Abnormalities in subcortical function and their treatment response in Wilson's disease.

Extensive neuroimaging abnormalities in subcortical regions build the pathophysiological basis of Wilson's disease (WD). Yet, subcortical topographic organization fails to articulate, leaving a huge gap in understanding the neural mechanism of WD. Thus, how functional abnormalities of WD subcortical regions influence complex clinical symptoms and response to treatment remain unknown. Using resting-state functional MRI data from 232 participants (including 130 WD patients and 102 healthy controls), we applied a connectivity-based parcellation technique to develop a subcortical atlas for WD. The atlas was further used to investigate abnormalities in subcortical function (ASF) by exploring intrasubcortical functional connectivity (FC) and topographic organization of cortico-subcortical FC. We further used support vector machine (SVM) to integrate these functional abnormalities into the ASF score, which serves as a biomarker for characterizing individual subcortical dysfunction for WD. Finally, the baseline ASF score and one-year treatment data of the follow-up WD patients were used to assess treatment response. A group set of subcortical parcellations was evaluated, in which 26 bilateral regions well recapitulated the anatomical nuclei of the subcortical areas of WD. The results of cortico-subcortical FC and intrasubcortical FC reveal that dysfunction of the somatomotor networks-lenticular nucleus-thalamic pathways is involved in complex symptoms of WD. The ASF score was able to characterize disease progression and was significantly associated with treatment response of WD. Our findings provide a comprehensive elaboration of functional abnormalities of WD subcortical regions and reveal their association with clinical presentations, improving our understanding of the functional neural underpinnings in WD. Furthermore, abnormalities in subcortical function could serve as a potential biomarker for understanding the disease progression and evaluating treatment response of WD.

Non-Covalent Interaction Enhancement on Active/Interfacial Layers via Two-Dimensional Vermiculite Doping for Efficient Organic Solar Cells.

Interface modification plays an important role in improving the power conversion efficiency (PCE) of organic solar cells (OSCs). However, the low non-covalent interaction between the cathode interface layer (CIL) and nonfullerene acceptor (NFA) directly affects the charge collection of OSCs. Here, the non-covalent interaction between the CIL and NFA is enhanced by introducing the 2D vermiculite (VML) in the poly(9,9-bis(3'-(N,N-dimethyl)-Nethylammonium-propyl-2,7-fluorene)-alt-2,7-(9,9-dioctylfluorene)) dibromide (PFN-Br) interface layer to form an efficient electron transport channel. As a result, the electron extraction efficiency from the active layer to the CIL is increased, and the PCE of OSCs based on PBDB-T:ITIC is boosted from 10.87% to 12.89%. In addition, the strategy of CIL doping VML is proven to be universal in different CIL materials, for which the PCE is boosted from 10.21% to 11.57% for OSCs based on PDINN and from 9.82% to 11.27% for OSCs based on PNDIT-F3N. The results provide a viable option for designing efficient CIL for high-performance non-fullerene OSCs, which may promote the commercialization of OSCs.

Large-scale networks changes in Wilson's disease associated with neuropsychiatric impairments: a resting-state functional magnetic resonance imaging study.

BACKGROUND: In Wilson's disease (WD) patients, network connections across the brain are disrupted, affecting multidomain function. However, the details of this neuropathophysiological mechanism remain unclear due to the rarity of WD. In this study, we aimed to investigate alterations in brain network connectivity at the whole-brain level (both intra- and inter-network) in WD patients through independent component analysis (ICA) and the relationship between alterations in these brain network functional connections (FCs) and clinical neuropsychiatric features to understand the underlying pathophysiological and central compensatory mechanisms. METHODS: Eighty-five patients with WD and age- and sex-matched 85 healthy control (HC) were recruited for resting-state functional magnetic resonance imaging (rs-fMRI) scanning. We extracted the resting-state networks (RSNs) using the ICA method, analyzed the changes of FC in these networks and the correlation between alterations in FCs and clinical neuropsychiatric features. RESULTS: Compared with HC, WD showed widespread lower connectivity within RSNs, involving default mode network (DMN), frontoparietal network (FPN), somatomotor network (SMN), dorsal attention network (DAN), especially in patients with abnormal UWDRS scores. Furthermore, the decreased FCs in the left medial prefrontal cortex (L_ MPFC), left anterior cingulate gyrus (L_ACC), precuneus (PCUN)within DMN were negatively correlated with the Unified Wilson's Disease Rating Scale-neurological characteristic examination (UWDRS-N), and the decreased FCs in the L_MPFC, PCUN within DMN were negatively correlated with the Unified Wilson's Disease Rating Scale-psychiatric symptoms examination (UWDRS-P). We additionally discovered that the patients with WD exhibited significantly stronger FC between the FPN and DMN, between the DAN and DMN, and between the FPN and DAN compared to HC. CONCLUSIONS: We have provided evidence that WD is a disease with widespread dysfunctional connectivity in resting networks in brain, leading to neurological features and psychiatric symptoms (e.g. higher-order cognitive control and motor control impairments). The alter intra- and inter-network in the brain may be the neural underpinnings for the neuropathological symptoms and the process of injury compensation in WD patients.

Therapeutic Drug Monitoring of Imatinib and N-Desmethyl Imatinib in Chronic Myeloid Leukemia Patients Using LC-MS/MS in a Cohort Study.

Imatinib is an oral tyrosine kinase inhibitor (TKI) and first-line therapy for patients with chronic myeloid leukemia (CML). There is a positive correlation between serum imatinib concentrations and treatment response. However, the specific relationship between the blood concentration of imatinib and its influencing factors remains unclear. This study collected basic information from 102 patients using imatinib as first-line treatment for CML. Further, we analyzed the individual differences in imatinib concentration and explored its influencing factors. Through intra-day and inter-day precision studies, we found that the precision for the imatinib assay methodology was within ±13% and that the recovery rate was above 85%. There is notable individual variation in the blood concentration of imatinib; the recommended treatment concentration is 860-1500 ng/mL, with only 41.40% of patients achieving this concentration. Also, there was a negative correlation between age and imatinib trough concentration (Ctrough ), as is observed between age and N-desmethyl imatinib. Moreover, compared with the adolescent group, the serum imatinib Ctrough for groups aged 17-47 and 48-68 years was significantly reduced. Further analysis shows that imatinib Ctrough values reaching therapeutic concentrations (59%) increased dramatically for patients with CML aged 17-47 years. Moreover, groups dosed with 400 mg/day resulted in therapeutic imatinib concentrations for 68% of patients with CML, which was the best performance. The established method was validated, with acceptable accuracy, precision, linearity, and stability, as required, and then successfully applied to the therapeutic drug monitoring of imatinib. Age, dose, and metabolites can influence the imatinib concentration and its therapeutic effect in patients with CML.

Cost-effectiveness of nivolumab versus sorafenib as first-line treatment for advanced hepatocellular carcinoma.

BACKGROUND: Nivolumab improves overall survival (OS) and is associated with less adverse events (AE) compared with sorafenib in the first-line treatment of advanced hepatocellular carcinoma (HCC). But which approach is the most cost-effective remains uncertain. This study aimed to evaluate the cost-effectiveness of nivolumab vs sorafenib as first-line therapy for patients with advanced HCC from the perspective of Chinese healthcare system. METHODS: A partitioned survival mode was constructed to evaluate the health and economic outcomes of nivolumab vs sorafenib as first-line treatment for advanced HCC. The clinical data and outcomes were obtained from CheckMate 459 trial. Medical costs and utilities were collected from published sources. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. One-way and probabilistic sensitivity analyses were used to examine model uncertainty. Additional subgroup and scenario analyses were performed. RESULTS: Treatment with nivolumab yielded an additional 0.27 QALYs with an incremental cost of $65,579.19 compared with sorafenib, leading to an ICER of $236,765.93/QALY in China. One-way sensitivity analysis found the model outputs to be most affected for hazard ratio (HR) of OS and the cost of nivolumab. Probabilistic sensitivity analysis showed that the probability of nivolumab being cost-effective was 0% at the willingness-to-pay (WTP) threshold of $38,201.19/QALY. The scenario analyses indicated altering the time horizon of the model did not reverse the economic results. CONCLUSION: Nivolumab as first-line treatment could gain more health benefits for advanced HCC compared with sorafenib, but was estimated not to be cost-effective at the commonly adopted WTP threshold of China.

Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune evasion.

To improve the efficacy of lenvatinib in combination with programmed death-1 (PD-1) blockade therapy for hepatocellular carcinoma (HCC), we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade, thus impeding HCC progression. After analysis of the CRISPR‒Cas9 screen, phosphatidylinositol-glycan biosynthesis class L (PIGL) ranked first in the positive selection list. PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment (TME) in vivo to support tumor cell survival. Specifically, nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20, which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells. PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importin α/ß1, thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20. Clinically, elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8 + T-cell enrichment in tumors. Clinically, our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.

Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase.

To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.

Clinical, economic and humanistic outcomes of medication therapy management services: A systematic review and meta-analysis.

Background: Medication therapy management (MTM) services is a method that can effectively improve patients' conditions, but the efficacy of economic and humanistic outcomes remain unclear. This systematic review and meta-analysis aim to use economic, clinical and humanistic outcomes to evaluate the multi-benefits of MTM services. Method: A systematic review and meta-analysis was conducted by retrieving PubMed, EMBASE, the Cochrane Library and ClinicalTrial.gov from the inception to April 2022. There were two reviewers screening the records, extracting the data, and assessing the quality of studies independently. Results: A total of 81 studies with 60,753 participants were included. MTM services were more effective in clinical outcomes with decreasing the rate of readmission (OR: 0.78; 95% CI: 0.73 to 0.83; I2 = 56%), emergency department visit (OR: 0.88; 95% CI: 0.81 to 0.96; I2 = 32%), adverse drug events (All-cause: OR: 0.68; 95% CI: 0.56 to 0.84; I2 = 61%; SAE: OR: 0.51; 95% CI: 0.33 to 0.79; I2 = 35%) and drug-related problems (MD: -1.37; 95% CI: -2.24 to -0.5; I2 = 95%), reducing the length of stay in hospital (MD: -0.74; 95% CI: -1.37 to -0.13; I2 = 70%), while the economic and humanistic outcomes were less effective. Conclusion: Our systematic review and meta-analysis demonstrated that MTM services had great ability to improve patients' clinical conditions while the efficacy of economic and humanistic outcomes, with some of the outcomes showing high degree of heterogeneity and possible publication bias, required more future studies to provide stronger evidence. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=349050], identifier [CRD42022349050].

Glutamate dehydrogenase1 supports HIF-1α stability to promote colorectal tumorigenesis under hypoxia.

Tumor cells surviving hypoxic stress acquire the ability to drive cancer progression. To explore the contribution of dehydrogenases to the low oxygen concentration response, we used siRNAs targeting 163 dehydrogenase-coding genes and discovered that glutamate dehydrogenase 1 (GDH1) plays a critical role in regulating colorectal cancer (CRC) cell survival under hypoxia. We observed that GDH1 deficiency had an inhibitory effect on CRC occurrence and impaired hypoxia-inducible factor 1-alpha (HIF-1α) stability even under hypoxia. Mechanistically, hypoxia triggered p300 recruitment to GDH1, promoting its acetylation at K503 and K527. GDH1 acetylation at K527 induced the formation of a GDH1 complex with EGLN1/HIF-1α; in contrast, GDH1 acetylation at K503 reinforced its affinity for α-ketoglutarate (αKG), and glutamate production. In line with this view, αKG is a product of GDH1 under normoxia, but hypoxia stimulation reversed GDH1 enzyme activity and αKG consumption by the EGLN1/HIF-1α complex, increasing HIF-1α stability and promoting CRC progression. Clinically, hypoxia-modulated GDH1 AcK503/527 can be used as a biomarker of CRC progression and is a potential target for CRC treatment.

Reading and writing of mRNA m6A modification orchestrate maternal-to-zygotic transition in mice.

N6-methyladenosine (m6A) modification has been shown to regulate RNA metabolism. Here, we investigate m6A dynamics during maternal-to-zygotic transition (MZT) in mice through multi-omic analysis. Our results show that m6A can be maternally inherited or de novo gained after fertilization. Interestingly, m6A modification on maternal mRNAs not only correlates with mRNA degradation, but also maintains the stability of a small group of mRNAs thereby promoting their translation after fertilization. We identify Ythdc1 and Ythdf2 as key m6A readers for mouse preimplantation development. Our study reveals a key role of m6A mediated RNA metabolism during MZT in mammals.

Recognition of Water-Induced Double-Edged Sword Effects in Photocatalytic Selective Oxidation of Toluene on Titanium Dioxide Clusters with Density Functional Theory Calculations.

Recently, water promotion effects in the selective oxidation of benzyl alcohol to benzaldehyde have been experimentally recognized and identified. However, the effects of water on the photocatalytic selective oxidation of toluene into benzaldehyde remain elusive. In this work, the Ti3O9H6 clusters in different solvents (water and toluene solvent) are used to study the water-induced effects in photocatalytic oxidation reactions in kinetics and thermodynamics using density functional theory (DFT) calculations. In addition, the influences of the OH groups on catalysts (Ti-OH bonds) from photocatalytic water splitting are also considered. The results clearly demonstrate the water-induced double-edged sword effects in the photocatalytic selective oxidation of toluene. We expect that our work can not only shed light on the mechanisms of photocatalytic selective oxidation of toluene into benzaldehyde and other activation reactions of sp3 C-H bonds but also design and modulate highly efficient photocatalysts.

Hematological toxicities in PARP inhibitors: A real-world study using FDA adverse event reporting system (FAERS) database.

OBJECTIVE: Poly ADP-ribose polymerase inhibitors (PARPis) have significantly improved clinical effects in gynecological oncology. However, PARPis could also induce severe organ system toxicities, including the hematological system. Our study aimed to extensively characterize the hematological toxicities of PARPis based on the real-world data. METHODS: Disproportionality analysis was used to evaluate the association between PARPis and hematotoxicity adverse events. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database between January 2015 and September 2021. The characteristics of PARPi-associated hematological toxicities, and the onset time and fatality proportion were further analyzed. RESULTS: Out of 24,045 adverse events reports, 4088 hematotoxicity reports (17.00%) were analyzed, with a median age of 64.95 (interquartile range [IQR] 51-71) years. All PARPis were detected with positive safety signals of hematological toxicities in four detection methods. Unexpected significant adverse events such as lymphadenopathy, lymphoedema, and metastases to lymph nodes might also occur. The median time-to-onset was 28 (IQR 10-101) days and the fatality proportion of hematological toxicities with PARPis was 8.76%, with a statistical difference in different PARPis. CONCLUSION: Hematological toxicities caused by PARPis preferred to occur early and might result in serious outcomes. Early identification and response to the PARPi-related hematological toxicities were important and further basic research were needed to confirm the mechanism of results in this study.

A validated UHPLC-MS/MS assay for rapid and sensitive determination of crisaborale in human plasma and its clinico-pharmacokinetic application.

Crisaborole ointment, 2%, is a non-steroidal, topical anti-inflammatory phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. To date, a specific analytic method of crisaborole in plasma has not been reported. The aim of this study was to develop a rapid, sensitive and robust UHPLC-MS/MS method for the quantitative detection of crisaborole in human plasma by using deuterated crisaborole-d4 as the internal standard (IS). The analyte was well extracted from human plasma with acetonitrile and subsequently eluted with gradient acetonitrile and water in short run time of 3.3 min. Negative electrospray ionization in multiple reaction monitoring mode was employed to acquire the quantification ion pairs of m/z 250.0→118.0 for crisaborole and m/z 254.0→121.9 for IS. The assay met the regulations of the US Food and Drug Administration and the European Medicines Agency for assay validation with a good linearity in the calibration range of 0.20-80 ng/mL. Intra-day and inter-day precision was less than 9.17% and the accuracy was - 2.29%-6.33% across all the quality control samples. The average extraction recovery of analyte and IS was 84.61% and 91.43%, respectively, and consistent over different quality control samples. The fully validated method was successfully used for the drug level measurement in ten healthy Chinese subjects receiving crisaborole ointment. Our novel UPLC-MS/MS assay for the quantification of plasma crisaborole concentrations in human samples may be easily used in clinical practice and help to reveal the pharmacokinetic profiles of crisaborole in Chinese population.

Enhanced photocatalytic toluene oxidation performance induced by two types of cooperative fluorine doping in polymeric carbon nitride with the first-principles calculations.

Fluorine atoms doping was reported in experiment to reduce the band gap, improve the oxidation potential of hole, and polarize the electron distribution of polymeric carbon nitride (PCN). However, the relationships between different types of F doping and the roles of F doping in electronic and optical properties remain elusive. In this work, we investigate several F doping types in PCN and analyze their different roles in electronic and optical properties with the first-principles calculations. The results show that two stable and cooperative F doping types are found, one is to form the C (sp3)-F bond (Fcorner type), and the other is F atom replacing amino group -NH2 (FN3 type) forming covalent C-F bond. The Fcorner doping reduces the energy level of valence-band maximum (VBM), causes excited electron-hole distribution polarized, and increases the hole distribution on F atoms, which strengthens the capacity of photocatalytic oxidation and improves the electron-hole separation efficiency, while FN3 type doping plays the roles of reducing the bandgap and improving the light absorption. In addition, under the synergistic action of two types of F doping, the adsorption energy of toluene on F-codoped PCN is greatly enhanced, improving the ability of photocatalytic activation of toluene. Our work develops a new understanding of F doping and reveals the roles of different types of F doping, providing a rationale for designing and regulating more efficient photocatalysts and improving the properties of photocatalytic toluene oxidation.

Lesions in White Matter in Wilson's Disease and Correlation with Clinical Characteristics.

BACKGROUND: Neuroimaging studies in Wilson's disease (WD) have identified various alterations in white matter (WM) microstructural organization. However, it remains unclear whether these alterations are localized to specific regions of fiber tracts, and what diagnostic value they might have. The purpose of this study is to explore the spatial profile of WM abnormalities along defined fiber tracts in WD and its clinical relevance. METHODS: Ninety-nine patients with WD (62 men and 37 women) and 91 age- and sex-matched controls (59 men and 32 women) were recruited to take part in experiments of diffusion-weighted imaging with 64 gradient vectors. The data were calculated by FMRIB Software Library (FSL) software and Automated Fiber Quantification (AFQ) software. After registration, patient groups and normal groups were compared by Mann-Whitney U test analysis. RESULTS: Compared with the controls, the patients with WD showed widespread fractional anisotropy reduction and mean diffusivity, radial diffusivity elevation of identified fiber tracts. Significant correlations between diffusion tensor imaging (DTI) parameters and the neurological Unified Wilson's Disease Rating Scale (UWDRS-N), serum ceruloplasmin, and 24-h urinary copper excretion were found. CONCLUSIONS: The present study has provided evidence that the metrics of DTI could be utilized as a potential biomarker of neuropathological symptoms in WD. Damage to the microstructure of callosum forceps and corticospinal tract may be involved in the pathophysiological process of neurological symptoms in WD patients, such as gait and balance disturbances, involuntary movements, dysphagia, and autonomic dysfunction.

Availability and Affordability of Therapeutic Monoclonal Antibodies After the New Medical Reform in Hubei Province, China.

OBJECTIVE: In 2017, China launched a new round of medical reform (NMR) to address the inaccessibility of high-priced drugs for patients with serious diseases. This study explored the impact of the NMR on the accessibility and affordability of high-priced monoclonal antibodies (mAbs), and the effective promotion policies after the NMR. METHODS: We used a standard method developed by the World Health Organization to conduct two surveys on the availability of mAbs and their prices before and after the NMR in the public hospitals in Hubei province, China. By interviewing hospital pharmacy experts, we identified the potential value of the current NMR in improving the access to therapeutic mAbs. RESULTS: The average availability of 13 mAbs increased by 8.1% in the surveyed hospitals of Hubei province after the NMR. The median unit price of 10 mAbs dropped by 34.3%. The average affordability of a treatment cycle of 10 mAbs dropped from 680 days to 298 days of the disposable daily income for a middle-income resident (56.2% reduction). The drug price negotiation of medical insurance inclusion and the promotion of consistent evaluation of generic and original drugs could effectively promote the accessibility of mAbs. However, the zero markup of drug pricing and the limit on the proportion of drug revenues in public hospitals showed certain negative effects on the availability of mAbs. CONCLUSION: Not all current NMR policies play a positive role in promoting the accessibility of mAbs. To further improve the accessibility of mAbs in the future in China, it is therefore critical to increase the investment in independent research and development of high-quality mAbs, establish localized guidelines for the rational use of mAbs in clinical practice, and have a cost-sharing mechanism for high-priced drugs with multiple stakeholders.

Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system.

Background: Semaglutide was approved for treatment of type 2 diabetes mellitus (T2DM) and chronic weight management in obesity or overweight adults. However, real-world data regarding its long-term gastrointestinal safety and tolerability in large sample population are incomplete. We evaluated semaglutide-associated gastrointestinal safety signals by data mining of the FDA pharmacovigilance database. Methods: Reporting odds ratio (ROR) was employed to quantify the signals of semaglutide-related gastrointestinal adverse events (AEs) from 2018 to 2022. Serious and non-serious cases were compared by Mann-Whitney U test or Chi-squared (χ2) test, and signals were prioritized using a rating scale. Results: We identified 5,442 cases of semaglutide-associated gastrointestinal AEs, with 45 signals detected, ranging from a ROR025 of 1.01 (hypoaesthesia oral) to 42.03 (eructation), among which 17 AEs were identified as new and unexpected signals. Patient age (p < 0.001) and body weight (p = 0.006) rather than sex (p = 0.251) might be associated with an increased risk of gastrointestinal AEs severity. Notably, the association between semaglutide and gastrointestinal disorders remained when stratified by age, body weight, sex and reporter type. One strong, 22 moderate and 22 weak clinical priority signals were defined. The median time-to-onset (TTO) for strong clinical priority signal was 23 days, while for moderate and weak, they were 6 and 7 days, respectively. All of the disproportionality signals had early failure type features, suggesting that the risk of gastrointestinal AEs occurrence gradually decreased over time. Conclusion: Our study provided a deeper and broader understanding of semaglutide's gastrointestinal safety profiles, which would help healthcare professionals to mitigate the risk of gastrointestinal AEs in clinical practice.

Multiple beneficial outcomes of medication therapy management interventions in randomized control trials and non-randomized control trials: A protocol for systematic review and meta-analysis.

BACKGROUND: Medication therapy management (MTM) service is an effective method to reduce medication-related problems and improve patients' multiple kinds of outcomes. However, the lack of comprehensive review for MTM services has hindered its development. As a result, we are aiming to evaluate the current benefits of MTM services with multiple outcomes. METHOD: An electronic search will be performed for randomized controlled trials (RCTs) or non-randomized control trials (NRCTs) that reported MTM services or pharmaceutical services as interventions from PubMed, The Cochrane Library, Embase, and ClinicalTrial. gov. The odds ratios, mean differences, and standard mean differences and their 95% confidence intervals (95% confidence intervals) will be calculated with fixed or random effect models. RESULTS: This study will evaluate the multiple benefits of MTM services in clinical endpoints, quality of life, economy, and drug-related problems. CONCLUSION: The results will review eligible studies released in the past twenty years and provide more comprehensive evidence of the efficacy of MTM services. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study.

Cost-effectiveness of osimertinib versus standard EGFR-TKI as first-line treatment for EGFR-mutated advanced non-small-cell lung cancer in China.

Objective: The purpose of this study was to estimate the cost-effectiveness of osimertinib for the first-line treatment of patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Methods: A Markov model was developed to simulate the outcomes and direct medical costs of osimertinib or standard EGFR-TKI in the first-line treatment of patients with previously untreated EGFR-mutated advanced NSCLC. Individual patient survival data were extracted from the FLAURA randomized clinical trial. Clinical costs and utilities' input estimates were collected from the local hospital and available literature reports. The quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), incremental net monetary benefit (INMB), and incremental net health benefit (INHB) were calculated for the two treatment strategies over a 10-year lifetime horizon. In addition, one-way sensitivity analysis, probabilistic sensitivity analysis, and subgroup analysis were performed to test the robustness of the model. Results: On baseline analysis, osimertinib achieved additional 0.39 QALYs and $15,443.78 incremental costs compared with standard EGFR-TKI (gefitinib or erlotinib), which resulted in the ICER of $39,369.53/QALY. The INMB was -$755.11, and the INHB was -0.02 QALYs at a WTP threshold of $37,663.26/QALY in China. The one-way sensitivity analysis showed that the utility of PFS had the strongest association with the ICER. Osimertinib had approximately 46.4% probability of being cost-effective at the WTP threshold of $37,663.26/QALY. Conclusion: First-line osimertinib therapy might not be cost-effective in China for patients with EGFR-mutated advanced NSCLC compared with standard EGFR-TKI based on its current marketed price. A significantly more favorable cost-effectiveness could be achieved when the price of osimertinib was reduced by 5%.

Cost-effectiveness analysis of olaparib as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in china.

Objective: The aim of this study was to investigate the cost-effectiveness of olaparib as the maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in China. Methods: A Markov model was developed to simulate the clinical course of typical patients with ovarian cancer in the SOLO2 trial. The Weibull survival model was employed to fit the Kaplan-Meier progression-free survival and overall survival probabilities of the olaparib and placebo strategies, respectively. The clinical and direct costs data were derived from randomized clinical trials and published reports. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were estimated over a 10-year lifetime horizon. Meanwhile, one-way and probabilistic sensitivity analyses were used to explore the impact of uncertainty on the model's outcomes. Results: Overall, the incremental effectiveness and cost of olaparib versus placebo were 0.56 QALYs and $43,292.92, respectively, resulting in an ICER of $77,620.56/QALY, higher than the willingness-to-pay (WTP) threshold of China ($31,498.70/QALY). The results were sensitive to the cost of olaparib and utility of PFS. Scenario analyses suggested that when the cost of olaparib was reduced by 60%, ICER decreased to $30,611.52/QALY, lower than the WTP threshold of China. Conclusion: The findings from the present analysis suggest that olaparib with a 60% discount as maintenance therapy might be cost effective in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in China.