Correlating Advanced Pharmacy Practice Experience Exam Scores and Pharmacist Licensure Status in a Single Program.

OBJECTIVE: Pharmacist licensure exam first-time pass rates have declined for several years. Predictors of licensure exam performance, including the Pharmacy College Admission Test, are no longer required, necessitating alternative strategies. Our aim is to assess the relationship between numerical scores on advanced pharmacy practice experience (APPE) exams and pharmacist licensure exams first-time pass rates. METHODS: We conducted a single-center, retrospective, observational analysis. APPE examination results between May 2020 and November 2023 were analyzed for association with licensure information from the Texas State Board of Pharmacy. Exam scores were collected for student cohorts graduating from 2021 to 2022 as study cohort data. Correlation between exam scores and probability of successful licensure was assessed using logistic regression. A classification and regression tree analysis identified the most significant threshold. Predictive ability of the best-fit model was prospectively validated using the 2023 graduate cohort. RESULTS: The overall licensure success rate was 80.6% for the study cohort (2021-2022, n = 206). Exam scores were well correlated to the likelihood of licensing success. The most significant threshold was 77.8%. The success rate was 82.5% vs 16.7% for those scoring above and below the threshold, respectively. The observed and predicted licensure success rates were 91.0% and 88.8%, respectively, in the validation cohort (2023, n = 89). The positive and negative prediction values were 94.9% and 40.0%, respectively. CONCLUSION: The performances on APPE exams were reasonable in predicting the first-time licensure success rate for a graduating class. Our assessment appears promising as a risk-stratification tool for students in gaining successful pharmacist licensure.

Lactate promotes the biofilm-to-invasive-planktonic transition in Salmonella enterica serovar Typhimurium via the de novo purine pathway.

Salmonella enterica serovar Typhimurium (S. Typhimurium) infection triggers an inflammatory response that changes the concentration of metabolites in the gut impacting the luminal environment. Some of these environmental adjustments are conducive to S. Typhimurium growth, such as the increased concentrations of nitrate and tetrathionate or the reduced levels of Clostridia-produced butyrate. We recently demonstrated that S. Typhimurium can form biofilms within the host environment and respond to nitrate as a signaling molecule, enabling it to transition between sessile and planktonic states. To investigate whether S. Typhimurium utilizes additional metabolites to regulate its behavior, our study delved into the impact of inflammatory metabolites on biofilm formation. The results revealed that lactate, the most prevalent metabolite in the inflammatory environment, impedes biofilm development by reducing intracellular c-di-GMP levels, suppressing the expression of curli and cellulose, and increasing the expression of flagellar genes. A transcriptomic analysis determined that the expression of the de novo purine pathway increases during high lactate conditions, and a transposon mutagenesis genetic screen identified that PurA and PurG, in particular, play a significant role in the inhibition of curli expression and biofilm formation. Lactate also increases the transcription of the type III secretion system genes involved in tissue invasion. Finally, we show that the pyruvate-modulated two-component system BtsSR is activated in the presence of high lactate, which suggests that lactate-derived pyruvate activates BtsSR system after being exported from the cytosol. All these findings propose that lactate is an important inflammatory metabolite used by S. Typhimurium to transition from a biofilm to a motile state and fine-tune its virulence.IMPORTANCEWhen colonizing the gut, Salmonella enterica serovar Typhimurium (S. Typhimurium) adopts a dynamic lifestyle that alternates between a virulent planktonic state and a multicellular biofilm state. The coexistence of biofilm formers and planktonic S. Typhimurium in the gut suggests the presence of regulatory mechanisms that control planktonic-to-sessile transition. The signals triggering the transition of S. Typhimurium between these two lifestyles are not fully explored. In this work, we demonstrated that in the presence of lactate, the most dominant host-derived metabolite in the inflamed gut, there is a reduction of c-di-GMP in S. Typhimurium, which subsequently inhibits biofilm formation and induces the expression of its invasion machinery, motility genes, and de novo purine metabolic pathway genes. Furthermore, high levels of lactate activate the BtsSR two-component system. Collectively, this work presents new insights toward the comprehension of host metabolism and gut microenvironment roles in the regulation of S. Typhimurium biology during infection.

Real-World Outcomes of Atezolizumab with Bevacizumab Treatment in Hepatocellular Carcinoma Patients: Effectiveness, Esophagogastroduodenoscopy Utilization and Bleeding Complications.

The IMbrave150 trial established atezolizumab with bevacizumab (A+B) as standard care for hepatocellular carcinoma (HCC), recommending an esophagogastroduodenoscopy (EGD) within 6 months of treatment initiation to prevent bleeding from esophagogastric varices. The necessity of mandatory EGD for all patients remains unclear. We retrospectively analyzed 112 HCC patients treated with A+B at five Canadian cancer centers from 1 July 2020 to 31 August 2022. A+B was the first-line therapy for 90% of patients, with median overall survival at 20.3 months and progression-free survival at 9.6 months. There was no survival difference between patients with bleeding and those without. Before A+B, 71% (n = 79) of patients underwent an EGD within 6 months, revealing varices in 41% (n = 32) and requiring intervention in 19% (n = 15). The overall bleeding rate was 15% (n = 17), with GI-specific bleeding occurring in 5% (n = 17). In the EGD group, GI-specific bleeding was 6% (n = 5) while in the non-EGD group, it was 3% (n = 1). Non-GI bleeding was observed in 10% (n = 11) of patients. Outcomes for HCC patients treated with A+B in Canada were comparable to IMbrave150. There was no increase in GI bleeding in patients without pre-treatment EGD, possibly supporting a selective EGD approach.

Outcomes of hepatocellular carcinoma patients treated in the lenvatinib and immunotherapy era (2018-2021) compared to the sorafenib era (2008-2018).

BACKGROUND: Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these landmark trials, sorafenib (SOR) served as the standard first-line treatment for a decade. Our study aimed to assess the outcomes of HCC patients treated during the SOR era (2008-2018) in contrast to those in the post-SOR era (2018-2021), of which the predominant first-line treatments were LEN or A + B. METHODS: Inclusion criteria of the study were all HCC patients in the Canadian province of Alberta who started first-line systemic therapy at cancer centers between 1 January 2008 and 31 December 2021. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), along with clinician-assessed response rate (RR), were subject to retrospective analysis. RESULTS: Of 372 total patients, 230 received treatment in the SOR era and 142 in the post-SOR era. The demographic and clinical characteristics for the SOR era and post-SOR era groups are as follows, respectively: the median age was 63 and 64 years, 80% and 81% were male, and 24% and 11% were of East Asian ethnicity. Before receiving systemic treatment, 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT in the two eras, respectively. In the post-SOR era, patients received A + B (23%), LEN (51%), and SOR (23%) as first-line treatment. There was a statistically significant improvement in RR (15% vs. 26%; p = 0.02), median PFS (3.8 months vs. 7.9 months; p < 0.0001), and median OS (9.8 months vs. 17.0 months; p < 0.0001). CONCLUSIONS: In this retrospective multicenter real-world study, HCC patients treated in the post-SOR era, where LEN and A + B were commonly used first-line treatments, exhibited superior OS, PFS, and RR compared to patients treated in the SOR era. The findings of this study affirm the tangible progress achieved in the real world in enhancing outcomes for HCC patients through advancements in treatments over the past 15 years.

Prevalence of the Cefazolin Inoculum Effect (CzIE) in Nasal Colonizing Methicillin-Susceptible Staphylococcus aureus in Patients from Intensive Care Units in Colombia and Use of a Modified Rapid Nitrocefin Test for Detection.

The cefazolin inoculum effect (CzIE) has been associated with poor clinical outcomes in patients with MSSA infections. We aimed to investigate the point prevalence of the CzIE among nasal colonizing MSSA isolates from ICU patients in a multicenter study in Colombia (2019-2023). Patients underwent nasal swabs to assess for S. aureus colonization on admission to the ICU and some individuals had follow-up swabs. We performed cefazolin MIC by broth-microdilution using standard and high-inoculum and developed a modified nitrocefin-based rapid test to detect the CzIE. Whole genome sequencing was carried out to characterize BlaZ types and allotypes, phylogenomics and Agr-typing. All swabs were subjected to 16S-rRNA metabarcoding sequencing to evaluate microbiome characteristics associated with the CzIE. A total of 352 patients were included; 46/352 (13%) patients were colonized with S. aureus; 22% (10/46) and 78% (36/46) with MRSA and MSSA, respectively. Among 36 patients that contributed with 43 MSSA colonizing isolates, 21/36 (58%) had MSSA exhibiting the CzIE. BlaZ type A and BlaZ-2 were the predominant type and allotype in 56% and 52%, respectively. MSSA belonging to CC30 were highly associated with the CzIE and SNP analyses supported transmission of MSSA exhibiting the CzIE among some patients of the same unit. The modified nitrocefin rapid test had 100%, 94.4% and 97.7% sensitivity, specificity and accuracy, respectively. We found a high prevalence point prevalence of the CzIE in MSSA colonizing the nares of critically-ill patients in Colombia. A modified rapid test was highly accurate in detecting the CzIE in this patient population.

In vitro evaluation of using ceftazidime/avibactam against carbapenem-resistant Acinetobacter baumannii.

OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a global concern as effective treatments are very limited. We previously used a modified susceptibility testing approach to predict growth suppression in carbapenem-resistant Enterobacterales, but there are uncertainties about the generalizability of the model. The objective of this study is to verify if a similar approach can be extended to CRAB. METHOD: A clinical isolate of CRAB resistant to ceftazidime/avibactam (CAZ/AVI, MIC = 32/4 mg/L) was examined. CAZ susceptibility was determined using increasing concentrations of AVI (0-64 mg/L), and MIC reduction was characterized with a sigmoid inhibitory maximum effect (Emax) model. The effectiveness of CAZ/AVI was validated in a hollow fibre infection model (HFIM) over 72 hours, using simulated unbound serum / epithelial lining fluid (ELF) exposures of 2.5 g over 2 hours every 8 hours. Baseline inocula of approximately 5.5 log CFU/mL were examined. RESULTS: An AVI concentration-dependent reduction in CAZ MIC was observed (r2 = 0.99). CAZ MIC was dramatically reduced from 512 mg/L (no AVI) to 32 mg/L (AVI = 4 mg/L), and further to 8 mg/L (AVI = 16 mg/L). Pharmacokinetic simulations were satisfactory in the HFIM (r2 > 0.96). Bacterial suppression was observed >24 hours with the serum exposure, but not that from the ELF. CONCLUSION: Using multiple AVI concentrations within the clinically relevant range, our susceptibility testing approach could have better insights of treatment outcome for infections caused by CRAB. This could potentially lead to effective intervention(s) overlooked by conventional susceptibility testing method. This case highlights the importance of site-specific drug exposures on determining treatment outcome.

Dual-Mode Imaging System for Early Detection and Monitoring of Ocular Surface Diseases.

The global prevalence of ocular surface diseases (OSDs), such as dry eyes, conjunctivitis, and subconjunctival hemorrhage (SCH), is steadily increasing due to factors such as aging populations, environmental influences, and lifestyle changes. These diseases affect millions of individuals worldwide, emphasizing the importance of early diagnosis and continuous monitoring for effective treatment. Therefore, we present a deep learning-enhanced imaging system for the automated, objective, and reliable assessment of these three representative OSDs. Our comprehensive pipeline incorporates processing techniques derived from dual-mode infrared (IR) and visible (RGB) images. It employs a multi-stage deep learning model to enable accurate and consistent measurement of OSDs. This proposed method has achieved a 98.7% accuracy with an F1 score of 0.980 in class classification and a 96.2% accuracy with an F1 score of 0.956 in SCH region identification. Furthermore, our system aims to facilitate early diagnosis of meibomian gland dysfunction (MGD), a primary factor causing dry eyes, by quantitatively analyzing the meibomian gland (MG) area ratio and detecting gland morphological irregularities with an accuracy of 88.1% and an F1 score of 0.781. To enhance convenience and timely OSD management, we are integrating a portable IR camera for obtaining meibography during home inspections. Our system demonstrates notable improvements in expanding dual-mode image-based diagnosis for broader applicability, effectively enhancing patient care efficiency. With its automation, accuracy, and compact design, this system is well-suited for early detection and ongoing assessment of OSDs, contributing to improved eye healthcare in an accessible and comprehensible manner.

Mechanisms of gelofusine protection in an in vitro model of polymyxin B-associated renal injury.

Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was used as an uptake inhibition control. Methionine was included in selected experiments as an antioxidant control. A polymyxin B concentration-dependent reduction in cell viability was observed. Increased viability was observed in megalin knockout cells following comparable polymyxin B exposures. Compared with polymyxin B exposure alone, concomitant gelofusine significantly increased cell viability as well as reduced LDH release, polymyxin B uptake, mitochondrial superoxide, and apoptosis. Gelofusine and methionine were more effective at reducing renal cell injury in combination than either agent alone. In conclusion, the mechanisms of renal protection by gelofusine involve decreasing cellular drug uptake, reducing subsequent oxidative stress and apoptosis activation. These findings would be valuable for translational research into clinical strategies to attenuate drug-associated acute kidney injury.NEW & NOTEWORTHY Gelofusine is a gelatinous saline solution with the potential to attenuate polymyxin-associated nephrotoxicity. We demonstrated that the mechanisms of gelofusine renal protection involve reducing polymyxin B uptake by proximal tubule cells, limiting subsequent oxidative stress and apoptosis activation. In addition, gelofusine was more effective at reducing cellular injury than a known antioxidant control, methionine, and a megalin knockout cell line, indicating that gelofusine likely has additional pharmacological properties besides only megalin inhibition.

An All-Soluble Fe/Mn-Based Alkaline Redox Flow Battery System.

Redox flow batteries (RFBs) are membrane-separated rechargeable flow cells with redox electrolytes, offering the potential for large-scale energy storage and supporting renewable energy grids. Yet, creating a cost-effective, high-performance RFB system is challenging. In this work, we investigate an Fe/Mn RFB alkaline system based on the [(TEA)Fe-O-Fe(TEA)]3-/4- and MnO4-/2- redox couples with a theoretical cell voltage of ∼1.43 V. This combination has not been systematically studied previously, but it can lead to a very low-cost and sustainable materials for high energy storage. Constant current cycling tests were performed at ±41 mA cm-2 between 20% and 80% SOC over 800 h (400 cycles) with an apparent Coulombic efficiency (CE) approaching 100%, while the voltage efficiency (VE) gradually decreased from ∼75.3% to ∼61.4% due to increasing internal resistances. The voltage efficiency loss can be mitigated through a periodic acid treatment to remove MnO2 deposits from the separator.

Assessing the Landscape in Medical Education Literature in Medical Oncology: A Scoping Review.

PURPOSE: Medical oncology and medical education (ME) have both expanded exponentially over the past 50 years; thus, it is important to understand the current status of postgraduate medical oncology education and develop ways to advance this field. This study undertakes a scoping review of ME literature in medical oncology to inform future scholarship in this area. METHODS: MEDLINE, Embase, ERIC, and Web of Science were searched to find peer-reviewed English language articles on postgraduate ME in medical oncology published from 2009 to 2020. Established scoping review methodologies were used in study design; articles were classified by specialty, learner training level, region of authorship, institution type, year of publication, journal type, study methodology, and research topic. Curriculum intervention, scholarship, and domain(s) of physician competency were also assessed. The results were interpreted using descriptive statistics and collated using predetermined conceptual frameworks. RESULTS: A total of 2,959 references were initially found across four databases. After title and abstract screening, 305 articles remained; after full-text review, 144 articles were included in final analysis. Postgraduate medical oncology education research is increasing, with the majority of articles published in North America. Quantitative studies were most common, primarily survey approaches. For physician competencies, professionalism and medical expertise comprised the large majority of article focuses, whereas very few articles addressed leadership or health advocacy. Curriculum development, professional development, and communication skills were dominant research themes while no articles discussed teacher training. CONCLUSION: Although areas such as professionalism and communication skills are well-studied, medical oncology ME research is lacking in leadership, health advocacy, and teacher training. This study provides valuable guidance for future ME research in medical oncology and establishes a benchmark to examine changes in educational scholarship over time.

The emergence of cefiderocol resistance in Pseudomonas aeruginosa from a heteroresistant isolate during prolonged therapy.

Cefiderocol is a siderophore cephalosporin designed to target multi-drug-resistant Gram-negative bacteria. Previously, the emergence of cefiderocol non-susceptibility has been associated with mutations in the chromosomal cephalosporinase (PDC) along with mutations in the PirA and PiuA/D TonB-dependent receptor pathways. Here, we report a clinical case of cefiderocol-resistant P. aeruginosa that emerged in a patient during treatment. This resistance was associated with mutations not previously reported, suggesting potential novel pathways to cefiderocol resistance.

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer).

WHAT IS THIS SUMMARY ABOUT?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.

Zileuton ameliorates aminoglycoside and polymyxin-associated acute kidney injury in an animal model.

OBJECTIVES: Aminoglycosides and polymyxins are antibiotics with in vitro activity against MDR Gram-negative bacteria. However, their clinical use is hindered by dose-limiting nephrotoxicity. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury. METHODS: Sprague Dawley rats (n = 10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 min before antibiotic administration. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥2× elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was also conducted to characterize the extent of kidney injury. RESULTS: Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100%, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton at 4 and 10 mg/kg, respectively. Histopathology confirmed reduced kidney injury in animals receiving amikacin concomitant with zileuton. CONCLUSIONS: Our pilot data suggest that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat MDR Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and dosing in humans.

A Practical Guide for the Systemic Treatment of Biliary Tract Cancer in Canada.

Biliary tract cancers (BTC) are rare and aggressive tumors with poor prognosis. Radical surgery offers the best chance for cure; however, most patients present with unresectable disease, and among those receiving curative-intent surgery, recurrence rates remain high. While other locoregional therapies for unresectable disease may be considered, only select patients may be eligible. Consequently, systemic therapy plays a significant role in the treatment of BTC. In the adjuvant setting, capecitabine is recommended following curative-intent resection. In the neoadjuvant setting, systemic therapy has mostly been explored for downstaging in borderline resectable tumours, although evidence for its routine use is lacking. For advanced unresectable or metastatic disease, gemcitabine-cisplatin plus durvalumab has become the standard of care, while the addition of pembrolizumab to gemcitabine-cisplatin has also recently demonstrated improved survival compared to chemotherapy alone. Following progression on gemcitabine-cisplatin, several chemotherapy combinations and biomarker-driven targeted agents have been explored. However, the optimum regimen remains unclear, and access to targeted agents remains challenging in Canada. Overall, this article serves as a practical guide for the systemic treatment of BTC in Canada, providing valuable insights into the current and future treatment landscape for this challenging disease.

In vitro model to simulate multiple drugs with distinct elimination half-lives.

OBJECTIVE: The prevalence of drug resistance in pathogens such as HIV and selected bacteria has been steadily rising, resulting in an increased need for using multiple agents concurrently. Agents used in these combination therapies may have different elimination half-lives in humans. There is an unmet need for in vitro models to evaluate the efficacy of these combinations to guide early drug development. In order to realistically reflect in vivo conditions, useful in vitro model systems must be capable of simulating multiple pharmacokinetic profiles with distinct elimination half-lives. The goal of this study was to experimentally simulate four pharmacokinetic profiles with distinct elimination half-lives in an in vitro hollow-fibre system. METHODS: For illustrative purposes, fluctuating exposures of ceftriaxone were simulated with distinct half-lives of 1, 2.5, 8, and 12 hours. A parallel experimental setup was used to independently connect four supplemental reservoirs to a central reservoir. Target maximum concentration was achieved by direct drug dosing into the central reservoir; supplemental reservoirs were also dosed to offset the rapid drug elimination rate from the central reservoir. Serial pharmacokinetic samples were obtained from the central reservoir, assayed by a spectrophotometric method, and characterized by a one-compartment model. RESULTS: The observed maximum concentrations and elimination half-lives were in agreement with the expected values obtained from the mathematical predictions. CONCLUSIONS: This in vitro experimental system can be used to evaluate the efficacy of up to four-drug combinations against multidrug-resistant bacteria or HIV-infected mammalian cells. The established framework represents an adaptable tool to advance the field of combination therapy.

Systemic exposure to bacterial amyloid curli alters the gut mucosal immune response and the microbiome, exacerbating Salmonella-induced arthritis.

The Salmonella biofilm-associated amyloid protein, curli, is a dominant instigator of systemic inflammation and autoimmune responses following Salmonella infection. Systemic curli injections or infection of mice with Salmonella Typhimurium induce the major features of reactive arthritis, an autoimmune disorder associated with Salmonella infection in humans. In this study, we investigated the link between inflammation and microbiota in exacerbating autoimmunity. We studied C57BL/6 mice from two sources, Taconic Farms and Jackson Labs. Mice from Taconic Farms have been reported to have higher basal levels of the inflammatory cytokine IL - 17 than do mice from Jackson Labs due to the differences in their microbiota. When we systemically injected mice with purified curli, we observed a significant increase in diversity in the microbiota of Jackson Labs mice but not in that of the Taconic mice. In Jackson Labs, mice, the most striking effect was the expansion of Prevotellaceae. Furthermore, there were increases in the relative abundance of the family Akkermansiaceae and decreases in families Clostridiaceae and Muribaculaceae in Jackson Labs mice. Curli treatment led to significantly aggravated immune responses in the Taconic mice compared to Jackson Labs counterparts. Expression and production of IL - 1ß, a cytokine known to promote IL - 17 production, as well as expression of Tnfa increased in the gut mucosa of Taconic mice in the first 24 hours after curli injections, which correlated with significant increases in the number of neutrophils and macrophages in the mesenteric lymph nodes. A significant increase in the expression of Ccl3 in colon and cecum of Taconic mice injected with curli was detected. Taconic mice injected with curli also had elevated levels of inflammation in their knees. Overall, our data suggest that autoimmune responses to bacterial ligands, such as curli, are amplified in individuals with a microbiome that promote inflammation.

Rapid In Vitro Assessment of Antimicrobial Drug Effect Bridging Clinically Relevant Pharmacokinetics: A Comprehensive Methodology.

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here, we present a comprehensive overview of a recently developed novel integrated methodology for rapid assessment of such efficacy, particularly against the emergence of resistant bacterial strains, as jointly researched by the authors in recent years. This methodology enables rapid in vitro assessment of the antimicrobial efficacy of single or multiple drugs in combination, following clinically relevant pharmacokinetics. The proposed methodology entails (a) the automated collection of longitudinal time-kill data in an optical-density instrument; (b) the processing of collected time-kill data with the aid of a mathematical model to determine optimal dosing regimens under clinically relevant pharmacokinetics for single or multiple drugs; and (c) in vitro validation of promising dosing regimens in a hollow fiber system. Proof-of-concept of this methodology through a number of in vitro studies is discussed. Future directions for the refinement of optimal data collection and processing are discussed.

The evolution of immune checkpoint inhibitor combinations in advanced hepatocellular carcinoma - A systematic review.

BACKGROUND AND OBJECTIVE: Since approval of sorafenib in 2008, systemic therapy has been established as the main treatment option for advanced hepatocellular carcinoma (HCC). Recently, immune checkpoints inhibitors (ICIs) have been extensively tested in this setting. Multiple ICI combination regimens have recently received regulatory approval and new data continues to emerge. The purpose of this review is to provide a comprehensive summary of the most up-to-date evidence on ICI combinations in advanced HCC. METHODS: A search of published and presented literature was conducted to identify phase III trials of ICI combinations in advanced HCC patients. Supplemental bibliographic search of review articles and meta-analyses was also conducted. Efficacy and safety data was summarized in text, tables, and plots. FINDINGS AND DISCUSSION: The literature search identified a total of six phase III trials assessing ICI combinations in advanced HCC. Two trials compared ICI plus anti-VEGF monoclonal antibody combinations to sorafenib, three trials compared ICI plus tyrosine kinase inhibitor (TKI) combinations to TKIs alone, and one trial compared a dual ICI regimen to sorafenib. Statistically significant survival benefits were seen with atezolizumab-bevacizumab and sintilimab-bevacizumab biosimilar as well as durvalumab-tremelimumab and camrelizumab-rivoceranib combinations. ICI combination regimens have also shown improvements in response rates and progression-free survival relative to the previous standard of care, sorafenib, and generally presented predictable and manageable safety profiles. CONCLUSION: ICI combinations represent the new standard of care for advanced HCC. Ongoing randomized trials and real-world evidence will further clarify the role of these combinations in this rapidly evolving field.