ABSTRACT
BACKGROUND: There is limited evaluation of approaches to identify patients with new onset bipolar affective disorder (BPAD) when using administrative datasets. METHODS: Using the Massachusetts All-Payer Claims Database (APCD), we identified individuals with a 2016 diagnosis of bipolar disorder with mania and examined patterns of psychiatric and medical care over the preceding 48â¯months. RESULTS: Among 4806 individuals aged 15-35â¯years with a 2016 BPAD with mania diagnosis, 3066 had 48â¯months of historical APCD data, and of those, 75â¯% involved information from ≥2 payors. After excluding individuals with historical BPAD or mania diagnoses, there were 583 individuals whose 2016 BPAD with mania diagnosis appeared to be new (i.e., 34 new diagnoses per 100,000 individuals aged 15-35â¯years). Most individuals received medical care, e.g., 98â¯% had outpatient visits, 76â¯% had Emergency Department (ED) visits, and 50â¯% had mental health-related ED visits during the 48â¯months prior to their first mania diagnosis. One-third (37.2â¯%) had a depressive episode before their initial BPAD with mania diagnosis. LIMITATIONS: Study was conducted in one state among insured individuals. We used administrative data, which permits evaluation of large populations but lacks rigorous, well-validated claims-based definitions for BPAD. There could be diagnostic uncertainty during illness course, and clinicians may differ in their diagnostic thresholds. CONCLUSIONS: Careful examination of multiple years of patient history spanning all payors is essential for identifying new onset BPAD diagnoses presenting with mania, which in turn is critical to estimating population rates of new disease and understanding the early course of disease.
ABSTRACT
BACKGROUND: Federally Qualified Health Centers (FQHCs) are a critical source of care for medically underserved populations and often serve as medical homes for individuals with serious mental illness (SMI). Many FQHCs provide mental health services and could facilitate access to mental health treatment within and outside of FQHCs. This study compared mental health care utilization and acute care events for adult Medicaid enrollees with SMI who receive care at Federally Qualified Health Centers (FQHCs) vs. other settings. METHODS: This study used the 2015-2016 Massachusetts All-Payer Claims Database to examine outpatient mental health care and acute care events for 32,330 Medicaid adults, ages 18-64 and with major depressive, bipolar, or schizophrenia spectrum disorders (SSD), who resided in FQHC service areas and received care from FQHCs vs. other settings in 2015. Multivariable linear regressions assessed associations between receiving care at FQHCs and outpatient mental health visits, psychotropic medication fills, and acute care events in 2016. RESULTS: There were 8,887 (27.5%) adults in the study population (N = 32,330) who had at least one FQHC visit in 2015. Those who received care at FQHCs were more likely to have outpatient mental health visits (73.3% vs. 71.2%) and psychotropic medication fills (73.2% vs. 69.0%, both p < .05), including antidepressants among those with depressive disorders and antipsychotics among those with SSD. They were more likely to have ED visits (74.0% vs. 68.7%), but less likely to be hospitalized (27.8% vs. 31.9%, both p < .05). However, there was no significant difference in the likelihood of having an acute psychiatric hospitalization (9.5% vs. 9.8%, p = .35). CONCLUSIONS: Among Medicaid enrollees with SMIs who had access to care at FQHCs, those receiving care at FQHCs were more likely to have outpatient mental health visits and psychotropic medication fills, with lower rates of hospitalization, suggesting potentially improved quality of outpatient care. Higher ED visit rates among those receiving care at FQHCs warrant additional investigation.
Subject(s)
Medicaid , Mental Disorders , Mental Health Services , Humans , United States , Adult , Medicaid/statistics & numerical data , Female , Male , Middle Aged , Mental Health Services/statistics & numerical data , Adolescent , Young Adult , Mental Disorders/therapy , Massachusetts , Quality of Health Care/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical data , Health Services Accessibility/statistics & numerical dataABSTRACT
Neuroinflammation is one of the main mechanisms involved in the progression of neurodegenerative diseases (NDs), and microglial activation is the main feature of neuroinflammation. Polaprezinc (Pol), a chelator of L-carnosine and zinc, is widely used as a clinical drug for gastric ulcers. However, its potential effects on NDs remain unexplored. In LPS-induced BV-2 microglia, we found that Pol reduced the generation of NO and ROS and revealed inhibited expression of iNOS, COX-2, and inflammatory factors such as IL-6, TNF-α, and 1L-1ß by Pol using qRT-PCR and Western blotting. These effects were found to be associated with the suppression of the NF-κB signaling pathway. Moreover, we evaluated the potential synergistic effects of aspergillusidone G (Asp G) when combined with Pol. Remarkably, co-treatment with low doses of Asp G enhanced the NO inhibition by Pol from approximately 30% to 80% in LPS-induced BV2 microglia, indicating a synergistic anti-inflammatory effect. A bioinformatics analysis suggested that the synergistic mechanism of Asp G and Pol might be attributed to several targets, including NFκB1, NRF2, ABL1, TLR4, and PPARα. These findings highlight the anti-neuroinflammatory properties of Pol and its enhanced efficacy when combined with Asp G, proposing a novel therapeutic strategy for managing neuroinflammation in NDs.
Subject(s)
Anti-Inflammatory Agents , Carnosine , Lipopolysaccharides , Microglia , NF-kappa B , Organometallic Compounds , Microglia/drug effects , Microglia/metabolism , Animals , Mice , Lipopolysaccharides/pharmacology , Carnosine/pharmacology , Carnosine/analogs & derivatives , Anti-Inflammatory Agents/pharmacology , NF-kappa B/metabolism , Organometallic Compounds/pharmacology , Zinc Compounds/pharmacology , Computational Biology , Cell Line , Signal Transduction/drug effects , Neuroinflammatory Diseases/drug therapy , Drug Synergism , Nitric Oxide/metabolism , Reactive Oxygen Species/metabolism , Nitric Oxide Synthase Type II/metabolismABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by neuroinflammation, for which gut dysbiosis may be implicated. Our previous study showed that treatment with Pseudostellaria heterophylla aqueous extract and one of its cyclopeptides, heterophyllin B, attenuate memory deficits via immunomodulation and neurite regeneration. However, whether Pseudostellaria heterophylla polysaccharide (PH-PS) exerts neuroprotective effects against AD and its underlying mechanisms remain unclear. The infrared spectrum, molecular weight, and carbohydrate composition of the PH-PS were determined. The results showed that PH-PS (Mw 8.771 kDa) was composed of glucose (57.78 %), galactose (41.52 %), and arabinose (0.70 %). PH-PS treatment ameliorated learning and spatial memory deficits, reduced amyloid ß build-up, and suppressed reactive glia and astrocytes in 5 × FAD mice. 16S rRNA sequencing further showed that PH-PS remodelled the intestinal flora composition by promoting probiotic microbiota, such as Lactobacillus, Muribaculum, Monoglobus, and [Eubacterium]_siraeum_group, and suppressing inflammation-related UCG-009 and Blautia. Additionally, PH-PS restored intestinal barrier function; ameliorated peripheral inflammation by reducing the secretion of inflammatory cytokines, thereby converting M1 microglia and A1 astrocyte toward beneficial M2 and A2 phenotypes; and contributed to Aß plaques clearance by upregulation of insulin degradation enzyme and neprilysin. Collectively, our findings demonstrate that PH-PS may prevent the progression of AD via modulation of the gut microbiota and regulation of glial polarisation, which could provide evidence to design a potential diet therapy for preventing or curing AD.
Subject(s)
Alzheimer Disease , Brain , Gastrointestinal Microbiome , Polysaccharides , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Gastrointestinal Microbiome/drug effects , Polysaccharides/pharmacology , Polysaccharides/chemistry , Mice , Brain/drug effects , Brain/metabolism , Amyloid beta-Peptides/metabolism , Disease Models, Animal , Juglandaceae/chemistry , Male , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistryABSTRACT
BACKGROUND: Sleep disorders, depression, and Alzheimer's disease (AD) are extensively reported as comorbidity. Although neuroinflammation triggered by microglial phenotype M1 activation, leading to neurotransmitter dysfunction and Aß aggregation, is considered as the leading cause of depression and AD, whether and how sub-chronic or chronic sleep deprivation (SD) contribute to the onset and development of these diseases remains unclear. METHODS: Memory and depression-like behaviors were evaluated in both SDs, and then circadian markers, glial cell phenotype polarization, cytokines, depression-related neurotransmitters, and AD-related gene/protein expressions were measured by qRT-PCR, enzyme-linked immunosorbent assay, high-performance liquid chromatography, and western-blotting respectively. RESULTS: Both SDs induced give-up behavior and anhedonia and increased circadian marker period circadian regulator 2 (PER2) expression, which were much worse in chronic than in the sub-chronic SD group, while brain and muscle ARNT-like protein-1 only decreased in the chronic-SD. Furthermore, increased microglial M1 and astrocyte A1 expression and proinflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α was observed in both SDs, which were more significant in chronic SD. Similarly, decreased norepinephrine and 5-hydroxytryptamine/5-hydroxyindoleacetic acid ratio were more significant, which corresponds to the worse depression-like behavior in chronic than sub-chronic-SD. With regard to AD, increased amyloid precursor protein (APP) and soluble (s)-APPß and decreased sAPPα in both SDs were more significant in the chronic. However, sAPPα/sAPPß ratio was only decreased in chronic SD. CONCLUSION: These findings suggest that both SDs induce depression-like changes by increasing PER2, leading to neuroinflammation and neurotransmitter dysfunction. However, only chronic SD induced memory impairment likely due to severer circadian disruption, higher neuroinflammation, and dysregulation of APP metabolism.
Subject(s)
Depression , Sleep Deprivation , Animals , Male , Mice , Sleep Deprivation/metabolism , Sleep Deprivation/complications , Depression/metabolism , Behavior, Animal/physiology , Neuroglia/metabolism , Phenotype , Neuroinflammatory Diseases/metabolism , Cytokines/metabolism , Mice, Inbred C57BL , Disease Models, Animal , Alzheimer Disease/metabolism , Microglia/metabolism , Anhedonia/physiology , Astrocytes/metabolismABSTRACT
Ten azaphilones including one pair of new epimers and three new ones, penineulones A-E (1-5) with the same structural core of angular deflectin, were obtained from a deep-sea derived Penicillium sp. SCSIO41030 fermented on a liquid medium. Their structures including absolute configurations were elucidated using chiral-phase HPLC analysis, extensive NMR spectroscopic and HRESIMS data, ECD and NMR calculations, and by comparing NMR data with literature data. Biological assays showed that the azaphilones possessed no antitumor and anti-viral (HSV-1/2) activities at concentrations of 5.0 µM and 20 µM, respectively. In addition, azaphilones 8 and 9 showed neuroprotective effects against Aß25-35-induced neurotoxicity in primary cultured cortical neurons at a concentration of 10 µM. Azaphilones 8 and 9 dramatically promoted axonal regrowth against Aß25-35-induced axonal atrophy. Our study indicated that azaphilones could be promising lead compounds for neuroprotection.
Subject(s)
Benzopyrans , Neuroprotective Agents , Penicillium , Penicillium/chemistry , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/isolation & purification , Benzopyrans/pharmacology , Benzopyrans/chemistry , Benzopyrans/isolation & purification , Animals , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/pharmacology , Pigments, Biological/pharmacology , Pigments, Biological/chemistry , Pigments, Biological/isolation & purification , Humans , Neurons/drug effects , Peptide Fragments/pharmacology , Peptide Fragments/chemistry , Molecular StructureABSTRACT
Fungal linear polyketides, such as α-pyrones with a 6-alkenyl chain, have been a rich source of biologically active compounds. Two new (1 and 2) and four known (3-6) 6-alkenylpyrone polyketides were isolated from a marine-derived strain of the fungus Arthrinium arundinis. Their structures were determined based on extensive spectroscopic analysis. The biosynthetic gene cluster (alt) for alternapyrones was identified from A. arundinis ZSDS-F3 and validated by heterologous expression in Aspergillus nidulans A1145 ΔSTΔEM, which revealed that the cytochrome P450 monooxygenase Alt2' could convert the methyl group 26-CH3 to a carboxyl group to produce 4 from 3. Another cytochrome P450 monooxygenase, Alt3', catalyzed successive hydroxylation, epoxidation, and oxidation steps to produce 1, 2, 5, and 6 from 4. Alternapyrone G (1) not only suppressed M1 polarization in lipopolysaccharide (LPS)-stimulated BV2 microglia but also stimulated dendrite regeneration and neuronal survival after Aß treatment, suggesting alternapyrone G may be utilized as a privileged scaffold for Alzheimer's disease drug discovery.
Subject(s)
Lipopolysaccharides , Neuroprotective Agents , Pyrones , Pyrones/pharmacology , Pyrones/chemistry , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Molecular Structure , Lipopolysaccharides/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Marine Biology , Microglia/drug effects , Microglia/metabolism , Ascomycota/chemistry , Polyketides/pharmacology , Polyketides/chemistry , Polyketides/isolation & purification , Aspergillus nidulans , Mice , Multigene Family , Cytochrome P-450 Enzyme System/metabolismABSTRACT
Importance: The Medicare Part D Low Income Subsidy (LIS) program provides millions of beneficiaries with drug plan premium and cost-sharing assistance. The extent to which LIS recipients experience subsidy losses with annual redetermination cycles and the resulting associations with prescription drug affordability and use are unknown. Objective: To examine how frequently annual LIS benefits are lost among Medicare Part D beneficiaries and how this is associated with prescription drug use and out-of-pocket costs. Design, Setting, and Participants: In this cohort study of Medicare Part D beneficiaries from 2007 to 2018, annual changes in LIS recipients among those automatically deemed eligible (eg, due to dual eligibility for Medicare and Medicaid) and nondeemed beneficiaries who must apply for LIS benefits were analyzed using Medicare enrollment and Part D event data. Subsidy losses were classified in 4 groups: temporary losses (<1 year); extended losses (≥1 year); subsidy reductions (change to partial LIS); and disenrollment from Medicare Part D after subsidy loss. Temporary losses could more likely represent subsidy losses among eligible beneficiaries. Multinomial logit models were used to examine associations between beneficiary characteristics and subsidy loss; linear regression models were used to compare changes in prescription drug cost and use in the months after subsidy losses vs before. Analyses were conducted between November 2022 and November 2023. Exposure: Subsidy loss at the beginning of each year among subsidy recipients in December of the prior year. Main Outcomes and Measures: The main outcomes were out-of-pocket costs and prescription drug fills overall and for 4 classes: antidiabetes, antilipid, antidepressant, and antipsychotic drugs. Results: In 2008, 731â¯070 full LIS beneficiaries (17%) were not deemed automatically eligible (39% were aged <65 years; 59% were female). Nearly all beneficiaries deemed automatically eligible (≥99%) retained the subsidy annually from 2007 to 2018, compared with 78% to 84% of nondeemed beneficiaries. Among nondeemed beneficiaries, disabled individuals younger than 65 years and racial and ethnic minority groups were more likely to have temporary subsidy losses vs none. Temporary losses were associated with an average 700% increase in out-of-pocket drug costs (+$52.72/mo [95% CI, 52.52-52.92]) and 15% reductions in prescription fills (-0.58 fills/mo [95% CI, -0.59 to -0.57]) overall. Similar changes were found for antidiabetes, antilipid, antidepressant, and antipsychotic prescription drug classes. Beneficiaries who retained their subsidy had few changes. Conclusions and Relevance: The conclusions of this cohort study suggest that efforts to help eligible beneficiaries retain Medicare Part D subsidies could improve drug affordability, treatment adherence, and reduce disparities in medication access.
Subject(s)
Medicare Part D , Prescription Drugs , Humans , Aged , Female , United States , Male , Prescription Drugs/therapeutic use , Cohort Studies , Ethnicity , Minority Groups , Antidepressive AgentsABSTRACT
BACKGROUND: Individuals with psychotic symptoms experience substantial morbidity and have shortened life expectancies; early treatment may mitigate the worst effects. Understanding care preceding a first psychotic disorder diagnosis is critical to inform early detection and intervention. STUDY DESIGN: In this observational cohort study using comprehensive information from the Massachusetts All-Payer Claims Database, we identified the first psychotic disorder diagnosis in 2016, excluding those with historical psychotic disorder diagnoses in the prior 48 months among those continuous enrollment data. We reviewed visits, medications, and hospitalizations 2012-2016. We used logistic regression to examine characteristics associated with pre-diagnosis antipsychotic use. STUDY RESULTS: There were 2505 individuals aged 15-35 years (146 per 100 000 similarly aged individuals in the database) with a new psychotic disorder diagnosis in 2016. Most (97%) had at least one outpatient visit in the preceding 48 months; 89% had a prior mental health diagnosis unrelated to psychosis (eg, anxiety [60%], depression [60%]). Many received psychotropic medications (77%), including antipsychotic medications (46%), and 68% had a visit for injury or trauma during the preceding 48 months. Characteristics associated with filling an antipsychotic medication before the psychotic disorder diagnosis included male sex and Medicaid insurance at psychosis diagnosis. CONCLUSIONS: In this insured population of Massachusetts residents with a new psychotic disorder diagnosis, nearly all had some healthcare utilization, visits for injury or trauma were common, and nearly half filled an antipsychotic medication in the preceding 48 months. These patterns of care could represent either pre-disease signals, delays, or both in receiving a formal diagnosis.
Subject(s)
Antipsychotic Agents , Psychotic Disorders , United States , Humans , Male , Antipsychotic Agents/therapeutic use , Psychotic Disorders/diagnosis , Psychotic Disorders/epidemiology , Psychotic Disorders/therapy , Early Diagnosis , Logistic Models , Psychotherapy , Observational Studies as TopicABSTRACT
Tilapia skin is a great source of collagen. Here, we aimed to isolate and identify the peptides responsible for combating dry eye disease (DED) in tilapia skin peptides (TSP). In vitro cell DED model was used to screen anti-DED peptides from TSP via Sephadex G-25 chromatography, LC/MS/MS, and in silico methods. The anti-DED activity of the screened peptide was further verified in the mice DED model. TSP was divided into five fractions (TSP-I, TSP-II, TSP-III, TSP-IV, and TSP-V), and TSP-II exerted an effective effect for anti-DED. A total of 131 peptides were identified using LC/MS/MS in TSP-II, and NGGPSGPR (NGG) was screened as a potential anti-DED fragment in TSP-II via in silico methods. In vitro, NGG restored cell viability and inhibited the expression level of Cyclooxygenase-2 (COX-2) protein in Human corneal epithelial cells (HCECs) induced by NaCl. In vivo, NGG increased tear production, decreased tear ferning score, prevented corneal epithelial thinning, alleviated conjunctival goblet cell loss, and inhibited the apoptosis of corneal epithelial cells in DED mice. Overall, NGG, as an anti-DED peptide, was successfully identified from TSP, and it may be devoted to functional food ingredients or medicine for DED.
Subject(s)
Dry Eye Syndromes , Tilapia , Humans , Animals , Mice , Tandem Mass Spectrometry , Dry Eye Syndromes/drug therapy , Peptides/pharmacology , Skin , Disease Models, AnimalABSTRACT
Neuroinflammation induced by microglial and astrocyte polarizations may contribute to neurodegeneration and cognitive impairment. Omega (n)-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory and neuroprotective effects, but conflicting results were reported after different n-3 PUFA treatments. This study examined both the change in glial polarizations in ageing rats and the differential effects of two omega-3 PUFAs. The results showed that both PUFAs improved spatial memory in ageing rats, with docosahexaenoic acid (DHA) being more effective than eicosapentaenoic acid (EPA). The imbalance between microglial M1/M2 polarizations, such as up-regulating ionized calcium binding adaptor molecule 1 (IBA1) and down-regulating CD206 and arginase-1 (ARG-1) was reversed in the hippocampus by both n-3 PUFAs, while the DHA effect on CD206 was stronger. Astrocyte A1 polarization presented increasing S100B and C3 but decreasing A2 parameter S100A10 in the ageing brain, which were restored by both PUFAs, while DHA was more effective on S100A10 than EPA. Consistent with microglial M1 activation, the concentration of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were significantly increased, which were attenuated by DHA, while EPA only suppressed IL-6. In correlation with astrocyte changes, brain-derived neurotrophic factor precursor was increased in ageing rats, which was more powerfully down-regulated by DHA than EPA. In summary, enhanced microglial M1 and astrocytic A1 polarizations may contribute to increased brain pro-inflammatory cytokines, while DHA was more powerful than EPA to alleviate ageing-associated neuroimmunological changes, thereby better-improving memory impairment.
Subject(s)
Cognitive Dysfunction , Fatty Acids, Omega-3 , Rats , Animals , Eicosapentaenoic Acid/pharmacology , Eicosapentaenoic Acid/metabolism , Docosahexaenoic Acids/pharmacology , Interleukin-6 , Fatty Acids, Omega-3/pharmacology , Fatty Acids, Omega-3/metabolism , Fatty Acids, Unsaturated , Cytokines/metabolism , Tumor Necrosis Factor-alpha , Cognitive Dysfunction/drug therapy , AgingABSTRACT
The aging of the world population and increasing stress levels in life are the major cause of the increased incidence of neurological disorders. Alzheimer's disease (AD) creates a huge burden on the lives and health of individuals and has become a big concern for society. Triterpenoid saponins (TS), representative natural product components, have a wide range of pharmacological bioactivities such as anti-inflammation, antioxidation, antiapoptosis, hormone-like, and gut microbiota regulation. Notably, some natural TS exhibited promising neuroprotective activity that can intervene in AD progress, especially in the early stage. Recently, studies have indicated that TS play a pronounced positive role in the prevention and treatment of AD. This review discusses the recent research on the neuroprotection of TS and proceeds to detail the action mechanisms of TS against AD, hoping to provide a reference for drug development for anti-AD.
Subject(s)
Alzheimer Disease , Saponins , Triterpenes , Humans , Alzheimer Disease/drug therapy , Antioxidants/pharmacology , Antioxidants/therapeutic use , Neuroprotection , Saponins/pharmacology , Saponins/therapeutic use , Triterpenes/pharmacology , Triterpenes/therapeutic useABSTRACT
Euryale ferox Salisb. (prickly water lily) is the only extent of the genus Euryale that has been widely distributed in China, India, Korea, and Japan. The seeds of E. ferox (EFS) have been categorized as superior food for 2000 years in China, based on their abundant nutrients including polysaccharides, polyphenols, sesquineolignans, tocopherols, cyclic dipeptides, glucosylsterols, cerebrosides, and triterpenoids. These constituents exert multiple pharmacological effects, such as antioxidant, hypoglycemic, cardioprotective, antibacterial, anticancer, antidepression, and hepatoprotective properties. There are very few summarized reports on E. ferox, albeit with its high nutritional value and beneficial activities. Therefore, we collected the reported literature (since 1980), medical classics, database, and pharmacopeia of E. ferox, and summarized the botanical classification, traditional uses, phytochemicals, and pharmacological effects of E. ferox, which will provide new insights for further research and development of EFS-derived functional products.
Subject(s)
Medicine, Chinese Traditional , Nymphaeaceae , Nymphaeaceae/chemistry , Antioxidants/pharmacology , Tocopherols , Phytochemicals/pharmacology , Plant Extracts/pharmacology , Plant Extracts/chemistryABSTRACT
Sarcopenia is a syndrome characterized by progressive loss of skeletal muscle mass, strength and function, which is one of the most important clinical features of cancer malnutrition, representing a poor prognostic indicator in oncology. Sarcopenia is commonly assessed by measuring the skeletal muscle index (SMI) of the third lumbar spine (L3) using computed tomography (CT). The primary aim of this meta-analysis was to study the association between low SMI and comprehensive clinicopathological characteristics as well as prognosis in patients with ovarian cancer. Data were searched in PubMed, EMBASE and Cochrane databases from inception to 10 June 2022. Studies evaluating the prognostic effect of SMI on ovarian cancer survival or chemotherapy-related side effects were included. The risk of bias and study quality were assessed via the Newcastle-Ottawa Scale (NOS). The search strategy yielded 1286 hits in all three databases combined. Thirteen studies were included for qualitative and quantitative analysis, comprising 1814 patients. Our meta-analysis revealed the significant association between low SMI and progression-free survival (PFS) [P = 0.02; hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.06-1.85], as well as 5-year overall survival (OS) [P = 0.02; odds ratio (OR): 1.35, 95% CI: 1.05-1.74]. Low SMI was also obviously associated with body mass index (BMI) < 25 (P < 0.00001; OR: 5.08, 95% CI: 3.54-7.30), FIGO stage (P = 0.02; OR: 1.62, 95% CI: 1.06-2.45) and R0 cytoreduction (P = 0.04;OR: 1.34, 95% CI: 1.01-1.79). There was no correlation between low SMI and histological types, pathological grades and chemotherapy-related toxicity. The quality of the evidence was relatively high according to NOS. Our meta-analysis indicated that sarcopenia assessed by SMI was associated with poor clinical characteristics and adverse prognosis in patients with ovarian cancer. Consensus should be reached on standardized cut-off values for defining sarcopenia in patients with ovarian cancer.
Subject(s)
Ovarian Neoplasms , Sarcopenia , Humans , Female , Sarcopenia/pathology , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Ovarian Neoplasms/complications , Ovarian Neoplasms/pathology , Prognosis , Tomography, X-Ray ComputedABSTRACT
Reynoutria multiflora roots are a classical herbal medicine with unique nourishing therapeutic effects. Anomalous vascular bundle (AVB) forming "cloudy brocade patterns" is a typical morphological feature of R. multiflora roots and has been empirically linked to its quality classification. However, scientific evidence, especially for AVB-specific specialised metabolites, has not been comprehensively revealed thus far. Herein, desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) analysis was applied to carry out an in situ analysis of specialised metabolites distributed specifically at the AVB and cork of R. multiflora roots. To enlarge the scope of compounds by DESI detection, various solvent systems including acetone, acetonitrile, methanol, and water were used to assist in the discoveries of 40 specialised metabolites with determined localization. A series of bioactive constituents including stilbenes, flavonoids, anthraquinones, alkaloids, and naphthalenes were found specifically around the brocade patterns. Notably, phospholipids were detected from R. multiflora roots by in situ analysis for the first time and were found mainly in the phloem of AVB (PAB). This is the first study to use gradient solvent systems in DESI-MSI analysis to locate the specialised metabolites distribution. The discovery of feature-specific compounds will bridge the empirical identification to precision quality control of R. multiflora roots.
Subject(s)
Alkaloids , Spectrometry, Mass, Electrospray Ionization , Spectrometry, Mass, Electrospray Ionization/methods , Reynoutria , Solvents , WaterABSTRACT
Model-free reinforcement learning algorithms based on entropy regularized have achieved good performance in control tasks. Those algorithms consider using the entropy-regularized term for the policy to learn a stochastic policy. This work provides a new perspective that aims to explicitly learn a representation of intrinsic information in state transition to obtain a multimodal stochastic policy, for dealing with the tradeoff between exploration and exploitation. We study a class of Markov decision processes (MDPs) with divergence maximization, called divergence MDPs. The goal of the divergence MDPs is to find an optimal stochastic policy that maximizes the sum of both the expected discounted total rewards and a divergence term, where the divergence function learns the implicit information of state transition. Thus, it can provide better-off stochastic policies to improve both in robustness and performance in a high-dimension continuous setting. Under this framework, the optimality equations can be obtained, and then a divergence actor-critic algorithm is developed based on the divergence policy iteration method to address large-scale continuous problems. The experimental results, compared to other methods, show that our approach achieved better performance and robustness in the complex environment particularly. The code of DivAC can be found in https://github.com/yzyvl/DivAC.
ABSTRACT
The disordered tubulin C-terminal tail (CTT), which possesses a higher degree of heterogeneity, is the target for the interaction of many proteins and cellular components. Compared to the seven well-described binding sites of microtubule-targeting agents (MTAs) that localize on the globular tubulin core, tubulin CTT is far less explored. Therefore, tubulin CTT can be regarded as a novel site for the development of MTAs with distinct biochemical and cell biological properties. Here, we designed and synthesized linear and cyclic peptides containing multiple arginines (RRR), which are complementary to multiple acidic residues in tubulin CTT. Some of them showed moderate induction and promotion of tubulin polymerization. The most potent macrocyclic compound 1f was found to bind to tubulin CTT and thus exert its bioactivity. Such RRR containing compounds represent a starting point for the discovery of tubulin CTT-targeting agents with therapeutic potential.
Subject(s)
Antineoplastic Agents , Tubulin , Tubulin/metabolism , Microtubules/metabolism , Antineoplastic Agents/pharmacology , Binding Sites , Tubulin Modulators/pharmacology , Tubulin Modulators/metabolismABSTRACT
Background: Oxidative stress, cholinergic deficiency, and neuroinflammation are hallmarks of most neurodegenerative disorders (NDs). Lipids play an important role in brain development and proper functioning. Marine-derived lipids have shown good memory-improving potentials, especially those from fish and microalgae. The cultivated macroalga Hizikia fusiforme is healthy food and shows benefits to memory, but the study is rare on the brain healthy value of its oil. Previously, we had reported that the Hizikia fusiforme functional oil (HFFO) contains arachidonic acid, 11,14,17-eicosatrienoic acid, phytol, and other molecules displaying in vitro acetylcholinesterase inhibitory and nitroxide scavenging activity; however, the in vivo effect remains unclear. In this study, we further investigated its potential effects against lipopolysaccharides (LPS)- or aluminum trichloride (AlCl3)-induced memory deficiency in zebrafish and its drug-related properties in silica. Methods: We established memory deficit models in zebrafish by intraperitoneal (i.p.) injection of lipopolysaccharides (LPS) (75 ng) or aluminum trichloride (AlCl3) (21 µg), and assessed their behaviors in the T-maze test. The interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), acetylcholine (ACh), and malondialdehyde (MDA) levels were measured 24 h after the LPS/AlCl3 injection as markers of inflammation, cholinergic activity, and oxidative stress. Furthermore, the interaction of two main components, 11,14,17-eicosatrienoic acid and phytol, was investigated by molecular docking, with the important anti-inflammatory targets nuclear factor kappa B (NF-κB) and cyclooxygenase 2 (COX-2). Specifically, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of HFFO were studied by ADMETlab. Results: The results showed that HFFO reduced cognitive deficits in zebrafish T-maze induced by LPS/AlCl3. While the LPS/AlCl3 treatment increased MDA content, lowered ACh levels in the zebrafish brain, and elevated levels of central and peripheral proinflammatory cytokines, these effects were reversed by 100 mg/kg HFFO except for MDA. Moreover, 11,14,17-eicosatrienoic acid and phytol showed a good affinity with NF-κB, COX-2, and HFFO exhibited acceptable drug-likeness and ADMET profiles in general. Conclusion: Collectively, this study's findings suggest HFFO as a potent neuroprotectant, potentially valuable for the prevention of memory impairment caused by cholinergic deficiency and neuroinflammation.
ABSTRACT
Importance: Young adults historically have had the highest uninsured rates among all age groups. In 2014, in addition to Medicaid expansion for adults with low income (≤133% of the federal poverty level [FPL]) through the Patient Protection and Affordable Care Act, Massachusetts also extended eligibility for children (≤150% FPL) to beneficiaries aged 19 to 20 years. Objective: To examine changes in insurance coverage continuity for Medicaid enrollees who turned age 19 years before and after eligibility policy changes. Design Setting and Participants: This cohort study used data from the Massachusetts All-Payer Claims Database (2012 to 2016) to compare coverage for Medicaid beneficiaries turning age 19 years before and after Medicaid expansion. Monthly coverage was examined for each cohort for 3 years as beneficiaries aged from 18 and 19 years to 19 and 20 years to 20 and 21 years. Analyses were performed between November 1, 2020, and May 12, 2022. Main Outcomes and Measures: In each year, the likelihood of being uninsured or having Medicaid, employer-sponsored insurance, or individual commercial coverage for 3 or more months was examined along with the likelihood of having continuous Medicaid enrollment for 12 or more and 24 or more months. Multivariable linear probability models were used to compare the likelihood of these outcomes for those in the postexpansion vs preexpansion cohorts, adjusting for sex, comorbidity levels, neighborhood socioeconomic status, and neighborhood race and ethnicity. Results: A total of 41 247 young adults turning age 18 to 19 years in the baseline year (20 876 [50.6%] men) were included in the study, with 20 777 in the preexpansion cohort and 20 470 in the postexpansion cohort. Enrollees who turned age 19 years after vs before the Medicaid eligibility expansion were less likely to have 3 or more uninsured months at ages 18 to 19 years (4.4% [n = 891] vs 22.9% [n = 4750]; adjusted difference, -18.4 [95% CI, -19.0 to -17.7] percentage points) and 19 to 20 years (13.2% [n = 2702] vs 35.8% [n = 7447]; adjusted difference, -22.4 [95% CI, -23.2 to -21.6] percentage points) and more likely to have continuous insurance coverage for 12 or more months (94.1% [n = 19 272] vs 63.7% [n = 13 234]; adjusted difference, 30.5 [95% CI, 29.7-31.2] percentage points) or 24 or more months (77.5% [n = 15 868] vs 44.4% [n = 9221]; adjusted difference, 33.0 [95% CI, 32.1-33.9] percentage points). Differences in the likelihood of having 3 or more uninsured months diminished at ages 20 to 21 years, when both groups had access to Medicaid (ie, in calendar years 2014 for the preexpansion cohort and 2016 for the postexpansion cohort). Conclusions and Relevance: In this cohort study of young adults in Massachusetts, the combination of expanding Medicaid to lower-income adults and increasing the age threshold for child Medicaid eligibility was associated with reduced likelihood of becoming uninsured among Medicaid enrollees entering adulthood.