ACPHS Research Commons (Albany College of Pharmacy and Health Sciences)
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RNA Polymerase III Regulates HIV Replication and Latency.
No full textThe elimination of HIV latent reservoirs is an extremely challenging task due to the interplay of multiple mechanisms regulating latency. Thus, we need to identify novel strategies to target heterogeneous reservoirs uniformly. Recent reports have provided intriguing evidence for the novel antiviral function of RNA Polymerase III (RNAP III), which remains to be further explored. In this study, we evaluated the role of RNA Pol III in regulating HIV latency and replication. We first demonstrated that the pharmacological inhibition of RNAP III can lead to a strong reactivation of latency in cell lines representing both T and monocytic cellular reservoirs. Next, we investigated the involvement of RNA Pol III in regulating HIV-1 replication using HIV-1 pseudotyped (DuoFluo) virus and HIV-1-Bal in THP-1 and Sup-T1 cells. We show that the pharmacological inhibition of RNAP III significantly induced HIV transcription. These findings were further confirmed in physiologically relevant primary CD4 T cells, and a consistent increase in HIV transcription was observed up to 72 h. Collectively, our study suggests that inhibition of RNAP III can increase the rate of HIV transcription, while the total HIV DNA remains unchanged. Overall, our study identifies a previously unknown role of RNA Pol III in restricting HIV transcription and advocates that targeting RNAP III-driven mechanisms could be a novel strategy to reactivate HIV latent reservoirs.Grant FundedR15 AI165295/AI/NIAID NIH HHS/United StatesR15 AI165295-01A1/National Institute of Allergy and Infectious Diseases (NIAID)https://pmc.ncbi.nlm.nih.gov/articles/PMC12474107/https://doi.org/10.3390/v1709127
Dalbavancin for Treatment of Staphylococcus aureus Bacteremia: The DOTS Randomized Clinical Trial.
No full textClinicalTrials.gov Identifier: NCT04775953.Importance: Dalbavancin is a long-acting intravenous lipoglycopeptide that may be effective for treatment of complicated Staphylococcus aureus bacteremia without requiring long-term intravenous access.Objective: To evaluate the efficacy and safety of dalbavancin vs standard therapy for completion of treatment of complicated S aureus bacteremia.Design, setting, and participants: Open-label, assessor-masked, randomized clinical trial conducted from April 2021 to December 2023 at 23 medical centers in the US (n = 22) and Canada (n = 1). Participant follow-up lasted 70 days (180 days for participants with osteomyelitis); date of final follow-up was December 1, 2023. Hospitalized adults with complicated S aureus bacteremia who achieved blood culture clearance following at least 72 hours but no more than 10 days of initial antibacterial therapy were included. Participants were excluded if they had central nervous system infection, retained infected prosthetic material, left-sided endocarditis, or severe immune compromise.Interventions: Participants were randomly assigned to receive either 2 doses of intravenous dalbavancin (n = 100; 1500 mg on days 1 and 8) or 4 to 8 total weeks of standard intravenous therapy (n = 100; cefazolin or antistaphylococcal penicillin if methicillin susceptible; vancomycin or daptomycin if methicillin resistant).Main outcomes and measures: The primary outcome was the desirability of outcome ranking (DOOR) at day 70, which involved 5 components (clinical success, infectious complications, safety complications, mortality, and health-related quality of life) and was assessed for superiority (achieved if the 95% CI for the probability of dalbavancin having a superior DOOR was >50%). Secondary outcomes included clinical efficacy at day 70 (prespecified noninferiority margin of 20%) and safety.Results: Of 200 participants randomized (mean [SD] age, 56 [16.2] years; 62 females [31%]), 167 (84%) survived to day 70 and had an efficacy assessment. Participants without a day 70 efficacy assessment were treated as clinical failures in the analyses. The probability of a more desirable day 70 outcome with dalbavancin vs standard therapy was 47.7% (95% CI, 39.8% to 55.7%). Regarding secondary outcomes, clinical efficacy was documented in 73 of 100 for dalbavancin and 72 of 100 for standard therapy (difference, 1.0% [95% CI, -11.5% to 13.5%]), meeting the noninferiority criterion. Serious adverse events were reported in 40 of 100 participants who received dalbavancin and 34 of 100 participants who received standard therapy; treatment-related adverse events were uncommon in both groups.Conclusions and relevance: Among adult participants with complicated S aureus bacteremia who achieved blood culture clearance, dalbavancin was not superior to standard therapy by desirability of outcome ranking. When considered with other efficacy and safety outcomes these findings may help inform use of dalbavancin in clinical practice.Grant fundedUM1 AI104681/AI/NIAID NIH HHS/United Stateshttps://pmc.ncbi.nlm.nih.gov/articles/PMC12351474/https://doi.org/10.1001/jama.2025.1254
Association between Duration of Candidemia and Clinical and Healthcare Resource Utilization Outcomes among Hospitalized Adult Patients with Candidemia Who Received Empiric Treatment with an Echinocandin Across United States Hospitals.
No full textClick on the Resource Link - may not be free.Background: Time to bloodstream clearance is a critical prognostic indicator in various infections, yet limited data exist on the relationship between time to mycological clearance and outcomes in candidemia. This study aimed to assess the association between the duration of candidemia and outcomes in adult, hospitalized patients receiving empiric echinocandin treatment across U.S. hospitals.Methods: A retrospective, multi-center study using the PINCI AI Healthcare Database (1/2016-4/2019) was conducted. Inclusion criteria: hospitalized adults (≥18 years) with Candida sp. identified on a clinical blood culture who received empiric echinocandin therapy (±2 days of index Candida sp. blood culture) for ≥ 3 days. Outcomes assessed were in-hospital mortality, length of stay (LOS), and hospital costs. The associations between increasing duration of candidemia relative to a single day of candidemia and outcomes were examined.Results: A total of 867 patients met the criteria. Multivariable analysis showed that patients with candidemia lasting more than one day had significantly higher mortality, longer LOS, and higher hospital costs compared to those with only one day of candidemia. For each additional day of candidemia, the adjusted odds of in-hospital mortality increased by 3%, the adjusted median hospital length of stay post index collection day increased by 1.0 days, and the adjusted median total costs post index collection day increased by $3006.Conclusion: Prolonged candidemia is associated with worse patient outcomes and higher healthcare costs. Further large-scale studies are needed to confirm these findings given the exploratory and observational nature of this study.https://doi.org/10.1093/cid/ciaf47
Exploring Genetic Pathways involved in Antibiotic Collateral Sensitivity through the Evolution of Antibiotic-Resistant Klebsiella Pneumoniae
No full textClick on the Resource Link to the ACPHS Library Catalog.Klebsiella pneumoniae is an opportunistic Gram-negative bacterium that causes a variety of infections including UTIs and pneumonias in immunocompromised/hospitalized patients. K. pneumoniae is a pathogen of concern because it is frequently multi-drug resistant (MDR). Due to scarcity of new antibiotics, treatment options for MDR infections are limited prompting exploration of effective combinations of existing antibiotics to identify synergistic combinations. Antibiotic synergy occurs when combinations of drugs are more effective together than either drug is separately. We are interested in understanding mechanisms of collateral sensitivity that may underlie synergistic antibiotic combinations and evolution of antibiotic resistance of K. pneumoniae mutants. Collateral sensitivity occurs when resistance to one drug causes sensitivity to another. Gentamicin-resistant cultures were evolved to levels over 100-fold greater than the MIC of wild-type (WT) K. pneumoniae MKP220 to explore mechanisms of collateral sensitivity, as a way of developing new combination therapies. Purification of gentamicin-resistant K. pneumoniae mutants was achieved by multiple rounds of streak purification and the MIC of gentamicin was determined for each isolate. Sensitivity to additional antibiotics was determined by comparing these strains to WT using disc diffusion assays and liquid growth curves. The growth rates and colony morphologies of the isolated strains' phenotypes were examined for physiological defects under various environmental conditions. Mutants of interest were chosen that showed a range of phenotype and gentamicin profiles. They were sent for whole genome sequencing to identify mutations that may underlie resistance and/or sensitivity. Multiple mutations were found in the selected strains including genes involved in energy production, cell membrane, stress responses, DNA replication, and other areas. Knockout mutations of three select genes were created in a WT background and compared to WT and parental strains for growth and resistance profiles. Identified mutations will illuminate the role in collateral sensitivity.MS in Molecular Bioscienceshttps://acphs.on.worldcat.org/oclc/154721700
Population pharmacokinetic analyses for telavancin using data from healthy subjects and patients with infections.
No full textClick on the Resource Link to access the article (may not be free).Telavancin is an intravenously administered lipoglycopeptide antibiotic active against clinically relevant gram-positive pathogens. In these analyses, a population pharmacokinetic (PK) model was constructed to describe the time course of telavancin in plasma and epithelial lining fluid (ELF) using data from healthy subjects and patients with complicated skin and skin-structure infections, hospital-acquired and ventilator-associated bacterial pneumonia, or uncomplicated bacteremia across Phases 1-4 of clinical development. Data from 1,205 individuals pooled from 21 studies contributed a total of 9,088 telavancin plasma concentrations. The final model for telavancin was a two-compartment model with zero-order intravenous input and linear elimination. Dialysis clearance was included as part of the base structural PK model; the relationship between telavancin clearance and creatinine clearance was included . Body weight, age, and infection type were identified as statistically significant predictors of the interindividual variability (IIV) in total clearance. Body weight, age, and infection type were also identified as statistically significant predictors of IIV for the central and peripheral volumes of distribution. Only body weight was found to be a significant predictor of the IIV in distributional clearance. The model for ELF did not reveal any appreciable biases and determined the average free-drug ELF penetration ratio to be 73.0%. In summary, the population PK model characterized the time course of telavancin in both plasma and ELF robustly, captured the impact of clinically meaningful patient covariate effects, including removal of drug due to hemodialysis, and provided reliable individual estimates of exposure in subjects enrolled in the clinical studies.https://doi.org/10.1128/aac.01382-24https://pmc.ncbi.nlm.nih.gov/articles/PMC12217474
Combination Effects of Aminolevulinic Acid and Mycophenolic Acid on Hacat Cell Proliferation and Inhibition of Inosine Monophosphate Dehydrogenase.
No full textDerivatives of mycophenolic acid (MPA) and 5-aminolevulinic acid photodynamic therapy (ALA-PDT) have been used separately to treat psoriasis, a chronic, inflammatory skin disease that is characterized by the unregulated hyperproliferation of epidermal keratinocytes and a T-cell-mediated immune response. However, the combination of these two therapies has not previously been explored. This study investigated the in vitro effects of combining MPA with ALA-PDT to suppress keratinocytes and the in vitro inhibition of inosine monophosphate dehydrogenase, a key enzyme. The effects of ALA, MPA, and their combination on protoporphyrin IX (PpIX) generation and cell viability in HaCaT cells, as well as the inhibition of IMPDH, were evaluated. Treatment of HaCaT cells with ALA, MPA, and their 1:1 molar combination showed that ALA alone induced PpIX production, with concentrations increasing from 5.25 ng/mL at 10 μM to 157.5 ng/mL at 1 mM. MPA did not increase PpIX on its own but had a modest synergistic effect with ALA at low concentrations (10 μM and 50 μM). The impact of blue light irradiation (465 nm) on cell viability was also assessed, revealing that ALA and ALA + MPA treatment led to significant reductions in HaCaT cell viability at higher concentrations (500 μM-1 mM), while MPA alone with blue light irradiation showed no cytotoxicity. The reduction in skin cell viability was enhanced when ALA was combined with MPA. Additionally, MPA effectively inhibited IMPDH activity in a dose-dependent manner, with 94-96% inhibition at concentrations of 100 μM and above. Interestingly, ALA weakly inhibited IMPDH, with a peak inhibition of 46% at 5 μM. At higher ALA concentrations, its inhibitory effect diminished, and it interfered with the potency of MPA's IMPDH2 inhibition, suggesting that ALA could modulate MPA's therapeutic action. These findings suggest that the combination of MPA with ALA-PDT may be a viable new treatment for psoriasis.https://doi.org/10.3390/molecules30061359https://pmc.ncbi.nlm.nih.gov/articles/PMC11946027
Maternal elaboration and children's episodic memory accuracy: A double-edged sword?
No full textClick on the resource link. May not be free.Grant FundedAmerican Psychology-Law Societyhttps://doi.org/10.1037/dev000192
Pivmecillinam for Treatment of Uncomplicated Urinary Tract Infection: New Efficacy Analysis.
No full textClick on the Resource Link to access the article (may not be free).In April 2024-over 40 years after its first approval in Europe-pivmecillinam received approval from the United States Food and Drug Administration (FDA) for the treatment of uncomplicated urinary tract infection (uUTI) in women aged ≥18 years, caused by susceptible isolates of Escherichia coli, Proteus mirabilis, and Staphylococcus saprophyticus. Herein, we describe the reanalysis from previously published clinical trials, conducted in accordance with current FDA efficacy criteria, which formed the basis for this regulatory approval.Of 14 studies reviewed, 3 randomized, controlled trials offered suitable subject-level data from patients with uUTI treated with 185 mg pivmecillinam 3 times daily for 3-7 days. Efficacy endpoints for reanalysis were rates of overall (composite clinical and microbiological), clinical, and microbiological response in the microbiological intention-to-treat population (urine culture ≥105 colony-forming units/mL; ≤2 microorganism species; no baseline pathogen nonsusceptible to active comparator).Across the 3 primary studies, overall success rates with pivmecillinam at test of cure (Days 7-15) were 62.0%-71.7% (clinical success, 63.5%-82.7%; microbiological success, 74.3%-86.9%). Overall success was higher for pivmecillinam than for placebo (95% confidence interval for the difference, 41.2-62.0) or ibuprofen (31.2-56.5) and similar to cephalexin (-15.6 to 7.4). Response to pivmecillinam was demonstrated in uUTIs caused by Enterobacterales, including E. coli, P. mirabilis, and Klebsiella pneumoniae, as well as gram-positive S. saprophyticus.This reanalysis of randomized, controlled trial data confirmed the efficacy of oral pivmecillinam in uUTI and was used to support its recent approval in the United States.https://doi.org/10.1093/cid/ciaf28
Multicenter evaluation of the safety and efficacy of varying doses of cangrelor used in acute cerebrovascular stenting in patients with acute ischemic stroke.
No full textClick on the Resource Link to access the article (may not be free).Background: Acute ischemic stroke often necessitates neuroendovascular interventions such as thrombectomy and, occasionally, stenting for large vessel occlusions or intracranial atherosclerotic disease. Effective antiplatelet therapy is essential during stenting to mitigate thrombosis risks, but consensus on optimal cangrelor dosing remains elusive. This study evaluates the safety and efficacy of various cangrelor doses used in acute cerebrovascular stenting.Methods: A multicenter, retrospective cohort study was conducted across 11 comprehensive stroke centers. Patients aged 18-85 with ischemic stroke who underwent emergent cerebrovascular stenting with cangrelor were included. Patients were categorized into low-dose cangrelor (<2 mcg/kg/min; LDC) and high-dose cangrelor (≥2 mcg/kg/min; HDC) cangrelor groups. Outcomes included thrombotic and bleeding complications both intra-procedurally and within 48 hours post-procedure.Results: A total of 230 patients were included in the analysis (LDC: 68; HDC: 162). Baseline characteristics were similar between groups. Thrombotic outcomes, including intraprocedural thrombosis (13% LDC vs 6% HDC; P=0.078) and thrombosis within 48 hours of the procedure (9% LDC vs 4% HDC; P=0.093), showed no statistical differences. Similarly, intraprocedural bleeding (6% LDC vs 5% HDC; P=0.753) and intracranial hemorrhage within 48 hours of the procedure (19% LDC vs 25% HDC; P=0.360) were not statistically different.Conclusions: Different cangrelor dosing regimens demonstrated no significant differences in thrombotic or bleeding complications during acute neuroendovascular stenting for ischemic stroke. Larger, prospective studies are warranted to refine optimal dosing strategies for cangrelor in this population.https://doi.org/10.1136/jnis-2025-02352
Adults’ perceptions of children’s ground rule applications during investigative interviews
No full textClick on the resource link. May not be free.Ground rules are a recommended portion of investigative interviews with children. The current study examined how adults perceive children’s application of the I Don’t Understand (IDU) or I Don’t Know (IDK) rules during investigative interviews. Jury-eligible adults (N = 716) viewed a transcript of a child alleging sexual abuse in a 2 (Child Age: 6 v. 10) × 2 (Rule Applied: IDU v. IDK) × 2 (Rule Application Frequency: 1-time v. 6-times) design. Adults perceived the child who applied a rule 1 time as more credible, less likely to have intentionally lied, and more likely to have understood what her statements would be used for than the child who applied a rule 6 times. Child age and type of rule applied had more limited effects. Results have implications for those who interview children, design interview interventions, and provide expert testimony regarding child witnesses.https://doi.org/10.1080/1068316X.2025.246777