Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals.

BACKGROUND AND AIMS: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.

Defining the observable processes of patient care related to social determinants of health.

INTRODUCTION: An understanding of social determinants of health (SDH) and patients' social circumstances is recommended to deliver contextualised care. However, the processes of patient care related to SDH in clinical settings have not been described in detail. Observable practice activities (OPAs) are a collection of learning objectives and activities that must be observed in daily practice and can be used to describe the precise processes for professionals to follow in specific situations (process OPA.) METHODS: We used a modified Delphi technique to generate expert consensus about the process OPA for patient care related to SDH in primary care settings. To reflect the opinions of various stakeholders, the expert panel comprised clinical professionals (physicians, nurses, public health nurses, social workers, pharmacists and medical clerks), residents, medical students, researchers (medical education, health care, sociology of marginalised people), support members for marginalised people and patients. The Delphi rounds were conducted online. In Round 1, a list of potentially important steps in the processes of care was distributed to panellists. The list was modified, and one new step was added. In Round 2, all steps were acknowledged with few modifications. RESULTS: Of 63 experts recruited, 61 participated, and all participants completed the Delphi rounds. A total of 14 observable steps were identified, which were divided into four components: communication, practice, maintenance and advocacy. The importance of ongoing patient-physician relationships and collaboration with professionals and stakeholders was emphasised for the whole process of care. DISCUSSION: This study presents the consensus of a variety of experts on the process OPA for patient care related to SDHs. Further research is warranted to investigate how this Communication-Practice-Maintenance-Advocacy framework could affect medical education, quality of patient care, and patient outcomes.

Current perception of social accountability of medical schools in Japan: A qualitative content analysis.

INTRODUCTION: The concept of social accountability in medical schools is globally accepted, but data regarding Japanese medical schools are lacking and unclear. This study aimed to elucidate the perception of social accountability of medical schools in Japan and compare this to global frameworks. METHODS: A document on Japanese medical accreditation standards (Basic Medical Education: Japanese Specifications WFME Global Standards for Quality Improvement) was used for this study. We included 45 medical schools in a qualitative content analysis done via inductive category formation. The documents were also assessed using the social obligation scale. RESULTS: Three main categories and 15 categories were identified. The three main categories were as follows: Issues in society, Quality assurance of medical school, and Improvement of individual quality. Most categories were common to those in global frameworks, but some were characteristic of the Japanese context. The distribution of schools on the social obligation scale in six elements varied mainly 'from responsibility to responsiveness' or equal unless the elements were promoted by national policy. CONCLUSIONS: The social accountability of Japanese medical schools is mostly common with the global frameworks. Our findings will help the social accountability of medical schools to become better understood and developed beyond contextual borders.

Impact of value similarity on social trust in medical students: a cross-sectional web survey.

BACKGROUND: Social trust in medical students is trust in the cluster of medical students and not individual medical students. Social trust in medical students seems critical in clinical practice since citizens often face unknown medical students for the first time. However, most previous research has focused on interpersonal trust in particular medical professions, and social trust in medical students has not been addressed sufficiently. In social science, the Salient Value Similarity model has demonstrated that the value similarity between professionals and citizens is associated with social trust. This research aimed to explore the relationship between social trust in medical students and the perception of value similarity. This study also aimed to determine whether the information of medical students strengthens social trust in them. METHODS: We conducted a cross-sectional study to investigate how the perception of value similarity affects social trust. The participants answered the social trust questionnaires before and after reading a brief summary of the medical education curriculum and certification via the internet in Japan. The model structure of social trust in medical students, including the perception of value similarity, was investigated using SEM. A paired t-test was used to examine the effect of informing citizens about the knowledge, skills, and professionalism requirements of students attending medical school on social trust by reading the brief summary. RESULTS: The study included 658 participants, who all answered a web questionnaire. Social trust in medical students was associated with the perception of ability and value similarity. Social trust in medical students, the perception of ability, and value similarity were improved by information about medical students. CONCLUSIONS: The perception of ability and value similarity seem to affect social trust in medical students. Information on medical education regarding the knowledge, skills, and professionalism of medical students may improve social trust in these students. Further research is required to sophisticate the model of social trust in medical students by exploring social trust in the medical students' supervisors in clinical settings.

Development and assessment of a vaccine administration training course for medical students.

BACKGROUND: Vaccine administration skills are very important for physicians, especially in the era of global pandemics. However, medical students have reported that practical sessions to develop these skills are insufficient. Therefore, the aim of our study was to develop a vaccination training course for medical students. We also examined its educational effectiveness. METHODS: 5th- and 6th-year medical students at the University of Tokyo were recruited to attend the vaccine administration training course in 2021. These students were our study participants. Our course consisted of an orientation part, which included a lecture on the indications, adverse events, and vaccination techniques of flu vaccines and practice on a simulator, and a main part in which the staff of the University of Tokyo Hospital were actually vaccinated. Before and after the main part of the course, study participants completed an online questionnaire that assessed their confidence in vaccine administration technique through a five-point Likert scale. We also surveyed their feedback about the course content and process. At the beginning and end of the main part, their technical competence in vaccination was assessed by two independent doctors. These doctors used a validated checklist scale (ranging from 16 to 80) and a global rating scale (ranging from 0 to 10). We used their mean scores for analysis. The quantitative data were analyzed through the Wilcoxon signed-rank test. For the qualitative data of the questionnaire, thematic analysis was conducted. RESULTS: All 48 course participants participated in our study. Participants' confidence in vaccination technique (Z = -5.244, p < 0.05) and vaccination skill significantly improved (checklist rating: Z = -5.852, p < 0.05; global rating: Z = -5.868, p < 0.05). All participants rated the course as, "overall educational." Our thematic analysis identified four emerging themes: interest in medical procedures, efficacy of supervision and feedback, efficacy of "near-peer" learning, and very instructive course. CONCLUSIONS: In our study, we developed a vaccine administration course for medical students, assessed their vaccination techniques and confidence in those techniques, and investigated their perceptions of the course. Students' vaccination skills and confidence improved significantly after the course, and they positively evaluated the course based on a variety of factors. Our course will be effective in educating medical students about vaccination techniques.

Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis.

The organoid culture technique has been recently applied to modeling carcinogenesis in several organs. To further explore its potential and gain novel insights into tumorigenesis, we here investigated whether pancreatic ductal adenocarcinoma (PDA) could be generated as subcutaneous tumors in immunocompromised nude mice, by genetic engineering of normal organoids. As expected, acute induction of KrasG12Din vitro occasionally led to development of tiny nodules compatible with early lesions known as pancreatic intraepithelial neoplasia (PanIN). KrasG12D-expressing cells were enriched after inoculation in the subcutis, yet proved rather declined during culture, suggesting that its advantage might depend on surrounding environments. Depletion of growth factors or concurrent Trp53 deletion resulted in its robust enrichment, invariably leading to development of PanIN or large high-grade adenocarcinoma, respectively, consistent with in vivo mouse studies for the same genotype. Progression from PanIN was also recapitulated by subsequent knockdown of common tumor suppressors, whereas the impact of Tgfbr2 deletion was only partially recapitulated, illustrating genotype-dependent requirement of the pancreatic niche for tumorigenesis. Intriguingly, analysis of tumor-derived organoids revealed that KrasG12D-expressing cells with spontaneous deletion of wild-type Kras were positively selected and exhibited an aging-related mutation signature in nude mice, mirroring the pathogenesis of human PDA, and that the sphere-forming potential and orthotopic tumorigenicity in syngenic mice were significantly augmented. These observations highlighted the relevance of the subcutis of nude mice in promoting PDA development despite its ectopic nature. Taken together, pancreatic carcinogenesis could be considerably recapitulated with organoids, which would probably serve as a novel disease model.

Kras-driven heterotopic tumor development from hepatobiliary organoids.

Cancers arising from the biliary tract are refractory to conventional therapies, requiring the development of novel therapeutics. However, only a limited number of genetically engineered mouse models have been created, partly because of time-consuming work required. Besides, liver-specific gene manipulation mostly resulted in concurrent development of hepatocellular carcinoma, another type of liver cancer, and gallbladder-restricted gene targeting is still not feasible. Consequently, establishment of cancer type-specific disease modeling remains a technical challenge. To address this issue, we took an alternative cell-based approach to quickly induce tumorigenesis ex vivo. Specifically, murine primary organoids from liver and gallbladder were transduced with lentiviral vectors to reconstitute genetic alterations common in biliary tract cancers, followed by inoculation in immunodeficient mice. Although any single genetic alteration did not induce tumors, mutant Kras and repression of major tumor suppressors cooperated for tumor development within 2 months. Induced lesions varied among normal, dysplastic and papillary lesions to adenocarcinoma, recapitulating multistep tumorigenesis even in a heterotopic situation. We further demonstrated that two putative oncogenes in intrahepatic cholangiocellular carcinoma, mutant Pik3ca and FGFR2-AHCYL1 fusion, were rather modest drivers for liver-derived organoids, probably requiring additional mutations or hepatic niche to robustly induce full-blown tumors. Thus, we showed that cancer cells could be readily generated from primary cells in the biliary tract, at least in cases where genetic factors play dominant roles. Collectively, this study will likely contribute to gaining mechanistic insights into biliary carcinogenesis and providing valuable resources for drug discovery.

Genomic profiles of colorectal carcinoma with liver metastases and newly identified fusion genes.

Every year, approximately 1.2 million cases of colorectal carcinoma (CRC) are newly diagnosed worldwide. Although metastases to distant organs are often fatal complications of CRC, little information is known as to how such metastatic lesions are formed. To reveal the genetic profiles for CRC metastasis, we conducted whole-exome RNA sequencing on CRC tumors with liver metastasis (LM) (group A, n = 12) and clinical stage-matched larger tumors without LM (group B, n = 16). While the somatic mutation profiles were similar among the primary tumors and LM lesions in group A and the tumors in group B, the A-to-C nucleotide change in the context of "AAG" was only enriched in the LM regions in group A, suggesting the presence of a DNA damage process specific to metastasis. Genes already known to be associated with CRC were mutated in all groups at a similar frequency, but we detected somatic nonsynonymous mutations in a total of 707 genes in the LM regions, but not in the tumors without LM. Signaling pathways linked to such "LM-associated" genes were overrepresented for extracellular matrix-receptor interaction or focal adhesion. Further, fusions of the ADAP1 (ArfGAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF6, an ADAP1-substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC. Additionally, recurrent ADAP1 fusion genes were unexpectedly discovered. As these fusions activate small GTPase, further experiments are warranted to examine their contribution to CRC carcinogenesis.

miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver.

Liver metastasis is a major lethal complication associated with colon cancer, and post-intravasation steps of the metastasis are important for its clinical intervention. In order to identify inhibitory microRNAs (miRNAs) for these steps, we performed 'dropout' screens of a miRNA library in a mouse model of liver metastasis. Functional analyses showed that miR-493 and to a lesser extent miR-493(*) were capable of inhibiting liver metastasis. miR-493 inhibited retention of metastasized cells in liver parenchyma and induced their cell death. IGF1R was identified as a direct target of miR-493, and its inhibition partially phenocopied the anti-metastatic effects. High levels of miR-493 and miR-493(*), but not pri-miR-493, in primary colon cancer were inversely related to the presence of liver metastasis, and attributed to an increase of miR-493 expression during carcinogenesis. We propose that, in a subset of colon cancer, upregulation of miR-493 during carcinogenesis prevents liver metastasis via the induction of cell death of metastasized cells.

Newly defined aberrant crypt foci as a marker for dysplasia in the rat colon.

Dysplasia represents a preneoplastic status in multistep colon carcinogenesis. Whereas laborious preparation of thin sections is required for its diagnosis, we here show that newly defined aberrant crypt foci (ACF) simply mark the majority of the dysplasia on the whole colon. Specifically, decoloring of the azoxymethane-treated rat colon after scoring classical ACF (cACF) resulted in visualization of a subset of aberrant crypts that remained densely stained. They were morphologically classified into three subtypes, of which two with compressed luminal openings proved highly correlated with dysplasia. Accordingly, we designated those foci harboring either of the two crypt subtypes as dysplasia-associated ACF (dACF). By serially applying different detection methods for known preneoplastic lesions to the same colon, we showed that most dACF had already been identified as cACF, and a few newly identified dACF contained an entire population of more advanced lesions, such as flat ACF and mucin-depleted foci. Consequently, integrative scoring of cACF and dACF enabled capture of all early lesions of the colon. Furthermore, 94% of the dACF showed dysplasia and 90% of the dysplastic lesions proved to be dACF. Thus, dACF is a promising marker for dysplasia, likely facilitating precise identification of the early stages of colon carcinogenesis.

The Usage of the Term "Social" in Japanese Primary Care Literature.

INTRODUCTION: There has been a growing recognition of the importance of incorporating a "social" perspective in primary care practice. However, the specific meaning of the term "social" in the context of primary care is often not clearly defined or explained in the literature. This study aims to explore the usage and interpretation of the term "social" in primary care discourse in Japan. METHODS: We collected papers containing the term "social" ("shakai-teki" in Japanese) from 810 papers published between 2010 and 2022 in the Official Journal of the Japan Primary Care Association. Through abductive coding, we examined how the term was employed and the different meanings attributed to it. RESULTS: The instances of using the term "social" were classified into five distinct categories: (i) non-medical, (ii) emphasizing the importance of topics, (iii) public as an object, (iv) connections with people who support health and well-being, and (v) structural inequities that are detrimental to health.  Conclusion: The analysis revealed that the term "social" in the context of primary care discourse was multifaceted and characterized by ambiguity. To ensure effective communication and clarity in discussions, it is crucial for primary care professionals to have a clear understanding of the intended meaning and implications of the term "social."

Residents' learning and behavior about tool-guided clinical assessment of social determinants of health.

Background: The specific dimensions of learners that have been impacted by educational programs related to social determinants of health (SDoH) remain unknown. This study aims to elucidate how learners are affected by postgraduate education (a single 90-min educational session) regarding tool-guided clinical assessment of patients' social backgrounds. Methods: A pretest-posttest design was utilized in which residents (postgraduate year (PGY) 1 or 2) and fellows in family medicine (PGY over 3) were recruited. Likert-type questions were developed based on previous qualitative findings. Participants answered these questions before, immediately after, and 1.5 months after the educational session on tool-guided clinical SDoH assessment. Paired-sample t-tests were used, and effect size was measured using Cohen's d. Results: A total of 114 residents and fellows participated. After the session, participants expressed more interest in knowing their patients' social backgrounds when considering how to address their patients and were more open to embracing a pre-established assessment framework. Participants also considered clinical skills related to SDoH as learnable and improved their attitude toward patients. They reported that they did not perform specific interventions related to SDoH within 1.5 months after the session. Unlike previous qualitative findings, their concern about the implementation of SDoH-related practices did not increase significantly. Conclusion: An educational session on tool-guided SDoH assessment may have a positive impact on learners' attitudes related to addressing patients' social backgrounds without fostering concerns.

Assessing Social Circumstances in Primary Care: Expert Consensus via Delphi Technique.

Background and Objective: In the Japanese primary care setting, a set of questions to screen patients' social circumstances has never been developed in a scientific manner. This project aimed to reach a consensus among diverse experts to develop a set of such questions, to meet the need for assessing patients' health-related social circumstances. Methods: We used a Delphi technique to generate expert consensus. The expert panel was composed of various clinical professionals, medical trainees, researchers, support members for marginalized people, and patients. We conducted multiple rounds of communication online. In round 1, the participants provided their opinions about what health care professionals should ask to assess patients' social circumstances in primary care settings. These data were analyzed into several themes. In round 2, all themes were confirmed by consensus. Results: Sixty-one people participated in the panel. All participants completed the rounds. Six themes were generated and confirmed: economic condition and employment, access to health care and other services, living in everyday life and leisure time, total physiological needs, tools and technology, and history of the patient's life. In addition, the panelists emphasized the importance of respecting the patient's preferences and values. Conclusion: A questionnaire, abbreviated by the acronym of HEALTH+P, was developed. Further research about its clinical feasibility and impact on patient outcomes is warranted.

Primary care physicians' perceptions of social determinants of health recommendations: a qualitative study.

BACKGROUND: Several organisations have called for primary care professionals to address social determinants of health (SDoH) in clinical settings. For primary care physicians to fulfill their community health responsibilities, the implications of the SDoH recommendations need to be clarified. AIM: To describe primary care physicians' views about being asked to address SDoH in clinical settings, from both positive and negative perspectives. DESIGN & SETTING: A qualitative study in Japan. Twenty-one physicians were purposively recruited. METHOD: 'Love and breakup letter' methodology was used to collect qualitative data that contained both positive and negative feelings. Participants wrote love and breakup letters about being asked to address SDoH in a clinical setting, then undertook an in-depth online interview. Data were analysed via thematic analysis using the framework approach. RESULTS: The following themes were identified: (i) primary care physicians take pride in being expected to address SDoH; (ii) primary care physicians rely on the recommendations as a partner, even in difficult situations; (iii) primary care physicians consider the recommendations to be bothersome, with unreasonable demands and challenges, especially when supportive surroundings are lacking; and (iv) primary care physicians reconstruct the recommendations on the basis of their experience. CONCLUSION: Primary care physicians felt both sympathy and antipathy towards recommendations asking them to address SDoH in their clinical practice. The recommendations were not followed literally, instead contributing to physicians' clinical mindlines. Professional organisations that plan to develop and publish recommendations about SDoH should consider how their recommendations might be perceived by their target audience.

The impact of patients' social backgrounds assessment on nursing care: Qualitative research.

Background: Although nurses are expected to address the social determinants of health (SDH) in clinical settings, the perspectives of front-line nurses on the integration of SDH into their clinical practice remain unclear. Understanding the dynamism of this integration and its outcomes can yield crucial insights into effective nursing care. This study aims to elucidate the integration and adoption of tool-based SDH assessment nursing programs and their impacts on daily nursing care. Methods: We conducted qualitative research at a small community-based hospital in Japan, where a tool-based program characterized by social background interviews and documentation was implemented. Nurses at the hospital were recruited via purposive and snowball sampling. After hypothesis generation, semi-constructed in-depth online interviews were conducted. Each interview lasted between 30 and 50 min. The data were analyzed via thematic analysis using the framework approach. Results: A total of 16 nurses participated. Participants' incorporation of the novel SDH assessment program was bolstered by prior learning and their recognition of its practical value. Institutional support and collaborative teamwork further facilitated the adoption of this innovation. Enhanced knowledge about the social contexts of their patients contributed to increased respect, empathy, and self-affirmation among participants, consequently enhancing the quality of nursing care. Conclusion: Through team-based learning, reflection, and support, nurses can integrate a tool-based SDH assessment program into their daily nursing practice. This program has the potential to empower nurses to deliver more holistic care and redefine their professional identity. Further research is warranted to assess patient-reported outcomes.

Development and Validation of a Performance Assessment Checklist Scale for Vaccine Administration.

Objective Vaccination technique is a crucial skill for medical trainees to learn, especially in the current coronavirus disease 2019 pandemic. To this end, validated assessment tools are essential in teaching appropriate techniques. However, valid instruments for assessing vaccine administration skills have not yet been developed. We therefore explored the development and validation of an assessment tool for vaccination techniques based on expert consensus. Methods We implemented a modified Delphi process to develop a vaccination technique assessment tool. We then conducted a validation study to establish the reliability and validity of the tool. Results Two rounds of the modified Delphi process were performed to generate a 19-item, vaccination performance assessment checklist. In the validation study, the linear weighted kappa value for inter-rater reliability of the overall checklist score was 0.725. Spearman's correlation coefficient between the mean checklist score and the global rating was 0.98 (p<0.01). Conclusions This is a pioneering study examining the development and validation of an assessment tool for vaccine administration techniques. The tool will be widely used in vaccination-related education.

Experience of residents learning about social determinants of health and an assessment tool: Mixed-methods research.

Background: Educating healthcare professionals about the social determinants of health is important in improving health outcomes of marginalized patients. Residents' experience of learning about the social determinants of health and a clinical assessment tool remains unclear. Methods: Residents participated in an online session about the social determinants of health and the assessment tool. Using the New World Kirkpatrick Model, we obtained data about participants' experience from various perspectives. The data were analyzed using a concurrent triangulation mixed-methods design. Results: The study included 20 out of 30 residents. Their response was good, and self-reported learning scores were increased by the session. They learned when to ask about patients' social conditions, what to ask, and how to coordinate medical care appropriately. Participants reported reflecting on their role as medical professionals and implementing new practices based on their learning, as well as concerns about addressing patients' social conditions. Conclusion: Through learning about the social determinants of health, and assessment tools, residents both acquired knowledge and skills, and reflected on their previous practice, accepted patients as they are, understood difficult patients better, and developed interprofessional collaboration. Medical education about the social determinants of health can trigger changes in residents' views.

Primary care nurses during the coronavirus disaster and their struggle: Qualitative research.

Background: Coronavirus disease 2019 (COVID-19) has substantially affected the health and lives of medical professionals. However, the experiences of nurses engaged in primary care remain unclear. We explored how nurses working in primary care were psychologically and socially affected by the COVID-19 disaster and how they overcame the difficulties experienced. Methods: We conducted a qualitative study of seven Japanese nurses working in primary care. Data collection was performed before, during, and after a workshop based on the Tojisha-Kenkyu (user-led research) framework to explore how the COVID-19 disaster affected the nurses and how they coped. Data were analyzed using inductive thematic analysis. Results: Three themes emerged from the analysis: effects of the COVID-19 disaster on nurses, nurses' newly found strength during the pandemic, and their changes and achievements through the Tojisha-Kenkyu framework. The first theme comprised four subthemes: fear of the unknown; difficulty in adaptation; dysfunction in patient care; and defilement and oppression. The second theme involved feeling in control and professionalism. The third theme, which was based on participants' discovery of "same and different" fellowships, showed work reconstruction and self-understanding, which alleviated their difficulties. Conclusions: The effect of the pandemic on nurses working in primary care ranges from work-related frustration to daily life issues. The Tojisha-Kenkyu method can help nurses to alleviate difficulties. Further research should be conducted to elucidate the constant burden on primary care professionals and establish appropriate occupational and daily life support during pandemics.