Characterizing and Comparing Adverse Drug Events Documented in 2 Spontaneous Reporting Systems in the Lower Mainland of British Columbia, Canada: Retrospective Observational Study

BackgroundRobust adverse drug event (ADE) reporting systems are crucial to monitor and identify drug safety signals, but the quantity and type of ADEs captured may vary by system characteristics. ObjectiveWe compared ADEs reported in 2 different reporting systems in the same jurisdictions, the Patient Safety and Learning System–Adverse Drug Reaction (PSLS-ADR) and ActionADE, to understand report variation. MethodsThis retrospective observational study analyzed reports entered into PSLS-ADR and ActionADE systems between December 1, 2019, and December 31, 2022. We conducted a comprehensive analysis including all events from both reporting systems to examine coverage and usage and understand the types of events captured in both systems. We calculated descriptive statistics for reporting facility type, patient demographics, serious events, and most reported drugs. We conducted a subanalysis focused on adverse drug reactions to enable direct comparisons between systems in terms of the volume and events reported. We stratified results by reporting system. ResultsWe performed the comprehensive analysis on 3248 ADE reports, of which 12.4% (375/3035) were reported in PSLS-ADR and 87.6% (2660/3035) were reported in ActionADE. Distribution of all events and serious events varied slightly between the 2 systems. Iohexol, gadobutrol, and empagliflozin were the most common culprit drugs (173/375, 46.2%) in PSLS-ADR, while hydrochlorothiazide, apixaban, and ramipril (308/2660, 11.6%) were common in ActionADE. We included 2728 reports in the subanalysis of adverse drug reactions, of which 12.9% (353/2728) were reported in PSLS-ADR and 86.4% (2357/2728) were reported in ActionADE. ActionADE captured 4- to 6-fold more comparable events than PSLS-ADR over this study’s period. ConclusionsUser-friendly and robust reporting systems are vital for pharmacovigilance and patient safety. This study highlights substantial differences in ADE data that were generated by different reporting systems. Understanding system factors that lead to varying reporting patterns can enhance ADE monitoring and should be taken into account when evaluating drug safety signals

Using ActionADE to create information continuity to reduce re-exposures to harmful medications: study protocol for a randomized controlled trial

Background: Repeat exposures to culprit medications are a common cause of preventable adverse drug events. Health information technologies have the potential to reduce repeat adverse drug events by improving information continuity. However, they rarely interoperate to ensure providers can view adverse drug events documented in other systems. We designed ActionADE to enable rapid documentation of adverse drug events and communication of standardized information across health sectors by integrating with legacy systems. We will leverage ActionADE’s implementation to conduct two parallel, randomized trials: patients with adverse drug reactions in the main trial and those diagnosed with non-adherence in a secondary trial. Primary objective of the main trial is to evaluate the effects of providing information continuity about adverse drug reactions on culprit medication re-dispensations over 12 months. Primary objective of the secondary trial is to evaluate the effect of providing information continuity on adherence over 12 months. Methods: We will conduct two parallel group, triple-blind randomized controlled trials in participating hospitals in British Columbia, Canada. We will enroll adults presenting to hospital with an adverse drug event to prescribed outpatient medication. Clinicians will document the adverse drug event in ActionADE. The software will use an algorithm to determine patient eligibility and allocate eligible patients to experimental or control. In the experimental arm, ActionADE will transmit information to PharmaNet, where adverse drug event information will be displayed in community pharmacies when re-dispensations are attempted. In the control arm, ActionADE will retain information in the local record. We will enroll 3600 adults with an adverse drug reaction into the main trial. The main trial’s primary outcome is re-dispensation of a culprit or same-class medication within 12 months; the secondary trial’s primary outcome will be adherence to culprit medication. Secondary outcomes include health services utilization and mortality. Discussion: These studies have the potential to guide policy decisions and investments needed to drive health information technology integrations to prevent repeat adverse drug events. We present an example of how a health information technology implementation can be leveraged to conduct pragmatic randomized controlled trials. Trial registration ClinicalTrials.gov NCT04568668 , NCT04574648 . Registered on 1 October 2020.Medicine, Faculty ofOther UBCNon UBCEmergency Medicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacult

Risk factors for addiction among patients receiving prescribed opioids: a systematic review protocol

Background: Opioid addiction prevention has become an urgent public health priority, with several countries declaring a state of emergency due to rising death tolls from opioid abuse. Reducing the risk of developing addiction among opioid-naïve patients exposed to prescribed opioids during the process of medical care may be an important primary prevention strategy. Our objective is to synthesize the available evidence about factors associated with the development of addiction among patients first exposed to prescribed opioids, with a focus on opioid-naïve patients. Methods: We will perform a systematic search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and other databases in collaboration with a health information specialist using a comprehensive search strategy. We will also supplement our search with a scan of the grey literature to identify relevant ongoing and unpublished studies. We will include studies reporting on risk factors for opioid addiction in patients prescribed opioid analgesic therapy through a prescription from a licensed medical professional, with a focus on opioid-naïve patients. We will exclude studies focusing on patients who are first exposed to illicit opioids, those who use prescription opioids for cancer pain, and/or who are palliative. Two reviewers will independently review titles, abstracts, and full texts for inclusion and exclusion criteria. They will then extract data from included full texts using standardized piloted data extraction forms and assess study quality through risk of bias assessment. We will synthesize the effect sizes of risk factors derived from clinically homogenous studies with similar designs and the remaining ones qualitatively. Discussion: Understanding risk factors for opioid addiction among patients who require analgesia has the potential to inform clinical care and opioid prescribing guidelines aiming to reduce opioid addiction. We will also use this information as a starting point for developing interventions for primary prevention.Medicine, Faculty ofOther UBCNon UBCEmergency Medicine, Department ofMedicine, Department ofReviewedFacult

Selinexor enhances NK cell activation against malignant B cells via downregulation of HLA-E

Selinexor is an FDA approved selective inhibitor of the nuclear export protein exportin-1 (XPO1) and causes specific cancer cell death via nuclear accumulation of tumor suppressor proteins. Design of rational studies for the use of selinexor in combination with other therapeutic agents, such as immunotherapies, requires a fundamental understanding of the effects of selinexor on the immune system. One important emerging area of immunotherapy are natural killer (NK) cell based therapeutics. NK cell function is tightly regulated by a balance of signals derived from multiple activating and inhibitory receptors. Thus in cancer, up-regulation of stress ligands recognised by activating receptors or down-regulation of HLA class I recognised by inhibitory receptors can result in an anti-cancer NK cell response. Changes in XPO1 function therefore have the potential to affect NK cell function through shifting this balance. We therefore sought to investigate how selinexor may affect NK cell function. Selinexor pre-treatment of lymphoma cells significantly increased NK cell mediated cytotoxicity against SU-DHL-4, JeKo-1 and Ramos cells, concurrent with increased CD107a and IFNγ expression on NK cells. In addition, selinexor enhanced ADCC against lymphoma cells coated with the anti-CD20 antibodies rituximab and obinutuzumab. In probing the likely mechanism, we identified that XPO1 inhibition significantly reduced the surface expression of HLA-E on lymphoma cell lines and on primary chronic lymphocytic leukemia cells. HLA-E binds the inhibitory receptor NKG2A and in accordance with this, selinexor selectively increased activation of NKG2A+ NK cells. Our data reveals that selinexor, in addition to its direct cytotoxic activity, also activates an anti-cancer immune response via disruption of the inhibitory NKG2A:HLA-E axis

Methods for evaluating adverse drug event preventability in emergency department patients

Background: There is a high degree of variability in assessing the preventability of adverse drug events, limiting the ability to compare rates of preventable adverse drug events across different studies. We compared three methods for determining preventability of adverse drug events in emergency department patients and explored their strengths and weaknesses. Methods: This mixed-methods study enrolled emergency department patients diagnosed with at least one adverse drug event from three prior prospective studies. A clinical pharmacist and physician reviewed the medical and research records of all patients, and independently rated each event’s preventability using a “best practice-based” approach, an “error-based” approach, and an “algorithm-based” approach. Raters discussed discordant ratings until reaching consensus. We assessed the inter-rater agreement between clinicians using the same assessment method, and between different assessment methods using Cohen’s kappa with 95% confidence intervals (95% CI). Qualitative researchers observed discussions, took field notes, and reviewed free text comments made by clinicians in a “comment” box in the data collection form. We developed a coding structure and iteratively analyzed qualitative data for emerging themes regarding the application of each preventability assessment method using NVivo. Results: Among 1356 adverse drug events, a best practice-based approach rated 64.1% (95% CI: 61.5–66.6%) of events as preventable, an error-based approach rated 64.3% (95% CI: 61.8–66.9%) of events as preventable, and an algorithm-based approach rated 68.8% (95% CI: 66.1–71.1%) of events as preventable. When applying the same method, the inter-rater agreement between clinicians was 0.53 (95% CI: 0.48–0.59), 0.55 (95%CI: 0.50–0.60) and 0.55 (95% CI: 0.49–0.55) for the best practice-, error-, and algorithm-based approaches, respectively. The inter-rater agreement between different assessment methods using consensus ratings for each ranged between 0.88 (95% CI 0.85–0.91) and 0.99 (95% CI 0.98–1.00). Compared to a best practice-based assessment, clinicians believed the algorithm-based assessment was too rigid. It did not account for the complexities of and variations in clinical practice, and frequently was too definitive when assigning preventability ratings. Conclusion: There was good agreement between all three methods of determining the preventability of adverse drug events. However, clinicians found the algorithmic approach constraining, and preferred a best practice-based assessment method.Medicine, Faculty ofNon UBCEmergency Medicine, Department ofPopulation and Public Health (SPPH), School ofOther UBCReviewedFacult

KIR2DS2 expression identifies NK cells with enhanced anticancer activity

NK cells are promising cellular therapeutics against hematological and solid malignancies. Immunogenetic studies have identified that various activating killer cell Ig-like receptors (KIRs) are associated with cancer outcomes. Specifically, KIR2DS2 has been associated with reduced incidence of relapse following transplant in hematological malignancies and improved outcomes in solid tumors, but the mechanism remains obscure. Therefore, we investigated how KIR2DS2 expression impacts NK cell function. Using a novel flow cytometry panel, we show that human NK cells with high KIR2DS2 expression have enhanced spontaneous activation against malignant B cell lines, liver cancer cell lines, and primary chronic lymphocytic leukemia cells. Surface expression of CD16 was increased on KIR2DS2high NK cells, and, accordingly, KIR2DS2high NK cells had increased activation against lymphoma cells coated with the clinically relevant anti-CD20 Abs rituximab and obinutuzumab. Bulk RNA sequencing revealed that KIR2DS2high NK cells have upregulation of NK-mediated cytotoxicity, translation, and FCGR gene pathways. We developed a novel single-cell RNA-sequencing technique to identify KIR2DS2+ NK cells, and this confirmed that KIR2DS2 is associated with enhanced NK cell–mediated cytotoxicity. This study provides evidence that KIR2DS2 marks a population of NK cells primed for anticancer activity and indicates that KIR2DS2 is an attractive target for NK-based therapeutic strategies

XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression

The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL

Predefined drop-down menu of COVID-19 related diagnoses allocated to the hospitalized primarily for COVID-19 category.

Predefined drop-down menu of COVID-19 related diagnoses allocated to the hospitalized primarily for COVID-19 category.</p

Factors associated with ventilation, critical care admission or mortality among 1,651 SARS-CoV-2 positive patients, according to the CDC admission classification.

OR = odds ratio; ICU = intensive care unit; CI = confidence interval. a active malignant neoplasm, transplant recipient, moderate/severe liver disease. Hospital site was included as a fixed effect in this model. For simplicity, site estimates were excluded from the table. (DOCX)</p