Specific Drug Classes Research Articles

Antihypertensive drugs demonstrate varying levels of hip fracture risk: A systematic review and meta-analysis

ObjectiveBy aggregating the literature, we evaluated the association between use of specific antihypertensive drugs and the risk of hip fractures compared with nonuse. Study design and settingWe systematically searched the Pubmed, Embase, and Cochrane databases from inception of each database until July 30, 2020 to identify articles including patients 18 years of age or older reporting on the association between antihypertensive drugs and the risk of hip fracture. Antihypertensive drugs were restricted to thiazides; beta-blockers; calcium-channel blockers; angiotensin-converting enzyme (ACE) inhibitors; and angiotensin receptor blockers. Nonusers encompass all patients that are not using the specific antihypertensive drug that has been reported. Unadjusted odds ratios with 95% confidence intervals (CIs) of the association between antihypertensive drug use and hip fractures were reported. Meta-analysis was performed when a minimum of five studies were identified for each antihypertensive drug class. Quality assessment was done using ROBINS-I tool. The GRADE approach was used to evaluate the certainty of the evidence. ResultsOf 962 citations, 22 observational studies were included; 9 studies had a cohort design and 13 studies were case-control studies. No randomized controlled trials were identified. We found very low certainty of evidence that both thiazides (pooled odds ratio: 0.85, 95% CI 0.73 to 0.99, p = 0.04) as well as beta-blockers (pooled odds ratio: 0.88, 95% CI 0.79 to 0.98, p = 0.02) were associated with a reduced hip fracture risk as compared to specific nonuse. One study, reporting on angiotensin receptor blockers, also suggested a protective effect for hip fractures, whereas we found conflicting findings in four studies for calcium-channel blockers and in two studies for ACE inhibitors. ConclusionAmong 22 observational studies, we found very low certainty of evidence that, compared to specific nonuse of antihypertensive drugs, use of thiazides, beta-blockers, and angiotensin receptor blockers were associated with a reduced protective hip fracture risk, while conflicting findings for calcium-channel blockers and ACE inhibitors were found. Given the low quality of included studies, further research –randomized controlled trials– are needed to definitively assess the causal relationship between specific antihypertensive drug classes and (relatively infrequent) hip fractures.

Anatomic and Clinical Pathology Characterization of Drug-Induced Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease) in Cynomolgus Macaques.

Sinusoidal obstruction syndrome (SOS) is a unique form of liver injury that occurs after exposure to chemotherapeutic drugs and toxins. The diagnosis of SOS in humans remains a challenge as the clinical criteria have low specificity and there are no reliable noninvasive biomarkers. The mechanism of injury is believed to be damage to liver endothelial cells, primarily sinusoidal endothelial cells (SECs), which leads to sinusoidal dilation, central venous fibrosis, and/or nodular regeneration. Nonclinical data suggest that this uncommon liver toxicity can be recapitulated in cynomolgus monkeys, and it is critical that pathologists are familiar with its characteristic clinicopathologic features. Elevations in liver enzymes, in particular aspartate aminotransferase, associated with isolated thrombocytopenia, should raise the suspicion of SEC injury for specific drug classes. Characterization of liver microscopic findings in monkeys benefits from the use of appropriate stains, such as reticulin stain, and VEGFR2 and CD34 immunohistochemical (IHC) stains. CD41 IHC demonstrates platelet accumulation in injured sinusoids, the likely cause of thrombocytopenia commonly reported in SOS. In conclusion, this report provides a comprehensive characterization of the pathology findings of drug-induced SOS in monkeys with the objectives of ensuring appropriate nonclinical recognition of the liability and informing clinical development strategy and monitoring.

Monitoring Adverse Effects of Antipsychotics and Antidepressants: A Population Based Study

Abstract: Aim: To monitor the nature and incidences adverse effects of both antipsychotics and antidepressants medicines in the psychiatry outpatient department. Objectives: Reporting the incidences of adverse effects and to establish the frequency of a specific class of drug. Identifying the system affected and the assessment of the management of the adverse effects by the physician. For the study, we have adopted Global Assessment Scale (GAS), Simpson-Angus Extra pyramidal Side Effects Scale (SAS) and The Antidepressant Side-Effect Checklist (ASEC). Materials and Methods: A prospective cohort study carried out in the psychiatry out-patient department. All the patients attending psychiatry outpatient department enrolled based on the pre-specified inclusion criteria and monitored for adverse effects. Causality also assessed by WHO-UMC causality assessment system and Naranjo Causality Assessment. Results: The incidence rate of adverse effects (46.07%) and 560 adverse effects documented. Weight gain (n=29, 9.2%) followed by drowsiness (n=27, 4.82%) are most commonly reported adverse effects. Atypical antipsychotics (n=279, 49.82%) were the most common class of psychotropic drugs implicated in adverse effects. Escitalopram (n=93, 37.80%) followed by olanzapine (n=53, 21.54%) associated with a maximum number of adverse effects. Central nervous system (n=225, 40.17%) was the most affected organ system followed by gastrointestinal system (n=130, 23.21%). Conclusion: Study revealed moderate incidences of adverse effects in patients attending the psychiatry outpatient department. Majority of the adverse effects reported during the study were mild in nature and not preventable. The role of a clinical pharmacist clearly elucidated regular intensive monitoring of adverse effects may improve the quality of patients’ care, reduction in the treatment cost and augmentation of the medication adherence among patients. Key words: Adverse effects, Pharmacovigilance, Antipsychotics, Antidepressants, Extra pyramidal side effects.

Considerations regarding choice of primary outcome in clinical trials in deprescribing.

Considerations regarding choice of primary outcome in clinical trials in deprescribing.

German Society of Rheumatology Recommendations for the management of glucocorticoid-induced Osteoporosis. German version

Glucocorticoids are of substantial therapeutic importance in the treatment of inflammatory diseases, but are also associated with bone mineral density loss, osteoporosis, and fractures, especially with long-term use. To develop recommendations for the management of glucocorticoid-induced osteoporosis (GIOP) in adult patients on long-term glucocorticoid (GC) treatment. Asystematic literature search (SLR) was conducted to synthesize the evidence for GIOP prevention and treatment options. Recommendations were developed based on SLR/level of evidence and by previously defined questions and in astructured group consensus process. Recommendations include supplementation with calcium and vitaminD under long-term GC therapy in adults. If specific osteologic treatment is indicated, we recommend bisphosphonates or denosumab as first-line treatment. If fracture risk is high, we recommend teriparatide as primary specific osteologic treatment. Denosumab should be used in cases of severe renal insufficiency, and specific osteologic treatment should not be given in pregnancy. For patients who have not reached the treatment goal, aswitch to another class of specific osteologic drugs should be performed. We recommend re-evaluation after atreatment duration of 3-5years or after termination of long-term GC treatment. This work aims to provide evidence-based and consensus-based recommendations for the best possible management of GIOP in Germany and to support treatment decisions.

Abstract 1194: MEK inhibition in combination with PI3K/AKT/MTOR is a promising therapeutic in basal bladder cancer

Abstract There are diverse resources available for data relevant to the drug screening of bladder cancer cell lines in 2D culture, such as the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases; however, 3D culture is more representative of in vivo response in patients. Moreover, drug screens in 3D reveal differential drug response and expression of genes and proteins that indicate the potential of more effective selection of drugs for specific patients: the basic tenet of personalized oncology. Therefore, we screened bladder cancer cell lines in 3D culture using a library of curated small-molecule inhibitors to identify compounds and classes of compounds with efficacy in bladder cancer. Genomic and transcriptomic data for these bladder cancer cell lines were used to correlate genomic molecular parameters with drug response with the aim of discerning biomarkers of response or to suggest plausible drug combinations. This allowed us to identify groups of tumors that are vulnerable to specific drugs or classes of drugs. We found that MEK inhibitors were a promising target among basal bladder cancers, an RNA-based molecular subtype of bladder cancer, especially aggressive and exhibiting poor prognosis. Furthermore, trametinib was found to be a “very active” MEK inhibitor in basal cancers, classified using drug sensitivity 3 (DSS3) scoring. PI3K/AKT/MTOR inhibitors target a parallel signaling pathway to MEK inhibition; therefore, we tested PI3K/AKT/MTOR combinations with trametinib in basal bladder cancer to query for synergistic properties. Additionally, we tested PI3K/AKT/MTOR combinations with trametinib using ex vivo organoids of bladder cancer patient samples collected directly at operation. Taken together, MEK inhibition is a promising therapeutic strategy in the basal subtype of bladder cancer, particularly in combination with parallel pathway inhibition. Moving forward, we plan to test PI3K/AKT/MTOR combinations with trametinib in trametinib-resistant basal bladder cancer cell lines to investigate how this affects signaling and re-sensitization to trametinib. Citation Format: Athena M. Apfel, Nathan M. Merrill, Nathalie M. Vandecan, Liwei Bao, Xu Cheng, Lluis A. Lopez-Barcons, Kathleen C. Day, Phillip L. Palmbos, Mark L. Day, Aaron M. Udager, Matthew B. Soellner, Sofia D. Merajver. MEK inhibition in combination with PI3K/AKT/MTOR is a promising therapeutic in basal bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1194.

Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host Tcells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor Tcell response invivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.

An overview of sample preparation in forensic toxicology

AbstractSample preparation is an important step in forensic toxicological analysis. With the technological advancements and the availability of mass spectrometers with increasing sensitivities, the need to remove potential interferences, such as matrix components or non‐relevant analytes to the analysis, is essential to optimizing an analytical method. Forensic toxicological analysis involves diverse analytes with a variety of chemical properties that need to be considered when selecting an appropriate sample preparation technique. The push for broad standards and best practice documents for forensic toxicology demonstrates the need for laboratories to ensure they meet the required capabilities to not only detect specific classes of drugs commonly encountered in forensic case work, but also ensure method validity. The objective of this article is to provide the forensic toxicology community a high‐level overview of biological matrices and their relevant components that should be considered during sample pre‐treatment as well as traditional and non‐traditional sample preparation techniques and present general applications.This article is categorized under: Toxicology > Drug Analysis

PIN1 Polypharmacy Among COVID-19 Patients: A Prisma-Based Systematic Review of Available Literature

Polypharmacy, the concomitant use of 5 or more medications, is highly prevalent among older adults and individuals with multimorbid conditions and has been linked to suboptimal clinical outcomes in various diseases. However, little is known about the impact of polypharmacy on clinical outcomes among COVID-19 patients. This systematic review summarizes available literature on the association between polypharmacy and specific drug classes, and clinical outcomes among COVID-19 patients.

Blood Pressure Changes Following Antihypertensive Medication Reduction, by Drug Class and Dose Chosen for Withdrawal: Exploratory Analysis of Data From the OPTiMISE Trial.

Aims: Deprescribing of antihypertensive drugs is recommended for some older patients with polypharmacy, but there is little evidence to inform which drug (or dose) should be withdrawn. This study used data from the OPTiMISE trial to examine whether short-term outcomes of deprescribing vary by drug class and dose of medication withdrawn. Methods: The OPTiMISE trial included patients aged ≥80 years with controlled systolic blood pressure (SBP; <150 mmHg), receiving ≥2 antihypertensive medications. This study compared SBP control, mean change in SBP and frequency of adverse events after 12 weeks in participants stopping one medication vs. usual care, by drug class and equivalent dose of medication withdrawn. Equivalent dose was determined according to the defined daily dose (DDD) of each medication type. Drugs prescribed below the DDD were classed as low dose and those prescribed at ≥DDD were described as higher dose. Outcomes were examined by generalized linear mixed effects models. Results: A total of 569 participants were randomized, aged 85 ± 3 years with controlled blood pressure (mean 130/69 mmHg). Within patients prescribed calcium channel blockers, higher dose medications were more commonly selected for withdrawal (90 vs. 10%). In those prescribed beta-blockers, low dose medications were more commonly chosen (87 vs. 13%). Withdrawal of calcium channel blockers was associated with an increase in SBP (5 mmHg, 95%CI 0–10 mmHg) and reduced SBP control (adjusted RR 0.89, 95%CI 0.80–0.998) compared to usual care. In contrast, withdrawal of beta-blockers was associated with no change in SBP (−4 mmHg, 95%CI −10 to 2 mmHg) and no difference in SBP control (adjusted RR 1.15, 95%CI 0.96–1.37). Similarly, withdrawal of higher dose medications was associated with an increase in SBP but no change in BP control. Withdrawal of lower dose medications was not associated with a difference in SBP or SBP control. There was no association between withdrawal of specific drug classes and adverse events. Conclusion: These exploratory data suggest withdrawal of higher dose calcium channel blockers should be avoided if the goal is to maintain BP control. However, low dose beta-blockers may be removed with little impact on blood pressure over 12-weeks of follow-up. Larger studies are needed to confirm these associations.

OPTIMAL DRUGS FOR MEDICATION REDUCTION: SECONDARY ANALYSIS OF THE OPTIMISE MEDICATION REDUCTION TRIAL

Objective: Deprescribing of antihypertensive medications is recommended in some elderly patients with polypharmacy and multi-morbidity. The OPTiMISE trial demonstrated that antihypertensive medication reduction can be achieved in two thirds of patients without changes in systolic blood pressure (SBP) control or serious adverse events at 12-week follow-up. The present analyses aimed to examine whether specific drug types were associated with more successful medication reduction in the intervention arm of the trial. Design and method: A total of 282 participants, aged at least 80 years with SBP &lt; 150 mmHg and receiving 2 or more antihypertensive medications were randomised to medication reduction and included in the present analyses. Successful medication reduction was defined by the proportion of participants maintaining reduced medications. Secondary outcomes examined the association between drug class and change in SBP and adverse events. Multivariate regression analyses were conducted to examine associations adjusted for age, sex, systolic blood pressure, cardiovascular disease, multimorbidity, polypharmacy and frailty. Results: Participants included in the analysis were aged 84.6 years, with controlled hypertension (mean SBP 129.4 mmHg), polypharmacy (mean 5.4 medications) and multimorbidity (98.8% participants had 2 or more morbidities). More participants withdrawing ACE inhibitors (79.4%) and beta-blockers (80.6%) were able to maintain medication reduction more than any other drug throughout 12-week follow-up. Half (50.0%) of participants who had these medications removed experienced no increase in SBP at follow-up. In multivariate analyses, calcium channel blockers were less likely to remain withdrawn at follow-up (OR 0.31, 95% CI 0.12 to 0.86), whilst withdrawal of beta-blockers was associated with a significant reduction in SBP (-9.5 mmHg, 95% CI -16.8 to -2.1 mmHg). There was no association between removal of specific drug classes and subsequent adverse events. Conclusions: In the OPTiMISE medication reduction trial, beta-blockers were more likely to be successfully reduced and have little impact of follow-up blood pressure than any other antihypertensive drug class. When considering reducing antihypertensive medications due to polypharmacy, beta-blockers should be targeted as a first-line therapy for deprescribing, followed by ACE inhibitors in older patients with controlled hypertension.

BLOOD PRESSURE LOWERING TREATMENT FOR PREVENTION OF CARDIOVASCULAR EVENTS IN PATIENTS WITH ATRIAL FIBRILLATION: AN INDIVIDUAL-PARTICIPANT DATA META-ANALYSIS

Objective: Randomised evidence showing that pharmacological blood pressure (BP) lowering can reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effect of BP-lowering treatment on fatal and non-fatal cardiovascular outcomes in patients with and without AF. Design and method: We extracted individual participant data from all trials with over 1,000 person-years of follow-up that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs vs placebo, or to more vs less intensive BP-lowering regimens. We investigated the effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline using fixed-effect one-stage individual participant data meta-analyses based on Cox proportional hazards models stratified by trial. Results: Twenty-two trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Patients with AF had lower BP at baseline than patients without AF (143/84 mmHg, SD 21/12mmHg) versus 155/88 mmHg, SD 21/13 mmHg, respectively). Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering, both in patients with and without AF. The hazard ratio for major cardiovascular events was 0.91 in patients with AF (95% confidence interval [0.83 – 1.00]) and 0.91 without AF (95% confidence interval [0.88 – 0.93]) for each 5-mmHg reduction in systolic BP, with no difference between subgroups (p = 0.91) (Figure). Similar patterns were observed for individual components of the composite primary outcome. In patients with AF, there was no evidence that treatment effects varied according to baseline systolic BP or use of specific drug classes. Conclusions: BP-lowering treatment reduces the risk of major cardiovascular events in patients with AF to a similar extent to that of patients without AF, even when baseline BP is below recommended treatment thresholds. Owing to their higher absolute cardiovascular risk, treatment in patients with AF is likely to result in greater absolute risk reduction than in patients without AF. Guidelines should be updated to clearly recommend pharmacological BP lowering for prevention of cardiovascular events in patients with AF.

Epidemiology and associated factors of polypharmacy in older patients in primary care: a northern Italian cross-sectional study

BackgroundA precondition for developing strategies to reduce polypharmacy and its well-known harmful consequences is to study its epidemiology and associated factors. The objective of this study was to analyse the prevalence of polypharmacy (defined as ≥8 prescribed drugs), of potentially inappropriate medications (PIMs) and major drug-drug interactions (DDIs) among community-dwelling general practice patients aged ≥75 years and to identify characteristics being associated with polypharmacy.MethodsThis cross-sectional study is derived from baseline data (patients’ demographic/biometric characteristics, diagnoses, medication-related data, cognitive/affective status, quality of life) of a northern-Italian cluster-RCT. PIMs and DDIs were assessed using the 2012 Beers criteria and the Lexi-Interact® database. Data were analysed using descriptive methods, Wilcoxon rank-sum tests, Fisher’s exact tests and Spearman correlations.ResultsOf the eligible patients aged 75+, 13.4% were on therapy with ≥8 drugs. Forty-three general practitioners and 579 patients participated in the study. Forty five point nine percent of patients were treated with ≥1 Beers-listed drugs. The most frequent PIMs were benzodiazepines/hypnotics (19.7% of patients) and NSAIDs (6.6%). Sixty seven point five percent of patients were exposed to ≥1 major DDI, 35.2% to ≥2 major DDIs. Antithrombotic/anticoagulant medications (30.4%) and antidepressants/antipsychotics (23.1%) were the most frequently interacting drugs. Polypharmacy was significantly associated with a higher number of major DDIs (Spearman’s rho 0.33, p < 0.001) and chronic conditions (Spearman’s rho 0.20, p < 0.001), higher 5-GDS scores (thus, lower affective status) (Spearman’s rho 0.12, p = 0.003) and lower EQ-5D-5L scores (thus, lower quality of life) (Spearman’s rho − 0.14, p = 0.001). Patients’ age/sex, 6-CIT scores (cognitive status), BMI or PIM use were not correlated with the number of drugs.ConclusionsThe prevalence of polypharmacy, PIMs and major DDIs was considerable. Results indicate that physicians should particularly observe their patients with multiple conditions, reduced health and affective status, independently from other patients’ characteristics. Careful attention about indication, benefit and potential risk should be paid especially to patients on therapy with specific drug classes identified as potentially inappropriate or prone to major DDIs in older persons (e.g., benzodiazepines, NSAIDs, protonic pump inhibitors, antithrombotics/anticoagulants, antidepressants/antipsychotics).Trial registrationThe cluster-RCT on which this cross-sectional analysis is based was registered with Current Controlled Trials Ltd. (ID ISRCTN: 38449870) on 2013-09-11.

Hidden Dangers: Recognizing Excipients as Potential Causes of Drug and Vaccine Hypersensitivity Reactions

Excipients are necessary as a support to the active ingredients in drugs, vaccines, and other products, and they contribute to their stability, preservation, pharmacokinetics, bioavailability, appearance, and acceptability. For both drugs and vaccines, these are rare reactions; however, for vaccines, they are the primary cause of immediate hypersensitivity. Suspicion for these "hidden dangers" should be high, in particular, when anaphylaxis has occurred in association with multiple chemically distinct drugs. Common excipients implicated include gelatin, carboxymethylcellulose, polyethylene glycols, and products related to polyethylene glycols in immediate hypersensitivity reactions and propylene glycol in delayed hypersensitivity reactions. Complete evaluation of a suspected excipient reaction requires detailed information from the product monograph and package insert to identify all ingredients that are present and to understand the function and structure for these chemicals. This knowledge helps develop a management plan that may include allergy testing to identify the implicated component and to give patients detailed information for future avoidance of relevant foods, drugs, and vaccines. Excipient reactions should be particularly considered for specific classes of drugs where they have been commonly found to be the culprit (eg, corticosteroids, injectable hormones, immunotherapies, monoclonal antibodies, and vaccines). We provide a review of the evidence-based literature outlining epidemiology and mechanisms of excipient reactions and provide strategies for heightened recognition and allergy testing.

Causality and avoidability of adverse drug reactions of antibiotics in hospitalized children: a cohort study.

Adverse drug reactions are a problem in healthcare systems worldwide. Children are more susceptible than adults, especially when exposed to specific drug classes, such as antibiotics. To assess the incidence, causality, severity, andavoidabilityof antibiotic-associated adverse drug reactions in hospitalized pediatric patients. Pediatric ward of a high-complexity public hospital in northeast Brazil. A prospective cohort study was conducted over six months, including children aged between 28days and 12years, hospitalized for more than 48h, and receiving antibiotics. Liverpool's causality and avoidability assessment tools were used.Primary outcome measures: Incidence of adverse drug reactions, causality, severity, and avoidability,major antibiotics implicated, risk factors. A total of 183 patients were followed, and 35 suspected adverse drug reactions were recorded overall incidence equal to 14.7%. Most adverse drug reactions were classified as moderate severity (76.7%), probable (57.1%) and defined (28.6%) causality, and unavoidable (66.7%). The affected organs were the gastrointestinal system (74.1%) and skin (25.9%). Major antibiotics implicated were ceftriaxone (40.7%), azithromycin (25.9%), and crystalline penicillin (11.1%). The number of antibiotics prescribed per patient during hospitalization and the length of stay were the risk factors identified. Causality and severity assessment indicated that most adverse drug reactions were probable and moderate. Possibly avoidable reactions occurred due to inappropriate prescribing when preventive measures were not implemented. Monitoring the use of antibiotics in children is essential to ensure the safety of these patients.

Abstract GS1-07: Treatment persistence of residual breast tumors through an embryonic diapause-like cancer cell state with suppressed myc activity

Abstract Systemic breast cancer treatments often fail to achieve complete and sustained responses due to drug-persistent residual tumor foci, the “seed” for eventual relapse. Recent clinical studies have revealed that the chemo-persistent tumor cells undergo extensive transcriptional reprogramming in response to neo-adjuvant treatment; however, the impact of this acquired molecular signature on the ability of residual cancer cells to survive during therapy is not clear. To further study the molecular hallmarks of chemo-persistent cancer cells, we analyzed the transcriptional signatures of post-treatment residual tumors in a large number of breast cancer patients from several neoadjuvant clinical studies. We observed that the treatment-persistent tumor cells had a distinct cellular state which molecularly resembles that of the embryonic diapause, a dormant stage of transiently suspended development in undifferentiated epiblasts triggered by stress and induced by suppression of Myc activity and overall biosynthesis. Remarkably, the propensity for residual tumors with an embryonic diapause-like (EDL) molecular signature was significantly associated with worse outcome in breast cancer patients. To dissect this distinct cancer cell state, we developed novel in vitro models using 3D breast cancer organoids which responded to cytotoxic treatment by generating longitudinally-persistent residual organoid fractions that phenotypically and molecularly simulated the in vivo emergence of post-treatment residual tumors in preclinical and clinical settings. The treatment-persistent tumor fractions in cancer organoids and in the respective in vivo xenografts did not exhibit significant genetic changes compared to baseline tumor cells, but had reduced apoptotic priming and an EDL transcriptional reprograming similar to that of residual tumors in patients. Similarly to embryonic diapause, residual persistent fractions in cancer organoids, xenografts and patient tumors had markedly suppressed Myc transcriptional output and biosynthetic levels. Ectopic induction of MYC expression enhanced acute chemotherapeutic cytotoxicity in breast cancer organoids. Conversely, suppression of MYC or pharmacological inhibition of Myc transcriptional co-activators, BET bromodomains, abrogated chemotherapeutic cytotoxicity and induced in breast cancer cells an EDL molecular signature characterized by below-baseline redox stress levels which were maintained during drug exposure. High-throughput interrogation of residual persistent breast cancer organoids indicated broad refractoriness to specific anticancer drug classes thought to operate through induction of cellular stress (e.g. agents targeting DNA or DNA-repair). However, maintaining the residual cells in dormancy after completion of cytotoxic chemotherapy via inhibition of Brd4/Myc axis or pharmacologically interfering with the diapause-like transcriptional reprogramming of treatment-persistent cancer cells represent potential therapeutic strategies to target chemo-persistent tumor cells. Overall, our study shows that breast tumors dynamically co-opt the stress survival mechanism of embryonic diapause to persist during treatment, and reveals an unexpected role of Myc as regulator of cancer cell entry into transient drug-refractory dormancy. The diapause-like persister organoid cancer models provide ex vivo tractability for studying the otherwise elusive, dormant, drug-refractory residual tumors, with potential implications in personalized medicine and drug discovery. Citation Format: Eugen Dhimolea, Ricardo De Matos Simoes, Dhvanir Kansara, Juliette Bouyssou, Jennifer Roth, Michal Sheffer, Rinath Jeselsohn, Nathanael Gray, Ulrich Steidl, Boris Bartholdy, Myles Brown, Aedin Culhane, Constantine Mitsiades. Treatment persistence of residual breast tumors through an embryonic diapause-like cancer cell state with suppressed myc activity [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-07.

Towards a Precision Medicine Approach Based on Machine Learning for Tailoring Medical Treatment in Alkaptonuria.

ApreciseKUre is a multi-purpose digital platform facilitating data collection, integration and analysis for patients affected by Alkaptonuria (AKU), an ultra-rare autosomal recessive genetic disease. It includes genetic, biochemical, histopathological, clinical, therapeutic resources and quality of life scores that can be shared among registered researchers and clinicians in order to create a Precision Medicine Ecosystem (PME). The combination of machine learning application to analyse and re-interpret data available in the ApreciseKUre shows the potential direct benefits to achieve patient stratification and the consequent tailoring of care and treatments to a specific subgroup of patients. In this study, we have developed a tool able to investigate the most suitable treatment for AKU patients in accordance with their Quality of Life scores, which indicates changes in health status before/after the assumption of a specific class of drugs. This fact highlights the necessity of development of patient databases for rare diseases, like ApreciseKUre. We believe this is not limited to the study of AKU, but it represents a proof of principle study that could be applied to other rare diseases, allowing data management, analysis, and interpretation.

Elevated Blood Pressure, Antihypertensive Medications and Bone Health in the Population: Revisiting Old Hypotheses and Exploring Future Research Directions

Blood pressure and bone metabolism appear to share commonalities in their physiologic regulation. Specific antihypertensive drug classes may also influence bone mineral density. However, current evidence from existing observational studies and randomized trials is insufficient to definitely suggest likely causal associations between blood pressure levels and use of blood-pressure lowering drugs on bone health outcomes, particularly on the risks of osteoporosis and fractures. Nevertheless, the availability and access to relevant large-scale biomedical data sources as well as developments in study designs and analytical approaches are providing opportunities to examine the nature of the association between blood pressure and bone health more reliably and in greater detail than has ever been possible. It is unlikely that a single source of data or study design can provide a definitive answer. However, with appropriate considerations of the strengths and limitations of the different data sources and analytical approaches, we should be able to advance our understanding of the role of raised blood pressure and its drug treatment on bone health outcomes. As elevated blood pressure and use of blood pressure-lowering drugs are highly prevalent, even small effects of these exposures on bone health outcomes could be important at a population level.

1675. Epidemiology of Urinary Tract Infections in the United States, 2009 - 2018

BackgroundUrinary tract infections (UTIs) are one of the most common bacterial infections. There is a lack of large epidemiologic studies evaluating the etiologies of UTIs in the United States. This study aimed to determine the prevalence of different UTI-causing organisms and their antimicrobial susceptibility profiles among patients being treated in a hospital setting.MethodsWe used the Premier Healthcare Database. Patients with a primary diagnosis code of cystitis, pyelonephritis, or urinary tract infection and had a urine culture from 2009- 2018 were included in the study. Both inpatients and patients who were only treated in the emergency department (ED) were included. We calculated descriptive statistics for uropathogens and their susceptibilities. Multi-drug-resistant pathogens are defined as pathogens resistant to 3 or more antibiotics. Resistance patterns are also described for specific drug classes, like resistance to fluoroquinolones. We also evaluated antibiotic use in this patient population and how antibiotic use varied during the hospitalization.ResultsThere were 640,285 individuals who met the inclusion criteria. Females make up 82% of the study population and 45% were age 65 or older. The most common uropathogen was Escherichia Coli (64.9%) followed by Klebsiella pneumoniae (8.3%), and Proteus mirabilis (5.7%). 22.2% of patients were infected with a multi-drug-resistant pathogen. We found that E. Coli was multi-drug resistant 23.8% of the time; Klebsiella pneumoniae was multi-drug resistant 7.4%; and Proteus mirabilis was multi-drug resistant 2.8%. The most common antibiotics prescribed were ceftriaxone, levofloxacin, and ciprofloxacin. Among patients that were prescribed ceftriaxone, 31.7% of them switched to a different antibiotic during their hospitalization. Patients that were prescribed levofloxacin and ciprofloxacin switched to a different antibiotic 42.8% and 41.5% of the time, respectively.Conclusion E. Coli showed significant multidrug resistance in this population of UTI patients that were hospitalized or treated within the ED, and antibiotic switching is common.Disclosures All Authors: No reported disclosures

The renin-angiotensin system in PTSD: a replication and extension.

Prior observational studies have suggested that medications targeting the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), may be associated with decreased PTSD symptoms. Given known sex differences in PTSD prevalence and cardiovascular disease, here we tested whether the effects of ACE-I/ARB status on PTSD differ by sex. We also expanded these observations with replication analyses in a large biorepository database. Participants in the initial sample included 840 trauma-exposed individuals recruited as part of the Grady Trauma Project. The Modified PTSD Symptom Scale (M-PSS) was administered and ACE-I/ARB status was determined by self-report. Replication analyses were conducted using a large biorepository database (Partners Healthcare Biobank, N = 116,389) with diagnoses and medication status based on available electronic health records. Among individuals treated with ACE-Is/ARBs in the initial sample, women had significantly higher M-PSS total and Re-experiencing severity compared to men (p's < 0.05). Analyses with the large biorepository sample robustly replicated the overall effects of ACE-I/ARB medication associated with lower rate of PTSD diagnosis (p < 0.001). We also demonstrated that this effect may be specific to the renin-angiotensin system as it did not replicate for beta-blockers, calcium channel blockers, or diuretics. When we examined more specific drug classes, results indicated that the ACE-I/ARB effect on PTSD may be driven more by ARBs (e.g., Losartan) than by ACE-Is. Post-hoc analyses indicated that racial differences may exist in these effects. Overall, our results replicate and extend prior observations that the renin-angiotensin system is associated with PTSD. Medications targeting this system may be worthy of further investigation for PTSD treatment. Our findings suggest that sex and race effects should be considered in future treatment research.