BACKGROUND: Extensive research has been undertaken to predict treatment response (TR) to antipsychotics. Most studies address TR to antipsychotics in general and as monotherapy, however, it is unknown whether patients might respond favourably to a combination of antipsychotics.
OBJECTIVE: This study aimed to identify differential predictors for TR to monotherapy with amisulpride or olanzapine compared to a combination of antipsychotics.
METHODS: Post-hoc analysis was conducted of data collected from the COMBINE-study, a double-blind, randomized, controlled trial. Demographic and disease-related measures were gathered at baseline to predict TR after eight weeks defined by the Positive and Negative Syndrome Scale. Missing values were accounted for by a random replacement procedure. Attrition effects and multicollinearity were analysed and sets of logistic regression models were calculated for different treatment groups.
RESULTS: Of the 321 randomized patients, 201 completed procedures until week eight and 197 were included in the analyses. For all treatment groups, early TR after two weeks and high subjective well-being under antipsychotics at baseline were robust predictors for TR. The propensity for early side effects also indicated a higher risk of later non-response. Specific parameter estimates were rather similar between treatment groups.
CONCLUSIONS: Early TR, drug-related subjective well-being, and early side effect propensity evolved as predictors for later TR whether to monotherapy or combination strategy. Accordingly, due to a lack of differential predictors, early and close monitoring of targeted and unwanted effects is indicated to guide respective treatment decisions.

BACKGROUND: To date, disease-modifying antirheumatic drugs (DMARDs) are widely used as the primary first-line treatment option for patients with rheumatoid arthritis (RA), and the curative effect of methotrexate (MTX) and leflunomide (LEF; MTX + LEF) is greater than that of single-agent MTX therapy, but the synergistic mechanism of MTX + LEF is unclear.
METHODS: First, we explored the mechanism of action of MTX + LEF in RA through network pharmacology and molecular docking. Venn diagram analysis revealed 97 overlapping gene targets of MTX + LEF-RA and STRING, along with Cytoscape plug-in MOCDE and cytoHubba; and GO enrichment analysis revealed that the functions of 97 synergistic targets were related to 123 molecular functions (MF), 63 cell components (CC), and 1,068 biological processes (BP). The Cytoscape plug-in ClueGO demonstrated that these targets were enriched in KEGG pathways of 52 terms, whereas 9 pivotal genes were mainly involved in the signaling pathways of estrogen, Ras, Rap1, PI3K-Akt, relaxin, TNF, AMPK, FoxO, prolactin, IL-17, and adherens junction. Finally, CETSA and DARTS validated the direct binding of MTX or LEF to the selected target proteins EGFR, PPARG, MMP9, and SRC in RAW264.7 cells.
RESULTS: We identified 292 MTX targets and 247 LEF targets from 7 databases. Furthermore, 2,814 potential targets of RA were identified by merging 1,925 targets from 7 databases and 999 differentially expressed genes (DEGs) between normal controls and patients with RA extracted from 5 GEO databases. Nine pivotal genes, ESR1, ALB, CASP3, EGFR, HSP90AA1, SRC, MMP9, PPARG, and IGF1, were identified. Molecular docking verified that both MTX and LEF strongly bind to most of the 9 pivotal proteins except ESR1 and IGF1.
CONCLUSIONS: These results contribute to our understanding of the enhancement mechanism of MTX combined with LEF and provide a targeted basis for the clinical treatment of RA.

Worldwide, the majority of countries are actively devising strategies to address the challenges associated with unregulated and unmanageable development, the decline in environmental quality and the depletion of valuable agricultural land. This has led to a growing emphasis on understanding land use and land cover. In order to determine a better land use policy, legislators and planners need to know the current distribution of agricultural and urban lands, as well as information about changes in their proportions. Our approach combines data centred on main four themes-geology, slope gradient, hydrographic network and land use-in order to exploit classifier complementarities in our targeted agricultural study area of Tamlouka Basin, Algeria. Landsat 8 OLI-TIRs multispectral imagery and Shuttle Radar Topography Mission (SRTM-1arc v3) were used experimentally for classification and Digital Elevation Model (DEM) analysis. The classification\'s accuracy is confirmed by comparing the results of the decision tree classification with the validation samples. Results of the combination of several maps of classifications from the different methods show that the Tamlouka alluvial plain, having an area of 19,300 ha and an average slope gradient of less than 2°, drains the elevated reliefs that surround it via hydrographic network. The plain occupies 37% of the total basin area, with over of 60% being used for crop cultivation, regardless of fallow land areas in agricultural rotation at that time. The slope has been identified as a crucial factor determining land use patterns in the study area. This result can be used in prospective watershed management.

OBJECTIVE: The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab.
METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 μg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 μg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events.
RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 μg/mL, interquartile rate [IQR], 12.3-18.5 μg/mL versus 15.9 μg/mL, IQR, 10.1-22.7 μg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal.
CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.

BACKGROUND: Plasma amyloid-β (Aβ), phosphorylated tau-181 (p-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) potentially aid in the diagnosis of neurodegenerative dementias. We aim to conduct a comprehensive comparison between different biomarkers and their combination, which is lacking, in a multicenter Chinese dementia cohort consisting of Alzheimer\'s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP).
METHODS: We enrolled 92 demented patients [64 AD, 16 FTD, and 12 PSP with dementia] and 20 healthy controls (HC). Their plasma Αβ, p-tau181, NfL, and GFAP were detected by highly sensitive-single molecule immunoassays. Αβ pathology in patients was measured by cerebrospinal fluid or/and amyloid positron emission tomography.
RESULTS: All plasma biomarkers tested were significantly altered in dementia patients compared with HC, especially Aβ42/Aβ40 and NfL showed significant performance in distinguishing AD from HC. A combination of plasma Aβ42/Aβ40, p-tau181, NfL, and GFAP could discriminate FTD or PSP well from HC and was able to distinguish AD and non-AD (FTD/PSP).
CONCLUSIONS: Our results confirmed the diagnostic performance of individual plasma biomarkers Aβ42/Aβ40, p-tau181, NfL, and GFAP in Chinese dementia patients and noted that a combination of these biomarkers may be more accurate in identifying FTD/PSP patients and distinguishing AD from non-AD dementia.

Introduction Combination antifungal regimens are frequently employed in the treatment of invasive fungal infections in patients who are immunocompromised, particularly for cancer and transplant patients. Terbinafine is a potential agent of interest for combination regimens. Methods We reviewed data over a six-year period examining patient outcomes in terms of both mortality and distribution of pathogens. The total number of patients in our study was 64. The use of terbinafine versus no terbinafine in combination therapy was assessed. Of the 64 patients analyzed, only 14 received terbinafine. Mortality was calculated for both groups, and demographics were analyzed by descriptive statistics. Results There was no statistical difference in mortality outcomes in either group. The addition of terbinafine was well tolerated and did not appear to result in any undue toxicity concerns. Discussion We wish to draw greater attention to this potential agent within our armamentarium for invasive fungal infections. To our knowledge, the total number of patients in our study, while small, represents the largest reported cohort in the literature to date. Sensitivities are crucial to be obtained for fungal pathogens as this likely undermined the utility of terbinafine in our study with larger than expected numbers of multidrug-resistant Fusarium. With limited patient numbers, a multicenter trial would be beneficial to further examine terbinafine in combination regimens.

The coronavirus disease (COVID-19) pandemic continues to threaten global public health. Remdesivir and monoclonal antibodies have shown promise for COVID-19 treatment of patients who are immunocompromised, including those with cancer, transplant recipients, and those with autoimmune disorder. However, the effectiveness and safety of this combination therapy for patients who are immunosuppressed remain unclear. We compared the efficacy and safety of combination therapy and remdesivir monotherapy for patients with mild-to-moderate COVID-19 who were immunosuppressed. Eighty-six patients treated in July 2021-March 2023 were analyzed. The combination therapy group (CTG) showed a statistically significant reduction in viral load compared with the monotherapy group (MTG) (p < 0.01). Patients in the CTG also experienced earlier resolution of fever than those in the MTG (p = 0.02), although this difference was not significant in the multivariate analysis (p = 0.21). Additionally, the CTG had significantly higher discharge rates on days 7, 14, and 28 than the MTG (p < 0.01, p < 0.01, and p = 0.04, respectively). No serious adverse events were observed with combination therapy. These findings suggest that combination therapy may improve the clinical outcomes of immunosuppressed COVID-19 patients by reducing the viral load and hastening recovery. Further studies are required to fully understand the benefits of this combination therapy for immunocompromised COVID-19 patients.

There is a dearth of studies investigating whether the combination of low-intensity statins with ezetimibe can reduce the risk of diabetes in patients requiring statin therapy. Therefore, we aimed to evaluate the effects of combination therapy on the prevention of glycated hemoglobin (HbA1c) elevation in patients without diabetes. Sixty-eight patients were randomly assigned in a 1:1 ratio to receive a combination of low-intensity rosuvastatin (5 mg/day) and ezetimibe (10 mg/day) or high-intensity rosuvastatin (20 mg/day). The primary endpoint was the absolute difference in the HbA1c levels at 12 weeks. The HbA1c level showed an overall elevation of 0.11% at 12 weeks compared to that at baseline (mean ± standard deviation: 5.78 ± 0.3%, 95% confidence interval [CI]: 5.86-6.07, p = 0.044). The HbA1c levels did not differ between the groups at 12 weeks (least square mean difference: 0.001, 95% CI: 0.164-0.16, p = 0.999). Our study found that the combination of low-intensity rosuvastatin and ezetimibe did not yield significant differences in HbA1c levels compared to high-intensity rosuvastatin alone after 12 weeks in patients without diabetes. This suggests that the combination of low-intensity rosuvastatin and ezetimibe may not be an effective strategy for preventing HbA1c elevation in patients without diabetes requiring statins.

Liver fibrosis is a chronic liver lesion caused by excessive deposition of the extracellular matrix after liver damage, resulting in fibrous scarring of liver tissue. The progression of liver fibrosis is partially influenced by the gut microbiota. Chitosan can play a therapeutic role in liver fibrosis by regulating the gut microbiota based on the \'gut-liver axis\' theory. Salvianolic acid B can inhibit the development of liver fibrosis by inhibiting the activation of hepatic stellate cells and reducing the production of extracellular matrix. In this study, the therapeutic effect of chitosan in combination with salvianolic acid B on liver fibrosis was investigated in a mouse liver fibrosis model. The results showed that the combination of chitosan and salvianolic acid B was better than the drug alone, improving AST/ALT levels and reducing the expression of α-SAM, COL I, IL-6 and other related genes. It improved the structure of gut microbiota and increased the abundance of beneficial bacteria such as Lactobacillus. The above results could provide new ideas for the clinical treatment of liver fibrosis.

Due to their diverse and unique physical properties, miktoarm star copolymers (μ-SCPs) have garnered significant attention. In our study, we employed α-monobomoisobutyryl-terminated polydimethylsiloxane (PDMS-Br) to carry out styrenics-assisted atom transfer radical coupling (SA ATRC) in the presence of 4-vinylbenzyl alcohol (VBA) at 0 °C. By achieving high coupling efficiency (χc = 0.95), we obtained mid-chain functionalized PDMS-VBAm-PDMS polymers with benzylic alcohols. Interestingly, matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) analysis revealed the insertion of only two VBA coupling agents (m = 2). Subsequently, the PDMS-VBA2-PDMS products underwent mid-chain extensions using ε-caprolactone (ε-CL) through ring-opening polymerization (ROP) with an efficient organo-catalyst at 40 °C, resulting in the synthesis of novel (PDMS)2-μ-(PCL)2 μ-SCPs. Eventually, novel (PDMS)2-μ-(PCL)2 μ-SCPs were obtained. The obtained PDMS-μ-PCL μ-SCPs were further subjected to examination of their solid-state self-assembly through small-angle X-ray scattering (SAXS) experiments. Notably, various nanostructures, including lamellae and hexagonally packed cylinders, were observed with a periodic size of approximately 15 nm. As a result, we successfully developed a simple and effective reaction combination (Є) strategy (i.e., SA ATRC-Є-ROP) for the synthesis of well-defined PDMS-μ-PCL μ-SCPs. This approach may open up new possibilities for fabricating nanostructures from siloxane-based materials.