Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom.

Background: Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear. Methods: We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190,613 men and 224,853 women with genotyping data from the UK Biobank. Among these participants, we analyzed 37,037 men with mLOY and 13,978 women with mLOX detected using Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization (MR) was conducted to estimate causal associations. Results: Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR=1.06, 95%CI:1.03-1.11). The associations were apparent in both never-smokers (HR=1.07, 95%:1.01-1.14) and ever-smokers (HR=1.05, 95%CI:1.01-1.11) as well as men > and ≤60 years of age. MR analyses supported causal associations between mLOY and atrial fibrillation (HRMR-PRESSO=1.15, 95%CI:1.13-1.18). Among post-menopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR=0.90, 95%CI:0.83-0.98). However, associations with mLOY and mLOX were not found for other heart diseases. Conclusions: Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

Pre-diagnostic free androgen and estradiol levels influence heart failure risk in both women and men: A prospective cohort study in the UK Biobank.

AIMS: Serum sex hormones have been linked to cardiovascular disease risk. However, their roles in the pathogenesis of heart failure (HF) in both men and women are unclear. We investigated the associations between free androgen, testosterone, and estradiol, and future risk of HF. METHODS AND RESULTS: This prospective cohort study evaluated UK Biobank participants free of prevalent cardiovascular disease and HF at baseline. Unitless free androgen, testosterone, and estradiol indices were generated using serum concentrations of total testosterone (nmol/L), estradiol (pmol/L), sex hormone binding globulin (SHBG, nmol/L), and albumin (g/L) in blood collected at enrolment. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF in relation to quartiles (Q) of free androgen (FAI), testosterone (FTI), estradiol (FEI) indices, and potential confounders. There were 180 712 men (including 5585 HF cases with FAI and 571 HF cases with FEI), and 177 324 women (including 2858 HF cases with FAI and 314 HF cases with FEI) with complete data. Increased FAI was associated with decreased HF risk in both men (HRQ4 vs. Q1: 0.86, 95% CI 0.79-0.94, p-trendcontinuous < 0.0001) and post-menopausal women (HRQ4 vs. Q1: 0.83, 95% CI 0.73-0.95). Similar inverse associations were observed for FTI only in men (HRQ4 vs. Q1: 0.91, 95% CI 0.83-0.98). Higher FEI was significantly associated with decreased HF risk among men (HRQ4 vs. Q1: 0.76, 95% CI 0.59-0.98), but was positively associated among pre-menopausal women (HRQ4 vs. Q1: 2.16, 95% CI 1.11-4.18). CONCLUSIONS: Sex hormones potentially influence HF pathogenesis and may offer pathways for interventions.

Do expressive writing interventions have positive effects on Koreans?: a meta-analysis.

Introduction: Expressive Writing (EW) is an intervention that focuses on individuals' writing down their thoughts and feelings about trauma or stressful events. Meta-analyses on EW studies have confirmed that EW has a positive effect. However, the heterogeneity of studies is high, so many studies have investigated boundary conditions and moderators. One of these moderators is the cultural difference in emotional suppression. Since EW focuses on the expression of suppressed thoughts and emotions, its effect might be slightly different for people in Asian cultures who show a high tendency to suppress their emotions. This study attempted to confirm the effect size of the EW interventions in Korea and examine whether these studies have different effect size from those based on Western cultures. Method: A total of 29 studies published in Korea until 2021 were analyzed. The effect size was calculated using the "dmetar," "meta," and "metafor" packages of the statistical program R 4.0.4. Results: The results were as follows. First, the effect size of EW intervention was 0.16, and we found that studies in the Korean context showed no significant difference from studies based on western meta-analysis. Second, the moderating variables that influenced the EW intervention were the writing type, the number of sessions, the time per session, and the measurement time. Discussion: The results of this study suggest that EW interventions benefit Koreans. And it is at least harmless and has a positive effect considering the efficiency and conciseness of interventions. Furthermore, the finding shows that EW interventions can be helpful even in the general population without apparent psychological problems. By considering moderators, we could structure more effective form of EW interventions for Koreans.

Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis.

The human brain choroid plexus (ChP) is a highly organized secretory tissue with a complex vascular system and epithelial layers in the ventricles of the brain. The ChP is the body's principal source of cerebrospinal fluid (CSF); it also functions as a barrier to separate the blood from CSF, because the movement of CSF through the body is pulsatile in nature. Thus far, it has been challenging to recreate the specialized features and dynamics of the ChP in a physiologically relevant microenvironment. In this study, we recapitulated the ChP structure by developing a microfluidic chip in accordance with established design rules. Furthermore, we used image processing and analysis to mimic CSF flow dynamics within a rlcking system; we also used a hydrogel containing laminin to mimic brain extracellular matrix (ECM). Human ChP cells were cultured in the ChP-on-a-chip with in vivo-like CSF dynamic flow and an engineered ECM. The key ChP characteristics of capillaries, the epithelial layer, and secreted components were recreated in the adjusted microenvironment of our human ChP-on-a-chip. The drug screening capabilities of the device were observed through physiologically relevant drug responses from breast cancer cells that had spread in the ChP. ChP immune responses were also recapitulated in this device, as demonstrated by the motility and cytotoxic effects of macrophages, which are the most prevalent immune cells in the ChP. Our human ChP-on-a-chip will facilitate the elucidation of ChP pathophysiology and support the development of therapeutics to treat cancers that have metastasized into the ChP.

Metabolomic Analysis of Vitamin E Supplement Use in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C22 lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C22 lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted p-value < 0.01). However, the inverse association between C22 lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases.

Serum metabolomic profile of hair dye use.

The International Agency for Research on Cancer reported that some chemicals in hair dyes are probably carcinogenic to those exposed to them occupationally. Biological mechanisms through which hair dye use may be related to human metabolism and cancer risk are not well-established. We conducted the first serum metabolomic examination comparing hair dye users and nonusers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Metabolite assays were conducted using ultrahigh performance liquid chromatography-tandem mass spectrometry. The association between metabolite levels and hair dye use was estimated using linear regression, adjusting for age, body mass index, smoking, and multiple comparisons. Among the 1,401 detected metabolites, 11 compounds differed significantly between the two groups, including four amino acids and three xenobiotics. Redox-related glutathione metabolism was heavily represented, with L-cysteinylglycine disulfide showing the strongest association with hair dye (effect size (ß) = - 0.263; FDR adjusted p-value = 0.0311), along with cysteineglutathione disulfide (ß = - 0.685; FDR adjusted p-value = 0.0312). 5alpha-Androstan-3alpha,17beta-diol disulfate was reduced in hair dye users (ß = - 0.492; FDR adjusted p-value = 0.077). Several compounds related to antioxidation/ROS and other pathways differed significantly between hair dye users and nonusers, including metabolites previously associated with prostate cancer. Our findings suggest possible biological mechanisms through which the use of hair dye could be associated with human metabolism and cancer risk.

3D microengineered vascularized tumor spheroids for drug delivery and efficacy testing.

Tumor angiogenesis is regarded as a promising target for limiting cancer progression because tumor-associated vasculature supplies blood and provides a path for metastasis. Thus, in vitro recapitulation of vascularized tumors is critical to understand the pathology of cancer and identify the mechanisms by which tumor cells proliferate, metastasize, and respond to drugs. In this study, we microengineered a vascularized tumor spheroid (VTS) model to reproduce the pathological features of solid tumors. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Notably, the hybrid spheroids also exhibited expression profiles associated with aggressive behavior. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. With the VTS chip showing a progressive tumor phenotype, we validated the suppressive effects of axitinib on tumor growth and angiogenesis, which depended on exposure dose and time, highlighting the significance of tumor vascularization to predict the efficacy of anticancer drugs. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow. Thus, our VTS model is a valuable platform with which to investigate the interactions between tumor microenvironments and explore therapeutic strategies in cancer. STATEMENT OF SIGNIFICANCE: We conducted an integrative study within a vascularized tumor spheroid (VTS) model. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Through RNA sequencing, we elucidated that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behavior such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow.

Metabolomic analysis of serum alpha-tocopherol among men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

BACKGROUND/OBJECTIVES: The role of vitamin E in chronic disease risk remains incompletely understood, particularly in an un-supplemented state, and evidence is sparse regarding the biological actions and pathways involved in its influence on health outcomes. Identifying vitamin-E-associated metabolites through agnostic metabolomics analyses can contribute to elucidating the specific associations and disease etiology. This study aims to investigate the association between circulating metabolites and serum α-tocopherol concentration in an un-supplemented state. SUBJECTS/METHODS: Metabolomic analysis of 4,294 male participants was conducted based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The associations between 1,791 known metabolites measured by ultra-high-performance LC-MS/GC-MS and HPLC-determined α-tocopherol concentration were estimated using multivariable linear regression. Differences in metabolite levels per unit difference in α-tocopherol concentration were calculated as standardized ß-coefficients and standard errors. RESULTS: A total of 252 metabolites were associated with serum α-tocopherol at the Bonferroni-corrected p value (p < 2.79 × 10-5). Most of these metabolites were of lipid and amino acid origin, with the respective subclasses of dicarboxylic fatty acids, and valine, leucine, and isoleucine metabolism, being highly represented. Among lipids, the strongest signals were observed for linoleoyl-arachidonoyl-glycerol (18:2/20:4)[2](ß = 0.149; p = 8.65 × 10-146) and sphingomyelin (D18:2/18:1) (ß = 0.035; p = 1.36 × 10-30). For amino acids, the strongest signals were aminoadipic acid (ß = 0.021; p = 5.01 × 10-13) and l-leucine (ß = 0.007; p = 1.05 × 10-12). CONCLUSIONS: The large number of metabolites, particularly lipid and amino acid compounds associated with serum α-tocopherol provide leads regarding potential mechanisms through which vitamin E influences human health, including its role in cardiovascular disease and cancer.

Assessment of the feasibility of developing a clinical pathway using a clinical order log.

A clinical pathway (CP) is a tool for effectively managing a care process. There are several research efforts on developing clinical pathways (CPs) in the process mining domain. However, the nature of the data affects data analysis results, and patient clinical variability makes it challenging to develop CPs. Thus, it is crucial to determine candidate care processes that can be standardized as CPs before applying process mining techniques. This paper proposed a method for assessing CP feasibility regarding clinical complexity using clinical order logs from electronic health records. The proposed method consists of data preparation, activity & trace homogeneity evaluations, and process inspection using process mining. Each step consists of metrics to measure the homogeneity of processes and a visualization method to demonstrate the diversity of processes based on the log. The case study was conducted with five surgical groups of patients from a tertiary hospital in South Korea to validate the proposed method. The five groups of patients were successfully assessed. In addition, the visualization methods helped clinical experts grasp the diversity of care processes.

A 28-year prospective analysis of serum vitamin E, vitamin E-related genetic variation and risk of prostate cancer.

OBJECTIVE: Investigate the relationship between serum α-tocopherol concentration and long-term risk of prostate cancer, and evaluate the interaction with vitamin E-related genetic variants and their polygenic risk score (PRS). METHODS: We conducted a biochemical analysis of 29,102 male Finnish smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and 2724 prostate cancer cases were identified during 28 years of follow-up. Cox proportional hazards models examined whether serum α-tocopherol concentrations were associated with prostate cancer risk. Among 8383 participants, three SNPs related to vitamin E status (rs964184, rs2108622, and rs11057830) were examined to determine whether they modified the relationship between serum α-tocopherol concentrations and prostate cancer risk, both individually and as a PRS using logistic regression models. RESULTS: No association was observed between serum α-tocopherol and prostate cancer risk (fifth quintile (Q5) vs. Q1 hazard ratio (HR) = 0.87, 95% confidence interval (95% CI) 0.75, 1.02; P-trend = 0.57). Though no interactions were seen by population characteristics, high α-tocopherol concentration was associated with reduced prostate cancer risk among the trial α-tocopherol supplementation group (Q5 quintile vs. Q1 HR = 0.79, 95% CI 0.64, 0.99). Finally, no associated interaction between the three SNPs or their PRS and prostate cancer risk was observed. CONCLUSION: Although there was a weak inverse association between α-tocopherol concentration and prostate cancer risk over nearly three decades, our findings suggest that men receiving the trial α-tocopherol supplementation who had higher baseline serum α-tocopherol concentration experienced reduced prostate cancer risk. Vitamin E-related genotypes did not modify the serum α-tocopherol-prostate cancer risk association.

Hair dye use and prostate cancer risk: A prospective analysis in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort.

BACKGROUND: According to the International Agency for Research on Cancer, some hair dye chemicals are considered mutagenic and carcinogenic in humans. One hospital-based study reported a positive association between hair dye use and prostate cancer risk, but no prospective analyses have been conducted. METHODS: This study investigated the association between hair dye use and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort, a large, well-characterized cohort of 29,133 male Finnish smokers. Participants completed questionnaires regarding lifestyle, medical, and risk factor information, including the use of hair dye, which was available for 98.8% of the cohort (28,795 men). Prostate cancer cases were identified through linkage with the Finnish Cancer Registry and the Finnish Mortality Register. Hazard ratios (HRs) and confidence intervals (CIs) were estimated via multivariable Cox proportional hazards regression. RESULTS: During a 28-year period of observation, 2703 incident prostate cancer cases were diagnosed. As reported at the baseline, 75 men used hair dye, and 13 of these men were subsequently diagnosed with prostate cancer. After adjustments for potential confounders, men who used hair dyes experienced substantially higher prostate cancer risk than men who did not (HR, 1.77; 95% CI, 1.03-3.05). CONCLUSIONS: This first prospective investigation of hair dye use and prostate cancer suggests that personal hair dye use may be related to increased risk. The findings warrant re-examination in other prospective cohorts along with studies evaluating specific hair dyes and possible underlying biological mechanisms.

Multivitamin Use and Overall and Site-Specific Cancer Risks in the National Institutes of Health-AARP Diet and Health Study.

BACKGROUND: Multivitamins are among the most commonly used supplements in the United States, but their effectiveness in preventing cancer remains unclear. OBJECTIVES: We prospectively examined the association between multivitamin use and risks of overall and site-specific cancer in a large, well-characterized cohort to ascertain potential preventive or harmful relationships. METHODS: We examined 489,640 participants ages 50-71 in the NIH-American Association of Retired Persons (AARP) Diet and Health Study who were enrolled from 1995 to 1998. We linked to 11 state cancer registries in order to identify incident cancers. Multivitamin use was assessed by a baseline questionnaire. Cox proportional hazards regression models of multivitamin use were used to estimate HRs and 95% CIs for cancer risks in men and women, adjusted for potential confounders, including age, BMI, smoking, physical activity, the Healthy Eating Index 2015 score, and use of single-vitamin/-mineral supplements. RESULTS: A slightly higher overall cancer risk was observed in men (but not women) who consumed 1 or more multivitamins daily compared to nonusers [HRs, 1.02 (95% CI: 1.01-1.04) and 1.03 (95% CI: 1.00-1.07), respectively; P-trend = 0.002]. The latter reflected higher risks for prostate cancer (HR, 1.04; 95% CI: 0.98-1.10; P-trend = 0.005), lung cancer (HR, 1.07; 95% CI: 0.96-1.20; P-trend = 0.003), and leukemia (HR, 1.26; 95% CI: 1.02-1.57; P-trend = 0.003). Taking more than 1 multivitamin daily was also strongly positively associated with the risk of oropharyngeal cancer in women (HR, 1.53, 95% CI: 1.04-2.24; P-trend < 0.0001). By contrast, daily multivitamin use was inversely associated with the colon cancer risk in both sexes (HR, 0.82; 95% CI: 0.73-0.93; P-trend = 0.0003). CONCLUSIONS: We found little evidence to support a cancer-preventive role for multivitamin use, with the exception of colon cancer, in both sexes in the NIH-AARP Diet and Health Study. In addition, slightly higher risks of overall, prostate, and lung cancer, as well as leukemia, were observed for greater multivitamin use in men, with a higher oropharyngeal cancer risk in women.

Human bone marrow-derived mesenchymal stem cells play a role as a vascular pericyte in the reconstruction of human BBB on the angiogenesis microfluidic chip.

A blood-brain barrier (BBB) on a chip similar to the in vivo BBB is important for evaluating the efficacy of reparative cell therapeutics for ischemic stroke in vitro. In this study, we established human BBB-like microvasculature on an angiogenesis microfluidic chip and analyzed the role of human pericytes (hPCs) and human astrocytes (hACs) on the architecture of human brain microvascular endothelial cells (hBMEC)-derived microvasculature on a chip. We found that human bone marrow mesenchymal stem cells (hBM-MSCs) play a role as perivascular pericytes in tight BBB reformation with a better vessel-constrictive capacity than that of hPCs, providing evidence of reparative stem cells on BBB repair rather than a paracrine effect. We also demonstrated that pericytes play an important role in vessel constriction, and astrocytes may induce the maturation of a capillary network. Higher expression of VEGF, SDF-1α, PDGFRß, N-cadherin, and α-SMA in hBM-MSCs than in hPCs and their subsequent downregulation with hBMEC co-culture suggest that hBM-MSCs may be better recruited and engaged in the BBB-microvasculature than hPCs. Collectively, the human BBB on a chip may be adopted as an alternative to evaluate in vitro cellular behavior and the engagement of cell therapeutics in BBB regeneration and may also be used for studying stroke.

Microvascularized tumor organoids-on-chips: advancing preclinical drug screening with pathophysiological relevance.

Recent developments of organoids engineering and organ-on-a-chip microfluidic technologies have enabled the recapitulation of the major functions and architectures of microscale human tissue, including tumor pathophysiology. Nevertheless, there remain challenges in recapitulating the complexity and heterogeneity of tumor microenvironment. The integration of these engineering technologies suggests a potential strategy to overcome the limitations in reconstituting the perfusable microvascular system of large-scale tumors conserving their key functional features. Here, we review the recent progress of in vitro tumor-on-a-chip microfluidic technologies, focusing on the reconstruction of microvascularized organoid models to suggest a better platform for personalized cancer medicine.

Self-detachable UV-curable polymers for open-access microfluidic platforms.

This study presents an ultraviolet (UV)-curable polymer which is applicable to open-access microfluidic platforms. The UV-curable polymer was prepared by mixing trimethylolpropane triacrylate (TMPTA), 1,6-hexanediol diacrylate (HDDA), polyethylene glycol-diacrylate (PEG-DA), and Irgacure 184. The polymer resin is optically transparent before and after UV-assisted curing and showed good biocompatibility when culturing multiple types of cells on the nanopatterned polymer substrate. The polymer has good adhesion with poly(dimethylsiloxane) (PDMS) even under large deformation and showed a low swelling ratio when exposed to water, suggesting a possibility to be used as a substrate for an organ on a chip. Furthermore, because the polymers have controllable hydrolysis ability depending on the composition, long-term 3D cell culture and subsequent biological analysis with harvested cells are possible. The self-detachable synthesized UV-curable polymer may help the advancement of biomedical studies using in vitro cell culture.

Urinary bisphenol A, phthalate metabolites, and obesity: do gender and menopausal status matter?

Previous studies of urinary bisphenol A (BPA), phthalate metabolites, and obesity risk have shown inconsistent results. Menopausal status is one of the main factors that affect hormone secretion change in women. In this study, we examined whether urinary BPA and phthalate metabolite levels are associated with obesity and whether the associations differ by sex and menopausal status in a sample of Korean adult populations. We recruited participants at three branches (Yeouido, Gangnam, and Gwanghwamun) of the Korea Medical Institute, a nationwide health check-up center, from 2015 to 2016. Urinary BPA level was measured by high-performance liquid chromatography-tandem mass spectrometry (Agilent 6490 Triple Quad LC-MS/MS; Agilent Technologies, CA, USA). Urinary six phthalate metabolites were analyzed with ultra-high-performance liquid chromatography-tandem mass spectrometry (TSQ Quantum Access Mass; Thermo Fisher Scientific, MA, USA). Participants with body mass index ≥ 25 kg/m2 were defined as general obesity group. Men with waist circumference (WC) ≥ 90 cm and women with WC ≥ 85 cm were defined as abdominal obesity group. Age, sex, alcohol intake, smoking, and exercise were considered in multivariate logistic regression models. Among the total of 702 participants, 211 participants were classified into the general obesity group, and 131 participants were classified into the abdominal obesity group. Urinary phthalate metabolite levels were not associated with general and abdominal obesity in men and women. However, in women, urinary BPA concentration was positively associated with abdominal obesity (OR = 1.50, 95% CI 1.00-2.26). Also, the association was stronger in postmenopausal women (OR = 2.23, 1.01-4.92), while it was weak in premenopausal women (OR = 1.31, 0.78-2.20). In this study, urinary BPA concentration was associated with abdominal obesity in women, especially postmenopausal women. Future studies should consider sex and menopausal status when investigating associations between urinary BPA, phthalate metabolites levels, and obesity.

Developing data-driven clinical pathways using electronic health records: The cases of total laparoscopic hysterectomy and rotator cuff tears.

OBJECTIVE: A clinical pathway is one of the tools used to support clinical decision making that provides a standardized care process in a specific context. The objective of this research was to develop a method for building data-driven clinical pathways using electronic health record data. MATERIALS AND METHODS: We proposed a matching rate-based clinical pathway mining algorithm that produces the optimal set of clinical orders for each clinical stage by employing matching rates. To validate the approach, we utilized two different datasets of deidentified inpatient records directly related to total laparoscopic hysterectomy (TLH) and rotator cuff tears (RCTs) from a hospital in South Korea. The derived data-driven clinical pathways were evaluated with knowledge-based models by health professionals using a delta analysis. RESULTS: Two different data-driven clinical pathways, i.e., TLH and RCTs, were produced by applying the matching rate-based clinical pathway mining algorithm. We identified that there were significant differences in clinical orders between the data-driven and knowledge-based models. Additionally, the data-driven clinical pathways based on our algorithm outperformed the models by clinical experts, with average matching rates of 82.02% and 79.66%, respectively. CONCLUSION: The proposed algorithm will be helpful for supporting clinical decisions and directly applicable in medical practices.

Effects of Combined Upper Limb Robotic Therapy in Patients With Tetraplegic Spinal Cord Injury.

OBJECTIVE: To confirm the effects of combined upper limb robotic therapy (RT) as compared to conventional occupational therapy (OT) in tetraplegic spinal cord injury (SCI) patients and to suggest the optimized treatment guidelines of combined upper limb RT. METHODS: After subject recruitment and screening for eligibility, the baseline evaluation for outcome measures were performed. We evaluated the Graded and Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP), the American Spinal Injury Association upper extremity motor score, grip and pinch strength, and the Spinal Cord Independence Measurement III (SCIM-III). In this study, the pre-tested participants were divided randomly into the RT and OT group. The utilized interventions included combined upper limb RT using ArmeoPower and Amadeo (RT group), or conventional OT (OT group) in addition to daily inpatient rehabilitation program. The participants underwent 40 minutes×3 sessions×5 weeks of interventions. RESULTS: A total of 30 tetraplegic SCI patients completed entire study program. After 5 weeks of intervention, both groups demonstrated increases in GRASSP-strength and SCIM-III. The manual muscle test scores of elbow flexion, elbow extension, 2-5th metacarpophalangeal extension, and SCIM-III subscores of bathing-upper, dressing-upper, and grooming as well as the GRASSP-qualitative prehension score were noted to have been significantly increased in the RT group as evaluated. The OT group showed improvements in the GRASSP-quantitative prehension score and some items in grip and pinch strength. There was no significant difference between the two groups in almost all measurements except for the SCIM-III bathing-upper subscore. CONCLUSION: Combined upper limb RT demonstrated beneficial effects on the upper limb motor function in patients with tetraplegic SCI, which were comparable with conventional OT.

3D Microfluidic Bone Tumor Microenvironment Comprised of Hydroxyapatite/Fibrin Composite.

Bone is one of the most common sites of cancer metastasis, as its fertile microenvironment attracts tumor cells. The unique mechanical properties of bone extracellular matrix (ECM), mainly composed of hydroxyapatite (HA) affect a number of cellular responses in the tumor microenvironment (TME) such as proliferation, migration, viability, and morphology, as well as angiogenic activity, which is related to bone metastasis. In this study, we engineered a bone-mimetic microenvironment to investigate the interactions between the TME and HA using a microfluidic platform designed for culturing tumor cells in 3D bone-mimetic composite of HA and fibrin. We developed a bone metastasis TME model from colorectal cancer (SW620) and gastric cancer (MKN74) cells, which has very poor prognosis but rarely been investigated. The microfluidic platform enabled straightforward formation of 3D TME composed the hydrogel and multiple cell types. This facilitated monitoring of the effect of HA concentration and culture time on the TME. In 3D bone mimicking culture, we found that HA rich microenvironment affects cell viability, proliferation and cancer cell cytoplasmic volume in a manner dependent on the different metastatic cancer cell types and culture duration indicating the spatial heterogeneity (different origin of metastatic cancer) and temporal heterogeneity (growth time of cancer) of TME. We also found that both SW620 and MKN72 cells exhibited significantly reduced migration at higher HA concentration in our platform indicating inhibitory effect of HA in both cancer cells migration. Next, we quantitatively analyzed angiogenic sprouts induced by paracrine factors that secreted by TME and showed paracrine signals from tumor and stromal cell with a high HA concentration resulted in the formation of fewer sprouts. Finally we reconstituted vascularized TME allowing direct interaction between angiogenic sprouts and tumor-stroma microspheroids in a bone-mimicking microenvironment composing a tunable HA/fibrin composite. Our multifarious approach could be applied to drug screening and mechanistic studies of the metastasis, growth, and progression of bone tumors.