A Scoping Review of the Use of Machine Learning in Health Economics and Outcomes Research: Part 1-Data From Wearable Devices.

OBJECTIVES: With the emerging use of machine learning (ML) techniques, there has been particular interest in using wearable data for health economics and outcomes research (HEOR). We aimed to understand the emerging patterns of how ML has been applied to wearable data in HEOR. METHODS: We identified studies published in PubMed between January 2016 and March 2021. Studies that included at least 1 HEOR-related Medical Subject Headings term, applied an ML, and used wearable data were eligible for inclusion. Two reviewers abstracted information including ML application types and data on which ML was applied and analyzed them using descriptive analyses. RESULTS: A total of 148 studies were identified from PubMed, among which 32 studies met the inclusion criteria. There has been an increase over time in the number of ML studies using wearable data. ML has been more frequently used for monitoring events in real time (78%) than to predict future events (22%). There has been a wide range of outcomes examined, ranging from general physical or mental health (24%) to more disease-specific outcomes (eg, disease incidence [19%] and progression [13%]) and treatment-related outcomes (eg, treatment adherence [9%] and outcomes [9%]). Data for ML models were more often derived from wearable devices with specific medical purposes (60%) than those without (40%). CONCLUSION: There has been a wide range of applications of ML to wearable data. Both medical and nonmedical wearable devices have been used as a data source, showing the potential for providing rich data for ML studies in HEOR.

Increased Molecular Conductance in Oligo[n]phenylene Wires by Thermally Enhanced Dihedral Planarization.

Coherent tunneling electron transport through molecular wires has been theoretically established as a temperature-independent process. Although several experimental studies have shown counter examples, robust models to describe this temperature dependence have not been thoroughly developed. Here, we demonstrate that dynamic molecular structures lead to temperature-dependent conductance within coherent tunneling regime. Using a custom-built variable-temperature scanning tunneling microscopy break-junction instrument, we find that oligo[n]phenylenes exhibit clear temperature-dependent conductance. Our calculations reveal that thermally activated dihedral rotations allow these molecular wires to have a higher probability of being in a planar conformation. As the tunneling occurs primarily through π-orbitals, enhanced coplanarization substantially increases the time-averaged tunneling probability. These calculations are consistent with the observation that more rotational pivot points in longer molecular wires leads to larger temperature-dependence on conductance. These findings reveal that molecular conductance within coherent and off-resonant electron transport regimes can be controlled by manipulating dynamic molecular structure.

Molecular and Genomic Analysis of the Virulence Factors and Potential Transmission of Hybrid Enteropathogenic and Enterotoxigenic Escherichia coli (EPEC/ETEC) Strains Isolated in South Korea.

Hybrid strains Escherichia coli acquires genetic characteristics from multiple pathotypes and is speculated to be more virulent; however, understanding their pathogenicity is elusive. Here, we performed genome-based characterization of the hybrid of enteropathogenic (EPEC) and enterotoxigenic E. coli (ETEC), the strains that cause diarrhea and mortality in children. The virulence genes in the strains isolated from different sources in the South Korea were identified, and their phylogenetic positions were analyzed. The EPEC/ETEC hybrid strains harbored eae and est encoding E. coli attaching and effacing lesions and heat-stable enterotoxins of EPEC and ETEC, respectively. Genome-wide phylogeny revealed that all hybrids (n = 6) were closely related to EPEC strains, implying the potential acquisition of ETEC virulence genes during ETEC/EPEC hybrid emergence. The hybrids represented diverse serotypes (O153:H19 (n = 3), O49:H10 (n = 2), and O71:H19 (n = 1)) and sequence types (ST546, n = 4; ST785, n = 2). Furthermore, heat-stable toxin-encoding plasmids possessing estA and various other virulence genes and transporters, including nleH2, hlyA, hlyB, hlyC, hlyD, espC, espP, phage endopeptidase Rz, and phage holin, were identified. These findings provide insights into understanding the pathogenicity of EPEC/ETEC hybrid strains and may aid in comparative studies, virulence characterization, and understanding evolutionary biology.

A Pragmatic Guide to Assessing Real Option Value for Medical Technologies.

OBJECTIVES: This study aimed to provide recommendations for identifying and implementing real option value (ROV) calculations in value assessment. METHODS: We identified the primary mechanisms through which ROV can be created based on a theoretical framework for ROV, assessed approaches for predicting future innovations and improvements in health, and described the steps for estimating ROV in a cost-effectiveness analysis framework. RESULTS: The 3 primary mechanisms by which ROV can be created are when a current treatment (1) prolongs survival to increase the proportion of patients who can receive future innovations, (2) slows disease progression to increase patients' eligibility for future innovations, and (3) directly affects the efficacy of future innovations. We provide 5 recommendations for implementing ROV in value assessment. First, the decision to quantify ROV should be based on a qualitative evaluation of whether the treatment can enable greater benefits from future innovations. Second, ROV should be quantified in the same value assessment framework (eg, cost-effectiveness analysis using quality-adjusted life-year) as the conventional value. Third, method for quantifying ROV should consider data availability, rate of innovation, and sources of future health improvements. Fourth, ROV estimate should be presented alongside the conventional value as a separate element due to its inherently large uncertainty. Finally, generalizability of ROV estimate should be evaluated, and local data should be used when available. CONCLUSIONS: ROV can arise from a variety of mechanisms that should be considered before investing in an ROV analysis. Calculating ROV includes exploring different approaches for forecasting future innovations and future improvements in health.

A Scoping Review of the Use of Machine Learning in Health Economics and Outcomes Research: Part 2-Data From Nonwearables.

OBJECTIVES: Despite the increasing interest in applying machine learning (ML) methods in health economics and outcomes research (HEOR), stakeholders face uncertainties in when and how ML can be used. We reviewed the recent applications of ML in HEOR. METHODS: We searched PubMed for studies published between January 2020 and March 2021 and randomly chose 20% of the identified studies for the sake of manageability. Studies that were in HEOR and applied an ML technique were included. Studies related to wearable devices were excluded. We abstracted information on the ML applications, data types, and ML methods and analyzed it using descriptive statistics. RESULTS: We retrieved 805 articles, of which 161 (20%) were randomly chosen. Ninety-two of the random sample met the eligibility criteria. We found that ML was primarily used for predicting future events (86%) rather than current events (14%). The most common response variables were clinical events or disease incidence (42%) and treatment outcomes (22%). ML was less used to predict economic outcomes such as health resource utilization (16%) or costs (3%). Although electronic medical records (35%) were frequently used for model development, claims data were used less frequently (9%). Tree-based methods (eg, random forests and boosting) were the most commonly used ML methods (31%). CONCLUSIONS: The use of ML techniques in HEOR is growing rapidly, but there remain opportunities to apply them to predict economic outcomes, especially using claims databases, which could inform the development of cost-effectiveness models.

Association between having a family member with dementia and perceptions of dementia preventability.

BACKGROUND: One's experience with dementia may affect their perceptions about dementia preventability, which in turn could influence preventive health behaviors. We aimed to examine how having a family history of dementia and caregiving experience are associated with perceptions about and self-efficacy for dementia preventability. METHODS: Cross-sectional, self-administered survey. Participants reported whether they have had a family member with dementia and, among those who reported having a family member with dementia, whether they served as a caregiver. Outcomes were perceptions about the likelihood of dementia preventability, self-efficacy for dementia prevention, and benefits of specific dementia prevention strategies. Associations were assessed via partial proportional odds model for ordinal outcome variables and logistic regression for binary outcome variables. RESULTS: Of 1,575 respondents, 71% had a family member with dementia, of which 42% served as a caregiver. People with a family member with dementia were less likely to believe that dementia is preventable (aOR = 0.75, 95% CI: 0.58, 0.96) and had lower self-efficacy for dementia prevention (aOR = 0.71, 95% CI: 0.56, 0.90). The subgroup analysis among those with caregiving experience was consistent with the primary findings, showing less belief in the likelihood of dementia preventability (aOR = 0.69, 95% CI: 0.46, 1.03) and self-efficacy (aOR = 0.75, 95% CI: 0.56, 1.00). CONCLUSION: Having a family member with dementia is associated with unfavorable perceptions about dementia preventability. Incorporating family history of dementia into communication efforts about dementia risk reduction may help address potential barriers to preventive health behaviors.

Modeling the Ex Post Real Option Value in Metastatic Melanoma Using Real-World Data.

OBJECTIVES: Real option value (ROV) is created when a drug enables a patient to live long enough to benefit from a future innovation. Few studies have quantified ROV in the real world. We aimed to estimate the ex post ROV for ipilimumab in metastatic melanoma using real-world data (RWD). METHODS: We developed a framework for calculating ROV using RWD, accounting for the health gain in the standard therapy arm and the uptake of future innovations. A Markov model was developed to estimate the quality-adjusted life-years (QALYs) gained with ipilimumab compared with chemotherapy for patients with or without subsequent cancer immunotherapy (CIT). A nationwide electronic health record-derived, deidentified database was used to estimate survival and uptake of CIT. RESULTS: The incremental QALYs gained for ipilimumab compared with chemotherapy without subsequent CIT were 1.74. With subsequent CIT, the incremental QALYs compared with chemotherapy increased by 0.92, 0.60, 0.33, 0.18, 0.10, and 0.02 when CIT became available 0, 3, 6, 9, 12, and 24 months after the initiation of first-line treatment, respectively. The results were most sensitive to the survival benefit of ipilimumab, the survival benefit of subsequent CIT, and the uptake of CIT. CONCLUSIONS: This is the first study to estimate ex post ROV using RWD. The ex post ROV was between 1% and 54% of conventional value for patients who received a diagnosis within 2 years before CIT availability. Further studies are needed to understand ROV in other disease areas, particularly those with longer survival times.

Emergence of Transferable mcr-9 Gene-Carrying Colistin-Resistant Salmonella enterica Dessau ST14 Isolated from Retail Chicken Meat in Korea.

Colistin is an important antibiotic currently used to manage infections caused by multidrug-resistant pathogens in both humans and livestock animals. A new mobile colistin-resistance (mcr-9) gene was recently discovered; this discovery highlighted the need for rigorous monitoring of bacterial resistance against colistin. Salmonella is one of the major pathogens responsible for foodborne illnesses; however, there is minimal information regarding the presence of mcr genes in foodborne Salmonella strains. The aim of this study was to investigate the presence of mcr genes among 178 Salmonella strains isolated from chicken meat in Korea. Antimicrobial susceptibility was measured using the broth microdilution method. Bioinformatics characterization of colistin-resistant strains and genetic environment of the mcr-9 gene were analyzed using next-generation sequencing. Transferability of the mcr-9 carrying colistin-resistant Salmonella strain was tested using broth-mating conjugation. Thirteen of the 178 Salmonella isolates showed colistin resistance, but only one strain, Salmonella Dessau ST14 (KUFSE-SAL043) from a traditional chicken market in Korea, carried an mcr family gene, mcr-9. This strain also carried other acquired antimicrobial resistance genes such as blaTEM-1B, qnrS1, and aac(6')-Iaa. Only the IncX1 plasmid replicon type was detected in this strain. In the strain KUFSE-SAL043, the mcr-9 gene was located between two insertion sequences, IS903B and IS26, followed by the downstream regulatory genes qseB-like and qseC-like, which were located between IS1R and ΔIS1R. Conjugation tests revealed that the mcr-9 gene was successfully transferred to Escherichia coli J53 at a mean frequency of 2.03 × 10-7. This is the first report of a transferable mcr-9 gene in Salmonella isolated from chicken meat in Korea, highlighting the possibility of transfer of colistin resistance. Therefore, the wide use of colistin should be reconsidered, and a One Health perspective should be adopted to monitor the antimicrobial resistance of Enterobacteriaceae strains in humans, livestock, and the environment.

PPARß/δ agonist GW501516 inhibits TNFα-induced repression of adiponectin and insulin receptor in 3T3-L1 adipocytes.

Previous reports have shown that PPARß/δ agonists ameliorate insulin resistance associated with type 2 diabetes mellitus (T2DM). To determine the role of PPARß/δ in tumor necrosis factor α (TNFα)-mediated insulin resistance, we investigated expression levels of adiponectin and insulin receptor (IR) in response to treatment with the PPARß/δ agonist GW501516 with or without TNFα, a proinflammatory cytokine, in differentiated 3T3-L1 adipocytes. GW501516 induced adipocyte differentiation and the expression of adiponectin in a dose-dependent manner in differentiated adipocytes. TNFα treatment reduced adiponectin expression at the end of differentiation. This effect was reversed by GW501516 co-treatment with TNFα. TNFα treatment decreased adipogenic marker genes such as PPARγ, aP2, resistin, and GLUT4, and GW501516 reversed the effects of TNFα. GW501516 treatment increased the expression of insulin receptor and inhibited TNFα-mediated repression of insulin receptor. Our results showed that GW501516 abrogated TNFα-induced insulin resistance. In summary, our study demonstrated that the PPARß/δ agonist, GW501516 reversed TNFα-induced decreases in adipocyte differentiation and adiponectin expression, and improved insulin sensitivity by increasing the expression of insulin receptor. Therefore, PPARδ may be a promising therapeutic target for treatment of insulin resistance in patients with T2DM.

Enhanced sulfurization reaction of molybdenum using a thermal cracker for forming two-dimensional MoS2 layers.

We propose a method to fabricate two-dimensional (2D) molybdenum disulfide (MoS2) layers to overcome issues in typical fabrication processes by promoting the sulfurization reaction of molybdenum (Mo). A thin sputtered-Mo layer was sulfurized using a sulfur (S) thermal cracker to form 2D MoS2 layers. The effects of key process parameters such as cracking-zone temperature (TC-zone), thickness of the sputtered-Mo layer, and Ar pressure during deposition of the Mo layer were systematically investigated. The degree of thermal treatment of evaporated S vapor is controlled by varying TC-zone. The higher TC-zone enabled easy formation of thin MoS2 layers at a low substrate temperature of 250 °C due to the greatly enhanced sulfurization reaction. The thickness of the final MoS2 layers was controlled by changing the initial thickness of the sputtered-Mo film. Ultra-thin MoS2 film about 2-layers-thick was obtained by sulfurizing a 2 Å-thick Mo film. The chemical state of the MoS2 layers largely depended on the Ar pressure during the sputtering process of the initial Mo. Lower Ar pressure enhanced MoS2 formation due to more efficient substitution of the MoS2 phase for the MoO3 phase. By using the S thermal cracker, we demonstrate a method to easily fabricate 2D MoS2 layers, excluding some problematic issues such as toxic and expensive reactants, non-vacuum conditions susceptible to contamination, and high substrate temperature.

Light-soaking effects and capacitance profiling in Cu(In,Ga)Se2 thin-film solar cells with chemical-bath-deposited ZnS buffer layers.

We fabricated Cu(In,Ga)Se2 (CIGS) solar cells with chemical-bath deposited (CBD) ZnS buffer layers with different deposition times. The conversion efficiency and the fill factor of the CIGS solar cells reveal a strong dependence on the deposition time of CBD-ZnS films. In order to understand the detailed relationship between the heterojunction structure and the electronic properties of CIGS solar cells with different deposition times of CBD-ZnS films, capacitance-voltage (C-V) profiling measurements with additional laser illumination were performed. The light-soaking effects on CIGS solar cells with a CBD-ZnS buffer layer were investigated in detail using current density-voltage (J-V) and C-V measurements with several different lasers with different emission wavelengths. After light-soaking, the conversion efficiency changed significantly and the double diode feature in J-V curves disappeared. We explain that the major reason for the improvement of efficiency by light-soaking is due to the fact that negatively charged and highly defective vacancies in the CIGS absorber near the interface of CBD-ZnS/CIGS were formed and became neutral due to carriers generated by ultra-violet absorption in the buffer layer.

Health Care Applicability of a Patient-Centric Web Portal for Patients' Medication Experience.

BACKGROUND: With the advent of the patient-centered care paradigm, it is important to examine what patients' reports of medication experience (PROME) mean to patient care. PROME available through a Web portal provide information on medication treatment options and outcomes from the patient's perspective. Patients who find certain PROME compelling are likely to mention them at their physician visit, triggering a discussion between the patient and the physician. However, no studies have examined PROME's potential applicability to patient care. OBJECTIVE: This study aimed to examine older (≥50 years) adults' perceptions of the health care applicability of a hypothetical PROME Web portal. Specifically, this study investigated whether PROME would facilitate patient-physician communication, and identified the preferred reporting items and the trusted sponsors of such a PROME Web portal. METHODS: We used a cross-sectional, self-administered, 5-point Likert scale survey to examine participants' perceptions of a hypothetical PROME Web portal that compared PROME for 5 common antihypertensive medications. Between August and December 2013, we recruited 300 members of 7 seniors' centers in a metropolitan area of a southeastern state of the United States to participate in the survey. RESULTS: An overwhelming majority of study participants (243/300, 81.0%) had a favorable perception of PROME's health care applicability. They were mostly positive that PROME would facilitate patient-physician communication, except for the perception that physicians would be upset by the mention of PROME (n=133, 44.3%). Further, 85.7% (n=257) of participants considered the PROME information trustworthy, and 72.0% (n=216) were willing to participate by reporting their own medication experiences. Study participants wanted the PROME Web portal to report the number of reviews, star ratings, and individual comments concerning different medication attributes such as side effects (224/809, 27.7%), cost (168/809, 20.8%), and effectiveness (153/809, 18.9%). Finally, the PROME Web portal sponsorship was important to participants, with the most trusted sponsor being academic institutions (120/400, 30.0%). CONCLUSIONS: PROME, if well compiled through Web portals, have the potential to facilitate patient-physician communication.

p300 cooperates with c-Jun and PARP-1 at the p300 binding site to activate RhoB transcription in NSC126188-mediated apoptosis.

The anti-cancer agent NSC126188 induces apoptosis of stomach carcinoma NUGC-3 cells by inducing RhoB expression. Here, we present that the p300 binding site in the RhoB promoter is crucial for the binding of p300 and its partner transcription factors to activate RhoB transcription in NSC126188-mediated apoptosis. NSC126188 increased expression of p300 and c-Jun. Conversely, knockdown of p300 decreased RhoB expression in the presence of NSC126188. We found that poly(ADP-ribose) polymerase-1 (PARP-1) was associated with the p300 binding site and that PARP-1 knockdown inhibited NSC126188-mediated RhoB expression. In the cells treated with NSC126188, p300, PARP-1, and c-Jun interacted and bound the p300 binding site. Furthermore, chromatin immunoprecipitation (ChIP) analysis revealed strong p300 binding and weak c-Jun binding at the p300 binding site of RhoB promoter in cells treated with NSC126188. We also demonstrated that c-Jun played a crucial role in p300 binding. However, PARP-1 did not directly bind the p300 binding site, suggesting a bridging role between p300 and c-Jun. Electrophoretic mobility shift assays demonstrated a complex comprising p300/c-Jun/PARP-1 that bound wild type, but not a mutated, p300 binding site. In addition, overexpression of p300, PARP-1, or c-Jun dramatically enhanced RhoB promoter activity when it contained the wild type sequence but not mutated sequences, indicating the crucial role of the p300 binding site in NSC126188-induced transcription of RhoB. Taken together, these data suggest that p300 is recruited and cooperates with c-Jun and PARP-1 at the p300 binding site to activate RhoB transcription during NSC126188-mediated apoptosis.

Estriol blunts postprandial blood glucose rise in male rats through regulating intestinal glucose transporters.

Despite increased total food intake in healthy, late-stage pregnant women, their peak postprandial blood sugar levels are normally much lower than the levels seen in healthy nonpregnant women. In this study, we sought to determine whether estriol (E3), an endogenous estrogen predominantly produced during human pregnancy, contributes to the regulation of the postprandial blood glucose level in healthy normal rats. In vivo studies using rats showed that E3 blunted the speed and magnitude of the blood glucose rise following oral glucose administration, but it did not appear to affect the total amount of glucose absorbed. E3 also did not affect insulin secretion, but it significantly reduced the rate of intestinal glucose transport compared with vehicle-treated animals. Consistent with this finding, expression of the sodium-dependent glucose transporter 1 and 2 was significantly downregulated by E3 treatment in the brush-border membrane and basolateral membrane, respectively, of enterocytes. Most of the observed in vivo effects were noticeably stronger with E3 than with 17ß-estradiol. Using differentiated human Caco-2 enterocyte monolayer culture as an in vitro model, we confirmed that E3 at physiologically relevant concentrations could directly inhibit glucose uptake via suppression of glucose transporter 2 expression, whereas 17ß-estradiol did not have a similar effect. Collectively, these data showed that E3 can blunt the postprandial glycemic surge in rats through modulating the level of intestinal glucose transporters.

Design, synthesis and docking study of 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives as inhibitors of protein tyrosine phosphatase 1B.

A series of novel 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives was designed, and synthesized based on our previous studies. Also their activities were evaluated as competitive inhibitors of protein tyrosine phosphatase 1B (PTP1B). Compounds 6d-6g, 7b, 7c, 7e, 7j, 7k, 7m, 14b and 14e-14f showed potent inhibitory effects against PTP1B, and compound 7e, the most potent among the series, had an IC50 of 4.6 µM. Also a Surflex-Dock docking model of 7e was studied. Compound 7e showed a negative binding energy of -7.35 kcal/mol and a high affinity to PTP1B residues (Gly220, Ala217, Arg221, Asp181, Ser216, Cys215, Phe182, Gln262 and Ile219) in the active sites, indicating that it may stabilize the open form and generate tighter binding to the catalytic sites of PTP1B.

Photooxidation driven formation of Fe-Au linked ferrocene-based single-molecule junctions.

Metal-metal contacts, though not yet widely realized, may provide exciting opportunities to serve as tunable and functional interfaces in single-molecule devices. One of the simplest components which might facilitate such binding interactions is the ferrocene group. Notably, direct bonds between the ferrocene iron center and metals such as Pd or Co have been demonstrated in molecular complexes comprising coordinating ligands attached to the cyclopentadienyl rings. Here, we demonstrate that ferrocene-based single-molecule devices with Fe-Au interfacial contact geometries form at room temperature in the absence of supporting coordinating ligands. Applying a photoredox reaction, we propose that ferrocene only functions effectively as a contact group when oxidized, binding to gold through a formal Fe3+ center. This observation is further supported by a series of control measurements and density functional theory calculations. Our findings extend the scope of junction contact chemistries beyond those involving main group elements, lay the foundation for light switchable ferrocene-based single-molecule devices, and highlight new potential mechanistic function(s) of unsubstituted ferrocenium groups in synthetic processes.

Genetic and virulence characteristics of hybrid Shiga toxin-producing and atypical enteropathogenic Escherichia coli strains isolated in South Korea.

Introduction: The predominant hybrid pathogenic E. coli, enterohemorrhagic E. coli (EHEC), combines characteristics of Shiga toxin-producing E. coli (STEC) and enteropathogenic E. coli (EPEC), contributing to global outbreaks with severe symptoms including fatal consequences. Since EHEC infection was designated as a notifiable disease in 2000 in South Korea, around 2000 cases have been reported, averaging approximately 90 cases annually. Aim: In this work, genome-based characteristic analysis and cell-based assay of hybrid STEC/aEPEC strains isolated from livestock feces, animal source foods, and water in South Korea was performed. Methods: To identify the virulence and antimicrobial resistance genes, determining the phylogenetic position of hybrid STEC/aEPEC strains isolated in South Korea, a combination of real-time PCR and whole-genome sequencing (WGS) was used. Additionally, to assess the virulence of the hybrid strains and compare them with genomic characterization, we performed a cell cytotoxicity and invasion assays. Results: The hybrid STEC/aEPEC strains harbored stx and eae genes, encoding Shiga toxins and E. coli attachment/effacement related protein of STEC and EPEC, respectively. Furthermore, all hybrid strains harbored plasmid-carried enterohemolysin(ehxCABD), a key virulence factor in prevalent pathogenic E. coli infections, such as diarrheal disease and hemolytic-uremic syndrome (HUS). Genome-wide phylogenetic analysis revealed a close association between all hybrid strains and specific EPEC strains, suggesting the potential acquisition of Stx phages during STEC/aEPEC hybrid formation. Some hybrid strains showed cytotoxic activity against HeLa cells and invasive properties against epithelial cells. Notably, all STEC/aEPEC hybrids with sequence type (ST) 1,034 (n = 11) exhibited higher invasiveness than those with E2348/69. This highlights the importance of investigating potential correlations between STs and virulence characteristics of E. coli hybrid strains. Conclusion: Through genome-based characterization, we confirmed that the hybrid STEC/aEPEC strains are likely EPEC strains that have acquired STEC virulence genes via phage. Furthermore, our results emphasize the potential increased danger to humans posed by hybrid STEC/aEPEC strains isolated in South Korea, containing both stx and eaeA, compared to STEC or EPEC alone.

Anti-diabetic effect of amorphastilbol through PPARα/γ dual activation in db/db mice.

Peroxisome proliferator-activated receptors (PPARs) have been considered as desirable targets for metabolic syndrome treatments, even though their specific agonists have several side effects, including body weight gain, edema, and tissue failure. The effects of amorphastilbol (APH) on glucose- and lipid metabolism were investigated with in vitro 3T3-L1 adipocyte systems and in vivo db/db mice model. APH selectively stimulates the transcriptional activities of both PPARα and PPARγ, which are able to enhance fatty acid oxidation and glucose utilization. Furthermore, APH improves glucose and lipid impairment in db/db mice. More importantly, there are no significant side effects, such as weight gain or hepatomegaly, in APH-treated animals, implying that APH do not adversely affect liver or lipid metabolism. All our data suggest that APH can be used as potential therapeutic agents against type 2 diabetes and related metabolic disorders, including obesity, by enhancing glucose and lipid metabolism.

How does cumulative evidence from older adult-specific trials influence clinical practice? A difference-in-differences analysis in early-stage breast cancer.

BACKGROUND: Despite increasing focus on conducting cancer clinical trials in older adults, it is unclear whether such evidence influences practice patterns. We aimed to estimate the impact of cumulative evidence from older adult-specific trial results from the CALGB 9343 and PRIME II trials that found post-lumpectomy irradiation has little benefit among older adults with early-stage breast cancer (ESBC). METHODS: Patients diagnosed with ESBC between 2000 and 2018 were identified from the SEER registry data. We examined the incremental immediate effect, incremental average yearly effect, and cumulative effect of a series of CALGB 9343 and PRIME II results on the utilization level of post-lumpectomy irradiation. We conducted difference-in-differences analyses, comparing those aged 70 or older vs. <65 years old. RESULTS: The initial 5-year CALGB 9343 results in 2004 led to a significant immediate (-0.038, 95% CI: -0.064, -0.012) and average yearly decrease (-0.008, 95% CI: -0.013, -0.003) in the probability of irradiation use among those aged 70 or older compared to those below 65 years of age. 11-year CALGB 9343 results in 2010 significantly accelerated the average yearly effect by 1.7 percentage points (95% CI: -0.030, -0.004). The other later results did not significantly change the time trend. The cumulative effect of all results between 2004 and 2018 was -26.3 percentage points (95% CI: -0.29, -0.24). CONCLUSION: Cumulative evidence from older adult-specific trials in ESBC led to decreasing use of irradiation over time among elderly patients. The rate of decrease after the initial results was accelerated by long-term follow-up results.

Can we predict trial failure among older adult-specific clinical trials using trial-level factors?

INTRODUCTION: Conducting older adult-specific clinical trials can help overcome the lack of clinical evidence for older adults due to their underrepresentation in clinical trials. Understanding factors contributing to the successful completion of such trials can help trial sponsors and researchers prioritize studies and optimize study design. We aimed to develop a model that predicts trial failure among older adult-specific cancer clinical trials using trial-level factors. MATERIALS AND METHODS: We identified phase 2-4 interventional cancer clinical trials that ended between 2008 and 2019 and had the minimum age limit of 60 years old or older using Aggregate Analysis of ClinicalTrials.gov data. We defined trial failure as closed early for reasons other than interim results or toxicity or completed with a sample of <85% of the targeted size. Candidate trial-level predictors were identified from a literature review. We evaluated eight types of machine learning algorithms to find the best model. Model fitting and testing were performed using 5-fold nested cross-validation. We evaluated the model performance using the area under receiver operating characteristic curve (AUROC). RESULTS: Of 209 older adult-specific clinical trials, 87 were failed trials per the definition of trial failure. The model with the highest AUROC in the validation set was the least absolute shrinkage and selection operator (AUROC in the test set = 0.70; 95% confidence interval [CI]: 0.53, 0.86). Trial-level factors included in the best model were the study sponsor, the number of participating centers, the number of modalities, the level of restriction on performance score, study location, the number of arms, life expectancy restriction, and the number of target size. Among these factors, the number of centers (odds ratio [OR] = 0.83, 95% CI: 0.71, 0.94), study being in non-US only vs. US only (OR = 0.32, 95% CI: 0.12, 0.82), and life expectancy restriction (OR = 2.17, 95% CI: 1.04, 4.73) were significantly associated with the trial failure. DISCUSSION: We identified trial-level factors predictive of trial failure among older adult-specific clinical trials and developed a prediction model that can help estimate the risk of failure before a study is conducted. The study findings could aid in the design and prioritization of future older adult-specific clinical trials.