Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials.

Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal ß -oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. SIGNIFICANCE STATEMENT: This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.

TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.

A novel bluetongue virus serotype 2 strain isolated from a farmed Florida white-tailed deer (Odocoileus virginianus) arose from reassortment of gene segments derived from co-circulating serotypes in the Southeastern USA.

Bluetongue disease is a reportable animal disease that affects wild and farmed ruminants, including white-tailed deer (WTD). This report documents the clinical findings, ancillary diagnostics, and genomic characterization of a novel reassortant bluetongue virus serotype 2 (BTV-2) strain isolated from a dead Florida farmed WTD in 2022. Our analyses support that this BTV-2 strain likely stemmed from the acquisition of genome segments from co-circulating BTV strains in Florida and Louisiana. In addition, our analyses also indicate that genetically uncharacterized BTV strains may be circulating in the Southeastern USA; however, the identity and reassortant status of these BTV strains cannot be determined based on the VP2 and VP5 genome sequences. Hence, continued surveillance based on complete genome characterization is needed to understand the genetic diversity of BTV strains in this region and the potential threat they may pose to the health of deer and other ruminants.

Effectiveness of BNT162b2 COVID-19 primary series vaccination in children aged 5-17 years in the United States: a cohort study.

BACKGROUND: COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study's objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. METHODS: This cohort study identified children aged 5-17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. RESULTS: There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36-40%]) and hospital/ED-diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56-65%]). VE estimates were lowest among children 5-11 years and during the Omicron-variant era. CONCLUSIONS: Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED-diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. REGISTRATION: The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf ).

Incidence, prevalence, and medical costs of pressure injuries in Taiwan from 2001 to 2015: Results of a retrospective cohort study.

AIMS AND OBJECTIVES: This study aims to analyse the trends in the incidence, prevalence and medical costs of pressure injuries (PIs) among genders in Taiwan. BACKGROUND: The treatment of PIs is complex and costly, often leading to complications and increased mortality. This issue significantly impacts healthcare quality and incurs substantial medical and social costs, warranting attention. METHODS: A retrospective cohort study was conducted using data from Taiwan's National Health Insurance Database to obtain and calculate the incidence, prevalence, and medical costs of PIs in the country between 2001 and 2015 as well as to analyse high-risk groups and the medical care utilisation of patients following the STROBE reporting guidelines. RESULTS: Between 2001 and 2015, 15,327 incident case of PIs were diagnosed. During the study period, the prevalence rate of PIs per 100,000 population rose from 26.3 to 189.6, with approximately 11.5%-16.3% of patients undergoing surgical debridement. The PIs prevalence rate increased by 7.2-fold, and hospitalisation costs accounted for 91.7%-96.0% of the total medical costs. Patients with older age, comorbidities, poorer financial status and lower education levels were found to be likely to develop PIs. These predisposing factors differed between males and females. The prevalence of PIs was higher in patients ≥75 years old than in patients from other age groups. Moreover, PI-related medical expenses have been increasing annually. CONCLUSIONS: In Taiwan, the rising incidence of PIs is driving up medical costs. Effective care and prevention of PIs necessitate a comprehensive plan from the entire healthcare system. RELEVANCE TO CLINICAL PRACTICE: This research fills a gap in the available data on the incidence, prevalence, and medical costs of PIs in Taiwan and Asia. PATIENT OR PUBLIC CONTRIBUTION: The findings can be used to help develop clinical guidelines for preventive education and treatment of PIs.

Anesthesia nurses' self-perceived roles, competencies, and attitudes toward patient safety culture.

AIM: This study aimed to explore anesthesia nurses' (ANs) perceptions of roles, competencies, and attitudes towards patient safety culture, along with predictive factors for patient safety culture. INTRODUCTION: The 2021 guidelines from the International Council of Nurses aim to ensure global access to safe surgical and anesthesia care by 2030. However, in Taiwan, the roles and competencies of ANs are still evolving. Many have a limited understanding, posing potential risks to patient safety. METHODS: A cross-sectional study was conducted, involving ANs from five hospitals within a healthcare foundation. ANs' self-perceived roles and competencies were assessed using a structured questionnaire based on the CanMEDS framework from the International Federation of Nurse Anesthetists. Additionally, data were collected using the Chinese version of the Safety Attitudes Questionnaire. Reporting followed the STROBE guideline. RESULTS: Among 200 ANs, a consensus emerged favored all roles and competencies, with positive attitudes toward patient safety culture. Remarkably, self-perceived competencies, working in regional hospitals, and working in medical centers significantly predicted ANs' attitude toward patient safety culture. DISCUSSION: The study results can assist ANs in gaining a deeper understanding of their roles and competencies. Considering predictive factors, strengthening ANs' competencies may contribute to enhancing patient safety culture. CONCLUSION AND IMPLICATION FOR NURSING AND HEALTH POLICY: Our results informed nursing leaders and policymakers in Taiwan and other countries regarding ANs' perceptions of roles and competencies. Nurse managers could consider the specific factors influencing ANs' attitudes toward patient safety culture and make great efforts to develop strategies aimed at enhancing their competencies.

Exploring the world of active play: A comprehensive review of global surveillance and monitoring of active play based on the global matrix data.

A valid assessment tool that measures active play is not yet available due to the sporadic and spontaneous nature of play, as well as the potential differences in how active play is understood and measured across different age groups, cultures, and contexts. The purpose of this review was to identify the scope and gaps in the measurement of active play based on data gathered from 68 countries that participated in the Global Matrix (GM) initiative, led by the Active Healthy Kids Global Alliance (AHKGA). GM is the global-level, biennial evaluation system of physical activity related behaviors among children and youth, including the Active Play indicator, and the sources of influence using letter grades (ranging between "A" and "F"). Based on the identified scope and gaps, this study offers recommendations for future research dedicated to the measurement/surveillance of active play. Out of the 68 countries involved in the previous GM (2014-22), 55% of the grades remained unassigned due to insufficient data on the Active Play indicator. The high number of unassigned grades, combined with the absence of valid measurement tool, highlight a need for a standardized measurement tool for improved global data generation of active play among children and youth. Our findings emphasize the need to address challenges in measuring active play. This review offers future considerations, research recommendations specific to the GM initiative, and two sets of age- and location-specific (indoor and outdoor settings) questionnaire items along with guidelines for its use. Together, these elements provide a roadmap for guiding future research and evaluation efforts on active play.

Field test of quantum key distribution with high key creation efficiency.

Quantum key distribution (QKD) promises unconditional security for communication. However, the random choices of the measurement basis in QKD usually result in low key creation efficiency. This drawback is overcome in the differential-phase-shift QKD, provided that each photon can be prepared in a large number of time slots with a proper waveform. In this work we develop a miniature room-temperature 1550-nm single-photon source to generate narrowband single photon in 50 time slots with a nearly optimal waveform for achieving unity key creation efficiency. By utilizing these single photons in the field test, we demonstrate the differential-phase-shift QKD with a key creation efficiency of 97%. Our work shows that the practical QKD can benefit from the narrowband single photons with controllable waveforms.

Report card grades on physical activity for children and adolescents from 18 Asian countries: Patterns, trends, gaps, and future recommendations.

Background: Physical inactivity is a persistent and worsening population health concern in Asia. Led by the Active Healthy Kids Global Alliance, Global Matrix (GM) initiative provides an opportunity to explore how regional and cultural differences across 18 Asian countries relate to physical activity (PA) participation among children and adolescents. Objectives: To synthesize evidence from the GM2.0 to GM4.0 (2016-2022) in Asian countries. Methods: Report Card grades on behavioral/individual and sources of influence indicators were reported from 18 Asian countries. Letter grades were converted into numerical values for quantitative analyses. Based on this, cross-sectional and longitudinal analyses were conducted to investigate patterns and trends. Qualitative evidence synthesis was performed based on Report Card grades and published papers to identify gaps and suggest future recommendations. Results: In total, 18 countries provided grades for at least one round of GM, 12 countries provided grades for at least two rounds, and seven countries provided grades for all three GMs. Of possible grades, 72.8%, 69.2%, and 76.9% of the grades were assigned from GM 2.0 to GM 4.0, respectively. In terms of the Report Card grades, there was a slight decrease in behavioral/individual indicators from "D+" in GM 2.0 to "D-" in GM 3.0 but this reverted to "D" in GM 4.0. For the sources of influence, a "C" grade was given in all three rounds of GM. Longitudinal observation of seven Asian countries that provided grades in all three rounds of GM revealed that grades are generally stable for all indicators with some country-specific fluctuations. In future GM initiatives and research, considerations should be made to provide more accurate and rich data and to better understand contextual challenges in evaluating certain indicators such as Active Transportation, Active Play, and Physical Fitness in particular. Further, macro level factors such as socioeconomic/cultural disparities and gender-specific barriers, ideology, or climate change should also be proactively considered in future research as these factors are becoming increasingly relevant to indicators of GM and United Nation's Sustainable Development Goals. Conclusions: Participation from Asian countries in GM has increased over the years, which demonstrates the region's enthusiasm, capacity, and support for global PA promotion efforts. The efforts to promote a physically active lifestyle among children and adolescents should be a collective interest and priority of the Asia region based on the gaps identified in this paper.

Excessive O-GlcNAcylation Causes Heart Failure and Sudden Death.

BACKGROUND: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O-GlcNAcylation (the attachment of O-linked ß-N-acetylglucosamine [O-GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Failing myocardium is marked by increased O-GlcNAcylation, but whether excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure is unknown. METHODS: We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAcylation independent of pathologic stress. RESULTS: We found that OGT transgenic hearts showed increased O-GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O-GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O-GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc-mediated cardiac pathology. CONCLUSIONS: Our data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is beneficial against pressure overload-induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.

Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia.

BACKGROUND: Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat. RESULTS: A total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events. CONCLUSIONS: Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia. Registration: URL: https://www.isrctn.com; Unique identifier ISRCTN16123934.

Rapid, inexpensive fabrication of electrophoretic microdevices for fluorescence detection.

The laser print, cut, and laminate (PCL) method for microfluidic device fabrication can be leveraged for rapid and inexpensive prototyping of electrophoretic microchips useful for optimizing separation conditions. The rapid prototyping capability allows the evaluation of fluidic architecture, applied fields, reagent concentrations, and sieving matrix, all within the context of using fluorescence-compatible substrates. Cyclic olefin copolymer and toner-coated polyethylene terephthalate (tPeT) were utilized with the PCL technique and bonding methods optimized to improve device durability during electrophoresis. A series of separation channel designs and centrifugation conditions that provided successful loading of sieving polymer in less than 3 min was described. Separation of a 400-base DNA sizing ladder provided calculated base resolution between 3 and 4 bases, a greater than 18-fold improvement over separations on similar substrates. Finally, the accuracy and precision capabilities of these devices were demonstrated by separating and sizing DNA fragments of 147 and 167 bases as 148.62 ± 2 and 166.48 ± 3 bases, respectively.

A deep learning-based method for the diagnosis of vertebral fractures on spine MRI: retrospective training and validation of ResNet.

PURPOSE: To improve the performance of less experienced clinicians in the diagnosis of benign and malignant spinal fracture on MRI, we applied the ResNet50 algorithm to develop a decision support system. METHODS: A total of 190 patients, 50 with malignant and 140 with benign fractures, were studied. The visual diagnosis was made by one senior MSK radiologist, one fourth-year resident, and one first-year resident. The MSK radiologist also gave the binary score for 15 qualitative imaging features. Deep learning was implemented using ResNet50, using one abnormal spinal segment selected from each patient as input. The T1W and T2W images of the lesion slice and its two neighboring slices were considered. The diagnostic performance was evaluated using tenfold cross-validation. RESULTS: The overall reading accuracy was 98, 96, and 66% for the senior MSK radiologist, fourth-year resident, and first-year resident, respectively. Of the 15 imaging features, 10 showed a significant difference between benign and malignant groups with p < = 0.001. The accuracy achieved by using the ResNet50 deep learning model for the identified abnormal vertebral segment was 92%. Compared to the first-year resident's reading, the model improved the sensitivity from 78 to 94% (p < 0.001) and the specificity from 61 to 91% (p < 0.001). CONCLUSION: Our deep learning-based model may provide information to assist less experienced clinicians in the diagnosis of spinal fractures on MRI. Other findings away from the vertebral body need to be considered to improve the model, and further investigation is required to generalize our findings to real-world settings.

Computerized tool and interdisciplinary care for older patients with delirium in the emergency department: a novel model in Taiwan.

AIMS: A computerized tool and interdisciplinary care were implemented to develop a novel model for older patients with delirium in the emergency department (ED). METHODS: We developed a computerized tool using a delirium triage screen and brief confusion assessment in the hospital information system, performed education for the healthcare providers, and developed a continuous care protocol. Comparisons for outcomes between pre- and post-intervention periods were performed. RESULTS: Compared with the pre-intervention period, patients in the post-intervention period had shorter hospitalization stay, lower expenditure of hospitalization, more likely to return home, lower ED revisits of ≤ 3 days, re-hospitalization of ≤ 14 days, and mortality of ≤ 1 month. All mentioned differences were not statistically significant. CONCLUSIONS: A novel model was successfully developed for delirium management in older patients in the ED. Outcome differences were not significant; however, the result is promising, which gives us an important reference in the future.

Guillain-Barré Syndrome After High-Dose Influenza Vaccine Administration in the United States, 2018-2019 Season.

BACKGROUND: The Vaccine Safety Datalink (VSD) identified a statistical signal for an increased risk of Guillain-Barré syndrome (GBS) in days 1-42 after 2018-2019 high-dose influenza vaccine (IIV3-HD) administration. We evaluated the signal using Medicare. METHODS: We conducted early- and end-of-season claims-based self-controlled risk interval analyses among Medicare beneficiaries ages ≥65 years, using days 8-21 and 1-42 postvaccination as risk windows and days 43-84 as control window. The VSD conducted chart-confirmed analyses. RESULTS: Among 7 453 690 IIV3-HD vaccinations, we did not detect a statistically significant increased GBS risk for either the 8- to 21-day (odds ratio [OR], 1.85; 95% confidence interval [CI], 0.99-3.44) or 1- to 42-day (OR, 1.31; 95% CI, 0.78-2.18) risk windows. The findings from the end-of-season analyses were fully consistent with the early-season analyses for both the 8- to 21-day (OR, 1.64; 95% CI, 0.92-2.91) and 1- to 42-day (OR, 1.12; 95% CI, 0.70-1.79) risk windows. The VSD's chart-confirmed analysis, involving 646 996 IIV3-HD vaccinations, with 1 case each in the risk and control windows, yielded a relative risk of 1.00 (95% CI, 0.06-15.99). CONCLUSIONS: The Medicare analyses did not exclude an association between IIV3-HD and GBS, but it determined that, if such a risk existed, it was similar in magnitude to prior seasons. Chart-confirmed VSD results did not confirm an increased risk of GBS.

MitoTox: a comprehensive mitochondrial toxicity database.

BACKGROUND: Mitochondria play essential roles in regulating cellular functions. Some drug treatments and molecular interventions have been reported to have off-target effects damaging mitochondria and causing severe side effects. The development of a database for the management of mitochondrial toxicity-related molecules and their targets is important for further analyses. RESULTS: To correlate chemical, biological and mechanistic information on clinically relevant mitochondria-related toxicity, a comprehensive mitochondrial toxicity database (MitoTox) was developed. MitoTox is an electronic repository that integrates comprehensive information about mitochondria-related toxins and their targets. Information and data related to mitochondrial toxicity originate from various sources, including scientific journals and other electronic databases. These resources were manually verified and extracted into MitoTox. The database currently contains over 1400 small-molecule compounds, 870 mitochondrial targets, and more than 4100  mitochondrial toxin-target associations. Each MitoTox data record contains over 30 fields, including biochemical properties, therapeutic classification, target proteins, toxicological data, mechanistic information, clinical side effects, and references. CONCLUSIONS: MitoTox provides a fully searchable database with links to references and other databases. Potential applications of MitoTox include toxicity classification, prediction, reference and education. MitoTox is available online at http://www.mitotox.org .

Trends in Erythropoiesis-stimulating agent use and blood transfusions for chemotherapy-induced anemia throughout FDA's risk evaluation and mitigation strategy lifecycle.

PURPOSE: Erythropoiesis-stimulating agents (ESAs), indicated for treating some patients with chemotherapy-induced anemia (CIA), may increase the risk of tumor progression and mortality. FDA required a Risk Evaluation and Mitigation Strategy (REMS) to mitigate these risks. We assessed REMS impact on ESA administration and red blood cell (RBC) transfusion as surrogate metrics for REMS effectiveness. METHODS: Retrospective cohort study including data from January 1, 2006 to December 31, 2018 for beneficiaries ≥65 years enrolled in Centers for Medicare & Medicaid Services (CMS) Medicare Parts A/B with a cancer diagnosis; patients with other indications for ESA use were excluded. Study time was divided into five periods demarcated by issuance of CMS National Coverage Determination (NCD) (Pre-NCD, Pre-REMS) and REMS milestones (Grace Period, REMS, post-REMS). Study outcomes were monthly proportion of chemotherapy episodes (CTEs) with concomitant ESA administration, with post-CTE ESA administration, and with RBC transfusions. RESULTS: Of 1 778 855 beneficiaries treated with CT, 308742 received concomitant ESA for CIA. The proportion of CTEs with concomitant and post-CTE ESA administration decreased Pre-REMS (9.0 percentage points [pp] and 3.5 pp, respectively). There were no significant post-REMS changes in the proportion of CTEs with concomitant (0.0 pp) and post-CTE ESA administration (0.1 pp). Fluctuation in RBC transfusions was <4 pp throughout the study period. CONCLUSIONS: Medicare beneficiaries showed a substantive decrease in ESA administration after NCD, with minimal impact by the REMS and its removal. Small changes in RBC transfusion over the study period were likely due to a national secular trend.

Transcriptomic and Metabolic Network Analysis of Metabolic Reprogramming and IGF-1 Modulation in SCA3 Transgenic Mice.

Spinocerebellar ataxia type 3 (SCA3) is a genetic neurodegenerative disease for which a cure is still needed. Growth hormone (GH) therapy has shown positive effects on the exercise behavior of mice with cerebellar atrophy, retains more Purkinje cells, and exhibits less DNA damage after GH intervention. Insulin-like growth factor 1 (IGF-1) is the downstream mediator of GH that participates in signaling and metabolic regulation for cell growth and modulation pathways, including SCA3-affected pathways. However, the underlying therapeutic mechanisms of GH or IGF-1 in SCA3 are not fully understood. In the present study, tissue-specific genome-scale metabolic network models for SCA3 transgenic mice were proposed based on RNA-seq. An integrative transcriptomic and metabolic network analysis of a SCA3 transgenic mouse model revealed that metabolic signaling pathways were activated to compensate for the metabolic remodeling caused by SCA3 genetic modifications. The effect of IGF-1 intervention on the pathology and balance of SCA3 disease was also explored. IGF-1 has been shown to invoke signaling pathways and improve mitochondrial function and glycolysis pathways to restore cellular functions. As one of the downregulated factors in SCA3 transgenic mice, IGF-1 could be a potential biomarker and therapeutic target.

Moscatilin Inhibits Metastatic Behavior of Human Hepatocellular Carcinoma Cells: A Crucial Role of uPA Suppression via Akt/NF-κB-Dependent Pathway.

Hepatocellular carcinoma (HCC) frequently shows early invasion into blood vessels as well as intrahepatic metastasis. Innovations of novel small-molecule agents to block HCC invasion and subsequent metastasis are urgently needed. Moscatilin is a bibenzyl derivative extracted from the stems of a traditional Chinese medicine, orchid Dendrobium loddigesii. Although moscatilin has been reported to suppress tumor angiogenesis and growth, the anti-metastatic property of moscatilin has not been elucidated. The present results revealed that moscatilin inhibited metastatic behavior of HCC cells without cytotoxic fashion in highly invasive human HCC cell lines. Furthermore, moscatilin significantly suppressed the activity of urokinase plasminogen activator (uPA), but not matrix metalloproteinase (MMP)-2 and MMP-9. Interestingly, moscatilin-suppressed uPA activity was through down-regulation the protein level of uPA, and did not impair the uPA receptor and uPA inhibitory molecule (PAI-1) expressions. Meanwhile, the mRNA expression of uPA was inhibited via moscatilin in a concentration-dependent manner. In addition, the expression of phosphorylated Akt, rather than ERK1/2, was inhibited by moscatilin treatment. The expression of phosphor-IκBα, and -p65, as well as κB-luciferase activity were also repressed after moscatilin treatment. Transfection of constitutively active Akt (Myr-Akt) obviously restored the moscatilin-inhibited the activation of NF-κB and uPA, and cancer invasion in HCC cells. Taken together, these results suggest that moscatilin impedes HCC invasion and uPA expression through the Akt/NF-κB signaling pathway. Moscatilin might serve as a potential anti-metastatic agent against the disease progression of human HCC.

HMDB 4.0: the human metabolome database for 2018.

The Human Metabolome Database or HMDB (www.hmdb.ca) is a web-enabled metabolomic database containing comprehensive information about human metabolites along with their biological roles, physiological concentrations, disease associations, chemical reactions, metabolic pathways, and reference spectra. First described in 2007, the HMDB is now considered the standard metabolomic resource for human metabolic studies. Over the past decade the HMDB has continued to grow and evolve in response to emerging needs for metabolomics researchers and continuing changes in web standards. This year's update, HMDB 4.0, represents the most significant upgrade to the database in its history. For instance, the number of fully annotated metabolites has increased by nearly threefold, the number of experimental spectra has grown by almost fourfold and the number of illustrated metabolic pathways has grown by a factor of almost 60. Significant improvements have also been made to the HMDB's chemical taxonomy, chemical ontology, spectral viewing, and spectral/text searching tools. A great deal of brand new data has also been added to HMDB 4.0. This includes large quantities of predicted MS/MS and GC-MS reference spectral data as well as predicted (physiologically feasible) metabolite structures to facilitate novel metabolite identification. Additional information on metabolite-SNP interactions and the influence of drugs on metabolite levels (pharmacometabolomics) has also been added. Many other important improvements in the content, the interface, and the performance of the HMDB website have been made and these should greatly enhance its ease of use and its potential applications in nutrition, biochemistry, clinical chemistry, clinical genetics, medicine, and metabolomics science.