Regenerative Role of Lrig1+ Cells in Kidney Repair.

BACKGROUND: In response to severe kidney injury, the kidney epithelium displays remarkable regenerative capabilities driven by adaptable resident epithelial cells. To date, it has been widely considered that the adult kidney lacks multipotent stem cells; thus, the cellular lineages responsible for repairing proximal tubule damage are incompletely understood. Leucine-rich repeats and immunoglobulin-like domains protein 1-expressing cells (Lrig1+ cells) have been identified as a long-lived cell in various tissues that can induce epithelial tissue repair. Therefore, we hypothesized that Lrig1+ cells participate in kidney development and tissue regeneration. METHODS: We investigated the role of Lrig1+ cells in kidney injury using mouse models. The localization of Lrig1+ cells in the kidney was examined throughout mouse development. The function of Lrig1+ progeny cells in acute kidney injury repair was examined in vivo using a tamoxifen-inducible Lrig1-specific Cre recombinase-based lineage tracing in three different kidney injury mouse models. Additionally, we conducted single-cell RNA-sequencing to characterize the transcriptional signature of Lrig1+ cells and to trace their progeny. RESULTS: Lrig1+ cells were present during kidney development and contributed to formation of the proximal tubule and collecting duct structures in mature mouse kidneys. In three-dimensional culture, single Lrig1+ cells demonstrated long-lasting propagation and differentiated into the proximal tubule and collecting duct lineages. These Lrig1+ proximal tubule cells highly expressed progenitor-like and quiescence-related genes, giving rise to a novel cluster of cells with regenerative potential in adult kidneys. Moreover, these long-lived Lrig1+ cells expanded and repaired damaged proximal tubules in response to three types of acute kidney injury in mice. CONCLUSIONS: These findings highlight the critical role of Lrig1+ cells in kidney regeneration.

Plasma protein signatures of adult asthma.

BACKGROUND: Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma. METHODS: Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non-case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non-case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta-analyzed using inverse-variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy (n = 207), asthma without atopy (n = 554), atopy without asthma (n = 147), compared to neither (n = 948)). RESULTS: Meta-analysis of 4860 proteins identified 115 significantly (FDR<0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR<0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75-0.79 in training set; AUC = 0.72, 95% CI = 0.69-0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma-atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis. CONCLUSION: This first large-scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management.

Cancer-Related Dysfunctional Beliefs About Sleep Mediate the Influence of Sleep Disturbance on Fear of Progression Among Patients With Surgically Resected Lung Cancer.

BACKGROUND: Lung cancer is associated with significant psychological distress, including fear of progression (FoP). Because insomnia and depression are highly prevalent and associated with FoP, we examined the association between FoP, insomnia, and depression in cancer patients. Furthermore, we tested the mediation effect of cancer-related dysfunctional beliefs about sleep (C-DBS) on this association. METHODS: We analyzed data collected from patients with surgically resected non-small cell lung cancer from a single-center randomized controlled study investigating digital healthcare applications. Baseline demographic and clinical variables were collected. In addition, self-reported questionnaires including the Fear of Progression Questionnaire-Short Form, Patients Health Questionnaire-9 items (PHQ-9), Insomnia Severity Index, and C-DBS were administered. RESULTS: Among the 320 enrolled patients with lung cancer, a regression model showed that FoP was predicted by age (ß = -0.13, P = 0.007), PHQ-9 (ß = 0.35, P < 0.001), and C-DBS (ß = 0.28, P < 0.001). Insomnia did not directly influence FoP, but C-DBS mediated the association. Depression directly influenced FoP, but C-DBS did not mediate this association. CONCLUSION: Among patients with surgically resected lung cancer, C-DBS mediated the effects of severity of insomnia on FoP. Depression directly influenced FoP, but C-DBS did not influence this association. To reduce FoP among patients with lung cancer, C-DBS should be addressed in the cognitive behavioral therapy module.

Examining sociocultural factors in widowhood and cognitive function among older Chinese immigrants: findings from the PINE study.

Objectives: Although there is growing evidence on widowhood and cognitive function, existing studies have shown mixed results. Little is known about protective factors that may contribute to resilience, thereby ameliorate the adverse effect of widowhood on cognition among older Asian immigrants. This study explored potential moderators (i.e. social support, acculturation, leisure activities) in the association between widowhood and cognitive function among older Chinese immigrants.Method: The study sample included 2,515 adults aged 60 or older who completed two waves (2011-2013 and 2013-2015) of the Population Study of Chinese Elderly in Chicago. Cognitive function was indexed by global cognitive function and episodic memory. Linear regression analyses were conducted with interaction terms.Results: Our results show that social support moderated the relationship between widowhood and global cognitive function, and acculturation moderated the relationship between widowhood and episodic memory. The adverse effect of widowhood on cognitive function was more pronounced at lower levels of social support and acculturation.Conclusion: Our findings indicate buffering roles of social support and acculturation in cognitive health among older Chinese immigrants who experience widowhood. Providing supportive programs and interventions to increase social support and acculturation is suggested to promote cognitive function in this population.

WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury.

BACKGROUND & AIMS: WAP 4-disulfide core domain protein 2 (WFDC2), also known as human epididymis protein 4, is a small secretory protein that is highly expressed in fibrosis and human cancers, particularly in the ovaries, lungs, and stomach. However, the role of WFDC2 in carcinogenesis is not fully understood. The present study aimed to investigate the role of WFDC2 in gastric carcinogenesis with the use of preneoplastic metaplasia models. METHODS: Three spasmolytic polypeptide-expressing metaplasia (SPEM) models were established in both wild-type and Wfdc2-knockout mice with DMP-777, L635, and high-dose tamoxifen, respectively. To reveal the functional role of WFDC2, we performed transcriptomic analysis with DMP-777-treated gastric corpus specimens. RESULTS: Wfdc2-knockout mice exhibited remarkable resistance against oxyntic atrophy, SPEM emergence, and accumulation of M2-type macrophages in all 3 SPEM models. Transcriptomic analysis revealed that Wfdc2-knockout prevented the up-regulation of interleukin-33 (IL33) expression in the injured mucosal region of SPEM models. Notably, supplementation of recombinant WFDC2 induced IL33 production and M2 macrophage polarization, and ultimately promoted SPEM development. Moreover, long-term treatment with recombinant WFDC2 was able to induce SPEM development. CONCLUSIONS: WFDC2 expressed in response to gastric injury promotes SPEM through the up-regulation of IL33 expression. These findings provide novel insights into the role of WFDC2 in gastric carcinogenesis.

Comparative effectiveness of smartphone healthcare applications for improving quality of life in lung cancer patients: study protocol.

BACKGROUND: Although pulmonary rehabilitation is helpful for patients following lung cancer surgery, rehabilitation is not widely available, due in part to a lack of medical resources. Recent developments in digital health care have overcome the space limitations associated with in-person health care. This study will evaluate and compare the efficacy of three different smartphone healthcare systems in patients with lung cancer. METHODS: This single center randomized controlled study is designed to evaluate the efficacy of digital healthcare applications for lung cancer patients after thoracoscopic lung resection. A total of 320 patients will be enrolled and randomized 1:1:1:1 into four different groups, with one group each using the smartphone applications NOOM, Walkon, and Efilcare and the fourth being the control group without intervention. Questionnaires will be administered to patients at baseline and after 3, 6, and 12 months. The primary endpoint will be the score on the EuroQol five-dimension index. Secondary endpoints will include other questionnaires about quality of life and dyspnea. DISCUSSION: This prospective randomized controlled study may allow assessments and comparisons of the efficacy of various smartphone applications in patients who undergo lung cancer surgery. This process may enable the introduction of healthcare interventions that maintain quality of life in patients with lung cancer. Trial registration CRIS, KCT0005447. Registered 06 October 2020, https://cris.nih.go.kr/cris/search/detailSearch.do/19346.

Production and Provision of Context-Based Patient-Specific Educational Resources.

BACKGROUND: Patient education is generally accompanied by instructive materials. The Korean government has recommended the provision of patient-specific educational materials (PEMs) via an electronic medical record (EMR) certification system. However, there are currently no clear standards or guidelines for including PEMs in current domestic educational materials. We investigated the benefits of integrating PEMs with the EMR certification system and the methods by which this integration can be achieved. METHODS: We developed and administered three structured Delphi surveys to 26 healthcare providers in clinical settings based on data collected from separate semi-structured advisory interviews with five experts. The surveys included the following topics: 1) expected effects of patient-specific education and health-related notifications/alarms, 2) desirable methods for providing PEMs, and 3) appropriate fee-setting and government support. We distributed the Delphi surveys via e-mail and calculated the average and standard deviation of the survey responses. RESULTS: PEMs are expected to have significant educational effects, such as the provision of surgery/intervention-related information, and will improve the understanding of various treatment processes/procedures. The preferred method for providing PEMs was via automatic request after receiving confirmation from healthcare providers. The provision of these materials was based on set fees and government support. The average fee per session was set at approximately USD 23 (as of October 2021, USD 1 = KRW 1,196). CONCLUSION: In this study, we investigated the prerequisites, contents, methods, and fees related to the provision of effective and efficient PEMs. The study findings can facilitate the production and provision of PEMs.

Perceived Risk of Re-Identification in OMOP-CDM Database: A Cross-Sectional Survey.

BACKGROUND: The advancement of information technology has immensely increased the quality and volume of health data. This has led to an increase in observational study, as well as to the threat of privacy invasion. Recently, a distributed research network based on the common data model (CDM) has emerged, enabling collaborative international medical research without sharing patient-level data. Although the CDM database for each institution is built inside a firewall, the risk of re-identification requires management. Hence, this study aims to elucidate the perceptions CDM users have towards CDM and risk management for re-identification. METHODS: The survey, targeted to answer specific in-depth questions on CDM, was conducted from October to November 2020. We targeted well-experienced researchers who actively use CDM. Basic statistics (total number and percent) were computed for all covariates. RESULTS: There were 33 valid respondents. Of these, 43.8% suggested additional anonymization was unnecessary beyond, "minimum cell count" policy, which obscures a cell with a value lower than certain number (usually 5) in shared results to minimize the liability of re-identification due to rare conditions. During extract-transform-load processes, 81.8% of respondents assumed structured data is under control from the risk of re-identification. However, respondents noted that date of birth and death were highly re-identifiable information. The majority of respondents (n = 22, 66.7%) conceded the possibility of identifier-contained unstructured data in the NOTE table. CONCLUSION: Overall, CDM users generally attributed high reliability for privacy protection to the intrinsic nature of CDM. There was little demand for additional de-identification methods. However, unstructured data in the CDM were suspected to have risks. The necessity for a coordinating consortium to define and manage the re-identification risk of CDM was urged.

Determinants of Discretionary and Non-Discretionary Service Utilization among Caregivers of People with Dementia: Focusing on the Race/Ethnic Differences.

Using Andersen's behavioral model of service utilization, this study aimed to understand how predisposing, enabling, and need factors were associated with two types of service utilization among caregivers of people with dementia. Caregiver participants (N = 637) were from the Resources for Enhancing Alzheimer's Caregivers Health (REACH II) study. Binary logistic and linear regression analyses were conducted to predict whether participants used services and the frequency of such service utilization. Results showed that some enabling and need factors were significantly associated with both discretionary and non-discretionary service utilization. Results also indicated some need factors were significant factors of the frequency of use for both discretionary and non-discretionary services. In addition, being Hispanic or African American moderated the association between some enabling or needs factors and service utilization. Practice attention needs to be paid on several enabling and needs factors among Hispanic and African American caregivers of people with dementia.

Serial Hydrolysis for the Simultaneous Analysis of Catecholamines and Steroids in the Urine of Patients with Alopecia Areata.

Catecholamines and steroids are well-known neurotransmitters and hormones that rapidly change the excitability of neurons. Alopecia areata is a disease for which the exact cause is unknown, but it is considered to be associated with stress, and so the simultaneous analysis of catecholamines and steroids is required for the diagnosis of alopecia areata. Thus, we herein report the simultaneous analysis of catecholamines and steroids bearing different functional groups for the first time, during which it was necessary to carry out a serial hydrolysis procedure. Following hydrolysis of the urine samples to produce the free forms from the urinary conjugates, ethyl acetate extractions were carried out, and chemical derivatization was performed using dansyl chloride to increase the sensitivity of the liquid chromatography-tandem mass spectrometry method. The matrix effects and recoveries of this analytical method were validated, giving values of 85.4-122.9% and 88.8-123.0%, respectively. In addition, the method accuracy and precision were assessed, giving values of 0.4-21.5% and 2.0-21.6% for the intra-day and inter-day precisions, respectively. This validated method was then applied to identify differences between patients with and without alopecia areata, wherein the metanephrine content was found to be significantly higher in the alopecia areata patient group. This quantitative profiling method can also be applied to steroid-dependent diseases, as well as catecholamine-related diseases.

Chondrogenic differentiation of human ASCs by stiffness control in 3D fibrin hydrogel.

In cell-based tissue engineering, fibrin hydrogel can be utilized to produce scaffolds to treat cartilage. However, the optimal fibrin formulation for cartilage regeneration has not yet been studied. This study aimed to find the optimal fibrin formulation and determine whether fibrin optimized with human adipose-derived stem cells (hASCs) increased the in-vivo chondrogenic potential. To find the optimal formulation, fibrin constructs were divided into twelve groups with different ratios of fibrinogen (10, 20, 30, and 50 mg/mL) to thrombin (10, 50, and 100 IU/mL), following which the physical and biological properties of cell-free and cell-embedded fibrin were investigated. The results from cell-free hydrogels showed that increases in the concentrations of fibrinogen and thrombin corresponded to increases in stiffness and initial weight. Moreover, hydrogel degradation was inhibited in high-concentration formulations. In cell-embedded fibrin constructs, the variation of gel formulation did not affect cell viability. However, cell behavior depended on the gel formulation. hASCs within high-concentration fibrinogen formulation maintained a round morphology similar to natural chondrocytes. Variations in thrombin concentration had a lesser effect on cell morphology. In terms of in-vivo cartilage formation, the formulation with 30 mg/mL fibrinogen and 100 IU/mL thrombin showed the highest cartilage formation, as evidenced through collagen type II alpha 1 chain (COL2) and safranin-O, 4 weeks after implantation. The results may lead to optimally designed 3D bio-scaffolds in which we can control both cell survival and chondrogenic potential for cartilage tissue engineering. Scaffolds made with the optimal fibrin formulation can be applied to develop cell therapies with mesenchymal stem cells to treat osteoarthritis.

Understanding Time Series Patterns of Weight and Meal History Reports in Mobile Weight Loss Intervention Programs: Data-Driven Analysis.

BACKGROUND: Mobile apps for weight loss provide users with convenient features for recording lifestyle and health indicators; they have been widely used for weight loss recently. Previous studies in this field generally focused on the relationship between the cumulative nature of self-reported data and the results in weight loss at the end of the diet period. Therefore, we conducted an in-depth study to explore the relationships between adherence to self-reporting and weight loss outcomes during the weight reduction process. OBJECTIVE: We explored the relationship between adherence to self-reporting and weight loss outcomes during the time series weight reduction process with the following 3 research questions: "How does adherence to self-reporting of body weight and meal history change over time?", "How do weight loss outcomes depend on weight changes over time?", and "How does adherence to the weight loss intervention change over time by gender?" METHODS: We analyzed self-reported data collected weekly for 16 weeks (January 2017 to March 2018) from 684 Korean men and women who participated in a mobile weight loss intervention program provided by a mobile diet app called Noom. Analysis of variance (ANOVA) and chi-squared tests were employed to determine whether the baseline characteristics among the groups of weight loss results were different. Based on the ANOVA results and slope analysis of the trend indicating participant behavior along the time axis, we explored the relationship between adherence to self-reporting and weight loss results. RESULTS: Adherence to self-reporting levels decreased over time, as previous studies have found. BMI change patterns (ie, absolute BMI values and change in BMI values within a week) changed over time and were characterized in 3 time series periods. The relationships between the weight loss outcome and both meal history and self-reporting patterns were gender-dependent. There was no statistical association between adherence to self-reporting and weight loss outcomes in the male participants. CONCLUSIONS: Although mobile technology has increased the convenience of self-reporting when dieting, it should be noted that technology itself is not the essence of weight loss. The in-depth understanding of the relationship between adherence to self-reporting and weight loss outcome found in this study may contribute to the development of better weight loss interventions in mobile environments.

The Use of Mobile Personal Health Records for Hemoglobin A1c Regulation in Patients With Diabetes: Retrospective Observational Study.

BACKGROUND: The effectiveness of personal health records (PHRs) in diabetes management has already been verified in several clinical trials; however, evidence of their effectiveness in real-world scenarios is also necessary. To provide solid real-world evidence, an analysis that is more accurate than the analyses solely based on patient-generated health data should be conducted. OBJECTIVE: This study aimed to conduct a more accurate analysis of the effectiveness of using PHRs within electronic medical records (EMRs). The results of this study will provide precise real-world evidence of PHRs as a feasible diabetes management tool. METHODS: We collected log data of the sugar function in the My Chart in My Hand version 2.0 (MCMH 2.0) app from Asan Medical Center (AMC), Seoul, Republic of Korea, between December 2015 and April 2018. The EMR data of MCMH 2.0 users from AMC were collected and integrated with the PHR data. We classified users according to whether they were continuous app users. We analyzed and compared their characteristics, patterns of hemoglobin A1c (HbA1c) levels, and the proportion of successful HbA1c control. The following confounders were adjusted for HbA1c pattern analysis and HbA1c regulation proportion comparison: age, sex, first HbA1c measurement, diabetes complications severity index score, sugar function data generation weeks, HbA1c measurement weeks before MCMH 2.0 start, and generated sugar function data count. RESULTS: The total number of MCMH 2.0 users was 64,932, with 7453 users having appropriate PHRs and diabetes criteria. The number of continuous and noncontinuous users was 133 and 7320, respectively. Compared with noncontinuous users, continuous users were younger (P<.001) and had a higher male proportion (P<.001). Furthermore, continuous users had more frequent HbA1c measurements (P=.007), shorter HbA1c measurement days (P=.04), and a shorter period between the first HbA1c measurement and MCMH 2.0 start (P<.001). Diabetes severity-related factors were not statistically significantly different between the two groups. Continuous users had a higher decrease in HbA1c (P=.02) and a higher proportion of regulation of HbA1c levels to the target level (P=.01). After adjusting the confounders, continuous users had more decline in HbA1c levels than noncontinuous users (P=.047). Of the users who had a first HbA1c measurement higher than 6.5% (111 continuous users and 5716 noncontinuous users), continuous users had better regulation of HbA1c levels with regard to the target level, 6.5%, which was statistically significant (P=.04). CONCLUSIONS: By integrating and analyzing patient- and clinically generated data, we demonstrated that the continuous use of PHRs improved diabetes management outcomes. In addition, the HbA1c reduction pattern was prominent in the PHR continuous user group. Although the continued use of PHRs has proven to be effective in managing diabetes, further evaluation of its effectiveness for various diseases and a study on PHR adherence are also required.

Leisure activity, gender and depressive symptoms among dementia caregivers: findings from the REACH II.

Objectives: Providing care to individuals with dementia places burden on family caregivers, which may relate to depressive symptoms. Although leisure activities may serve as a coping resource to relieve caregiving stress, only a few studies exist on how leisure and depressive symptoms associate in dementia caregivers. Moreover, less is known about the role of gender in this relationship. Thus, this study examined the relationship among leisure activity, gender and depressive symptoms.Method: A cutoff score (≥10) on the short form of the Center for Epidemiological Studies Depression Scale was used to measure presence of depressive symptoms. Independent variables were frequency of engagement in and satisfaction with leisure activities.Results: Logistic regression analyses from 632 dementia caregivers in the Resources for Enhancing Alzheimer's Caregiver Health II Study showed that more frequent and higher satisfaction in leisure engagement were negatively related to having depressive symptoms. Moreover, the negative association between frequent leisure engagement and depressive symptoms was more pronounced among male caregivers.Conclusion: Providing respite care for dementia caregivers to engage in leisure can be a promising coping strategy for this population. Also, gender difference in leisure-depressive symptoms relationship suggests different support needed for male and female caregivers in addition to leisure.

Evaluation of gastric microbiome and metagenomic function in patients with intestinal metaplasia using 16S rRNA gene sequencing.

BACKGROUND: Despite recent advances in studies on the gastric microbiome, the role of the non-Helicobacter pylori gastric microbiome in gastric carcinogenesis remains unclear. We evaluated the characteristics of the gastric microbiome and metagenomic functions in patients with IM. METHODS: Participants were classified into six groups according to disease status (chronic superficial gastritis [CSG], intestinal metaplasia [IM], and cancer) and H. pylori- infection status (H. pylori-positive and H. pylori-negative). The gastric microbiome was analyzed in mucosal tissues at the gastric antrum by 16S rRNA gene sequencing. Moreover, we assessed the metagenome including the type IV secretion system (T4SS) gene, as T4SS proteins are essential for transferring CagA from H. pylori- into the human gastric epithelium. RESULTS: Among the 138 included patients, 48, 9, 23, 14, 12, and 32 were classified into the H. pylori-negative CSG, H. pylori-negative IM, H. pylori-negative cancer, H. pylori-positive CSG, H. pylori-positive IM, and H. pylori-positive cancer groups, respectively. Cyanobacteria were predominant in the H. pylori-negative CSG group compared to in the H. pylori-negative IM and H. pylori-negative cancer groups (H. pylori-negative CSG vs H. pylori-negative IM vs H. pylori-negative cancer: 14.0% vs 4.2% vs 0.04%, P < 0.001). In contrast, Rhizobiales were commonly observed in the H. pylori-negative IM group (H. pylori-negative CSG vs H. pylori-negative IM vs H. pylori-negative cancer: 1.9% vs 15.4% vs 2.8%, P < 0.001). The relative abundance of Rhizobiales increased as H. pylori-infected stomachs progressed from gastritis to IM. In the H. pylori-negative IM group, genes encoding T4SS were prevalent among the metagenome. Additionally, after H. pylori- eradication therapy, the gastric microbiome was similar to the microbiome observed after spontaneous clearance of H. pylori-. CONCLUSIONS: The relative abundance of Rhizobiales was higher in patients with H. pylori-negative IM than in those with H. pylori-negative CSG or cancer. Additionally, T4SS genes were highly observed in the metagenome of patients with IM. Highly abundant T4SS proteins in these patients may promote gastric carcinogenesis.

Wide variation and patterns of physicians' responses to drug-drug interaction alerts.

OBJECTIVES: Providing physicians with alerts about potentially harmful drug-drug interactions (DDIs) is only moderately effective due to high alert override rates. To understand high override behavior on DDI alerts, we investigated how physicians respond to DDIs and their behavior patterns and variations. DESIGN: Retrospective system log data analysis and records review (sampling 2% of total overrides). SETTING: A large tertiary academic hospital. PARTICIPANTS: About 560 physicians and their override responses to DDI alerts generated from 1 September to 31 December 2014. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): DDI alert frequency and override rate. RESULTS: We found significant variation in both the number of alerts and override rates at the levels of physicians, departments and drug-class pairs. Physician-level variations were wider for residents than for faculty staff (number of alerts: t = 254.17, P = 0.011; override rates: t = -4.77, P < 0.0001). Using the number of alerts and their override rate, we classified physicians into four groups: inexperienced incautious users, inexperienced cautious users, experienced cautious users and experienced incautious users. Medical department influenced both alert numbers and override rates. Nearly 90% of the overrides involved only five drug-class combinations, which had a wide range of appropriateness in the chart review. CONCLUSION: The variations at drug-class levels suggest issues with system design and the DDI rules. Department-level variation may be best addressed at the department level, and the rest of the variation appears related to individual physician responses, suggesting the need for interventions at an individual level.

Vitamin C-linker-conjugated tripeptide AHK stimulates BMP-2-induced osteogenic differentiation of mouse myoblast C2C12 cells.

Vitamin C-linker-conjugated Ala-His-Lys tripeptide (Vit C-AHK) is a derivative of Vitamin C-conjugated tripeptides, which were originally developed as a component of a product for collagen synthesis enhancement or human dermal fibroblast growth. Here, we investigated the effect of Vit C-AHK on bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Vit C-AHK enhanced proliferation of C2C12 cells and induction of BMP-2-induced alkaline phosphatase, a typical marker of osteoblast differentiation. Vit C-AHK also stimulated the phosphorylation and translocation of Smad1/5/8 to the nucleus and phosphorylation of mitogen-activated protein kinases (MAPKs) including ERK1/2 and p38. In addition, Vit C-AHK enhanced the BMP-2-induced mRNA expression of osteoblast differentiation-related genes such as ALP, BMP-2, Osteocalcin, and Runx2. Our results suggest that Vit C-AHK exerts an enhancing effect on osteoblast proliferation and differentiation through activation of Smad1/5/8 and MAPK ERK1/2 and p38 signaling and without significant cytotoxicity. These results provide important data for the development of peptide-based bone-regenerative agents and treatment of bone-related disorders.

Is Blockchain Technology Suitable for Managing Personal Health Records? Mixed-Methods Study to Test Feasibility.

BACKGROUND: There are many perspectives on the advantages of introducing blockchain in the medical field, but there are no published feasibility studies regarding the storage, propagation, and management of personal health records (PHRs) using blockchain technology. OBJECTIVE: The purpose of this study was to investigate the usefulness of blockchains in the medical field in relation to transactions with and propagation of PHRs in a private blockchain. METHODS: We constructed a private blockchain network using Ethereum version 1.8.4 and conducted verification using the de-identified PHRs of 300 patients. The private blockchain network consisted of one hospital node and 300 patient nodes. In order to verify the effectiveness of blockchain-based PHR management, PHRs at a time were loaded in a transaction between the hospital and patient nodes and propagated to the whole network. We obtained and analyzed the time and gas required for data transaction and propagation on the blockchain network. For reproducibility, these processes were repeated 100 times. RESULTS: Of 300 patient records, 74 (24.7%) were not loaded in the private blockchain due to the data block size of the transaction block. The remaining 226 individual health records were classified into groups A (80 patients with outpatient visit data less than 1 year old), B (84 patients with outpatient data from between 1 and 3 years before data collection), and C (62 patients with outpatient data 3 to 5 years old). With respect to mean transaction time in the blockchain, C (128.7 seconds) had the shortest time, followed by A (132.2 seconds) and then B (159.0 seconds). The mean propagation times for groups A, B, and C were 1494.2 seconds, 2138.9 seconds, and 4111.4 seconds, respectively; mean file sizes were 5.6 KB, 18.6 KB, and 45.38 KB, respectively. The mean gas consumption values were 1,900,767; 4,224,341; and 4,112,784 for groups A, B, and C, respectively. CONCLUSIONS: This study confirms that it is possible to exchange PHR data in a private blockchain network. However, to develop a blockchain-based PHR platform that can be used in practice, many improvements are required, including reductions in data size, improved personal information protection, and reduced operating costs.

Widowhood, leisure activity engagement, and cognitive function among older adults.

OBJECTIVES: Maintaining cognitive function is an essential aspect of successful aging. Widowhood is a salient life transition that can affect older adults' cognitive function. Leisure engagement has received increasing attention because it is still modifiable in later life to help prevent cognitive decline. Nonetheless, limited longitudinal studies have examined how widowhood influences cognitive function, and even fewer studies have tested the role of leisure activities in this relationship. METHOD: This study delineated the mechanism of widowhood, leisure activity engagement, and cognitive function among older adults using a national longitudinal dataset, the Health and Retirement Study, and its supplementary dataset, the Consumption and Activities Mail Survey, which repeatedly measured individuals' leisure activity engagement. RESULTS: Findings showed no significant association between widowhood and cognitive function during a 4-year period. However, engagement in mental activities moderated the impact of widowhood on cognitive function. Specifically, the benefit of mental activity engagement on cognition was more pronounced among individuals who were recently widowed compared to those who were married. This implies a protective role of mental activities in the relationship between widowhood and cognitive function. CONCLUSION: Interventions with mentally stimulating activities at the community level to retain cognition among individuals in early phase widowhoodare suggested. Future studies are necessary to explore whether other factors such as changes in physical and mental health and intergenerational support from adult children during widowhood may further influence this mechanism among widowhood, leisure activities, and cognitive function.

Knockdown of Pyruvate Kinase M2 Inhibits Cell Proliferation, Metabolism, and Migration in Renal Cell Carcinoma.

Emerging evidence indicates that the activity of pyruvate kinase M2 (PKM2) isoform is crucial for the survival of tumor cells. However, the molecular mechanism underlying the function of PKM2 in renal cancer is undetermined. Here, we reveal the overexpression of PKM2 in the proximal tubule of renal tumor tissues from 70 cases of patients with renal carcinoma. The functional role of PKM2 in human renal cancer cells following small-interfering RNA-mediated PKM2 knockdown, which retarded 786-O cell growth was examined. Targeting PKM2 affected the protein kinase B (AKT)/mechanistic target of the rapamycin 1 (mTOR) pathway, and downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A and glucose transporter-1, and other downstream signaling key proteins. PKM2 knockdown changed glycolytic metabolism, mitochondrial function, adenosine triphosphate (ATP) level, and intracellular metabolite formation and significantly reduced 786-O cell migration and invasion. Acridine orange and monodansylcadaverine staining, immunocytochemistry, and immunoblotting analyses revealed the induction of autophagy in renal cancer cells following PKM2 knockdown. This is the first study to indicate PKM2/AKT/mTOR as an important regulatory axis mediating the changes in the metabolism of renal cancer cells.