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Background: Extracellular vesicles (EVs) are a heterogeneous family of small vesicles released by donor cells and absorbed by recipient cells, which represent important mediators with fundamental roles in both physiological and pathological conditions. EVs are present in a large variety of biological fluids and have a great diagnostic and prognostic value. They have gained the interest of the scientific community due to their extreme versatility. In fact, they allow us to hypothesize new therapeutic strategies since, in addition to being cell signal mediators, they play an important role as biomarkers, drug vehicles, and potential new therapeutic agents. They are also involved in immunoregulation, have the ability to transmit resistance to a drug from one cell to a more sensitive one, and can act as drug delivery systems. Objective: The main reciprocal interactions between EVs and immunosuppressive drugs will be presented. Results: The known interactions between EVs and immunosuppressive drugs, in particular cyclosporin, glucocorticoids, rapamycin, methotrexate, cyclophosphamide, eculizumab, infliximab, certolizumab, etanercept, glatiramer acetate, and fingolimod are presented. Conclusion: This review provides relevant information on the links between EVs and immunosuppressive drugs with a focus on EVs' role as tools to assess the effects of immunosuppressants, suggesting innovative properties and new possible therapeutic uses.

Knowledge about current trends and epidemiology in poisonings is important to maintain quality in diagnostics, treatment and prevention. We performed a cross-sectional study of all cases (n = 261) admitted with drug poisoning to Aalborg University Hospital during 1 year in 2017–2018. Median age was 30 (22–49) years, and 58% were female. Fifty percent were suicide attempts. In most cases, involved drugs were identified by history taking; blood analysis barely revealed any additional paracetamol and salicylicate poisonings. Drugs prescribed to the patient or available over the counter were involved in nearly two thirds of cases. Weak analgesics dominated by paracetamol (n = 91, 35%) was the most frequently involved group of drugs followed by opioids and benzodiazepines. Gender differences were observed with respect to involvement of weak analgesics and central stimulants. A higher prevalence of unidentified involved drugs was observed in 26 cases (10%) in which the length of admission exceeded 2 days and/or intensive care was needed. No deaths, cardiac arrhythmias or physical complications occurred. Thus, current handling of the acute poisoning seems effective in most cases. However, a more tailored use of blood analyses including a toxicological screen in selected cases may represent an opportunity for improvement.

Tramadol is an effective alternative local anaesthetic (LA) agent available in dentistry. This review aims to help guide practice by providing clinicians with relevant data regarding adverse effects (AE) associated with locally administered tramadol in the oral environment. A systematic search of three electronic databases was performed to identify relevant studies reporting AE associated with locally administered tramadol in the oral setting. Selected studies were reviewed and included based on inclusion and exclusion criteria. Data collected included: publication year, study design, participant numbers, adverse effects and follow-up duration. Fifteen articles were included comprising of 547 tramadol participants across eight exodontia and seven non-exodontia studies. Thirty-eight associated AE were reported. Nausea was the most commonly reported (4.6%), followed by dizziness (1.3%), vomiting (0.7%) and local erythema (0.4%). No other AE were reported. The prevalence of total AE was similar in ≥ 50 mg tramadol doses (7.2–7.3%); however the total affected number is not dose dependent. The prevalence of AE and affected participants was less when tramadol was used as a sole LA rather than as an adjunct (5.6% vs. 7.9% and 3.4–5.6% vs. 6.3%, respectively). Thus, tramadol is a safe LA agent with a low prevalence of AE when administered in the dental setting.

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, and DPYD variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU treatment. The patient was treated effectively with alternative systemic therapy. Routine pretreatment DPYD genotyping is recommended by the European Medicines Agency, and guidelines for use of 5-FU in DPD deficient patients are available. However, outside the province of Quebec, routine pretreatment screening for DPD deficiency remains unavailable in Canada. It is likely our patient would have died from 5-FU toxicity under the current standard of care, but instead provides an example of the potential benefit of DPYD screening on patient outcomes.

Hydroxychloroquine has attracted attention in the treatment of COVID-19. Many conflicting findings have been reported regarding the efficacy and safety of this drug, which has been used safely in the rheumatological diseases for years. However, these studies lacked measurement methods that allow accurate assessment of hydroxychloroquine and its metabolite levels. The aim of this study was to measure hydroxychloroquine and its metabolite levels in whole blood samples of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) and scleroderma (Scl) by a robust, simple and accurate validated tandem mass spectrometric method, and to investigate the relationship between these levels with drug-related adverse effects and disease activity scores. The validated LC-MS/MS method was applied to measure blood hydroxychloroquine and its metabolite levels of patients with RA, SLE, SS, Scl. Various haematological and biochemical parameters were measured with Beckman-Coulter AU 5800 and Beckman Coulter LH 780 analyzers, respectively. QTc intervals were calculated with Bazett's formula, and the patients were followed up by clinicians in terms of clinical findings and adverse effects. Hydroxychloroquine levels of patients were similar to previous studies. There was a negative correlation between disease activity scores and hydroxychloroquine levels, while the highest correlation was between QTc interval, creatinine and GFR levels with desethylchloroquine. Bidetylchloroquine had the highest correlation with RBC count and liver function tests. Our findings showed that hydroxychloroquine and its metabolite levels were associated with disease activity scores, renal, hepatic function, QTc prolongation, and hematological parameters.

Coronavirus disease-2019 (COVID-19) has affected more than 220 million individuals since the global pandemic began. There is an urgent need for safe and effective vaccines, and vaccinations, such as mRNA vaccines, have been initiated worldwide. However, the adverse effects of these vaccines remain unclear. We herein present a case of an 80-year-old female on maintenance hemodialysis who developed takotsubo cardiomyopathy 4 days after receiving the first dose of the Pfizer-BioNTech COVID-19 vaccine. There was no obvious trigger for the onset of takotsubo cardiomyopathy other than the COVID-19 vaccination, which was the most significant event preceding her presentation. Echocardiograms obtained during her admission allowed us to monitor and show the recovery of left ventricular wall motion. We confirmed the diagnosis of takotsubo cardiomyopathy based on the findings, including transient left ventricular dysfunction, electrocardiographic abnormalities, an elevated troponin level, and the absence of occlusive coronary artery disease. In the present case, the vaccination may have triggered emotional or physical stress. Although difficulties are associated with proving the causal relationship in the present case, the temporal relationship between the vaccination and the onset of takotsubo cardiomyopathy is highly suggestive. The adverse effects associated with the vaccine are typical of COVID-19 vaccines administered to date, most of which are acceptable. Therefore, despite our experience of the present case, we still recommend the vaccination for COVID-19 because takotsubo cardiomyopathy induced by the COVID-19 vaccine is extremely rare and the prognosis of the patient was good. We herein present the first case of a patient on hemodialysis who developed takotsubo cardiomyopathy after receiving COVID-19 vaccination.

SARS-CoV-2, a recently emerged zoonotic virus, has resulted in unstoppable high morbidity and mortality rates worldwide. However, due to a limited knowledge of the dynamics of the SARS-CoV-2 infection, it has been observed that the current COVID-19 therapy has led to some clinical repercussions. We discuss the adverse effects of drugs for COVID-19 primarily based on some clinical trials. As therapeutic efficacy and toxicity of therapy may vary due to different, genetic determinants, sex, age and the ethnic background of test subjects, hence biomarker-based personalized therapy could be more appropriate. We will share our thoughts on the current landscape of personalized therapy as a roadmap to fight against SARS-CoV-2 or another emerging pathogen.

Mahmoodullah Azimi,1 Wazhma Masoom Dehzad,1 Mohammad Asif Atiq,1 Barin Bahain,1 Abdullah Asady2 1Department of Clinical Pharmacology, Kabul University of Medical Sciences, Kabul, Afghanistan; 2Department of Microbiology, Kabul University of Medical Sciences, Kabul, AfghanistanCorrespondence: Abdullah AsadyDepartment of Microbiology, Kabul University of Medical Sciences, Kabul, AfghanistanTel +93731087928Email asady_abdullah@yahoo.comPurpose: To evaluate the occurrence, extent, and severity of adverse reactions associated with the vaccine of COVID-19 (ChAdOx1 nCoV-19 vaccine or AstraZeneca) among Kabul University of Medical Sciences staff.Patients and Methods: A retrospective observational, interview-based study was conducted from 4 to 20 April, 2021, to evaluate the adverse reactions associated with the vaccine of COVID-19 (ChAdOx1 nCoV-19 vaccine or AstraZeneca) among the staff and lecturers of the Kabul University of Medical Sciences, Kabul, Afghanistan. Participants were interviewed following the administration of the first dose of the AstraZeneca vaccines. They were asked to report any adverse reactions that occurred within 8– 10 days after vaccination. The frequency, duration, severity, and outcome of the reactions were recorded. Association of the adverse reactions was analysed with the ages of participants and previous infection with SARS CoV-2.Results: The most common adverse reactions reported by the participants were muscle pain (68.3%), local pain (58.8%) at the site of injection (68.3%), fever (66.3%) and fatigue (66.3%). Almost half of the respondents reported chills, joint pain and headache after receiving the first shot of the vaccine. The frequency of adverse reactions was higher in participants aged 40 years or less, and in those previously infected with SARS CoV-2. The severity of most adverse reactions was mild to moderate. No serious case or death was reported.Conclusion: The adverse reactions reported by the participants were mild to moderate in severity, and for a short duration. The findings of this study help us to address the vaccine hesitancy caused by worries about severe adverse effects associated with the COVID-19 vaccine.Keywords: adverse effects, COVID-19, vaccine, ChAdOx1 nCoV-19, AstraZeneca

The coronavirus disease 2019 (COVID-19) vaccines are categorized according to the manufacturing technique, including mRNA vaccines and adenovirus vector vaccines. According to previous studies, the reported efficacy of the COVID-19 vaccine is excellent regardless of the type of vaccine, and the majority of studies have shown similar results for safety. Most of the adverse reactions after vaccination were mild or moderate grade, and severe reactions were reported in a very small proportion. However, the adverse reactions that might occur after nationwide vaccinations can contribute to crowding of emergency departments, and this can further lead to significant obstacles to providing necessary treatment for life-threatening conditions. Therefore, as emergency physicians, we would like to present some concerns and suggestions to prevent these predictable problems.

Purpose The COVID-19 pandemic has galvanized the development of new vaccines at an unprecedented pace. Since the widespread implementation of vaccination campaigns, reports of ocular adverse effects after COVID-19 vaccinations have emerged. This review summarizes ocular adverse effects possibly associated with COVID-19 vaccination, and discusses their clinical characteristics and management. Methods Narrative Literature Review. Results Ocular adverse effects of COVID-19 vaccinations include facial nerve palsy, abducens nerve palsy, acute macular neuroretinopathy, central serous retinopathy, thrombosis, uveitis, multiple evanescent white dot syndrome, Vogt-Koyanagi-Harada disease reactivation, and new-onset Graves’ Disease. Studies in current literature are primarily retrospective case series or isolated case reports – these are inherently weak in establishing association or causality. Nevertheless, the described presentations resemble the reported ocular manifestations of the COVID-19 disease itself. Hence, we hypothesize that the human body’s immune response to COVID-19 vaccinations may be involved in the pathogenesis of the ocular adverse effects post-COVID-19 vaccination. Conclusion Ophthalmologists and generalists should be aware of the possible, albeit rare, ocular adverse effects after COVID-19 vaccination.

Psychosis, a break in reality which is manifested as hallucinations, delusions or the disruption in thought process, is the hallmark of schizophrenia. Despite novel pharmacotherapy advancements of antipsychotic medications that have resulted in some patients having the ability to return to social settings and thereby decreasing psychotic symptoms and reducing hospital admissions, there is still a sub-population of patients who remain symptomatic. Treatment-resistant schizophrenia is defined as failure of treatment with at least two different antipsychotics with the proper length of treatment and titration. Clozapine has been heralded as a drug to resolve the puzzle of treatment-resistant schizophrenia. Clozapine has one side effect that is well known, being the development of agranulocytosis. However, there is another side effect that can limit clozapine’s use and can also be life-threatening. Recently, at the end of January 2020, the FDA issued a communications statement which “[strengthened] an existing warning that constipation caused by the schizophrenia medicine clozapine can, uncommonly, progress to serious bowel complications.” After identifying ten cases of constipation from between 2006 to 2016 that progressed to hospitalization, surgery, and even death, the FDA focused their attention on this often overlooked, common side effect, especially when considering the strong anticholinergic effects of clozapine. Although patients are screened by their physicians for agranulocytosis by weekly lab monitoring, constipation is also a complication that needs to be identified and treated. Much like opioid-induced constipation, constipation can also be reduced with the use of laxatives and reduction in the co-prescribing of anticholinergic therapies with clozapine.

International audience; Eribulin is widely used in the treatment of metastatic breast cancer, with a manageable toxicity profile. This aggressive disease often requires systemic and local treatments, comprising surgery or radiotherapy. However, eribulin is usually discontinued during radiation therapy due to the lack of data concerning the safety of this combination, especially in the setting of repeat locoregional radiation therapy. Our patient was diagnosed with ER positive invasive ductal carcinoma of the left breast initially treated by surgery, radiation therapy, chemotherapy, and hormone therapy. She then received various lines of chemotherapy for multiple triple-negative relapses in the left axillary region. Since October 2020, she has been treated by eribulin. In order to improve local control, it was decided to add local radiation therapy to the region of recurrence in addition to systemic therapy. She underwent radiation therapy concomitantly with eribulin from February to March 2021. Treatment was very well tolerated, and no acute toxicity was reported. This is the first published case of repeat locoregional radiation therapy in combination with eribulin.

BackgroundTo verify the efficacy and safety of an inexpensive standardized regimen for multidrug-resistant tuberculosis (MDR-TB) with low resistance to isoniazid (INH), a multicenter prospective study was conducted in eastern China.MethodsPatients diagnosed as MDR-TB with low concentration INH resistance and rifampicin resistance, second-line/injectable agents sensitive were prospectively enrolled, given the regimen of Amikacin (Ak)–Fluoroquinolones (FQs)–Cycloserine (Cs)–Protionamide (Pto)–PasiniaZid (Pa)–Pyrazinamide (Z) for 6 months followed by 12 months of FQs–Cs–Pto–Pa–Z, and then followed up for treatment outcomes and adverse events (AEs).ResultsA total of 114 patients were enrolled into the study. The overall favorable treatment rate was 79.8% (91/114). Among 91 cases with favorable treatment, 75.4% (86/114) were cured and 4.4% (5/114) were completed treatment. Regarding to unfavorable outcomes, among 23 cases, 8.8% (10/114) had failures, 8.8% (10/114) losing follow up, 0.9% (1/114) had treatment terminated due to intolerance to drugs and 1.8% (2/114) died. Treatment favorable rate was significantly higher in newly treated MDR-TB (91.7%, 33/36) than that in retreated MDR-TB (74.4%, 58/78,p0.03). The investigators recorded 42 AEs occurrences in 30 of 114 patients (26.3%). Clinicians rated most AEs as mild or moderate (95.24%, 40/42).ConclusionsThe regimen was proved to be effective, safe and inexpensive. It is suitable for specific drug resistant population, especially for newly-treated patients, which could be expected to be developed into a short-course regimen.Clinical trials registrationChina Clinical Trial Registry ChiCTR-OPC-16009380

Antibodies targeting the PD-1, PD-L1, and CTLA-4 immune checkpoint axis have been used in a variety of tumor types. They achieve anti-tumor activity through activating the patient’s own immune system to target immune response evading cancer cells. However, this unique mechanism of action may cause immune-related adverse events, irAEs. One of these irAEs is myocarditis which is associated with an alarming mortality rate. In this study we presented clinical cases of myocarditis from safety trial datasets submitted to the U.S. Food and Drug Administration, FDA. Additionally, we analyzed over fourteen million FDA Adverse Event Reporting System, FAERS, submissions. The statistical analysis of the FAERS data provided evidence of significantly increased reporting of myocarditis in patients administered immune checkpoint inhibitors alone, in combination with another immune checkpoint inhibitor, the kinase inhibitor axitinib, or chemotherapy, for all cancer types, when compared to patients administered chemotherapy. All combination therapies led to further increased reporting odds ratios of myocarditis. We further analyzed the occurrence of myocarditis by stratifying the reports into sub-cohorts based on specific cancer types and treatment/control groups in major cancer immunotherapy efficacy trials and confirmed the observed trend for each cohort.

Drug use during pregnancy is not common. Drug-induced liver injury (DILI) is a potential complication that is rare but can adversely affect both the mother and the fetus. Although many drugs can directly cause hepatotoxicity, idiosyncratic liver injury is common in pregnancy. Underreporting of adverse drug reactions, lack of adequate literature regarding drug safety in pregnancy, and the inherent difficulty in diagnosing DILI during pregnancy make the management of this condition challenging. This review attempts to describe the existing literature regarding DILI in pregnancy, which is mainly in the form of case reports; several studies have looked at the safety of antithyroid drugs, antiretroviral drugs, and paracetamol, which have an indication for use in pregnancy; the relevant data from these studies with regard to DILI has been presented. In addition, the review describes the diagnosis of DILI, grading the disease severity, assessment of causality linking the drug to the adverse event, regulatory guidelines for evaluating the potential of drugs to cause liver injury, efforts to ensure better participation of women in clinical trials and studies in pregnant women population in particular, and the challenges involved in generating adequate research evidence. The establishment of DILI registries in various countries is an encouraging development; however, there is a need for promoting active, spontaneous reporting of adverse events during pregnancy to ensure rapid generation of evidence regarding the safety of a drug in pregnant women.

Measurement of adverse effects of psychological therapy is inconsistent due to ambiguity about the concept. The perspective of people undertaking psychological therapy (that is, experts by experience) has largely been overlooked. This study will investigate whether there is consensus between the opinions of professionals and experts by experience. The Delphi method was used. In Round 1 thematic analysis was used to analyse qualitative responses. Wilcoxon rank-sum tests were used to examine group differences in Rounds 2 and 3. The study protocol was prospectively registered, reference osf.io/f9wp7. Fifty-one professionals and 51 experts by experience generated 147 potential adverse effects in Round 1, across 9 themes; including ‘therapy amplifies problem’, ‘emotional lability’ and ‘sense of self’. Each item was rated for overall consensus in Rounds 2 (n = 62) and 3 (n = 63). Thirty-eight items were rated as essential, very important or important to include on a list of potential adverse effects. A further 12 items were rated as important by the expert by experience group only. Professionals were more conservative in their ratings. There appeared to be consensus between professionals and experts by experience on what to include in a list of adverse effects of psychological therapy (the EDAPT), including novel adverse effects which have not been previously considered. Further research is required to understand which adverse effects are necessary, unnecessary, or indeed harmful to psychotherapy outcomes.

Background Despite evidence supporting the safety of breast implants, some women associate their implants with adverse health effects and have called this syndrome “breast implant illness.” We sought to characterize breast implant illness symptoms and to report how implant removal affects their symptoms.Methods An anonymous 20 question survey was administered to the Facebook group: “UTAH Breast Implant Illness” to characterize the symptoms these women attributed to their breast implants. Several questions allowed us to evaluate how implant removal affected women’s symptoms.Results Of the 182 respondents, 97% report that implants negatively affect their health and 95% identify these symptoms with breast implant illness. Ninety-six percent of respondents had implants placed for cosmetic reasons and 51% had silicone implants. The most common symptoms associated with breast implant illness are brain fog (95%), fatigue (92%), joint pain (80%), and hair loss (74%). Sixty percent of respondents learned about breast implant illness from family/friends and/or social media platforms (56%), 40% of respondents had their implants removed, and 97% report relief of their symptoms post-removal (23% complete, 74% partial). Following explantation, there was a significant improvement in all but one reported symptom. An association was found between the number of symptoms reported prior to explantation and the number of symptoms resolving following explantation.Conclusions Breast implant illness is a syndrome characterized by fatigue, decreased focus, hair loss, and joint pain after the placement of breast implants. Nearly all patients report improvement of symptoms after implant removal. Significant efforts should be made to better understand breast implant illness and its etiology.

Preservatives in multidose formulations of topical ophthalmic medications are crucial for maintaining sterility but can be toxic to the ocular surface. Benzalkonium chloride (BAK)—used in approximately 70% of ophthalmic formulations—is well known to cause cytotoxic damage to conjunctival and corneal epithelial cells, resulting in signs and symptoms of ocular surface disease (OSD) including ocular surface staining, increased tear break-up time, and higher OSD symptom scores. These adverse effects are more problematic with chronic exposure, as in lifetime therapy for glaucoma, but can also manifest after exposure as brief as seven days. Multiple strategies are available to minimize or eliminate BAK exposure, among them alternative preservatives, preservative-free formulations including sustained release drug delivery platforms, and non-pharmacological therapies for common eye diseases and conditions. In this paper, we review the cytotoxic and clinical effects of BAK on the ocular surface and discuss existing and emerging options for ocular disease management that can minimize or eliminate BAK exposure.