Biochimie. 2023 Apr 14:S0300-9084(23)00086-X. doi: 10.1016/j.biochi.2023.04.009. Online ahead of print.

ABSTRACT

Type 2 diabetes mellitus (DM) poses a major burden for the treatment and control of tuberculosis (TB). Characterization of the underlying metabolic perturbations in DM patients with TB infection would yield insights into the pathophysiology of TB-DM, thus potentially leading to improvements in TB treatment. In this study, a multimodal metabolomics and lipidomics workflow was applied to investigate plasma metabolic profiles of patients with TB and TB-DM. Significantly different biological processes and biomarkers in TB-DM vs. TB were identified using a data-driven, knowledge-based framework. Changes in metabolic and signaling pathways related to carbohydrate and amino acid metabolism were mainly captured by amide HILIC column metabolomics analysis, while perturbations in lipid metabolism were identified by the C18 metabolomics and lipidomics analysis. Compared to TB, TB-DM exhibited elevated levels of bile acids and molecules related to carbohydrate metabolism, as well as the depletion of glutamine, retinol, lysophosphatidylcholine, and phosphatidylcholine. Moreover, arachidonic acid metabolism was determined as a potential important factor in the interaction between TB and DM pathophysiology. In a correlation network of the significantly altered molecules, among the central nodes, chenodeoxycholic acid was robustly associated with TB and DM. Fatty acid (22:4) was a component of all significant modules. In conclusion, the integration of multimodal metabolomics and lipidomics provides a thorough picture of the metabolic changes associated with TB-DM. The results obtained from this comprehensive profiling of TB patients with DM advance the current understanding of DM comorbidity in TB infection and contribute to the development of more effective treatment.

PMID:37062470 | DOI:10.1016/j.biochi.2023.04.009

J Sci Med Sport. 2023 Mar;26(3):181-182. doi: 10.1016/j.jsams.2023.02.007. Epub 2023 Mar 6.

NO ABSTRACT

PMID:37061291 | DOI:10.1016/j.jsams.2023.02.007

Clin Gastroenterol Hepatol. 2023 Apr 13:S1542-3565(23)00270-7. doi: 10.1016/j.cgh.2023.03.044. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor-(TNF)α antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1*05 genotype and risk of immunogenicity with TNFα antagonists.

METHODS: Through a systematic review till 14 July, 2022, we identified studies in patients with IMIDs treated with TNFα antagonists, which reported the risk of immunogenicity and/or secondary loss of response in patients with HLA-DQA1*05 variants. Primary outcome was risk of immunogenicity. We performed random effects meta-analysis and used GRADE to appraise certainty of evidence.

RESULTS: On meta-analysis of 13 studies (3,756 patients, median follow-up, 12m; 41% with variants), HLA-DQA1*05 variants were associated with 75% higher risk of immunogenicity compared to wild type [relative risk (RR), 1.75 (95% CI, 1.37-2.25)] with considerable heterogeneity (I2=62%) (low certainty evidence). Positive and negative predictive value of HLA-DQA1*05 variants for predicting immunogenicity was 30% and 80%, respectively. Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs- and TNFα antagonist-type, modified this association. Patients with HLA-DQA1*05 variants experienced 2.2-fold higher risk of secondary loss of response [six cohorts; RR, 2.24 (1.67-3.00), I2=0%] (moderate certainty evidence).

CONCLUSION: Variants in HLA-DQA1*05 are associated with an increased risk in immunogenicity and secondary loss of response in patients with IMIDs treated with TNFα antagonists. However, the positive and negative predictive value is moderate, and decisions on concomitant use of IMMs to prevent immunogenicity should be individualized based on all factors that influence drug clearance.

PMID:37061107 | DOI:10.1016/j.cgh.2023.03.044

Expert Rev Clin Pharmacol. 2023 Apr 15. doi: 10.1080/17512433.2023.2203381. Online ahead of print.

NO ABSTRACT

PMID:37060346 | DOI:10.1080/17512433.2023.2203381

Redox Biol. 2023 Apr 5;62:102696. doi: 10.1016/j.redox.2023.102696. Online ahead of print.

ABSTRACT

As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE-/- mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.

PMID:37058999 | DOI:10.1016/j.redox.2023.102696

Circ Res. 2023 Apr 14. doi: 10.1161/CIRCRESAHA.122.321833. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiac contractile function requires high energy from mitochondria, and Ca2+ from the sarcoplasmic reticulum (SR). Via local Ca2+ transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca2+ overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering.

METHODS: We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype.

RESULTS: Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive β-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury.

CONCLUSIONS: We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca2+/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca2+ signaling.

PMID:37057625 | DOI:10.1161/CIRCRESAHA.122.321833

Frontline Gastroenterol. 2022 Nov 17;14(3):258-262. doi: 10.1136/flgastro-2022-102342. eCollection 2023.

NO ABSTRACT

PMID:37056322 | PMC:PMC10086732 | DOI:10.1136/flgastro-2022-102342

Eur J Surg Oncol. 2023 Apr 13:S0748-7983(23)00438-9. doi: 10.1016/j.ejso.2023.04.001. Online ahead of print.

ABSTRACT

Despite the wide reportage of prognostic factors for glioblastoma (GBM), it is difficult to determine how these factors interact to affect patients' survival. To determine the combination of prognostic factors, we retrospectively analyzed the clinic data of 248 IDH wild-type GBM patients and built a novel prediction model. The survival variables of patients were identified via univariate and multivariate analyses. In addition, the score prediction models were constructed by combining classification and regression tree (CART) analysis with Cox regression analysis. Finally, the prediction model was internally validated using the bootstrap method. Patients were followed for a median of 34.4 (interquartile range, 26.1-46.0) months. Multivariate analysis identified gross total resection (GTR) (HR 0.50, 95% CI: 0.38-0.67), unopened ventricles (HR 0.75 [0.57-0.99]), and MGMT methylation (HR 0.56 [0.41-0.76]) as favorable independent prognostic factors for PFS. GTR (HR 0.67 [0.49-0.92]), unopened ventricles (HR 0.60 [0.44-0.82]), and MGMT methylation (HR 0.54 [0.38-0.76]) were favorable independent prognostic factors for OS. In the process of building the model, we incorporated GTR, ventricular opening, MGMT methylation status, and age. The model had six and five terminal nodules in PFS and OS respectively. We grouped terminal nodes with similar hazard ratios together to form three sub-groups with different PFS and OS (P < 0.001). After the internal verification of bootstrap method, the model had a good fitting and calibration. GTR, unopened ventricles, and MGMT methylation were independently associated with more satisfactory survival. The novel score prediction model which we construct can provide a prognostic reference for GBM.

PMID:37076410 | DOI:10.1016/j.ejso.2023.04.001

Food Sci Nutr. 2023 Jan 13;11(4):1657-1670. doi: 10.1002/fsn3.3217. eCollection 2023 Apr.

ABSTRACT

Antioxidants are compounds that inhibit the oxidation of other molecules and protect the body from the effects of free radicals, produced either by normal cell metabolism or as an effect of pollution and exposure to other external factors and are responsible for premature aging and play a role in cardiovascular disease. degenerative diseases such as cataracts, Alzheimer's disease, and cancer. While many antioxidants are found in nature, others are obtained in synthetic form and reduce oxidative stress in organisms. This review highlights the pharmacological relevance of antioxidants in fruits, plants, and other natural sources and their beneficial effect on human health through the analysis and in-depth discussion of studies that included phytochemistry and their pharmacological effects. The information obtained for this review was collected from several scientific databases (ScienceDirect, TRIP database, PubMed/Medline, Scopus, Web of Science), professional websites, and traditional medicine books. Current pharmacological studies and evidence have shown that the various natural antioxidants present in some fruits, seeds, foods, and natural products have different health-promoting effects. Adopting functional foods with high antioxidant potential will improve the effective and affordable management of free radical diseases while avoiding the toxicities and unwanted side effects caused by conventional medication.

PMID:37051367 | PMC:PMC10084981 | DOI:10.1002/fsn3.3217

Molecules. 2023 Mar 31;28(7):3128. doi: 10.3390/molecules28073128.

ABSTRACT

Herein, the antitumor activity of a novel synthetic analog with 5,8-quinolinedione scaffold, diethyl (2-(2-chlorophenyl)-4,9-dioxo-4,9-dihydrofuro [3,2-g]quinolin-3-yl)phosphonate (AJ-418) was investigated on two breast cancer cell lines. This analog was selected from a small library of synthetic quinolinediones on the basis of its strong antiproliferative activity against MCF-7 and MDA-MB-231 cells and 4-5-fold lower cytotoxicity towards healthy MCF-10A cells. The morphology of MCF-7 and MDA-MB-231 cancer cells treated with AJ-418 changed drastically, while non-tumorigenic MCF-10A cells remained unaffected. In MCF-7 cells, after 24 h incubation, the increased number of apoptotic cells coincided with a decrease in proliferation and cell viability. The 24 h treatment of MDA-MB-231 cells with the tested compound reduced their cell viability and proliferation rate; however, a significant pro-apoptotic effect was visible only after longer incubation times (48 h and 72 h). Then, the maximum tolerated dose (MTD) of compound AJ-418 in C3H mice after subcutaneous administration was determined to be 160 mg/kg, showing that this analog was well tolerated and can be further evaluated to assess its potential therapeutic effect in tumor-bearing mice.

PMID:37049894 | DOI:10.3390/molecules28073128

JACC Cardiovasc Interv. 2023 Apr 10;16(7):826-828. doi: 10.1016/j.jcin.2023.02.008.

NO ABSTRACT

PMID:37045503 | DOI:10.1016/j.jcin.2023.02.008

Cell Rep Med. 2023 Apr 11:101021. doi: 10.1016/j.xcrm.2023.101021. Online ahead of print.

ABSTRACT

Swen et al.1 examine the utility of multi-gene pharmacogenetic testing in a large multi-national cohort. They show fewer adverse drug reactions among patients receiving testing and prescribing recommendations based on genotype results compared with those receiving usual care.

PMID:37084734 | DOI:10.1016/j.xcrm.2023.101021

Drug Metab Dispos. 2023 Apr 11:DMD-AR-2023-001310. doi: 10.1124/dmd.123.001310. Online ahead of print.

ABSTRACT

Single-nucleotide substitutions of human flavin-containing monooxygenase 3 (FMO3) identified in the whole-genome sequences of the updated Japanese population reference panel (now containing 38,000 subjects) were investigated. In this study, 2 stop codon mutations, 2 frameshifts, and 43 amino-acid-substituted FMO3 variants were identified. Among these 47 variants, 1 stop codon mutation, 1 frameshift, and 24 substituted variants were already recorded in the National Center for Biotechnology Information database. Functionally impaired FMO3 variants are known to be associated with the metabolic disorder trimethylaminuria; consequently, the enzymatic activities of the 43 substituted FMO3 variants were investigated. Twenty-seven recombinant FMO3 variants expressed in bacterial membranes had similar activities toward trimethylamine N-oxygenation (~75-125%) to that of wild-type FMO3 (98 min-1). However, 6 recombinant FMO3 variants (Arg51Gly, Val283Ala, Asp286His, Val382Ala, Arg387His, and Phe451Leu) had moderately decreased (≈50%) activities toward trimethylamine N-oxygenation, and 10 recombinant FMO3 variants (Gly11Asp, Gly39Val, Met66Lys, Asn80Lys, Val151Glu, Gly193Arg, Arg387Cys, Thr453Pro, Leu457Trp, and Met497Arg) showed severely decreased FMO3 catalytic activity (<10%). Because of the known deleterious effects of FMO3 C-terminal stop codons, the four truncated FMO3 variants (Val187SerfsTer25, Arg238Ter, Lys416SerfsTer72, and Gln427Ter) were suspected to be inactive with respect to trimethylamine N-oxygenation. The FMO3 p.Gly11Asp and p.Gly193Arg variants were located within the conserved sequences of flavin adenine dinucleotide (positions 9-14) and NADPH (positions 191-196) binding sites, which are important for FMO3 catalytic function. Whole-genome sequence data and kinetic analyses revealed that 20 of the 47 nonsense or missense FMO3 variants had moderately or severely impaired activity toward N-oxygenation of trimethylaminuria. Significance Statement The number of single-nucleotide substitutions in human FMO3 recorded in the expanded Japanese population reference panel database was updated. One novel stop mutation, FMO3 p.Gln427Ter; one novel frameshift (p.Lys416SerfsTer72); and 19 novel amino-acid-substituted FMO3 variants were identified, along with p.Arg238Ter, p.Val187SerfsTer25, and 24 amino-acid-substituted variants already recorded with individual rs numbers. Recombinant FMO3 Gly11Asp, Gly39Val, Met66Lys, Asn80Lys, Val151Glu, Gly193Arg, Arg387Cys, Thr453Pro, Leu457Trp, and Met497Arg variants showed severely decreased FMO3 catalytic activity, possibly associated with the metabolic disorder trimethylaminuria.

PMID:37041084 | DOI:10.1124/dmd.123.001310

Pediatr Pulmonol. 2023 Apr 10. doi: 10.1002/ppul.26412. Online ahead of print.

ABSTRACT

INTRODUCTION: Reports of neuropsychiatric symptoms proximal to cystic fibrosis transmembrane conductance regulator (CFTR) modulator initiation are emerging, but their prevalence and management remain poorly characterized.

METHODS: Retrospective chart review was used to categorize symptom trajectories of all adults at a single CF Center who initiated elexacaftor/tezacaftor/ivacaftor (ETI) before March 2022 and subsequently had ≥1 outpatient visit with the consulting CF psychiatrist. For those who developed neuropsychiatric symptoms probably related to ETI and modified treatment in response, the strategy resulting in greatest improvement with acceptable physical course and tolerability was identified. Ratings were made by a psychiatrist not involved in clinical care.

RESULTS: Of 148 adults initiating ETI, 31 were psychiatrically evaluated, 16 of whom developed new/worsening and unexpected neuropsychiatric symptoms probably related to ETI, including neurocognitive (word finding, brain fog, memory, attention/concentration), insomnia, depression, anxiety, fatigue/low energy, mania/hypomania, other distress. This group had higher maximum lifetime Generalized Anxiety Disorder-7 scores (14.42 ± 0.96; p = 0.05) than those with improved, unchanged, or worsening/possibly related symptoms (N = 15; 9.9 ± 1.82). Treatment strategies resulting in much/very much improvement included pharmacologic interventions, psychotherapy, and dose reduction/discontinuing ETI.

CONCLUSIONS: Although many people initiating ETI experience improved physical and mental health and quality of life, a subset report worsening neurocognition, mood, and anxiety. As novel therapies are developed, ascertaining and evaluating neuropsychiatric symptoms in clinical and research settings is advisable. Larger studies are needed to characterize prevalence, course, and risk factors (e.g., age, gender, clinical status, pharmacokinetics/pharmacogenomics, drug-drug interactions) for neuropsychiatric adverse events related to CFTR modulators and guide effective management.

PMID:37036050 | DOI:10.1002/ppul.26412

JHEP Rep. 2023 Feb 26;5(5):100716. doi: 10.1016/j.jhepr.2023.100716. eCollection 2023 May.

ABSTRACT

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is emerging as the most common cause of liver disease. For evaluation of therapies, there is a pressing need to identify non-invasive, mechanism-based biomarkers. A pro-fibrotic process relevant to human NASH involves a pathway in which a transcriptional regulator called TAZ (WWTR1) in hepatocytes induces the secretion of pro-fibrotic Indian hedgehog (IHH). We therefore reasoned that circulating IHH may be a useful mechanism-based marker to assess changes in NASH fibrosis.

METHODS: Circulating IHH was assessed in wild-type and hepatocyte-TAZ-silenced NASH mice and in three separate cohorts of patients with mild-moderate NASH.

RESULTS: Circulating IHH was elevated in mice with diet-induced NASH compared with chow-fed mice or with NASH mice in which hepatocyte TAZ was silenced, which is an effective means to decrease NASH fibrosis. In patients with fatty liver disease with or without NASH, NASH fibrosis was associated with increased concentrations of circulating IHH.

CONCLUSIONS: The results of these analyses support further investigation to determine whether circulating IHH may be useful as a mechanism-based indicator of target engagement in anticipated future clinical trials testing NASH fibrosis therapies that block the IHH pathway.

IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is a common cause of liver disease. Circulating biomarkers that reflect liver fibrosis in NASH would be very useful to evaluate therapies. One mechanism of NASH fibrosis with potential as a therapeutic target involves a liver-secreted protein called Indian hedgehog (IHH). We report that circulating levels of IHH in experimental and human NASH associates with NASH and NASH-associated liver fibrosis, providing the premise for further investigation into using circulating IHH to evaluate anticipated future NASH therapies that block the IHH pathway in liver.

PMID:37035456 | PMC:PMC10074197 | DOI:10.1016/j.jhepr.2023.100716

Clin Pharmacol Ther. 2023 Apr 9. doi: 10.1002/cpt.2903. Online ahead of print.

ABSTRACT

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (SNRIs; i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19 and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A which do not support their clinical use in antidepressant prescribing.

PMID:37032427 | DOI:10.1002/cpt.2903

Behav Brain Res. 2023 Apr 6:114423. doi: 10.1016/j.bbr.2023.114423. Online ahead of print.

ABSTRACT

Persicaria minor (P. minor) is a herbal plant with many uses in food, perfume, and the medical industry. P. minor extract contains flavonoids with antioxidant and anticholinesterase capacity, which could enhance cognitive functions. P. minor extract has been proven to enhance memory. However, its role in an animal model of chronic cerebral hypoperfusion (CCH), which resembles human vascular dementia, has yet to be explored. Therefore, the present study investigates the effects of chronic (14 days) administration of aqueous P. minor extract on different stages of learning and memory processes and the metabolic pathways involved in the chronic cerebral hypoperfused rats induced by the permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery. Chronic treatment of P. minor extract at doses of 200 and 300mg/kg, enhanced recognition memory of the PBOCCA rats. P. minor extract (200mg/kg) was also found to restore the spatial memory impairment induced by CCH. A high dose (300mg/kg) of the P. minor extract significantly increased the expression of both ACh and GABA neurotransmitters in the hippocampus. Further, distinctive metabolite profiles were observed in rats with different treatments. Three major pathways involved in the cognitive enhancement mechanism of P. minor were identified. The present findings demonstrated an improving effect of P. minor extract on memory in the CCH rat model, suggesting that P. minor extract could be a potential treatment for vascular dementia and Alzheimer's patients. P. minor is believed to improve cognitive deficits by regulating pathways involved in retinol, histidine, pentose, glucuronate, and CoA metabolism.

PMID:37030545 | DOI:10.1016/j.bbr.2023.114423

Small. 2023 Apr 8:e2300395. doi: 10.1002/smll.202300395. Online ahead of print.

ABSTRACT

Phenytoin (PHT) is a first-line antiepileptic drug in clinics, which could decrease neuronal bioelectric activity by blocking the voltage-operated sodium channels. However, the intrinsically low blood-brain-barrier (BBB)-crossing capability of PHT and upregulated expression level of the efflux transporter p-glycoprotein (P-gp) coded by the gene Abcb1 in epileptic neurons limit its efficacy in vivo. Herein, a nanointegrated strategy to overcome PHT resistance mechanisms for enhanced antiepileptic efficacy is reported. Specifically, PHT is first incorporated into calcium phosphate (CaP) nanoparticles through biomineralization, followed by the surface modification of the PEGylated BBB-penetrating TAT peptide. The CaP@PHT-PEG-TAT nanoformulation could effectively cross the BBB to be taken in by epileptic neurons. Afterward, the acidic lysosomal environment would trigger their complete degradation to release Ca2+ and PHT into the cytosol. Ca2+ ions would inhibit mitochondrial oxidative phosphorylation to reverse cellular hypoxia to block hypoxia-inducible factor-1α (Hif1α)-Abcb1-axis, as well as disrupt adenosine triphosphate generation, leading to simultaneous suppression of the expression and drug efflux capacity of P-gp to enhance PHT retention. This study offers an approach for effective therapeutic intervention against drug-resistant epilepsy.

PMID:37029709 | DOI:10.1002/smll.202300395

Oncologist. 2023 Apr 7:oyad050. doi: 10.1093/oncolo/oyad050. Online ahead of print.

ABSTRACT

BACKGROUND: Severe chemotherapy-related toxicities are frequent among older patients. The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) and the Cancer and Aging Research Group Study (CARG) score were both developed to predict these events.

PATIENTS AND METHODS: The objective of this study was to evaluate the scores' predictive performance in a prospective cohort, which included patients aged 70 years and older referred for a geriatric assessment prior to chemotherapy for a solid tumor. The main endpoints were grades 3/4/5 toxicities for the CARG score and grades 4/5 hematologic toxicities and grades 3/4/5 non-hematologic toxicities for the CRASH score.

RESULTS: A total of 248 patients were included, of which 150 (61%) and 126 (51%) experienced at least one severe adverse event as defined respectively in CARG and CRASH studies. The incidence of adverse events was not significantly greater in the intermediate and high-risk CARG groups than in the low-risk group (odds ratio (OR) [95% CI] = 0.3 [0.1-1.4] (P = .1) and 0.4 [0.1-1.7], respectively). The area under curve (AUC) was 0.55. Similarly, the incidence of severe toxicities was no greater in the intermediate-low, intermediate-high, and high-risk CRASH groups than in the low-risk CRASH group (OR [95%CI] = 1 [0.3-3.6], 1 [0.3-3.4], and 1.5 [0.3-8.1], respectively). The AUC was 0.52. The type of cancer, performance status, comorbidities, body mass index, and MAX2 index were independently associated with grades 3/4/5 toxicities.

CONCLUSION: In an external cohort of older patients referred for a pretherapeutic GA, the CARG and CRASH scores were poor predictors of the risk of chemotherapy severe toxicities.

PMID:37027521 | DOI:10.1093/oncolo/oyad050

Heliyon. 2023 Mar 28;9(4):e14968. doi: 10.1016/j.heliyon.2023.e14968. eCollection 2023 Apr.

ABSTRACT

OBJECTIVES: To describe hospital spending and length of stay for mental disorders in Hunan, China.

METHODS: We extracted hospital care data for Hunan province from the Chinese National Health Statistics Network Reporting System. Patients with mental disorders (ICD-10 codes: F00 to F99) as the principal diagnosis and hospitalized between January 1, 2017 and December 31, 2019 were included. We retrieved information on age, sex, number of comorbidities, diagnosis, level of hospital, hospital costs, date of admission and discharge, length of stay (LOS), and method of payment of eligible participants. Spending at the provincial level, and spending and LOS at the individual level were described. Quantile regression and linear regression were conducted to investigate factors for hospital cost and LOS for major mental disorders.

RESULTS: The 2019 annual spending on mental disorders in Hunan province was 160 million US dollars, and 71.7% was paid by insurance. The annual spending on schizophrenia was 84 million dollars, contributing to a primary burden of mental disorders. The median spending for mental disorders was $1,085 per patient, and the median hospital stay was 22 days. The study identified several significant factors associated with hospital cost and LOS, including age, sex, comorbidity, and level of the hospital. In particular, a higher level of the hospital was associated with a higher hospital spending but a shorter LOS. Women with schizophrenia had a comparable hospital spending but a significantly shorter LOS than men with schizophrenia.

CONCLUSION: Hospitalization spending for patients with mental disorders is substantial. Schizophrenia is the major burden of hospitalization for mental disorders. While patients treated at a higher level of hospital had higher spending, they stayed shorter in these hospitals.

PMID:37025795 | PMC:PMC10070638 | DOI:10.1016/j.heliyon.2023.e14968