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The innate immune protein calprotectin ablates the bactericidal activity of β-lactam antibiotics.
Full text linkβ-lactam antibiotics are among the most widely used treatments for bacterial infections, yet therapeutic failure is common even when no genetic resistance is detected. Understanding how host factors influence antibiotic efficacy is critical for improving outcomes. Here, we identify a host-derived mechanism of antibiotic tolerance mediated by calprotectin (CP), a zinc-binding protein released in large quantities by neutrophils during infection. We show that CP induces tolerance to β-lactam antibiotics in Staphylococcus aureus by chelating zinc and inactivating autolysins, zinc-dependent enzymes required for cell wall degradation and bacterial lysis following β-lactam treatment. This protective effect was specific to β-lactam antibiotics at concentrations of CP showing minimal impact on bacterial growth or metabolic state. Mechanistic studies revealed that CP inhibits the autolytic activity of Atl, the major S. aureus autolysin, by depriving the enzyme of its zinc cofactor. In a murine infection model, the efficacy of oxacillin was significantly enhanced in CP-deficient mice, demonstrating that CP impairs β-lactam activity in vivo. These findings reveal a form of immune-mediated antibiotic tolerance driven by metal sequestration and suggest that zinc availability at infection sites plays a critical role in shaping treatment outcomes
Differential roles of Rad18 in repressing carcinogen- and oncogene-driven mutagenesis in vivo
Full text linkThe DNA repair protein RAD18 activates “Y-family” trans-lesion synthesis (TLS) DNA polymerases that are DNA damage-tolerant and potentially error-prone. RAD18 is also frequently overexpressed and pathologically activated in cancer cells. However, the extent to which RAD18 shapes cancer genomes and impacts tumorigenesis is unclear. Therefore, we tested the effect of Rad18 status on chemically induced and oncogene-driven tumorigenesis. In a chemically induced oral carcinogenesis model, acute (2–16 days) 4NQO treatment induces expression of Rad18 and TLS polymerase mRNAs in mouse oral epithelial cells prior to the emergence of oral squamous cell carcinomas (OSCCs). Chronic (8-week) 4NQO treatment leads to the onset of oral tumors that is accelerated in Rad18−/− mice when compared with Rad18+/+ animals. Analysis of OSCC exomes reveals increased levels of G(C)>T(A) transversions in Rad18−/− tumors when compared with Rad18+/+. Therefore, Rad18 promotes error-free bypass of 4NQO-induced DNA lesions and suppresses 4NQO-induced oral carcinogenesis. In a KrasG12D-induced lung carcinogenesis model, Rad18 deficiency did not affect rates or incidence of oncogene-induced lung tumors or mutations. Taken together, we demonstrate that Rad18 has context-specific tumor-suppressive activity. Given the prevalence of 4NQO-like environmental exposures, RAD18 is highly likely to shape human cancer genomes and perhaps influence other aspects of the tumorigenic process
Implementation Challenges of a Multi-Center Financial Navigation Intervention: A Qualitative Analysis of Operational Process Data
Full text linkIntroduction The Lessening the Impact of Financial Toxicity (LIFT) intervention—a financial navigation intervention—demonstrated preliminary effectiveness. Scaling LIFT to an eight-site single-arm trial, however, posed implementation challenges that were not present in the single-site pilot study. Here, we analyze factors influencing LIFT implementation. Methods We used a deductive-inductive hybrid qualitative approach to analyze transcribed meeting recordings from 55 technical assistance (TA) and 23 peer support (PS) calls with financial navigators (FN). First, we deductively coded all implementation-relevant content into the five domains of the Consolidated Framework for Implementation Research (CFIR). We then inductively generated themes and sub-themes within each of the CFIR domains. Coder reliability was assessed at multiple points during coding via coder consensus. Results The qualitative analysis of nearly 78 h of TA and PS calls with FNs resulted in 18 themes and 91 sub-themes across the six CFIR domains. Outer setting themes (7 themes, 37 sub-themes) included institutional workforce problems, limited organizational resources for specific needs, and the unpredictability of external resource application success. Determinants in the inner setting (3 themes, 18 sub-themes) included existing clinical infrastructure and navigators’ competing responsibilities in the clinic. Determinants in the individual domain (2 themes, 11 sub-themes) were the navigator workload and the patient motivation to engage in LIFT. Determinants in the innovation domain (2 themes, 5 sub-themes) were the intervention structure (ie, sequence and timing of LIFT activities). The most common implementation strategies (ie, process; 4 themes, 23 sub-themes) were pacing intervention content to meet patient needs, reframing the study to appeal to patients, and changing intervention delivery (eg, allowing phone visits). Conclusions This analysis highlights the challenges of implementing FN across multiple oncology sites, with workforce and administrative barriers being key challenges. Operational process data such as TA and PS calls can provide valuable information to guide implementation.Cancer-related financial hardship is common, and financial navigation (FN) interventions such as the Lessening the Impact of Financial Toxicity (LIFT) program aim to mitigate financial hardship. While LIFT demonstrated preliminary effectiveness in a single-site pilot, scaling to eight oncology sites introduced new implementation challenges. This study examined factors influencing LIFT implementation across sites using qualitative analysis of 78 hours of transcribed recordings from 55 technical assistance and 23 peer support calls with financial navigators. Guided by the Consolidated Framework for Implementation Research (CFIR), we identified determinants across five domains: Outer setting, inner setting, individuals, process, and innovation. Eighteen themes and 91 sub-themes emerged. Outer setting factors included workforce shortages, limited institutional resources for patient needs (eg, housing), and the unpredictability of external financial aid. Inner setting factors involved existing clinical infrastructure and navigators’ competing clinical responsibilities. Individual-level factors included navigator workload and patient motivation to engage. Innovation-related factors centered on the structure and timing of LIFT activities, while process-related determinants included pacing intervention delivery, reframing LIFT to align with patient needs, and adapting delivery methods (eg, phone visits during COVID-19). Overall, findings highlight the breadth of implementation challenges when implementing financial navigation across multiple sites. Routine analysis of operational data can inform ongoing program tailoring and enhance financial navigation implementation in oncology care
The Erosion of Value: A Meta-Analysis of Collection Rate Losses and PPO Adjustments in Modern Dental Practice
Full text linkThe financial architecture of the private dental practice has undergone a fundamental transformation over the last two decades, characterized principally by the decoupling of clinical production from realized revenue. This report provides an exhaustive meta-analysis of the "percent loss on collection rate," a critical key performance indicator (KPI) that measures the operational and financial friction introduced by Preferred Provider Organization (PPO) participation. Synthesizing data from over 100 peer-reviewed sources, industry white papers, and economic surveys ranging from 2020 to 2025, this analysis quantifies the magnitude of this loss and explores its second-order effects on practice sustainability.
The findings indicate that the average modern dental practice faces a gross collection loss ranging from 30% to 45% of its production capacity. This loss is not merely a function of contractual fee adjustments, which form the "visible" portion of the deficit, but is compounded by "invisible" factors including administrative denial rates, claim bundling, downcoding, and the inflationary erosion of reimbursement purchasing power. The report identifies that while overhead costs have surged due to labor market tightness and supply chain inflation—with some categories seeing 20% increases—reimbursement rates have remained stagnant or regressed. This creates a dangerous "profit squeeze" where the marginal profit of specific procedures approaches zero or becomes negative.
Furthermore, this document analyzes the long-term implications of suppressed collection rates on practice valuation (EBITDA multiples), highlighting how low-collection practices are penalized by private equity and DSO buyers. Finally, it outlines evidence-based mitigation strategies, ranging from aggressive fee schedule negotiation and revenue cycle management (RCM) optimization to the strategic adoption of membership plans and fee-for-service (FFS) transitions
Association between maternal genome-wide polygenic scores for psychiatric and neurodevelopmental disorders and adverse perinatal events: A Danish population-based study
Full text linkBackground Phenotypic links between psychiatric disorders and adverse perinatal events are increasingly reported, but mechanisms remain unclear. We aim to assess how polygenic scores (PGS) for eight psychiatric conditions influence perinatal risk. Methods 13,085 primiparous mothers and their corresponding birth information were included in the main analysis. PGS for psychiatric conditions were estimated using GWAS data (excluding the iPSYCH cohort) via LDpred2 and used as exposures. Ten adverse perinatal events from the Danish Medical Birth Registry served as outcomes. Associations were analysed using logistic or multinomial regression, with false discovery rate (FDR) correction applied. Results We found that PGS for psychiatric conditions was associated with heavy smoking (ADHD, anxiety and depression), lower likelihood of being overweight/obese (schizophrenia, anorexia nervosa, and OCD), very young maternal age (<20 years) at childbirth (ADHD, depression, and anxiety), and non-cohabitation (ADHD, schizophrenia, anxiety and depression). Little evidence of an association between maternal PGS for psychiatric conditions and birth weight, gestational age and labour presentation were identified. We identified a novel dose-response relationship in which higher PGS for ADHD, anxiety, and depression were associated with a greater cumulative burden of adverse perinatal events, whereas higher PGS for anorexia nervosa and OCD were linked to a lower burden. Conclusions High genetic liability for psychiatric conditions may partly explain the observed phenotypic associations between maternal mental illness and adverse perinatal events, with higher genetic liability generally associated with either an increase or decrease in the cumulative burden of adverse perinatal events in a dose-response-like manner
Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels
Full text linkCuproptosis involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron-sulfur cluster proteins, leading to cell death. Pharmacologic induction of cuproptosis has been proposed as a cancer therapy. Here, we find that glioblastoma (GBM) stem cells (GSCs) displayed relative resistance to cuproptosis with circadian variation of intracellular copper levels. CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase copper transporting alpha (ATP7A). Circadian control of copper homeostasis was mediated by the core clock transcription factor, brain and muscle ARNT-like 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back into the circadian circuitry through sequestosome 1/p62-mediated lysosomal degradation of BMAL1. Targeting the circadian clock or fatty acid desaturation augmented cuproptosis antitumor effects. Crosstalk between the core circadian clock and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance, which may inform development of combination therapies for GBM
Society for Healthcare Epidemiology of America supports environmental stewardship and sustainability while protecting patients and healthcare personnel position statement of the SHEA Board
Full text linkThe leading cause of climate change and global warming is the increase in greenhouse gas emissions. The health impacts of climate change and extreme weather events include temperature-associated illnesses and deaths, air pollution-associated chronic respiratory illness, water-and foodborne infections, and vector-borne and zoonotic infections
Maternal psychiatric disorders before, during, and after pregnancy: a national cohort study in Sweden.
Full text linkMaternal mental health is a critical public health issue, yet the evidence on rates of incident psychiatric disorders before, during, and after pregnancy is limited. This study aimed to describe the calendar time trends and characterize and compare the risk of maternal psychiatric disorders before, during, and after pregnancy. Leveraging the national and regional registers in Sweden, we conducted a cohort study of all women who gave birth 2003-2019 in Sweden (1,799,010 pregnancies from 1,052,977 women). We identified any incident diagnosis of psychiatric disorders recorded during three periods: the preconceptional year, pregnancy, and the postpartum year. We calculated age and calendar year standardized incidence rate (SIR) of psychiatric disorders annually, and by week across three periods. We further estimated the incidence rate ratio (IRR) using the rate during corresponding preconceptional weeks as the reference. The SIR of maternal psychiatric disorder overall increased from 2003-2019, especially for preconceptional disorders. During the preconceptional year the weekly SIR of any psychiatric disorder was stable at around 25 per 1000 person-years. The SIR gradually decreased during pregnancy to a minimum of 4 per 1000 person-years and bounced back to the preconceptional levels during the postpartum year. This trend was similar in all subtypes of psychiatric disorders, except for depression and psychosis for which an increase was noted at 5-15 and 0-20 postpartum weeks, respectively. An increased incidence rate of maternal psychiatric disorder diagnosed before, during, and after pregnancy was found over time. Our findings suggest an increased risk of depression and psychosis shortly after delivery, although a lowered risk of other psychiatric disorders during and after pregnancy, compared to before pregnancy
Building Pharmacoequity through Student and Trainee Education, Service, and Global Outreach
Full text linkStudents and trainees are integral to clinical pharmacology, as they have the potential to shape the field. This perspective highlights how the ASCPT Student and Trainee Community engages members worldwide, providing opportunities and resources to advance scientific and professional development. It also discusses strategies to foster equitable access and how these efforts promote pharmacoequity, including peer mentorship, international engagement, fair access to leadership roles, and diverse representation