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: Introduction: Many HIV‐positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced‐prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 Methods: The REALITY trial enrolled from June 2013 to April 2015. A decision‐analytic model was developed to estimate the cost‐effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard‐prophylaxis, enhanced‐prophylaxis, standard‐prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced‐prophylaxis (CrAg‐positive) or standard‐prophylaxis (CrAg‐negative), the second to enhanced‐prophylaxis (CrAg‐positive) or enhanced‐prophylaxis without fluconazole (CrAg‐negative) and the third to standard‐prophylaxis with fluconazole (CrAg‐positive) or without fluconazole (CrAg‐negative). The model estimated costs, life‐years and quality‐adjusted life‐years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results: Enhanced‐prophylaxis was cost‐effective at cost‐effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost‐effectiveness ratio (ICER) of US$157 per QALY in the CD4 Conclusions: The REALITY enhanced‐prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost‐effective. Efforts should continue to ensure that components are accessed at lowest available prices., Introduction In low‐ and middle‐income settings, more than a third of HIV‐positive individuals starting antiretroviral therapy (ART) present with advanced disease (CD4 ≤ 200 cells/mm[sup.3]); over half of these have [...]

Purpose: To evaluate the association between the HER2 score as provided by the Oncotype DX Recurrence Score (RS) assay, tumor characteristics, and outcomes in early-stage, ER + HER2-negative breast cancer (BC)., Methods: All women insured by the Clalit Health Services, with early-stage, ER + HER2-negative BC who underwent RS testing between 2008 and 2011 were included. Patient/tumor characteristics and Kaplan-Meier estimates for distant recurrence-free survival (DRFS) and overall survival (OS) were compared by HER2 category, based on the HER2 score provided by the RS assay: lower HER2 score group representing the lower third of the HER2 score range (≤ 8.5); higher HER2 score group representing the upper 2 thirds of the HER2 score range (8.6-10.7)., Results: 1535 patients were included (948 node negative, 587 node positive); 330 (21.5%) were categorized as lower HER2 score and 1205 (78.5%) as higher HER2 score. Compared to the higher HER2 score group, the lower score group included a significantly higher proportion of patients with RS ≥ 26 in both node-negative (41% vs. 13.6%, P < .001) and node-positive diseases (36% vs. 19.4%, P < .001). Compared to the higher HER2 score group, the lower score group had significantly lower Oncotype ER and PR scores and lower proportion of lobular disease. Age and tumor size were comparable between the HER2 score groups. Within each RS category, DRFS and OS were not associated with the HER2 score., Conclusion: Lower HER2 score was associated with higher RS results. Further study is desired to elucidate the role and significance of HER2 expression in early-stage, ER + HER2-negative., Competing Interests: Declarations Competing interests Author HG reports personal fee from: AstraZeneca (Honorarium), Gilead (Honorarium and consulting), Eli-Lilly (Honorarium and consulting), MSD (Honorarium and consulting), Novartis (Honorarium and consulting), Pfizer (Honorarium and consulting), Roche (Honorarium), Rhenium Oncotest (Honorarium and consulting), all not related to the submitted manuscript. Author RY reports personal fees from: Roche (consulting, invited speaker, Research grant), Pfizer (consulting), Novartis (consulting, invited speaker), Rhenium (consulting), Medison (invited speaker), MSD (consulting, invited speaker), Astra-Zeneca (consulting, invited speaker), Eli Lilly (consulting, invited speaker), Gilead (consulting), Stemline (invited speaker, consulting) all not related to submitted manuscript. Author SPS reports: Roche (consultancy, advisory board, speaker's bureau, travel grant), Novartis (consultancy, advisory board, speaker's bureau), Pfizer (consultancy, advisory board, speaker's bureau, travel grant, Institutional independent research grant), Astra-Zeneca (consultancy, advisory board, speaker's bureau), Gilead (consultancy, advisory board, speaker's bureau, travel grant), Eli Lily (consultancy, advisory board, speaker's bureau), MSD (consultancy, advisory board, speaker's bureau), Stemline (consultancy), all via institutional fees and not related to the submitted manuscript. Author AS reports: Roche(consultancy, advisory board, speaker's bureau, travel grant), Novartis (consultancy, advisory board, speaker's bureau), Pfizer (consultancy, advisory board, speaker's bureau, travel grant, institutional independent research grant), Astra-Zeneca (consultancy, advisory board, speaker's bureau), Gilead (consultancy, advisory board, speaker's bureau, travel grant), Lily (consultancy, advisory board, speaker's bureau), MSD (consultancy, advisory board, speaker's bureau), Stemline (consultancy), all via institutional fees and not related to the submitted manuscript. Author AS reports: Eli Lilly (consulting, advisory board, speakers bureau), Pfizer (consulting, advisory board, speakers bureau), Roche (consulting, advisory board, speakers bureau, research grant), Novartis (consulting, advisory board, speakers bureau, research grant), Gilead (consulting, advisory board), MSD (consulting, advisory board, speakers bureau, travel grant), Astra-Zenca (consulting, advisory board), Progenetics (consulting, advisory board), Rhenium (consulting, advisory board), Neopharm (travel grant), Celgene (travel grant), Medison (travel grant), all not related to the submitted work. Author ABS reports being a consultant for Oncotest Rhenium, and Exact Sciences, related to the submitted manuscript, and to Pfizer, Can-Fite, and MDI, not related to the submitted manuscript. Author SMS reports: research grant from Can-Fite, AstraZeneca, Bioline RX, BMS, Halozyme, Clovis Oncology, CTG Pharma, Exelexis, Geicam, Halozyme, Incyte, Lilly, Moderna, Teva pharmaceuticals, and Roche, and owning stocks and options in CTG Pharma, DocBoxMD, Tyrnovo, VYPE, Cytora, and CAN-FITE, all not related to the submitted manuscript. All other authors have no conflicts of interest. This study was funded by Oncotest-Rhenium. The funder played no role in the design and conduct of the analysis or its interpretation, and the decision to submit the manuscript for publication., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Home visiting nurses contribute to end-of-life home care in an aging society. However, few previous studies reported patient outcomes based on nursing practices. This study aimed to examine the correlation between the number of them and the change in home death proportion., Methods: We divided the number of home visiting nurses into four categories: absent, shortage, medium, and abundant. This study adopted the interaction term between the nurse categories and year as the major exposure variable, and home death proportion per municipality as the objective variable. We estimated the average marginal effects (AME) as the change in home death proportion from 2015 to 2020., Results: The total number of home visiting nurses was 36,483 in 2015 and 65,868 in 2020. The coefficients of the interaction term were statistically significant in medium and abundant municipalities (Medium: 1.26 (95% CI: 0.49-2.04), Abundant: 2.15 (95% CI: 0.76-3.55)). Increased home death proportion were estimated as AME: 1.56% (95% CI: 0.99-2.13), 1.35% (95% CI: 0.85-1.84), 2.82% (95% CI: 2.30-3.35), and 3.71% (95% CI: 2.44-4.99) in the absent, shortage, medium, and abundant areas, respectively., Conclusions: To increase the proportion of home deaths, municipalities require a certain number of home visiting nurses., (© 2024 The Author(s). Public Health Nursing published by Wiley Periodicals LLC.)

Background: Whether germline BRCA (gBRCA) pathogenic variants (PV) affect prognosis of women with triple negative breast cancer (TNBC) and whether it has implications for treatment decisions in the neoadjuvant setting is unclear., Methods: This is a retrospective two-center cohort study comprising all women with early stage TNBC who have completed genetic testing and were treated with neoadjuvant dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and carboplatin. All eligible patients treated between 10.2014 and 3.2020 were included. Data on clinico-pathological, pathological response, overall survival (OS) and disease-free survival (DFS) were evaluated. Differences in clinico-pathological features and outcomes were analyzed according to gBRCA status., Results: Sixty-four women were included in the final analysis, of which 31 had gBRCA PV (gBRCA carriers) and 33 were gBRCA wild-type. Clinico-pathological characteristics were similar between both groups. The odds for pathological complete response (pCR) were significantly higher in gBRCA carriers (74.2%) compared to BRCA wild-type women (48.5%), p = 0.035. At a median follow-up of 30 months, gBRCA carriers had significantly favorable OS (HR = 8.64, 95% CI 1.08-69.21, p = 0.042). The difference in DFS did not reach statistical significance (HR = 7.4, 95% CI 0.91-60.27, p = 0.062). The favorable OS for gBRCA carriers remained significant in multivariate analysis (p = 0.029) and was noted regardless of pathological response (p = 0.018)., Conclusion: Compared to wild-type, gBRCA carriers with locally advanced TNBC treated with neoadjuvant chemotherapy containing carboplatin had a higher pCR rate and better outcomes. These results strengthen the contention that gBRCA status should be considered when tailoring treatment decisions in women with locally advanced TNBC., (© 2024. The Author(s).)

Introduction: The Lesbian, Gay, Bisexual, and Transgender Development of Clinical Skills Scale (LGBT-DOCSS) is a validated self-assessment tool for health and mental health professionals who provide healthcare for sexual and gender minority patients. This study aimed to develop and validate a Japanese version of LGBT-DOCSS (LGBT-DOCSS-JP) and examine its psychometric properties., Methods: LGBT-DOCSS was translated into Japanese and cross-culturally validated using cognitive debriefing. We then evaluated the structural validity, convergent and discriminant validity, internal consistency, and test-retest reliability of LGBT-DOCSS-JP using an online survey., Results: Data were analyzed for 381 health and mental health professionals aged 20 years or older from three suburban medical institutions. The confirmatory factor analysis indicated that the original three-factor model did not fit well with LGBT-DOCSS-JP. Exploratory factor analysis revealed four new factors: Attitudinal Awareness, Basic Knowledge, Clinical Preparedness, and Clinical Training. Convergent and discriminant validity were supported using four established scales that measured attitudes toward lesbians and gay men, genderism and transphobia, authoritarianism and conventionalism, and social desirability. The internal consistency of LGBT-DOCSS-JP was supported by the Cronbach's alpha values for the overall scale (0.84), and for each of its subscales (Attitudinal Awareness and Basic Knowledge both 0.87, Clinical Preparedness 0.78, and Clinical Training 0.97). The test-retest reliability for the overall LGBT-DOCSS-JP was supported by an intraclass correlation coefficient score of 0.86., Conclusions: LGBT-DOCSS-JP has the potential to serve as a valuable tool in the development and assessment of effective curricula for LGBT healthcare education, as well as a means to promote self-reflection among trainees and professionals., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: YK and EY serve as members of the board of Nijiiro Doctors, an organization dedicated to promoting awareness and education within the medical community regarding LGBTQ issues, while also providing support for the LGBTQ community. EY has received speaker’s honoraria from Stryker Japan K.K. MM’s son-in-law worked at IQVIA Services Japan K.K., which is a contract research organization and a contract sales organization. MM’s son-in-law works at Syneos Health Clinical K.K. which is a contract research organization and a contract sales organization. The other authors declare that no competing interests exist., (Copyright: © 2024 Kanakubo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Mutations in genes involved in DNA damage repair (DDR), a hallmark of cancer, are associated with increased cancer cell sensitivity to certain therapies. This study sought to evaluate the association of DDR pathogenic variants with treatment efficacy in patients with advanced non-small cell lung cancer (NSCLC)., Methods: A retrospective cohort of consecutive patients with advanced NSCLC attending a tertiary medical center who underwent next-generation sequencing in 01/2015-8/2020 were clustered according to DDR gene status and compared for overall response rate (ORR), progression-free survival (PFS) (patients receiving systemic therapy), local PFS (patients receiving definitive radiotherapy), and overall survival (OS) using log-rank and Cox regression analyses., Results: Of 225 patients with a clear tumor status, 42 had a pathogenic/likely pathogenic DDR variant (pDDR), and 183 had no DDR variant (wtDDR). Overall survival was similar in the two groups (24.2 vs. 23.1 months, p = 0.63). The pDDR group had a higher median local PFS after radiotherapy (median 45 months vs. 9.9 months, respectively; p = 0.044), a higher ORR (88.9% vs. 36.2%, p = 0.04), and a longer median PFS (not reached vs. 6.0 months, p = 0.01) in patients treated with immune checkpoint blockade. There was no difference in ORR, median PFS, and median OS in patients treated with platinum-based chemotherapy., Conclusion: Our retrospective data suggest that in patients with stage 4 NSCLC, pathogenic variants in DDR pathway genes may be associated with higher efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). This should be further explored prospectively., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Data regarding the prevalence and clinical relevance of BRCA mutations in non-small cell lung cancer (NSCLC) is limited. Our objective was to evaluate the impact of pathogenic BRCA variants detected by tumour next-generation sequencing (NGS) on disease course and response to therapy., Methods: We performed a retrospective analysis of all consecutive NSCLC patients with available NGS reports in a single institution between 01/2015 and 08/2020. Pathogenicity of identified mutations was determined according to American College of Medical Genetics (ACMG) guidelines. Log rank and cox regression analyses were used to determine the association between BRCA mutation status, overall survival (OS) and progression-free survival (PFS) under various front-line treatment modalities for advanced disease., Results: Out of 445 patients with NGS data (54% tissue, 46% liquid), 109 (24.5%) patients had a documented BRCA variant; 5.6% (25/445) had a pathogenic/likely pathogenic variant ( pBRCA ). Forty percent (10/25) of pBRCA patients had no co-occurring NSCLC driver mutations. Patients with pBRCA NSCLC had a less prominent smoking history [mean 42.6 (29.2) vs. 25.7 (24.0) pack years; P=0.024]. Median PFS with first-line chemo-immunotherapy was significantly prolonged for pBRCA patients (n=7) compared with wild-type BRCA ( wtBRCA ) patients (n=30) (HR =0.279; P=0.021, 95% CI: 0.094-0.825)., Conclusions: pBRCA -mutated NSCLC can represent a specific subtype of pulmonary carcinoma. Patients whose tumours harbor pBRCA mutations present with a less prominent smoking history and exhibit prolonged PFS with chemo-immunotherapy combinations compared with wtBRCA controls. In a subset of these patients, pBRCA is the sole identifiable putative driver mutation, hinting at a significant role for BRCA loss in oncogenesis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-594/coif). DAG has received institutional research funding from BMS, Merck and Janssen, and consulting fees from Vivio Health. He has also held an unpaid advisory and leadership role at Optimal Cancer Care Alliance. He holds personal stock at Viviohealth and TailorMed. ED has received institutional research funding from Astra Zeneca, and consulting/speaking fees from Roche, Astra Zeneca, Pfizer, Merck Sharpe & Dohme, Bristol Myers Squibb, Novartis, Takeda, Sanofi, Merck Serono, Medison Pharma, and Janssen Israel. She has also received support for attending meetings and/or travel from Merck Serono and Medison Pharma. In addition, ED participated in data safety monitoring boards at Roche, Astra Zeneca, Pfizer, Merck Sharpe & Dohme, Bristol Myers Squibb, Novartis, Takeda, Sanofi, Merck Serono, Medison Pharma, and Janssen Israel. ED also has occupied a chair position at the Israeli Society for Clinical Oncology and Radiotherapy (ISCORT), is an ESMO faculty member, and an IASLC mesothelioma committee member. NP has received advisory fees & honorarium from, and has performed research with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, FoundationMedicine, Gaurdant360, Merk, MSD Novartis, NovellusDx, Pfizer, Roche, and Takeda. He has also received support for attending meetings and/travel from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, FoundationMedicine, Gaurdant360, Merk, MSD, Novartis, NovellusDx, Pfizer, Roche, Takeda. AZ has received consulting fees from AstraZeneca, Oncohost, Steba MSD, Takeda Nixio and Medison. She has also received payments for lectures from BMS, Novartis, Takeda, MSD, Pfizer and Roche. In addition, AZ received support for attending meetings and/or statements from Janssen, has participated on a data safety monitoring board at Beyond Cancer, and holds stock/stock options at Nixio. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Introduction: The social determinants of health have been gaining recognition, confirming that multidimensional biopsychosocial assessment is essential to improving the health of individuals. This trend has led to the development of conceptual models and measurement tools assessing 'patient complexity', understood as a complex interplay of biopsychosocial factors, to improve the efficiency and effectiveness of care; however, the variety of meanings encompassed by the term has led to confusion in the interpretation of patient complexity such that there is no consensus regarding the definition or conceptualisation of patient complexity. The primary objective of this scoping review is to identify and map what is known about the key characteristics of patient complexity through multiple database searches., Methods and Analysis: This study will follow an established framework for conducting scoping reviews. The data will be extracted through searches of MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, PsycINFO, The Cochrane Library and Google Scholar. Included articles will have: investigated participants aged 19 years or older, with any health condition; described patient complexity, a model for patient complexity, or a measurement tool for patient complexity; and been published in English from 1 January 1970 to April 2022. Article selection and data extraction will be conducted independently by two reviewers and if necessary for consensus, a third reviewer. A descriptive summary will be prepared to explain how the results apply to the scoping review questions. The findings will be a detailed mapping of the health dimensions that emerge from the classification of the extracted data. Subsequently, a definition of patient complexity will be developed., Ethics and Dissemination: This review does not require ethical approval, as we will use publicly available data. The study findings will be disseminated through a relevant conference presentation and a peer-reviewed journal. This protocol is registered on the Open Science Framework (www.osf.io/hpa3c)., Competing Interests: Competing interests: MM’s son-in-law is a past employee of IQVIA Services Japan K.K., a contract research organisation and a contract sales organisation, and a current employee of Syneos Health Clinical K.K., a contract research organisation and a contract sales organisation. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aimed to elucidate the relationship between patient complexity and healthcare costs in a primary care setting on a Japanese island., Design: Cross-sectional study., Setting: Tarama Clinic, Okinawa Miyako Hospital, on Tarama Island, Okinawa Prefecture, Japan., Participants: Patients who visited Tarama Clinic from 1 April 2018 to 30 June 2018, were aged 20 years or above, were resident in Tarama Village and had decision-making capacity., Outcome Measures: Patient complexity scored using Patient Centred Assessment Method (PCAM), healthcare costs per person per year/visit and participant characteristics., Results: We included 355 study participants. The means (SD) of the total PCAM scores and healthcare costs per person per year/visit were 21.4 (5.7) and 1056.4 (952.7)/125.7 (86.7) in US dollars, respectively. Spearman's rank correlation coefficients between the total PCAM scores and healthcare costs per person per year/visit were 0.33 and 0.28 (p values <0.0001 and <0.0001), respectively. The healthcare costs per person tended to be relatively low in the patient groups with the highest complexity. In the groups, the proportion of those with psychological conditions tended to be higher and those with cardiovascular diseases tended to be lower than in the other groups. Multiple regression analysis showed that total PCAM scores were associated with healthcare costs per person per year/visit, which were log-transformed: the regression coefficients were 3.87×10 -2  and 2.34×10 -2 , respectively; the p values were <0.001 and <0.001, respectively., Conclusions: This study clarified the association between patient complexity and healthcare costs in a primary care setting on a Japanese island. We found that such costs tended to be relatively low in patient groups with the highest complexity. In primary care, healthcare costs probably do not accurately reflect the value of services provided by medical institutions; it may be essential to introduce a system that provides incentives for problem-solving approaches to social issues., Competing Interests: Competing interests: MM’s son-in-law worked at IQVIA Services Japan K.K., which is a contract research organisation and contract sales organisation. MM’s son-in-law works at Syneos Health Clinical K.K., which is a contract research organisation and contract sales organisation. The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: During a pandemic, when there are many barriers to providing preventive care, chronic disease management, and early response to acute common diseases for primary care providers, it is unclear whether primary care attributes contribute to reducing hospitalization. We aimed to examine the association between core primary care attributes and total hospitalizations during the COVID-19 pandemic., Methods: We conducted a nationwide prospective cohort study during the pandemic using a representative sample of the Japanese adult population aged 40 to 75 years. Primary care attributes (first contact, longitudinality, coordination, comprehensiveness, and community orientation) were assessed using the Japanese version of Primary Care Assessment Tool (JPCAT). The primary outcome measure was any incidence of hospitalization during a 12-month period from May 2021 through April 2022., Results: Data from 1,161 participants were analyzed (92% follow-up rate). After adjustment for possible confounders, overall primary care attributes (assessed by the JPCAT total score) were associated in a dose-dependent manner with a decrease in hospitalizations (odds ratio [OR] = 0.37, 95% CI, 0.16-0.83 for the highest score quartile, compared with no usual source of care). All associations between each domain score of the JPCAT and hospitalization were statistically significant when comparing the highest quartile with no usual source of care., Conclusions: Our study revealed that the provision of primary care, particularly high-quality primary care, was associated with decreased total hospitalization, even during a pandemic when there are many barriers to providing usual medical care. These findings support policies that seek to strengthen primary care systems during and after the COVID-19 pandemic., (© 2023 Annals of Family Medicine, Inc.)

Background: Evidence is still limited on the prevalence of multimorbidity and complex multimorbidity in Japan, as well as their associated factors. Additionally, no studies regarding multimorbidity and complex multimorbidity in Japan have used patient data obtained directly from medical records. The primary objective was to clarify the prevalence of multimorbidity and complex multimorbidity using patient data obtained directly from medical records. The secondary objective was to elucidate factors associated with multimorbidity and complex multimorbidity., Methods: We conducted a cross-sectional study at Tarama Clinic on Tarama Island, a remote island in Okinawa, Japan. Among patients who visited Tarama Clinic from April 1 to June 30, 2018, those who were ≥ 20 years of age, lived on Tarama Island, and had capacity to give consent were eligible for study inclusion. We collected the following data using medical records, medical expense receipts, and self-administered questionnaires: multimorbidity and complex multimorbidity, participants' characteristics, and potentially associated factors. Multimorbidity was defined as having ≥ 2 among 17 chronic health conditions, in accordance with previous studies conducted in Japan, and having ≥ 2 among 16 chapters of the International Classification of Primary Care, 2nd edition (ICPC-2). Complex multimorbidity was defined as having ≥ 3 among 16 chapters of the ICPC-2., Results: We included 355 study participants. Descriptive analysis showed multimorbidity prevalence measured using the 17 chronic health conditions in this area was 30.0% (age ≥ 20 years) and 57.5% (age ≥ 65 years). Multimorbidity prevalence measured using the ICPC-2 was 32.9% (age ≥ 20 years) and 60.3% (age ≥ 65 years). We also found a 20.9% (age ≥ 20 years) and 45.1% (age ≥ 65 years) prevalence of complex multimorbidity, respectively. Poisson regression with robust error variance showed that age ≥ 60 years was associated with multimorbidity. Age ≥ 60 years (adjusted prevalence ratio [aPR] 1.887 and 1.831 for ages 60-79 and ≥ 80 years, respectively) and being unemployed (aPR 1.251) were associated with complex multimorbidity. However, having hazardous drinking or more was inversely associated with complex multimorbidity (aPR 0.745)., Conclusions: The population-based prevalence of multimorbidity and its upward trend with increasing age on a remote island in Japan was consistent with previous reports in the country. Multimorbidity was associated with age 60 years or older, and complex multimorbidity was associated with age 60 years or older, being unemployed, and not having hazardous drinking or more. Our study findings indicated a possible association between the coexistence of diseases and social determinants of health (SDH) in Japan. To improve care for patients with multimorbidity and complex multimorbidity, more research that takes SDH into account is warranted, and evidence-based policymaking is essential for Japan. The present study can provide a foundation for accumulating such evidence., (© 2022. The Author(s).)

Objectives: The objective of this study was to examine the structural validity and internal consistency of the original English version of the Patient Centred Assessment Method (PCAM) in a primary care setting in a Japanese island area., Design: Cross-sectional study., Setting: A clinic on a remote island in Okinawa, Japan, that provides general outpatient and 24-hour emergency services., Participants: This study included 355 patients who visited Tarama Clinic from 1 April 2018 to 30 June 2018, were aged ≥20 years, lived in Tarama Village and had decision-making capacity., Main Outcome Measures: Patient complexity scored by the PCAM., Results: The mean (SD) PCAM score was 21.4 (5.7). The distribution was skewed to the right and there were no ceiling and floor effects. Confirmatory factor analysis found that the previously reported two-factor and three-factor structures did not show a good fit (root mean square error of approximation 0.18 and 0.16, comparative fit index 0.83 and 0.89 and standardised root mean square residual 0.14 and 0.11, respectively). Exploratory factor analysis revealed a new two-factor structure: 'Biomedical complexity' and 'Psychosocial complexity'. The Cronbach's alpha values for the total PCAM score, the 'Biomedical complexity' factor, and the 'Psychosocial complexity' factor were 0.81, 0.82 and 0.74, respectively., Conclusions: In this study, confirmatory factor analysis found that the data did not fit sufficiently using the previously reported two-factor and three-factor structures. Instead, exploratory factor analysis revealed a new two-factor structure, for which the Cronbach's alpha values exceeded the threshold level. Therefore, the structural validity and internal consistency of the English version of the PCAM were verified in a primary care setting in a Japanese island area., Competing Interests: Competing interests: YS, HY and SY are former trainees of the Jikei Clinical Research Programme for Primary-care. MM received lecture fees and lecture travel fees from the Centre for Family Medicine Development of the Japanese Health and Welfare Co-operative Federation. MM is an adviser for the Centre for Family Medicine Development Practice-Based Research Network and a programme director of the Jikei Clinical Research Programme for Primary-care. MM’s son-in-law worked at IQVIA Services Japan K.K., which is a contract research organisation and a contract sales organisation. MM’s son-in-law works at Syneos Health Clinical K.K., which is a contract research organisation and a contract sales organisation., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recent data suggest that human epidermal growth factor receptor 2 (HER2)-low breast cancer may represent a distinct entity. We aimed to compare disease characteristics and outcomes between HER2-low and HER2-0 in estrogen receptor (ER) positive, early-stage breast cancer., Methods: A single center retrospective study comprising all women with ER positive, HER2 negative early breast cancer, for whom an Oncotype DX test was performed between 2005 and 2012. Women were grouped to HER2-low (immunohistochemistry +1 or +2 and in situ hybridization not amplified) or HER2-0. Clinico-pathological features and Oncotype recurrence score (RS) were collected. Data on overall-survival (OS), disease-free survival (DFS) and distant disease-free survival (DDFS) were evaluated according to HER2 expression status., Results: 608 women were included, of which 304 women had HER2-0 and 304 had HER2-low disease. Lobular subtype was significantly more common in HER-0 compared to HER2-low disease (17% vs. 8%, p = 0.005). The prevalence of other clinic-pathological characteristics and long-term prognosis were comparable between both groups. For women with high genomic risk (RS > 25), HER2-low expression was associated with significantly favorable OS (HR = 0.31, 95% CI 0.11-0.78, p = 0.01), DFS (HR = 0.40, 95% CI 0.20-0.82, p = 0.01) and DDFS (HR = 0.26, 95% CI 0.11-0.63, P = 0.002) compared to women with HER2-0. For women with low genomic risk (RS ≤ 25), long-term prognosis was unrelated to HER2 expression., Conclusion: The prognostic impact of HER2-low expression in early-stage luminal disease varies across the genomic risk, with significant favorable outcomes of HER2-low expression compared to HER2-0 in women with high genomic risk., Competing Interests: Declaration of competing interest All other authors have no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Menstrual and parity history might impact the risk for breast cancer. Data on the impact of these factors on other tumor characteristics are limited., Methods: A single center retrospective cohort study comprising all women with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative, early breast cancer whose tumors were sent to OncotypeDX analysis. The prespecified subgroups were investigated: age of menarche (< 12 vs. ≥ 12 years), number of deliveries (0 vs. ≥ 1 childbirth and ≥ 5 childbirth vs. other), age of first delivery (≥ 30 years vs. younger age) and postmenopausal compared to premenopausal. The impact of age of menopause was also assessed categorically, using early (< 45 years) and late age of menopause (> 55 years). Differences in tumor characteristics were evaluated using T-test or Mann Whitney for continuous variables or Fisher's exact test for categorical variables. Outcomes were assessed by Kaplan-Meier survival analysis, with the log-rank test., Results: A total of 620 women were included. After median follow-up of 10.4 years, early menopause was associated with significantly worse disease-free survival (HR = 2.26, p = 0.004) and overall-survival (HR = 2.60, p = 0.004), and multiparity was associated with significant worse disease-free survival (HR = 2.16, p = 0.026). These differences remain significant in multivariate analyses. Post-menopausal women were more likely to have stronger ER intensity (p = 0.002) but progesterone receptor (PR) positivity was less frequent (p = 0.009(. Early age of menarche was associated with PR positivity (p = 0.039). No other associations were found between the evaluated subgroups and tumor characteristics., Conclusions: The impact of endogenous estrogen exposure had little effect on breast cancer characteristics of early stage, luminal disease. Early menopause and multiparity were associated with worse outcome., (© 2021. The Author(s).)

Background: Locoregional therapy (LRT) in de novo metastatic disease is controversial with inconsistent results from randomized control trials (RCTs)., Methods: RCTs comparing LRT and systemic therapy to standard therapy alone in de novo metastatic breast cancer were identified. Hazard ratios (HRs) and their associated 95% confidence intervals (CIs) were computed and pooled in a meta-analysis using generic inverse variance. Overall survival (OS) and time to locoregional progression data were extracted for the intention to treat (ITT) population. Data on OS for pre-specified subgroups defined by tumor subtype and by site of metastases were also extracted., Results: Analyses included 4 trials comprising 970 patients. LRT included standard surgery to the primary breast tumor in all studies, and adjuvant radiation per standard of care was required in 3 studies. Compared to standard treatment, LRT was not associated with improved OS in the ITT population (HR 0.97, 95% CI 0.72-1.29, p = 0.81). However, LRT was associated with improved time to locoregional progression (HR 0.36, 95% CI 0.14-0.95, p = 0.04). LRT was not associated with improved OS in any tumor subtypes, including hormone receptor positive (HR 0.96, 95% CI 0.65-1.43), triple negative (HR 1.4, 95% CI 0.50-3.91) and human epidermal growth factor receptor 2 positive disease (HR 0.93, 95% CI 0.68-1.28). Additionally, LRT did not improve OS in bone only disease (HR 0.97, 95% CI 0.58-1.62) and in visceral disease (HR = 1.02, 95% CI 0.77-1.35). Our critical appraisal has identified some methodological problems in the design and conduct of the studies included that could affect the meta-analysis result., Conclusions: LRT in de novo metastatic breast cancer is not associated with improved OS. Results are consistent among different breast cancer subgroups. However, this conclusion should be interpreted with caution in view of the limitations identified in meta-analysis., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients receiving chemotherapy are at high risk for severe infections and complications such as acute respiratory syndrome. The most commonly used adjuvant chemotherapy protocols (docetaxel-cyclophosphamide every 3 weeks or the dose-dense regimen, doxorubicin-cyclophosphamide every 2 weeks followed by paclitaxel) incorporate granulocyte-colony stimulating factor (G-CSF). G-CSF is routinely administered to prevent chemotherapy-associated neutropenia but often results in significant neutrophilia. The present case describes a patient with breast cancer who was successfully treated for severe COVID-19 respiratory syndrome while under adjuvant chemotherapy (docetaxel-cyclophosphamide) treatment and long-term G-CSF support. In addition, the potential effect of G-CSF on the respiratory deterioration of the patient given its cardinal role in innate inflammation and, accordingly, the cytokine storm associated with COVID-19 was described. The case described in the present study indicated how solutions to the immunity challenges faced when treating a patient with chemotherapy may be the source of a larger problem within the coronavirus COVID-19 pandemic., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Yerushalmi et al.)

Background: There are scarce data on venous thromboembolism (VTE) rates among non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICI). The Khorana Score (KS), used to guide thromboprophylaxis in cancer patients, was validated in patients receiving chemotherapy., Objective: To assess VTE rates and KS performance among NSCLC patients treated with ICI or chemotherapy., Methods: We performed a retrospective cohort study of NSCLC patients starting either ICI or platinum-based chemotherapy. The 6-month cumulative incidence of VTE in the ICI and chemotherapy cohorts and hazard ratios (HR) with 95% confidence intervals (CI) were calculated, using death as a competing risk. Subgroup analysis of low (0-1) and high (≥2) KS risk groups was performed., Results: The study included 345 NSCLC patients receiving single agent ICI (n = 176) or chemotherapy (n = 169). The 6-month cumulative incidence of VTE was 7.1% in the chemotherapy cohort and 4.5% in the ICI cohort (HR for chemotherapy = 1.6, 95% CI 0.66-3.9). Among chemotherapy treated patients, the high-risk KS group had a trend toward a higher VTE incidence, compared with patients with a low-risk KS (HR 3.04, 95% CI 0.82-11.22). Among ICI-treated patients, the high-risk KS group had a trend toward a lower VTE incidence compared with the low-risk group (HR 0.17, 95% CI 0.02-1.36)., Conclusions: VTE rates were higher among NSCLC patients treated with platinum-based chemotherapy than those treated with ICI alone, though the precision of the relative estimate is low. The KS did not identify high-risk ICI-treated patients, suggesting that an ICI-specific risk model is warranted., (© 2021 International Society on Thrombosis and Haemostasis.)

Introduction: The impact of exogenous estrogen exposure on breast cancer characteristics and outcomes is not well described. We aimed to investigate the effect of prior treatment with oral contraceptives (OCT), hormone replacement therapy (HRT), and fertility treatments on early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer., Methods: This is a single-center retrospective cohort study comprising all women with ER-positive, HER2-negative, early breast cancer whose tumors were sent to Oncotype DX analysis between 2005 and 2012. Data on prior exposures to OCT, HRT, and fertility treatments were collected. The impact of these exposures on prespecified histopathological features was assessed including tumor size, nodal status, intensity of the hormonal receptors, grade, Oncotype recurrence score, Ki67, and lymphovascular and perineural invasion. The impact of these exposures on disease-free survival (DFS) and overall survival (OS) was also evaluated., Results: A total of 620 women were included, of which 19% had prior exposure to OCT, 30% to HRT, and 11% to fertility treatments. OCT use was associated with smaller (≤1 cm) tumors (p = 0.023) and were less likely to have grade 3 disease (p = 0.049). No other associations were found between exogenous estrogen exposure and tumor characteristics. Median follow-up was 10.4 years. Ten-year DFS was 85.7%, and it was not influenced by exogenous exposure. Ten-year OS was 90.2%, and OCT was associated with improved OS in univariate analysis (HR = 0.31, 95% CI: 0.11-0.85), but this difference did not remain significant in multivariate analysis (p = 0.275)., Conclusion: The impact of exogenous estrogen exposure on ER-positive, HER2-negative early breast cancer characteristics is limited. In the long term, none of the evaluated exposures had negative effect on DFS and OS., (© 2021 S. Karger AG, Basel.)

Objectives: The primary objective of this study was to develop the Japanese version of the Patient Centred Assessment Method (PCAM) and its user guide. The secondary objective was to examine the validity and reliability in the primary care setting., Design: Cross-sectional study., Setting: Three family physician teaching clinics located in urban residential areas in Tokyo, Japan., Participants: Patients who were aged 20 years or older, and who had an appointment with physicians at the three participating clinics., Main Outcome Measures: Patient complexity measured by PCAM and complexity/burden level measured by a Visual Analogue Scale (VAS)., Results: Although confirmatory factor analysis using a model described in a previous study revealed that the indices did not meet the criteria for good fit, exploratory factor analysis revealed a new three-factor structure of 'Personal well-being,' 'Social interaction' and 'Needs for care/service.' Cronbach's alpha of PCAM was 0.86. Spearman's rank correlation coefficients between PCAM scores and VAS scores were 0.51 for complexity (p<0.001) and 0.41 for burden (p<0.001). There were 42 patients (14.3% of total patients) with PCAM scores greater than its mean of 16.5 but with complexity VAS scores less than its mean of 20.8., Conclusions: The Japanese version of PCAM and its user guide were developed through Japanese translation and cultural adaptation by cognitive debriefing. PCAM is a valid and reliable tool to assess patient complexity in the primary care settings in Japan. Additionally, although the correlation between total PCAM scores and complexity/burden as assessed by VAS was moderate, PCAM can more precisely identify patient complexity than skilled physician's intuition., Competing Interests: Competing interests: MM received lecture fees and lecture travel fees from the Centre for Family Medicine Development of Japanese Health and Welfare Co-operative Federation. MM is an adviser of the Centre for Family Medicine Development practice-based research network. MM is a program director of The Jikei Clinical Research Program for Primary-care. YS, SY, MK, TW and TT are former trainees of The Jikei Clinical Research Program for Primary-care. TW currently is and SY, MK and TT used to be family physicians at the Centre for Family Medicine Development of Japanese Health and Welfare Co-operative Federation. RM, RH and DH have nothing to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: An ageing society includes high patient complexity. Various biopsychosocial problems result in a high burden for health-related professionals. The direct relationship between the burden and patient complexity, however, has not been reported. We aimed to examine correlations between the burden for the attending physicians and nurses, and Patient Centred Assessment Method (PCAM) scores of patient complexity., Design: Prospective cohort study., Setting: A regional secondary care hospital in Japan., Participants: We included all inpatients admitted to our acute care unit between 1 July 2014 and 30 September 2014. Exclusion criteria were age <20 years, refusal to participate in the study and length of stay fixed at the time of admission., Main Predictor: PCAM total score in the initial phase of hospital admission., Main Outcome: The burden for each profession (measured on a Visual Analogue Scale)., Results: In total, 201 inpatients participated [female/male=98/103, mean (SD) age of 77.4±11.9 years]. Spearman's rank correlation coefficients between the burden and the PCAM score ranged from 0.23 to 0.32. All p values were <0.05. Multivariate analysis was conducted using multilevel mixed-effects linear regression to determine the association between the burden and the PCAM score in two models. Model 1 used the total PCAM score as the predictive variable. Model 2 used the PCAM factors, patient-oriented complexity and medicine-oriented complexity, as predictive variables. In Model 2, with the burden of physicians, medicine-oriented complexity was statistically significant, whereas with the burden of nurses, both age and patient-oriented complexity were statistically significant., Conclusions: PCAM scores correlated with the burden for physicians and nurses. Individual PCAM factors affected the burden for each profession differently., Competing Interests: Competing interests: SY worked at Ouji Coop Hospital. YF and TW work as part-time physicians at Ouji Coop Hospital. MM is an adviser of Centre for Family Medicine Development practice-based research network. MM received lecture fee and travel fee for lecture from Centre for Family Medicine Development. MM received the grant from Japan Society for the Promotion of Science. SY and TW were former residents in family medicine at the Centre for Family Medicine Development. MM is a Program Director for Jikei Clinical Research Program of Primary-care. YF is a lecturer of Jikei Clinical Research Program for Primary-care. YS is a trainee of Jikei Clinical Research Program for Primary-care. SY, HW, TY and TW were former trainees of Jikei Clinical Research Program for Primary-care. This work was supported by a research grant of fiscal year 2015 from The Jikei University School of Medicine and Postgraduate Medical School. There is no potential competing interest to be declared relevant to this work other than the above description., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the presence and predictors of depression and anxiety in pet owners after a diagnosis of cancer in their pets., Design: Cross-sectional study., Setting: A veterinary medical centre specialised in oncology for dogs and cats and two primary veterinary clinics in Japan., Participants: The participants for analysis were 99 owners of a pet with cancer diagnosis received in the past 1-3 weeks and 94 owners of a healthy pet., Main Outcome Measures: Self-reported questionnaires were used to assess depression and anxiety. Depression was assessed using the Center of Epidemiologic Studies Depression Scale, and anxiety was measured by using the State-Trait Anxiety Inventory-Form JYZ., Results: Depression scores were significantly higher in owners of a pet with cancer than owners of a healthy pet, even after adjustment for potential confounders (p<0.001). Within the owners of a pet with cancer, depression was significantly more common in those who were employed than those who were unemployed (p=0.048). State anxiety scores were significantly higher in owners of a pet with cancer than owners of a healthy pet, even after adjustment for potential confounders, including trait-anxiety scores (p<0.001). Furthermore, in owners of a pet with cancer, state anxiety was higher in owners with high trait anxiety (p<0.001) and in owners whose pets had a poor prognosis (p=0.027)., Conclusion: The results indicate that some owners tended to become depressed and anxious after their pets had received a diagnosis of cancer. Employment may be a predictor of depression. High trait anxiety and a pet with a poor prognosis may increase owners' state anxiety. Including the pet in a family genogram and attention to the pet's health condition may be important considerations for family practice., Competing Interests: Competing interests: MM received a lecture fee from the Japan Small Animal Medical Center, MM is an adviser of the Centre for Family Medicine Development practice-based research network, MM received a lecture fee and lecture travel fee from the Centre for Family Medicine Development, MM received a grant from the Japan Society for the Promotion of Science and MM is a Program Director of the Jikei Clinical Research Program for Primary-care., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lymphovascular invasion (LVI) is considered a negative prognostic factor in early breast cancer, but its role in decision-making regarding adjuvant chemotherapy is unclear in the current era of molecular profiling. This study sought to evaluate the association of LVI status with the recurrence score (RS) on the multigene Oncotype DX (ODX) assay and its impact on outcome., Methods: Patients with early estrogen receptor-positive breast cancer who underwent ODX analysis in 2005-2012 were retrospectively identified. Clinical data were collected from the medical records. The Cox proportional-hazards ratio was used to determine recurrence rates. The prognostic significance of LVI was evaluated by competing risks analysis., Results: LVI was detected in 38 of 657 patients (6%). LVI was not associated with ODX RS (p = 0.225). However, it was significantly associated with other known prognostic factors and with worse 5-year disease-free survival (HR 2.93; 95% CI 1.02-8.39; p = 0.04). Overall survival (OS) analysis according to the ODX subgroups showed that the presence of LVI was associated with worse 5-year OS (p = 0.04) only in the intermediate-risk group, while LVI had no effect on the low- or high-risk groups., Conclusions: Although LVI was not significantly associated with a higher ODX RS, it may infer a worse outcome, especially in ODX intermediate-risk patients., (© 2018 S. Karger AG, Basel.)

Objective: This study examined the effects of resistance training of swallowing muscles in community-dwelling older individuals with dysphagia., Methods: A cluster randomized controlled trial was performed in day-service and day-care facilities. The participants were older (≥65 y) community-dwelling individuals with dysphagia. The intervention group performed a tongue resistance exercise and a head flexion exercise against manual resistance. Both groups received a brochure on dysphagia rehabilitation. The primary endpoint was an improvement in dysphagia assessed by the Eating Assessment Tool (EAT-10) score. Tongue pressure was the secondary endpoint., Results: Participants included 47 men and 57 women, with a mean age ± standard deviation of 80 ± 7 y. At baseline, the median EAT-10 score was 7 (interquartile range, 5-12). A total of 91 patients, 43 in the intervention group (8 clusters) versus 48 in the control group (11 clusters), were assessed postintervention. The percentage of participants with EAT-10 scores <3 was not statistically significantly different between the two groups (intervention group, 23% versus control group, 19%, P = 0.598). Postintervention median EAT-10 scores were 6 (interquartile range, 3-10) in each group (P = 0.665) and mean tongue pressure was 23.9 ± 10.0 versus 25.9 ± 10.9 kPa (P = 0.376). The intervention did not significantly affect the EAT-10 score or tongue pressure in a mixed effects random intercept model. The Mini Nutritional Assessment Short Form score correlated significantly with the postintervention EAT-10 score., Conclusions: Resistance training of swallowing muscles did not improve dysphagia in this study. Better nutritional status correlated independently with improved swallowing function., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Several instruments for evaluating patient complexity have been developed from a biopsychosocial perspective. Although relationships between the results obtained by these instruments and the length of stay in hospital have been examined, many instruments are complicated and not easy to use. The Patient Centred Assessment Method (PCAM) is a candidate for practical use. This study aimed to test the validity and reliability of the PCAM and examine the correlations between length of hospital stay and PCAM scores in a regional secondary care hospital in Japan., Design: Prospective cohort study., Participants and Setting: Two hundred and one patients admitted to Ouji Coop Hospital between July 2014 and September 2014., Main Predictor: PCAM total score in initial phase of hospital admission., Main Outcome: Length of stay in hospital., Results: Among 201 patients (Female/Male=98/103) with mean (SD) age of 77.4±11.9 years, the mean PCAM score was 25±7.3 and mean (SD) length of stay in hospital (LOS) 34.1±40.9 days. Using exploratory factor analysis to examine construct validity, PCAM evidently has a two-factor structure, comprising medicine-oriented and patient-oriented complexity. The Spearman rank correlation coefficient for evaluating criterion-based validity between PCAM and INTERMED was 0.90. For reliability, Cronbach's alpha was 0.85. According to negative binomial regression analyses, PCAM scores are a statistically significant predictor (p<0.001) of LOS after adjusting for age, gender, Mini Nutritional Assessment Short-Form, Charlson Comorbidity Index, serum sodium concentration, total number of medications and whether public assistance was required. In another model, each factor in PCAM was independently correlated with length of stay in hospital after adjustment (medicine-oriented complexity: p=0.001, patient-oriented complexity: p=0.014)., Conclusion: PCAM is a reliable and valid measurement of patient complexity and PCAM scores have a significant correlation with hospital length of stay., Competing Interests: Competing interests: SY worked at Ouji Coop Hospital. YF, SM and TW work as part-time physicians at Ouji Coop Hospital. MM is an adviser of Centre for Family Medicine Development practice-based research network. MM received lecture fee and travel fee for lecture from Centre for Family Medicine Development. MM received the grant from Japan Society for the Promotion of Science. YN received the grant from Japan Society for the Promotion of Science. SY is a resident in family medicine of Centre for Family Medicine Development. TW was a former resident in family medicine of Centre for Family Medicine Development. MM is a Program Director of Jikei Clinical Research Program for Primary-care. YF is a lecturer of Jikei Clinical Research Program for Primary-care. SY, HW, SM, TH, HI and TW were former trainees of Jikei Clinical Research Program for Primary-care. This work was supported by a research grant of fiscal year 2015 from The Jikei University School of Medicine and Postgraduate Medical School. There is no potential competing interest to be declared relevant to this work other than the above description., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)