Results of Leveraging Pharmaceutical Patient Assistance Programs to Expand Access to High Cost Medications in a Student-Run Free Clinic.

High costs make many medications inaccessible to patients in the United States. Uninsured and underinsured patients are disproportionately affected. Pharmaceutical companies offer patient assistance programs (PAPs) to lower the cost-sharing burden of expensive prescription medications for uninsured patients. PAPs are used by various clinics, particularly oncology clinics and those caring for underserved communities, to expand patients' access to medications. Prior studies describing the implementation of PAPs in student-run free clinics have demonstrated cost-savings during the first few years of using PAPs. However, there is a lack of data regarding the efficacy and cost savings of longitudinal use of PAPs across several years. This study describes the growth of PAP use at a student-run free clinic in Nashville, Tennessee over ten years, demonstrating that PAPs can be used reliably and sustainably to expand patients' access to expensive medications. From 2012 to 2021, we increased the number of medications available through PAPs from 8 to 59 and the number of patient enrollments from 20 to 232. In 2021, our PAP enrollments demonstrated potential cost savings of over $1.2 million. Strategies, limitations, and future directions of PAP use are also discussed, highlighting that PAPs can be a powerful tool for free clinics in serving underserved communities.

SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway.

Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.

Loss of Forkhead box M1 promotes erythropoiesis through increased proliferation of erythroid progenitors.

Forkhead box M1 (FOXM1) belongs to the forkhead/winged-helix family of transcription factors and regulates a network of proliferation-associated genes. Its abnormal upregulation has been shown to be a key driver of cancer progression and an initiating factor in oncogenesis. FOXM1 is also highly expressed in stem/progenitor cells and inhibits their differentiation, suggesting that FOXM1 plays a role in the maintenance of multipotency. However, the exact molecular mechanisms by which FOXM1 regulates human stem/progenitor cells are still uncharacterized. To understand the role of FOXM1 in normal hematopoiesis, human cord blood CD34+ cells were transduced with FOXM1 short hairpin ribonucleic acid (shRNA) lentivirus. Knockdown of FOXM1 resulted in a 2-fold increase in erythroid cells compared to myeloid cells. Additionally, knockdown of FOXM1 increased bromodeoxyuridine (BrdU) incorporation in erythroid cells, suggesting greater proliferation of erythroid progenitors. We also observed that the defective phosphorylation of FOXM1 by checkpoint kinase 2 (CHK2) or cyclin-dependent kinases 1/2 (CDK1/2) increased the erythroid population in a manner similar to knockdown of FOXM1. Finally, we found that an inhibitor of FOXM1, forkhead domain inhibitor-6 (FDI-6), increased red blood cell numbers through increased proliferation of erythroid precursors. Overall, our data suggest a novel function of FOXM1 in normal human hematopoiesis.

The impact of climate change on atopic dermatitis and mental health comorbidities: a review of the literature and examination of intersectionality.

Climate change, fueled by increasing concentrations of greenhouse gases, is associated with rising temperatures, extreme weather events, increased aeroallergen production, and air pollution. Our understanding that many inflammatory cutaneous diseases carry important mental health comorbidities is expanding. Simultaneously, the detrimental impacts of climate change on human health are now widely recognized as a global public health crisis. Importantly, these climate-associated phenomena exacerbate the environmental triggers of atopic dermatitis (AD) and are also associated with amplification of comorbid mental health conditions in AD including depression, anxiety, trauma-related disorders, and psychotic spectrum disorders. This review is the first to examine the nexus of climate change, atopic dermatitis, and mental health comorbidities and emphasizes the disproportionate impacts of climate change in vulnerable and marginalized populations.

Improving annual albuminuria testing for individuals with diabetes.

BACKGROUND: Annual albuminuria screening detects the early stages of nephropathy in individuals with diabetes. Because early detection of albuminuria allows for interventions that lower the risk of developing chronic kidney disease, guidelines recommend annual testing for all individuals with type 2 diabetes mellitus and for those with type 1 diabetes for at least 5 years. However, at the Eskind Diabetes Clinic at the Vanderbilt University Medical Center, testing occurred less frequently than desired. METHODS: A quality improvement team first analysed the clinic's processes, identifying the lack of a systematic approach to testing as the likely cause for the low rate. The team then implemented two successive interventions in a pilot of patients seen by nurse practitioners in the clinic. In the first intervention, staff used a dashboard within the electronic health record while triaging each patient, pending an albuminuria order if testing had not been done within the past year. In the second intervention, clinic leadership sent daily reminders to the triage staff. A statistical process control chart tracked monthly testing rates. RESULTS: After 6 months, annual albuminuria testing increased from a baseline of 69% to 82%, with multiple special-cause signals in the control chart. CONCLUSIONS: This project demonstrates that a series of simple interventions can significantly impact annual albuminuria testing. This project's success likely hinged on using an existing workflow to systematically determine if a patient was due for testing and prompting the provider to sign a pended order for an albuminuria test. Other diabetes/endocrinology and primary care clinics can likely implement a similar process and so improve testing rates in other settings. When coupled with appropriate interventions to reduce the development of chronic kidney disease, such interventions would improve patient outcomes, in addition to better adhering to an established quality metric.

Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond-Blackfan anemia through induction of miR-26a.

Diamond-Blackfan anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity and suppression of NLK expression both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data indicate that the effects of metformin on erythroid proliferation and differentiation are mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3' untranslated region (3'UTR) to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treatment of DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.

MMP9 inhibition increases erythropoiesis in RPS14-deficient del(5q) MDS models through suppression of TGF-ß pathways.

The del(5q) myelodysplastic syndrome (MDS) is a distinct subtype of MDS, associated with deletion of the ribosomal protein S14 (RPS14) gene that results in macrocytic anemia. This study sought to identify novel targets for the treatment of patients with del(5q) MDS by performing an in vivo drug screen using an rps14-deficient zebrafish model. From this, we identified the secreted gelatinase matrix metalloproteinase 9 (MMP9). MMP9 inhibitors significantly improved the erythroid defect in rps14-deficient zebrafish. Similarly, treatment with MMP9 inhibitors increased the number of colony forming unit-erythroid colonies and the CD71+ erythroid population from RPS14 knockdown human BMCD34+ cells. Importantly, we found that MMP9 expression is upregulated in RPS14-deficient cells by monocyte chemoattractant protein 1. Double knockdown of MMP9 and RPS14 increased the CD71+ population compared with RPS14 single knockdown, suggesting that increased expression of MMP9 contributes to the erythroid defect observed in RPS14-deficient cells. In addition, transforming growth factor ß (TGF-ß) signaling is activated in RPS14 knockdown cells, and treatment with SB431542, a TGF-ß inhibitor, improved the defective erythroid development of RPS14-deficient models. We found that recombinant MMP9 treatment decreases the CD71+ population through increased SMAD2/3 phosphorylation, suggesting that MMP9 directly activates TGF-ß signaling in RPS14-deficient cells. Finally, we confirmed that MMP9 inhibitors reduce SMAD2/3 phosphorylation in RPS14-deficient cells to rescue the erythroid defect. In summary, these study results support a novel role for MMP9 in the pathogenesis of del(5q) MDS and the potential for the clinical use of MMP9 inhibitors in the treatment of patients with del(5q) MDS.