Efficacy Of Combination Research Articles

Efficacy and safety of praziquantel plus artemisinin-based combinations versus praziquantel in the treatment of Kenyan children with Schistosoma mansoni infection: open-label, randomized, head-to-head, non-inferiority trial.

Praziquantel alone is insufficient for the control of schistosomiasis due to poor efficacy against juvenile worms and increasing concerns about the risk of drug resistance. We compared the efficacy and safety of praziquantel combined with four different artemisinin-based combinations to praziquantel alone in treating Schistosoma mansoni infection in Kenyan children. In this randomized, open-label, five-arm, head-to-head, non-inferiority trial, children (aged 9-15 years) with S. mansoni infection according to duplicate Kato Katz thick smears from a stool sample in the Mwea irrigation scheme of central Kenya, were enrolled. Participants were randomly assigned (1:1:1:1:1) via a computer-generated block randomization procedure to receive a single oral dose of praziquantel (PZQ) (40 mg/kg/day) alone or in combination with a 3-day course (4 mg/kg of artesunate) of artesunate plus sulfalene-pyrimethamine (As + SP), artesunate plus amodiaquine (As + AQ), artesunate plus mefloquine (As + MQ) or dihydroartemisinin-piperaquine (DHAP). Laboratory technicians were masked to treatment allocation, but participants, clinicians, and study nurses were not. The primary outcomes were the cure rate and frequency of adverse events, which were assessed 6 weeks after treatment in the available case population using a per-protocol analysis. The non-inferiority margin was set at -10% for the risk difference in cure rates between combination therapy and PZQ alone. Between 12 September 2018 and 11 January 2019, 540 participants were assigned to receive PZQ alone (n = 108), PZQ plus As + SP (n = 108), PZQ plus As + AQ (n = 108), PZQ plus As + MQ (n = 108), or PZQ plus DHAP (n = 108). Primary outcome data were available for 523 (96.9%) participants. The cure rate was 82.5% (85/103) in PZQ alone, 81.7% (85/104) in PZQ plus As + SP, 76.2% (80/105) in PZQ plus As + AQ, 88.7% (94/106) in PZQ plus As + MQ, and 85.7% (90/105) in PZQ plus DHAP arm. Non-inferiority was declared for PZQ plus As + MQ (difference 6.2 [95% confidence interval: -3.3 to 15.6]) and PZQ plus DHAP (3.2 [-6.7 to 13.1]) but not for PZQ plus As + SP (-0.8 [-11.2 to 9.6]) or PZQ plus As + AQ (-6.3 [-17.3 to 4.6]). Adverse events were reported by 26% (138/540) of participants, including abdominal pain, headache, and vomiting. There were no serious adverse events. Alternatives to praziquantel should include praziquantel plus artesunate-mefloquine or praziquantel plus dihydroartemisinin-piperaquine. However, further multicentre trials are needed in different epidemiological settings and population groups to confirm these findings.CLINICAL TRIALSThis study is registered with the Pan-African Clinical Trials Registry under PACTR202001919442161.

A Pilot One and Two-Year Prospective, Blinded Clinical Evaluation of Efficacy, and Safety of Combined Treatment With Crosslinked Hyaluronic Acid Dermal Filler and Barbed Polydioxanone Suspension Threads for Mid-Face Contour Enhancement.

The combination of hyaluronic acid (HA) fillers and polydioxanone (PDO) thread lifting is gaining popularity for mid-face rejuvenation, especially among the Asian population. Despite the common use of these techniques, there is a paucity of long-term studies assessing their combined efficacy and safety. This study aims to evaluate the efficacy and safety of combined HA filler and PDO thread treatment for mid-face rejuvenation over a 24-month period in a Korean population. This prospective, blinded, single-center, open-label trial included 11 Korean subjects, aged 29-70 years, with mid-face volume loss graded 1-4 on the antero-medial cheek fullness scale. Participants were treated with crosslinked HA dermal fillers and PDO threads. Assessments were conducted using the Global Aesthetic Improvement Scale (GAIS), investigator-led clinical evaluations, and volumetric measurements using the Morpheus 3D system at baseline, 6, 12, and 24 months post-treatment. Quantitative analysis revealed a significant reduction in mid-face width from an average baseline of 149.27-145.00 mm at 24 months (p < 0.00001). Similarly, lower-face width decreased from 130.36 to 117.27 mm at 24 months (p < 0.00001). The GAIS scores demonstrated high levels of subject satisfaction, with 9 out of 11 patients reporting consistent satisfaction or improvement over 24 months. Minimal adverse events were reported, and no serious complications occurred. The combination of HA fillers and PDO threads was effective in achieving and maintaining long-term improvements in facial volume and contour. The Morpheus 3D system provided objective volumetric data, which supported the subjective improvements observed by patients and investigators. The study results highlight the benefits of ongoing neocollagenesis and tissue remodeling beyond the dissolution period of the materials. The combination of HA filler injections and PDO thread lifting offers a promising and minimally invasive option for long-term mid-face rejuvenation with high patient satisfaction and a favorable safety profile. Further studies are warranted to confirm these findings across diverse populations and compare this approach with other aesthetic treatments.

Efficacy and safety of the combination of envafolimab and lenvatinib in unresectable hepatocellular carcinoma: a single-arm, multicentre, exploratory phase II clinical study.

Currently, therapeutic combinations of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents have shown promising outcomes and have the potential to establish a new standard of care. The efficacy and safety of the first-line combination of envafolimab (an ICI) and lenvatinib (an anti-tumor angiogenesis drug) for the treatment of patients with inoperable hepatocellular carcinoma (HCC) have not been demonstrated. Unresectable HCC patients with an Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 1 and a Child-Pugh score ≤ 7 who had not received systemic therapy were included in this single-arm, exploratory, multicentre phase II clinical study. All patients were required to meet the criteria of being at least 18 years of age, having no history of other malignancies, and existing at least one measurable lesion. The patients were treated with envafolimab (150mg, QW, subcutaneous) in combination with lenvatinib (12 mg for patients weighing over 60 kg, 8 mg for patients weighing under 60 kg). The co-primary endpoint of the study was overall survival (OS), while surrogate endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Between March 2022 and April 2023, 36 patients were enrolled, 30 of whom were treated with envafolimab plus lenvatinib. At data cutoff, the median follow-up duration was 20 months (95% CI 18.9-21.1). Among the 30 assessable patients (patients treated according to the trial protocol), the median overall survival (mOS) and median progression-free survival (mPFS) for the therapy comprising envafolimab alongside lenvatinib were 18.5 months (95% CI 13.2-23.8) and 9.4 months (95% CI 1.6-15.6), respectively. The ORR and the DCR (evaluated according to mRECISTcriteria) reached 40% and 80%, respectively. In terms of safety, 23 patients (76.7%) experienced at least one treatment-related adverse event (TRAE), of which the most common was elevated aspartate aminotransferase (AST, 23.3%). Furthermore, grade 3 and higher TRAEs occurred in 30%. This study demonstrates that envafolimab in combination with lenvatinib exhibits favourable anti-cancer activity and a manageable safety profile for the first-line treatment of patients with unresectable HCC.

Drug Interaction Studies of Cabamiquine:Ganaplacide Combination against Hepatic Plasmodium berghei.

New antimalarial combination therapies with novel modes of action are required to counter the emergence and spread of Plasmodium drug resistance against existing therapeutics. Here, we present a study to evaluate the preventive activity of a combination of clinical antimalarial drug candidates, cabamiquine and ganaplacide, that have multistage activity against the liver and blood stages of Plasmodium infection. Cabamiquine (DDD107498, M5717) inhibits parasite protein synthesis, and ganaplacide (KAF156) inhibits protein trafficking, blocks the establishment of new permeation pathways, and causes endoplasmic reticulum expansion. The pharmacodynamic parameters of a combination of the two compounds were assessed employing a pharmacometrics approach in conjunction with in vitro-in silico checkerboard analysis. The in vitro study was performed on a previously established 3D infection platform based on human hepatic cell lines that sustain infection by rodent P. berghei parasites. The in vivo efficacy of this drug combination was assessed against the liver stage of the P. berghei. Our results show that the combination of both drugs at the tested concentrations does not interfere with the drugs respective mode of action or affect hepatocyte cell viability. The drug combination was fully effective in preventing the appearance of blood stage parasites when a systemic plasma Cav0-24/EC50 ratio >2 for ganaplacide and >5 for cabamiquine was achieved. These findings demonstrate that chemoprevention using a combination of cabamiquine and ganaplacide has the potential to target the asymptomatic liver stage of Plasmodium infection and prevent the development of parasitemia.

Clinical Outcomes of Using Dexmedetomidine, ProDex and Popfol for Sedation during Mechanical Ventilation in Patients Hospitalized in the Intensive Care Unit: A Triple Blinded Clinical Trial

Background: Sedation plays a crucial role in the care of intensive care unit (ICU) patients, addressing the challenges presented by factors such as agitation, anxiety, and delirium, particularly during mechanical ventilation (MV). Dexmedetomidine and propofol are commonly used sedatives, each with its unique characteristics and side effects. Combining these agents has been proposed to optimize effectiveness and minimize adverse effects. This study aims to compare the efficacy of the dexmedetomidine-propofol combination with dexmedetomidine alone and propofol alone for sedation during mechanical ventilation in ICU patients. Methods: A triple-blinded clinical trial was conducted in Isfahan, Iran, involving patients eligible for spinal fusion surgery and mechanical ventilation. Patients were randomized into three groups: dexmedetomidine alone (DO), propofol alone (PO), and a combination of both drugs (DP) dexmedetomidine-propofol (ProDex). Various dosages and infusion protocols were carefully administered, and patients were assessed for demographic and clinical variables. Hemodynamic parameters and sedation levels were monitored, and statistical analysis was performed. Results: The study involved 87 patients, with the ProDex group demonstrating the shortest mechanical ventilation duration. Hemodynamic stability was observed in the ProDex group, with significantly lower systolic blood pressure and heart rate compared to other groups. Sedation scores did not differ significantly among groups, suggesting similar sedative effects. The ProDex group exhibited favorable outcomes despite differences in hemodynamic variables. Conclusion: The dexmedetomidine-propofol combination appears effective in minimizing side effects associated with monotherapy sedation, leading to favorable clinical outcomes. This study contributes valuable insights into optimizing sedation strategies for mechanically ventilated ICU patients.

Evaluating the Efficacy of Combined Platelet-Rich Plasma and Microneedling for Aesthetic Rejuvenation of the Periorbital Area: A Randomized, Blinded Cohort Study.

Microneedling, a technique involving controlled dermal microwounding, and platelet-rich plasma (PRP) injections are both employed for skin rejuvenation. While both treatments individually show promise, limited research has explored their combined efficacy. This study aimed to evaluate the effectiveness of combining PRP injections with microneedling for aesthetic concerns around the eyes under standardized conditions. This single-center, longitudinal cohort study was conducted from October 2017 to October 2020. Thirteen adult participants (mean age 35, 92.3% female) with aesthetic concerns in the periorbital area underwent combined PRP and microneedling treatment. Standardized photographs were taken preprocedure, at 1 week, and 3 months. Photographs were evaluated by three blinded dermatologists using validated photonumeric scales. Participants completed a self-assessment questionnaire at the 1-week follow-up regarding skin homogeneity, texture, pigmentation, and wrinkles. Self-reported outcomes indicated perceived improvements in skin homogeneity (72.7% reporting mild or significant improvement) and texture (81.8% reporting mild, moderate, or significant improvement). Improvements in pigmentation and wrinkles were less pronounced. Dermatologists' assessments revealed no significant differences in skin attributes before and after treatment. Despite subjective reports of improvement, objective evaluations by independent dermatologists did not demonstrate significant changes. Variability in outcomes might be attributed to differences in study design, treatment protocols, and assessment methods. Further research with larger sample sizes and multiple treatment sessions is needed to better understand the benefits of combining PRP with microneedling for periorbital rejuvenation.

Efficacy of colistin-based combinations against pandrug-resistant whole-genome-sequenced Klebsiella pneumoniae isolated from hospitalized patients in Egypt: an in vitro/vivo comparative study

BackgroundColistin resistance significantly constrains available treatment options and results in the emergence of pandrug-resistant (PDR) strains. Treating PDR infections is a major public health issue. A promising solution lies in using colistin-based combinations. Despite the availability of in vitro data evaluating these combinations, the in vivo studies remain limited.ResultsThirty colistin-resistant Klebsiella pneumoniae (ColRKp) isolates were collected from hospitalized patients. Colistin resistance was detected using broth microdilution, and antimicrobial susceptibility was tested using the Kirby-Bauer method against 18 antibiotics. Extremely high resistance levels were detected, with 17% of the isolates being PDR. Virulence profiling, assessed using Anthony capsule staining, the string test, and the crystal violet assay, indicated the predominance of non-biofilm formers and non-hypermucoid strains. The isolates were screened for mcr genes using polymerase chain reaction. Whole-genome sequencing (WGS) and bioinformatics analysis were performed to characterize the genomes of PDR isolates. No plasmid-borne mcr genes were detected, and WGS analysis revealed that PDR isolates belonged to the high-risk clones: ST14 (n = 1), ST147 (n = 2), and ST383 (n = 2). They carried genes encoding extended-spectrum β-lactamases and carbapenemases, blaCTX-M-15 and blaNDM-5, on conjugative IncHI1B/IncFIB plasmids, illustrating the convergence of virulence and resistance genes. The most common mechanism of colistin resistance involved alterations in mgrB. Furthermore, deleterious amino acid substitutions were also detected within PhoQ, PmrC, CrrB, ArnB, and ArnT. Seven colistin-containing combinations were compared using the checkerboard experiment. Synergy was observed when combining colistin with tigecycline, doxycycline, levofloxacin, ciprofloxacin, sulfamethoxazole/trimethoprim, imipenem, or meropenem. The efficacy of colistin combined with either doxycycline or levofloxacin was assessed in vitro using a resistance modulation assay, and in vivo, using a murine infection model. In vitro, doxycycline and levofloxacin reversed colistin resistance in 80% and 73.3% of the population, respectively. In vivo, the colistin + doxycycline combination demonstrated superiority over colistin + levofloxacin, rescuing 80% of infected animals, and reducing bacterial bioburden in the liver and kidneys while preserving nearly intact lung histology.ConclusionsThis study represents the first comparative in vitro and in vivo investigation of the efficacy of colistin + doxycycline and colistin + levofloxacin combinations in clinical PDR ColRKp isolates characterized at a genomic level.

Synergistic growth suppression of Fusarium oxysporum MLY127 through Dimethachlon Nanoencapsulation and co-application with Bacillus velezensis MLY71

Fusarium oxysporum is a destructive plant pathogen with robust survival mechanisms, complicating control efforts. This study aimed to develop nanoformulated fungicides, screen antagonistic bacteria, and evaluate their combined efficacy. A novel self-emulsifying nanoemulsion (DZW) was formulated using zein and benzaldehyde-modified wheat gluten (BgWG) as carriers for dimethachlon (DTN). The preparation process optimized material ratios and emulsification techniques. Concurrently, antagonistic bacterial strains against F. oxysporum were screened via the plate standoff method, identifying Bacillus velezensis MLY71 as both antagonistic and compatible with DTN. The DZW nanoemulsion achieved a particle size of 93.22 nm, an encapsulation efficiency (EE) of 90.57%, and a DTN loading capacity (LC) of 67.09%, with sustained release over 96 h. The combination of DTN (0.04 mg·mL⁻¹) and B. velezensis MLY71 (1 × 10⁴ CFU·mL⁻¹) achieved a 76.66% inhibition rate against F. oxysporum MLY127, 1.71 times greater than DTN alone, indicating significant synergy. At a DTN concentration of 0.20 mg·mL⁻¹, the combination of DZW and MLY71 showed a synergy coefficient of 1.33. This synergy was also observed in soil environments, indicating its adaptability for controlling soil-borne pathogens. As sustainable management continues to gain attention in agricultural disease control, this study offers a promising strategy for achieving higher efficacy with the same fungicide dose or satisfactory control with reduced fungicide application. The excellent drug-loading performance of BgWG also expanded the applications of the wheat by-product gluten.

Postoperative Analgesic Efficacy of Clavipectoral Plane Block and Serratus Posterior Superior Intercostal Plane Block Combination in Clavicle Surgeries: A Report of 10 Cases.

This case series included 10 patients who underwent clavicular fracture surgery under general anesthesia. A novel analgesic approach combining 2 distinct nerve block techniques-serratus posterior superior intercostal plane block (SPSIPB) and clavipectoral plane block (CPPB)-was used for postoperative pain management. SPSIPB provided sensory blockade for the innervation of the clavicular skin, whereas CPPB targeted the clavipectoral fascia. The combination of SPSIPB and CPPB demonstrated variable efficacy in controlling postoperative pain. Future studies may explore potential improvements through dosage optimization, the use of adjuvants, or targeting higher anatomical levels.

Combined action of two synthetic ultrashort antimicrobial peptides exhibiting synergistic effects against clinically significant resistant bacteria

Background and Aim: The emergence and proliferation of multidrug-resistant bacteria pose a global health crisis. This issue arises from the overuse and misuse of antibiotics, coupled with the pharmaceutical industry’s limited development of new drugs, which is constrained by financial disincentives and regulatory hurdles. This study aimed to investigate the combined antibacterial efficacy and safety profile of the combined ultrashort antimicrobial peptides (AMPs) WW-185 and WOW against antibiotic-resistant bacterial strains. Materials and Methods: The WW-185 and WOW peptides were synthesized through solid-phase methods and purified using reverse-phase high-performance liquid chromatography, and their purity was confirmed by mass spectrometry. Antibacterial activity was evaluated using broth dilution and checkerboard assays to assess both individual and combined effects of the peptides against Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus [MRSA]) and Escherichia coli (including extended-spectrum beta-lactamases [ESBL]-producing strains). The synergy between the peptides was quantified using fractional inhibitory concentration indices. Hemolytic activity was also assessed to determine cytotoxicity toward red blood cells. Results: The combination of WW-185 and WOW exerted synergistic effects against both MRSA and ESBL-producing E. coli, with reduced minimal inhibitory concentrations compared with the individual treatments. The peptides exhibited minimal hemolytic activity, indicating low toxicity. Conclusion: The combination of the ultrashort AMPs WW-185 and WOW shows promising synergistic antibacterial effects against resistant bacteria, with potential for further therapeutic development due to their enhanced efficacy and low toxicity. Keywords: antimicrobial agents, bacterial infections, multidrug resistance, synergistic effects, ultra-short peptides.

In vitro activity of amphotericin B in combination with imipenem/colistin against mixed cultures of Candida spp. and Gram-negative bacteria.

A new direction of research was established due to biofilms' infections caused by a mixture of fungal and bacterial species. Diagnosis of these infections becomes more difficult and high doses of drugs are used in treatment, especially in critically ill patients. The aim of the current study was to examine the effects of amphotericin B, in combination with imipenem or colistin against Candida albicans - Acinetobacter baumannii- Proteus mirabilis and Candida tropicalis - Acinetobacter baumannii -Proteus mirabilis polymicrobial biofilms. According to the microdilution method of the Clinical Laboratory Standards Institute (CLSI) published in documents M27-A3 (2008) and M07-A10 (2015) respectively, the susceptibility of the clinical isolates Candida yeasts to amphotericin B and Gram-negative bacteria to imipenem and colistin was determined. A Checkerboard assay was employed to evaluate the efficacy of drugs combinations. The 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide (MTT) reduction assay was used to quantify the biofilms. The combination amphotericin B/colistin and amphotericin B/imipenem did not produce obvious effects against the polymicrobial biofilms formed for 48 hours. Whereas colistin alone produced strong effects against Candida albicans-Acinetobacter baumannii and Candida albicans - Acinetobacter baumannii -Proteus mirabilis compared to Candida tropicalis - Acinetobacter baumannii and Candida tropicalis - Acinetobacter baumannii - Proteus mirabilis polymicrobial biofilms. For mixed Candida spp. bacterial biofilms, these results point to the difficulties in eradicating these biofilms, as well as in preventing their development.

Phase 2, Multicenter, Open-label, Nonrandomized Study of Neoadjuvant Chemotherapy Liposomal Irinotecan With 5-Fluorouracil, Leucovorin, and Oxaliplatin, Followed by Chemoradiotherapy in Patients With Rectal Cancer in a Watch-and-Wait Program.

To evaluate the efficacy of neoadjuvant chemotherapy combination with liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin in patients with locally advanced rectal cancer. This was a phase 2, nonrandomized, multicenter study in adults with stage II or III rectal cancer and an Eastern Cooperative Oncology Group performance status of 0 to 1. Total neoadjuvant therapy (TNT) consisted of neoadjuvant chemotherapy combination with liposomal irinotecan (60mg/m2), oxaliplatin (60mg/m2), leucovorin (400mg/m2), and fluorouracil (2400mg/m²), followed by chemoradiotherapy [ie, capecitabine (825mg/m2) and radiotherapy according to the standard of care]. The primary efficacy endpoint was the proportion of patients who achieved clinical complete response (cCR), defined as the normalization of pelvic magnetic resonance imaging, rectoscopy, computed tomography scan, and tumor markers. The median follow-up was 32.3 months. Of the 30 patients who underwent TNT and were evaluated, 6 (20.0%; 95% CI: 5.2%-34.8%) patients achieved a cCR. There were no deaths. The median disease-free survival (DFS) for patients with cCR was not reached after a follow-up of 32 months; the 1-year DFS rate was 90.0% (95% CI: 71.0%-100%), and the 2-year and 3-year DFS rates were 80.0% (95% CI: 55.0%-100%). No grade ≥4 adverse events (AEs) were observed. Grade 3 AEs occurred in 18 patients (60%), most frequent was diarrhea (n = 9, 30%). Eleven (36.7%) patients experienced serious AEs, with diarrhea being the most frequent (n = 6, 20.0%). TNT with 5-fluorouracil, leucovorin, and oxaliplatin and chemoradiation is a safe and effective therapeutic alternative for the management of locally advanced rectal cancer.

Evaluation of Meropenem and Gentamicin Synergy on Klebsiella pneumonaie

Objective: Antimicrobial resistance is a severe global problem, causing both medical and economic results. Klebsiella pneumoniae (K. pneumoniae) is a gram-negative bacterium that plays a major role in these burdens due to its widespread resistance mechanisms. This study searchs for the synergy and antagonism between meropenem and gentamicin using the disk diffusion method and compares these findings with results from the checkerboard method. If the results are consistent, validating the reliability of the disk diffusion method, it could be a cost-effective alternative to other testing methods. Methods: The checkerboard method is used to assess the interaction of two antimicrobial agents (synergistic, indifferent, or antagonistic) by preparing a grid of wells containing varying concentrations of the agents. The fractional inhibitory concentration index (FICI) is calculated to evaluate the combination's efficacy. In the disc diffusion method, the antimicrobial activity of an agent is determined by placing discs soaked in the agent on an agar plate inoculated with bacteria. After incubation, the diameter of the inhibition zone is measured to assess susceptibility. Results: No synergy or antagonism was detected in any of the 30 Klebsiella pneumaniae isolates by either method. Conclusion: The disc diffusion method is a cost-effective and reliable alternative to other in vitro synergy tests, especially when facilities are limited.

Recombinant Production of Ib-AMP4 and Oncorhyncin II Antimicrobial Peptides and Antimicrobial Synergistic Assessment on the Treatment of Staphylococcus aureus Under in vitro Condition.

Methicillin-resistant Staphylococcus aureus (MRSA) is a significant and prevalent pathogen that poses a major challenge in healthcare environments. In light of the growing threat posed by multidrug-resistant organisms like MRSA, there is an urgent need for alternative therapeutic strategies. One promising avenue of research involves the use of antimicrobial peptides (AMPs). These naturally occurring molecules, which are part of the innate immune response in many organisms, have garnered attention for their ability to combat a wide range of pathogens. This study aimed to produce recombinant versions of Ib-AMP4 and Oncorhyncin II and to evaluate their combined effects against MRSA (NCTC10442). Escherichia coli BL21(DE3] served as the expression host for the synthesized variants of the Ib-AMP4 and Oncorhyncin II genes. The antimicrobial efficacy of these peptides against MRSA S. aureus (NCTC1042] was evaluated using a comprehensive methodology that encompassed the determination of the minimum inhibitory concentration (MIC), the performance of time-kill assays, and the analysis of growth kinetics. The individual antimicrobial activities of Ib-AMP4 and Oncorhyncin II were assessed, revealing minimum inhibitory concentrations (MICs) of 27.75 μg/mL and 40.125 μg/mL against S. aureus (MRSA) (NCTC10442), respectively. The application of a checkerboard assay to evaluate the combination of these antimicrobial peptides (AMPs) demonstrated a synergistic interaction, which was further validated through time-kill and growth kinetic studies. When administered at double the MIC, a significant reduction in the log10 CFU/mL of MRSA (NCTC 10442) was observed, underscoring the synergistic bacteriostatic effect mediated by the fractional inhibitory concentration (FIC) index of the two peptides. Antimicrobial peptides (AMPs) have attracted significant interest owing to the growing intricacy of microbial infections. They constitute a promising category of novel antibiotics that warrant further investigation for the treatment of S. aureus infections and the enhancement of wound healing. Although certain AMPs can operate autonomously, others may necessitate a synergistic approach alongside conventional antibiotics. Studies examining the combined efficacy of Oncorhyncin II and Ib-AMP4 against MRSA in vitro have revealed their effectiveness.

Comparison of Butorphanol-Azaperone-Medetomidine and Nalbuphine-Medetomidine-Azaperone for Immobilization of White-Tailed Deer (Odocoileus virginianus).

Butorphanol-azaperone-medetomidine (BAM) is commonly used for white-tailed deer (Odocoileus virginianus) immobilization in captive and free-ranging populations. It is a federally regulated controlled substance requiring stringent regulatory compliance, complicating field application. A prescription-only drug combination, nalbuphine-medetomidine-azaperone® (NalMed-A) provides a less-regulated alternative for use by wildlife professionals. Efficacy and safety of these drug combinations for immobilization of deer have not been compared in a controlled trial, and reports of dose-specific effects of NalMed-A on white-tailed deer physiology are lacking. Additionally, residual effects of these drugs on deer behavior, food consumption, and stress response have not been reported. In February through April 2021, we immobilized 30 captive female, adult white-tailed deer in three treatment groups (n=10 each). Hand-injected doses were 1.5 mL BAM intramuscularly (IM; 41.0 mg butorphanol, 13.6 mg azaperone, 16.4 mg medetomidine), 1.5 mL NalMed-A IM (60.0 mg nalbuphine, 15.0 mg medetomidine, 15.0 mg azaperone), and 2.0 mL NalMed-A IM (80.0 mg nalbuphine, 20.0 mg medetomidine, 20.0 mg azaperone). We compared quality of immobilizations and reversals and times to induction and reversal among treatments, collected biological samples to measure stress hormones and blood gases, and conducted observations to determine treatment-related variations in behaviors. When an effective dose was administered, both BAM and NalMed-A produced rapid and smooth immobilization and recovery after reversal. All treatments in combination with manual restraint caused some degree of hyperthermia, hypoxemia, hypercarbia, bradycardia, respiratory and metabolic acidosis, and elevated lactate and serum cortisol. At 60 d, all deer were still alive, with no apparent residual effects. Vital signs of deer exposed to manual restraint and these drug combinations should be monitored closely, with supportive therapy provided when needed. We suggest BAM and NalMed-A are safe for immobilizing deer in situations similar to our trials, although doses may perform differently in deer remotely injected without manual restraint.

Dual inhibition of HERs and PD-1 counteract resistance in KRASG12C-mutant head and neck cancer

BackgroundBasket clinical trials targeting the KRASG12C-mutation in solid tumors have shown initial promise, including in orphan KRASG12C head and neck cancer (HNC). However, development of resistance to KRASG12C-mutant-specific inhibitors (KRASG12Ci) remains a major obstacle. Here, we investigated the intrinsic (tumor-cell autonomus) and tumor-microenvironment (TME) mechanisms of resistance to the KRASG12Ci—MRTX849 and AMG510 in a unique syngenic murine KRASG12C-mutated HNC cell line.MethodsWestern-blotting was used for protein abundance and activation, overexpression, and ligand activation studies to verify the intrinsic mechanism of resistance to KRASG12Ci in KRASG12C-mutated HNC cell line, 4NQO-L. In vitro KRASG12C-acquired-resistant cells were developed from 4NQO-L (4NQO-L-AcR). MRTX849/lapatinib combination efficacy, and CD8+ T-cells depletion, were assessed in C57BL/6 J mice and supplementation of anti-PD-1 (αPD-1) to MRTX849/lapatinib was also performed in 4NQO-L– KRASG12Ci-senisitve and 4NQO-L-AcR tumors. Immunohistochemistry (IHC) and Immunoflourescence (IF) analyses were performed to profile the TME and programmed death-ligand 1 (PD-L1) expression in tumors.ResultsActivation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of αPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with αPD-1 did not improve the outcome.ConclusionsOur study highlights the critical need for blocking both intrinsic and extrinsic mechanisms of resistance for the prolonged response and shows that such treatment is ineffective in KRASG12Ci-AcR tumors.

A comparison of the diagnostic capability of Kato-Katz and real-time PCR for the assessment of treatment efficacy of ivermectin and albendazole combination against T. trichiura infections.

Trichuris trichiura is humans' second most prevalent soil-transmitted helminth (STH) infection after Ascaris lumbricoides, affecting approximately 4.6 million people worldwide. Despite its sub-optimal sensitivity, especially in low prevalence and infection intensity settings, the modified Kato-Katz (K-K) is still recommended as a diagnostic method by the World Health organization (WHO) guidelines. Within a randomized clinical trial (RCT) comprising four treatment arms with two different anthelmintics, the present study reports an important secondary research objective to determine the diagnostic agreement between K-K and real-time PCR evaluating treatment efficacy against T. trichiura. The parasitological results were analyzed, including cure rates (CR) of a subgroup of 94 participants positive at baseline for T. trichiura eggs for both techniques. The single-dose albendazole (ALB) arm resulted in significantly lower CRs than experimental arms of albendazole/ivermectin (ALB/IVM) combinations. The overall diagnostic agreement between both techniques was 88.7% [κ = 0.8 (P<0.001)]. Concordance between eggs per gram and Ct values was moderate, with the discordance source likely stemming from lighter infection intensities. These findings indicate that real-time PCR is a suitable alternative for CR estimation in helminthiasis clinical trials. It also highlights the need to identify the most accurate diagnostic tools for RCTs, that would benefit from guiding principles to achieve harmonization across studies and are not necessarily the same as those used for epidemiological surveys. Clinical Trials.gov (NCT04041453).

Diagnostic Efficacy of Combined CT Guided Fine Needle Aspiration and Core Needle Biopsy Versus Either Technique Alone in Peripheral Lung Lesions

Background: Precise cytological and histological diagnosis is crucial in the era of targeted therapy for lung lesions. Both Fine Needle Aspiration Cytology (FNAC) and Core Needle Biopsy (CNB) are established diagnostic techniques, yet their individual and combined efficacy remains debated. Objective: To evaluate the diagnostic yield of combined CT-guided FNAC and CNB versus either technique alone in peripheral lung lesions. Methods: This prospective study enrolled 110 patients with undiagnosed peripheral lung lesions at the National Institute of Diseases of Chest and Hospital (NIDCH) during 2023. CT-guided FNAC was performed using a 22-gauge spinal needle, followed by CNB using an 18-gauge Trucut needle in the same setting. Six FNAC smears were prepared and stained with hematoxylin and eosin, while CNB specimens were processed as paraffin-embedded blocks. Results were classified into four categories: inadequate, negative, suspicious, and positive for malignancy. Results: The diagnostic yield of the combined approach was 99.1%, compared to 89.1% for FNAC alone and 98.2% for CNB alone. FNAC showed 85.1% sensitivity while CNB demonstrated 97.7% sensitivity. Both methods achieved 100% specificity and positive predictive value. The negative predictive value was 77.3% for FNAC versus 95.7% for CNB. Among malignant lesions (n=87), CNB provided definitive diagnosis in cases where FNAC showed suspicious findings (10 cases). For benign lesions (n=22), CNB showed superior diagnostic capability, particularly in granulomatous inflammation and chronic pneumonitis. Procedure-related complications were minimal (3.6%) with no major adverse events. Conclusion: Combined FNAC and CNB approach provides superior diagnostic yield compared to either technique alone. While CNB demonstrated higher individual diagnostic accuracy, the combined approach offered maximum diagnostic precision without significantly increasing complications. This strategy is particularly valuable for cases ...

Integrated proteomics and metabolomics analyses reveal new insights into the antitumor effects of valproic acid plus simvastatin combination in a prostate cancer xenograft model associated with downmodulation of YAP/TAZ signaling

BackgroundDespite advancements in therapeutic approaches, including taxane-based chemotherapy and androgen receptor-targeting agents, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable tumor, highlighting the need for novel strategies that can target the complexities of this disease and bypass the development of drug resistance mechanisms. We previously demonstrated the synergistic antitumor interaction of valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitory activity, with the lipid-lowering drug simvastatin (SIM). This combination sensitizes mCRPC cells to docetaxel treatment both in vitro and in vivo by targeting the cancer stem cell compartment via mevalonate pathway/YAP axis modulation.MethodsHere, using a combined proteomic and metabolomic/lipidomic approach, we characterized tumor samples derived from 22Rv1 mCRPC cell-xenografted mice treated with or without VPA/SIM and performed an in-depth bioinformatics analysis.ResultsWe confirmed the specific impact of VPA/SIM on the Hippo–YAP signaling pathway, which is functionally related to the modulation of cancer-related extracellular matrix biology and metabolic reprogramming, providing further insights into the molecular mechanism of the antitumor effects of VPA/SIM.ConclusionsIn this study, we present an in-depth exploration of the potential to repurpose two generic, safe drugs for mCRPC treatment, valproic acid (VPA) and simvastatin (SIM), which already show antitumor efficacy in combination, primarily affecting the cancer stem cell compartment via MVP/YAP axis modulation. Bioinformatics analysis of the LC‒MS/MS and 1H‒NMR metabolomics/lipidomics results confirmed the specific impact of VPA/SIM on Hippo–YAP.

Expert opinion on the prescription practice of a combination of rabeprazole and domperidone for managing nighttime heartburn in GERD among Indian patients

The synergistic effect of Rabeprazole and Domperidone suggested a more comprehensive treatment strategy, targeting both acid suppression and motility enhancement in GERD management in several clinical studies. However, studies regarding their prescription practices of this combination is scarce. This study aimed to gather comprehensive insights into various aspects of gastroesophageal reflux disease (GERD) management in Indian settings.This cross-sectional study was conducted from June 2023 to December 2023 using a 24-item structured questionnaire distributed via email and online platforms. Clinicians completed the survey independently, with the option to skip questions and provided written informed consent. The questionnaire covered GERD management aspects, including patient demographics, clinical challenges, treatment preferences, efficacy of treatment combinations, patient adherence, use of guidelines, comorbidities, risk factors and patient education methods.According to 39% of clinicians, 31-40 GERD patients per month report nighttime heart burn, while another 39% reported it as 21-30 cases monthly. Majority of the clinicians (95.65%) preferred rabeprazole for its longer action in managing nighttime heartburn in GERD. According to 96% and 89% of the clinicians, respectively, the combination of rabeprazole and domperidone was favored for managing nighttime heartburn and was more effective than other PPI combinations. Nearly 93% stated that this combination provides the fastest relief. The recommendation for taking the combination once a day was made by 67% of clinicians and 59% reported that their patients felt relieved within 1-2 weeks. Helirab D was preferred due to its advanced release profile 2 (ARP2) technology by 50% of clinicians.There was a strong clinical preference for using a combination of rabeprazole and domperidone to manage nighttime heartburn in patients with GERD. This combination seems to have advantages in terms of effectiveness, quick onset of action and relief for patients. The once-daily dosing schedule and formulation technology (ARP2) may be contributing factors to its popularity among clinicians.