Implementation of a Pharmacist-Driven Contraception Service at a Safety-Net Health-System.

Background: Access to safe, effective, and appropriate contraception significantly reduces the rates of unintended pregnancies; however, this preventative care is not always easily accessible. There is a high patient demand for contraception visits that is often delayed or unmet due to lack of access to traditional providers. Pharmacists are highly accessible and can help manage this high demand, yet clinical pharmacists as providers of contraception services remains a gap in published literature. Objective: Develop and implement a pharmacist-led contraception service at a safety-net health-system. Methods: A comprehensive pharmacist-led clinical contraception service was created to improve patient access. To support this project, a collaborative practice agreement (CPA) was developed and enhancements were built into an electronic medical record. The CPA allowed the pharmacist to complete contraception-related interventions such as ordering urine pregnancy tests, prescribing hormonal and emergency contraceptives, and manage adverse effects. The piloting pharmacist was available at the Narcotics Treatment Program (NTP) clinic one half-day each week for scheduled and same-day visits. Results: Within the initial five half-day clinic sessions at NTP, the pharmacist had written seven prescriptions, including three for emergency contraceptives. Of all patients seen for this service at NTP, only one had been using a method of contraception consistently prior to their visit. Conclusion: The interventions that were able to be made by the pharmacist highlighted the need for improved access to contraceptives. Pharmacist-managed services in sexual and reproductive health can help fill this gap. Patients also self-reported ease of access as a benefit to this service.

A Multicenter, Retrospective Outcome Analysis of Vancomycin Area Under the Curve versus Trough-Based Dosing Strategies in Patients with Burn OR Inhalational Injuries (MONITOR).

Vancomycin is a glycopeptide antibiotic that requires close therapeutic monitoring. Prolonged exposure to elevated concentrations increases risk for serious adverse effects such as nephrotoxicity. However, sub-therapeutic concentrations may lead to bacterial resistance and clinical failure or death. The most recent Infectious Diseases Society of America (IDSA) publication regarding therapeutic monitoring of vancomycin recommends utilizing area under the curve (AUC)-based monitoring to maximize clinical success. Despite the guideline recommendation for AUC-guided dosing, many institutions still use trough-only monitoring in their practices, including those caring for patients with acute burn injuries. Following burn injury, patients are at a higher risk for infections, multi-organ failure, and pharmacokinetic alterations. The primary objective of this multi-center retrospective study is to determine optimal therapeutic monitoring of vancomycin by comparing clinical success between AUC vs. trough-based monitoring in burn patients. MONITOR was a multicenter, retrospective study of patients with thermal or inhalation injury admitted to one of 13 burn centers from 1/1/17 to 8/31/22 who received vancomycin. Demographic and clinical course data, including acute kidney injury (AKI) incidence and clinical success were obtained. Patients were evaluated for clinical success and grouped according to method of monitoring and adjusting doses: AUC vs. trough-based monitoring. Clinical success was a composite definition and lack of meeting any 1 of 5 criteria: 1) persistent infection, 2) relapse, 3) antibiotic failure (clinical worsening), 4) AKI, 5) death. Five-hundred seventeen vancomycin courses were assessed from 485 patients. There was no difference in the rate of clinical success between AUC monitored and the trough-only monitored groups. Incidence of AKI was higher in the trough-only group; however, was not statistically significant after controlling for renal function on admission, past medical history of chronic kidney disease (CKD), and concomitant nephrotoxins.

Mobilization with Femoral Catheters in the Burn ICU: A retrospective review following change in practice guidelines.

Femoral catheters are a known barrier for Burn ICU mobility progression due to the anatomical location and potential risk of complications. The purpose of this study was to examine outcomes and complication rates following implementation of femoral catheter mobilization guidelines, as well as determine safety and feasibility of mobilization with femoral catheters in place within the burn population. Retrospective review was completed on 17 patients prior to and following implementation of new femoral catheter mobility guidelines, 34 patients total. Burn therapy notes were reviewed for burn admissions with at least one femoral catheter in place, including arterial, central, and dialysis catheters. Demographic data, admission statistics, line placement timelines, and active mobility achieved during therapy sessions were recorded for both the non-mobilization (NMG) and mobilization groups (MG). The 34 patients reviewed had 99 total lines placed (30 NMG, 69 MG). Change in mobility protocols for the MG resulted in more therapy sessions (n=516 vs 281) and a significant increase in active mobility sessions (n=83 vs 5, p < 0.001), including 146 total mobility activities such as transitions to chairs, tilt table, sitting edge of bed (EOB), standing, active chair transfers, ambulation, and cycle ergometry. No catheter associated adverse events occurred during active mobility sessions and no complications were associated with participation in mobility. This study supports that the presence of femoral catheters alone should not limit the progression of mobility interventions. Using clinical judgement and specialty training, burn therapists can safely mobilize burn ICU patients with femoral catheters in place.

Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.

An Appraisal of Pharmacotherapy-Pertinent Literature Published in 2021 and 2022 for Clinicians Caring for Patients With Thermal or Inhalation Injury.

Studies focusing on pharmacotherapy interventions to aid patients after thermal injury are a minor focus in burn injury-centered studies and published across a wide array of journals, which challenges those with limited resources to keep their knowledge current. This review is a renewal of previous years' work to facilitate extraction and review of the most recent pharmacotherapy-centric studies in patients with thermal and inhalation injury. Twenty-three geographically dispersed, board-certified pharmacists participated in the review. A Medical Subject Heading-based, filtered search returned 2336 manuscripts over the previous 2-year period. After manual review, 98 (4%) manuscripts were determined to have a potential impact on current pharmacotherapy practice. The top 10 scored manuscripts are discussed. Only 17% of those reviewed were assessed to likely have little effect on current practice. The overall impact of the current cohort was higher than previous editions of this review, which is encouraging. There remains a need for investment in well-designed, high-impact, pharmacotherapy-pertinent research for patients sustaining thermal or inhalation injuries.

Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia.

We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival. LPCs not only capture patient-specific mutations but also retain serial re-plating ability, demonstrating their biological relevance. Notably, LPC content represents an independent prognostic factor in multivariate analyses including clinical guidelines of risk stratification. Our findings suggest that LPCs provide a robust functional measure of AML, enabling quantitative and rapid assessment of a wide range of patients. This highlights the potential of LPCs as a valuable prognostic factor in AML management.

Chemical genomics reveals targetable programs of human cancers rooted in pluripotency.

Overlapping principles of embryonic and tumor biology have been described, with recent multi-omics campaigns uncovering shared molecular profiles between human pluripotent stem cells (hPSCs) and adult tumors. Here, using a chemical genomic approach, we provide biological evidence that early germ layer fate decisions of hPSCs reveal targets of human cancers. Single-cell deconstruction of hPSCs-defined subsets that share transcriptional patterns with transformed adult tissues. Chemical screening using a unique germ layer specification assay for hPSCs identified drugs that enriched for compounds that selectively suppressed the growth of patient-derived tumors corresponding exclusively to their germ layer origin. Transcriptional response of hPSCs to germ layer inducing drugs could be used to identify targets capable of regulating hPSC specification as well as inhibiting adult tumors. Our study demonstrates properties of adult tumors converge with hPSCs drug induced differentiation in a germ layer specific manner, thereby expanding our understanding of cancer stemness and pluripotency.

Evaluation of the Role of a Clinical Pharmacist on Medication Management in an Adult Burn Clinic via a Collaborative Drug Therapy Management Protocol.

Historically, pharmacists have not been formally involved in managing burn clinic patients. Collaborative Drug Therapy Management (CDTM) protocols allow pharmacists working within a defined context to independently assume responsibility for direct patient care activities. The objective of this study was to evaluate the number and type of medication-related interventions made by a clinical pharmacist, in an adult burn clinic, via a CDTM protocol. The protocol allows pharmacists to independently manage the following disease states: pain, agitation, delirium, insomnia, venous thromboembolism, skin/soft tissue infections, and hypermetabolic complications. All pharmacist visits between 1/1/22 and 9/22/22 were included. A total of 16 patients were seen at 28 visits with a clinical pharmacist for a total of 148 interventions. Patients were mostly males (81%) with a mean ± SD age of 41 ± 15 years. The majority of patients were in-state (94%), with 9 (56%) being from an outlying county. Patients were seen for a median (IQR) of 2 (1,2) visits. Interventions were made at all visits (100%) with a median of 5 (4,6) per visit. Interventions (per visit) included medication reconciliation [28 (100%)], a median of 1 (0,2) medication ordered or adjusted, labs ordered at 7 (25%) visits, with adherence and patient education both reviewed at over 90% of visits. To the best of our knowledge, ours is the first burn center to implement a Clinical Pharmacist CDTM Protocol, with a pharmacist directly impacting transitions of care. This may serve as a framework for other sites. Future directions include continuing to track data for medication adherence and access, billing/reimbursement, and clinical outcomes.

Reprogramming of Acute Myeloid Leukemia Patients Cells: Harboring Cancer Mutations Requires Targeting of AML Hierarchy.

Screening of primary patient acute myeloid leukemia (AML) cells is challenging based on intrinsic characteristics of human AML disease and patient-specific conditions required to sustain AML cells in culture. This is further complicated by inter- and intra-patient heterogeneity, and "contaminating" normal cells devoid of molecular AML mutations. Derivation of induced pluripotent stem cells (iPSCs) from human somatic cells has provided approaches for the development of patient-specific models of disease biology and has recently included AML. Although reprogramming patient-derived cancer cells to pluripotency allows for aspects of disease modeling, the major limitation preventing applications and deeper insights using AML-iPSCs is the rarity of success and limited subtypes of AML disease that can be captured by reprogramming to date. Here, we tested and refined methods including de novo, xenografting, naïve versus prime states and prospective isolation for reprogramming AML cells using a total of 22 AML patient samples representing the wide variety of cytogenetic abnormalities. These efforts allowed us to derive genetically matched healthy control (isogenic) lines and capture clones found originally in patients with AML. Using fluorescently activated cell sorting, we revealed that AML reprogramming is linked to the differentiation state of diseased tissue, where use of myeloid marker CD33 compared to the stem cell marker, CD34, reduces reprogramming capture of AML+ clones. Our efforts provide a platform for further optimization of AML-iPSC generation, and a unique library of iPSC derived from patients with AML for detailed cellular and molecular study.

Characterization of vitamin D deficiency and use of a standardized supplementation protocol in orthopaedic trauma patients.

PURPOSE: The objectives of this study were to assess the incidence of vitamin D deficiency in orthopaedic trauma patients, evaluate the safety and efficacy of a vitamin D supplementation protocol, and investigate the utility of vitamin D supplementation in reducing nonunions. METHODS: Three hundred seventy patients with operative tibia and/or fibula fractures were retrospectively reviewed. Both overall and matched cohorts were analysed. RESULTS: Ninety-eight per cent (n = 210) were found to have vitamin D insufficiency (serum 25(OH)D level < 30 ng/ml). There were no cases of vitamin D toxicity following vitamin D replacement. Median follow-up vitamin D level was 22.7 ng/mL. No statistical difference between union rates was found between either the two consecutive cohorts or matched cohorts. CONCLUSION: This vitamin D replacement protocol was a safe treatment for hypovitaminosis D, but post hoc analysis shows there would need to be over 1200 matched patients to achieve adequate power.

REPRODUCTIVE OPHTHALMOLOGY: The Intersection of Inherited Eye Diseases and Reproductive Technologies.

PURPOSE: To propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing. METHODS: Retrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children. RESULTS: Preimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children. CONCLUSION: A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases.

Challenges in Cell Fate Acquisition to Scid-Repopulating Activity from Hemogenic Endothelium of hiPSCs Derived from AML Patients Using Forced Transcription Factor Expression.

The generation of human hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) represents a major goal in regenerative medicine and is believed would follow principles of early development. HSCs arise from a type of endothelial cell called a "hemogenic endothelium" (HE), and human HSCs are experimentally detected by transplantation into SCID or other immune-deficient mouse recipients, termed SCID-Repopulating Cells (SRC). Recently, SRCs were detected by forced expression of seven transcription factors (TF) (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1, and SPI1) in hPSC-derived HE, suggesting these factors are deficient in hPSC differentiation to HEs required to generate HSCs. Here we derived PECAM-1-, Flk-1-, and VE-cadherin-positive endothelial cells that also lack CD45 expression (PFVCD45-) which are solely responsible for hematopoietic output from iPSC lines reprogrammed from AML patients. Using HEs derived from AML patient iPSCs devoid of somatic leukemic aberrations, we sought to generate putative SRCs by the forced expression of 7TFs to model autologous HSC transplantation. The expression of 7TFs in hPSC-derived HE cells from an enhanced hematopoietic progenitor capacity was present in vitro, but failed to acquire SRC activity in vivo. Our findings emphasize the benefits of forced TF expression, along with the continued challenges in developing HSCs for autologous-based therapies from hPSC sources.

Five-Year Retrospective Analysis of a Vented Mobility Algorithm in the Burn ICU.

Early mobilization with mechanically ventilated patients has received significant attention within recent literature; however, limited research has focused specifically on the burn population. The purpose of this single-center, retrospective analysis was to review the use of a burn critical care mobility algorithm, to determine the safety and feasibility of a burn vented mobility program, share limitations preventing mobility progression at our facility, and discuss unique challenges to vented mobility with intubated burn patients. A retrospective review was completed for all intubated burn center admissions between January 2015 and December 2019. Burn therapy notes were then reviewed for data collection, during the intubation period, using stages of the mobility algorithm. In the 5-year period following initial implementation, the vented mobility algorithm was utilized on 127 patients with an average TBSA of 22.8%. No adverse events occurred. Stage 1 (range of motion) was completed with 100% of patients (n = 127). Chair mode of bed, stage 2a, was utilized in 39.4% (n = 50) of patients, while 15.8% (n = 20) of patients were dependently transferred to the cardiac chair in stage 2b. Stage 3 (sitting on the edge of the bed) was completed with 25% (n = 32) of patients, with 11% (n = 14) progressing to stage 5 (standing), and 3.9% (n = 5) actively transferring to a chair. In the 5 years, only 4.7% (n = 6) reached stage 6 (ambulation). The most common treatment limitations were medical complications (33%) and line placement (21%). Early mobilization during mechanical ventilation is safe and feasible within the burn population, despite challenges, including airway stability, sedation, and line limitations.

A Review of the Most Impactful Published Pharmacotherapy-Pertinent Literature of 2019 and 2020 for Clinicians Caring for Patients With Thermal or Inhalation Injury.

Keeping abreast with current literature can be challenging, especially for practitioners caring for patients sustaining thermal or inhalation injury. Practitioners caring for patients with thermal injuries publish in a wide variety of journals, which further increases the complexity for those with resource limitations. Pharmacotherapy research continues to be a minority focus in primary literature. This review is a renewal of previous years' work to facilitate extraction and review of the most recent pharmacotherapy-centric studies in patients with thermal and inhalation injury. Sixteen geographically dispersed, board-certified pharmacists participated in the review. A MeSH-based, filtered search returned 1536 manuscripts over the previous 2-year period. After manual review and exclusions, only 98 (6.4%) manuscripts were determined to have a potential impact on current pharmacotherapy practices and included in the review. A summary of the 10 articles that scored highest are included in the review. Nearly half of the reviewed manuscripts were assessed to lack a significant impact on current practice. Despite an increase in published literature over the previous 2-year review, the focus and quality remain unchanged. There remains a need for investment in well-designed, high impact, pharmacotherapy-pertinent research for patients sustaining thermal or inhalation injuries.

Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics.

Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.

Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients.

The aberrant expression of dopamine receptors (DRDs) in acute myeloid leukemia (AML) cells has encouraged the repurposing of DRD antagonists such as thioridazine (TDZ) as anti-leukemic agents. Here, we access patient cells from a Phase I dose escalation trial to resolve the cellular and molecular bases of response to TDZ, and we extend these findings to an additional independent cohort of AML patient samples tested preclinically. We reveal that in DRD2+ AML patients, DRD signaling in leukemic progenitors provides leukemia-exclusive networks of sensitivity that spare healthy hematopoiesis. AML progenitor cell suppression can be increased by the isolation of the positive enantiomer from the racemic TDZ mixture (TDZ+), and this is accompanied by reduced cardiac liability. Our study indicates that the development of DRD-directed therapies provides a targeting strategy for a subset of AML patients and potentially other cancers that acquire DRD expression upon transformation from healthy tissue.

Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions.

Histone variants (HVs) are a subfamily of epigenetic regulators implicated in embryonic development, but their role in human stem cell fate remains unclear. Here, we reveal that the phosphorylation state of the HV H2A.X (γH2A.X) regulates self-renewal and differentiation of human pluripotent stem cells (hPSCs) and leukemic progenitors. As demonstrated by CRISPR-Cas deletion, H2A.X is essential in maintaining normal hPSC behavior. However, reduced levels of γH2A.X enhances hPSC differentiation toward the hematopoietic lineage with concomitant inhibition of neural development. In contrast, activation and sustained levels of phosphorylated H2A.X enhance hPSC neural fate while suppressing hematopoiesis. This controlled lineage bias correlates to occupancy of γH2A.X at genomic loci associated with ectoderm versus mesoderm specification. Finally, drug modulation of H2A.X phosphorylation overcomes differentiation block of patient-derived leukemic progenitors. Our study demonstrates HVs may serve to regulate pluripotent cell fate and that this biology could be extended to somatic cancer stem cell control.

Human pluripotent stem cells identify molecular targets of trisomy 12 in chronic lymphocytic leukemia patients.

Identifying precise targets of individual cancers remains challenging. Chronic lymphocytic leukemia (CLL) represents the most common adult hematologic malignancy, and trisomy 12 (tri12) represents a quarter of CLL patients. We report that tri12 human pluripotent stem cells (hPSCs) allow for the identification of gene networks and targets specific to tri12, which are controlled by comparative normal PSCs. Identified targets are upregulated in tri12 leukemic cells from a cohort of 159 patients with monoclonal B cell lymphocytosis and CLL. tri12 signaling patterns significantly influence progression-free survival. Actionable targets are identified using high-content drug testing and functionally validated in an additional 44 CLL patient samples. Using xenograft models, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor is potent and selective against human tri12 CLL versus healthy patient-derived xenografts. Our study uses hPSCs to uncover targets from genetic aberrations and apply them to cancer. These findings provide immediate translational potential as biomarkers and targets for therapeutic intervention.

Pregnancy from mosaic embryo transfer: genetic counseling considerations.

PURPOSE OF REVIEW: The transfer of mosaic embryos during an IVF procedure is becoming more common. There is limited information regarding the outcomes for such transfers, making it difficult to establish best practices for prenatal counseling of patients considering transfer of mosaic embryos. In addition, genetic counseling may be delivered by different providers in the preimplantation and pregnancy timeframes which can contribute to inconsistent information. RECENT FINDINGS: There are many types of aneuploid results from preimplantation genetic testing for aneuploidy (PGT-A), with mosaicism being a possibility. Recent studies have reported normal prenatal diagnostic results, pregnancy and birth outcomes with mosaic embryo transfers. Reproductive and prenatal society guidelines recommend diagnostic testing in pregnancy following a mosaic result by PGT-A. Prenatal genetic counseling providers should consider the available information from the PGT-A result, emphasizing the benefits and limitations of each available prenatal test in detecting the fetal chromosome complement. SUMMARY: While transfer of mosaic embryos can allow couples without euploid embryos to have a chance of a viable pregnancy, further studies are necessary to better guide this decision-making. In addition, better coordination between reproductive providers and prenatal providers could improve prenatal care.

Timing the First Pediatric Tracheostomy Tube Change: A Randomized Controlled Trial.

OBJECTIVE: The first pediatric tracheostomy tube change often occurs within 7 days after placement; however, the optimal timing is not known. The primary objective was to determine the rate of adverse events of an early tube change. Secondary objectives compared rates of significant peristomal wounds, sedation requirements, and expedited intensive care discharges. STUDY DESIGN: Prospective randomized controlled trial. SETTING: Tertiary children's hospital between October 2018 and April 2020. METHODS: A randomized controlled trial enrolled children under 24 months to early (day 4) or late (day 7) first tracheostomy tube changes. RESULTS: Sixteen children were enrolled with 10 randomized to an early change. Median age was 5.9 months (interquartile range, 5.4-8.3), and 86.7% required tracheostomy for respiratory failure. All tracheostomy tube changes were performed without adverse events. There were no accidental decannulations. Significant wounds developed in 10% of children with early tracheostomy tube changes and 83.3% of children with late tracheostomy tube changes (odds ratio [OR], 45.0; 95% CI, 2.3-885.6; P = .01). This significant reduction in wound complications justified concluding trial enrollment. Hours of dexmedetomidine sedation (P = .11) and boluses of midazolam during the first 7 days (P = .08) were no different between groups. After the first change, 90% of the early group were discharged from intensive care within 5 weeks compared to 33.3% of patients in the late group (OR, 18.0; 95% CI, 1.2-260.9; P = .03). CONCLUSION: The first tracheostomy tube change in children can occur without adverse events on day 4, resulting in fewer significant peristomal wounds and earlier intensive care discharge.