Potency of a small molecule that targets the molluscum contagiosum virus processivity factor increases when conjugated to a tripeptide.

We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity.

Causes and outcomes of non-chemotherapy induced neutropenic fever in hospitalized adults: An observational study.

Neutropenic fever in adults undergoing chemotherapy for cancer treatment is a medical emergency and has been the focus of numerous studies. However, there is a paucity of data about non-chemotherapy induced neutropenic fever (non-CINF). We retrospectively reviewed 383 adults with neutropenic fever hospitalized at one academic medical center between October 2015 and September 2020 to characterize the frequency, causes, and outcomes of non-CINF. Twenty-six percent of cases of neutropenic fever were non-chemotherapy induced. Among these, the major causes of neutropenia were hematologic malignancy, infection, and rheumatologic disease, and the major causes of fever were infections. Patients with non-CINF had a higher 30-day mortality than those with chemotherapy induced neutropenic fever (25% vs 13%, P = .01). Non-CINF constituted > 25% of neutropenic fever events in hospitalized adults and was associated with a high mortality rate.

Assessing Longitudinal Treatment Efficacies and Alterations in Molecular Markers Associated with Glutamatergic Signaling and Immune Checkpoint Inhibitors in a Spontaneous Melanoma Mouse Model.

Previous work done by our laboratory described the use of an immunocompetent spontaneous melanoma-prone mouse model, TGS (TG-3/SKH-1), to evaluate treatment outcomes using inhibitors of glutamatergic signaling and immune checkpoint for 18 weeks. We showed a significant therapeutic efficacy with a notable sex-biased response in male mice. In this follow-up 18-week study, the dose of the glutamatergic signaling inhibitor was increased (from 1.7 mg/kg to 25 mg/kg), which resulted in improved responses in female mice but not male mice. The greatest reduction in tumor progression was observed in male mice treated with single-agent troriluzole and anti-PD-1. Furthermore, a randomly selected group of mice was removed from treatment after 18 weeks and maintained for up to an additional 48 weeks demonstrating the utility of the TGS mouse model to perform a ≥1-year preclinical therapeutic study in a physiologically relevant tumor-host environment. Digital spatial imaging analyses were performed in tumors and tumor microenvironments across treatment modalities using antibody panels for immune cell types and immune cell activation. The results suggest that immune cell populations and cytotoxic activities of T cells play critical roles in treatment responses in these mice. Examination of a group of molecular protein markers based on the proposed mechanisms of action of inhibitors of glutamatergic signaling and immune checkpoint showed that alterations in expression levels of xCT, γ-H2AX, EAAT2, PD-L1, and PD-1 are likely associated with the loss of treatment responses. These results suggest the importance of tracking changes in molecular markers associated with the mechanism of action of therapeutics over the course of a longitudinal preclinical therapeutic study in spatial and temporal manners.

PROTAC-mediated degradation of HIV-1 Nef efficiently restores cell-surface CD4 and MHC-I expression and blocks HIV-1 replication.

The HIV-1 Nef accessory factor enhances the viral life cycle in vivo, promotes immune escape of HIV-infected cells, and represents an attractive antiretroviral drug target. However, Nef lacks enzymatic activity and an active site, complicating traditional occupancy-based drug development. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on an existing hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the cereblon E3 ubiquitin ligase thalidomide-binding domain in vitro and triggered Nef degradation in a T cell expression system. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cells in vivo.

A Narrative Commentary on the Use of a Rational Emotive Behavior Therapy-Informed Group to Address Irrational Beliefs, Posttraumatic Stress Disorder, and Comorbidities.

Irrational beliefs of Demandingness, Catastrophizing, Low Frustration Tolerance, and Depreciation have demonstrated prevalence in disparate areas of life, including psychopathology, the military, politics, religion, and education. Individuals with mental health concerns, such as Post-Traumatic Stress Disorder (PTSD), endorse elevations in such thoughts compared to the general population. This commentary describes the rationale for focusing on irrational beliefs in efforts to address PTSD and presents the Rational Emotive Behavior Therapy (REBT)-Informed Group for PTSD as a potential novel application of a well-established intervention. In support of these suggestions, we present a narrative review of the published work on irrational beliefs and REBT tenets as relevant for PTSD. We then introduce and describe the REBT-Informed Group intervention, summarize the prior preliminary research conducted by our group, and present some novel data from a re-analysis of this prior work. We end with commentary related to future directions of REBT approaches for PTSD to address limitations and expand the impact of the treatment to military and other Veteran or civilian populations.

Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

Sexual Identity Disclosure and Alcohol Experiences Among LGBTQ+ Adolescents.

Sexual and gender minority youth (SGMY) report greater alcohol use in comparison to their heterosexual counterparts. Prior research has found that elevated alcohol use among SGMY can be explained by minority stress experiences. Sexual identity outness may be another factor that drives alcohol use among SGMY, given that outness is associated with alcohol use among older sexual and gender minority samples. We examined how patterns of sexual identity outness were associated with lifetime alcohol use, past-30-day alcohol use, and past-30-day heavy episodic drinking. Data were drawn from the LGBTQ National Teen Survey (N = 8884). Participants were SGMY aged 13 to 17 (mean age = 15.59) years living in the US. Latent class analysis was used to identify sexual identity outness patterns. Multinomial regressions were used to examine the probability of class membership by alcohol use. Six outness classes were identified: out to all but teachers (n = 1033), out to siblings and peers (n = 1808), out to siblings and LGBTQ+ peers (n = 1707), out to LGBTQ+ peers (n = 1376), mostly not out (n = 1653), and very much not out (n = 1307). SGMY in classes characterized by greater outness to peers, friends, and family had greater odds of lifetime alcohol use compared with SGMY in classes characterized by lower outness. These findings suggest that SGMY with greater sexual identity outness may be a target for alcohol use prevention programming. Differences in sexual identity outness may be explained by minority stress factors.

Development and validation of a risk model for hospital-acquired venous thrombosis: the Medical Inpatients Thrombosis and Hemostasis study.

BACKGROUND: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients. OBJECTIVES: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission. METHODS: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM. RESULTS: The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race. CONCLUSION: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.

PROTAC-mediated Degradation of HIV-1 Nef Efficiently Restores Cell-surface CD4 and MHC-I Expression and Blocks HIV-1 Replication.

The HIV-1 Nef accessory factor is critical to the viral life cycle in vivo where it promotes immune escape of HIV-infected cells and viral persistence. While these features identify Nef as an attractive antiretroviral drug target, Nef lacks enzymatic activity and an active site, complicating development of occupancy-based drugs. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on a previously reported hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the Cereblon E3 ubiquitin ligase, resulting in ubiquitylation of Nef and proteolytic degradation. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation of Nef is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cells in vivo .

Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; PC [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.

OECD 414 supplementary prenatal developmental toxicity study of sodium molybdate dihydrate in the rat and benchmark dose evaluation.

In a continuing investigation of the potential for reproductive and developmental toxicity of molybdenum (Mo), consequent to the previous published OECD studies [1,2] and as directed by the European Chemicals Agency [3], a supplemental rat GLP-compliant Prenatal Developmental Toxicity (PNDT) study was conducted to investigate higher dose levels of sodium molybdate dihydrate (SMD) in an identical study design (OECD 414)[4] to Murray et al. 2014a [1], at dietary concentrations calculated to provide target Mo levels of 80 and 120 mg/kg bw/day (the maximum-tolerated dose). There was no effect on post-implantation loss, litter size, sex ratio or the incidence of external, visceral or skeletal fetal malformations or variations. Fetal weight was reduced proportionate to maternal dose. Minimal differences observed in the ossification status of some extremities of fetuses from females receiving 120 mg Mo/kg bw/day were confirmed as transient by skeletal examination of PND 21 pups from a further group of females receiving the same dose regime. There was no evidence of copper depletion in serum, placenta or liver. A benchmark dose evaluation using continuous and dichotomous approaches by combining the fetal body weight data from this study and the previous study determined that the BMD05 ranged from 47 to 57 mg Mo/kg bw/day, depending on the modelling approach and the BMDL05 estimates ranged from 37 to 47 mg Mo/kg bw/day. These levels are considered a more statistically robust point of departure for risk assessment for reproductive effects than the established NOAEL of 40 mg Mo/kg bw/day.

The effect of a reduction in irrational beliefs on Posttraumatic Stress Disorder (PTSD), depression, and anxiety symptoms in a group treatment for post-9/11 Veterans.

Previous research has indicated that a Rational Emotive Behavior Therapy (REBT)-Informed Group focused on changing irrational beliefs to address comorbid depression and anxiety (as well as anger and guilt) in a combat Veteran population diagnosed with Posttraumatic Stress Disorder (PTSD) demonstrated significant reductions in depression and PTSD symptoms at posttreatment. However, mechanisms of change associated with improvement have not been evaluated. REBT theory suggests that a decline in irrational beliefs predicts a decrease in PTSD, depression, and anxiety symptoms. This study aimed to test this tenet of REBT theory in a naturalistic treatment setting. Participants (N = 86) were post-9/11 combat Veterans, engaged in the REBT-Informed Group between October 2016 and February 2020. Results of hierarchical multiple regression analyses indicated that a reduction in irrational beliefs predicted notable decreases in PTSD, depression, and anxiety symptoms controlling for several covariates. This study extends previous research demonstrating the success of the REBT-Informed Group with combat Veterans and gives support to REBT theory regarding the effect of a decline in irrational beliefs. Future directions include replication of findings with Veterans who experienced military sexual trauma (MST), pre-9/11 Veterans, those at other military or Veterans Affairs (VA) medical centers, and civilians to determine generalizability.

The 21st Century Cures Act: Inpatient Clinician Perceptions of Changes to Information Sharing at an Academic Medical Center.

Introduction To comply with the Information Blocking Rule in the 21st Century Cures Act, many hospitals began to release inpatient electronic health information such as clinical notes and results to patients immediately, starting in April 2021. We sought to understand the perceptions of hospital-based clinicians regarding the impact of these changes in information sharing on clinicians and patients. Materials and methods We developed and distributed an electronic survey to 122 inpatient attending physicians, resident physicians, and physician assistants within the internal medicine and family medicine departments at an academic medical center. The survey asked clinicians to rate their comfort with information-sharing protocols and describe their perceptions of the impact of immediate information sharing on their documentation habits and patient interactions following the implementation of the Cures Act. Results The survey response rate was 37.7% (46/122). Of the respondents, 56.5% felt comfortable with the note-sharing process, 84.8% reported omitting specific information from their notes to prevent patients from reading it, and 39.1% of clinicians agreed that patients have found clinical notes "more confusing than helpful." Conclusions Immediate sharing of electronic health information has the potential to be a powerful tool for communicating with hospitalized patients. However, our results show many hospital-based clinicians report limited comfort with the note-sharing process and perceive it to be confusing to patients. Efforts are needed to educate clinicians regarding information sharing, understand patient and family perspectives, and develop best practices to enhance communication through electronic notes.

Amide- and bis-amide-linked highly potent and broadly active antifungal agents for the treatment of invasive fungal infections- towards the discovery of pre-clinical development candidate FC12406.

Most fungal infections are common, localized to skin or mucosal surfaces and can be treated effectively with topical antifungal agents. However, while invasive fungal infections (IFIs) are uncommon, they are very difficult to control medically, and are associated with high mortality rates. We have previously described highly potent bis-guanidine-containing heteroaryl-linked antifungal agents, and were interested in expanding the range of agents to novel series so as to reduce the degree of aromaticity (with a view to making the compounds more drug-like), and provide broadly active high potency derivatives. We have investigated the replacement of the central aryl ring from our original series by both amide and a bis-amide moieties, and have found particular structure-activity relationships (SAR) for both series', resulting in highly active antifungal agents against both mold and yeast pathogens. In particular, we describe the in vitro antifungal activity, absorption, distribution, metabolism and elimination (ADME) properties, and off-target properties of FC12406 (34), which was selected as a pre-clinical development candidate.

Development of a computable phenotype using electronic health records for venous thromboembolism in medical inpatients: the Medical Inpatient Thrombosis and Hemostasis study.

Background: Accurate and efficient methods to identify venous thromboembolism (VTE) events in hospitalized people are needed to support large-scale studies. Validated computable phenotypes using a specific combination of discrete, searchable elements in electronic health records to identify VTE and distinguish between hospital-acquired (HA)-VTE and present-on-admission (POA)-VTE would greatly facilitate the study of VTE, obviating the need for chart review. Objectives: To develop and validate computable phenotypes for POA- and HA-VTE in adults hospitalized for medical reasons. Methods: The population included admissions to medical services from 2010 to 2019 at an academic medical center. POA-VTE was defined as VTE diagnosed within 24 hours of admission, and HA-VTE as VTE identified more than 24 hours after admission. Using discharge diagnosis codes, present-on-admission flags, imaging procedures, and medication administration records, we iteratively developed computable phenotypes for POA-VTE and HA-VTE. We assessed the performance of the phenotypes using manual chart review and survey methodology. Results: Among 62,468 admissions, 2693 had any VTE diagnosis code. Using survey methodology, 230 records were reviewed to validate the computable phenotypes. Based on the computable phenotypes, the incidence of POA-VTE was 29.4 per 1000 admissions and that of HA-VTE was 3.6 per 1000 admissions. The POA-VTE computable phenotype had positive predictive value and sensitivity of 88.8% (95% CI, 79.8%-94.0%) and 99.1% (95% CI, 94.0%- 99.8%), respectively. Corresponding values for the HA-VTE computable phenotype were 84.2% (95% CI, 60.8%-94.8%) and 72.3% (95% CI, 40.9%-90.8%). Conclusion: We developed computable phenotypes for HA-VTE and POA-VTE with adequate positive predictive value and sensitivity. This phenotype can be used in electronic health record data-based research.

Integrating High-Value Care Concepts into Preclinical Medical Education: A Practical Approach.

Objectives: Although some US medical schools have incorporated high-value care into their preclinical curriculum, there is no standardized approach and major curricular overhaul can be prohibitively onerous. The objectives of this study were to develop a feasible and effective high-value care curriculum, integrate it into an existing pre-clinical course, and assess student and faculty perceptions of the educational value of the curriculum. Methods: Between 2019 and 2021, University of Vermont preclinical medical students participating in the Students & Trainees Advocating for Resource Stewardship (STARS) program collaborated with the faculty director of the preclinical pathophysiology course to identify Choosing Wisely® recommendations relevant to course topics. For each recommendation, STARS students created a case-based, multiple-choice question, answer key and rationale to accompany standard course materials. At each year's course completion, participating students and faculty were invited to complete a survey to assess their perceptions of the curriculum. Results: Seventeen case-based questions were integrated into existing pathophysiology course sessions each year. Over the 3-year period, 420 students and 35 teaching faculty participated in the course, and 171 (40.7%) students and 24 (68.6%) faculty completed the post-course survey. Among student respondents, 80% agreed the curriculum increased their awareness of high-value care, 79% agreed they would be more likely to apply high-value care concepts during their medical career, and 92% agreed it was valuable to discuss Choosing Wisely® recommendations during the second year of medical school. Conclusion: A student-led initiative to incorporate high-value care content within an existing pre-clinical course was well-received by medical students, who reported increased awareness of and intention to apply high-value care principles. This model may offer a feasible and effective approach to high-value care education in the absence of an extensive formal curriculum.

Levamisole derivatives as immune modulators for the treatment of amyotrophic lateral sclerosis (ALS).

Aim: To discover derivatives of the anthelmintic drug levamisole, which has been reported to possess immune-modulatory properties, as treatments for amyotrophic lateral sclerosis (ALS), which has been suggested to be in part an autoimmune disease. Results: We have synthesized ten analogs of the racemic version of levamisole, tetramisole, as well as eleven analogs on a related system. All of the analogs have been tested for their ability to affect the response of five ALS-relevant cytokines. Conclusion: We have discovered a number of interesting derivatives that have encouraging cytokine response data and good metabolic stability, with the potential to have a positive impact on ALS either as single agents, or in combination.

Aim: To discover derivatives of the antiparasitic worm drug levamisole, which has been reported to be able to modulate the immune response, as treatments for amyotrophic lateral sclerosis (ALS), which has been suggested to be in part an autoimmune disease. Results: We have synthesized ten analogs of a variation of levamisole, tetramisole, as well as 11 analogs on a related system. All of the analogs have been tested for their ability to affect the response of five ALS-relevant immune-modulatory substances (cytokines). Conclusion: We have discovered a number of interesting derivatives that have encouraging cytokine response data and good metabolic stability, with the potential to have a positive impact on ALS either as single agents, or in combination.

Promoting scholarship in improvement science: A model for academic clinical departments.

Introduction: Clinical departments at academic medical centers strive to deliver clinical care, provide education and training, support faculty development, and promote scholarship. These departments have experienced increasing demands to improve the quality, safety, and value of care delivery. However, many academic departments lack a sufficient number of clinical faculty members with expertise in improvement science to lead initiatives, teach, and generate scholarship. In this article, we describe the structure, activities, and early outcomes of a program within an academic department of medicine to promote scholarly improvement work. Methods: The Department of Medicine at the University of Vermont Medical Center launched a Quality Program with three primary goals: (a) improve care delivery, (b) provide education and training, and (c) promote scholarship in improvement science. The program serves as a resource center for students, trainees and faculty, offering education and training, analytic support, consultation in design and methodology, and project management. It strives to integrate education, research, and care delivery to learn, apply evidence and improve health care. Results: Over the first 3 years of full implementation, the Quality Program supported an average of 123 projects annually, including prospective clinical quality improvement initiatives, retrospective assessment of clinical programs and practices, and curriculum development and evaluation. The projects have yielded a total of 127 scholarly products, defined as peer-reviewed publications and abstracts, posters, and oral presentations at local, regional, and national conferences. Conclusions: The Quality Program may serve as a practical model for promoting care delivery improvement, training, and scholarship in improvement science while advancing the goals of a learning health system at the level of an academic clinical department. Dedicated resources within such departments offer the potential to enhance care delivery while promoting academic success for faculty and trainees in improvement science.

Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (CIA) complex.

Iron-sulfur (Fe-S) clusters are unique, redox-active co-factors ubiquitous throughout cellular metabolism. Fe-S cluster synthesis, trafficking, and coordination result from highly coordinated, evolutionarily conserved biosynthetic processes. The initial Fe-S cluster synthesis occurs within the mitochondria; however, the maturation of Fe-S clusters culminating in their ultimate insertion into appropriate cytosolic/nuclear proteins is coordinated by a late-acting cytosolic iron-sulfur assembly (CIA) complex in the cytosol. Several nuclear proteins involved in DNA replication and repair interact with the CIA complex and contain Fe-S clusters necessary for proper enzymatic activity. Moreover, it is currently hypothesized that the late-acting CIA complex regulates the maintenance of genome integrity and is an integral feature of DNA metabolism. This review describes the late-acting CIA complex and several [4Fe-4S] DNA metabolic enzymes associated with maintaining genome stability.