Exploring depressive symptom trajectories in COVID-19 patients with clinically mild condition in South Korea using remote patient monitoring: longitudinal data analysis.

Background: During the height of the COVID-19 pandemic, the Korean government temporarily allowed full scale telehealth care for safety and usability. However, limited studies have evaluated the impact of telehealth by analyzing the physical and/or mental health data of patients with COVID-19 diagnosis collected through telehealth targeting Korean population. Objective: This study aimed to identify subgroup of depressive symptom trajectories in patients with clinically mild COVID-19 using collected longitudinal data from a telehealth-based contactless clinical trial. Methods: A total of 199 patients with COVID-19 were accrued for contactless clinical trial using telehealth from March 23 to July 20, 2022. Depressive symptoms were measured using the patient health questionnaire-9 on the start day of quarantine, on the final day of quarantine, and 1 month after release from quarantine. Additionally, acute COVID-19 symptoms were assessed every day during quarantine. This study used a latent class mixed model to differentiate subgroups of depressive symptom trajectories and a logistic regression model with Firth's correction to identify associations between acute COVID-19 symptoms and the subgroups. Results: Two latent classes were identified: class 1 with declining linearity at a slow rate and class 2 with increasing linearity. Among COVID-19 symptoms, fever, chest pain, and brain fog 1 month after release from quarantine showed strong associations with class 2 (fever: OR, 19.43, 95% CI, 2.30-165.42; chest pain: OR, 6.55, 95% CI, 1.15-34.61; brain fog: OR, 7.03, 95% CI 2.57-20.95). Sleeping difficulty and gastrointestinal symptoms were also associated with class 2 (gastrointestinal symptoms: OR, 4.76, 95% CI, 1.71-14.21; sleeping difficulty: OR, 3.12, 95% CI, 1.71-14.21). Conclusion: These findings emphasize the need for the early detection of depressive symptoms in patients in the acute phase of COVID-19 using telemedicine. Active intervention, including digital therapeutics, may help patients with aggravated depressive symptoms.

Identification of Predictors for Clinical Deterioration in Patients With COVID-19 via Electronic Nursing Records: Retrospective Observational Study.

BACKGROUND: Few studies have used standardized nursing records with Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) to identify predictors of clinical deterioration. OBJECTIVE: This study aims to standardize the nursing documentation records of patients with COVID-19 using SNOMED CT and identify predictive factors of clinical deterioration in patients with COVID-19 via standardized nursing records. METHODS: In this study, 57,558 nursing statements from 226 patients with COVID-19 were analyzed. Among these, 45,852 statements were from 207 patients in the stable (control) group and 11,706 from 19 patients in the exacerbated (case) group who were transferred to the intensive care unit within 7 days. The data were collected between December 2019 and June 2022. These nursing statements were standardized using the SNOMED CT International Edition released on November 30, 2022. The 260 unique nursing statements that accounted for the top 90% of 57,558 statements were selected as the mapping source and mapped into SNOMED CT concepts based on their meaning by 2 experts with more than 5 years of SNOMED CT mapping experience. To identify the main features of nursing statements associated with the exacerbation of patient condition, random forest algorithms were used, and optimal hyperparameters were selected for nursing problems or outcomes and nursing procedure-related statements. Additionally, logistic regression analysis was conducted to identify features that determine clinical deterioration in patients with COVID-19. RESULTS: All nursing statements were semantically mapped to SNOMED CT concepts for "clinical finding," "situation with explicit context," and "procedure" hierarchies. The interrater reliability of the mapping results was 87.7%. The most important features calculated by random forest were "oxygen saturation below reference range," "dyspnea," "tachypnea," and "cough" in "clinical finding," and "oxygen therapy," "pulse oximetry monitoring," "temperature taking," "notification of physician," and "education about isolation for infection control" in "procedure." Among these, "dyspnea" and "inadequate food diet" in "clinical finding" increased clinical deterioration risk (dyspnea: odds ratio [OR] 5.99, 95% CI 2.25-20.29; inadequate food diet: OR 10.0, 95% CI 2.71-40.84), and "oxygen therapy" and "notification of physician" in "procedure" also increased the risk of clinical deterioration in patients with COVID-19 (oxygen therapy: OR 1.89, 95% CI 1.25-3.05; notification of physician: OR 1.72, 95% CI 1.02-2.97). CONCLUSIONS: The study used SNOMED CT to express and standardize nursing statements. Further, it revealed the importance of standardized nursing records as predictive variables for clinical deterioration in patients.

Exploring Nursing Care for Patients With COVID-19 Using International Classification for Nursing Practice-Based Nursing Records.

This study explored nursing care topics for patients with the coronavirus disease 2019 admitted to the wards and intensive care units using International Classification for Nursing Practice-based nursing narratives. A total of 256630 nursing statements from 555 adult patients admitted from December 2019 to June 2022 were extracted from the clinical data warehouse. The International Classification for Nursing Practice concepts mapped to 301 unique nursing statements that accounted for the top 90% of all cumulative nursing narratives were used for analysis. The standardized number of nursing statements for each concept was calculated according to the types of nursing care and compared between the two groups. The most documented topics were related to infection; physical symptoms such as sputum, cough, dyspnea, and shivering; and vital signs including blood oxygen saturation and body temperature. Nurses in the intensive care units frequently documented concepts related to the directly monitored and assessed physical signs such as consciousness, pupil reflex, and skin integrity, whereas nurses in wards documented more concepts related to symptoms patients complained. This study showed that the International Classification for Nursing Practice-based nursing records can be used as source of information to identify nursing care for patients with coronavirus disease 19.

Nurses' Burden of Elimination Care: Sequential Explanatory Mixed-Methods Design.

Background: Inpatients commonly experience problems with elimination due to incontinence, urinary retentions, and complications with indwelling catheters. Although elimination care (EC) is an important nursing area, few studies explore the burden of EC on nurses. Aim: To identify the burden on EC by analyzing nurses' opinions using sequential explanatory mixed method. Methods: This research was conducted using a sequential explanatory mixed-methods design. A total of 59 nurses at a tertiary hospital in South Korea participated in the study from January 1 to March 31, 2022. For quantitative analysis, information about number of delays of work due to EC, required time for serving bedpan or diaper changes, percentage of EC per shift, and percentage of patients who need EC was collected through a survey. For qualitative analysis, focus group interviews were conducted to identify factors that put a burden on EC. Important themes were derived by analyzing nurses' opinions on EC. Results: For nurses in intensive care units, general wards, and integrated nursing care wards, the number of work delays due to EC was 3.6 ± 1.5, 2.3 ± 1.2, and 4.8 ± 2.4 (p<0.01), respectively. The mean percentage of EC work out of total nursing tasks per shift was 36.2 ± 19.0, 29.3 ± 14.4, and 43.8 ± 14.1 (p=0.02), respectively. The mean percentage of patients requiring EC out of patients a nurse cares was 85.4 ± 16.6, 41.3 ± 26.1, and 58.8 ± 21.9 (p<0.01), respectively. Following qualitative analysis, four themes related to nurses' EC burden were derived: physical burden, frequent care needs, delay of other jobs due to EC, and complications. Among them, frequent care needs were found to be the primary factor requiring consideration to reduce nurses' burden. Conclusion: This research found that EC is one of the most burdensome tasks that nurses want to avoid. To alleviate their burden, effective EC protocol or smart medical devices assisting with EC should be developed.

Trajectories of Anxiety Symptoms for COVID-19 Patients Using Multimodal Data Collected from Telemedicine.

We designed and developed Remote Patient Monitoring (RPM) system specific for coronavirus (COVID-19) patients, and collected multimodal data. Using the collected data, we explored the trajectories of anxiety symptoms for 199 COVID-19 patients quarantined at home. Two classes were identified using latent class linear mixed model. Thirty-six patients showed an exacerbation of anxiety. Presence of initial psychological symptoms, pain on the start day of quarantine, and abdominal discomfort at one month after finishing the quarantine were associated with exacerbation of anxiety.

Mapping Korean National Health Insurance Claim Codes for Laboratory Test to SNOMED CT.

The aim of this study was to map Korean national health insurance claims codes for laboratory tests to SNOMED CT. The mapping source codes were 4,111 claims codes for laboratory test and mapping target codes were the International Edition of SNOMED CT released on July 31, 2020. We used rule-based automated and manual mapping methods. The mapping results were validated by two experts. Out of 4,111 codes, 90.5% were mapped to the concepts of procedure hierarchy in SNOMED CT. Of them, 51.4% of the codes were exactly mapped to SNOMED CT concepts, and 34.8% of the codes were mapped to SNOMED CT concepts as one-to-one mapping.

A SNOMED CT Mapping Guideline for the Local Terms Used to Document Clinical Findings and Procedures in Electronic Medical Records in South Korea: Methodological Study.

BACKGROUND: South Korea joined SNOMED International as the 39th member country. To ensure semantic interoperability, South Korea introduced SNOMED CT (Systemized Nomenclature of Medicine-Clinical Terms) in 2020. However, there is no methodology to map local Korean terms to SNOMED CT. Instead, this is performed sporadically and independently at each local medical institution. The quality of the mapping, therefore, cannot be guaranteed. OBJECTIVE: This study aimed to develop and introduce a guideline to map local Korean terms to the SNOMED CT used to document clinical findings and procedures in electronic health records at health care institutions in South Korea. METHODS: The guidelines were developed from December 2020 to December 2022. An extensive literature review was conducted. The overall structures and contents of the guidelines with diverse use cases were developed by referencing the existing SNOMED CT mapping guidelines, previous studies related to SNOMED CT mapping, and the experiences of the committee members. The developed guidelines were validated by a guideline review panel. RESULTS: The SNOMED CT mapping guidelines developed in this study recommended the following 9 steps: define the purpose and scope of the map, extract terms, preprocess source terms, preprocess source terms using clinical context, select a search term, use search strategies to find SNOMED CT concepts using a browser, classify mapping correlations, validate the map, and build the final map format. CONCLUSIONS: The guidelines developed in this study can support the standardized mapping of local Korean terms into SNOMED CT. Mapping specialists can use this guideline to improve the mapping quality performed at individual local medical institutions.

The Association of Acute Signs and Symptoms of COVID-19 and Exacerbation of Depression and Anxiety in Patients With Clinically Mild COVID-19: Retrospective Observational Study.

BACKGROUND: To date, the association between acute signs and symptoms of COVID-19 and the exacerbation of depression and anxiety in patients with clinically mild COVID-19 has not been evaluated. OBJECTIVE: This study was designed to assess the correlation between acute signs and symptoms of COVID-19 and the exacerbation of depression and anxiety in patients with clinically mild COVID-19 at a residential treatment center in South Korea. METHODS: This retrospective study assessed 2671 patients with COVID-19 admitted to 4 residential treatment centers operated by Seoul National University Hospital, South Korea, from March 2020 to April 2022. Depression and anxiety were assessed using the 2-item Patient Health Questionnaire (PHQ-2) and 2-item Generalized Anxiety Disorder (GAD-2) scale, respectively. The exacerbation of depression and anxiety symptoms was identified from the differences in PHQ-2 and GAD-2 scores between admission and discharge, respectively. The patients' clinical characteristics, including acute signs and symptoms of COVID-19, GAD-2 and PHQ-2 scores, were obtained from electronic health records. Demographic characteristics, a summary of vital signs, and COVID-19 symptoms were analyzed and compared between the patient groups with and those without exacerbated PHQ-2 and GAD-2 scores using the chi-square test. We applied logistic regression to identify the association between acute signs and symptoms of COVID-19 and the exacerbation of depression and anxiety. RESULTS: Sleep disorders were associated with exacerbated depression (odds ratio [OR] 1.09, 95% CI 1.05-1.13) and anxiety (OR 1.1, 95% CI 1.06-1.14), and the sore throat symptom was associated with exacerbated anxiety symptoms (OR 1.03, 95% CI 1.00-1.07). Patients with abnormal oxygen saturation during quarantine were more likely to have exacerbated depression (OR 1.27, 95% CI 1.00-1.62), and those with an abnormal body temperature during quarantine were more likely to experience anxiety (OR 1.08, 95% CI 1.01-1.16). As anticipated, patients who experienced psychological symptoms at admission were more likely to experience depression (OR 1.91, 95% CI 1.52-2.41) and anxiety (OR 1.98, 95% CI 1.54-2.53). Meanwhile, the PHQ-2 and GAD-2 scores measured at admission revealed that lower the score, higher the possibility of exacerbation of both depression (OR 0.15, 95% CI 0.11-0.22) and anxiety (OR 0.13, 95% CI 0.10-0.19). CONCLUSIONS: Results from this study suggest the importance of further interventions for patients with abnormal oxygen saturation, abnormal body temperatures, sore throat, and sleep disorder symptoms or initial psychological symptoms to mitigate the exacerbation of depression and anxiety. In addition, this study highlights the usability of short and efficient scales such as the PHQ-2 and GAD-2 in the assessment of the mental health of patients with clinically mild COVID-19 symptoms who were quarantined at home during the pandemic era.

Weight Reduction Interventions Using Digital Health for Employees with Obesity: A Systematic Review.

Purpose: This study aimed to systematically review the literature on randomized controlled trials on weight reduction interventions using digital health for employees with obesity. Methods: All relevant articles published until September 2021 were systematically identified from six electronic databases: MEDLINE, EMBASE, CINAHL, PsycINFO, RISS, and KISS. Data selection and extraction were independently performed by three researchers. Methodological quality was assessed using the JBI Critical Appraisal Checklist for Randomized Controlled Trials. The results were narratively synthesized. Results: Eleven studies were included in the systematic review. All studies had a low risk of bias. The settings and sample sizes of the included studies were different. The contents of the interventions included nutrition, physical activity, behavioral change, incentives, and motivation. Four studies were based on social cognitive theory. A total of ten studies delivered web-based intervention, while the other used tele-monitoring device. A wide range of intervention strategies was used including providing online resources, tele-counseling, and patient-tailored advice. As a result of the intervention, a total of seven studies showed a significant weight reduction in both the intervention and comparison groups, with significant differences between groups. Conclusion: Until now, use of digital health in weight reduction interventions for employees with obesity has been conducted on a web-based. Various contents such as nutrition, physical activity and theories were explored. Further study is required using more diverse delivery methods such as mobile application, use of wearable devices.

Building and implementing a contactless clinical trial protocol for patients with COVID-19: A Korean perspective.

Introduction: To effectively manage patients with coronavirus disease 2019 (COVID-19) while minimizing contact between medical staff, clinical trial protocol that facilitates contactless patient management was designed to predict deterioration of disease condition and monitor mental health status. Methods: Through consultation with infectious disease specialists and psychiatrists, this study identified main clinical indicators related to respiratory and non-respiratory outcomes, and mental health. Telehealth devices that could collect relevant data indicators were explored. The following three modes were identified: wearable devices, video calls, and online questionnaires. Clinical trial protocol was implemented to patients confirmed with COVID-19 infection and admitted to Seongnam residential treatment centers between September 1, 2021 and December 30, 2021. Data were collected from wearable devices, video calls, online questionnaires, and from electronic health records. Participant satisfaction was assessed through an online survey at the time of discharge. Results: In total, 120 asymptomatic and mildly symptomatic COVID-19 patients participated in this trial. Seven types of physiological and life log data were collected from 87 patients using wearable devices, video and audio recordings, and online mental health-related questionnaire. Most participants were satisfied with the overall trial process, but perceived difficulties in using telehealth devices. Conclusion: This trial collected simultaneously generated multimodal patient data using various telehealth devices in a contactless setting for COVID-19 patients. Data collected in this study will be used to build a remote patient management system based on the prediction algorithms.

Hot flushes and sweating, sleep problems, joint and muscular discomfort, and physical and mental exhaustion in breast cancer survivors during the first 24 months of tamoxifen therapy: a prospective observational study.

Purpose: This study aimed to explore symptom trajectories over 24 months for hot flushes and sweating, sleep problems, joint and muscular discomfort, and physical and mental exhaustion experienced by premenopausal women diagnosed with tamoxifen-treated breast cancer. Methods: A total of 104 patients participated in the study. The menopausal symptoms were examined using the Menopausal Rating Scale at baseline, 3-6, 12, and 18-24 months after initiating tamoxifen. The changes over four time points were analyzed using repeated measures analysis of variance. The chi-square test was used to examine the differences between "no symptom-to-mild" and "moderate-to-extremely severe" 3-6 months after initiating tamoxifen according to the patients' chemotherapy treatment experiences. Results: All menopausal symptoms occurred in > 70% of patients with breast cancer and persisted until 24 months. More than 50% of patients experienced four menopausal symptoms, with at least two at a serious severity level after initiating tamoxifen. Hot flushes and sweating occurred in the highest number of patients, recording high scores. Sleep problems and physical and mental exhaustion exhibited relatively high scores, even before tamoxifen initiation. There were significant changes over four time points in all symptoms. Young patients aged < 40 years experienced more severe sleep problems, and patients who had previously received chemotherapy experienced more severe joint and muscular discomfort. Conclusions: This study's findings may assist in alerting healthcare providers to menopausal symptoms that develop during tamoxifen therapy and the need for early and active intervention to minimize symptom occurrence and distress.

Mapping Korean National Health Insurance Pharmaceutical Claim Codes to SNOMED CT.

The objective of this study was to map pharmaceutical claim codes to SNOMED CT and thereby facilitate multicenter collaborative research and improve semantic interoperability. The claim codes were mapped to SNOMED CT using rule-based automated and manual methods. The maps were internally validated by terminologists and a pharmacist. Finally, 80% of all claim codes were mapped to the concepts of Pharmaceutical/biologic product hierarchy in SNOMED CT. Of them, 50.6% of the codes were exactly mapped to one clinical drug branch concept.

Effect of a mobile app-based cultural competence training program for nurses: A pre- and posttest design.

BACKGROUND: Importance of providing culturally competent nursing care and cultural competence training for nurses has increased due to diversification of the cultural backgrounds of patients in South Korea. Currently there is little cultural competence training provided to nurses in South Korea. OBJECTIVES: This study aimed to develop and evaluate a mobile app-based cultural competence training program for nurses working at a tertiary teaching hospital in South Korea. DESIGN: A one group pre- and posttest intervention design. SETTINGS: A tertiary teaching hospital in South Korea. PARTICIPANTS: A total of 49 nurses participated in the study. METHODS: A mobile app-based cultural competence training program for nurses was developed using the five stages of the ADDIE instructional model. Cultural competence scores were compared between pre- and posttest using the paired t-test. The differences in cultural competence scores between pre- and posttests were also compared by participant characteristics using analysis of variance, the Kruskal-Wallis test, and the Mann-Whitney-Wilcoxon test. RESULTS: The mean total score of the nurses increased significantly after participating in the program, from 63.00 to 81.06 (p < 0.001). Comparisons of differences in cultural competence scores between pre- and posttests by participant characteristics revealed that the improvement in cultural competence was greater in those with no experience abroad for longer than 1 month compared to those who had experience abroad for longer than 1 month (p < 0.001) and in those who had never cared for a foreign patient compared to those who had cared for more than three foreign patients per week (p < 0.05). CONCLUSIONS: The mobile app-based cultural competence training program developed in this study was demonstrated to be effective in improving the cultural competence of nurses in South Korea. Our novel training program can be applied as on-the-job training to improve the cultural competence of nurses.

Mesenchymal Stem/Stromal Cell-Derived Exosomes for Immunomodulatory Therapeutics and Skin Regeneration.

Exosomes are nano-sized vesicles that serve as mediators for cell-to-cell communication. With their unique nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of producer cells, exosomes can be utilized as cell-free therapeutics. Among exosomes derived from various cellular origins, mesenchymal stem cell-derived exosomes (MSC-exosomes) have gained great attention due to their immunomodulatory and regenerative functions. Indeed, many studies have shown anti-inflammatory, anti-aging and wound healing effects of MSC-exosomes in various in vitro and in vivo models. In addition, recent advances in the field of exosome biology have enabled development of specific guidelines and quality control methods, which will ultimately lead to clinical application of exosomes. This review highlights recent studies that investigate therapeutic potential of MSC-exosomes and relevant mode of actions for skin diseases, as well as quality control measures required for development of exosome-derived therapeutics.

Development of a Mobile Learning System for Nurses' Cultural Competency Training.

We developed a mobile learning system that provides cultural competency training courses for nurses at a university hospital in South Korea using the system development life cycle. The contents and functions of the system were identified from the literature review, expert's recommendations, and the users' requirements. An algorithm, database, and user interface were designed. The system was implemented using the Newin Touchclass authoring tool. We evaluated and modified the system based on heuristics evaluation.

Hepatoprotective Effect of Kombucha Tea in Rodent Model of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis.

Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). db/db mice that were fed methionine/choline-deficient (MCD) diets for seven weeks were treated for vehicle (M + V) or KT (M + K) and fed with MCD for four additional weeks. Histomorphological injury and increased levels of liver enzymes and lipids were evident in the M + V group, whereas these symptoms were ameliorated in the M + K group. The M + K group had more proliferating and less apoptotic hepatocytic cells than the M + V group. Lipid uptake and lipogenesis significantly decreased, and free fatty acid (FFA) oxidation increased in the M + K, when compared with the M + V group. With the reduction of hedgehog signaling, inflammation and fibrosis also declined in the M + K group. Palmitate (PA) treatment increased the accumulation of lipid droplets and decreased the viability of primary hepatocytes, whereas KT suppressed PA-induced damage in these cells by enhancing intracellular lipid disposal. These results suggest that KT protects hepatocytes from lipid toxicity by influencing the lipid metabolism, and it attenuates inflammation and fibrosis, which contributes to liver restoration in mice with NAFLD.

Perceived cultural differences in healthcare for foreign patients visiting South Korea: tool development and measurement.

BACKGROUND: We developed a 41-item tool measuring cultural differences in healthcare as perceived by foreign patients visiting South Korea. METHODS: The tool was tested on 256 foreign patients who visited three tertiary hospitals in Seoul, South Korea. Content validity was explored by two physicians and eight nurses working in an international healthcare department. Structural validity was tested via exploratory factor analysis and by testing two hypotheses: (1) there are perceived cultural differences between the South Korean healthcare and those of foreign patients' home countries (one-sample t-test); and, (2) Perceived cultural differences vary among language groups (analysis of variance). We also calculated Cronbach's alpha. RESULTS: The content validity index of the tool was 0.97. Exploratory factor analysis identified seven significant factors: hospital care and services, food, the healthcare system, communication, the healthcare facility, religion, and cultural values. The overall Cronbach's alpha for the tool was 0.96, indicating very high internal consistency. We found that foreign patients visiting South Korean hospitals perceived that the healthcare culture differed significantly from that of their home country. The perceived cultural differences varied significantly by language group. CONCLUSIONS: Nurses can use our new tool to understand the cultural differences of foreign patients and provide them with culturally competent nursing care.

Liver-Derived Exosomes and Their Implications in Liver Pathobiology.

The liver has a wide range of physiological functions in the body, and its health is maintained by complex cross-talk among hepatic cells, including parenchymal hepatocytes and nonparenchymal cells. Exosomes, which are one method of cellular communication, are endosomal-derived small vesicles that are released by donor cells and delivered to the target cells at both short and long distances. Because exosomes carry a variety of cargoes, including proteins, mRNAs, microRNAs and other noncoding RNAs originating from donor cells, exosomes convey cellular information that enables them to potentially serve as biomarkers and therapeutics in liver diseases. Hepatocytes release exosomes to neighboring hepatocytes or nonparenchymal cells to regulate liver regeneration and repair. Nonparenchymal cells, including hepatic stellate cells, liver sinusoidal endothelial cells, and cholangiocytes, also secrete exosomes to regulate liver remodeling upon liver injury. Exosomes that are released from liver cancer cells create a favorable microenvironment for cancer growth and progression. In this review, we summarize and discuss the current findings and understanding of exosome-mediated intercellular communication in the liver, with a particular focus on the function of exosomes in both health and disease. Based on the current findings, we suggest the potential applications of exosomes as biomarkers and therapeutics for liver diseases.

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice.

BACKGROUND/AIMS: Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver's response to malarial infection. METHODS: Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot. RESULTS: Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1ß, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-ß, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin ß4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice. CONCLUSION: Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.