A narrative review of updates in deprescribing research.

BACKGROUND/OBJECTIVES: Deprescribing is a strategy intended to reduce harms associated with potentially inappropriate medications. Reflective of the growing interest in deprescribing, there has been an increase in related research to better understand the landscape, opportunities for improvement, how best to develop and implement interventions, and remaining knowledge gaps that can be addressed with additional study. DESIGN: We conducted a narrative review of recent deprescribing literature. SETTING: As part of the US Deprescribing Network's inaugural conference in October 2020, we presented a narrative review of recent deprescribing literature to an audience with a range of clinical and research expertise. PARTICIPANTS: We searched four databases for English-language articles published between January 1, 2019 and August 31, 2020. MEASUREMENTS: We evaluated titles, abstracts, and full-length manuscripts for relevance, novelty, rigor and variety of methods; we also aimed for broad representation of authors, institutions, and nations. RESULTS: The initial search returned 199 citations, from which we reviewed 18 full-length manuscripts, selecting 10 articles to present. Salient themes included missed opportunities to deprescribe in potentially eligible patients, with variable impact of medication- and patient-level factors, along with differing perspectives and behaviors between geriatricians, internists, and cardiologists. Clinical, financial, and economic drivers were also evaluated. Finally, attention was given to issues applicable to deprescribing research, including difficulty recruiting trial participants, perspectives of investigators, and integration of findings into clinical practice. CONCLUSION: This narrative review summarizes key advances in the field while also identifying priority areas for additional research.

Challenges in pharmacotherapy for older adults: a framework for pharmacogenomics implementation.

Older adults are at high risk for inappropriate prescribing, developing polypharmacy, adverse drug events and poor treatment outcomes due to multimorbidity and geriatric syndromes. Pharmacogenomics could allow healthcare professionals to provide optimal patient care while minimizing the risk of adverse drug events and simplifying complex medication regimens. The implementation of pharmacogenomics in geriatrics medicine requires a broad multilayered bottom-up approach. These include curriculum redesign, rethinking experiential education and patient and provider education. There are barriers associated with adopting pharmacogenomics into clinical practice. These barriers may include economic factors, workflow and informatics support. However, addressing these barriers primarily requires creating a culture of innovative practices in patient care, ongoing interprofessional continuing education and an interdisciplinary approach for patient care.

An Interprofessional Workshop to Enhance De-prescribing Practices Among Health Care Providers.

INTRODUCTION: De-prescribing is a complex behavior that benefits from a multifaceted approach to learning. We sought to create and deliver a 1-day interprofessional workshop to enhance de-prescribing knowledge and skills among health care professionals. METHODS: Workshop development was based on the Adult Learning Theory and the Theoretical Domains Framework. The workshop addressed provider-related barriers, was created and delivered by an interprofessional team, and combined didactic and active learning techniques. Targeted participants included physicians, advanced practice providers (nurse practitioners and physician's assistants), pharmacists, and clinic staff. Interprofessional workgroups were created a priori. Participants were asked to complete a postprogram evaluation, including whether they would implement changes to practice, teaching, research, or administrative duties after participation. RESULTS: We created an in-person, 5.5 credit hour, interprofessional de-prescribing workshop that comprised six sessions: (1) polypharmacy and de-prescribing overview; (2) identification of potentially inappropriate medications; (3) prioritization of medications for de-prescribing; (4) design and implementation of a de-prescribing plan; (5) principles for a patient-centered approach; and (6) suggestions for successful collaboration. Forty-one participants attended the workshop, and 38 (92.7%) completed the postprogram assessment. Participants felt they were likely to implement changes in practice, teaching, research, or administrative duties, rating themselves with a mean of 9.2 (SD = 1.06) on a 1 to 10 scale. Ultimately, 96.6% would recommend the workshop to others. DISCUSSION: Based on participant feedback, the workshop catalyzed intention to change practice, teaching, research, or administrative duties. Other institutions seeking to change the complex behavior of de-prescribing may wish to model this development and delivery strategy.

Medicine, pharmacy and nursing trainees' perceptions of curriculum preparation to deprescribe and interprofessional roles in the deprescribing process.

With increasing rates of polypharmacy among older adults, preparedness of current and future health care professionals to identify and deprescribe potentially inappropriate medications (PIMs) is critical. Medicine (n = 28), pharmacy (n = 35) and nursing (n = 11) trainees enrolled in an interprofessional course completed a survey assessing preparedness, confidence and attitudes toward deprescribing, and perception of interprofessional roles in the process. Pharmacy (p = .001) and nursing (p = .007) felt that their curriculum prepared them better to identify and deprescribe PIMs compared to medicine trainees. Pharmacy trainees perceived significantly more barriers to deprescribing compared to medicine (p = .003), but not nursing trainees. Physicians and pharmacists were perceived as the main drivers of the deprescribing process. Current curricular content should be modified to address lack of preparedness to deprescribe in clinical practice. Addressing such gaps as part of an interprofessional team may increase interprofessional role recognition and translate into changes in clinical practice as trainees move into the workforce.

Palliative Care Interventions for Patients with Heart Failure: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically characterize interventions and effectiveness of palliative care for advanced heart failure (HF) patients. BACKGROUND: Patients with advanced heart failure experience a high burden of distressing symptoms and diminished quality of life. Palliative care expertise with symptom management and healthcare decision-making benefits HF patients. METHODS: A systematic PubMed search was conducted from inception to June 2016 for studies of palliative care interventions for HF patients. Studies of humans with a HF diagnosis who underwent a palliative care intervention were included. Data were extracted on study design, participant characteristics, intervention components, and in three groups of outcomes: patient-centered outcomes, quality-of-death outcomes, and resource utilization. Study characteristics were examined to determine if meta-analysis was possible. RESULTS: The fifteen identified studies varied in design (prospective, n = 10; retrospective, n = 5). Studies enrolled older patients, but greater variability was found for race, sex, and marital status. A majority of studies measuring patient-centered outcomes demonstrated improvements including quality of life and satisfaction. Quality-of-death outcomes were mixed with a majority of studies reporting clarification of care preferences, but less improvement in death at home and hospice enrollment. A meta-analysis in three studies found that home-based palliative care consults in HF patients lower the risk of rehospitalization by 42% (RR = 0.58; 95% Confidence Interval 0.44, 0.77). DISCUSSION: Available evidence suggests that home and team-based palliative interventions for HF patients improve patient-centered outcomes, documentation of preferences, and utilization. Increased high quality studies will aid the determination of the most effective palliative care approaches for the HF population.

Medication Complexity, Medication Number, and Their Relationships to Medication Discrepancies.

BACKGROUND: Medication reconciliation to identify discrepancies is a National Patient Safety Goal. Increasing medication number and complex medication regimens are associated with discrepancies, nonadherence, and adverse events. The Medication Regimen Complexity Index (MRCI) integrates information about dosage form, dosing frequency, and additional directions. OBJECTIVE: This study evaluates the association of MRCI scores and medication number with medication discrepancies and commissions, a discrepancy subtype. METHODS: This was a retrospective cohort study of a convenience sample of 104 ambulatory care patients seen from April 2010 to July 2011 within the Department of Veterans Affairs. Primary outcomes included any medication discrepancy and commissions. Primary exposures included MRCI scores and medication number. Multivariable logistic regression models associated MRCI scores and medication number with discrepancies. Receiver operating characteristic (ROC) curves provided discrepancy thresholds. RESULTS: For the 104 patients analyzed, the median MRCI score was 25 (interquartile range [IQR] = 14-43), and the median medication number was 8 (IQR = 5-13); 60% of patients had any discrepancy, whereas 36% had a commission. In adjusted analyses, patients with MRCI scores ≥25 or medication number ≥8 were more likely to have commissions (odds ratio [OR] = 3.64, 95% CI = 1.41-9.41; OR = 4.51, 95% CI = 1.73-11.73, respectively). The unadjusted ROC threshold for commissions was 36 for MRCI (sensitivity, 59%; specificity, 82%) and 9 for medication number (sensitivity 68%; specificity 67%). CONCLUSION: Patients with either MRCI scores ≥25 or ≥8 medications were more likely to have commissions. Given equal performance in predicting discrepancies, the efficiency and simplicity of medication number supports its use in identifying patients for intensive medication review beyond medication reconciliation.

Increasing anticholinergic burden and delirium in palliative care inpatients.

BACKGROUND: Delirium may complicate the hospital course and adversely impact remaining quality of life for palliative care inpatients. Medications with anticholinergic properties have been linked to delirium within elderly populations via serum anticholinergic assays. AIM: The aim of this study is to determine whether increasing anticholinergic burden, as measured using a clinical assessment tool, is associated with an increase in delirium among palliative care inpatients. DESIGN: This study was completed as a retrospective, case-control study. SETTING/PARTICIPANTS: Veterans admitted to the Veterans Affairs Boston Healthcare System and consulted to the palliative care service were considered for inclusion. Increase in anticholinergic burden from admission through hospital day 14 was assessed using the Anticholinergic Risk Scale. Presence of delirium was determined by use of a validated chart review instrument. RESULTS: A total of 217 patients were analyzed, with a mean age of 72.9 (±12.8) years. The overall delirium rate was 31% (n = 67). Patients with an increase in Anticholinergic Risk Scale (n = 72 (33%)) were 40% more likely to experience delirium (odds ratio = 1.44, 95% confidence interval = 1.07-1.94) compared to those without increase (n = 145 (67%)). After adjustment for age, brain metastasis, intensive care unit admission, illness severity, opiate use, and admission Anticholinergic Risk Scale using multivariable modeling, delirium risk remained significantly higher in patients with an Anticholinergic Risk Scale increase compared to those without increase (adjusted odds ratio = 1.43, 95% confidence interval = 1.04-1.94). CONCLUSION: An increase in Anticholinergic Risk Scale from admission was associated with delirium in palliative care inpatients. While additional study is needed, anticholinergic burden should be increased cautiously in palliative inpatients, and those with increases should be closely followed for delirium.

Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress.

Previous studies have shown that dormant licensed replication origins can be exploited to enhance recovery from replication stress. Since tumor cells express high levels of origin-licensing proteins, we examined whether depletion of such factors might specifically sensitize tumor versus nontumor cells. Consistent with previous findings, we observed that three tumor-derived cell lines overexpress ORC1, a licensing component, compared with four nontumor cell lines and that a greater level of ORC1 was required to maintain viability in the tumor cells. We determined siRNA-mediated knockdown conditions for each line that maximally reduced ORC1 but did not impact upon viability, which we considered would optimally deplete dormant origins. ORC1 depletion hypersensitized the tumor-derived cells to hydroxyurea and H202 but did not affect the sensitivity of the nontumor lines. Similar results were observed following depletion of ORC6 or CDC6. Furthermore, codepletion of p53 and ORC1 modestly impaired viability of 1BR3hTERT nontumor fibroblasts and more dramatically caused hypersensitivity to hydroxyurea. Finally, overexpression of the c-Myc oncogene combined with ORC1 depletion in nontumor BJhTERT cells diminished viability. Collectively, these findings suggest that tumor cells may have a reliance on origin-licensing capacity, suggesting that licensing factors could represent a target for drug-based cancer therapy.

SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo.

PURPOSE: The Aurora family of serine/threonine kinases (Aurora-A, Aurora-B, and Aurora-C) plays a key role in cells orderly progression through mitosis. Elevated expression levels of Aurora kinases have been detected in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors. We characterized the biological and pharmacological properties of SNS-314, an ATP-competitive, selective, and potent inhibitor of Aurora kinases. METHODS: We studied the biochemical potency and selectivity of SNS-314 to inhibit Aurora kinases A, B, and C. The inhibition of cellular proliferation induced by SNS-314 was evaluated in a broad range of tumor cell lines and correlated to inhibition of histone H3 phosphorylation, inhibition of cell-cycle progression, increase in nuclear content and cell size, loss of viability, and induction of apoptosis. The dose and administration schedule of SNS-314 was optimized for in vivo efficacy in mouse xenograft models of human cancer. RESULTS: In the HCT116 human colon cancer xenograft model, administration of 50 and 100 mg/kg SNS-314 led to dose-dependent inhibition of histone H3 phosphorylation for at least 10 h, indicating effective Aurora-B inhibition in vivo. HCT116 tumors from animals treated with SNS-314 showed potent and sustained responses including reduction of phosphorylated histone H3 levels, increased caspase-3 and appearance of increased nuclear size. The compound showed significant tumor growth inhibition in a dose-dependent manner under a variety of dosing schedules including weekly, bi-weekly, and 5 days on/9 days off. CONCLUSIONS: SNS-314 is a potent small-molecule inhibitor of Aurora kinases developed as a novel anti-cancer therapeutic agent for the treatment of diverse human malignancies.

2-Aminobenzimidazoles as potent Aurora kinase inhibitors.

This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

Discovery of a potent and selective aurora kinase inhibitor.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.

DNA double-strand break repair defects in syndromes associated with acute radiation response: at least two different assays to predict intrinsic radiosensitivity?

PURPOSE: Human diseases associated with acute radiation responses are rare genetic disorders with common clinical and biological features including radiosensitivity, genomic instability, chromosomal aberrations, and frequently immunodeficiency. To determine what molecular assays are predictive of cellular radiosensitivity whatever the genes mutations, the existence of a quantitative correlation between cellular radiosensitivity and unrepaired DNA double-strand breaks (DSB) repair defects was examined in a collection of 40 human fibroblasts representing 8 different syndromes. MATERIALS AND METHODS: A number of techniques such as pulsed-field gel electrophoresis, plasmid assay and immunofluorescence with antibodies against MRE11, MDC1, 53BP1 and phosphorylated forms of H2AX, DNA-PK were applied systematically. RESULTS AND CONCLUSIONS: Survival fraction at 2 Gy was found to be inversely proportional to the amount of unrepaired DSB, whatever the genes mutations and the assay applied. However, no single assay discriminates the full range of human radiosensitivity. Particularly, nuclear foci formed by the phosphorylation of H2AX do not predict well moderate radiosensitivities. Our findings suggest the existence of an ATM-dependent interplay between the activation of DNA-PK and MRE11. A classification of diseases according their cellular radiosensitivity, their molecular response to radiation and the functional assays permitting their evaluation is proposed.