Evaluation of the Effect of Lorlatinib on CYP2B6, CYP2C9, UGT, and P-Glycoprotein Substrates in Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVE: Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5'-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter. METHODS: Thirty-two patients received a single oral dose of a probe drug on Day - 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed. RESULTS: Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration-time curve from time zero to infinity (AUC∞) and maximum (peak) plasma drug concentration (Cmax) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC∞ and Cmax of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively. CONCLUSIONS: Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT. CLINICALTRIALS: gov: NCT01970865.

Multi-prong quality improvement approach for increasing mother's own milk use for very low birth weight infants.

OBJECTIVE: Evaluate a single center quality improvement (QI) collaborative designed to increase the provision of mother's own milk (MOM) at discharge to premature infants through evidence-based practices while targeting perinatal health disparities. DESIGN: This QI initiative was designed for preterm infants admitted to a single-center NICU within 24 h of life. Interventions were implemented between March 2022 and June 2022. MOM provision rates were compared between baseline (August 2021-February 2022), and after interventions (March 2022-December 2022). RESULTS: The percentage of mothers who discontinued pumping during the infant hospitalization decreased from 49% to 35% (p < 0.01). Infant discharge diet with MOM improved from 36% to 58% (p < 0.001). Pump frequency at two weeks increased from 4.0 ± 2.6 to 5.1 ± 2.4 (p = 0.026). CONCLUSION: Our collaborative increased the percentage of preterm infants receiving MOM at discharge and reduced the number of mothers who discontinue pumping during the NICU hospitalization.

The Association Between Facility Affiliations and Revenue Generation in Skilled Nursing Facilities - An Exploratory Study.

Background: Although hospitals have been the traditional setting for interventional and rehabilitative care, skilled nursing facilities (SNFs) can offer a high-quality and less costly alternative than hospitals. Unfortunately, the financial health of SNFs is often a matter of concern. To partially address these issues, SNF leaders have increased engagement in a number of affiliations to assist in improving quality and reducing operational costs, including Accountable Care Organizations (ACOs), Health Information Exchanges (HIEs), and participation in Bundled Payment for Care Improvement (BPCI) programs. What is not well understood is what impact these affiliations have on the financial viability of the host organizations. Given these factors, this study aims to identify what association, if any, exists between SNF affiliations and revenue generation. Methods: Data from calendar year 2022 for n=13,447 SNFs in the US were assessed using multivariate regression analysis. We evaluated two separate dependent measures of revenue generation capacity: net patient revenue per bed and net patient revenue per discharge and considered three unique facility affiliations including (1) ACOs, (2) HIEs, and (3) BPCI participants. Results: Six multivariable linear regressions revealed that ACO affiliation is negatively associated with revenue generation on both dependent measures, while HIE affiliation and BPCI participation reflected mixed results. Conclusion: A better understanding of the financial impact of SNFs' affiliations may prove insightful. By carefully considering the value of each affiliation, and how each is applicable to any given market, policymakers, funding agencies, and facility leaders may be able to better position SNFs for more sustainable financial performance in a challenging economic environment.

A Multipathway Phosphopeptide Standard for Rapid Phosphoproteomics Assay Development.

Recent advances in methodology have made phosphopeptide analysis a tractable problem for many proteomics researchers. There are now a wide variety of robust and accessible enrichment strategies to generate phosphoproteomes while free or inexpensive software tools for quantitation and site localization have simplified phosphoproteome analysis workflow tremendously. As a research group under the Association for Biomolecular Resource Facilities umbrella, the Proteomics Standards Research Group has worked to develop a multipathway phosphopeptide standard based on a mixture of heavy-labeled phosphopeptides designed to enable researchers to rapidly develop assays. This mixture contains 131 mass spectrometry vetted phosphopeptides specifically chosen to cover as many known biologically interesting phosphosites as possible from seven different signaling networks: AMPK signaling, death and apoptosis signaling, ErbB signaling, insulin/insulin-like growth factor-1 signaling, mTOR signaling, PI3K/AKT signaling, and stress (p38/SAPK/JNK) signaling. Here, we describe a characterization of this mixture spiked into a HeLa tryptic digest stimulated with both epidermal growth factor and insulin-like growth factor-1 to activate the MAPK and PI3K/AKT/mTOR pathways. We further demonstrate a comparison of phosphoproteomic profiling of HeLa performed independently in five labs using this phosphopeptide mixture with data-independent acquisition. Despite different experimental and instrumentation processes, we found that labs could produce reproducible, harmonized datasets by reporting measurements as ratios to the standard, while intensity measurements showed lower consistency between labs even after normalization. Our results suggest that widely available, biologically relevant phosphopeptide standards can act as a quantitative "yardstick" across laboratories and sample preparations enabling experimental designs larger than a single laboratory can perform. Raw data files are publicly available in the MassIVE dataset MSV000090564.

Using Mitra sampling to support first-in-human pharmacokinetic evaluations for PF-07059013.

Aim: A sensitive and selective method for the determination of PF-07059013 in dried blood collected by Mitra™ tips was developed and qualified from 50 to 50,000 ng/ml. Materials & methods: PF-07059013 is isolated from 10 µl of human dried blood by extraction with methanol and analyzed by HPLC-MS/MS. Results & conclusions: In addition to routine validation elements, impact of hematocrit and Mitra tip's lot-to-lot variation on assay accuracy were evaluated. The qualified method was used in one clinical study with excellent performance. Correlation coefficient between blood concentrations obtained from liquid-incurred blood samples and dried-incurred blood samples is 0.95. Clinical Trial Registration: NCT04323124 (ClinicalTrials.gov).

NCCN Guidelines® Insights: Survivorship, Version 1.2023.

The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.

Strategies and lessons learned for smoke and Tobacco-Free policy change on community colleges with community-based support.

Objective: Community colleges face challenges to becoming smoke-free and have higher smoking prevalence rates than four-year colleges. This case study examines how Sacramento Taking Action Against Nicotine Dependence (STAND), a community-based organization's project, achieved tobacco-free policies at California's second largest community college district. Methods: Data sources describing the STAND policymaking activities (2001-2016) include evaluation reports and key informant interviews (n = 9) with community college nursing staff, former STAND staff, and other Sacramento tobacco control partners. Reports and interview transcripts were analyzed using content analysis. Results: Collecting campus data and engaging campus champions were key strategies to demonstrate internal support for stronger policies, as STAND faced resistance from the District leadership. External momentum encouraged the campuses to adopt 100% smoke, tobacco and vape-free policies. Conclusion: Community-based organizations can facilitate long-term support for smoke and tobacco-free campus policymaking efforts at community colleges, as internal and external support is demonstrated for more comprehensive policies.

Lack of an Effect of Supratherapeutic Dose of Venlafaxine on Cardiac Repolarization in Healthy Subjects.

This single-center, randomized, 3-way crossover thorough QT study evaluated the effect of steady-state supratherapeutic venlafaxine (Effexor) on cardiac repolarization. Fifty-four healthy adults received double-blinded extended-release venlafaxine 450 mg/d and placebo and open-label positive-control moxifloxacin 400 mg. The postdose QT intervals corrected for heart rate using the Fridericia formula (QTcF) were assessed on day 14 with an analysis of covariance using a mixed-effects model. At each time, the upper bound of the 2-sided 90%CI for time-matched least-squares (LS) mean difference between venlafaxine and placebo did not exceed the predefined cutoff of 10 milliseconds; the highest 90%CI upper bound was 5.8 milliseconds 24 hours postdose, demonstrating the lack of effect of venlafaxine on the QTc interval (primary objective). Assay sensitivity was established because the lower bound of the 2-sided 90%CI for LS mean difference in QTcF between moxifloxacin and placebo was 7.413 milliseconds on day 14 (postdose 3 hours). The exposure-response analysis demonstrated no evidence of increase in QTcF with increase in venlafaxine and desvenlafaxine concentrations. Also, supratherapeutic venlafaxine was found to be safe and well tolerated. Overall, the results demonstrated the lack of significant prolongation of the QTc interval with supratherapeutic venlafaxine 450 mg/d.

Novel Antibodies for the Simple and Efficient Enrichment of Native O-GlcNAc Modified Peptides.

Antibodies against posttranslational modifications (PTMs) such as lysine acetylation, ubiquitin remnants, or phosphotyrosine have resulted in significant advances in our understanding of the fundamental roles of these PTMs in biology. However, the roles of a number of PTMs remain largely unexplored due to the lack of robust enrichment reagents. The addition of N-acetylglucosamine to serine and threonine residues (O-GlcNAc) by the O-GlcNAc transferase (OGT) is a PTM implicated in numerous biological processes and disease states but with limited techniques for its study. Here, we evaluate a new mixture of anti-O-GlcNAc monoclonal antibodies for the immunoprecipitation of native O-GlcNAcylated peptides from cells and tissues. The anti-O-GlcNAc antibodies display good sensitivity and high specificity toward O-GlcNAc-modified peptides and do not recognize O-GalNAc or GlcNAc in extended glycans. Applying this antibody-based enrichment strategy to synaptosomes from mouse brain tissue samples, we identified over 1300 unique O-GlcNAc-modified peptides and over 1000 sites using just a fraction of sample preparation and instrument time required in other landmark investigations of O-GlcNAcylation. Our rapid and robust method greatly simplifies the analysis of O-GlcNAc signaling and will help to elucidate the role of this challenging PTM in health and disease.

Automating UbiFast for High-throughput and Multiplexed Ubiquitin Enrichment.

Robust methods for deep-scale enrichment and site-specific identification of ubiquitylation sites are necessary for characterizing the myriad roles of protein ubiquitylation. To this end we previously developed UbiFast, a sensitive method for highly multiplexed ubiquitylation profiling where K-ϵ-GG peptides are enriched with anti-K-ε-GG antibody and labeled on-antibody with isobaric labeling reagents for sample multiplexing. Here, we present robotic automation of the UbiFast method using a magnetic bead-conjugated K-ε-GG antibody (mK-ε-GG) and a magnetic particle processor. We report the identification of ∼20,000 ubiquitylation sites from a TMT10-plex with 500 µg input per sample processed in ∼2 h. Automation of the UbiFast method greatly increased the number of identified and quantified ubiquitylation sites, improved reproducibility, and significantly reduced processing time. The automated method also significantly reduced variability across process replicates compared with the manual method. The workflow enables processing of up to 96 samples in a single day making it suitable to study ubiquitylation in large sample sets. Here we demonstrate the applicability of the method to profile small amounts of tissue using breast cancer patient-derived xenograft (PDX) tissue samples.

Exploring the Microbiome-Wide Lysine Acetylation, Succinylation, and Propionylation in Human Gut Microbiota.

Lysine acylations are important post-translational modifications that are present in both eukaryotes and prokaryotes and regulate diverse cellular functions. Our knowledge of the microbiome lysine acylation remains limited due to the lack of efficient analytical and bioinformatics methods for complex microbial communities. Here, we show that the serial enrichment using motif antibodies successfully captures peptides containing lysine acetylation, propionylation, and succinylation from human gut microbiome samples. A new bioinformatic workflow consisting of an unrestricted database search confidently identified >60,000 acetylated, and ∼20,000 propionylated and succinylated gut microbial peptides. The characterization of these identified modification-specific metaproteomes, i.e., meta-PTMomes, demonstrates that lysine acylations are differentially distributed in microbial species with different metabolic capabilities. This study provides an analytical framework for the study of lysine acylations in the microbiome, which enables functional microbiome studies at the post-translational level.

Facilitators and Barriers Surrounding the Role of Administration in Employee Job Satisfaction in Long-Term Care Facilities: A Systematic Review.

Previous literature has shown how associate engagement has positively impacted on productivity, job satisfaction, safety, retention, consumer sentiment, and financial performance in hospitals and healthcare systems. However, a lack of research showing the relationship between associate engagement and job satisfaction within the long-term care environment has existed. Our objective was to investigate characteristics within the long-term care environment that promote and detract from associate job satisfaction and extrapolate the best practices in maintaining job satisfaction and engagement. This systematic review queried CINAHL, PubMed (MEDLINE), and Academic Search Ultimate databases for peer-reviewed publications for facilitators and barriers commensurate with employee job satisfaction in long-term care facilities using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Kruse Protocols. The authors identified 11 facilitators for job satisfaction and 18 barriers to job satisfaction in the 60 selected articles. The top four facilitators were Supportive Leadership, Capable and Motivated Employees, Positive Organizational Values, and Social Support Mechanisms. The top four barriers were condescending management style, high job demands, lack of self-care, and lack of training with medically complex patients. The systematic review revealed the importance of maintaining satisfied employees in the long-term care workplace through am emphasis leadership and on the facilitators identified to best serve their associates and improve care for residents.

Correction to: The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.

In the original article, the reference 4 has been published and cited incorrectly.

Antimicrobial Stewardship at the Core of COVID-19 Response Efforts: Implications for Sustaining and Building Programs.

We describe traditional antimicrobial stewardship program (ASP) activities with a discussion of how these activities can be refocused in the setting of the COVID-19 pandemic. Additionally, we discuss possible adverse consequences of ASP attention diversion on COVID-19 response efforts and overall implications for future pandemic planning. We also discuss ASP in collaboration with other groups within health systems and how COVID-19 may affect these relationships long term. Despite the paucity of literature on Antimicrobial Stewardship and COVID-19, the potential contributions of ASPs during a pandemic are numerous. ASPs can develop strategies to identify patients with COVID-19-like-illness; this is particularly useful when these patients are missed at the time of health system entry. ASPs can also play a critical role in the management of potential drug shortages, developing local treatment guidelines, optimizing the use of antibiotics, and in the diagnostic stewardship of COVID-19 testing, among other roles. Importantly, it is often difficult to ascertain whether critically ill patients who are hospitalized with COVID-19 have concurrent or secondary bacterial infections-ASPs are ideally situated to help optimize antimicrobial use for these patients via a variety of mechanisms. ASPs are uniquely positioned to aid in pandemic response planning and relief efforts. ASPs are already integrated into health systems and play a key role in optimizing antimicrobial prescribing. As ASPs assist in COVID-19 response, understanding the role of ASPs in pandemic relief efforts may mitigate damage from future outbreaks.

Targeted Quantification of Peptides Using Miniature Mass Spectrometry.

Proteomics by mass spectrometry (MS) allows for the identification of amino acid/peptide sequences in complex mixtures. Peptide analysis and quantitation enables screening of protein biomarkers and targeted protein biomarker analysis for clinical applications. Whereas miniature mass spectrometers have primarily demonstrated point-of-care analyses with simple procedures aiming at drugs and lipids, it would be interesting to explore their potential in analyzing proteins and peptides. In this work, we adapted a miniature MS instrument for peptide analysis. A mass range as wide as 100-2000 m/z was achieved for obtaining peptide spectra using this instrument with dual linear ion traps. MS2 and MS3 can be performed to analyze a wide range of peptides. The parameters of pressure, electric potentials, and solution conditions were optimized to analyze peptides with molecular weights between 900 and 1800 Da. The amino acid sequences were identified using both beam-type and in-trap collision-induced dissociation, and the results were comparable to those obtained by a commercial quadrupole time-of-flight mass spectrometer. With product ion monitoring scan mode, peptide quantitation was performed with a limit of detection of 20 nM achieved for the Met peptide. The method developed has also been applied to the analysis of the trypsin-digested cell lysate of SKBR3 cells with a low expression level of the Met gene.