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BACKGROUND: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (IKr) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. METHODS: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. RESULTS: Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and IKr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. IKr reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. CAVIN1, essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin. CONCLUSIONS: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.
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Canal de Potássio ERG1 , Células-Tronco Pluripotentes Induzidas , Síndrome do QT Longo , Miócitos Cardíacos , Sotalol , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Canal de Potássio ERG1/genética , Canal de Potássio ERG1/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Sotalol/farmacologia , Potenciais de Ação/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Canais de Potássio Éter-A-Go-Go/genética , MasculinoRESUMO
Over the past decade, in vivo gene replacement therapy has significantly advanced, resulting in market approval of numerous therapeutics predominantly relying on adeno-associated viral vectors (AAV). While viral vectors have undeniably addressed several critical healthcare challenges, their clinical application has unveiled a range of limitations and safety concerns. This review highlights the emerging challenges in the field of gene therapy. At first, we discuss both the role of biological barriers in viral gene therapy with a focus on AAVs, and review current landscape of in vivo human gene therapy. We delineate advantages and disadvantages of AAVs as gene delivery vehicles, mostly from the safety perspective (hepatotoxicity, cardiotoxicity, neurotoxicity, inflammatory responses etc.), and outline the mechanisms of adverse events in response to AAV. Contribution of every aspect of AAV vectors (genomic structure, capsid proteins) and host responses to injected AAV is considered and substantiated by basic, translational and clinical studies. The updated evaluation of recent AAV clinical trials and current medical experience clearly shows the risks of AAVs that sometimes overshadow the hopes for curing a hereditary disease. At last, a set of established and new molecular and nanotechnology tools and approaches are provided as potential solutions for mitigating or eliminating side effects. The increasing number of severe adverse reactions and, sadly deaths, demands decisive actions to resolve the issue of immune responses and extremely high doses of viral vectors used for gene therapy. In response to these challenges, various strategies are under development, including approaches aimed at augmenting characteristics of viral vectors and others focused on creating secure and efficacious non-viral vectors. This comprehensive review offers an overarching perspective on the present state of gene therapy utilizing both viral and non-viral vectors.
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Dependovirus , Terapia Genética , Vetores Genéticos , Humanos , Terapia Genética/efeitos adversos , Dependovirus/genética , AnimaisRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established. METHODS: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne, Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry. RESULTS: Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P=0.03 versus cTnT), and 43 of 57 ([75%] P<0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%] P<0.001) on admission was confirmed in 87 independent cases from an international registry. In the Franco-German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2-16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2-38.0]; P<0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients (P<0.001), respectively. CONCLUSIONS: cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis.
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Miocardite , Humanos , Miocardite/induzido quimicamente , Miocardite/diagnóstico , Inibidores de Checkpoint Imunológico , Biomarcadores , Creatina Quinase , Prognóstico , Troponina TRESUMO
As the number of vaccinated individuals has increased, there have been increasing reports of cutaneous hypersensitivity reactions. The main COVID-19 vaccines administered include messenger ribonucleic acid vaccines, non-replicating viral vector vaccines, inactivated whole-virus vaccines, and protein-based vaccines. These vaccines contain active components such as polyethylene glycol, polysorbate 80, aluminum, tromethamine, and disodium edetate dihydrate. Recent advances in understanding the coordination of inflammatory responses by specific subsets of lymphocytes have led to a new classification based on immune response patterns. We categorize these responses into four patterns: T helper (Th)1-, Th2-, Th17/22-, and Treg-polarized cutaneous inflammation after stimulation of COVID-19 vaccines. Although the association between COVID-19 vaccination and these cutaneous adverse reactions remains controversial, the occurrence of rare dermatoses and their short intervals suggest a possible relationship. Despite the potential adverse reactions, the administration of COVID-19 vaccines is crucial in the ongoing battle against severe acute respiratory syndrome coronavirus 2.
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Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , SARS-CoV-2/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , Toxidermias/etiologia , Toxidermias/imunologiaRESUMO
BACKGROUND: Lenvatinib plus pembrolizumab significantly improved efficacy compared with chemotherapy in patients with advanced endometrial cancer (aEC) regardless of microsatellite instability status or histologic subtype, who had disease progression following prior platinum-based therapy, in Study-309/KEYNOTE-775. The safety profile of the combination was generally consistent with that of each monotherapy drug and of the combination in patients with endometrial cancer and other solid tumors. Given the medical complexity of patients with aEC, this paper aims to characterize key adverse reactions (ARs) of the combination treatment and review management strategies, providing a guide for AR management to maximize anticancer benefits and minimize treatment discontinuation. MATERIALS AND METHODS: In Study-309/KEYNOTE-775, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks) or chemotherapy (doxorubicin or paclitaxel). The incidence and median time to the first onset of ARs, dose modifications, and concomitant medications are described. Key ARs characterized include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight decreased, proteinuria, and palmar-plantar erythrodysesthesia syndrome. RESULTS: As expected, the most common any-grade key ARs included: hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders. Grades 3-4 key ARs with incidence ≥10% included: hypertension, fatigue, and weight decreased. Key ARs first occurred within approximately 3 months of treatment initiation. AR management strategies consistent with the prescribing information and the study protocol are discussed. CONCLUSION: Successful AR management strategies for lenvatinib plus pembrolizumab include education of the patient and entire treatment team, preventative measures and close monitoring, and judicious use of dose modifications and concomitant medications. CLINICALTRIALS.GOV ID: NCT03517449.
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Neoplasias do Endométrio , Hipertensão , Hipotireoidismo , Doenças Musculoesqueléticas , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Endométrio/tratamento farmacológico , Diarreia/tratamento farmacológico , Fadiga/etiologia , Hipertensão/tratamento farmacológico , Doenças Musculoesqueléticas/tratamento farmacológico , Doenças Musculoesqueléticas/etiologiaRESUMO
Vitamin D deficiency has been reported to be associated with allergic diseases and dermatological disorders. We investigated the role of vitamin D in drug-induced non-immediate hypersensitivity reactions by measuring serum vitamin D levels in 60 patients diagnosed with non-immediate drug hypersensitivity reactions and in 60 patients who tolerated the same medication without any allergic reactions. The results showed that serum vitamin D levels were significantly lower in patients with severe cutaneous adverse reactions (SCARs) (13.56 ± 6.23 ng/mL) compared to patients with mild reactions (17.50 ± 7.49 ng/mL) and the drug-tolerant control group (17.42 ± 7.28 ng/mL), with p values of 0.031 and 0.015, respectively. The proportion of severe vitamin D deficiency (< 10 ng/mL) was much higher in SCAR patients compared to drug-tolerant subjects (36.7% vs. 11.7%, p value = 0.005). After adjusting for age, gender, region of residence, and concurrent illnesses, patients with severe vitamin D deficiency had significantly increased in-hospital mortality (odds ratio 16.04; 95% CI, 1.25-206.12, p value = 0.03). In conclusion, the risk of developing SCARs and in-hospital mortality was increased in patients with severe vitamin D deficiency. Further investigations should be conducted to elucidate the role of vitamin D in the development of SCARs.
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Hipersensibilidade , Deficiência de Vitamina D , Humanos , Cicatriz , Deficiência de Vitamina D/complicações , Vitamina D , Vitaminas , Hipersensibilidade/complicaçõesRESUMO
BACKGROUND: Recent advances in the management of pancreatic neuroendocrine tumors (pNETs) highlight the potential benefits of temozolomide, an alkylating agent, for these patients. In this meta-analysis, we aimed to assess the outcome of temozolomide, alone or in combination with other anticancer medications in patients with advanced pNET. METHODS: Online databases of PubMed, Web of Science, Embase, the Cochrane Library, and ClinicalTrials.gov were searched systematically for clinical trials that reported the efficacy and safety of temozolomide in patients with advanced pNET. Random-effect model was utilized to estimate pooled rates of outcomes based on Response Evaluation Criteria in Solid Tumors criteria, biochemical response, and adverse events (AEs). RESULTS: A total of 14 studies, providing details of 441 individuals with advanced pNET, were included. The quantitative analyses showed a pooled objective response rate (ORR) of 41.2% (95% confidence interval, CI, of 32.4%-50.6%), disease control rate (DCR) of 85.3% (95% CI of 74.9%-91.9%), and a more than 50% decrease from baseline chromogranin A levels of 44.9% (95% CI of 31.6%-49.0%). Regarding safety, the results showed that the pooled rates of nonserious AEs and serious AEs were 93.8% (95% CI of 88.3%-96.8%) and 23.7% (95% CI of 12.0%-41.5%), respectively. The main severe AEs encompassed hematological toxicities. CONCLUSIONS: In conclusion, our meta-analysis suggests that treatment with temozolomide, either as a monotherapy or in combination with other anticancer treatments might be an effective and relatively safe option for patients with advanced locally unresectable and metastatic pNET. However, additional clinical trials are required to further strengthen these findings. This study has been registered in PROSPERO (CRD42023409280).
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Tumores Neuroectodérmicos Primitivos , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Temozolomida/efeitos adversos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologiaRESUMO
We present a case of a 30-year-old man with relapsing-remitting multiple sclerosis who developed psoriasiform dermatitis following his second course of ocrelizumab. This resolved with topical therapies and discontinuation of treatment. Cases of psoriasiform rashes have been increasingly reported in the use of ocrelizumab and are possibly due to B-cell (CD20) depletion and T-cell overregulation. Nevertheless, skin-related adverse reactions are not yet considered in the risk management plans of anti-CD20 treatments in multiple sclerosis.
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Anticorpos Monoclonais Humanizados , Esclerose Múltipla Recidivante-Remitente , Psoríase , Humanos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Adulto , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Fatores Imunológicos/efeitos adversos , Toxidermias/etiologia , Toxidermias/patologiaRESUMO
OBJECTIVES: Although potential adverse effects of lithium treatment on renal and endocrine systems have been extensively investigated, most prior studies are limited by selected populations and short follow-up. METHODS: Within the Psychiatric Services of the Central Denmark Region, we identified all patients with bipolar disorder and ≥1 serum-lithium (se-Li) measurements between January 1, 2013, and July 20, 2022, and reference patients with bipolar disorder matched on age, sex, and baseline creatinine. Outcomes were diagnoses of renal, thyroid and parathyroid disease, and blood tests measuring creatinine, estimated glomerular filtration rate (eGFR), thyroid-stimulating hormone (TSH), parathyroid hormone (PTH) and calcium. Analyses included unadjusted multilevel regression to describe changes in biochemical markers, and adjusted Cox regression to compare rates of disease/biochemical outcomes between lithium users and reference patients. RESULTS: Among 1646 lithium users (median age 36 years, 63% women) and 5013 reference patients, lithium users had decreasing TSH and eGFR, stable PTH, and increasing calcium levels over time. Lithium use was associated with increased rates of renal, thyroid and parathyroid disease, and levels of biochemical markers outside normal ranges (hazard rate ratios: 1.07-11.22), but the absolute number of severe outcomes was low (e.g., chronic kidney disease: N = 10, 0.6%). Notably, the rate of blood testing was substantially higher among lithium users than among reference patients (e.g., mean number of creatinine tests during the second year of follow-up: lithium users = 2.5, reference patients = 1.4). CONCLUSIONS: Severely adverse renal and endocrine outcomes are rare during lithium treatment. Observational studies of long-term lithium treatment are prone to detection bias.
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Transtorno Bipolar , Doenças das Paratireoides , Humanos , Feminino , Adulto , Masculino , Lítio/efeitos adversos , Glândula Tireoide , Estudos de Coortes , Cálcio , Compostos de Lítio/efeitos adversos , Creatinina , Doenças das Paratireoides/induzido quimicamente , Tireotropina , BiomarcadoresRESUMO
BACKGROUND AND OBJECTIVES: Haemovigilance (HV) systems aim to improve transfusion outcomes in patients and donor safety. An important question for blood regulators is how to ensure an effective HV system. MATERIALS AND METHODS: We retrospectively analysed the HV reports submitted to Paul-Ehrlich-Institut over the last two decades. RESULTS: Between 2011 and 2020, 50.86 million units of blood components were used, and 8931 suspected serious donor and recipient adverse reactions (SARs), 874 serious adverse events (SAEs) and 12,073 donor look-backs were reported. Following implementation of specific risk-minimization measures (RMMs) between 2000 and 2010, SAR reporting rates decreased for transfusion-transmitted viral infections (TTVIs), transfusion-related acute lung injury (TRALI) and transfusion-transmitted bacterial infections (TTBIs), while increasing for other serious adverse transfusion reactions. Within this decade, the overall blood component use decreased. CONCLUSION: Long-term data collection forms the basis to establish trends and changes in reporting and to evaluate the effect of RMM. Standardized criteria for reaction types, seriousness and imputability assessments and availability of a denominator are important elements. Central data collection and independent assessment allow for monitoring HV data in a nationwide context over time. Stakeholder involvement and transparent feedback on the benefit of RMM will help to achieve the objectives of HV.
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PURPOSE: To determine whether switching to contrast media based on the sharing of N-(2,3-dihydroxypropyl) carbamoyl side chain reduces the recurrence of iodinated contrast media (ICM)-associated adverse drug reactions (ADRs). MATERIALS AND METHODS: This single-center retrospective study included 2133 consecutive patients (mean age ± SD, 56.1 ± 11.4 years; male, 1052 [49.3%]) who had a history of ICM-associated ADRs and underwent contrast-enhanced CT examinations. The per-patient and per-exam-based recurrence ADR rates were compared between cases of switching and non-switching the ICM from ICMs that caused the previous ADRs, and between cases that used ICMs with common and different carbamoyl side chains from ICMs that caused the previous ADRs. Downgrade rates (no recurrence or the occurrence of ADR less severe than index ADRs) were also compared. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were additionally performed. RESULTS: In per-patient analysis, switching of ICM showed a lower recurrence rate (switching, 10.4% [100/965] vs. non-switching, 28.4% [332/1168]), with the adjusted odds ratio (OR) of 0.27 (95% CI: 0.21, 0.34; p < 0.001). The result was consistent in PSM (OR, 0.29 [95% CI: 0.22, 0.39]; p < 0.001), IPTW (OR, 0.28 [95% CI: 0.22, 0.36]; p < 0.001), and in per-exam analysis (5.5% vs. 13.8%; OR, 0.32 [95% CI: 0.27, 0.37]; p < 0.001). There was lower per-exam recurrence (5.0% [195/3938] vs. 7.8% [79/1017]; OR, 0.63 [95% CI: 0.47, 0.83]; p = 0.001) and higher downgrade rates (95.6% [3764/3938] vs. 93.3% [949/1017]; OR, 1.51 [95% CI: 1.12, 2.03]; p = 0.006) when using different side chain groups. CONCLUSION: Switching to an ICM with a different carbamoyl side chain reduced the recurrent ADRs and their severity during subsequent examinations. CLINICAL RELEVANCE STATEMENT: Switching to an iodinated contrast media with a different carbamoyl side chain reduced the recurrent adverse drug reactions and their severity during subsequent examinations.
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AIMS: A key reason for the failure of antituberculosis (anti-TB) treatment is missed doses (instances where medication is not taken). Adverse drug reactions (ADRs) are 1 cause of missed doses, but the global evidence, their relative contribution to missed doses vs. other causes, the patterns of missed doses due to ADRs and the specific ADRs associated with missed doses have not been appraised. We sought to address these questions through a scoping review. METHODS: MEDLINE, Embase and Web of Science were searched on 3 November 2021 using terms around active TB, missed doses and treatment challenges. Studies reporting both ADR and missed dose data were examined (PROSPERO: CRD42022295209). RESULTS: Searches identified 108 eligible studies: 88/108 (81%) studies associated ADRs with an increase in missed doses; 33/61 (54%) studies documenting the reasons for missed doses gave ADRs as a primary reason. No studies examined patterns of missed doses due to ADRs; 41/108 (38%) studies examined associations between 68 types of ADR (across 15 organ systems) and missed doses. Nuance around ADR-missed doses relations regarding drug susceptibility testing profile and whether the missed doses originated from the patient, healthcare professionals, or both were found. CONCLUSION: There is extensive evidence that ADRs are a key driver for missed doses of anti-TB treatment. Some papers examined specific ADRs and none evaluated the patterns of missed doses due to ADRs, demonstrating a knowledge deficit. Knowing why doses both are and are not missed is essential in providing targeted interventions to improve treatment outcomes.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Mycobacterium tuberculosis , Humanos , Testes de Sensibilidade Microbiana , Pessoal de Saúde , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Antituberculosos/efeitos adversos , Sistemas de Notificação de Reações Adversas a MedicamentosRESUMO
PURPOSE OF REVIEW: To summarise the evidence regarding which patients might benefit from deprescribing antihypertensive medications. RECENT FINDINGS: Older patients with frailty, multi-morbidity and subsequent polypharmacy are at higher risk of adverse events from antihypertensive treatment, and therefore may benefit from antihypertensive deprescribing. It is possible to examine an individual's risk of these adverse events, and use this to identify those people where the benefits of treatment may be outweighed by the harms. While such patients might be considered for deprescribing, the long-term effects of this treatment strategy remain unclear. Evidence now exists to support identification of those who are at risk of adverse events from antihypertensive treatment. These patients could be targeted for deprescribing interventions, although the long-term benefits and harms of this approach are unclear. PERSPECTIVES: Randomised controlled trials are still needed to examine the long-term effects of deprescribing in high-risk patients with frailty and multi-morbidity.
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Anti-Hipertensivos , Desprescrições , Hipertensão , Humanos , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Fragilidade , Hipertensão/tratamento farmacológico , PolimedicaçãoRESUMO
BACKGROUND: COVID-19 is a new infectious disease. To investigate whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the adverse reactions of subcutaneous specific immunotherapy (SCIT) in children. METHODS: This study was conducted by collecting relevant data from children who underwent house dust mite SCIT from April 3, 2021, to March 18, 2023, including information on the time of COVID-19 infection, symptoms, and adverse reactions after each allergen injection. A mixed effects model was used to analyze the changes in adverse reactions before and after the COVID-19 infection. RESULTS: Among the records of adverse reactions from 2658 injections in 123 children who underwent SCIT, the overall adverse reaction rate before COVID-19 infection was 39.8% and 30.0% after COVID-19 infection. Compared with pre-infection with COVID-19, the risks of overall adverse reactions, local adverse reactions, and systemic adverse reactions of immunotherapy after COVID-19 infection were reduced (odds ratio [OR] = 0.24, 0.31, and 0.28, all P < 0.05). Among the local adverse reactions, the incidence of the unvaccinated group was the highest (15.3% vs. 7.1%). The incidence of overall and local adverse reactions to SCIT decreased in 2-vaccinated COVID-19 recipients (OR = 0.29-0.31, P < 0.05). CONCLUSIONS: In children, SARS-CoV-2 infection does not increase the incidence of adverse reactions to SCIT. This finding can provide a basis for the implementation of allergen-specific immunotherapy (AIT) during the COVID-19 pandemic.
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COVID-19 , Dessensibilização Imunológica , SARS-CoV-2 , Humanos , COVID-19/terapia , COVID-19/imunologia , Criança , Estudos Retrospectivos , Masculino , Feminino , Pré-Escolar , SARS-CoV-2/imunologia , Injeções Subcutâneas , Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos , Adolescente , Animais , Pyroglyphidae/imunologia , Alérgenos/imunologia , Alérgenos/efeitos adversos , Alérgenos/administração & dosagem , LactenteRESUMO
BACKGROUND: People with gender dysphoria are treated with hormone therapy for gender reassignment. The indication of this therapy was initially for the opposite sex, and information on potential adverse drug reaction (ADR) is lacking. OBJECTIVE: To describe ADR associated with gender transition medication in transgender individuals reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: Data from the FAERS database up to June 2023 were examined, focusing on reports of gender transition medication use in the context of gender dysphoria. The ADRs were categorized using the Medical Dictionary for Regulatory Activities at both Preferred Term and System Organ Class (SOC) levels. Descriptive statistics summarized report counts, medication types, indications, and ADR severity. RESULTS: For individuals assigned female at birth undergoing gender transition to male (transgender men), 82 reports (230 ADRs) were analyzed, with an average age of 29.5 years. Transgender hormonal therapy was cited in 72% of reports, predominantly from the United States (67.1%). A striking 88% were categorized as serious ADRs, primarily SOC injury, poisoning, and procedural complications (26.5%), followed by psychiatric disorders (14.8%) and nervous system disorders (12.2%). Among those assigned sex male at birth transitioning to female (transgender women) (81 reports, 237 ADRs), mean age was 33.3 years, with 58% indicating use for gender dysphoria. A significant proportion (53.6%) were serious ADRs, primarily SOC: injury, poisoning, and procedural complications (26.6%). CONCLUSIONS AND RELEVANCE: The FAERS data reveal significant ADRs in transgender individuals using hormone therapy, sometimes unintended for their recipient gender. Population-level studies are crucial to enhance transgender health care. Spontaneous surveillance databases like FAERS illuminate off-label ADRs, urging health care providers to approach hormone therapies with informed caution.
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AIM: Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population. METHODS: From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12 weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders. RESULTS: In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p = 0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p = 0.015) in the univariate analysis and 0.315 (p = 0.023) in the multivariate analysis. CONCLUSIONS: In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry with the number UMIN000043798.
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PURPOSE: Antipsychotic agents, which may increase the risk of infection through dopaminergic dysregulation, are prescribed to a fraction of patients following critical illness. We compared the rate of recurrent sepsis among patients who filled a prescription for antipsychotics with high- or low-D2 affinity. METHODS: Population-based cohort with active comparator design. We included sepsis survivors older than 65 years with intensive care unit admission and new prescription of antipsychotics in Ontario 2008-2019. The primary outcome were recurrent sepsis episodes within 1 year of follow-up. Patients who filled a prescription within 30 days of hospital discharge for high-D2 affinity antipsychotics (e.g., haloperidol) were compared with patients who filled a prescription within 30 days of hospital discharge for low-D2 affinity antipsychotics (e.g., quetiapine). Multivariable zero-inflated Poisson regression models with robust standard errors adjusting for confounding at baseline were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: Overall, 1879 patients filled a prescription for a high-D2, and 1446 patients filled a prescription for a low-D2 affinity antipsychotic. Patients who filled a prescription for a high-D2 affinity antipsychotic did not present a higher rate of recurrent sepsis during 1 year of follow-up, compared with patients who filled a prescription for a low-D2 affinity antipsychotic (IRR: 1.12; 95% CI: 0.94, 1.35). CONCLUSIONS: We did not find conclusive evidence of a higher rate of recurrent sepsis associated with the prescription of high-D2 affinity antipsychotics (compared with low-D2 affinity antipsychotics) by 1 year of follow-up in adult sepsis survivors with intensive care unit admission.
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Antipsicóticos , Sepse , Adulto , Humanos , Antipsicóticos/efeitos adversos , Estudos de Coortes , Reinfecção , Prescrições , Sepse/tratamento farmacológico , Sepse/epidemiologiaRESUMO
BACKGROUND: Methotrexate (MTX) combination therapy with biological agents has gained increasing interest. Here, we assessed the efficacy and tolerability of the MTX combination therapy in patients with Crohn's disease (CD). METHODS: We performed a multicenter observational study with 185 patients with CD with MTX and biologics combination therapy; the patients were recruited from three IBD Clinics in Korea. We evaluated the outcomes of the MTX combination therapy and examined the predictive factors of clinical and endoscopic remission. RESULTS: MTX was administered orally to 62.7% of patients; the mean dose was 15.5 mg per week, and the mean treatment duration was 36 months. Of the 169 patients treated with MTX combination therapy for over 6 months, the steroid-free clinical remission rates were 34.3%, 26.0%, 29.8%, and 32.7% at 4, 12, 18, and 24 months, respectively. Previous thiopurine use was a significant negatively associated independent factor (p < 0.001), and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of steroid-free clinical remission (p = 0.035). Ninety-six patients underwent follow-up endoscopy after 28 months, and 36 (37.5%) achieved endoscopic remission. Longer disease duration (p = 0.006), ileocolonic type of Montreal location (p = 0.036), and baseline C-reactive protein (CRP) level of more than 5 mg/L (p = 0.035) were significant negatively associated independent factors and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of endoscopic remission (p = 0.037). CONCLUSIONS: MTX combination therapy with biologics was effective and tolerable in patients with CD.
Assuntos
Produtos Biológicos , Doença de Crohn , Humanos , Produtos Biológicos/uso terapêutico , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Indução de Remissão , Resultado do TratamentoRESUMO
PURPOSE: This study aimed to develop and psychometrically evaluate a patient-reported outcome measure (PROM), SAlivary, LAcrimal, NaSal (SALANS), to document patients' symptoms after radioactive iodine (RAI) treatment for differentiated thyroid cancer (DTC). METHODS: We generated and iteratively revised SALANS items based on expert input, focus group discussions and feedback from cognitive testing (n = 17). We administered an initial SALANS measure with 39 items to patients diagnosed with DTC in the past two years (n = 105). Exploratory factor analysis (EFA) examined the factor structure of the SALANS items. We assessed the consistency reliability and related the total and subscale scores of the final SALANS to existing PROMs to assess validity. RESULTS: The final SALANS consisted of 33 items and six subscales (sialadenitis, taste, xerostomia, dry eyes, epiphora, and nasal) with six factors extracted by EFA. The six subscales demonstrated good internal reliability (α range = 0.87-0.92). The SALANS total score showed good convergent validity with the Xerostomia Inventory (r = 0.86) and good discriminant validity with a measure of spirituality (r = - 0.05). The mean SALANS total score was significantly higher (d = 0.5, p < 0.04) among patients who had RAI compared to those who did not have RAI. CONCLUSION: Preliminary evidence suggests that SALANS is a novel and reliable PROM to assess the type and frequency all symptoms experienced after RAI treatment for DTC. Future work is needed to further validate and develop the scale.
Assuntos
Radioisótopos do Iodo , Medidas de Resultados Relatados pelo Paciente , Psicometria , Neoplasias da Glândula Tireoide , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Radioisótopos do Iodo/uso terapêutico , Radioisótopos do Iodo/efeitos adversos , Reprodutibilidade dos Testes , Adulto , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/psicologia , Idoso , Inquéritos e Questionários , Análise Fatorial , Qualidade de Vida , Xerostomia/etiologia , Xerostomia/psicologiaRESUMO
BACKGROUND: Capecitabine is an oral prodrug of the active metabolite 5-fluorouracil, which has been used effectively in human colorectal, head and neck, and mammary carcinomas. Capecitabine has several properties that make it an attractive treatment option for dogs: (i) it is relatively inexpensive, (ii) it has a short half-life in humans, allowing for rapid plasma concentration changes to be achieved with dosage adjustments, (iii) it is effective for treating carcinomas in humans, for which there are no widely-effective oral chemotherapy options in dogs, and (iv) it is thought to preferentially target cancer cells due to different expression of thymidine phosphorylase, thereby decreasing the risk of off-target side effects. However, capecitabine has not been widely explored as a chemotherapy agent for dogs. The goal of this study was to determine the plasma disposition of capecitabine in dogs following a single oral dose and to document any adverse events associated with capecitabine administration over the course of 5 weeks. RESULTS: Capecitabine was well tolerated throughout the 5-week study period when administered to 5 dogs with naturally occurring carcinomas at 750 mg/m[Formula: see text] by mouth once daily for 14 consecutive days in a 3-week cycle. No dogs withdrew from the study due to adverse events or other causes. The median AUC[Formula: see text] was 890 h[Formula: see text]ng/ml (range 750-1100 h[Formula: see text]ng/ml); however, the maximum blood concentration and time to reach that concentration of capecitabine was highly variable after a single dose. CONCLUSIONS: Capecitabine appears well-tolerated as an oral chemotherapy agent for dogs with carcinomas, although individualized dosing may be necessary, and further studies are warranted.