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Background: Liver injury from drug-drug interactions (DDIs), notably with anti-tuberculosis drugs such as isoniazid, poses a significant safety concern. Electronic medical records contain comprehensive clinical information and have gained increasing attention as a potential resource for DDI detection. However, a substantial portion of adverse drug reaction (ADR) information is hidden in unstructured narrative text, which has yet to be efficiently harnessed, thereby introducing bias into the research. There is a significant need for an efficient framework for the DDI assessment., Methods: Using a Chinese natural language processing (NLP) model, we extracted 25,130 adverse drug reaction (ADR) records, dividing them into sets for training an automated normalization model. The trained models, in conjunction with liver function laboratory tests, were used to thoroughly and efficiently identify liver injury cases. Ultimately, we applied a case-control study design to detect DDI signals increasing isoniazid's liver injury risk., Results: The Logistic Regression model demonstrated stable and superior performance in classification task. Based on laboratory criteria and NLP, we identified 128 liver injury cases among a cohort of 3,209 patients treated with isoniazid. Preliminary screening of 113 drug combinations with isoniazid highlighted 20 potential signal drugs, with antibacterials constituting 25%. Sensitivity analysis confirmed the robustness of signal drugs, especially in cardiac therapy and antibacterials., Conclusion: Our NLP and machine learning approach effectively identifies isoniazid-related DDIs that increase the risk of liver injury, identifying 20 signal drugs, mainly antibacterials. Further research is required to validate these DDI signals., Competing Interests: Declarations. Ethics approval and consent to participate: This retrospective study was conducted under the Declaration of Helsinki. Ethical approval was not required for this study as it was conducted using anonymized electronic medical records. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Adverse drug reactions are more prevalent in geriatric patients and are frequently associated with a range of polypharmacy-related issues as well as some physiological aging-related alterations. These affect the pharmacokinetic and pharmacodynamic properties of drugs. This study aimed to assess the magnitude of ADRs and their contributing factors among geriatric patients admitted at Comprehensive Specialized Hospitals of the Amhara Region., Methods: A multicenter prospective cohort study was carried out from May 2023 to August 2023 on geriatric patients admitted to four randomly selected comprehensive hospitals in the Amhara region. We used logistic regression to find the factors influencing the occurrence of ADRs. A P value of less than 0.05 was deemed statistically significant., Results: During the study's follow-up period, 373 patients in total were included. An incidence rate of 31.10% (95% CI: 26.38-35.82) was obtained from the identification of 121 ADRs in total. The organ most frequently affected by ADRs was the gastrointestinal tract (28.92%), followed by the cardiovascular system (19.01%), and the drug class most often implicated in ADRs was antibiotics (21.49%), then anticoagulants (12.40%). ADRs were substantially linked to being overweight (P < 0.001), having been hospitalized in the previous six months (P = 0.000), and hyperpolypharmacy (p = 0.047). 93.39% of all ADRs received the interventions. 85.12% of the adverse drug reactions were successfully resolved., Conclusions: This study found that over one-third of older people and individuals admitted to the hospital experienced ADRs. Overweight, hyperpolypharmacy, and patients who had previously been admitted during the preceding six months were significantly linked with the occurrence of ADRs. Improving the drug safety of elderly patients, particularly those who are admitted, should be a greater priority for healthcare professionals., Competing Interests: Declarations Ethics approval and consent to participate The ethical review committee of Debre Tabor University’s College of Health Science, Department of Pharmacy has approved ethical authorization with reference number 058/2023. A support letter was sent to each of the four comprehensive hospitals. The directors of those healthcare organizations were then asked to sign a letter approving the usage of patient records as a source of data. Participants were informed about the purpose and design of the study before data collection. Furthermore, they provided their official consent to participate in the research. Written informed consent was obtained from all the study participants. Patients’ medical registration numbers (MRNs) were swapped out for new codes during the data collecting and entry process. Besides, to protect its confidentiality, the gathered data was similarly kept in a locked cabinet and on a computer with a strong password. The study followed Helsinki legislation in terms of doing it in a properly anonymous and confidential manner. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: In randomised controlled trials with efficacy-related primary outcomes, adverse events are collected to monitor potential intervention harms. The analysis of adverse event data is challenging, due to the complex nature of the data and the large number of unprespecified outcomes. This is compounded by a lack of guidance on best analysis approaches, resulting in widespread inadequate practices and the use of overly simplistic methods; leading to sub-optimal exploitation of these rich datasets. To address the complexities of adverse events analysis, statistical methods are proposed that leverage existing structures within the data, for instance by considering groupings of adverse events based on biological or clinical relationships., Methods: We conducted a methodological scoping review of the literature to identify all existing methods using structures within the data to detect signals for adverse reactions in a trial. Embase, MEDLINE, Scopus and Web of Science databases were systematically searched. We reviewed the analysis approaches of each method, extracted methodological characteristics and constructed a narrative summary of the findings., Results: We identified 18 different methods from 14 sources. These were categorised as either Bayesian approaches (n=11), which flagged events based on posterior estimates of treatment effects, or error controlling procedures (n=7), which flagged events based on adjusted p-values while controlling for some type of error rate. We identified 5 defining methodological characteristics: the type of outcomes considered (e.g. binary outcomes), the nature of the data (e.g. summary data), the timing of the analysis (e.g. final analysis), the restrictions on the events considered (e.g. rare events) and the grouping systems used., Conclusions: We found a large number of analysis methods that use the group structures of adverse events. Continuous methodological developments in this area highlight the growing awareness that better practices are needed. The use of more adequate analysis methods could help trialists obtain a better picture of the safety-risk profile of an intervention. The results of this review can be used by statisticians to better understand the current methodological landscape and identify suitable methods for data analysis - although further research is needed to determine which methods are best suited and create adequate recommendations., (© 2024. The Author(s).)

Background: Pregnant women belong to the special population of drug therapy, and their physiological state, pharmacokinetics and pharmacodynamics are significantly different from the general population. Drug safety during pregnancy involves two generations, which is a hot issue widely concerned in the whole society. Global Trigger Tool (GTT) of the Institute for Healthcare Improvement (IHI) has been wildly used as a patient safety measurement strategy by several institutions and national programs, and the effectiveness had been demonstrated. But only one study reports the use of GTT in obstetric delivery until now. The aim of the study is to establish triggers detecting adverse drug events (ADEs) suitable for obstetric inpatients on the basis of the GTT, to examine the performance of the obstetric triggers in detecting ADEs experienced by obstetric units compared with the spontaneous reporting system and GTT, and to assess the utility and value of the obstetric trigger tool in identifying ADEs of obstetric inpatients., Methods: Based on a literature review searched in PubMed and CNKI from January of 1997 to October of 2023, retrospective local obstetric ADEs investigations, relevant obstetric guidelines and the common adverse reactions of obstetric therapeutic drugs were involved to establish the initial obstetric triggers. According to the Delphi method, two rounds of expert questionnaire survey were conducted among 16 obstetric and neonatological physicians and pharmacists until an agreement was reached. A retrospective study was conducted to identity ADEs in 300 obstetric inpatient records at the Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital from June 1 to September 30, 2018. Two trained junior pharmacists analyzed the first eligible records independently, and the included records reviewed by trained pharmacist and physician to identify ADEs. Sensitivity and specificity of the established obstetric triggers were assessed by the number of ADEs/100 patients and positive predictive value with the spontaneous reporting system (SRS) and GTT. Excel 2010 and SPSS22 were used for data analysis., Results: Through two rounds of expert investigation, 39 preliminary triggers were established that comprised four modules (12 laboratory tests, 9 medications, 14 symptoms, and 4 outcomes). A total of 300 medical records were reviewed through the obstetric triggers, of which 48 cases of ADEs were detected, with an incidence of ADEs of 16%. Among the 39 obstetric triggers, 22 (56.41%) were positive and 11 of them detected ADEs. The positive predictive value (PPV) was 36.36%, and the number of ADEs/100 patients was 16.33 (95% CI, 4.19-17.81). The ADE detection rate, positive trigger rate, and PPV for the obstetric triggers were significantly augmented, confirming that the obstetric triggers were more specific and sensitive than SRS and GTT., Conclusion: The obstetric triggers were proven to be sensitive and specific in the active monitoring of ADE for obstetric inpatients, which might serve as a reference for ADE detection of obstetric inpatients at medical institutions., (© 2024. The Author(s).)

Background: Older patients are vulnerable to experiencing drug related problems (DRPs), which may result in emergency department (ED) visits. However, it is not standard practice to conduct medications reviews during ED visit. The aim of this study was to assess the number of DRPs in older patients living with frailty at the ED, identified through pharmacist-led medication reviews within a geriatric care team, and to determine the acceptance rate of pharmacists' recommendations among hospital physicians and general practitioners or elderly care specialists., Methods: A retrospective observational study was performed in patients ≥ 70 years living with frailty at the ED at Tergooi Medical Center. Pharmacist-led medication reviews were conducted to identify and classify DRPs as part of a larger geriatric assessment. The acceptance rate of given recommendations was determined during follow-up., Results: A total of 356 ED visits were included. The mean (standard deviation, SD) age of patients was 83 (6.8) years. About 76% of patients had at least one DRP. In total, 548 DRPs were identified with a mean of 1.5 DRP (SD 1.3) per patient. The acceptance rate of medication recommendations in admitted patients was 55%, and 32% among general practitioners/elderly care specialists in discharged patients., Conclusions: Pharmacist-led medication reviews as part of a geriatric care team identified DRPs in 76% of older patients living with frailty at the ED. The acceptance rate was substantially higher in admitted patients compared to discharged patients., (© 2023. The Author(s).)

Introduction: Detecting safety signals attributed to a drug in scientific literature is a fundamental issue in pharmacovigilance. The constant increase in the volume of publications requires the automation of this tedious task, in order to find and extract relevant articles from the pack. This task is critical, as serious Adverse Drug Reactions (ADRs) still account for a large number of hospital admissions each year., Objectives: The aim of this study is to develop an augmented intelligence methodology for automatically identifying relevant publications mentioning an established link between a Drug and a Serious Adverse Event, according to the European Medicines Agency (EMA) definition of seriousness., Methods: The proposed pipeline, called LiSA (for Literature Search Application), is based on three independent deep learning models supporting a precise detection of safety signals in the biomedical literature. By combining a Bidirectional Encoder Representations from Transformers (BERT) algorithms and a modular architecture, the pipeline achieves a precision of 0.81 and a recall of 0.89 at sentences level in articles extracted from PubMed (either abstract or full-text). We also measured that by using LiSA, a medical reviewer increases by a factor of 2.5 the number of relevant documents it can collect and evaluate compared to a simple keyword search. In the interest of re-usability, emphasis was placed on building a modular pipeline allowing the insertion of other NLP modules to enrich the results provided by the system, and extend it to other use cases. In addition, a lightweight visualization tool was developed to analyze and monitor safety signal results., Conclusions: Overall, the generic pipeline and the visualization tool proposed in this article allows for efficient and accurate monitoring of serious adverse drug reactions from the literature and can easily be adapted to similar pharmacovigilance use cases. To facilitate reproducibility and benefit other research studies, we also shared a first benchmark dataset for Serious Adverse Drug Events detection., (© 2022. The Author(s).)

Background: Adverse drug reaction (ADR) of medications remains an obstacle to achieving optimal disease outcomes. This study aimed to assess the prevalence and associated factors of ADR among Heart failure (HF) patients hospitalized at Mbarara Regional and Referral Hospital., Method: A prospective observational study was conducted among hospitalized HF patients from November 2021 to January 2022. Univariate and multivariate logistic regression was employed to determine factors associated with the ADR., Result: Overall, 118 HF patients were included in the study with a median age of 43 years. A total of 164 ADRs were identified during the follow-up period of 1011 days. The incidence of new ADRs was 106 ADRs/1000 person-days. The prevalence of ADR was 59.3%. Of the 164 ADRs, 118(71.9%) were probable. The gastrointestinal system was the most frequently (27.5%) affected system. Over half (86, 52.4%) of the ADRs were mild and 96(58.5%) were preventable. Age group 19-59(AOR 0.15[0.03-0.35] at 95%CI, p = 0.013), herbal use (AOR 3.07[1.01-9.32] at 95%CI, p = 0.048), poly-pharmacy (AOR 8.7[2.4-15.77] at 95%CI, p &lt; 0.001) and drug-drug interaction (AOR 6.06[2.79-12.5] at 95%CI, p = 0.004) were significantly associated with ADRs among HF patients., Conclusion: More than half of the hospitalized HF patients experienced at least one ADR during their hospital stay. The use of herbal medicines, poly-pharmacy, and drug-drug interaction were associated with a high risk of ARDs whereas the age group 19-59 years was less likely to experience ADRs., (© 2022. The Author(s).)

Background: The effectiveness of interventions to improve medication safety in older inpatients is unclear, given a paucity of properly designed intervention studies applying clinically relevant endpoints such as hospital-acquired preventable Adverse Drug Events (pADEs) and unrecognized Adverse Drug Events (uADEs). Therefore, we conducted a quality improvement study and used hospital-acquired pADEs and uADEs as main outcomes to assess the effect of an intervention aimed to improve medication safety in older inpatients., Method: The study followed an interrupted time series design and consisted of three equally spaced sampling points during baseline and during intervention measurements. Each sampling point included between 80 to 90 patients. A total of 500 inpatients ≥65 years and admitted to internal medicine wards of three Dutch hospitals were included. An expert team retrospectively identified and assessed ADEs via a structured patient chart review. The findings from baseline measurement and meetings with the internal medicine and hospital pharmacy staff were used to design the intervention. The intervention consisted of a structured medication review by hospital pharmacists, followed by face-to-face feedback to prescribers, on average 3 days per week., Results: The rate of hospital-acquired pADEs per 100 hospitalizations was reduced by 50.6% (difference 16.8, 95% confidence interval (CI): 9.0 to 24.6, P <  0.001), serious hospital-acquired pADEs by 62.7% (difference 12.8, 95% CI: 6.4 to 19.2, P <  0.001), and uADEs by 51.8% (difference 11.2, 95% CI: 4.4 to 18.0, P <  0.001). Additional analyses confirmed the robustness of the intervention effect, but residual bias cannot be excluded., Conclusions: The intervention significantly decreased the overall and serious hospital-acquired pADE occurrence in older inpatients, and significantly improved overall ADE recognition by prescribers., Trial Registration: International Standard Randomized Controlled Trial Number Register, trial registration number: ISRCTN64974377 , registration date (date assigned): 07/02/2011., (© 2022. The Author(s).)

Background: Adverse drug events (ADEs) can be prevented by deploying clinical decision support systems (CDSS) that directly assist physicians, via computerized order entry systems, and clinical pharmacists performing medication reviews as part of medical rounds. However, physicians using CDSS are known to be exposed to the alert-fatigue phenomenon. Our study aimed to assess the performance of PharmaCheck-a CDSS to help clinical pharmacists detect high-risk situations with the potential to lead to ADEs-and its impact on clinical pharmacists' activities., Methods: Twenty clinical rules, divided into four risk classes, were set for the daily screening of high-risk situations in the electronic health records of patients admitted to our General Internal Medicine Department. Alerts to clinical pharmacists encouraged them to telephone prescribers and suggest any necessary treatment adjustments. PharmaCheck's performance was assessed using the intervention's positive predictive value (PPV), which characterizes the proportion of interventions for each alert triggered. PharmaCheck's impact was assessed by considering clinical pharmacists as a filter for ruling out futile alerts and by comparing the final clinical PPV with a pharmacist (the proportion of interventions that led to a change in the medical regimen) to the final clinical PPV without a pharmacist., Results: Over 132 days, 447 alerts were triggered for 383 patients, leading to 90 interventions (overall intervention PPV = 20.1%). By risk class, intervention PPVs made up 26.9% (n = 65/242) of abnormal laboratory value alerts, 3.1% (4/127) of alerts for contraindicated medications or medications to be used with caution, 28.2% (20/71) of drug-drug interaction alerts, and 14.3% (1/7) of inadequate mode of administration alerts. Clinical PPVs reached 71.0% (64/90) when pharmacists filtered alerts and 14% (64/242) if they were not doing it., Conclusion: PharmaCheck enabled clinical pharmacists to improve their traditional processes and broaden their coverage by focusing on 20 high-risk situations. Alert management by pharmacists seemed to be a more effective way of preventing risky situations and alert-fatigue than a model addressing alerts to physicians exclusively. Some fine-tuning could enhance PharmaCheck's performance by considering the information quality of triggers, the variability of clinical settings, and the fact that some prescription processes are already highly secured., (© 2022. The Author(s).)

Background: Globally, it is estimated that the number of older adults will become 2 billion by 2050. The identification of the predictors of adverse drug reaction (ADR) in hospitalized older patients is crucial to the development of prediction tools and preventive strategies to mitigate the burden of ADRs. This study aimed to determine the predictors of hospital-acquired ADR occurrence among hospitalized older adults in a low-income country., Methods: We conducted a prospective cohort of older adults admitted to medical, oncology, and surgery wards at Mbarara Regional Referral Hospital (MRRH) for a consecutive 6 months where each patient was followed up daily from admission to discharge. We used Edwards and Aronson's definition of ADR and the Naranjo ADR Causality Scale. We employed Beer's criteria and Lexicomp to determine potentially inappropriate medications, and drug interactions, respectively. We conducted univariate and multivariable logistic regression using Statistical Package for the Social Science (SPSS) Version 23.0., Results: Out of 523 participants with median (Inter Quartile Range) age of 67 (62-76) years, 256 (48.9%) experienced at least one ADR. Independent predictors of occurrence of hospital acquired ADRs included age of 60-75 (Adjusted odds ratio (AOR) = 1.97, 95% C.I: 1.14-3.41; p value = 0.015) compared to > 75 years, previous ADR in 1 year (AOR = 2.43, 95% C.I: 1.42-4.17; p value = 0.001), potentially inappropriate medication (AOR = 4.56, 95% C.I: 2.70-7.70; p value< 0.001), polypharmacy (AOR = 3.29, 95% C.I: 1.98-5.46; p value< 0.001)), having a Charlison Comorbidity Index (CCI) ≥ 6 (AOR = 8.47, 95% C.I: 4.85-14.99; p value< 0.001), having heart failure (AOR = 2.83, 95% C.I: 1.34-6.02; p value = 0.007) or kidney disease (AOR = 1.95, 95% C.I: 1.05-3.61; p value = 0.034) and a hospital stay > 10 days (AOR = 3.53, 95% C.I: 1.89-6.61; p value< 0.001) compared to < 5 days., Conclusion: The current prevalence of ADR is higher than previously reported in high-income countries. Disease-related factors followed by medication-related factors were shown to be the most important predictors of hospital-acquired ADRs. CCI and PIM showed the strongest association with ADR. The predictors of ADRs identified in our study were generally comparable with those reported by previous studies., Plain Language Title: Conditions that predispose older patients to experience harmful effects from their medications while in hospital. Identifying the conditions that predispose older adults to incur harmful effects of their medications helps to plan on how best to predict, take precautions and closely follow up on them and thus, to prevent these undesirable outcomes. This study aimed to identify these conditions which determine which older adults are higher risk to incur these harmful undesirable effects of medicines. Everydayduring their hospital stay, we closely followed older patients who were 60 years and above from their entry to the hospital wards until they left the hospital. We interviewed the participants, reviewed their medication files and we also examined them physically to identify any unwanted and harmful outcome from their current medications. Out of 523 participants, almost half of them experienced at least one harmful or undesired effect related to their medicine. Conditions which predisposed them to experience a harmful effect from their medicines included being in age bracket of 60-75 years, having a history of experiencing harmful outcomes from medicines in the previous 1 year, taking a medication which was listed as potentially inappropriate for older adults, taking 5 or more medications concurrently, having a lower 10 years survival chance, having heart or kidney disease and a hospital stay > 10 days., (© 2022. The Author(s).)

Background: It has been hypothesized that polypharmacy may increase the frequency of multidrug interactions (MDIs) where one drug interacts with two or more other drugs, amplifying the risk of associated adverse drug events (ADEs). The main objective of this study was to determine the prevalence of MDIs in medication lists of elderly ambulatory patients and to identify the medications most commonly involved in MDIs that amplify the risk of ADEs., Methods: Medication lists stored in the electronic health record (EHR) of 6,545 outpatients ≥60 years old were extracted from the enterprise data warehouse. Network analysis identified patients with three or more interacting medications from their medication lists. Potentially harmful interactions were identified from the enterprise drug-drug interaction alerting system. MDIs were considered to amplify the risk if interactions could increase the probability of ADEs., Results: MDIs were identified in 1.3 % of the medication lists, the majority of which involved three interacting drugs (75.6 %) while the remainder involved four (15.6 %) or five or more (8.9 %) interacting drugs. The average number of medications on the lists was 3.1 ± 2.3 in patients with no drug interactions and 8.6 ± 3.4 in patients with MDIs. The prevalence of MDIs on medication lists was greater than 10 % in patients prescribed bupropion, tramadol, trazodone, cyclobenzaprine, fluoxetine, ondansetron, or quetiapine and greater than 20 % in patients prescribed amiodarone or methotrexate. All MDIs were potentially risk-amplifying due to pharmacodynamic interactions, where three or more medications were associated with the same ADE, or pharmacokinetic, where two or more drugs reduced the metabolism of a third drug. The most common drugs involved in MDIs were psychotropic, comprising 35.1 % of all drugs involved. The most common serious potential ADEs associated with the interactions were serotonin syndrome, seizures, prolonged QT interval and bleeding., Conclusions: An identifiable number of medications, the majority of which are psychotropic, may be involved in MDIs in elderly ambulatory patients which may amplify the risk of serious ADEs. To mitigate the risk, providers will need to pay special attention to the overlapping drug-drug interactions which result in MDIs., (© 2021. The Author(s).)

Background: In recent years, the application of immunotherapy combined with chemotherapy in the first-line lung cancer has showed significant benefit in improving long-term survival. Immunotherapy also has risks of immune-related pneumonitis (IRP) after long-term treatment. Despite the treatment strategy of the IRP has been very clear. However, the mechanism is unclear., Case Presentation: A 73-year-old male patient was diagnosed with left lung adenocarcinoma IVa, EGFR, ALK, ROS1 negative. The patient received anti-PD1 antibody combined with pemetrexed and cisplatin. After 5 cycles of treatment, partial response was obtained. Subsequently, the patient continued the treatment of anti-PD1 antibody combined with pemetrexed. Before the 7th cycle, the CT found a new lesion in the basal segment of the right lower lobe. It was diagnosed with IRP and pneumocystis jirovecii. The patient did not give trimethoprim-sulphamethoxazole (TMP-SMX) and corticosteroids, symptoms and radiological lesions had improved. We describe the report of immune-related pneumonitis trigged by anti PD-1 and monitored the dynamic changes of CD 4+ , CD 8+ T lymphocytes, MDSC and Treg cells in the bilateral bronchoalveolar alveolar lavage fluid. From the point of view of immune cells, the mechanism of immune reconstitution inflammatory syndrome is confirmed. Based on the current case report and literature, this study proposes a potential mechanism of the onset., Conclusion: Immune reconstitution inflammatory syndrome may be potential mechanism of IRP. This study may improve our understanding of the pathogenesis underlying IRP. We believe the detection and dynamic monitoring CD4 + , CD8 + T lymphocytes, MDSC and Treg cells can provide more accurate procedures., (© 2021. The Author(s).)

Background: Adverse drug events (ADE) represent one of the main causes of admission to emergency department (ED). Their detection, documentation, and reporting are essential to avoid readmission. We hypothesize that a pharmacist-initiated multidisciplinary transition of care program combining ED pharmacist contribution and medications' data transfer between inpatient and outpatient caregivers will reduce emergency visits related to ADE METHOD/DESIGN: This is a prospective, open-label, randomized controlled trial. The primary aim of the study is 6-month ED readmission related to the same ADE. Three hundred forty-six adult patients with an ADE detected by a binomial pharmacist-physician will be recruited from the ED of an University Hospital and will be randomized in two groups: [1] experimental group (multidisciplinary transition of care program and medications' data transfer between inpatient and outpatient caregivers) and [2] control group (usual care). Patients will be followed up over a period of 6 months. Endpoints will be carried out blindly of the randomization arm. The primary endpoint is the rate of patients who had at least one readmission in the ED for the same reason at 6 months (data collected during a phone call with the patient and the general practitioner). Trials registered NCT03725046., Discussion: The trial results will have implications for the role of the clinical pharmacist in an emergency department. If successful, the intervention could be considered for implementation across other hospitals., Trial Registration: ClinicalTrials.gov NCT03725046 . Registered on 30 October 2018., (© 2021. The Author(s).)

Background: Campylobacter fetus is an uncommon Campylobacter species, and its infections mainly cause infective endocarditis, aortic aneurysm, and meningitis rather than enteritis. It is more likely to be detected in blood than Campylobacter jejuni or Campylobacter coli, specifically reported in 53% of patients. In our case, C. fetus was detected in both blood and cerebrospinal fluid (CSF) cultures., Case Presentation: A 33-year-old woman, who was on maintenance chemotherapy for acute lymphoblastic leukemia (ALL), presented to our clinic with chief complaints of severe headache and nausea. Blood and CSF cultures revealed C. fetus. We administrated meropenem 2 g intravenously (IV) every 8 h for 3 weeks, and she was discharged without neurological sequelae., Conclusion: We encountered a case of C. fetus meningitis without gastrointestinal symptoms, neck stiffness or jolt accentuation in a patient with ALL. Undercooked beef was considered the source of C. fetus infection in this case, suggesting that the need for a neutropenic diet and safe food handling be considered., (© 2021. The Author(s).)

Background: Children are more vulnerable to adverse drug reactions (ADRs) due to complex changes in the body during the growth process and lack specific pharmacoepidemiologic studies. Causality and Avoidability assessment of ADRs are relevant to clinical guidelines development and pharmacovigilance. This study aimed to translate and transcultural adapt two new tools-Liverpool Causality Assessment Tool (LCAT) and the Liverpool Avoidability Assessment Tool (LAAT)-to Brazilian-Portuguese and evaluate the psychometric properties of these tools to analyse ADRs in Brazilian children., Methods: The validation of the cross-cultural adaptation of tools was obtained by the functional (conceptual, semantic, operational, and measurement) equivalence between the original and translated versions of each instrument. The translated version of LCAT and LAAT was applied to assessing the twenty-six case reports of suspected adverse drug reactions in a Brazilian teaching paediatric hospital. The inter-rater reliability (a pharmacist and a physician) was evaluated using Cronbach's alpha. The exact agreement percentages (%EA) and extreme disagreement (%ED) were computed. Overall Kappa index was calculated with a 95% confidence interval., Results: There was a need to modify some terms translated into Portuguese for semantic and conceptual equivalence. The Cronbach's alpha coefficient values obtained were 0.95 and 0.85, and the weighted Kappa (95% confidence interval) were 0.82 (0.67-0.97) and 0.68 (0.45-0.91) for LCAT and LAAT, respectively. The Brazilian-Portuguese versions of the LCAT and LAAT showed reliable and valid tools for the diagnosis and follow-up of ADRs in children., Conclusion: The methodological approach allowed the translation, transcultural adaptation, and validation to Brazilian-Portuguese of two easy and quick to perform tools for causality and avoidability of ADRs in children by a multidisciplinary expert specialist committee, including the authors of original tools. We believe these versions may be applied by professionals (patient safety teams) and researchers in Brazil in groups or by a single reviewer., Trial Registration: This study was evaluated and approved by the Research Ethics Committee (Instituto de Pediatria e Puericultura Martagão Gesteira - Federal University of Rio de Janeiro - Number: 3.264.238.

Background: Randomised controlled trials (RCTs) provide valuable information for developing harm profiles but current analysis practices to detect between-group differences are suboptimal. Drug trials routinely screen continuous clinical and biological data to monitor participant harm. These outcomes are regularly dichotomised into abnormal/normal values for analysis. Despite the simplicity gained for clinical interpretation, it is well established that dichotomising outcomes results in a considerable reduction in information and thus statistical power. We propose an automated procedure for the routine implementation of the distributional method for the dichotomisation of continuous outcomes proposed by Peacock and Sauzet, which retains the precision of the comparison of means., Methods: We explored the use of a distributional approach to compare differences in proportions based on the comparison of means which retains the power of the latter. We applied this approach to the screening of clinical and biological data as a means to detect 'signals' for potential adverse drug reactions (ADRs). Signals can then be followed-up in further confirmatory studies. Three distributional methods suitable for different types of distributions are described. We propose the use of an automated approach using the observed data to select the most appropriate distribution as an analysis strategy in a RCT setting for multiple continuous outcomes. We illustrate this approach using data from three RCTs assessing the efficacy of mepolizumab in asthma or COPD. Published reference ranges were used to define the proportions of participants with abnormal values for a subset of 10 blood tests. The between-group distributional and empirical differences in proportions were estimated for each blood test and compared., Results: Within trials, the distributions varied across the 10 outcomes demonstrating value in a practical approach to selecting the distributional method in the context of multiple adverse event outcomes. Across trials, there were three outcomes where the method chosen by the automated procedure varied for the same outcome. The distributional approach identified three signals (eosinophils, haematocrit, and haemoglobin) compared to only one when using the Fisher's exact test (eosinophils) and two identified by use of the 95% confidence interval for the difference in proportions (eosinophils and potassium)., Conclusion: When dichotomisation of continuous adverse event outcomes aids clinical interpretation, we advocate use of a distributional approach to retain statistical power. Methods are now easy to implement. Retaining information is especially valuable in the context of the analysis of adverse events in RCTs. The routine implementation of this automated approach requires further evaluation.

Background: This retrospective study was to assess and compare the toxicity and efficacy of concurrent chemoradiotherapy (CCRT) with S-1 or docetaxel and cisplatin in patients with locally advanced esophageal squamous cell carcinoma (ESCC)., Methods: Patients with locally advanced ESCC who received CCRT with S-1 (70 mg/m 2 twice daily on days 1-14, every 3 weeks for 2 cycles, S-1 group) or docetaxel (25 mg/m 2 ) and cisplatin (25 mg/m 2 ) on day 1 weekly (DP group) between 2014 and 2016 were retrospectively analyzed. Radiotherapy was delivered in 1.8-2.0 Gy per fraction to a total dose of 50-60 Gy. Treatment-related toxicities (Common Terminology Criteria for Adverse Events version 4.0), response rate, and survival outcomes were compared between groups., Results: A total of 175 patients were included in this study (72 in the S-1 group and 103 in the DP group). Baseline characteristics were well balanced between the two groups. The incidence of grade 3-4 adverse events were significantly lower in the S-1 group than that of the DP group (22.2% vs. 45.6%, p = 0.002). In the DP group, elderly patients (> 60 years) had a significantly higher rate of grade 3-4 adverse events than younger patients (58.1% vs. 31.3%, p = 0.01). The objective overall response rate (complete response + partial response) was 68.1% in the S-1 group, and 73.8% the DP group (p = 0.497). The 3-year overall survival was 34.7% in the S-1 group, and 38.8% in the DP group (p = 0.422). The 3-year progression free survival in the DP group was higher than that in the S-1 group but without significant difference (33.0% vs. 25.0%, p = 0.275)., Conclusion: CCRT with S-1 is not inferior to CCRT with docetaxel and cisplatin and is better tolerated in in elderly patients with locally advanced ESCC.

Background: Administrative health data are increasingly used to detect adverse drug events (ADEs). However, the few studies evaluating diagnostic codes for ADE detection demonstrated low sensitivity, likely due to narrow code sets, physician under-recognition of ADEs, and underreporting in administrative data. The objective of this study was to determine if combining an expanded ICD code set in administrative data with e-prescribing data improves ADE detection., Methods: We conducted a prospective cohort study among patients newly prescribed antidepressant or antihypertensive medication in primary care and followed for 2 months. Gold standard ADEs were defined as patient-reported symptoms adjudicated as medication-related by a clinical expert. Potential ADEs in administrative data were defined as physician, ED, or hospital visits during follow-up for known adverse effects of the study medication, as identified by ICD codes. Potential ADEs in e-prescribing data were defined as study drug discontinuations or dose changes made during follow-up for safety or effectiveness reasons., Results: Of 688 study participants, 445 (64.7%) were female and mean age was 64.2 (SD 13.9). The study drug for 386 (56.1%) patients was an antihypertensive, and for 302 (43.9%) an antidepressant. Using the gold standard definition, 114 (16.6%) patients experienced an ADE, with 40 (10.4%) among antihypertensive users and 74 (24.5%) among antidepressant users. The sensitivity of the expanded ICD code set was 7.0%, of e-prescribing data 9.7%, and of the two combined 14.0%. Specificities were high (86.0-95.0%). The sensitivity of the combined approach increased to 25.8% when analysis was restricted to the 27% of patients who indicated having reported symptoms to a physician., Conclusion: Combining an expanded diagnostic code set with e-prescribing data improves ADE detection. As few patients report symptoms to their physician, higher detection rates may be achieved by collecting patient-reported outcomes via emerging digital technologies such as patient portals and mHealth applications.

Background: The use of potentially inappropriate medication (PIM) in population of older adults may result in adverse drug events (ADE) already after short term exposure, especially when it is prescribed to patients with chronic kidney disease (CKD). In order to limit ADE in the treatment of older adults PIM lists have been constructed as a source of information for healthcare professionals. The aim of this study was to estimate the utilization of PIM and incidence of ADE in older adults (≥70 years) with CKD., Methods: We conducted a retrospective population-wide cohort study including patients from Lower Austria who were 70 years or older and diagnosed with CKD in the period from 2008 to 2011. Utilization of PIM was estimated from prescriptions filled by target population. We estimated risks of hospitalization due to ADE within 30 days after incident PIM prescription and compared them to a PIM-free control group by using marginal structural models (MSM)., Results: We identified 11,547 patients (women: 50.6%, median age in 2008: 78 years) who fulfilled the inclusion criteria. In total 24.7 and 8.1% of all prescriptions from that period contained a medication with a substance listed in the EU (7)-PIM and AT-PIM list, respectively. Proton pump inhibitors and Ginkgo biloba were the most often prescribed PIMs in this population. 94.6 and 79.3% patients filled at least one EU(7)-PIM and AT-PIM prescription, respectively. Despite the relatively high utilization of PIM there was only a low incidence of clinically relevant ADE. No event type exceeded the threshold level of 1% in the analysis of risks of ADE after filling a prescription for PIM. Nevertheless, MSM analysis showed an increased risk for 11 drugs and reduced risk for 4 drugs., Conclusions: PIM prescription was common among older adults with CKD, however, only a small number of these drugs eventually led to hospitalization due to ADE within 30 days after incident PIM was filled. In the absence of a clinically important PIM-related increase in risk, an assessment of potential ADE severity to a PIM list by using a warning score system seems prudent.

Background: Potentially inappropriate medication (PIM) use has adverse effects on health, particularly in elder patients. Various country-specific explicit criteria have been developed to measure the appropriateness of prescribing worldwide. However, it is difficult to apply the criteria developed from other regions to measure and guide the local prescribing practice in Hong Kong. This study aims to develop a Hong Kong-specific PIM assessing tool from previously published criteria and validate this tool using the modified Delphi method., Methods: A disease-oriented Hong Kong-specific preliminary PIM list was developed based on nine sets of reference criteria selected from a literature review. Any medication or medication class appeared in at least two sets of the reference criteria as well as its related medical conditions were selected as PIM candidates. After examining the availability of PIM candidates by the Hong Kong Hospital Authority drug formulary, the Hong Kong-specific preliminary PIM list was validated by a two-round of modified Delphi process. Eight experts from different specialties were invited to rate the degree of inappropriateness of each PIM candidate using a five-point Likert scale. The experts were also encouraged to propose therapeutic alternatives and new PIM candidates not covered by the preliminary PIM list. The PIM candidates that the expert panel didn't reach consensus on were excluded from the final Hong Kong-specific PIM list., Results: After two rounds of the Delphi process, eight PIM candidates remained questionable and thus were excluded from the PIM list. The final Hong Kong-specific PIM list included a total of 164 statements applicable to older adults aged 65 years or above, among which 77 were under PIMs independent of diagnoses, and 87 were under PIMs considering specific medical conditions., Conclusions: The Hong Kong-specific PIM list can be used as a quality measure and an educational tool to improve the local prescribing quality. Further studies should validate its association with adverse health outcomes in clinical and research settings.

Background: Randomised controlled trials (RCTs) provide valuable information and inform the development of harm profiles of new treatments. Harms are typically assessed through the collection of adverse events (AEs). Despite AEs being routine outcomes collected in trials, analysis and reporting of AEs in journal articles are continually shown to be suboptimal. One key challenge is the large volume of AEs, which can make evaluation and communication problematic. Prominent practice is to report frequency tables of AEs by arm. Visual displays offer an effective solution to assess and communicate complex information; however, they are rarely used and there is a lack of practical guidance on what and how to visually display complex AE data., Methods: In this article, we demonstrate the use of two plots identified to be beneficial for wide use in RCTs, since both can display multiple AEs and are suitable to display point estimates for binary, count, or time-to-event AE data: the volcano and dot plots. We compare and contrast the use of data visualisations against traditional frequency table reporting, using published AE information in two placebo-controlled trials, of remdesivir for COVID-19 and GDNF for Parkinson disease. We introduce statistical programmes for implementation in Stata., Results/case Study: Visualisations of AEs in the COVID-19 trial communicated a risk profile for remdesivir which differed from the main message in the published authors' conclusion. In the Parkinson's disease trial of GDNF, the visualisation provided immediate communication of harm signals, which had otherwise been contained within lengthy descriptive text and tables. Asymmetry in the volcano plot helped flag extreme events that were less obvious from review of the frequency table and dot plot. The dot plot allowed a more comprehensive representation by means of a more detailed summary., Conclusions: Visualisations can better support investigators to assimilate large volumes of data and enable improved informal between-arm comparisons compared to tables. We endorse increased uptake for use in trial publications. Care in construction of visual displays needs to be taken as there can be potential to overemphasise treatment effects in some circumstances.

The enthusiasm for immune checkpoint inhibitors (ICIs), an efficient tumor treatment model different from traditional treatment, is based on their unprecedented antitumor effect, but the occurrence of immune-related adverse events (irAEs) is an obstacle to the prospect of ICI treatment. IrAEs are a discrete toxicity caused by the nonspecific activation of the immune system and can affect almost all tissues and organs. Currently, research on biomarkers mainly focuses on the gastrointestinal tract, endocrine system, skin and lung. Several potential hypotheses concentrate on the overactivation of the immune system, excessive release of inflammatory cytokines, elevated levels of pre-existing autoantibodies, and presence of common antigens between tumors and normal tissues. This review lists the current biomarkers that might predict irAEs and their possible mechanisms for both nonspecific and organ-specific biomarkers. However, the prediction of irAEs remains a major clinical challenge to screen and identify patients who are susceptible to irAEs and likely to benefit from ICIs.

Background: Aging populations are often accompanied by comorbidity and polypharmacy, leading to increases in adverse drug reactions (ADRs). We sought to evaluate the causes and characteristics of ADRs in older Korean adults (≥65 years) in comparison to younger individuals (< 65 years)., Methods: Of 37,523 cases reported at a Korean pharmacovigilance center from 2011 to 2018, we reviewed 18,842 ADRs of certain or probable causality on the basis of WHO-UMC criteria. We estimated the number of ADRs per 1000 patients exposed to the major culprit drugs, and incidence rate ratios were obtained to assess high- and low-risk medications in older adults., Results: In total, 4152 (22.0%) ADRs were reported for 3437 older adults (mean age, 74.6 years and 57.3% female). Tramadol (rate ratio, 1.32; 95% confidence interval [CI], 1.21-1.44; P < 0.001) and fentanyl (1.49, 1.16-1.92, P = 0.002) posed higher risks of ADRs in the older adults, whereas nonsteroidal anti-inflammatory drugs (NSAIDs) (0.35, 0.30-0.40, P < 0.001) and iodinated contrast media (ICM) (0.82, 0.76-0.89, P < 0.001) posed lower risks. Ratios of serious ADRs to NSAIDs (odds ratio, 2.16; 95% CI, 1.48-3.15; P < 0.001) and ICM (2.09, 1.36-3.21, P = 0.001) were higher in the older adults than in the younger patients. Analgesics primarily elicited cutaneous ADRs in the younger patients and gastrointestinal reactions in the older adults. ICM more commonly led to anaphylaxis in the older adults than the younger patients (3.0% vs. 1.6%, P = 0.019)., Conclusion: For early detection of ADRs in older adults, better understanding of differences in the causes and characteristics thereof in comparison to the general population is needed.

Background: The aim of this study was to translate and linguistically validate the U.S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) into Simplified Chinese for use in Singapore., Methods: All 124 items of the English source PRO-CTCAE item library were translated into Simplified Chinese using internationally established translation procedures. Two rounds of cognitive interviews were conducted with 96 cancer patients undergoing adjuvant treatment to determine if the translations adequately captured the PRO-CTCAE source concepts, and to evaluate comprehension, clarity and ease of judgement. Interview probes addressed the 78 PRO-CTCAE symptom terms (e.g. fatigue), as well as the attributes (e.g. severity), response choices, and phrasing of 'at its worst'. Items that met the a priori threshold of ≥20% of participants with comprehension difficulties were considered for rephrasing and retesting. Items where < 20% of the sample experienced comprehension difficulties were also considered for rephrasing if better phrasing options were available., Results: A majority of PRO-CTCAE-Simplified Chinese items were well comprehended by participants in Round 1. One item posed difficulties in ≥20% and was revised. Two items presented difficulties in < 20% but were revised as there were preferred alternative phrasings. Twenty-four items presented difficulties in < 10% of respondents. Of these, eleven items were revised to an alternative preferred phrasing, four items were revised to include synonyms. Revised items were tested in Round 2 and demonstrated satisfactory comprehension., Conclusions: PRO-CTCAE-Simplified Chinese has been successfully developed and linguistically validated in a sample of cancer patients residing in Singapore.

Background: Falls are common undesirable events for older adults in institutions. Even though the patient's fall risk may be scored on admission, the medication-induced fall risk may be ignored. This study developed a preliminary categorization of fall-risk-increasing drugs (FRIDs) to be added as a risk factor to the existing fall risk assessment tool routinely used in geriatric care units., Methods: Medication use data of older adults who had experienced at least one fall during a hospital ward or a nursing home stay within a 2-year study period were retrospectively collected from patient records. Medicines used were classified into three risk categories (high, moderate and none) according to the fall risk information in statutory summaries of product characteristics (SmPCs). The fall risk categorization incorporated the relative frequency of such adverse drug effects (ADEs) in SmPCs that were known to be connected to fall risk (sedation, orthostatic hypotension, syncope, dizziness, drowsiness, changes in blood pressure or impaired balance). Also, distribution of fall risk scores assessed on admission without considering medications was counted., Results: The fall-experienced patients (n = 188, 128 from the hospital and 60 from nursing home records) used altogether 1748 medicaments, including 216 different active substances. Of the active substances, 102 (47%) were categorized as high risk (category A) for increasing fall risk. Fall-experienced patients (n = 188) received a mean of 3.8 category A medicines (n = 710), 53% (n = 375) of which affected the nervous and 40% (n = 281) the cardiovascular system. Without considering medication-related fall risk, 53% (n = 100) of the patients were scored having a high fall risk (3 or 4 risk scores)., Conclusion: It was possible to develop a preliminary categorization of FRIDs basing on their adverse drug effect profile in SmPCs and frequency of use in older patients who had experienced at least one documented fall in a geriatric care unit. Even though more than half of the fall-experienced study participants had high fall risk scores on admission, their fall risk might have been underestimated as use of high fall risk medicines was common, even concomitant use. Further studies are needed to develop the FRID categorization and assess its impact on fall risk.

Background: The Global Trigger Tool (GTT),which is a method using "triggers" to review medical record retrospectively to identify possible adverse events. Several studies showed that the GTT was effective. However, there were only a few localized trigger tools that had been established to detect pediatric adverse drug events (ADEs) in China. This study aimed to establish a pediatric trigger tool based on GTT, to examine the performance by detecting pediatric inpatients ADEs in a Chinese hospital (a retrospective review), and to investigate the factors associating with the occurrence of ADEs., Methods: The triggers were established by three steps including literature search, triggers extraction and revision, and experts investigation. A retrospective cohort study was conducted to detect ADEs by using 200 pediatric inpatient records of Sichuan Provincial People's Hospital., Results: Thirty-three preliminary triggers were established, and 2 rounds of experts investigation were conducted. Finally, 33 triggers were established. In the retrospective review, the positive trigger rate was 64.0%, while the positive predictive value (PPV) was 24.9%. The occurrence of inpatients with ADEs was 20.5%. ADEs/100 admissions were 49.0. ADEs/1000 patient days were 46.89. The most common ADE categories were leukocyte disorders, skin disorders and platelet disorders. The severity of 39 ADEs was grade 1, 55 ADEs was grade 2, 4 ADEs was grade 3. The highest frequency of ADE-related drugs was antineoplastic, followed by antibacterial. The length of stay and the leukemia in the diagnosed diseases were positively correlated with ADEs., Conclusions: The 33 pediatric triggers may detect ADEs effectively, but still need to be optimized. This study may provide some references for further research in order to improve the rationality and safety of medication.

Background: Drug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so in the elderly cohort of patients. Despite this, the concept of its prevention through prospective analysis has largely remained unexamined. We evaluated the utility of recently validated adverse drug reactions (ADR) avoidability tool in a cohort of elderly patients with DILI., Methods: We examined 38 DILI-drug pairs from n=38 patients in a prospective cohort of patients presenting with adverse drug reactions to a Weill Cornell-affiliated tertiary hospital between February 2019 and January 2020. DILI outcomes were adjudicated by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Two clinical pharmacologists and two general physicians utilized the Liverpool adverse drug reactions avoidability tool (LAAT) and the modified Hallas tools to rate the preventability of DILI-drug pairs. Inter-rater, exact agreement proportions, as well as intraclass correlation coefficients were generated and expressed as ordinal outcomes., Results: The cases examined for the determination of DILI avoidability had probability likelihood of "probable" or "highly probable" by the updated RUCAM scale. Examination of the 38 DILI-drug pairs (n= 38 patients) resulted in a total of 152 ordinal outcome decisions. We found about 32.3% (50/152) and 34.2% (52/152) of DILI-drug pairs were rated as "avoidable" ("probable" or "definite") by the LAAT and the modified Hallas tools respectively. The overall median Krippendorf's kappa with the LAAT was 0.61 (SE 0.12, CI 0.36, 0.85) and for modified Hallas tool was 0.53 (SE 0.18; CI 0.16, 0.89). The inter-rater correlation coefficient (ICC) for the LAAT and modified Hallas were 0.50 [0.32, 0.65] and 0.63 [0.48, 0.76] respectively. Exact pairwise agreement was present in 30/38 (IQR 29.5, 34.5), and 28/38 (IQR 27.5-35.5) of DILI-ADR pairs using the LAAT and modified Hallas tools respectively., Conclusion: We found a significant proportion of drug-induced liver injury adjudicated by the updated RUCAM scale in elderly hospitalized cohort of patients were avoidable with significant implication for therapeutic commissioning as well as cost effectiveness interventions in this cohort of patients.

Background: Sintilimab blocks the interaction between programmed death-1 (PD-1) and its ligands. The safety and efficacy of sintilimab combined with oxaliplatin/capecitabine (CapeOx) as first-line treatment were evaluated in patients with gastric (G)/gastroesophageal junction (GEJ) adenocarcinoma in a phase Ib clinical trial., Methods: Patients with locally advanced or metastatic G/GEJ adenocarcinoma without previous systemic treatment were enrolled as one cohort of a multi-cohort study. Sintilimab was administered at a dose of 200 mg intravenously (IV) in combination with CapeOx (1000 mg/m 2 capecitabine orally, bid, D1-14 and 130 mg/m 2 oxaliplatin IV, D1) every 21 days for up to 6 cycles. After combination treatment, patients continued to receive sintilimab (200 mg) at 3 weekly intervals as maintenance therapy until progressive disease (PD), unacceptable toxicity, withdrawal of informed consent, or for up to 24 months. Adverse events (AEs) were monitored to assess safety in terms of their frequency, intensity and causality. The efficacy endpoints included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Tumor mutation burden (TMB) was evaluated for its association with clinical response., Results: A total of 20 patients were enrolled and received sintilimab plus CapeOx. All patients reported treatment-related AEs (TRAEs). Grade 3-4 TRAEs were found in 11 (55.0%) patients. Seventeen patients obtained partial response and the ORR was 85.0% (95% CI: 62.1-96.8%). Three (15.0%) had stable disease and DCR was 100.0% (95% CI: 83.2-100.0%). As data cutoff of May 1, 2019, the median follow-up was 7.8 months. The median PFS was 7.5 months (95% CI: 6.2-9.4) and median OS had not been reached. The OS rates at 6 months and 12 months were 100.0 and 68.0%. No association was observed between TMB and efficacy., Conclusions: Sintilimab combined with CapeOx as first-line treatment demonstrated acceptable safety and promising efficacy., Trial Registration: ClinicalTrials.gov, NCT02937116 . Registered 8 October 2016.

Background: Frail older adults living in residential aged care facilities (RACFs) usually experience comorbidities and are frequently prescribed multiple medications. This increases the potential risk of inappropriate prescribing and its negative consequences. Thus, optimising prescribed medications in RACFs is a challenge for healthcare providers., Objective: Our aim was to systematically review interventions that increase the appropriateness of medications used in RACFs and the outcomes of these interventions., Methods: Systematic review and meta-analysis of randomised control trials (RCTs) and cluster randomised control trials (cRCTs) were performed by searching specified databases (MEDLINE, PubMed, Google scholar, PsycINFO) for publications from inception to May 2019 based on defined inclusion criteria. Data were extracted, study quality was assessed and statistically analysed using RevMan v5.3. Medication appropriateness, hospital admissions, mortality, falls, quality of life (QoL), Behavioural and Psychological Symptoms of Dementia (BPSD), adverse drug events (ADEs) and cognitive function could be meta-analysed., Results: A total of 25 RCTs and cRCTs comprising 19,576 participants met the inclusion criteria. The studies tested various interventions including medication review (n = 13), staff education (n = 9), multi-disciplinary case conferencing (n = 4) and computerised clinical decision support systems (n = 2). There was an effect of interventions on medication appropriateness (RR 0.71; 95% confidence interval (CI): 0.60,0.84) (10 studies), and on medication appropriateness scales (standardised mean difference = - 0.67; 95% CI: - 0.97, - 0.36) (2 studies). There were no apparent effects on hospital admission (RR 1.00; 95% CI: 0.93, 1.06), mortality (RR 0.98; 95% CI: 0.86, 1.11), falls (RR 1.06; 95% CI: 0.89,1.26), ADEs (RR 1.04; 95% CI: 0.96,1.13), QoL (standardised mean difference = 0.16; 95% CI:-0.13, 0.45), cognitive function (weighted mean difference = 0.69; 95% CI: - 1.25, 2.64) and BPSD (RR 0.68; 95% CI: 0.44,1.06) (2 studies)., Conclusion: Modest improvements in medication appropriateness were observed in the studies included in this systematic review. However, the effect on clinical measures was limited to drive strong conclusions.

Background: Pancreatic cancer has a poor prognosis and few choices of therapy. For patients with adequate performance status, FOLFIRINOX or gemcitabine plus nab-paclitaxel are preferred first-line treatment. 5-Fluorouracil (5-FU)-based therapy (e.g. FOLFIRI, OFF, or FOLFOX) are often used in patients who previously received gemcitabine-based regimens. A systematic review was conducted of the safety and efficacy of FOLFOX for metastatic pancreatic cancer following prior gemcitabine-based therapy. A Bayesian fixed-effect meta-analysis with adjustment of patient performance status (PS) was conducted to evaluate overall survival (OS) and compare outcomes with nanoliposomal irinotecan combination therapy., Methods: PubMed.gov , FDA.gov , ClinicalTrials.gov , congress abstracts, Cochrane.org library, and EMBASE database searches were conducted to identify randomized controlled trials of advanced/metastatic disease, prior gemcitabine-based therapy, and second-line treatment with 5-FU and oxaliplatin. The database search dates were January 1, 1990-June 30, 2019. Endpoints were OS and severe treatment-related adverse events (TRAEs). Trial-level PS scores were standardized by converting Karnofsky grade scores to Eastern Cooperative Oncology Group (ECOG) Grade, and overall study-weighted PS was calculated based on weighted average of all patients., Results: Of 282 studies identified, 11 randomized controlled trials (N = 454) were included in the meta-analysis. Baseline weighted PS scores predicted OS in 10 of the 11 studies, and calculated PS scores of 1.0 were associated with a median OS of 6.3 months (95% posterior interval, 5.4-7.4). After adjusting for baseline PS, FOLFOX had a similar treatment effect profile (median OS, range 2.6-6.7 months) as 5-FU/leucovorin plus nanoliposomal irinotecan therapy (median OS, 6.1 months; 95% confidence interval 4.8-8.9). Neutropenia and fatigue were the most commonly reported Grade 3-4 TRAEs associated with FOLFOX., Conclusions: Baseline PS is a strong prognostic factor when interpreting the efficacy of 5-FU and oxaliplatin-based therapy of pancreatic cancer after progression on first-line gemcitabine-based regimens. When baseline PS is considered, FOLFOX has a similar treatment effect as 5-FU and nanoliposomal irinotecan therapy and a comparable safety profile. These findings suggest that 5-FU and oxaliplatin-based therapies remain an acceptable and alternative second-line treatment option for patients with pancreatic cancer and adequate PS (e.g. ECOG 0-1) following gemcitabine treatment.

Background: While clinical trials are considered the gold standard for detecting adverse events, often these trials are not sufficiently powered to detect difficult to observe adverse events. We developed a preliminary approach to predict 135 adverse events using post-market safety data from marketed drugs. Adverse event information available from FDA product labels and scientific literature for drugs that have the same activity at one or more of the same targets, structural and target similarities, and the duration of post market experience were used as features for a classifier algorithm. The proposed method was studied using 54 drugs and a probabilistic approach of performance evaluation using bootstrapping with 10,000 iterations., Results: Out of 135 adverse events, 53 had high probability of having high positive predictive value. Cross validation showed that 32% of the model-predicted safety label changes occurred within four to nine years of approval (median: six years)., Conclusions: This approach predicts 53 serious adverse events with high positive predictive values where well-characterized target-event relationships exist. Adverse events with well-defined target-event associations were better predicted compared to adverse events that may be idiosyncratic or related to secondary target effects that were poorly captured. Further enhancement of this model with additional features, such as target prediction and drug binding data, may increase accuracy.

Background: Geriatric patients are at high risk of Drug Related Problems (DRPs) due to multi- morbidity associated polypharmacy, age related physiologic changes, pharmacokinetic and pharmacodynamics alterations. These patients often excluded from premarketing trials that can further increase the occurrence of DRPs. This study aimed to identify drug related problems and determinants in geriatric patients admitted to medical and surgical wards, and to evaluate the impact of clinical pharmacist interventions for treatment optimization., Methods: A prospective interventional study was conducted among geriatric patients admitted to medical and surgical wards of Jimma University Medical Center from April to July 2017. Clinical pharmacists reviewed patients drug therapy, identified drug related problems and provided interventions. Data were analyzed by using SPSS statistical software version 20.0. Descriptive statistics were performed to determine the proportion of drug related problems. Logistic regression analyses were performed to identify the determinants of drug related problems., Results: A total of 200 geriatric patients were included in the study. The mean age of the participants was 67.3 years (SD7.3). About 82% of the patients had at least one drug related problems. A total of 380 drug related problems were identified and 670 interventions were provided. For the clinical pharmacist interventions, the prescriber acceptance rate was 91.7%. Significant determinants for drug related problems were polypharmacy (adjusted odds ratio [AOR] = 4.350, 95% C.I: 1.212-9.260, p = 0.020) and number of comorbidities (AOR = 1.588, 95% C.I: 1.029-2.450, p = 0.037)., Conclusions: Drug related problems were substantially high among geriatric inpatients. Patients with polypharmacy and co-morbidities had a much higher chance of developing DRPs. Hence, special attention is needed to prevent the occurrence of DRPs in these patients. Moreover, clinical pharmacists' intervention was found to reduce DRPs in geriatric inpatients. The prescriber acceptance rate of clinical pharmacists' intervention was also substantially high.

Objective: Incidence and clinical outcomes of medication prescribing errors are common and potentially more harmful in the pediatric population than in the adult population. Hence, this study was aimed to assess the prevalence and types of medication prescribing errors in the pediatric wards of Nekemte Referral Hospital (NRH)., Results: Of 384 pediatric patients included in the study, 241 (63%) were males and 116 (30.21%) of them were aged between 1-3 years. About 241 (62.76%) of the patients were treated based on empirical diagnosis and only 10 (2.60%) pediatrics had co-morbid disease. The most category of medication prescribing error was dosing error 251 (48.6%) followed by incorrect drug selection 98 (19.0%). Being critically ill (AOR = 5.31, 95% CI = 1.80-12.31, p = 0.003), route of administration via IV (AOR = 3.98, 95% CI = 1.85-11.15, p = 0.011) and via IV + IM route (AOR = 2.22, 95% CI = 1.05-9.25, p = 0.045) as well as 4-6 medications per patient (AOR = 3.10, 95% CI = 3.43-12.42, p = 0.012) and > 6 medications per patient (AOR = 7.23, 95% CI = 3.91-21.45, p < 0.001) were independent predictors of medication prescribing errors. Antibiotics were the most common classes of drugs responsible for prescribing errors.

Background: Sequence symmetry analysis (SSA) is a signal detection method that can be used to assist with adverse drug event detection. It provides both a risk estimate and a data visualisation. Published methods provide results in the form of an adjusted sequence ratio, which adjusts for underlying market trends of medicine use, however no method for adjusting the visualisation is available. We aimed to develop and evaluate another method of adjustment for prescribing trends and apply it to the SSA visualisation., Methods: The SSA method relies on incident prescriptions for pairs of medicines of interest. Smoothing curves were fitted to the frequency distributions of incident medicine use. When divided and normalised, these curves yielded a set of proportions related to differences in prescribing trends over follow-up. These were then used to adjust the unit counts for incident prescriptions in the SAA visualisation and to calculate the sequence ratio. Curve fitting was also used to identify the proportional relationship between sequences over time for SSA and is presented as a supplementary visualisation to the SSA. We compared the sensitivity and specificity of our method with that from the SSA method of Tsiropolous et al. RESULTS: Curve-fit adjusted SSA visualisations yielded adjusted sequence ratios very close to those of Tsiropolous, with a p-value of 0.999 for the two sample Kolmogorov-Smirnov test. Results for sensitivity and specificity derived from adjusted sequence ratios were also practically the same. The curve-fit method graphically indicates the proportionality of the sequence and provides a useful supplement of net differences between the two sides of the SSA visualisation. Additionally, we found that incident prescriptions for patients common to both distributions are best precluded from adjustment calculations, leaving only incident prescriptions for patients unique to one or other distribution. This improved the accuracy of SSA in some atypical instances with negligible affect on accuracy elsewhere., Conclusions: Our curve-fit method is equivalent to current methods in the literature for adjusting prescribing trends in SAA, with the advantage of providing adjustment incorporated in the SAA visualisation.

Background: PHARAO is a decision support system developed to evaluate the risk for a set of either common or serious side-effects resulting from a combination of pharmacodynamic effects from a patient's medications. The objective of this study was to investigate the validity of the risk scores for the common side-effects generated by PHARAO in older patients., Methods: Side-effects included were sedation, constipation, orthostatic symptoms, anticholinergic and serotonergic effects. The alerts generated by PHARAO were tested in 745 persons ≥65 years old. Dispensed prescriptions retrieved from the Swedish prescribed drug register were used to generate the pharmacological risk scores of patients' medications. Symptoms possibly related to side-effects were extracted from medical records data., Results: The PHARAO system generated 776 alerts, most often for the risk of anticholinergic symptoms. The total specificity estimates of the PHARAO system were 0.95, 0.89 and 0.78 for high, intermediate and low risk alerts, respectively. The corresponding sensitivity estimates were between 0.12 and 0.37. The negative predictive value was 0.90 and the positive predictive value ranged between 0.20-0.25., Conclusions: The PHARAO system had a high specificity and negative predictive value to detect symptoms possibly associated with the of patients' medications, while the sensitivity and positive predictive value were low. The PHARAO system has the potential to minimise the risk of over-alerts in combination with a drug-drug interaction alert system, but should be used in connection with a medical evaluation of the patient.

Background: While dermatomyositis is often associated with malignancy, several autoimmune diseases like myositis can be caused by immune checkpoint inhibitors. Differentially diagnosing malignancy-associated dermatomyositis or myositis caused by immune checkpoint inhibitors is sometimes difficult, particularly when a patient with malignancy shows the symptoms of myositis after checkpoint inhibitor administration. We experienced such a case in which we had difficulties in diagnosing paraneoplastic dermatomyositis or drug-associated myositis. In this case, all of our team initially assumed that the diagnosis was myositis caused by immune checkpoint inhibitors. However, it turned out finally that the diagnosis was paraneoplastic dermatomyositis. Because the diagnosis was unexpected, we report here., Case Presentation: We report the case of a 71-year-old Japanese man who developed clinical symptoms of myositis, such as muscle aches and weakness, after initiation of nivolumab therapy for his gastric cancer. He was initially diagnosed with nivolumab-induced myositis, because the myositis symptoms appeared after nivolumab administration, and nivolumab is known to trigger various drug-associated autoimmune diseases. However, according to his characteristic skin lesions, the type of muscle weakness, his serum marker profiles, electromyography of his deltoid muscle, and magnetic resonance imaging, he was finally diagnosed as having paraneoplastic dermatomyositis. Accordingly, treatment with intravenously administered corticosteroid pulse treatment, immunoglobulin injection, and tacrolimus was applied; his symptoms subsequently improved. However, to our regret, at day 142 after administration, he died due to rapid worsening of his gastric cancer., Conclusion: Differentially diagnosing paraneoplastic dermatomyositis or drug-associated myositis caused by immune checkpoint inhibitors is difficult in some cases. The differential diagnosis is crucial because it influences the decision regarding the appropriateness of the use of immunosuppressive treatment against the autoimmune diseases as well as the decision regarding the appropriateness of the continuous use of immune checkpoint inhibitors against the primary cancers. Because subclinical autoimmune disease may become overt after administering immune checkpoint inhibitors, non-apparent autoimmune diseases, which have already existed, should also be considered to avoid the delay of appropriate treatment, when symptoms of autoimmune diseases are recognized.

Background: Predicting adverse drug reactions (ADRs) has become very important owing to the huge global health burden and failure of drugs. This indicates a need for prior prediction of probable ADRs in preclinical stages which can improve drug failures and reduce the time and cost of development thus providing efficient and safer therapeutic options for patients. Though several approaches have been put forward for in silico ADR prediction, there is still room for improvement., Methods: In the present work, we have used machine learning based approach for cardiovascular (CV) ADRs prediction by integrating different features of drugs, biological (drug transporters, targets and enzymes), chemical (substructure fingerprints) and phenotypic (therapeutic indications and other identified ADRs), and their two and three level combinations. To recognize quality and important features, we used minimum redundancy maximum relevance approach while synthetic minority over-sampling technique balancing method was used to introduce a balance in the training sets., Results: This is a rigorous and comprehensive study which involved the generation of a total of 504 computational models for 36 CV ADRs using two state-of-the-art machine-learning algorithms: random forest and sequential minimization optimization. All the models had an accuracy of around 90% and the biological and chemical features models were more informative as compared to the models generated using chemical features., Conclusions: The results obtained demonstrated that the predictive models generated in the present study were highly accurate, and the phenotypic information of the drugs played the most important role in drug ADRs prediction. Furthermore, the results also showed that using the proposed method, different drugs properties can be combined to build computational predictive models which can effectively predict potential ADRs during early stages of drug development.

Background: Second line anti-tuberculosis drugs are substantially complex, long term, more costly, and more toxic than first line anti-tuberculosis drugs. In Ethiopia, evidence on the incidence and predictors of adverse drug events has been limited. Thus, this study aimed at assessing incidence and predictors of major adverse drug events among drug resistant tuberculosis patients on second line tuberculosis treatment in Amhara Regional State public hospitals, Ethiopia., Methods: A multi-center retrospective cohort study was conducted on 570 drug resistant tuberculosis Patients. Data were entered in to EPI-Data version 4.2.0.0 and exported to Stata version 14 for analysis. Proportional hazard assumption was checked. The univariate Weibull regression gamma frailty model was fitted. Cox-Snell residual was used to test goodness of fit and Akaike Information Criteria (AIC) for model selection. Hazard ratio with 95% CI was computed and variables with P-value < 0.05 in the multivariable analysis were taken as significant predictors for adverse drug event., Results: A total of 570 patients were followed for 5045.09 person-month (PM) observation with a median follow-uptime of 8.23 months (Inter Quartile Range (IQR) =2.66-23.33). The overall incidence rate of major adverse drug events was 5.79 per 100 PM (95% CI: 5.16, 6.49). Incidence rate at the end of 2nd, 4th, and 6th months was 13.73, 9.25, 5.97 events per 100 PM observations, respectively. Age at 25-49 (Adjusted Hazard Ratio (AHR) = 3.36, 95% CI: 1.36, 8.28), and above 50 years (AHR = 5.60, 95% CI: 1.65, 19.05), co-morbid conditions (AHR = 2.74 CI: 1.12, 6.68), and anemia (AHR = 3.25 CI: 1.40, 7.53) were significant predictors of major adverse drug events., Conclusion: The incidence rate of major adverse drug events in the early 6 months of treatment was higher than that of the subsequent months. Age above 25 years, base line anemia, and co-morbid conditions were independent predictors of adverse drug events. Thus, addressing significant predictors and strengthening continuous follow-ups are highly recommended in the study setting.

Background: Adverse Drug Reactions (ADRs) are of great public health concern. FDA-approved drug labeling summarizes ADRs of a drug product mainly in three sections, i.e., Boxed Warning (BW), Warnings and Precautions (WP), and Adverse Reactions (AR), where the severity of ADRs are intended to decrease in the order of BW > WP > AR. Several reported studies have extracted ADRs from labeling documents, but most, if not all, did not discriminate the severity of the ADRs by the different labeling sections. Such a practice could overstate or underestimate the impact of certain ADRs to the public health. In this study, we applied the Medical Dictionary for Regulatory Activities (MedDRA) to drug labeling and systematically analyzed and compared the ADRs from the three labeling sections with a specific emphasis on analyzing serious ADRs presented in BW, which is of most drug safety concern., Results: This study investigated New Drug Application (NDA) labeling documents for 1164 single-ingredient drugs using Oracle Text search to extract MedDRA terms. We found that only a small portion of MedDRA Preferred Terms (PTs), 3819 out of 21,920 or 17.42%, were observed in a whole set of documents. In detail, 466/3819 (12.0%) PTs were in BW, 2023/3819 (53.0%) were in WP, and 2961/3819 (77.5%) were in AR sections. We also found a higher overlap of top 20 occurring BW PTs with WP sections compared to AR sections. Within the MedDRA System Organ Class levels, serious ADRs (sADRs) from BW were prevalent in Nervous System disorders and Vascular disorders. A Hierarchical Cluster Analysis (HCA) revealed that drugs within the same therapeutic category shared the same ADR patterns in BW (e.g., nervous system drug class is highly associated with drug abuse terms such as dependence, substance abuse, and respiratory depression)., Conclusions: This study demonstrated that combining MedDRA standard terminologies with data mining techniques facilitated computer-aided ADR analysis of drug labeling. We also highlighted the importance of labeling sections that differ in seriousness and application in drug safety. Using sADRs primarily related to BW sections, we illustrated a prototype approach for computer-aided ADR monitoring and studies which can be applied to other public health documents.

Background: The aim of this trial is to evaluate the effect of SENATOR software on incident, adverse drug reactions (ADRs) in older, multimorbid, hospitalized patients. The SENATOR software produces a report designed to optimize older patients' current prescriptions by applying the published STOPP and START criteria, highlighting drug-drug and drug-disease interactions and providing non-pharmacological recommendations aimed at reducing the risk of incident delirium., Methods: We will conduct a multinational, pragmatic, parallel arm Prospective Randomized Open-label, Blinded Endpoint (PROBE) controlled trial. Patients with acute illnesses are screened for recruitment within 48 h of arrival to hospital and enrolled if they meet the relevant entry criteria. Participants' medical history, current prescriptions, select laboratory tests, electrocardiogram, cognitive status and functional status are collected and entered into a dedicated trial database. Patients are individually randomized with equal allocation ratio. Randomization is stratified by site and medical versus surgical admission, and uses random block sizes. Patients randomized to either arm receive standard routine pharmaceutical clinical care as it exists in each site. Additionally, in the intervention arm an individualized SENATOR-generated medication advice report based on the participant's clinical and medication data is placed in their medical record and a senior medical staff member is requested to review it and adopt any of its recommendations that they judge appropriate. The trial's primary outcome is the proportion of patients experiencing at least one adjudicated probable or certain, non-trivial ADR, during the index hospitalization, assessed at 14 days post-randomization or at index hospital discharge if it occurs earlier. Potential ADRs are identified retrospectively by the site researchers who complete a Potential Endpoint Form (one per type of event) that is adjudicated by a blinded, expert committee. All occurrences of 12 pre-specified events, which represent the majority of ADRs, are reported to the committee along with other suspected ADRs. Participants are followed up 12 (+/- 4) weeks post-index hospital discharge to assess medication quality and healthcare utilization. This is the first clinical trial to examine the effectiveness of a software intervention on incident ADRs and associated healthcare costs during hospitalization in older people with multi-morbidity and polypharmacy., Trial Registration Number: Clinicaltrials.gov NCT02097654 , 27 March 2014.

Background: The benefit of medication reviews for long-term care (LTC) residents has been generally recognized throughout health care systems. Whereas many studies showed the impact of comprehensive medication reviews performed by specialized clinical pharmacists, little is known about the impact of medication reviews performed by community pharmacists. Involving them in the provision of medication reviews may help satisfy the increasing demand for ensuring medication safety., Methods: Community pharmacists supplying drugs to the LTC facilities performed a medication review for German LTC residents aged at least 65 years and taking five or more drugs per day based on the patients' medication only. Documented potential drug-related problems (DRPs) and the implementation rate of pharmaceutical interventions were evaluated descriptively. To assess the quality of the medication reviews, we developed a corresponding reference system based on the analysis of two experienced clinical pharmacists., Results: Twelve pharmacies performed medication reviews for 94 LTC residents. Overall, the pharmacists documented 154 potential DRPs (mean 1.6 per patient, SD 1.5) of which the most common were drug-drug interactions (40%) followed by potentially inappropriate medication (PIM) (16%) and inappropriate dosages (14%). 33% of the pharmacists' interventions to solve DRPs were successfully implemented, mostly dosage adjustments. The identification of potentially severe drug-drug interactions and PIM showed the highest agreement (88 and 73%) with the reference system., Conclusions: The medication review program of community pharmacists for LTC residents led to the identification of relevant DRPs. The reference system assessing the quality of the service can contribute to its transparency and reveals the potential for its improvement. The community pharmacists' knowledge of the LTC residents and their relation to the prescribers is crucial for providing successful medication reviews.

Background: In silico prediction of potential drug side-effects is of crucial importance for drug development, since wet experimental identification of drug side-effects is expensive and time-consuming. Existing computational methods mainly focus on leveraging validated drug side-effect relations for the prediction. The performance is severely impeded by the lack of reliable negative training data. Thus, a method to select reliable negative samples becomes vital in the performance improvement., Methods: Most of the existing computational prediction methods are essentially based on the assumption that similar drugs are inclined to share the same side-effects, which has given rise to remarkable performance. It is also rational to assume an inverse proposition that dissimilar drugs are less likely to share the same side-effects. Based on this inverse similarity hypothesis, we proposed a novel method to select highly-reliable negative samples for side-effect prediction. The first step of our method is to build a drug similarity integration framework to measure the similarity between drugs from different perspectives. This step integrates drug chemical structures, drug target proteins, drug substituents, and drug therapeutic information as features into a unified framework. Then, a similarity score between each candidate negative drug and validated positive drugs is calculated using the similarity integration framework. Those candidate negative drugs with lower similarity scores are preferentially selected as negative samples. Finally, both the validated positive drugs and the selected highly-reliable negative samples are used for predictions., Results: The performance of the proposed method was evaluated on simulative side-effect prediction of 917 DrugBank drugs, comparing with four machine-learning algorithms. Extensive experiments show that the drug similarity integration framework has superior capability in capturing drug features, achieving much better performance than those based on a single type of drug property. Besides, the four machine-learning algorithms achieved significant improvement in macro-averaging F1-score (e.g., SVM from 0.655 to 0.898), macro-averaging precision (e.g., RBF from 0.592 to 0.828) and macro-averaging recall (e.g., KNN from 0.651 to 0.772) complimentarily attributed to the highly-reliable negative samples selected by the proposed method., Conclusions: The results suggest that the inverse similarity hypothesis and the integration of different drug properties are valuable for side-effect prediction. The selection of highly-reliable negative samples can also make significant contributions to the performance improvement.

Background: First-generation antipsychotics (FGAs) are associated with a range of adverse events which can significantly reduce patients' quality of life and contribute to non-adherence. The aim of this study was to assess the prevalence and management practice of first generation antipsychotics induced side effects among schizophrenic patients., Methods: The study was conducted at Amanuel Mental Specialized Hospital from March to June, 2017. Data from patients were collected using a pretested structured questionnaire. Demographics and side effects of antipsychotics were collected by face to face interview. Clinical characteristics, medications and previous history of adverse drug events were extracted from medical records using data abstraction format. The data were analyzed using statistical software for social sciences (SPSS) version 20. Descriptive statistics and chi-square tests were done. Statistical significance was considered at p < 0.05., Results: Out of 356 participants, 300 of them had complete data and were included in the study. The mean age of participants was 33.71 ± 10.2 years. The majority, 195(65.0%), of participants were males. Most of the participants, 293(97.7%), developed FGA medication induced side effects. One hundred sixty three (54.3%) participants were treated with Trihexyphenidyl for FGAs induced side effects. Dose reduction of antipsychotics was done for 51(17.0%) participants. Most of the participants' side effects were not managed according to American Psychiatric Association guideline; 178 (82.4%). The most common types of FGAs induced side effects were cardiovascular side effects 169(56.3%); sedation and CNS side effects 149(49.6%); and extrapyramidal side effects 114(38.0%). There is a significant association between occurrence of side effects of FGAs and duration of illness (P = 0.04)., Conclusions: The prevalence of first generation antipsychotics induced side effects was high. However, management practice of the side effects was minimal.

Background: The main purpose of dose-finding studies in Phase I trial is to estimate maximum tolerated dose (MTD), which is the maximum test dose that can be assigned with an acceptable level of toxicity. Existing methods developed for single-agent dose-finding assume that the dose-toxicity relationship follows a specific parametric potency curve. This assumption may lead to bias and unsafe dose escalations due to the misspecification of parametric curve., Methods: This paper relaxes the parametric assumption of dose-toxicity relationship by imposing a Dirichlet process prior on unknown dose-toxicity curve. A hybrid algorithm combining the Gibbs sampler and adaptive rejection Metropolis sampling (ARMS) algorithm is developed to estimate the dose-toxicity curve, and a two-stage Bayesian nonparametric adaptive design is presented to estimate MTD., Results: For comparison, we consider two classical continual reassessment methods (CRMs) (i.e., logistic and power models). Numerical results show the flexibility of the proposed method for single-agent dose-finding trials, and the proposed method behaves better than two classical CRMs under our considered scenarios., Conclusions: The proposed dose-finding procedure is model-free and robust, and behaves satisfactorily even in small sample cases.

Background: Under-reporting of adverse drug reactions (ADRs) is a major challenge for pharmacovigilance in Africa. This study sets out to assess the level of awareness of Ghanaian patients about ADRs and ADR-reporting and explores how different patients in Ghana recognize an ADR and the steps they take when they experience an ADR., Methods: This was a two-part study consisting of a survey to quantify the awareness of Ghanaian patients on ADRs and ADR-reporting, and in-depth interviews to explore how patients recognize an ADR and the steps they take thereafter. Participants were selected from 28 health care facilities (HCF) in rural and urban areas in 4 out of the 10 administrative regions of Ghana. Chi-square tests were used to examine associations between demographic variables and i) awareness of ADRs and ADR-reporting, ii) ADR experience and iii) awareness of the Ghana Food and Drug Authority (Ghana-FDA) and its patient reporting system (PRS). Only participants that indicated they experienced an ADR were included for the in-depth interviews. Data was investigated for participants' awareness of ADRs, ADR reporting and steps taken when they experience ADRs., Results: Of the total 572 participants enrolled in the study, 14% indicated they were unaware of ADRs and were excluded. Of the remaining 491 participants, 38% had experienced an ADR, of which 67% reported the ADR, 68% of them reported it to a doctor. Only 3% of the 491 participants were aware of the Ghana-FDA's PRS. The interview phase consisted of 33 patients who had experienced an ADR. Three key findings from the interview phase were; most participants recognized an ADR themselves, the symptoms of the ADR were the most mentioned reason for reporting and participants experienced a wide variety of obstacles in ADR-reporting., Conclusions: Most Ghanaian patients appear unaware of or unable/unwilling to use formal national channels for ADR reporting like the Ghana-FDA PRS. Motivation for ADR reporting appeared mainly personal and not communal. These findings warrant further attention in order to increase patient reporting of ADRs.

Background: Trial participants in placebo groups report experiencing adverse events (AEs). Existing systematic reviews have not been synthesized, leaving questions about why these events occur as well as their prevalence across different conditions unanswered., Objectives: (1) To synthesize the evidence of prevalence of AEs in trial placebo groups across different conditions. (2) To compare AEs in trial placebo groups with AEs reported in untreated groups within a subset of randomized trials., Search Methods: We searched PubMed for records with the word "nocebo" in the title and "systematic" in any field. We also contacted experts and hand-searched references of included studies., Study Eligibility: We included any systematic review of randomized trials where nocebo effects were reported. We excluded systematic reviews of non-randomized studies., Participants and Interventions: We included studies in any disease area., Study Appraisal and Synthesis Methods: We appraised the quality of the studies using a shortened version of the Assessment of Multiple Systematic Reviews tool (AMSTAR) tool. We reported medians and interquartile ranges (IQRs) of AEs. Among the trials within the review that included untreated groups, we compared the prevalence of AEs in untreated groups with the prevalence of AEs in placebo groups., Results: We identified 20 systematic reviews. These included 1271 randomized trials and 250,726 placebo-treated patients. The median prevalence of AEs in trial placebo groups was 49.1% (IQR 25.7-64.4%). The median rate of dropouts due to AEs was 5% (IQR 2.28-8.4%). Within the 15 of trials that reported AEs in untreated groups, we found that the AE rate in placebo groups (6.51%) was higher than that reported in untreated groups (4.25%)., Limitations: This study was limited by the quality of included reviews and the small number of trials that included untreated groups., Conclusions and Implications of Key Findings: AEs in trial placebo groups are common and cannot be attributed entirely to natural history. Trial methodologies that reduce AEs in placebo groups while satisfying the requirement of informed consent should be developed and implemented.

Background: In recent years there has been a substantial increase in the use of over-the-counter (OTC) products around the world. While they are assumed to be safe by consumers, they can potentially lead to adverse effects and drug interactions particularly in older adults., Methods: We assessed the patterns of OTC products used by older adults admitted to the cardiology service in a tertiary care medical center in the USA over a three month period. We conducted a retrospective chart review where older adults with cardiovascular diseases (CVD) who were taking at least one OTC product at home were included., Results: Out of 404 patients who were admitted to the cardiology service, 281 (69.6%) were taking OTC products. Patients were taking a total of 659 OTC products; mean of 2.35 ± 1.57 and the range varied from 1 to 9 products. The most commonly used products were vitamins (37.3%), followed by laxatives (17%), minerals (13.6%), stomach acid reducers (9%), and analgesics (3.6%). OTC users were found to be suffering from more comorbidities and received more prescription medications as compared to non-users. Gender and age did not have an impact on the use of OTC products while patients with atrial fibrillation, sleep apnea and gastro-esophageal reflux disease were more likely to use OTC products., Conclusion: Use of OTC products is quite frequent in older adults with CVD in our study. Clinicians should ask about OTC product usage and counsel patients about the risks and benefits associated with their use.

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.

Background: Risk factors associated with opioid-induced adverse reactions (OIARs) in the elderly population have not been well defined. The objective of this study was to determine effects of various risk factors on incidence of OIARs in male elderly patients., Methods: A retrospective cohort study in Korea Veterans Hospital was performed. Data were analyzed in male patients aged 65 years and older who received morphine, oxycodone, or codeine. Binomial variables describing patient-related and drug-related characteristics were constructed. Associations between these variables and frequency of OIARs were determined. Odds ratio (OR) and adjusted odds ratio (AOR) were calculated from univariate and multivariable analyses, respectively. Attributable risk was obtained by (1-1/OR)*100%., Results: Of 316 patients, 28% experienced at least one adverse event. The most common adverse events were gastrointestinal problems (n = 59) and central nerve system adverse effects (n = 20). The odds of OIARs in patients with opioid use ≥12 weeks was increased by 80% compared to those with opioid use < 12 weeks. Attributable risk of GABA analogues was 64~78% in constructed Models. Compared to codeine users, patients using morphine and oxycodone had 653 and 473% increased odds for OIARs, respectively. MME ≥ 60 mg/day had a 317% increased odds for OIARs (95% CI: 1.92-9.04) compared to MME < 60 mg/day. Opioid combination therapy had a 139% increased odds for OIARs compared to monotherapy., Conclusions: These findings have significant implications for clinical use of opioid in elderly patients. Our study suggests that low dose short-term use will pose less risk of OIARs for the elderly, whereas concomitant use of GABA analogues, strong opioids and dual-opioid therapy may increase the risk of OIARs. Therefore, clinician should carefully monitor patients when starting opioid therapy in older population.

Background: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level., Methods: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well., Results: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects., Conclusions: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.