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In South Africa, medicinal plants are frequently used to treat infections, with the Faraday muthi market in Johannesburg ensuring accessibility to these medicines. This study aimed to determine the in vitro interactive antimicrobial and toxicity profiles of commonly traded traditional medicinal plants at the Faraday muthi market, with a range of conventional antimicrobials. Minimum inhibitory concentration (MIC) assays were conducted to determine the in vitro interactive profiles and tested against the ESKAPE pathogens (Enterococcus faecium ATCC 27270, Staphylococcus aureus ATCC 29212, Klebsiella pneumoniae ATCC 13883, Acinetobacter baumannii ATCC 19606, Pseudomonas aeruginosa ATCC 27853, Enterobacter cloacae ATCC 13460) and yeasts, Candida albicans ATCC 10231 and Candida glabrata ATCC 90030. The fractional inhibitory concentration index (ΣFIC) was determined to classify interactions as synergistic, additive, non-interactive or antagonistic. The brine-shrimp lethality assay (BSLA) was conducted to determine the toxicity of synergistic interactions. A total of 816 plant: antibiotic combinations were tested against the ESKAPE pathogens, with 392 combinations exhibiting a definitive ΣFIC. Synergy (6.63 %), antagonism (47.45 %), additive (8.67 %) and non-interactive (37.24 %) profiles were observed. Medicinal plants were most widely synergistic with azithromycin against S. aureus. Hypoxis hemerocallidea with azithromycin against S. aureus (ΣFIC 0.06) was the most synergistic, with no toxicity evident in the BLSA (6.06 % mortality). The most antagonistic interaction was with Eucalyptus sideroxylon and amoxicillin against K. pneumoniae (ΣFIC 138.12). Furthermore, a total of 136 plant: antifungal combinations were tested, where a definitive ΣFIC was obtained for 84 of the combinations. No synergy was observed, but 61.91 % of the combinations were antagonistic. The most antagonistic plant: antifungal combination was observed with Senecio serratuoloides and nystatin against C. albicans (ΣFIC 34.6). The vast antagonism against the ESKAPE pathogens (47.49 %) and yeasts (61.90 %) is cause for concern, particularly with antimicrobial resistance development. The most toxic combinations in the BSLA were when azithromycin was combined with Synaptolepis oliveriana (54.50 % average mortality after 48 h) and with Warburgia salutaris (100 % average mortality after 48 h). The synergy and antagonism observed in this study warrants further investigation for clinical translation, to determine potentially beneficial or harmful combinations where applicable. [ABSTRACT FROM AUTHOR]

An adequate provision of essential plant nutrients to cash crops such as potatoes not only ensures higher productivity and desired tuber quality but also promotes better development under unfavorable environments. The present trial was planned to investigate and understand the effects of various treatments of mineral fertilizers viz., nitrogen (N), phosphorus (P), and potassium (K) (NPK) in individual and combined forms on potato crops. Experimental treatments were comprised various combinations viz., control (no addition of any type of fertilizer); N = 150 kg ha−1; P = 75 kg ha−1; K = 225 kg ha−1; NP = N + P; NK = N + K; PK = P + K; NPK = N + P + K in soil. The results indicated that different combinations of NPK fertilizer in individual and combined forms not only influence the growth attributes such as stem diameter (83.96%) and tuber yields (180.09%) but also enhance photosynthetic attributes by improving the total chlorophyll (135.63%), carotenoids contents (143.75%), and potato quality by increasing tuber starch contents (78.75%), plant sucrose contents (52.86%) and sucrose enzyme activity (69.68%). A linear decrease in the lipid per oxidation attributes was observed where a combined application of NPK was applied. It was obvious that all the yield and quality attributes were enhanced by the combined application of NPK fertilization and then decreased gradually with the individual application of NPK fertilization. In contrast, though, the P and K application in combined form showed inferior response as compared to NP and NK fertilization. A clear and significant change in potato plants was observed under the various types of treatments especially related to the content and uptake of NPK in plants. Moreover, a highly significant relationship was observed between the balanced combination of NPK fertilization with tuber quality. This study underscores the importance of balanced fertilization practices in bolstering growth, yield, tuber quality, and antioxidative defense mechanisms and mitigating oxidative damage in potato crops. [ABSTRACT FROM AUTHOR]

AbstractThis article investigates the determinants of general trust in a society. A novel method – fuzzy set Qualitative Comparative Analysis (fsQCA) – is applied, which is consistent with the assumption that the recipe for high or low trust implies a combination of several conditions, and there can be different combinations that all produce the same outcome. It also relaxes the assumption of symmetry: conditions associated with low trust need not mirror conditions associated with high trust, with opposite signs. In this article, data about 79 countries are analysed using fsQCA in order to determine different combinations that would lead to low or high general trust. The results show that for general trust in a society, the Anna Karenina principle seems to apply: all high-trust societies are alike, but for low trust levels, there are many recipes. [ABSTRACT FROM AUTHOR]

AbstractTriciribine (TCN) is a tricyclic nucleoside. Its synthesis was first described in 1971. Subsequent studies have indicated that TCN plays a role in inhibiting DNA synthesis and was revealed to possess a higher selectivity for Akt. Although a single dose of TCN demonstrated limited activity in solid tumors at the clinical level, combinations of TCN with various agents, such as specific inhibitors, tyrosine kinase inhibitor dasatinib, ErbB inhibitor tipifarnib, IGF1-R inhibitor NVP-AEW541, mTORC1 inhibitor RAD-001, TNF-related apoptosis-inducing ligand, PPARγ agonist, 1,25(OH)2D3, gemcitabine, and paclitaxel, have been reported to be efficient against various malignancies such as pancreatic, breast, prostate cancer, insulinoma, gut neuroendocrine tumor, and hepatocellular carcinoma at the preclinical level. Other than malignancies, through Akt inhibition activity, TCN has also been demonstrated potential for treating lung injuries, including those encountered in COVID-19 infections. [ABSTRACT FROM AUTHOR]

An analysis of the harmonic series reveals a geometric structure of atomic hydrogen that defines the minimum radius of the bound electron. Subsequently, hydrogen's energy states, velocities, and angular momentum are determined. Based on these findings, a theoretical value is determined for Planck's reduced constant and the electron rest mass. In addition, an examination of hydrogen's quantum energy states suggests that they are the result of a combinatorial effect. [ABSTRACT FROM AUTHOR]

Fungal infections present a challenge when it comes to topical treatment failure thereby necessitating the need for more effective topical delivery systems. Essential oils have demonstrated noteworthy antifungal activity; however, their volatility limits therapeutic use for skin conditions. This study aimed to investigate the antifungal activity of essential oils alone and in combination. Thereafter, antifungal nanoparticulate formulations were designed using three essential oil combinations against Microsporum canis, Trichophyton mentagrophytes and Candida albicans. The antifungal activity was investigated using the broth microdilution assay to determine the minimum inhibitory concentration (MIC). The formulations were prepared by forming nanoparticles (polymer-based and composite lipid-polymer-based systems), with the preferred formulation encapsulating the essential oil combinations. Characterisation of the formulations was performed with a Zeta-sizer and using attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR). The in vitro antifungal activity of the three nanoparticulate formulations was then determined, where a significant (p = 0.002) increase in the average antidermatophyte activity could be observed for all three formulations. The combination of A. sativum and C. martinii displayed the lowest MIC value across all three reference strains (MIC values 0.06-0.38 mg mL-1) and the formulation maintained the antifungal activity with MIC values ranging 0.08-0.36 mg mL-1. A successful combination of essential oils with antifungal activity was achieved thereby emphasising an effective nanoparticulate formulation. [ABSTRACT FROM AUTHOR]

Aims Antimicrobial resistance continues to be a growing concern, resulting in increased use of drug combinations. Antibiotic adjuvants are an emerging strategy that may potentiate an antibiotics efficacy. Ibuprofen's polypharmacological properties have been investigated for their antimicrobial and host-modulating potential. This study aimed to investigate the potential of a novel multidrug combination involving ibuprofen, essential oil compounds (EOCs), and conventional antimicrobials against skin pathogens. Methods and Results The minimum inhibitory concentrations of ibuprofen, conventional antimicrobials, and EOCs were determined and then combined and tested against 14 (reference and clinical) skin pathogens. The cytotoxicity was analysed using the MTT assay, whilst the anti-inflammatory effects were evaluated using lipopolysaccharide activated RAW264.7 murine macrophages. Four pairwise (Ibuprofen and antibiotic) (ΣFIC 0.33–0.50) and three triple (Ibuprofen and antibiotic with EOC) (ΣFIC 0.44–0.47) synergistic antimicrobial interactions were identified. These combinations demonstrated cell viability of 77.59%–100%. No combination significantly reduced nitric oxide production. Conclusion The results from this study provide insight into the potential of a multidrug combination involving ibuprofen with conventional antimicrobials and EOCs against common skin pathogens. [ABSTRACT FROM AUTHOR]

Aims This study aimed to explore potential synergistic effects of medicinal dyes with antimicrobials against pathogens responsible for skin infections. Methods and results Antimicrobial testing was conducted using minimum inhibitory concentrations and minimum bactericidal/fungicidal concentration assays. The fractional inhibitory index (ΣFIC) of combinations was calculated, and isobolograms were constructed on selected combinations. Toxicity studies were conducted using the brine-shrimp lethality assay. Combination (1:1 ratio) studies noted that 26% of dye-antibiotic combinations were synergistic against the Gram-positive strains, 15% against the Gram-negative strains, and 14% against the yeasts. The Mercurochrome: Betadine® combination noted synergy at ratios against all the Staphylococcus aureus strains with ΣFIC values ranging from 0.05 to 0.48. The combination of Gentian violet with Gentamycin noted a 15-fold decrease in toxicity, and a selectivity index of 977.50 against the Escherichia coli (DSM 22314) strain. Time-kill studies were conducted on the combinations with the highest safe selectivity index (SI) value and lowest safe SI value i.e. Gentian violet with Gentamycin and Malachite green with Neomycin. Both combinations demonstrated better antimicrobial activity in comparison to the independent values and the controls. Conclusion This study highlights the potential for medicinal dye combinations as a treatment for skin infections. [ABSTRACT FROM AUTHOR]

This work introduces a novel cue that consumption advisers, like stylists and interior designers, can use to signal expertise: combinatory recommendations. In a combinatory recommendation, a person offers an opinion about compatibility among multiple products intended for joint usage. Across nine studies conducted in the lab and field, the authors find that offering a combinatory recommendation signals greater expertise (Study 1a, Study 2a) and, specifically, greater depth of knowledge (Study 1b), compared with other types of recommendations involving the same number of products. This effect does not depend on the helpfulness of the adviser (Study 2b) but is qualified by features of the recommendation itself (Study 3a) as well as the type of combination recommended (Study 3b). Importantly, the authors find this effect to have important downstream consequences, as the increased perceptions of expertise that follow a combinatory recommendation improve consumers' attitudes both toward products included in the recommendation and toward subsequent recommendations made by the adviser (Study 4, Study 5). The real-world persuasive value of combinatory recommendations is also tested in a field study (Study 6) that explores the effect of combinatory recommendations on click-through rates of Instagram advertisements. [ABSTRACT FROM AUTHOR]

Time series forecasting plays an increasingly important role in modern business decisions. In today's data-rich environment, people often aim to choose the optimal forecasting model for their data. However, identifying the optimal model requires professional knowledge and experience, making accurate forecasting a challenging task. To mitigate the importance of model selection, we propose a simple and reliable algorithm to improve the forecasting performance. Specifically, we construct multiple time series with different sub-seasons from the original time series. These derived series highlight different sub-seasonal patterns of the original series, making it possible for the forecasting methods to capture diverse patterns and components of the data. Subsequently, we produce forecasts for these multiple series separately with classical statistical models (ETS or ARIMA). Finally, the forecasts are combined. We evaluate our approach on widely used forecasting competition data sets (M1, M3, and M4) in terms of both point forecasts and prediction intervals. We observe performance improvements compared with the benchmarks. Our approach is particularly suitable and robust for the data with higher frequency. To demonstrate the practical value of our proposition, we showcase the performance improvements from our approach on hourly load data that exhibit multiple seasonal patterns. [ABSTRACT FROM AUTHOR]

The combination of aspirin (ASP) and clopidogrel (CLD) has demonstrated efficacy in managing coronary syndromes, including unstable angina and myocardial infarction. This regimen prevents clotting and effectively reduces the risk of vascular events by inhibiting both adenosine diphosphate and the cyclooxygenase pathway. Furthermore, cholesterol-lowering agents such as statins are also employed as a preventive measure for patients with acute coronary syndromes (ACS). This article reviews the current analytical methods for the quantitative determination of aspirin in combination with clopidogrel, or the combination of the two drugs with one of the statins, in various marketed formulations in the period of 2005 -2024. The most commonly used methods for determining these combinations include chromatographic techniques such as high-pressure liquid chromatography (HPLC) and thin-layer chromatography (TLC), as well as spectrophotometric methods. Recent trends in the analysis of these combination samples show a preference for HPLC (60%), thin-layer chromatography (TLC) (22.5%) and spectrophotometric methods (17.5%) reflecting a general shift towards more sensitive methods with higher resolution capabilities. These methods also offer the advantages of requiring smaller quantities of samples and reagents and shorter analysis times.

The combination of aspirin (ASP) and clopidogrel (CLD) has demonstrated efficacy in managing coronary syndromes, including unstable angina and myocardial infarction. This regimen prevents clotting and effectively reduces the risk of vascular events by inhibiting both adenosine diphosphate and the cyclooxygenase pathway. Furthermore, cholesterol-lowering agents such as statins are also employed as a preventive measure for patients with acute coronary syndromes (ACS). This article reviews the current analytical methods for the quantitative determination of aspirin in combination with clopidogrel, or the combination of the two drugs with one of the statins, in various marketed formulations in the period of 2005 -2024. The most commonly used methods for determining these combinations include chromatographic techniques such as high-pressure liquid chromatography (HPLC) and thin-layer chromatography (TLC), as well as spectrophotometric methods. Recent trends in the analysis of these combination samples show a preference for HPLC (60%), thin-layer chromatography (TLC) (22.5%) and spectrophotometric methods (17.5%) reflecting a general shift towards more sensitive methods with higher resolution capabilities. These methods also offer the advantages of requiring smaller quantities of samples and reagents and shorter analysis times. [ABSTRACT FROM AUTHOR]

The present study aims to evaluate the antibacterial activity of five commercially available essential oils (EOs), Lavender (LEO), Clove (CEO), Oregano (OEO), Eucalyptus (EEO), and Peppermint (PEO), against the most-known MDR Gram-positive and Gram-negative bacteria—Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), and Pseudomonas aeruginosa (ATCC 27853)—alone and in various combinations. Gas Chromatography–Mass Spectrometry (GC-MS) analysis established their complex compositions. Then, their antibacterial activity—expressed as the inhibition zone diameter (IZD) value (mm)—was investigated in vitro by the diffusimetric antibiogram method, using sterile cellulose discs with Ø 6 mm impregnated with 10 µL of sample and sterile borosilicate glass cylinders loaded with 100 µL; the minimum inhibitory concentration (MIC) value (µg/mL) for each EO was calculated from the IZD values (mm) measured after 24 h. The following EO combinations were evaluated: OEO+CEO, CEO+EEO, CEO+PEO, LEO+EEO, and EEO+PEO. Then, the influence of each dual combination on the activity of three conventional antibacterial drugs—Neomycin (NEO), Tetracycline (TET), and Bacitracin (BAC)—was investigated. The most active EOs against S. aureus and E. coli were LEO and OEO (IZD = 40 mm). They were followed by CEO and EEO (IZD = 20–27 mm); PEO exhibited the lowest antibacterial activity (IZD = 15–20 mm). EEO alone showed the highest inhibitory activity on P. aeruginosa (IZD = 25–35 mm). It was followed by CEO, LEO, and EEO (IZD = 7–11 mm), while PEO proved no antibacterial action against it (IZD = 0 mm). Only one synergic action was recorded (OEO+CEO against P. aeruginosa); EEO+PEO revealed partial synergism against S. aureus and CEO+PEO showed additive behavior against E. coli. Two triple associations with TET showed partial synergism against E. coli, and the other two (with NEO and TET) evidenced the same behavior against S. aureus; all contained EEO+PEO or CEO+PEO. Most combinations reported indifference. However, numerous cases involved antagonism between the constituents included in the double and triple combinations, and the EOs with the strongest antibacterial activities belonged to the highest antagonistic combinations. A consistent statistical analysis supported our results, showing that the EOs with moderate antibacterial activities could generate combinations with higher inhibitory effects based on synergistic or additive interactions. [ABSTRACT FROM AUTHOR]

Copyright of Ecosistemas y Recursos Agropecuarios is the property of Universidad Juarez Autonoma de Tabasco and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Yuhang Wang,1,* Chunsun Li,2,* Huan Zhang,1 Yulong Chi,1 Yun Cai1 1Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies Center of PLA General Hospital, Beijing, People’s Republic of China; 2Laboratory of Department of Pulmonary and Critical Care Medicine, PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Cai, Center of Medicine Clinical Research, Department of Pharmacy, Medical Supplies center of PLA General Hospital, Postal Address: 28 Fu Xing Road, Beijing, 100853, People’s Republic of China, Tel +86-10-6693-7166, Fax +86-10-8821-4425, Email caicai_hh@126.comObjective: Pseudomonas aeruginosa (PA) often displays drug resistance and biofilm-mediated adaptability. Here, we aimed to evaluate the antibiofilm efficacy of azithromycin-based combination regimens.Methods: Minimum inhibitory concentrations (MICs), minimal biofilm eradication concentrations (MBECs), and MBEC-combination of azithromycin, colistin, amikacin, and levofloxacin to bioluminescent strain PAO1 and carbapenem-resistant PAO1 (CRPAO1) were assessed. An animal biofilm infection model was established and detected using a live animal bio-photonic imaging system.Results: In vitro, PAO1 and CRPAO1 were susceptible to colistin, amikacin, and levofloxacin, while they were unsusceptible to azithromycin. The combinations based on azithromycin have no synergistic effect on biofilm in vitro. In vivo, azithromycin plus colistin or levofloxacin could shorten the PAO1 biofilm eradication time, which totally eradicates the biofilm in all mice on the 8th or 6th day, while monotherapy only eradicate biofilm in 70% or 80% mice on the 8th day. For CRPAO1 biofilm, only azithromycin–colistin combination and colistin monotherapy eradicated the bacteria in 60% and 40% of mice at the 6th day.Conclusion: Azithromycin-based combinations containing levofloxacin or colistin had no synergistic effect in vitro, and they are promising for clinical applications due to the good synergistic activity against PAO1 biofilms in vivo.Keywords: Pseudomonas aeruginosa, biofilm, azithromycin, combinations

Efforts to develop new artemisinin triple combination therapies effective against artemisinin-tolerant strains of Plasmodium falciparum based on rational combinations comprising artemisone or other amino-artemisinins, a redox active drug and a third drug with a different mode of action have now been extended to evaluation of three potential redox partners. These are the diethyl analogue AD01 of methylene blue (MB), the benzo [α]phenoxazine PhX6, and the thiosemicarbazone DpNEt. IC50 values in vitro against CQ-sensitive and resistant P. falciparum strains ranged from 11.9 nM for AD01--41.8 nM for PhX6. PhX6 possessed the most favourable pharmacokinetic (PK) profile: intrinsic clearance rate CLint was 21.47 ± 1.76 mL/min/kg, bioavailability was 60% and half-life was 7.96 h. AD01 presented weaker, but manageable pharmacokinetic properties with a rapid CLint of 74.41 ± 6.68 mL/min/kg leading to a half-life of 2.51 ± 0.07 h and bioavailability of 15%. DpNEt exhibited a half-life of 1.12 h and bioavailability of 8%, data which discourage its further examination, despite a low CLint of 10.20 mL/min/kg and a high Cmax of 6.32 µM. Efficacies of AD01 and PhX6 were enhanced synergistically when each was paired with artemisone against asexual blood stages of P. falciparum NF54 in vitro. The favourable pharmacokinetics of PhX6 indicate this is the best partner among the compounds examined thus far for artemisone. Future work will focus on extending the drug combination studies to artemiside in vitro, and conducting efficacy studies in vivo for artemisone with each of PhX6 and the related benzo[α]phenoxazine SSJ-183. [ABSTRACT FROM AUTHOR]

Compounds that potentiate the activity of clinically available antibiotics provide a complementary solution, except for developing novel antibiotics for the rapid emergence of multidrug-resistant Gram-negative bacteria (GNB). We sought to identify compounds potentiating polymyxin B (PMB), a traditional drug that has been revived as the last line for treating life-threatening GNB infections, thus reducing its nephrotoxicity and heterogeneous resistance in clinical use. In this study, we found a natural product, sanguinarine (SA), which potentiated the efficacy of PMB against GNB infections. The synergistic effect of SA with PMB was evaluated using a checkerboard assay and time–kill curves in vivo and the murine peritonitis model induced by Escherichia coli in female CD-1 mice in vivo. SA assisted PMB in accelerating the reduction in bacterial loads both in vitro and in vivo, improving the inflammatory responses and survival rate of infected animals. The subsequent detection of the intracellular ATP levels, membrane potential, and membrane integrity indicated that SA enhanced the bacterial-membrane-breaking capacity of PMB. A metabolomic analysis showed that the inhibition of energy metabolism, interference with nucleic acid biosynthesis, and the blocking of L-Ara4N-related PMB resistance may also contribute to the synergistic effect. This study is the first to reveal the synergistic activity and mechanism of SA with PMB, which highlights further insights into anti-GNB drug development. [ABSTRACT FROM AUTHOR]

In this paper, it is shown that a positive integer t can be written as t = ∑ i = 0 r − 1 (− 1) i (r − 1 , i) (t + r − 1 − i , r). It is also proved that the two expressions for number of codewords of weight t , obtained in Theorem 1[P. Kumar, M. Sangwan and S. K. Arora, The weight distributions of some irreducible cyclic codes of length p n and 2 p n , Adv. Math. Commun.9 (2015) 277–289] and in Theorem 1 Case (i)[G. Vega, The weight distribution for any irreducible cyclic code of length p m , Appl. Algebra Eng. Commun. Comput.29(4) (2018) 363–370] are same. [ABSTRACT FROM AUTHOR]

Abstract Background Schistosomiasis control relies on praziquantel for preventive chemotherapy. Alternative drugs are needed for the treatment and control of schistosomiasis. Praziquantel is effective against adult schistosome worms but ineffective against larval stages of the parasite and cannot prevent re-infection or interrupt the transmission of infection. Continued reliance on praziquantel for wide-scale schistosomiasis control will likely accelerate the emergence of drug resistance. Artemisinin derivatives are effective against the juvenile stages but ineffective against adult worms. The SCHISTOACT study aimed to evaluate the efficacy and safety of praziquantel plus one of four artemisinin-based combinations in treating Schistosoma mansoni infection in Kenya. Methods The SCHISTOACT study is an open-label, head-to-head, five-arm, proof-of-concept, non-inferiority, individually randomized controlled trial with a follow-up of 12 weeks. A total of 540 primary school-aged children from the Mwea area, Kirinyaga County in central Kenya, diagnosed with S. mansoni infection (by Kato-Katz method) are randomly allocated (1:1:1:1:1) to a single dose of praziquantel plus a 3-day course of artesunate-sulfalene/pyrimethamine, or artesunate-amodiaquine, or artesunate plus mefloquine, or dihydroartemisinin-piperaquine, or praziquantel control arm. The primary endpoints are efficacy (cure rate, assessed by microscopy) and safety (adverse events) of each study arm 6 weeks after treatment. Secondary endpoints include cumulative cure rate, egg reduction rate, and re-infection 12 weeks after treatment. The non-inferiority margin is set at − 10 for the risk difference in cure rates between praziquantel and the combined treatment. Discussion This study assesses a strategy for repurposing artemisinin-based combination therapies (ACTs) for treating schistosomiasis. It adopts a head-to-head comparison of four different ACTs to test a non-inferiority hypothesis and to strengthen local capacity to conduct clinical trials for interventions against neglected tropical diseases. Trial registration Pan-African Clinical Trials Registry PACTR202001919442161 . Retrospectively registered on 6 January 2020

Abstract Background Inhibitors of Poly (ADP-Ribose) Polymerases (PARP) provide clinical benefit to patients with breast and ovarian cancers, by compromising the DNA repair activity of cancer cells. Although these agents extend progression-free survival in many patients, responses can be short lived with many patients ultimately progressing. Identification of combination partners that increase dependence of cancer cells to the DNA repair activity of PARPs may represent a strategy to increase the utility of PARP inhibitors. Protein arginine methyltransferase 5 (PRMT5) regulates DNA damage response pathways through splicing and protein modification, and inhibitors of PRMT5 have recently entered clinical trials. Methods The effect of PRMT5 inhibition on the levels of DNA damage and repair markers including γH2AX, RAD51, and 53BP1 was determined using high content immunofluorescent imaging. The anti-proliferative activity of the combination of PRMT5 and PARP inhibitors was evaluated using in vitro models of breast and ovarian cancers using both cell lines and ex vivo patient derived xenografts. Finally, the combinations of PRMT5 and PARP inhibitors were evaluated in cell line xenograft models in vivo. Results Inhibition of PRMT5 by GSK3326595 led to increased levels of markers of DNA damage. The addition of GSK3326595 to the PARP inhibitor, niraparib, resulted in increased growth inhibition of breast and ovarian cancer cell lines and patient derived spheroids. In vivo, the combination improved the partial effects on tumor growth inhibition achieved by either single agent, producing complete tumor stasis and regression. Conclusion These data demonstrate that inhibition of PRMT5 induced signatures of DNA damage in models of breast and ovarian cancer. Furthermore, combination with the PARP inhibitor, Niraparib, resulted in increased anti-tumor activity in vitro and in vivo. Overall, these data suggest inhibition of PRMT5 as a mechanism to broaden and enhance the clinical application of PARP inhibitors.

Efforts to develop new artemisinin triple combination therapies effective against artemisinin-tolerant strains of Plasmodium falciparum based on rational combinations comprising artemisone or other amino-artemisinins, a redox active drug and a third drug with a different mode of action have now been extended to evaluation of three potential redox partners. These are the diethyl analogue AD01 of methylene blue (MB), the benzo [α]phenoxazine PhX6, and the thiosemicarbazone DpNEt. IC50 values in vitro against CQ-sensitive and resistant P. falciparum strains ranged from 11.9 nM for AD01–41.8 nM for PhX6. PhX6 possessed the most favourable pharmacokinetic (PK) profile: intrinsic clearance rate CLint was 21.47 ± 1.76 mL/min/kg, bioavailability was 60% and half-life was 7.96 h. AD01 presented weaker, but manageable pharmacokinetic properties with a rapid CLint of 74.41 ± 6.68 mL/min/kg leading to a half-life of 2.51 ± 0.07 h and bioavailability of 15%. DpNEt exhibited a half-life of 1.12 h and bioavailability of 8%, data which discourage its further examination, despite a low CLint of 10.20 mL/min/kg and a high Cmax of 6.32 µM. Efficacies of AD01 and PhX6 were enhanced synergistically when each was paired with artemisone against asexual blood stages of P. falciparum NF54 in vitro. The favourable pharmacokinetics of PhX6 indicate this is the best partner among the compounds examined thus far for artemisone. Future work will focus on extending the drug combination studies to artemiside in vitro, and conducting efficacy studies in vivo for artemisone with each of PhX6 and the related benzo[α]phenoxazine SSJ-183.

Synonymies of two species described from specimens collected in Argentina are established: Aphis mulinicola syn. n. from the also Argentine species Aphis mulini, and Aphis mulguraeae syn. n. from the cosmopolitan species Aphis gossypii. Two species of Brachyunguis also described from Argentine specimens, are transferred to the genus Aphis: Aphis blanchardi comb. n. of Brachyunguis blanchardi and Aphis bahamondesi comb. n. from Brachyunguis bahamondesi. Alate viviparous and oviparous females and males of A. mulini are described and the life cycle of this species is established, it is holocyclic monoecicous. [ABSTRACT FROM AUTHOR]

The properties of silk make it a promising material for medical applications, both in human and veterinary medicine. Its predominant amino acids, glycine and alanine, exhibit low chemical reactivity, reducing the risk of graft rejection, a notable advantage over most synthetic polymers. Hence, silk is increasingly used as a material for 3D printing in biomedicine. It can be used to build cell scaffolding with the desired cytocompatibility and biodegradability. In combination with gelatine, silk can be used in the treatment of arthritis, and as a hydrogel, to regenerate chondrocytes and mesenchymal cells. When combined with gelatine and collagen, it can also make skin grafts and regenerate the integumentary system. In the treatment of bone tissue, it can be used in combination with polylactic acid and hydroxyapatite to produce bone clips having good mechanical properties and high immunological tolerance. Furthermore, silk can provide a good microenvironment for the proliferation of bone marrow stem cells. Moreover, research is underway to produce artificial blood vessels using silk in combination with glycidyl methacrylate. Silk vascular grafts have demonstrated a high degree of patency and a satisfactory degree of endothelial cells coverage. [ABSTRACT FROM AUTHOR]

The diffusion technology has been developed for the formation of binary clusters involving elements of group III and V in silicon. It is shown that by controlling the concentration of elements of group III and V atoms, multilayer silicon-based heterojuns can be formed in the surface region of silicon with enriched AIIIBV nanocrystals, followed by enriched with various combinations of Si2AIIIBV unit cells (1 – 5 m thick). This creates a practical new material based on silicon - a continuous graded-gap structure, i.e. heterojunsby a smooth transition from the band gap of III – V semiconductor compounds to the band gap of silicon. [ABSTRACT FROM AUTHOR]

Purpose of Review: It is clear from epidemiological studies that patients at high and very-high risk of atherosclerotic cardiovascular diseases (ASCVD) risk do not reach lipid guideline–recommended targets. Thus, fixed-dose combinations of statins/ezetimibe, bempedoic acid/ezetimibe and statins/fibrates may represent a further armamentarium in the field of lipid-lowering approaches in these individuals. Recent Findings: The combination therapy of moderate-intensity statin with ezetimibe is not inferior to high-intensity statin monotherapy in reducing cardiovascular outcomes. Drug discontinuation or dose reduction is inferior with fixed-dose combination. The fixed-dose combination of bempedoic acid with ezetimibe is superior to bempedoic acid in monotherapy in lowering LDL-C and in reducing high-sensitivity C-reactive protein concentrations. The combination fenofibrate with atorvastatin is superior to monotherapies in lowering triglycerides. Summary: Lipid-lowering fixed-dose combinations may guarantee a higher therapy adherence, representing a better approach to control plasma lipids and thus ameliorate ASCVD burden. Additional studies will define the advantages on cardiovascular outcomes in high and very high-risk patients. [ABSTRACT FROM AUTHOR]

The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered supportive roles for the mevalonate pathway in numerous cellular processes that support oncogenesis, most recently macropinocytosis. Central to the diverse mechanisms of statin sensitivity is an acquired dependence on one mevalonate pathway output, protein geranylgeranylation. New chemical prenylation probes and the discovery of a novel geranylgeranyl transferase hold promise to deepen our understanding of statin mechanisms of action. Further, insights into statin selection and the counterproductive role of dietary geranylgeraniol highlight how we should assess statins in the clinic. Lastly, rational combination strategies preview how statins will enter the oncology toolbox.

Background: Inhibitors of Poly (ADP-Ribose) Polymerases (PARP) provide clinical benefit to patients with breast and ovarian cancers, by compromising the DNA repair activity of cancer cells. Although these agents extend progression-free survival in many patients, responses can be short lived with many patients ultimately progressing. Identification of combination partners that increase dependence of cancer cells to the DNA repair activity of PARPs may represent a strategy to increase the utility of PARP inhibitors. Protein arginine methyltransferase 5 (PRMT5) regulates DNA damage response pathways through splicing and protein modification, and inhibitors of PRMT5 have recently entered clinical trials. Methods: The effect of PRMT5 inhibition on the levels of DNA damage and repair markers including γH2AX, RAD51, and 53BP1 was determined using high content immunofluorescent imaging. The anti-proliferative activity of the combination of PRMT5 and PARP inhibitors was evaluated using in vitro models of breast and ovarian cancers using both cell lines and ex vivo patient derived xenografts. Finally, the combinations of PRMT5 and PARP inhibitors were evaluated in cell line xenograft models in vivo. Results: Inhibition of PRMT5 by GSK3326595 led to increased levels of markers of DNA damage. The addition of GSK3326595 to the PARP inhibitor, niraparib, resulted in increased growth inhibition of breast and ovarian cancer cell lines and patient derived spheroids. In vivo, the combination improved the partial effects on tumor growth inhibition achieved by either single agent, producing complete tumor stasis and regression. Conclusion: These data demonstrate that inhibition of PRMT5 induced signatures of DNA damage in models of breast and ovarian cancer. Furthermore, combination with the PARP inhibitor, Niraparib, resulted in increased anti-tumor activity in vitro and in vivo. Overall, these data suggest inhibition of PRMT5 as a mechanism to broaden and enhance the clinical application of PARP inhibitors. [ABSTRACT FROM AUTHOR]

This review provides • Overview on repurposing types and trends in approvals. • The bridging study requirements for reformulations and new combinations. • Regulatory and intellectual property considerations with special emphasis on reformulations and new combinations. • Discussions of the need of an integrated intellectual property and regulatory strategy for the development of repurposed drug products. Repurposing is considered an attractive approach for developing new drug products. However, it consists of challenges relating to intellectual property (IP) protection, and regulatory approvals. This study aimed to analyze the recent trends in repurposed drugs approved by USFDA from 2010 to 2020 and to assess the challenges connected with bridging study requirements, patent protection, and exclusivities. Out of 1001 NDAs, 570 were approved via 505(b)(2) pathway. Of 570 NDAs, the highest number of approvals are allied to type 5-new formulations (42.4%), followed by type 3-new dosage forms (26.4%) and type 4-new combinations (13.1%). Of 570 NDAs, 470 are considered to examine the patent and exclusivity protection of which 341 have patent and/or exclusivity. A total of 97 type-3 and type-5 and 14 type-4 drugs have been approved based on human bioavailability/bioequivalence (BA/BE) data. For 131 type-3 and type-5 and 34 type-4 drugs, the applicants conducted new clinical (efficacy and/or safety) studies along with BA/BE (100 drugs) or without BA/BE (65 drugs) studies. In this review, mechanistic reasons for conducting new clinical investigations, IP and regulatory considerations along with broader perspective on new pharmaceutical approaches employed in 505(b)(2) drugs are illustrated that provide guidance for development of reformulations and combinations. [ABSTRACT FROM AUTHOR]

Presented here are new combinations made in advance of publication of an Annotated Checklist for the Flora of Nevada. New combinations of Aliciella latifolia var. imperialis, Androsace elongata var. acuta, Arceuthobium abietinum var. grandae, Arceuthobium abietinum var. magnificae, Arceuthobium abietinum var. mathiasenii, Arceuthobium abietinum var. wiensii, Artemisia cana var. bolanderi, Askellia pygmaea var. ramosa, Boechera fernaldiana var. vivariensis, Calystegia sepium var. limnophila, Camissoniopsis pallida var. hallii, Cassiope mertensiana var. californica, Centaurea stoebe var. micranthos, Chloropyron maritimum var. canescens, Chloropyron maritimum var. palustre, Chloropyron maritimum var. parryi, Chylismia brevipes var. pallidula, Chylismia cardiophylla var. cedrosensis, Chylismia cardiophylla var. robusta, Chylismia claviformis var. aurantiaca, Chylismia claviformis var. cruciformis, Chylismia claviformis var. funerea, Chylismia claviformis var. lancifolia, Chylismia claviformis var. peeblesii, Chylismia claviformis var. peirsonii, Chylismia claviformis var. purpurascens, Chylismia claviformis var. rubescens, Chylismia claviformis var. wigginsii, Chylismia claviformis var. yumae, Chylismia scapoidea var. brachycarpa, Chylismia scapoidea var. macrocarpa, Chylismia scapoidea var. utahensis, Chylismia walkeri var. tortilis, Crepis runcinata var. hallii, Dianthus armeria var. armeriastrum, Eremothera boothii var. alyssoides, Eremothera boothii var. condensata, Eremothera boothii var. decorticans, Eremothera boothii var. desertorum, Eremothera boothii var. villosa, Eriastrum diffusum var. coachellae, Eriastrum diffusum var. utahense, Eriastrum eremicum var. markianum, Eriastrum eremicum var. yageri, Eriastrum eremicum var. zionis, Festuca brachyphylla var. breviculmis, Gilia aliquanta var. breviloba, Gilia brecciarum var. jacens, Gilia brecciarum var. neglecta, Gilia cana var. bernardina, Gilia cana var. speciformis, Gilia cana var. speciosa, Gilia cana var. triceps, Gilia ochroleuca var. bizonata, Gilia ochroleuca var. exilis, Gilia ochroleuca var. vivida, Hedeoma nana var. californica, Hulsea vestita var. inyoensis, Ipomopsis tenuituba var. latiloba, Langloisia setosissima var. punctata, Leontodon saxatilis var. longirostris, Leptosiphon chrysanthus var. decorus, Leptosiphon nuttallii var. howellii, Leptosiphon nuttallii var. pubescens, Linanthus bigelovii var. johnsonii, Linanthus pungens var. pulchriflorus, Linanthus watsonii var. dolomiticus, Monardella breweri var. lanceolata, Monardella linoides var. sierrae, Navarretia leptalea var. bicolor, Navarretia leucocephala var. bakeri, Navarretia leucocephala var. minima, Navarretia leucocephala var. pauciflora, Navarretia leucocephala var. plieantha, Navarretia linearifolia var. pinnatisecta, Noccaea fendleri var. glauca, Orthocarpus cuspidatus var. copelandii, Pedicularis attollens var. protogyna, Penstemon thompsoniae var. jaegeri, Pentagramma triangularis var. maxonii, Pentagramma triangularis var. rebmanii, Pentagramma triangularis var. semipallida, Pentagramma triangularis var. viscosa, Perideridia parishii var. latifolia, Phragmites australis var. americanus, Poa abbreviata var. marshii, Poa abbreviata var. pattersonii, Polygonum aviculare var. buxiforme, Proboscidea louisiana var. fragrans, Rhodiola integrifolia var. leedyi, Rhodiola integrifolia var. neomexicana, Rosa woodsii var. puberulenta, Sagina decumbens var. occidentalis, and Veronica wormskjoldii var. nutans, are made. [ABSTRACT FROM AUTHOR]

The rapid rise in research and development following the discovery of photodynamic therapy to establish novel photosensitizers and overcome the limitations of the technology soon after its clinical translation has given rise to a few significant milestones. These include several novel generations of photosensitizers, the widening of the scope of applications, leveraging of the offerings of nanotechnology for greater efficacy, selectivity for the disease over host tissue and cells, the advent of combination therapies with other similarly minimally invasive therapeutic technologies, the use of stimulus-responsive delivery and disease targeting, and greater penetration depth of the activation energy. Brought together, all these milestones have contributed to the significant enhancement of what is still arguably a novel technology. Yet the major applications of photodynamic therapy still remain firmly located in neoplasms, from where most of the new innovations appear to launch to other areas, such as microbial, fungal, viral, acne, wet age-related macular degeneration, atherosclerosis, psoriasis, environmental sanitization, pest control, and dermatology. Three main value propositions of combinations of photodynamic therapy include the synergistic and additive enhancement of efficacy, the relatively low emergence of resistance and its rapid development as a targeted and high-precision therapy. Combinations with established methods such as chemotherapy and radiotherapy and demonstrated applications in mop-up surgery promise to enhance these top three clinical tools. From published in vitro and preclinical studies, clinical trials and applications, and postclinical case studies, seven combinations with photodynamic therapy have become prominent research interests because they are potentially easily applied, showing enhanced efficacy, and are rapidly translating to the clinic. These include combinations with chemotherapy, photothermal therapy, magnetic hyperthermia, cold plasma therapy, sonodynamic therapy, immunotherapy, and radiotherapy. Photochemical internalization is a critical mechanism for some combinations. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify the combinations of chronic comorbidities associated with length of stay (LOS) among multimorbid medical inpatients.Multinational retrospective cohort of 126,828 medical inpatients with multimorbidity, defined as ≥2 chronic diseases (data collection: 2010-2011). We categorized the chronic diseases into comorbidities using the Clinical Classification Software. We described the 20 combinations of comorbidities with the strongest association with prolonged LOS, defined as longer than or equal to country-specific LOS, and reported the difference in median LOS for those combinations. We also assessed the association between the number of diseases or body systems involved and prolonged LOS.The strongest association with prolonged LOS (odds ratio [OR] 7.25, 95% confidence interval [CI] 6.64-7.91, P

Combinations of medicinal plants ensure the collective work of several active components, which can lead to an additive or synergistic effect. We have chosen the bur-marigold-calendula-hawthorn combination to obtain an antiallergic herbal medicine, in which the bur-marigold is the main plant, calendula is a helper plant that helps in the fight against accompanying symptoms, and hawthorn harmonizes the action of the first 2 plants. The aim of the work – the study of possible synergistic interactions in a multicomponent herbal antiallergic preparation by calculating the correlation between the content of polyphenols in various combinations of plant extracts and their antioxidant activity. Both individual extracts of a bur-marigold herb, calendula flowers and hawthorn leaves and flowers and a combined target extract with the ratio of herbal drugs (6:3:1) were obtained. Two and three component ompositions were obtained by mixing extracts in appropriate ratios. The content of polyphenols was determined by SPhU 2.0, 2.8.14. The antioxidant activity was determined by the neocuproin method. The Pearson Correlation was used to calculate the relationship between the content of polyphenols in extracts and their antioxidant activity. The maximum amount of polyphenols was found in the hawthorn extract (7.2%), in the bur-marigolg extract – 5.5%, and in the calendula extract – 3.4%. When adding calendula extract to the bur-marigold extract, the antioxidant activity was expected to decrease, thus an additive effect is observed; for the combination of bur-marigold /hawthorn 1:0.5, an increase in antioxidant activity (110.6%) was observed compared to the expected value, which may be synergism; for the combination of calendula/hawthorn, an increase in activity was observed. For 3-component combinations, it was found that only the combination of bur-marigold/calendula/hawthorn 1:0.5:0.5 showed greater activity (112%) than the target extract, all others combinations showed activity within the limits of possible variations (± 10%) of the components. When calculating the correlation between the content of polyphenols in the combinations and their activity using the Pearson coefficient, a strong positive correlation was found. The correlation between the content of polyphenols in various combinations of plant extracts and their antioxidant activity of a multicomponent herbal antiallergic preparation was studied. In 2-component combinations an additive effect was found when determining antioxidant activity, and an assumption was made about the ability of a synergism only for a combination of bur-marigold/hawthorn 1:0.5. All analyzed 3-component compositions showed antioxidant activity within the limits of possible variations (± 10%) of the components. A strong positive correlation was found between the content of polyphenols in the combinations and their activity.

Cellular signaling is generally understood as the support of communication between contiguous cells belonging to the same tissue or cells being far apart of each other, at a molecular scale, when the message emitted by the transmitters is traveling in liquid or solid matter to reach recipient targets. Subcellular signaling is also important to ensure the proper cell constitution and functioning. However cell signaling is mostly used in the first understanding, to describe how the message sent from one point to another one, will reach a target where it will be interpreted. The Cellular Communication Network (CCN) factors (Perbal et al. 2018) constitute a family of biological regulators thought to be responsible for signaling pathways coordination (Perbal 2018). Indeed, these proteins interact with a diverse group of cell receptors, such as integrins, low density lipoprotein receptors, heparan sulfate proteoglycan receptors (HSPG), and the immunoglobulin superfamily expressed exclusively in the nervous system, or with soluble factors such as bone morphogenetic proteins (BMPS) and other growth factors such as vascular endothelial growth factor, fibroblastic growth factor, and transforming growth factor (TGFbeta). Starting from the recapitulation of basic concepts in enzymology and protein-ligands interactions, we consider, in this manuscript, interpretations of the mechanistic interactions that have been put forward to explain the diversity of CCN proteins biological activities. We suggest that the cross-talks between superfamilies of proteins under the control of CCNs might play a central role in the coordination of developmental signaling pathways [ABSTRACT FROM AUTHOR]

Many approaches are being pursued to address the major global health challenge posed by the increasing resistance of pathogenic bacteria to antibacterial agents. One of the promising approaches being investigated includes the design and development of multiple action-based small-molecule antibacterials. Aspects of this broad area have been reviewed previously, and recent developments are addressed in this update review covering the literature mainly over the past three years. Considerations encompassing drug combinations, single-molecule hybrids and prodrugs are summarised in regard to the intentional design and development of multiple-action agents with a focus on potential triple or greater activities in bacteria. The hope for such single agents or combinations of single agents is that resistance development will be significantly hindered, and they may be useful in tackling bacterial disease caused by both resistant and non-resistant bacteria. [ABSTRACT FROM AUTHOR]

Harnessing the immune system with immune-checkpoint(s) blockade (ICB) has dramatically changed the treatment landscape of advanced melanoma patients in the last decade. Indeed, durable clinical responses and long-term survival can be achieved with anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and anti-Programmed cell Death-1 (PD-1) monoclonal antibodies (mAb) either alone or in combination. Despite these unprecedented results, due to intrinsic or acquired resistance to ICB-based immunotherapy, about half of metastatic melanoma (MM) patients neither respond to therapy nor experience durable clinical benefit or long-term survival. To improve the efficacy of ICB therapy among a larger proportion of MM patients, in addition to the targeting of immune-checkpoint(s) inhibitors (ICI) such as CTLA-4 or PD-1, several co-stimulatory molecules, such as Inducible T-cell COStimulator (ICOS), CD137 and OX40, have been investigated in MM, with initial signs of activity. Thus, a number of MM patients have been exposed to co-inhibitory and co-stimulatory mAb in the course of their disease. Being aware of the clinical outcome of such patients may pave the way to novel and more effective clinical approaches and therapeutic sequences for MM patients. Here we report a paradigmatic clinical case of a cutaneous MM patient who achieved multiple and durable complete responses, leading to an extraordinary long-term survival with sequential ICB therapies, suggesting the possibility to build a highly effective continuum of care with co-inhibitory and co-stimulatory therapeutic mAb. [ABSTRACT FROM AUTHOR]

The increasing prevalence of infections with multidrug-resistant (MDR), extensively-drug resistant (XDR) or difficult-to-treat drug resistant (DTR) Gram-negative bacilli (GNB), including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter species, and Escherichia coli poses a severe challenge. The rapid growing of multi-resistant GNB as well as the considerable deceleration in development of new anti-infective agents have made polymyxins (e.g. polymyxin B and colistin) a mainstay in clinical practices as either monotherapy or combination therapy. However, whether the polymyxin-based combinations lead to better outcomes remains unknown. This review mainly focuses on the effect of polymyxin combination therapy versus monotherapy on treating GNB-related infections. We also provide several factors in designing studies and their impact on optimizing polymyxin combinations. An abundance of recent in vitro and preclinical in vivo data suggest clinical benefit for polymyxin-drug combination therapies, especially colistin plus meropenem and colistin plus rifampicin, with synergistic killing against MDR, XDR, and DTR P. aeruginosa, K. pneumoniae and A. baumannii. The beneficial effects of polymyxin-drug combinations (e.g. colistin or polymyxin B + carbapenem against carbapenem-resistant K. pneumoniae and carbapenem-resistant A. baumannii, polymyxin B + carbapenem + rifampin against carbapenem-resistant K. pneumoniae, and colistin + ceftolozan/tazobactam + rifampin against PDR-P. aeruginosa) have often been shown in clinical setting by retrospective studies. However, high-certainty evidence from large randomized controlled trials is necessary. These clinical trials should incorporate careful attention to patient's sample size, characteristics of patient's groups, PK/PD relationships and dosing, rapid detection of resistance, MIC determinations, and therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

To plan therapies for Hepatocellular Carcinoma (HCC), staging methods are necessary. The most often employed HCC management recommendation is the Barcelona Clinic Liver Cancer (BCLC) staging system. Transarterial Chemoembolisation (TACE) is the go- to therapy for BCLC stage B (intermediate HCC). Numerous studies back the use of TACE in individuals with early and advanced HCC. TACE may be an option for individuals who are not candidates for Radiofrequency Ablation (RFA) or Hepatic Resection (HR) for BCLC stage 0 (very early HCC). TACE with RFA offers superior local tumour suppression than RFA alone in BCLC stage. Patients awaiting liver transplants may benefit from TACE as a bridging treatment. When compared to supportive care approaches, TACE improves survival for BCLC-B patients. Patients with BCLC-C stage HCC are treated in the first instance with sorafenib. The combination of sorafenib and TACE has demonstrated efficacy in slowing the development of tumours. Patients with HCC and portal venous thrombosis have superior survival results with TACE combined with radiation. Taking all of these facts into account, it is obvious that TACE, either alone or in conjunction with other therapies, plays a crucial part in the treatment of HCC at every stage. Patients with HCC should get a variety of treatments, and the best TACE candidates should be chosen using a more accurate patient classification approach.

Compounds that potentiate the activity of clinically available antibiotics provide a complementary solution, except for developing novel antibiotics for the rapid emergence of multidrug-resistant Gram-negative bacteria (GNB). We sought to identify compounds potentiating polymyxin B (PMB), a traditional drug that has been revived as the last line for treating life-threatening GNB infections, thus reducing its nephrotoxicity and heterogeneous resistance in clinical use. In this study, we found a natural product, sanguinarine (SA), which potentiated the efficacy of PMB against GNB infections. The synergistic effect of SA with PMB was evaluated using a checkerboard assay and time–kill curves in vivo and the murine peritonitis model induced by Escherichia coli in female CD-1 mice in vivo. SA assisted PMB in accelerating the reduction in bacterial loads both in vitro and in vivo, improving the inflammatory responses and survival rate of infected animals. The subsequent detection of the intracellular ATP levels, membrane potential, and membrane integrity indicated that SA enhanced the bacterial-membrane-breaking capacity of PMB. A metabolomic analysis showed that the inhibition of energy metabolism, interference with nucleic acid biosynthesis, and the blocking of L-Ara4N-related PMB resistance may also contribute to the synergistic effect. This study is the first to reveal the synergistic activity and mechanism of SA with PMB, which highlights further insights into anti-GNB drug development.

Type-2 Diabetes Mellitus is a complex, chronic illness characterized by persistent high blood glucose levels. Patients can be prescribed anti-diabetes drugs as single agents or in combination depending on the severity of their condition. Metformin and empagliflozin are two commonly prescribed anti-diabetes drugs which reduce hyperglycemia, however their direct effects on macrophage inflammatory responses alone or in combination are unreported. Here, we show that metformin and empagliflozin elicit proinflammatory responses on mouse bone-marrow-derived macrophages with single agent challenge, which are modulated when added in combination. In silico docking experiments suggested that empagliflozin can interact with both TLR2 and DECTIN1 receptors, and we observed that both empagliflozin and metformin increase expression of Tlr2 and Clec7a. Thus, findings from this study suggest that metformin and empagliflozin as single agents or in combination can directly modulate inflammatory gene expression in macrophages and upregulate the expression of their receptors. [ABSTRACT FROM AUTHOR]

Viola odorata L. oil is frequently recommended in the aromatherapeutic literature for treating respiratory, urinary, and skin infections; however, antimicrobial evidence is lacking. In addition, in aromatherapy, combinations of essential oils are predominantly utilized with the goal of achieving therapeutic synergy, yet no studies investigating the interaction of essential oil combinations with V. odorata oil exists. This study thus aimed to address these gaps by investigating the antimicrobial activity of three Viola odorata oil samples, sourced from different suppliers, independently and in combination with 20 different commercial essential oils, against micro-organisms involved in respiratory, skin, and urinary tract infections associated with global resistance trends. These pathogens include several of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) The chemical profile of the oils was determined using gas chromatography coupled with mass spectrometry. The minimum inhibitory concentrations (MIC) were determined using the broth micro-dilution method. The interactive profiles for the combinations were assessed by calculating the fractional inhibitory concentration index (ΣFIC). The main compounds varied across the three samples, and included phenethyl alcohol, isopropyl myristate, 2-nonynoic acid, methyl ester, α-terpineol, α-cetone, and benzyl acetate. The V. odorata oil samples displayed overall poor antimicrobial activity when tested alone; however, the antimicrobial activity of the combinations resulted in 55 synergistic interactions where the combination with Santalum austrocaledonicum resulted in the lowest MIC values as low as 0.13 mg/mL. The frequency of the synergistic interactions predominantly occurred against Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterococcus faecium with noteworthy MIC values ranging from 0.25–1.00 mg/mL. This study also reports on the variability of V. odorata oils sold commercially. While this warrants caution, the antimicrobial benefit in combination provides an impetus for further studies to investigate the therapeutic potential. [ABSTRACT FROM AUTHOR]

Combinations between antibiotics and other antimicrobial substances such as plant essential oils represent one of the most promising advances against drug-resistant microorganisms. This study aimed to evaluate the antimicrobial effects of different combinations of two essential oils (EO) with its major components and antibiotics (cephalosporines) against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Candida albicans using the microdilution method. Two plants widely growing in north Algeria, Thymus algeriensis and Salvia officinalis, were investigated. GC/MS was carried out to analyze the chemical composition of essential oils extracted from these plants through the hydrodistillation method. Extraction yields were evaluated at 2.3% for Thymus algeriensis and 3.18% for Salvia officinalis. GC/MS analysis revealed the existence of 29 and 18 essential oil components for Thymus algeriensis and Salvia officinalis, respectively. The major components were thymol (45.067%) and carvacrol (12.24%) for Thymus algeriensis, camphor (18.72%), 1,8-cineol (11.75%) and viridiflorol (10.57%) for Salvia officinalis. Synergistic interaction was observed with cefazoline-Thymus algeriensis essential oil, eucalyptol-Salvia officinalis essential oil and thymol-eucalyptol combinations tested against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Candida albicans. Additional effect was noted with cefotaxime-alpha pinene and Thymus algeriensis essential oil-eucalyptol combinations tested against Staphylococcus aureus and Candida albicans. However, no significant action was observed among the following combinations: cefotaxime-thymol, eucalyptol-alpha pinene, and thymol-Thymus algeriensis essential oil tested against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Candida albicans. [ABSTRACT FROM AUTHOR]

India is the largest producer and consumer of pulses in the world contributing around 25-28 % of the total global production. Among the pulses, blackgram is the third most important pulse crop cultivated in India after chickpea and pigeonpea. In spite of being a pulse crop grown in large areas, the productivity stands too low due to various biotic and abiotic stresses. Among the various biotic stresses, the infestation of powdery mildew accounts for major losses to the crop. A field experiment was conducted during rabi 2022 to evaluate the efficacy of a fungicide (carbendazim) and its combination with two commonly used biorationals (novaluron and spinosad) as well as a foliar nutrient (19:19:19) against powdery mildew. Among all the treatments, carbendazim (PDI: 25.83) was effective and on par with all of its insecticidal mixtures viz., novaluron + carbendazim (PDI: 26.02), spinosad + carbendazim (PDI: 26.32), spinosad + carbendazim + 19:19:19 (PDI: 26.78) and novaluron + carbendazim + 19:19:19 (PDI: 26.91). [ABSTRACT FROM AUTHOR]

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• Retrospective study of 303 CRE-infected patients treated with ceftazidime/avibactam. • Age, empiric aminoglycoside use, and ICU stay were associated with 30-day mortality. • Patients receiving an aminoglycoside were more likely to be in the ICU. • A subanalysis in only the patients who received an aminoglycoside was performed. • In subanalysis, adding aminoglycoside trended toward protectiveness of mortality. Ceftazidime/avibactam is one of the preferred treatment options for carbapenem-resistant Enterobacterales (CRE). However, the benefit of combining ceftazidime/avibactam with another antibiotic remains unclear. To identify variables associated with treatment failure during the use of ceftazidime/avibactam for CRE infections and assess the effect of combining an aminoglycoside with ceftazidime/avibactam. This was a retrospective cohort study of patients with a positive CRE culture treated with ceftazidime/avibactam between 2015 and 2021 in 134 Veterans Affairs (VA) facilities. The primary outcome was 30-day mortality and the secondary outcome was in-hospital mortality. A subanalysis in patients who received an aminoglycoside was also performed. A total of 303 patients were included. The overall 30-day and in-hospital mortality rates were 12.5% and 24.1%, respectively. Age (aOR 1.052, 95% CI 1.013–1.093), presence in the ICU (aOR 2.704, 95% CI 1.071–6.830), and receipt of an aminoglycoside prior to initiation of ceftazidime/avibactam (aOR 4.512, 95% CI 1.797–11.327) were independently associated with 30-day mortality. In the subgroup of patients that received an aminoglycoside (n = 77), their use in combination with ceftazidime/avibactam had a 30-day mortality aOR of 0.321 (95% CI, 0.089–1.155). In veterans treated with ceftazidime/avibactam for CRE infections, increased age, receipt of an empiric aminoglycoside, and presence in the ICU at the time of index culture were associated with higher 30-day mortality. Among patients who received an aminoglycoside, their use in combination with ceftazidime/avibactam trended toward protectiveness of 30-day mortality, suggesting a potential role for this combination to treat CRE infections in patients who are more severely ill. [Display omitted] [ABSTRACT FROM AUTHOR]