Impact of medication characteristics and adverse drug events on hospital admission after an emergency department visit: Prospective cohort study.

OBJECTIVES: Emergency department (ED) overcrowding is a problem for the delivery of adequate and timely emergency care. To improve patient flow and the admission process, the quick prediction of a patient's need for admission is crucial. We aimed to investigate the variables associated with hospitalisation after an ED visit, with a particular focus on the variables related to medication. METHODS: This prospective study was conducted from 2011 to 2018 in subacute medical ED of a French University Hospital. Specialised EDs (paediatric, gynaecologic, head and neck and psychiatric) and the outpatient unit of the ED were not included. Participation in this study was proposed to all adult patients who underwent a medication history interview with a pharmacist. Pharmacists conducted structured interviews for the completion of the medication history and the detection of adverse drug events (ADE). Relations between patient characteristics and hospitalisation were analysed using logistic regression. RESULTS: Among the 14 511 included patients, 5972 (41.2%) were hospitalised including 69 deaths. In total, 7458 patients (51.4%) took more than 5 medications and 2846 patients (19.6%) had an ADE detected during the ED visit. In hospitalised patients, bleeding (32.2%) and metabolic disorders (16.8%) were the most observed ADE symptoms. Variables associated with increased hospital admission included 2 demographic variables (age, male gender), 4 clinical variables (renal and hepatic failures, alcohol addiction, ED visit for respiratory reason) and 6 medication-related variables (medications >5, use of blood, systemic anti-infective, metabolism and antineoplastic/immunomodulating medications and ADE). CONCLUSION: We identified variables associated with hospitalisation including drug-related variables. These results point out the importance and the relevance of collecting medication data in a subacute medical ED (study registered on ClinicalTrials.gov, NCT03442010).

Medication Errors at Hospital Admission and Discharge: Risk Factors and Impact of Medication Reconciliation Process to Improve Healthcare.

OBJECTIVE: First, the aim of the study was to assess the prevalence, characteristics, and severity of unintended medication discrepancies (UMDs) and medication errors (MEs) at admission and discharge of hospitalization. Second, the aim of the study was to identify clinical and hospitalization factors associated with risk of UMDs as well as characteristics of the medication reconciliation process associated with UMDs detection. METHODS: This prospective observational study included all adult patients admitted from 2013 to 2015 in the Endocrinology-Diabetology-Nutrition Department of Montpellier Hospital, France. Clinical pharmacists conducted medication reconciliation by collecting the best possible medication history from different sources and comparing it with admission and discharge prescriptions to identify discrepancies. Unintended medication discrepancies corrected by the physician were considered as MEs. Risk factors of UMDs were identified with logistic regression. RESULTS: Of 904 patients included, 266 (29.4%) had at least one UMD, at admission or at discharge. In total, 378 (98.2%) of 385 UMDs were considered to be MEs. Most MEs were omissions (59.3%). Medication errors were serious or very serious in 36% of patients and had potentially moderate severity in almost 40% of patients. The risk of UMDs increased constantly with the number of treatments (P < 0.001). Thyroid (adjusted odds ratio [OR] = 1.79, 95% CI = 1.12-2.86) and infectious diseases (adjusted OR = 1.80, 95% CI = 1.17-2.78) were associated with UMDs risk at admission. The best type of source for the detection of UMDs was the general practitioner or nurse (OR = 2.64, 95% CI = 1.51-4.63). CONCLUSIONS: Unintended medication discrepancies are frequent at hospital and depend on intrinsic clinical parameters but also on practice of medication reconciliation process, such as number and type of sources used.

Clinical, Economic, and Organizational Impact of the Clinical Pharmacist in an Orthopedic and Trauma Surgery Department.

AIM: The aim of this study was to evaluate the clinical, economic, and organizational impact of clinical pharmacist services added to an adult orthopedic and trauma surgery unit in a university hospital. METHODS: This was a prospective, observational study performed from January to February 2017. All pharmacists' interventions were documented, and their clinical, economic, and organizational impact and the probability of adverse drug events (ADEs) were assessed using the clinical, economic and organizational scale three-dimensional scale. An expert panel composed of three clinical pharmacists, one surgeon and one anesthetist classified the pharmacist intervention. The potential clinical impact was determined through a consensus by the expert panel. Cost avoidance was calculated for serious ADEs with a major impact by avoiding an additional cost of €4912 per event and taking into account the probability of ADE occurrence. RESULTS: The pharmacists performed 1014 interventions for 28 days with a 95.3% acceptance rate by prescribers. Thirty-nine interventions were rated to have a major clinical impact (3.8%). The organizational impact was estimated favorable for 856 (84.4%) pharmacist interventions. Cost avoidance was estimated at €24,364, and the indirect costs benefit was estimated at €11,864 during the study. The cost-benefit ratio of the clinical pharmacist intervention was €1.94 in savings for every €1 invested. CONCLUSIONS: Clinical pharmacist services in an orthopedic and trauma surgery department have the potential to improve patient outcomes and avoid healthcare costs. Furthermore, the presence of a pharmacist in surgical units allows for communication between the unit and the pharmacy, which produces better fluidity and improves the quality of care.

Adverse Drug Events Detected by Clinical Pharmacists in an Emergency Department: A Prospective Monocentric Observational Study.

OBJECTIVES: Adverse drug events (ADEs) are a major public health issue in hospitals. They are difficult to detect because of incomplete or unavailable medication history. In this study, we aimed to assess the rate and characteristics of ADEs identified by pharmacists in an emergency department (ED) to identify factors associated with ADEs. METHODS: In this prospective observational study, we included consecutive adult patients presenting to the ED of a French 2600-bed tertiary care university hospital from November 2011 to April 2015. Clinical pharmacists conducted structured interviews and collected the medication history to detect ADEs (i.e., injuries resulting directly or indirectly from adverse drug reactions and noncompliance to medication prescriptions). Unsure ADE cases were reviewed by an expert committee. Relations between patient characteristics, type of ED visit, and ADE risk were analyzed using logistic regression. RESULTS: Among the 8275 included patients, 1299 (15.7%) presented to the ED with an ADE. The major ADE symptoms were bleeding, endocrine problems, and neurologic disorders. Moreover, ADEs led to the ED visit, hospitalization, and death in 87%, 49.3%, and 2.2% of cases, respectively. Adverse drug event risk was independently associated with male sex, ED visit for neurological symptoms, visit to the ED critical care unit, or ED short stay hospitalization unit, use of blood, anti-infective, antineoplastic, and immunomodulating drugs. CONCLUSIONS: This study improves the knowledge about ADE characteristics and on the patients at risk of ADE. This could help ED teams to better identify and manage ADEs and to improve treatment quality and safety.

STADE-HF (sST2 As a help for management of HF): a pilot study.

AIMS: Biomarkers are not recommended until now to guide the management of patients with heart failure (HF). Soluble suppression of tumorigenicity 2 (sST2) appears as a promising biomarker. The current study considered pre-discharged sST2 values as a guide for medical management in patients admitted for acute HF decompensation, in an attempt to reduce hospital readmission. METHODS AND RESULTS: STADE-HF was a blinded prospective randomized controlled trial and included 123 patients admitted for acute HF. They were randomized into the usual treatment group (unknown sST2 level) or the interventional treatment group, for whom sST2 level was known and used on Day 4 of hospitalization to guide the treatment. The primary endpoint was the readmission rate for any cause at 1 month. It occurred in 10 patients (19%) in the usual group and 18 (32%) in the sST2 group without statistical difference (P = 0.11). Post hoc analysis in the whole group shows that the mean duration of hospitalization was lower in patients with low sST2 (<37 ng/mL) at admission vs. high sST2 (8.5 ± 9.5 vs. 14.8 ± 14.9 days, respectively, P = 0.003). In addition, a decrease in sST2 greater than 18% is significantly associated with a lower readmission rate. CONCLUSIONS: Soluble suppression of tumorigenicity 2-guided therapy over a short period of time does not reduce readmissions. However, sST2 was clearly associated with duration of hospitalization, and the decrease in sST2 was associated with decreased rehospitalizations. Long-term outcome using sST2-guided therapy deserves further investigations.

Decreased RNF41 expression leads to insulin resistance in skeletal muscle of obese women.

CONTEXT: Toll-like receptor 4 (TLR4) activation contributes to obesity-associated insulin resistance in skeletal muscles (SM). TLR4 signaling involves two pathways: the myeloid differentiation primary response gene 88 (MyD88) leading to inflammatory cytokines production and the toll/interleukin-1 receptor domain-containing adapter-inducing interferon (IFN) I (TRIF)-dependent pathways leading to type 1 interferon (IFNI) and interferon stimulated genes (ISG) expression. The E3 ubiquitin ligase RNF41 allows the preferential activation of the TRIF-IFNI pathway; however, its role in insulin response has not been reported. METHODS: We measured RNF41 level and IFNI pathway activation (ISG expression) in SM biopsies of obese insulin sensitive (OIS) and obese insulin resistant (OIR) women. Then we isolated and differentiated in myotubes, primary human SM cell progenitors from OIS and OIR SM biopsies. We modulated RNF41 and ISG expression in these myotubes and investigated their effects on insulin response. RESULTS: RNF41 expression is down-regulated in vivo in OIR SM and myotubes compared to OIS SM and myotubes. TLR4 activation with palmitate induces TRIF-IFNI pathway and ISG in OIS myotubes but not in OIR myotubes. Inhibition of RNF41 expression with siRNF41 in OIS myotubes treated with palmitate attenuates insulin response, IFNI pathway activation and ISG induction, mimicking OIR phenotype. Further, overexpression of RNF41 in OIR myotubes increases insulin response and ISG expression. Exposure to IFNI or to its inducer polyinosinic-polycytidylic acid, restores ISG expression and insulin sensitivity in OIR myotubes and OIS myotubes transfected with siRNF41. CONCLUSION: Our results identify RNF41 as essential to IFNI pathway activation in order to maintain muscle insulin sensitivity during human obesity.

Patients with diabetes are at high risk of serious medication errors at hospital: Interest of clinical pharmacist intervention to improve healthcare.

BACKGROUND: Medication errors (ME) are major public health issues in hospitals because of their consequences on patients' morbi-mortality. This study aims to evaluate the prevalence of ME at admission and discharge of hospitalization in diabetic and non-diabetic patients, and determine their potential clinical impact. METHOD: This prospective observational study was conducted at the Endocrinology-Diabetology-Nutrition Department. All adult patients admitted were eligible. A total of 904 patients were included, of which 671 (74.2%) with diabetes mellitus. Clinical pharmacists conducted medication reconciliation: they collected the Best Possible Medication History and then compared it with admission and discharge prescriptions to identify medication discrepancies. ME were defined as unintended medication discrepancies if corrected by the physician. RESULTS: Clinical pharmacists allowed correcting ME in 176/904 (19.5%) patients at admission and in 86/865 (9.9%) patients at discharge. More than half of ME were omissions. Diabetic patients were more affected by ME than non-diabetic patients, both at admission (22.1% vs 12.0%, p<0.001) and at discharge (11.4% vs 5.7%, p=0.01). The diabetic group also had more potentially severe and very severe ME. Diabetic patients had on average twice more medications than non-diabetic patients (8.7±4.5 vs 4.4±3.4, p<0.001). The polypharmacy associated with diabetes, but not diabetes mellitus itself, was identified as a risk factor of ME. CONCLUSIONS: The intervention of clinical pharmacists allowed correcting 378 ME in 25.8% of the cohort before they caused harm. Clinicians, pharmacists and other health care providers should therefore work together to improve patients' safety, in particular in high-risk patients such as diabetic patients.

Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women.

CONTEXT: Obesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity. OBJECTIVES: We compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development. METHODS: 30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression. RESULTS: Systemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR. CONCLUSION: Our results show that systemic IR occurs without any change in systemic and tissues inflammation. We identified a muscle defect in insulin response as an early mechanism of IR development in grade I obese post-menopausal women.

Characterization of a novel PXR isoform with potential dominant-negative properties.

BACKGROUND & AIMS: The nuclear Pregnane X Receptor (PXR, NR1I2) plays a pivotal role in xenobiotic metabolism. Here, we sought to characterize a new PXR isoform (hereafter called small PXR or sPXR) stemming from alternative transcription starting sites downstream of a CpG Island located near exon 3 of the human PXR gene. METHODS: Quantitative RT-PCR, western blot, methylation-specific PCR, luciferase reporter assays, electro-mobility shift assays, and stable sPXR overexpression were used to examine sPXR expression and function in hepatocellular cell lines, healthy human liver (n=99), hepatocellular adenomas (HCA, n=91) and hepatocellular carcinoma samples (HCC, n=213). RESULTS: Liver sPXR mRNA expression varied importantly among individuals and encodes a 37kDa nuclear protein consisting of the ligand-binding domain of PXR that behaves as a dominant-negative of PXR transactivation properties. In vitro methylation of the sPXR upstream promoter abolished its activity, while the demethylation agent 5-aza-2-deoxycytidine increased sPXR mRNA expression in several cell lines. Finally, we observed that sPXR mRNA expression displayed significant differences related to HCA or HCC biology. CONCLUSIONS: This novel PXR isoform, displaying a dominant-negative activity and regulated by DNA methylation, is associated with outcomes of patients with HCC treated by resection, suggesting that it represents a key modulator of PXR.

Pregnane X Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation.

BACKGROUND: Clinical efficacy of chemotherapy in colorectal cancer is subjected to broad inter-individual variations leading to the inability to predict outcome and toxicity. The topoisomerase I inhibitor irinotecan (CPT-11) is worldwide approved for the treatment of metastatic colorectal cancer and undergoes extensive peripheral and tumoral metabolism. PXR is a xenoreceptor activated by many drugs and environmental compounds regulating the expression of drug metabolism and transport genes in detoxification organs such as liver and gastrointestinal tract. Considering the metabolic pathway of irinotecan and the tissue distribution of Pregnane x Receptor (PXR), we hypothesized that PXR could play a key role in colon cancer cell response to irinotecan. RESULTS: PXR mRNA expression was quantified by RT-quantitative PCR in a panel of 14 colon tumor samples and their matched normal tissues. PXR expression was modulated in human colorectal cancer cells LS174T, SW480 and SW620 by transfection and siRNA strategies. Cellular response to irinotecan and its active metabolic SN38 was assessed by cell viability assays, HPLC metabolic profiles and mRNA quantification of PXR target genes. We showed that PXR was strongly expressed in colon tumor samples and displayed a great variability of expression. Expression of hPXR in human colorectal cancer cells led to a marked chemoresistance to the active metabolite SN38 correlated with PXR expression level. Metabolic profiles of SN38 showed a strong enhancement of SN38 glucuronidation to the inactive SN38G metabolite in PXR-expressing cells, correlated with an increase of UDPglucuronosyl transferases UGT1A1, UGT1A9 and UGT1A10 mRNAs. Inhibition of PXR expression by lentivirus-mediated shRNA, led to SN38 chemoresistance reversion concomitantly to a decrease of UGT1A1 expression and SN38 glucuronidation. Similarly, PXR mRNA expression levels correlated to UGT1A subfamily expression in human colon tumor biopsies. CONCLUSION: Our results demonstrate that tumoral metabolism of SN38 is affected by PXR and point to potential therapeutic significance of PXR quantification in the prediction of irinotecan response. Furthermore, our observations are pharmacologically relevant since many patients suffering from cancer diseases are often exposed to co-medications, food additives or herbal supplements able to activate PXR. A substantial part of the variability observed among patients might be caused by such interactions.