formation of a hollow in the granule. In addition, it was also found that generation of a crack in the adhered drug layer and air flow into the granules might be involved in forming the hollow in the structure. Observation of the granulation of formulations with different types of drugs and polymers indicated that negative pressure in the granules occurred and the granules caved in when the hollow was formed. The hollow-forming speed and the shell density of the hollow granules depended on the particular drug and polymer. Taken together, the granulation mechanism of HSGs was determined and this information will be valuable for HSGs technology development.

Background: Advance care planning (ACP) is recommended as part of the management of patients with heart failure (HF). Aims: To develop and validate ACP support tools for patients with HF. Methods: An ACP support tool was developed based on a systematic literature review. A multi-center, prospective before and after study was conducted to evaluate the usefulness of the support tool. This study included 21 patients with HF, 11 patients formed the control group and 10 patients were part of the intervention group who received ACP from medical staff using the ACP support tools developed for this study. Participants of the study were surveyed about their experience of ACP using a 6-point Likert scale. Findings: All of the healthcare professionals (n=9) involved in the study found the ACP tool useful and about 90% of patients considered the support tool useful. The score for ‘the patient did not feel anxious about the future after receiving ACP discussion’ was significantly higher (3.5 [3.0, 4.0] vs 2.0 [1.0, 3.0]; P=0.04) in the intervention group that used the ACP tool. Conclusion: ACP support tools are useful to manage patients with HF and could enable effective ACP without increasing patient anxiety.

ObjectivesDyspnoea in patients with chronic obstructive pulmonary disease (COPD) is frequent and often persists despite conventional treatment. This study aimed to evaluate the efficacy and safety of oral morphine for dyspnoea in Japanese COPD patients.MethodsWe conducted a multi-institutional, prospective, before–after study of morphine in COPD patients with dyspnoea at rest in seven hospitals. Patients received 12 mg of oral morphine per day (or 8 mg per day if low body weight or renal impairment). Primary outcome was change in the numerical rating scale (NRS) of current dyspnoea in the evening from Day 0 to Day 2. Secondary outcomes included changes in dyspnoea intensity in the evening from Day 0 to Day 1, dyspnoea intensity between the morning from Day 0 to Day 1 and Day 2, vital signs, nausea, somnolence, anorexia and other adverse events (AEs).ResultsA total of 35 patients were enrolled in this study between October 2014 and January 2018. One patient did not receive study treatment. Data from 34 patients was analysed. The NRS of dyspnoea intensity in the evening significantly decreased from 3.9 on Day 0 (95% CI: 3.1 to 4.8) to 2.4 on Day 2 (95% CI: 1.7 to 3.1; p=0.0002). Secondary outcomes significantly improved in a similar manner. There were no apparent changes in the mean scores of the opioid-related AEs and vital signs. One patient experienced grade 3 lung infection not associated with morphine. Other AEs were mild.ConclusionOral morphine is effective in alleviating dyspnoea in Japanese COPD patients.Trial registrationUMIN000015288 (http://www.umin.ac.jp/ctr/index.htm).

INTRODUÇÃO: Infecções causadas por Streptococcus pneumoniae são uma das maiores causas de morbidade e mortalidade no mundo, particularmente em países em desenvolvimento, gerando um impacto clínico e econômico significante. Crianças com menos de dois anos de idade, adultos com mais de 60 anos e pessoas com condições crônicas são as populações mais afetadas. Devido ao aumento da resistência a antibióticos e do impacto crescente das consequências da doença, vem sendo discutida a prevenção primária por meio das vacinas antipneumocócicas como uma das estratégias de saúde pública mais eficaz na redução da carga da doença. OBJETIVO: Revisar sistematicamente e avaliar a qualidade do relato dos estudos de avaliação econômica da vacina pneumocócica polissacarídea 23-valente em idosos, com o intuito de comparar as diferentes estratégias metodológicas adotadas pelos estudos publicados e discutir os parâmetros e premissas que possam ter influenciado os resultados dos modelos econômicos. MÉTODOS: Pesquisou-se nas bases de dados eletrônicas Medical Literature Analysis and Retrieval System Online (via PubMed), Excerpta Medica database, Cochrane reviews, Centre for Reviews and Dissemination Database, Web of Science, Scopus Citation Index e Literatura LatinoAmericana e do Caribe em Ciências da Saúde por avaliações econômicas completas da vacina pneumocócica polissacarídea 23-valente, publicadas até março de 2016. Dois revisores independentes selecionaram artigos relevantes de acordo com critérios de inclusão e exclusão e extraíram seus dados. As principais características dos estudos e métodos (dados clínicos e econômicos, custo e relação de custo-efetividade incremental) foram extraídas e comparadas. Custos foram atualizados para dólar internacional de 2016. RESULTADOS: Vinte e sete avaliações econômicas publicadas entre 1980 e 2016 foram incluídas na revisão sistemática, grande parte publicada nos Estados Unidos e na Europa. Apenas três estudos foram conduzidos na América Latina (dois no Brasil, um na Colômbia). Soma-se a esse cenário de comparação entre a vacinação e a não vacinação com a vacina pneumocócica polissacarídea 23-valente, três estudos que também cotejaram a vacina pneumocócica polissacarídea 23valente com a conjugada 13-valente. Todos os estudos utilizaram modelos estáticos. A maioria considerou horizonte temporal para toda a vida (44,4%) ou de cinco a seis anos de horizonte (33,3%). Apenas três estudos consideraram a proteção indireta causada pela imunização da vacina pneumocócica conjugada 13-valente em crianças no modelo. Apesar da diversidade de síndromes clínicas incluídas, das diferentes definições de cada síndrome clínica, da variação nas estimativas de eficácia e de coberturas vacinais e dos custos hospitalares e ambulatoriais das doenças pneumocócicas, a maioria dos estudos incluídos apresentou relações de custo-efetividade incremental favoráveis (menos de US$ 50.000,00 por ano de vida ganho ou por ano de vida ajustado pela qualidade, Quality Adjusted Life Year) e algumas vezes econômicas. Nos estudos, a relação de custo-efetividade incremental variou de costsaving a US$ 84.636,00 por ano de vida ajustado pela qualidade (Quality Adjusted Life Year). As estimativas de impacto da doença, a eficácia/efetividade da vacina pneumocócica polissacarídea 23valente e os efeitos da proteção indireta pela imunização em crianças foram os parâmetros que mais influenciaram os resultados do modelo. Em relação à qualidade do relato dos estudos, as principais limitações foram: descrição clara e completa do resumo, declaração do financiamento do estudo e declaração dos conflitos de interesse. CONCLUSÃO: Esta revisão sistemática revelou que os resultados de custo-efetividade foram variados, de cost-saving a não custo-efetivo. Estudos de custo-efetividade bem estruturados da vacina pneumocócica polissacarídea 23-valente que representam a epidemiologia atual e reduzem a incerteza de parâmetros chave, como a eficácia/efetividade da vacina, são extremamente importantes para auxiliar no processo de decisão INTRODUCTION: Infections caused by Streptococcus pneumoniae are one of the main causes of morbidity and mortality in the world, particularly in developing countries, generating a significant clinical and economic impact. Children under 2 years old, adults ³60 years old and populations with cronic conditions are the most affected populations. Due to the increase in antibiotic resistance and the increase of the disease\'s consequences, primary prevention of the disease is being discussed with antipneumococcal vaccination as one of the most effective public health strategies in reducing the burden of the disease. OBJECTIVE: To systematically review and evaluate the quality of the reported economic evaluation studies of the 23-valent pneumococcal polysaccharide vaccine in the elderly immunization with the aim to compare the different methodological strategies adopted by the published studies and discuss the parameters and premises that may have influenced the results of economic models. METHODS: It was searched in the electronic databases Medical Literature Analysis and Retrieval System Online (PubMed), Excerpta Medica database, Cochrane reviews, Centre for Reviews and Dissemination Database, Web of Science, Scopus Citation Index and Latin-American and Caribbean Health Sciences Literature for full economic evaluations of 23-valent pneumococcal polysaccharide vaccine published up to March 2016. Two independent reviewers screened articles according to inclusion and exclusion criterias and extracted the data. Main studies characteristics and methods (clinical and economic data, cost and incremental cost-effectiveness ratio) were extracted and compared. Costs were updated to 2016 International Dollar. RESULTS: Twenty seven evaluations published between 1980 and 2016 were included in the systematic review, most of them being published in the United States and Europe. Only three studies were conducted in Latin America (two in Brazil, one in Colombia). In addition to the scenario comparing 23-valent pneumococcal polysaccharide vaccine vaccination to non-vaccination, three studies also compared 23-valent pneumococcal polysaccharide vaccine to 13-valent pneumococcal conjugate vaccine. All studies used static models. The majority considered a lifetime time horizon (44.4%) or from 5 to 6 years of time horizon (33.3%). Only three studies considered the indirect protection from 13-valent pneumococcal conjugate vaccine immunization in children in the model. Despite the diversity of clinical syndromes included, from the different definitions of each clinical syndrome, the variation in vaccine efficacy and inpatient and outpatient costs for the pneumococcal disease, most of the included studies showed and favorable incremental cost-effectiveness ratio (less than US$ 50,000.00 per year of life or Quality Adjusted Life Year) and sometimes cost-saving. In the evaluations, incremental cost-effectiveness ratio ranged from cost-saving to US$ 84,636.00/Quality Adjusted Life Year. The estimates of disease burden, the efficacy/effectiveness of 23-valent pneumococcal polysaccharide vaccine, and the effects of herd protection from childhood immunization had most influence on the results. Regarding the study quality, the main limitations were: clear and complete summary description, statement of the study founding source and declaration of conflicts of interest. CONCLUSIONS: This systematic review revealed that the cost-effectiveness results have conflicting results, from cost-saving to not cost-effective at all. Welldesigned cost-effectiveness studies of 23-valent pneumococcal polysaccharide vaccine that represent the current epidemiological scenario and reduce uncertainty related to efficacy/effectiveness are extremely relevant to informing the decision-making process

Background Although the efficacy of parenteral morphine for alleviating dyspnea has been previously demonstrated in several studies, little is known regarding the efficacy of oral morphine for dyspnea among patients with cancer, including its response rate and predictive factors of effectiveness. Therefore, the aim of this study was to clarify the effectiveness of oral morphine on dyspnea in patients with cancer and elucidate the predictive factors of its effectiveness. Subjects, materials, and methods In this multicenter prospective observational study, we investigated the change in dyspnea intensity in patients with cancer before and after the administration of oral morphine by using a visual analog scale (VAS). We also administered a self-assessment questionnaire to determine whether the patients believed oral morphine was effective. Results Eighty patients were enrolled in the study, and 71 of these patients were eligible. The least square mean of the VAS scores for dyspnea intensity was 53.5 at baseline, which decreased significantly to 44.7, 40.8, and 35.0 at 30, 60, and 120 minutes after morphine administration, respectively. Fifty-four patients (76.1%) reported that oral morphine was effective on the self-assessment questionnaire. Among the background factors, a high score for "sense of discomfort" on the Cancer Dyspnea Scale (CDS) and a smoking history of fewer pack-years were associated with greater effectiveness. Conclusion Oral morphine was effective and feasible for treating cancer-related dyspnea. A higher score for "sense of discomfort" on the CDS and a smaller cumulative amount of smoking may be predictive factors of the effectiveness of oral morphine. Implications for practice This study demonstrated that oral morphine was effective in alleviating cancer-related dyspnea due to multiple factors including primary lung lesions, airway narrowing, and pleural effusion. Approximately 76% of patients reported that oral morphine was effective. A higher score for "sense of discomfort" on the Cancer Dyspnea Scale and a lower cumulative amount of smoking may be predictive factors for the effectiveness of oral morphine. Interestingly, respiratory rates in patients who reported the morphine to be effective decreased significantly after oral morphine administration, unlike the respiratory rates in "morphine-ineffective" patients.

The study analyzes a questionnaire on the potential discriminative characteristics of patients with incurable solidcancer, who either receivedor didnot receive palliative chemotherapy while receiving home-basedend -of-life care. From the standpoint of regional palliative care, we sought to investigate the influence of the timing of when chemotherapy was ceasedor withheldin home-basedend -of-life care in patients with incurable solidcancer. We plannedthe project to obtain scientific evidence about the timing of ceasing or withholding chemotherapy.The study includes all patients with solidcancer treatedwith or without palliative chemotherapy andwho diedat home in 2016 in Japan. We delivereda postcardof invitation to participate in the questionnaire to more than 2,000 home care doctors in Japan. The questionnaires were registeredas online surveys from May to November 2017. The questionnaire data were analyzed using nonparametric methods.We obtained information from 576 patients at 170 medical facilities from May to August 2017, but the study is currently ongoing; hence, we have released an interim report of the questionnaire results. Among the patients, 40%receivedchemotherapy and 60%didnot since the time of the first incurable solidcancer diagnosis.The majority 60% of patients not receiving chemotherapy was a setback to our project. However, as the questionnaire survey continues, we wouldlike to analyze these data after collecting more results.

SR-0379 is a functional peptide that has wound healing effect with anti-microbial action, making it an ideal drug to prevent infection. To evaluate the safety, efficacy, and pharmacokinetics of SR-0379 for the treatment of leg ulcers, a physician-initiated, phase I/IIa, first-in-patient clinical study was designed. A multi-center, double-blind, randomized clinical study was conducted from October 2015 to September 2016. The inclusion criteria for leg ulcers were (1) diabetes or critical limb ischemia and (2) wound size, Dermatology: peptide drug development for skin ulcers Chronic leg ulcers result in substantial impairment of patient quality of life with a socioeconomic impact both in terms of medical care and missed work days. A teams led by Hironori Nakagami at Osaka University originally identified a functional peptide, SR-0379, and evaluated the safety and efficacy of SR-0379 for the treatment of leg ulcers in a physician-initiated, first-in-patient, a multi-center, double-blind, randomized clinical study. In the evaluation of efficiency, the skin ulcer reduction rates were improved for the SR-0379 treated groups in a dose-dependent manner, compared for the placebo group with no causal adverse events. Since treatment with SR-0379 for chronic leg ulcers was safe, well tolerated, and effective in this initial clinical trial, the clinical trial on next stage will be designed toward peptide drug development.

tudy Objective To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. Design Pharmacogenetic analysis of patients enrolled in a previously published study. Patients One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation. Measurements and Main Results ABCC2 c.−24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.−76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.−76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, pT polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.−76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.

ContextUnspecified Ulcerative Rectocolitis is a chronic disease that affects between 0.5 and 24.5/105 inhabitants in the world. National and international clinical guidelines recommend the use of aminosalicylates (including mesalazine) as first-line therapy for induction of remission of unspecified ulcerative rectocolitis, and recommend the maintenance of these agents after remission is achieved. However, multiple daily doses required for the maintenance of disease remission compromise compliance with treatment, which is very low (between 45% and 65%). Use of mesalazina in granules (2 g sachet) once daily - Pentasa® sachets 2 g - can enhance treatment adherence, reflecting in an improvement in patients' outcomes.ObjectiveTo evaluate the evidence on the use of mesalazine for the maintenance of remission in patients with unspecified ulcerative rectocolitis and its effectiveness when taken once versus more than once a day. From an economic standpoint, to analyze the impact of the adoption of this dosage in Brazil's public health system, considering patients' adherence to treatment.MethodsA decision tree was developed based on the Clinical Protocol and Therapeutic Guidelines for Ulcerative Colitis, published by the Ministry of Health in the lobby SAS/MS n° 861 of November 4 th, 2002 and on the algorithms published by the Associação Brasileira de Colite Ulcerativa e Doença de Crohn, aiming to get the cost-effectiveness of mesalazine once daily in granules compared with mesalazine twice daily in tablets.ResultsThe use of mesalazine increases the chances of remission induction and maintenance when compared to placebo, and higher doses are associated with greater chance of success without increasing the risk of adverse events.ConclusionThe use of a single daily dose in the maintenance of remission is effective and related to higher patient compliance when compared to the multiple daily dose regimens, with lower costs. ContextoA retocolite ulcerativa inespecífica é uma doença crônica que atinge entre 0,5 e 24,5/105 habitantes no mundo. Diretrizes clínicas nacionais e internacionais recomendam o emprego de aminosalicilatos (entre eles, a mesalazina) como terapia de primeira linha na indução da remissão da retocolite ulcerativa inespecífica, com manutenção destes agentes após a remissão. Mas as múltiplas doses diárias necessárias comprometem a adesão ao tratamento, que é muito baixa (entre 45% e 65%). A utilização de mesalazina em grânulos (sachê 2 g) dose única diária - Pentasa®sachê 2 g - pode aumentar a aderência ao tratamento, refletindo numa melhora nos desfechos dos pacientes.ObjetivoAvaliar as evidências sobre o uso de mesalazina para a manutenção da remissão em pacientes com retocolite ulcerativa inespecífica e sua eficácia quando tomada uma vez versus mais de uma vez ao dia. Do ponto de vista econômico, avaliar o impacto que a adoção desta posologia teria para o sistema público de saúde do país, comparada ao tratamento padrão atual, considerando a adesão dos pacientes.MétodosFoi elaborada uma árvore de decisão construída a partir do Protocolo Clínico e Diretrizes Terapêuticas de Colite Ulcerativa, publicado pelo Ministério da Saúde na portaria SAS/MS n° 861, de 04 de novembro de 2002, e de algoritmos publicados pela Associação Brasileira de Colite Ulcerativa e Doença de Crohn, objetivando-se obter o custo-efetividade da mesalazina dose única diária em grânulos comparado com mesalazina duas vezes ao dia em comprimidos.ResultadosO emprego de mesalazina aumenta as chances de indução da remissão e sua manutenção, quando comparado a placebo, sendo que doses maiores se associam a maior chance de sucesso sem aumento no risco de eventos adversos.ConclusãoO emprego de dose única diária na manutenção da remissão é efetivo e relacionado à maior adesão do paciente em comparação a posologias com múltiplas doses diárias, além de ter menor custo.

Transcatheter Aortic Valve Implantation for the Treatment of Severe Aortic Valve Stenosis in Inoperable Patients under the Perspective of the Brazilian Supplemental Health System Cost-Effectiveness Analysis Background: Transcatheter aortic valve implantation (TAVI) is a new modality of treatment especially dedicated to patients with high surgical risk. In these patients, TAVI increased survival and improved quality of life when compared to standard treatment (drug therapy with or without percutaneous aortic balloon valvuloplasty). Our objective was to perform a cost-efficacy analysis of the implementation of TAVI in the Brazilian Supplemental Health System. Methods: We developed a predictive model to assess the cost-effectiveness of the procedure in the long-term, and a Weibull regression analysis with a time horizon of 5 and 10 years, to estimate survival data for over 24 months. In addition, a deterministic sequential Markov model was developed. Results were expressed as incremental cost-effectiveness ratio (ICER) per years of life saved and progression-free years of life. Results: In a standard scenario

Objective: To estimate the cost-effectiveness of a new strategy that uses an amino acid formula in the elimination diet of infants with suspected cow’s milk allergy (CMA). Methods: This pharmacoeconomic study was developed from the perspective of the Brazilian Public Healthcare System. The new strategy proposes using an amino acid formula in the diagnostic elimination diet of infants (≤ 24 months) with suspected CMA. Our rationale is that infants who do not respond to the amino acid formula do not suffer from CMA. Patients with a positive oral challenge test receive a therapeutic elimination diet based on Brazilian Food Allergy Guidelines. This approach was compared to the current recommendations of the Brazilian Food Allergy Guidelines. A decision model was constructed using TreeAge Pro 2012 software. Model inputs were based on a literature review and the opinions of a panel of experts. A univariate sensitivity analysis of incremental cost-effectiveness ratios was performed. Results: The mean cost per patient of the new amino acid formula strategy was R$3,341.57, while the cost of the current Brazilian guidelines strategy was R$3,641.08. The mean number of symptom-free days per patient, which was used as an indicator of effectiveness, was 900.6 and 875.7 days, respectively. The new strategy is therefore dominant. In the sensitivity analysis, the dominance was maintained with parameter variation. Limitations: This analysis did not evaluate the impact of the new strategy on quality of life or whether it improved the general well-being of infants with CMA or their parents. Conclusions: The new strategy, which uses an amino acid formula in the elimination diagnostic diet followed by an oral food challenge, is a dominant pharmacoeconomic approach that has a lower cost and results in an increased number of symptom-free days.

Objective To evaluate the cost-effectiveness of introducing universal vaccination of adults aged 60 years with the 23-valent pneumococcal polysaccharide vaccine (PPV23) into the National Immunization Program (NIP) in Brazil. Methods Economic evaluation using a Markov model to compare two strategies: (1) universal vaccination of adults aged 60 years with one dose of PPV23 and 2) current practice (vaccination of institutionalized elderly and elderly with underlying diseases). The perspective was from the health system and society. Temporal horizon was 10 years. Discount rate of 5% was applied to costs and benefits. Clinical syndromes of interest were invasive pneumococcal disease (IPD) including meningitis, sepsis and others and pneumonia. Vaccine efficacy against IPD was obtained from a meta-analysis of randomized control trials and randomized studies, whereas vaccine effectiveness against pneumonia was obtained from cohort studies. Resource utilization and costs were obtained from the Brazilian Health Information Systems. The primary outcome was cost per life year saved (LYS). Univariate and multivariate sensitivity analysis were performed. Results The universal vaccination strategy avoided 7,810 hospitalizations and 514 deaths, saving 3,787 years of life and costing a total of USD$31,507,012 and USD$44,548,180, respectively, from the health system and societal perspective. The universal immunization would result in ICERs of USD$1,297 per LYS, from the perspective of the health system, and USD$904 per LYS, from the societal perspective. Conclusion The results suggest that universal vaccination of adults aged 60 years with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is a very cost-effective intervention for preventing hospitalization and deaths for IPD and pneumonia is this age group in Brazil.

Palliative care improves the quality of life of patients and their families facing problems associated with life-threatening illnesses by promoting the prevention and relief of suffering. Palliative care in Japan has been developed mainly for cancer patients. At the National Center for Geriatrics and Gerontology, an end-of-life care team (EOLCT) has been developed to promote palliative care for patients without cancer. In the first 6 months of its operation, 109 requests were received by the team, 40% of which were for patients without cancer or related disease, including dementia, frailty due to advanced age, chronic respiratory failure, chronic heart failure, and intractable neurologic diseases. The main purpose of the EOLCT is to alleviate suffering. The relevant activities of the team include the use of opioids, providing family care, and giving support in decision-making (advance care planning) regarding withholding; enforcement; and withdrawal of mechanical ventilators, gastric feeding tubes, and artificial alimentation. The EOLCT is also involved in ongoing discussions of ethical problems. The team is actively engaged in the activities of the Japanese Geriatric Society and contributes to the development of decision-making guidelines for end-of-life by the Ministry of Health, Labour and Welfare. The EOLCT can be helpful in promoting palliative care for patients with diseases other than cancer. The team offers support during times of difficulty and decision-making.

Using Na+/Ca2+ exchanger (NCX1)-deficient mice, the pathophysiological role of Ca2+ overload via the reverse mode of NCX1 in ischemia/reperfusion-induced renal injury was investigated. Because NCX1(-/-) homozygous mice die of heart failure before birth, we used NCX1(+/-) heterozygous mice. NCX1 protein in the kidney of heterozygous mice decreased to about half of that of wild-type mice. Expression of NCX1 protein in the tubular epithelial cells and Ca2+ influx via NCX1 in renal tubules were markedly attenuated in the heterozygous mice. Ischemia/reperfusion-induced renal dysfunction in heterozygous mice was significantly attenuated compared with cases in wild-type mice. Histological renal damage such as tubular necrosis and proteinaceous casts in tubuli in heterozygous mice were much less than that in wild-type mice. Ca2+ deposition in necrotic tubular epithelium was observed more markedly in wild-type than in heterozygous mice. Increases in renal endothelin-1 content were greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical endothelin-1 localization in necrotic tubular epithelium. When the preischemic treatment with KB-R7943 was performed, the renal functional parameters of both NCX1(+/+) and NCX1(+/-) acute renal failure mice were improved to the same level. These findings strongly support the view that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by renal endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury.

Background: Immunosuppressant such as tacrolimus have narrow therapeutic range and are often associated with increased risk of nefrotoxicity in individuals that receive this drug after renal transplantation. Variants in transporters genes have been associated with variability in plasma concentration of tacrolimus and higher risk of adverse effects. Our aim was to investigate the effect of SLCO1B1 (c.388A>G, c.521T>C) and SLCO2B1 (c.- 71T>C) variants on the efficacy and safety of tacrolimus immunosuppressive therapy in kidney transplant recipients. Methods: SLCO1B1 and SLCO2B1 polymorphisms were detected by TaqMan genotyping and were associated to tacrolimus pharmacokinetics and incidence of acute rejection or diarrhea. Results: Carriers of the allele SLCO1B1 c.388G had lower dose adjusted blood concentration (CO/D) of tacrolimus when compared to 388AA carriers, while SLCO1B1 c.521T>C had no effect. Carriers of CC genotype of SLCO2B1 c.-71T>C SNP had higher CO/D of tacrolimus when compared to TT carriers. When we consider the effect of the haplotype (c.388A>G and c.521T>C) of SLCO1B1 on tacrolimus CO/D and incidence of rejection, carriers of SLCO1B1 *1b haplotype had lower CO/D and lower incidence of rejection when compared to wild type haplotype *1a (p>0.05). Conclusions: SLCO1B1 and SLCO2B1 polymorphisms can contribute for a more safety immunossupressive treatment in kidney recipients.

It is unclear how hospitals should support a patient's decision to return home to die. Thus, we retrospectively examined the usefulness of support from an End-Of-Life Care Team in such difficult decision making. The subjects included non-cancer patients and the elderly. Our results suggest that the burden of making difficult decisions decreases with support from End- Of-Life Care Teams.

Choice of treatment and in-home palliative care are important for the cancer care of the elderly. In recent years, comprehensive geriatric assessment (CGA), which has been developed as a multidimensional evaluation method for the elderly, has been attracting attention for cancer care as well. CGA can be a common language for the choice of treatment and in-home palliative care of elderly cancer patients. Also, advance care planning (ACP), is important as a process that supports decision making. In the future, better choices of treatment will become available, and in-home palliative care will be improved by carrying out cancer care using CGA, while continuously carrying out ACP as an organization, realizing a high quality of life (QOL) of the elderly.

The National Center for Geriatrics and Gerontology in Japan implemented a home medical care support system for aged patients in April 2009. In this study, we report a case of terminal care system where a medical care intervention was carried out by a close coordination of visiting nurses and other staffs with a "at-home terminal care" brochure on hand, and we discussed how this system was brought forward satisfactory and how it affected this culture.

The aim of this study was to evaluate the role of home medical care support system to relieve the symptom and regional alliances for elderly cancer patients. We investigated clinical parameters to study the features of this system. The home medical care support system is designed for patients who are B75-year-old with decrease in activities of daily living and severe dementia. The support system plays a significant role in patients with impaired oral ingestion, dyspnea, delirium, and a poor general status.

Estrogens attenuate renal injury induced by ischemia/reperfusion (I/R), an effect that is related to nitric oxide production in the post-ischemic kidney. The compound 17beta-estradiol (E(2)-beta) acting via estrogen receptors (ERs) is known to activate endothelial nitric oxide synthase (eNOS) through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. We determined if this pathway contributes to the renoprotective effect of E(2)-beta in the uninephrectomized ischemia reperfusion rat model of acute renal injury. Treatment with E(2)-beta suppressed the I/R-induced increases in blood urea nitrogen, plasma creatinine, urine flow, and fractional excretion of sodium while augmenting creatinine clearance, renal blood flow, and urine osmolality, indicating attenuation of renal injury. Phosphorylation of Akt and eNOS protein was significantly increased 30-60 min after reperfusion in estradiol-treated compared to vehicle-treated rats. The protective effects of E(2)-beta and protein phosphorylation were reversed by the PI3K inhibitor wortmannin or the ER antagonist tamoxifen. Furthermore, the E(2)-beta-induced renoprotective effects were not seen in eNOS knockout mice with renal injury. We conclude that the E(2)-beta-induced renoprotective effect is due to activation of the PI3K/Akt pathway followed by increased eNOS phosphorylation in the post-ischemic kidney.

We evaluated the effects of SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline), a novel and selective Na+/Ca2+ exchange inhibitor, on ischemic acute renal failure. Ischemic acute renal failure in rats was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the contralateral nephrectomy. SEA0400 administration (0.3, 1 and 3 mg/kg, i.v.) before ischemia dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction and histological damage such as tubular necrosis. SEA0400 pretreatment at the higher dose suppressed the increment of renal endothelin-1 content after reperfusion. The ischemia/reperfusion-induced renal dysfunction was also overcome by post-ischemia treatment with SEA0400 at 3 mg/kg, i.v. In in vitro study, SEA0400 (0.2 and 1 μM) protected cultured porcine tubular cells (LLC-PK1) from hypoxia/reoxygenation-induced cell injury. These findings support the view that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury. The possibility exists that a selective Na+/Ca2+ exchange inhibitor such as SEA0400 is useful as effective therapeutic agent against ischemic acute renal failure in humans.