Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301.

Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in amyotrophic lateral sclerosis (ALS). Recently, we found that a subgroup of sporadic ALS (sALS) fibroblasts (sALS1) is characterized by metabolic profiles distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the transcriptome and metabolome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301. Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Moreover, weighted gene coexpression network analysis (WGCNA) was used to investigate the association of the metabolic and clinical features. We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2 and the controls. Furthermore, EH301 had strong protective effects against metabolic stress, an effect linked to the antiinflammatory and antioxidant pathways. WGCNA revealed that the ALS functional rating scale and metabotypes are associated with gene modules enriched for the cell cycle, immunity, autophagy and metabolic genes, which are modified by EH301. The meta-analysis of publicly available transcriptomic data from induced motor neurons by Answer ALS confirmed the functional associations of genes correlated with disease traits. A subset of genes differentially expressed in sALS fibroblasts was used in a machine learning model to predict disease progression. In conclusion, multiomic analyses highlighted the differential metabolic and transcriptomic profiles in patient-derived fibroblast sALS, which translate into differential responses to the investigational drug EH301.

Nicotinamide riboside and pterostilbene reduces markers of hepatic inflammation in NAFLD: A double-blind, placebo-controlled clinical trial.

BACKGROUND AND AIMS: The prevalence of NAFLD is increasing globally and on a path to becoming the most frequent cause of chronic liver disease. Strategies for the prevention and treatment of NAFLD are urgently needed. APPROACH AND RESULTS: A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy of daily NRPT (commercially known as Basis, a combination of nicotinamide riboside and pterostilbene) supplementation in 111 adults with NAFLD. The study consisted of three arms: placebo, recommended daily dose of NRPT (NRPT 1×), and a double dose of NRPT (NRPT 2×). NRPT appeared safe and well tolerated. At the end of the study, no significant change was seen in the primary endpoint of hepatic fat fraction with respect to placebo. However, among prespecified secondary outcomes, a time-dependent decrease in the circulating levels of the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) was observed in the NRPT 1× group, and this decrease was significant with respect to placebo. Furthermore, a significant decrease in the circulating levels of the toxic lipid ceramide 14:0 was also observed in the NRPT 1× group versus placebo, and this decrease was associated with a decrease in ALT in individuals of this group. A dose-dependent effect was not observed with respect to ALT, GGT, or ceramide 14:0 in the NRPT 2× group. CONCLUSIONS: This study demonstrates that NRPT at the recommended dose is safe and may hold promise in lowering markers of hepatic inflammation in patients with NAFLD.

Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer in the United States: A SEER-Medicare population-based study.

BACKGROUND: Evidence on overall survival (OS) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors is generally limited to data from clinical trials or a few observational studies with limited generalizability to Medicare population. The aim of this study was to determine OS benefits associated with CDK4/6 inhibitors in older Medicare patients with hormone receptor (HR)-positive and human epidermal growth factor receptor-2 overexpressing (HER2-) metastatic breast cancer (MBC). METHODS: In a retrospective cohort design, female patients aged ≥65 years with diagnosis of HR+/HER2- MBC from 2015 to 2017 who initiated first-line systemic therapy within 12 months of MBC diagnosis were selected from the Survey Epidemiology and End Results-Medicare database. The effect of treatment type (endocrine therapy [ET]+CDK4/6 inhibitor vs. ET alone) on OS was analyzed using Kaplan-Meier methods and multivariable Cox regression models. Adjusted hazard ratio (aHR) and 95% CIs were estimated. RESULTS: A total of 630 eligible patients were identified (169 patients treated with ET+CDK4/6 inhibitor and 461 patients treated with ET alone). In the Kaplan-Meier analysis, OS rate at 3 years after first-line treatment initiation was 73.0% for ET+CDK4/6 inhibitor versus 49.1% for ET alone (log-rank p < .0001). In Cox regression analysis, first-line ET+CDK4/6 inhibitor therapy was associated with 41% lower rate of mortality versus ET alone (aHR, 0.590; 95% CI, 0.423-0.823). CONCLUSIONS: The findings of this real-world study demonstrate significant OS benefit associated with ET+CDK4/6 inhibitor therapy over ET alone in an older Medicare population of patients with HR+/HER2- MBC, largely consistent with the evidence from clinical trials.

The Association Between Medication Use in Older Women with Early-Stage Operable Primary Breast Cancer and Decision Regarding Primary Treatment.

BACKGROUND: Polypharmacy is one factor contributing to increased mortality, hospitalization, and adverse drug reactions in older adults. The aim of this study was to measure the prevalence of polypharmacy in a cohort of older women with early-stage operable primary breast cancer and the relationship of polypharmacy to primary treatment decision and functional status. METHODS: A total of 139 patients with a new diagnosis of early-stage operable primary breast cancer proven histologically were recruited as part of a prospective study. The average age was 77 years. Assessment using a cancer-specific Comprehensive Geriatric Assessment (CGA) tool was conducted within 6 weeks of diagnosis of breast cancer. Association was determined between number of medications and treatment decision and physical status as measured by the CGA outcomes. Additional analysis was performed to determine the associations above with polypharmacy defined by ≥5 daily medications, and if cardiovascular-related diseases have a role in the treatment decision. RESULTS: Polypharmacy was present in 48% of patients (n = 139). CGA determined that polypharmacy was associated with greater comorbidity (P < .001), reduced physical status rated by physicians (P = .009) and patients (P = .019), and reduced ability to perform activities of instrumental ADLs (P = .008). Similar findings were present in the analysis of cardiovascular-related diseases. CONCLUSIONS: This work suggests that patients with polypharmacy are more likely to be frail. The number of medications could help us screen patients who should go on to receive full CGA.

Impact of CDK4/6 inhibitors on chemotherapy utilization in earlier therapy lines for HR+/HER2- metastatic breast cancer in the United States.

PURPOSE: Delaying chemotherapy remains a vital goal in therapeutic management of HR+/HER2- metastatic breast cancer (MBC). However, recent reports continue to highlight substantially high chemotherapy utilization in earlier therapy lines. In this study, we explored the impact of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy class, introduced in 2015, on early chemotherapy utilization in an older population of patients with HR+/HER2- MBC in the United States (US). METHODS: Using an interrupted time series design, patients with a confirmed diagnosis of MBC aged ≥ 65 years initiating systemic therapy during 2010-2019 were selected from the SEER-Medicare database. The proportion of chemotherapy use was summarized quarterly based on the date of treatment initiation separately in the first, second, and third lines. Segmented regression models adjusted for autocorrelation over time were fitted to estimate trends before and after the availability of CDK4/6 inhibitors in the first quarter of 2015. RESULTS: Of the 3244 eligible women (median age at diagnosis: 74 years), all initiated first-line therapy; 47.9% (n = 1581) initiated second-line therapy, and 50.1% (n = 792) initiated third-line therapy. Overall utilization of chemotherapy (alone or in combination) during the study period was 15.7% for the first line, 19.6% for the second line, and 24.8% for the third line. Chemotherapy utilization in the period immediately after introduction of CDK4/6 inhibitor therapy decline by estimated 2.5% in the first line (P = 0.408), 15.5% in the second line (P = 0.005), and 16.3% in the third line (P = 0.003). CONCLUSIONS: This population-based study illustrates that chemotherapy utilization in earlier therapy lines for HR+/HER2- MBC declined steadily between 2010 and 2019. These declines were significantly accelerated by the introduction of CDK4/6 therapy class in 2015, notably in the second- and third-line settings.

How do we define high and low dose intensity of heart failure medications: a scoping review.

BACKGROUND: Older adults with heart failure often experience adverse drug events with high doses of heart failure medications. Recognizing whether a patient is on a high or low dose intensity heart failure medication can be helpful for daily practice, since it could potentially guide the physician on which symptoms to look for, whether from overdosing or underdosing. However, the current guideline does not provide sufficient information about the dose intensity below the target dose. Furthermore, the definition of high or low-intensity heart failure medication is unclear, and there is no consensus. METHODS: To close the knowledge gap, we conducted a scoping review of the current literature to identify the most frequently used definition of high versus low doses of heart failure medications. We searched Pubmed, Embase, CINAHL, and Cochrane Library using comprehensive search terms that can capture the intensity of heart failure medications. RESULTS: We reviewed 464 articles, including 144 articles that had information about beta-blockers (BB), 179 articles about angiotensin-converting enzyme inhibitors (ACEi), 75 articles about angiotensin receptor blockers (ARB), 80 articles about diuretics, 37 articles about mineralocorticoid receptor antagonists (MRA), and 33 articles about angiotensin receptor-neprilysin inhibitor (ARNI). For hydralazine with isosorbide dinitrate or ivabradine, we could not identify any eligible articles. We identified 40 medications with most frequently used definitions of dose intensity. Four medications (nadolol, pindolol, cilazapril, and torsemide) did not reach consensus in definitions. Most of the BBs, ACEis, or ARBs used the definition of low being < 50% of the target dose and high being ≥ 50% of the target dose from the guideline. However, for lisinopril and losartan, the most commonly used definitions of high or low were from pivotal clinical trials with a pre-defined definition of high or low. CONCLUSION: Our comprehensive scoping review studies identified the most frequently used definition of dose intensity for 40 medications but could not identify the definitions for 4 medications. The results of the current scoping review will be helpful for clinicians to have awareness whether the currently prescribed dose is considered high - requiring close monitoring of side effects, or low - requiring more aggressive up-titration.

Emotional barriers and facilitators of deprescribing for older adults with cancer and polypharmacy: a qualitative study.

PURPOSE: To describe emotional barriers and facilitators to deprescribing (the planned reduction or discontinuation of medications) in older adults with cancer and polypharmacy. METHODS: Virtual focus groups were conducted over Zoom with 5 key informant groups: oncologists, oncology nurses, primary care physicians, pharmacists, and patients. All groups were video- and audio-recorded and transcribed verbatim. Focus group transcripts were analyzed using inductive content analysis, and open coding was performed by two coders. A codebook was generated based on the initial round of open coding and updated throughout the analytic process. Codes and themes were discussed for each transcript until consensus was reached. Emotion coding (identifying text segments expressing emotion, naming the emotion, and assigning a label of positive or negative) was performed by both coders to validate the open coding findings. RESULTS: All groups agreed that polypharmacy is a significant problem. For clinicians, emotional barriers to deprescribing include fear of moral judgment from patients and colleagues, frustration toward patients, and feelings of incompetence. Oncologists and patients expressed ambivalence about deprescribing due to role expectations that physicians "heal with med[ication]s." Emotional facilitators of deprescribing included the involvement of pharmacists, who were perceived to be neutral, discerning experts. Pharmacists described emotionally aware communication strategies when discussing deprescribing with other clinicians and expressed increased awareness of patient context. CONCLUSION: Deprescribing can elicit strong and predominantly negative emotions among clinicians and patients which could inhibit deprescribing interventions. The involvement of pharmacists in deprescribing interventions could mitigate these emotional barriers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05046171 . Date of registration: September 16, 2021.

Prescribing trends of proton pump inhibitors, antipsychotics and benzodiazepines of medicare part d providers.

BACKGROUND: Proton pump inhibitors, benzodiazepines, and antipsychotics are considered potentially inappropriate medications in older adults according to the American Geriatric Society Beers Criteria, and deprescribing algorithms have been developed to guide use of these drug classes. The objective of this study was to describe the number of beneficiaries prescribed these medications, provider specialty and regional trends in prescribing, and the aggregate costs for these claims in Medicare Part D. METHODS: This was a retrospective cross-sectional study using publicly available Medicare Provider Utilization and Payment Data: Part D Prescriber data for years 2013-2019. Descriptive statistics and the Cochrane-Armitage test were used to summarize the trends. RESULTS: Overall, 30.1%, 25.6%, 4.6% of Medicare Part D beneficiaries had a proton pump inhibitor, benzodiazepine, and antipsychotic claim in 2013, respectively. These rates decreased to 27.5%, 17.5%, 4.1% in 2019 (p-value < 0.0001). However, the number of standardized 30-day claims increased from 63 million in 2013 to 84 million in 2019 for proton pump inhibitors, remained steady for benzodiazepines and slightly increased (10 million to 13 million) for antipsychotics. Total aggregate costs decreased by almost $1.5 billion for proton pump inhibitor, $100 million for benzodiazepine, and $700 million for antipsychotic from 2013 to 2019 (p-value < 0.0001). Almost 93% of gastroenterologists prescribed a proton pump inhibitor, and 60% of psychiatrists prescribed benzodiazepines and antipsychotics all seven years. The Other region had the highest percentage of providers prescribing all three classes and the highest number of standardized 30-day benzodiazepine claims. CONCLUSIONS: The overall rate of use of proton pump inhibitors, benzodiazepines, and antipsychotics decreased from 2013-2019 among Medicare Part D beneficiaries. Despite the increase in raw number of standardized 30-day claims, the costs decreased which is likely due to generics made available. These prescribing trends may aid in identifying and targeting potential deprescribing interventions.

Prevalence of potential interactions of medications, including herbs and supplements, before, during, and after chemotherapy in patients with breast and prostate cancer.

BACKGROUND: The use of herbs and supplements (HS) is common among patients with cancer, yet limited information exists about potential medication interactions (PMIs) with HS use around chemotherapy. METHODS: Patients with breast or prostate cancer who had recently finished chemotherapy at 2 academic medical centers were surveyed by telephone. Interviewers inquired about all medications, including HS, before, during, and after chemotherapy. Micromedex, Lexicomp, and Natural Medicines Comprehensive Database interaction software programs were used to determine PMIs. RESULTS: A total of 67 subjects (age range, 39-77 years) were evaluated in this study. Participants were primarily White patients (73%) with breast cancer (87%). The median number of medications was 11 (range, 2-28) during the entire study and was highest during chemotherapy (7; range, 2-22). Approximately four-fifths (84%) used HS. A total of 1747 PMIs were identified, and they represented 635 unique PMIs across all 3 timeframes, with most occurring during chemotherapy. Prescription-related PMIs (70%) were the most common type, and they were followed by HS-related (56%) and anticancer treatment-related PMIs (22%). Approximately half of the PMIs (54%) were categorized as moderate interactions, and more than one-third (38%) were categorized as major interactions. Patient use of HS increased from 51% during chemotherapy to 66% after chemotherapy, and this correlated with an increased prevalence of HS PMIs (46% to 60%). HS users were more likely to be at risk for a major PMI than non-HS users (92% vs 70%; P = .038). CONCLUSIONS: The use of HS remains prevalent among patients with cancer and may place them at risk for PMIs both during chemotherapy and after the completion of treatment. LAY SUMMARY: This study evaluates the risk of potential medication interactions for patients with breast or prostate cancer undergoing chemotherapy. The results show that patients often use herbs and supplements during treatment. Prescription medications are most often associated with medication interactions, which are followed by herb and supplement-related interactions. More than one-third of potential medication interactions are considered major. Patients should be educated about the risk of herb and supplement-related medication interactions during treatment.

Delirium Among Hospitalized Older Adults With Acute Heart Failure Exacerbation.

BACKGROUND: Delirium among older adults hospitalized with acute heart failure is associated with increased mortality. However, studies concomitantly assessing the association of delirium with both clinical and economic outcomes in this population, such as mortality, hospital cost, or length of stay, are lacking. METHODS AND RESULTS: We conducted a retrospective observational study using National Inpatient Sample data from 2011 to 2014. Using multivariable logistic regression, we assessed the association of delirium with in-hospital mortality, then estimated the incremental hospital cost and excessive length of stay adjusting for demographic and clinical factors using multivariable generalized linear regression. The association of other medical complications on clinical and economic outcomes was also assessed. A total of 568,565 (weighted N = 2,826,131) hospitalizations of patients 65 years or older with acute heart failure from 2011 to 2014 were included in the final analysis. The reported prevalence of delirium was 4.53%. After multivariable adjustment, delirium was associated with a 2.35-fold increase in the odds of in-hospital mortality (95% confidence interval [CI] 2.23-2.47), which was lower than the odds ratio for sepsis/septicemia (5.36; 95% CI, 5.02-5.72) or respiratory failure (4.53; 95% CI, 4.38-4.69), but similar to that for acute kidney injury (2.39; 95% CI, 2.31-2.48) and higher than for non-ST elevation myocardial infarct (1.57; 95% CI, 1.46-1.68). Delirium increased the total hospital cost by $4,262 (95% CI, $4,002-4,521) and the length of stay by 1.73 days (95% CI, 1.68-1.78), which was slightly lower than, but similar to, acute kidney injury ($4,771; 95% CI, $4,644-4,897) and 1.82 days (95% CI, 1.79-1.84), and higher than non-ST elevation myocardial infarct ($1,907; 95% CI, $1,629-2,185) and 0.31 days (95% CI, 0.25-0.37). CONCLUSIONS: Delirium was associated with increased in-hospital mortality, total hospital cost, and length of stay, and the magnitude of the effect was similar to that for acute kidney injury. Enhanced efforts to prevent delirium are needed to decrease its adverse impact on clinical and economic outcomes for hospitalized older adults with acute heart failure.

Association of Polypharmacy and Potentially Inappropriate Medications With Physical Functional Impairments in Older Adults With Cancer.

BACKGROUND: Polypharmacy and potentially inappropriate medications (PIMs) are prevalent in older adults with cancer, but their associations with physical function are not often studied. This study examined the associations of polypharmacy and PIMs with physical function in older adults with cancer, and determined the optimal cutoff value for the number of medications most strongly associated with physical functional impairment. METHODS: This cross-sectional analysis used baseline data from a randomized study enrolling patients aged ≥70 years with advanced cancer starting a new systemic cancer treatment. We categorized PIM using 2015 American Geriatrics Society Beers Criteria. Three validated physical function measures were used to assess patient-reported impairments: activities of daily living (ADL) scale, instrumental activities of daily living (IADL) scale, and the Older Americans Resources and Services Physical Health (OARS PH) survey. Optimal cutoff value for number of medications was determined by the Youden index. Separate multivariate logistic regressions were then performed to examine associations of polypharmacy and PIMs with physical function measures. RESULTS: Among 439 patients (mean age, 76.9 years), the Youden index identified ≥8 medications as the optimal cutoff value for polypharmacy; 43% were taking ≥8 medications and 62% were taking ≥1 PIMs. On multivariate analysis, taking ≥8 medications was associated with impairment in ADL (adjusted odds ratio [aOR], 1.64; 95% CI, 1.01-2.58) and OARS PH (aOR, 1.73; 95% CI, 1.01-2.98). PIMs were associated with impairments in IADL (aOR, 1.72; 95% CI, 1.09-2.73) and OARS PH (aOR, 1.97; 95% CI, 1.15-3.37). A cutoff of 5 medications was not associated with any of the physical function measures. CONCLUSIONS: Physical function, an important component of outcomes for older adults with cancer, is cross-sectionally associated with polypharmacy (defined as ≥8 medications) and with PIMs. Future studies should evaluate the association of polypharmacy with functional outcomes in this population in a longitudinal fashion.

Quality of Life Assessment in Older Adults with Dementia: A Systematic Review.

INTRODUCTION: In the absence of a cure, dementia is often managed by minimizing risk factors contributing to quality of life (QOL). Attitudes to dementia in older adults may differ from those in relatively younger adults. The aim was to conduct a systematic review of the literature to determine how QOL was assessed in adults, 65 years and older with dementia, and identify factors that influence the reported scores. METHODS: A systematic review of full-text articles addressing QOL in older adults with dementia, published in English from January 1995 to September 2020, was conducted using PubMed and PsycINFO. We included studies that assessed QOL and involved participants 65 years and older. Studies were evaluated for inclusion by 2 independent pairs of reviewers. We assessed the quality of the studies using the Joanna Briggs Institute's Critical Appraisal Checklist. Study characteristics and findings were summarized. Analysis was by narrative synthesis. We identified social and clinical factors influencing QOL scores. RESULTS: Of the 1,010 articles identified, 19 met the inclusion criteria. These 19 studies involved 6,279 persons with dementia, with sample sizes from 32 to 1,366. Mean age of participants ranged from 77.1 to 86.6 years. Five measurement tools were identified; Quality of Life in Alzheimer Disease (QOL-AD), Alzheimer Disease-Related Quality of Life (ADRQL), Quality of Life in Late-Stage Dementia (QUALID), QUALIDEM (a dementia-specific QOL tool), and DEMQOL (health-related QOL for people with dementia). Self-ratings of QOL were higher than proxy ratings. Factors commonly influencing self-ratings of QOL included depression, functional impairment, and polypharmacy. Common factors that influenced proxy ratings included functional impairment, presence of neuropsychiatric symptoms, cognitive impairment, and caregiver burden. CONCLUSION: In evaluating QOL in dementia, self- and proxy reports may complement each other to ensure that all perspectives are addressed.

Comparative risk of adverse outcomes associated with nonselective and selective antimuscarinic medications in older adults with dementia and overactive bladder.

OBJECTIVE: The differential muscarinic receptor selectivity could cause selective antimuscarinics to offer advantages over nonselective agents with respect to adverse effects. The objective was to examine the comparative risk of falls/fractures and all-cause hospitalizations among older adults with dementia and overactive bladder (OAB) using nonselective and selective antimuscarinics METHODS/DESIGN: A retrospective cohort study design was conducted among older patients with dementia and OAB using incident antimuscarinics. The primary exposure was classified as nonselective (oxybutynin, tolterodine, trospium, and fesoterodine) and selective (solifenacin and darifenacin). Cox proportional-hazards regression using inverse probability of treatment weighting (IPTW) evaluated the risk of falls/fractures and all-cause hospitalizations within 6 months of nonselective and selective antimuscarinic use. RESULTS: The study cohort consisted of 13,896 (76.9%) nonselective and 4,179 (23.1%) selective antimuscarinic incident users. The unadjusted falls/fractures rate was 27.14% (3,772) for nonselective and 24.55% (1,026) for selective users (p-value< 0.01). The unadjusted all-cause hospitalizations rate was 24.14% (3,354) for nonselective and 21.58% (902) for selective users (p-value <0.01). The IPTW models did not find a significant difference in the risk of falls/fractures (Hazard Ratio [HR] 1.03; 95% Confidence Interval [CI] 0.99-1.07) and risk of all-cause hospitalizations (HR 1.04; 95% CI 0.99-1.08) between nonselective and selective antimuscarinics. Several sensitivity analyses corroborated the main findings. CONCLUSIONS: The study did not find a differential risk of falls/fractures and all-cause hospitalizations in older adults with dementia and OAB using nonselective and selective antimuscarinics. More research is needed to understand the role of pharmacodynamics and pharmacokinetics in the safety profile of antimuscarinics in dementia.

Identifying Geriatric Oncology Competencies for Medical Oncology Trainees: A Modified Delphi Consensus Study.

BACKGROUND: Most oncology trainees are not taught about the needs of older patients, who make up the majority of patients with cancer. Training of health care providers is critical to improve the care of older adults with cancer. There is no consensus about which geriatric oncology (GO) competencies are important for medical oncology trainees. Our objective was to identify GO competencies medical oncology trainees should acquire during training. MATERIALS AND METHODS: A modified Delphi consensus of experts in oncology medical education and GO was conducted. Experts categorized at what training stage proposed competencies should be attained: internal medicine, oncology, or GO training. Consensus was obtained if two thirds of experts agreed on the training stage at which the competency should be attained. RESULTS: A total of 78 potential competencies were identified, of which 35 (44.9%) proposed competencies were felt to be appropriate to be acquired during oncology training. The majority of the identified competencies pertained to prescribing of systemic therapy (n = 12) and psychosocial and supportive care (n = 13). No competencies related to geriatric assessment were identified for acquisition during oncology training. CONCLUSION: Experts in oncology education and geriatric oncology agreed upon a set of GO competencies appropriate for oncology trainees. These results provide the foundation for developing a GO curriculum for medical oncology trainees and will hopefully lead to better care of older adults with cancer. IMPLICATIONS FOR PRACTICE: The aging population will drive the projected rise in cancer incidence. Although aging patients make up the majority of patients diagnosed with cancer, oncologists rarely receive training on how to care for them. Training of health care providers is critical to improving the care of older adults with cancer. The results of this study will help form the foundation of developing a geriatric oncology curriculum for medical oncology trainees.

Associations of Polypharmacy and Inappropriate Medications with Adverse Outcomes in Older Adults with Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Polypharmacy (PP) and potentially inappropriate medications (PIM) are highly prevalent in older adults with cancer. This study systematically reviews the associations of PP and/or PIM with outcomes and, through a meta-analysis, obtains estimates of postoperative outcomes associated with PP in this population. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Register of Clinical Trials using standardized terms for concepts of PP, PIM, and cancer. Eligible studies included cohort studies, cross-sectional studies, meta-analyses, and clinical trials which examined outcomes associated with PP and/or PIM and included older adults with cancer. A random effects model included studies in which definitions of PP were consistent to examine the association of PP with postoperative complications. RESULTS: Forty-seven articles met the inclusion criteria. PP was defined as five or more medications in 57% of the studies. Commonly examined outcomes included chemotherapy toxicities, postoperative complications, functional decline, hospitalization, and overall survival. PP was associated with chemotherapy toxicities (4/9 studies), falls (3/3 studies), functional decline (3/3 studies), and overall survival (2/11 studies). A meta-analysis of four studies indicated an association between PP (≥5 medications) and postoperative complications (overall odds ratio, 1.3; 95% confidence interval [1.3-2.8]). PIM was associated with adverse outcomes in 3 of 11 studies. CONCLUSION: PP is associated with postoperative complications, chemotherapy toxicities, and physical and functional decline. Only three studies showed an association between PIM and outcomes. However, because of inconsistent definitions, heterogeneous populations, and variable study designs, these associations should be further investigated in prospective studies. IMPLICATIONS FOR PRACTICE: Polypharmacy and potentially inappropriate medications (PIM) are prevalent in older adults with cancer. This systematic review summarizes the associations of polypharmacy and PIM with health outcomes in older patients with cancer. Polypharmacy and PIM have been associated with postoperative complications, frailty, falls, medication nonadherence, chemotherapy toxicity, and mortality. These findings emphasize the prognostic importance of careful medication review and identification of PIM by oncology teams. They also underscore the need to develop and test interventions to address polypharmacy and PIM in older patients with cancer, with the goal of improving outcomes in these patients.

Risk of Mortality Associated with Non-selective Antimuscarinic medications in Older Adults with Dementia: a Retrospective Study.

BACKGROUND: Selective antimuscarinics may offer a favorable safety profile over non-selective antimuscarinics for the management of overactive bladder (OAB) in patients with dementia. OBJECTIVE: To test the hypothesis that non-selective antimuscarinics are associated with increased risk of mortality compared to selective antimuscarinics in older adults with dementia and OAB. DESIGN: Propensity score-matched retrospective new-user cohort design among Medicare beneficiaries in community settings. PATIENTS: Older adults with dementia and OAB with incident antimuscarinic use. MAIN MEASURES: The primary exposure was antimuscarinic medications classified as non-selective (oxybutynin, tolterodine, trospium, fesoterodine) and selective (solifenacin, darifenacin) agents. All-cause mortality within 180 days of incident antimuscarinic use formed the outcome measure. New users of non-selective and selective antimuscarinics were matched on propensity scores using the Greedy 5 → 1 matching technique. Cox proportional-hazards model stratified on matched pairs was used to evaluate the risk of mortality associated with the use of non-selective versus selective antimuscarinics in the sample. KEY RESULTS: The study identified 16,955 (77.6%) non-selective antimuscarinic users and 4893 (22.4%) selective antimuscarinic users. Propensity score matching yielded 4862 patients in each group. The unadjusted mortality rate at 180 days was 2.6% (126) for non-selective and 1.6% (78) for selective antimuscarinic users in the matched cohort (p value < 0.01). The Cox model stratified on matched pairs found 50% higher risk of 180-day mortality with non-selective antimuscarinics as compared to selective ones (hazard ratio (HR) 1.50; 95% confidence interval (CI) 1.04-2.16). The study findings remained consistent across multiple sensitivity analyses. CONCLUSIONS: Use of non-selective antimuscarinics was associated with a 50% increase in mortality risk among older adults with dementia and OAB. Given the safety concerns regarding non-selective antimuscarinic agents, there is a significant need to optimize their use in the management of OAB for older patients with dementia.

Risk of Mortality Associated With Atypical Antipsychotic use: A National Cohort Study of Older Adults With Depression and Parkinson's Disease.

OBJECTIVES: This study examined the risk of all-cause-mortality in patients with Parkinson's Disease (PD) and comorbid depression using inappropriate atypical antipsychotics (AAPs), based on the 2015 American Geriatrics Society Beers criteria. METHODS: A retrospective analysis of 2007-2010 Minimum Data Set linked Medicare data was conducted using a propensity-matched approach. The cohort included PD patients aged 65 years or older without schizophrenia or bipolar disorder who started AAPs. All patients had a diagnosis of comorbid depression. Risk of 6-month all-cause-mortality was compared across appropriate AAPs (aripiprazole, clozapine, or quetiapine) and inappropriate AAPs (olanzapine, asenapine, brexpiprazole, iloperidone, lurasidone, paliperidone, risperidone, or ziprasidone) using robust Cox regression models involving the matched cohort. RESULTS: All-cause mortality rate was 15.65% in appropriate AAP group (n = 6,038) and 16.91% in inappropriate AAP group (n = 6,038) over 6-month follow-up in the matched cohort. The robust Cox proportional hazards models revealed increased risk of all-cause mortality (hazard ratio [HR] 1.13 [95% confidence interval {CI}: 1.01-1.28)] for patients who used inappropriate compared to appropriate AAPs. Risk of death was also higher for risperidone compared to quetiapine (HR: 1.20 [95% CI: 1.03-1.40]) in sensitivity analysis. However, there was a significant relationship between pneumonia and death in all analyses. The impact of inappropriate AAP use on mortality was not significant when pneumonia was modeled as a mediator. CONCLUSIONS: Inappropriate AAP use is associated with a higher risk of all-cause-mortality in older patients with PD which is mainly mediated by pneumonia. Therefore, inappropriate AAP use should be avoided to improve quality of care in PD.

Safety Assessment of High-Purity, Synthetic Nicotinamide Riboside (NR-E) in a 90-Day Repeated Dose Oral Toxicity Study, With a 28-Day Recovery Arm.

Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3 shown to preferentially elevate the nicotinamide adenine dinucleotide (NAD+) metabolome compared to other vitamin B3 forms (nicotinic acid and nicotinamide). Although daily requirements of vitamin B3 are typically met through the diet, recent studies have shown that additional supplementation with NR may be an effective method to counter the age-related decline in NAD+ levels as NR bypasses the rate-limiting step in NAD+ biosynthesis. Furthermore, pharmaceutical applications of NR for age-related disorders have been proposed. In this study, the safety of a high-purity, nature-identical, synthetic NR (NR-E), manufactured under the guidelines of good manufacturing practices for dietary supplements (21 CFR 111) as well as for drugs (21 CFR 210), was investigated in a 90-day oral toxicity study in Sprague Dawley rats at 300, 500, and 1,200 mg/kg/d. There were no mortality or clinical observations attributable to the test substance at any dose. A small but statistically significant decrease in body weight was observed at day 92 in the 1,200 mg/kg/d NR-treated male rats only. In contrast to a previously published safety assessment using a different synthetic NR (NIAGEN), whose no-observed-adverse-effect-level (NOAEL) was reported to be 300 mg/kg/d, there were no adverse changes in clinical pathology parameters and no notable macroscopic or microscopic findings or treatment-related effects at similar doses. In the current study, the NOAEL for systemic toxicity of NR-E in Sprague-Dawley rats was conservatively determined to be 500 mg/kg/d for males (solely based on body weight) and 1,200 mg/kg/d for females.

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation.

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD.

The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: Prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer.

BACKGROUND: The concomitant use of tyrosine kinase inhibitors (TKIs) and proton pump inhibitors (PPIs) is a significant concern because of potential drug-drug interaction that reduces TKI absorption, thus potentially reducing the effectiveness of TKIs. The objective of this study was to evaluate the prevalence and predictors of concomitant TKI-PPI receipt and its impact on survival and therapy discontinuation in older adults with cancer. METHODS: This retrospective study used linked Surveillance, Epidemiology, and End Results-Medicare data for the years 2007 through 2012. In total, 12,538 patients with lung cancer, renal cell cancer, chronic myelogenous leukemia, liver cancer, or pancreatic cancer were included. The primary exposure variable was concomitant receipt of TKI-PPI, defined as at least 30 days of PPI use in the first 90 days from the start of the TKI (exposure period). The outcomes measured were overall survival and discontinuation of therapy in 90 days and 1 year after the end of the exposure period. Cox proportional-hazards regression with inverse probability of treatment weighting was used to evaluate the association between exposure and outcome. RESULTS: The overall prevalence of TKI-PPI receipt was 22.7%. Predictors that were associated with increased use included polypharmacy and prior PPI receipt. TKI-PPI use decreased survival in 90 days (hazard ratio, 1.16; 95% confidence interval, 1.05-1.28) and in 1 year (hazard ratio, 1.10; 95% confidence interval, 1.04-1.18) but was not associated with discontinuation. CONCLUSIONS: Nearly 1 in 4 older adults with cancer who receive TKIs also receive PPIs concomitantly, and concomitant use is associated with an increased risk of death. Concerted efforts to manage medications are needed to identify and reduce the receipt of PPIs when TKIs are initiated.