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OBJECTIVE: This study examined the prevalence, severity and risk factors of anaemia among adult people living with HIV attending an antiretroviral therapy centre in Woreta Primary Hospital, Woreta town, Ethiopia. DESIGN: Hospital-based retrospective cross-sectional study. SETTING: Public health facility that provides HIV care in Woreta town. PARTICIPANTS: A total of 289 medical records of adults living with HIV/AIDS on highly active antiretroviral therapy from February 2019 to September 2023 at government hospital were reviewed using a systematic sampling method. The data were entered using Epi-info V.7 and exported to SPSS V.23 for data analysis. The data were analysed using bivariate and then multivariate logistic regression models in order to identify variables associated with anaemia. At the 95% CI level, variables having a p value of <0.05 were deemed to be statistically significant predictors. PRIMARY OUTCOME: Prevalence and severity of anaemia and its predictors among adult patients living with HIV on antiretroviral therapy in Woreta Primary Hospital. RESULTS: The total prevalence of anaemia was 31.5% (95% CI 28.9 to 33.8). The prevalence of mild, moderate and severe anaemia was 20.42%, 10.38% and 0.70%, respectively. Predictors independently linked with anaemia were female sex (adjusted OR (AOR) 1.08), age ≥40 years (AOR 1.21), lived with HIV >10 years (AOR 2.31), CD4 counts <200 cells/µL (AOR 3.81), non-suppressed viral load (AOR 1.28), history of opportunistic infections (AOR 1.54), WHO clinical stages III and IV (AOR 1.37 and 2.23, respectively) and history of parasitic infestation (AOR 2.81). CONCLUSIONS: A sizeable proportion of participants were found anaemic. Female sex, older age, longer periods lived with the virus, lower CD4 count, non-suppressed viral load, history of opportunistic infections, WHO clinical stages III and IV and history of parasitic infestation were the contributing factors. Therefore, to improve the anaemic status and living circumstances of patients living with HIV, immediate action on the linked factors is needed, such as monitoring for maintenance of CD4 counts >200 cells/µL and avoiding progression of HIV to the advanced WHO clinical stages, suppressed viral load, preventing opportunistic infections and parasitic infestation.
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Anemia , Terapia Antirretroviral Altamente Activa , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piridonas , Humanos , Femenino , Masculino , Adulto , Estudios Transversales , Estudios Retrospectivos , Anemia/epidemiología , Etiopía/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Prevalencia , Persona de Mediana Edad , Factores de Riesgo , Piridonas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Recuento de Linfocito CD4 , Adulto Joven , Inhibidores de Integrasa VIH/uso terapéutico , Índice de Severidad de la Enfermedad , PiperazinasAsunto(s)
Fármacos Anti-VIH , Farmacorresistencia Viral , Emtricitabina , Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Emtricitabina/uso terapéutico , Piridonas/uso terapéutico , Piperazinas/uso terapéutico , Tenofovir/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Hepatitis B/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/uso terapéutico , Masculino , Femenino , AmidasRESUMEN
The systematic review and meta-analysis titled "The Effects of Dabrafenib and/or Trametinib Treatment in BRAF V600-Mutant Glioma" provides a critical evaluation of these targeted therapies for a challenging subset of gliomas. This review is notable for its comprehensive data integration, offering a robust assessment of the efficacy and safety of dabrafenib and trametinib. By focusing on BRAF V600 mutations, it contributes valuable insights into personalized treatment strategies. However, limitations include study heterogeneity and a lack of long-term follow-up data, which hinder the generalizability and complete understanding of treatment effects. Additionally, while the review emphasizes therapeutic potential, it requires a thorough evaluation of adverse effects. Future research should address these limitations by providing more consistent data, longer follow-up, and a balanced view of treatment risks and benefits.
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Neoplasias Encefálicas , Glioma , Imidazoles , Mutación , Oximas , Proteínas Proto-Oncogénicas B-raf , Piridonas , Pirimidinonas , Humanos , Oximas/uso terapéutico , Pirimidinonas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Piridonas/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Imidazoles/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genéticaRESUMEN
BACKGROUND: An increase in the prevalence of HIV drug resistance (HIVDR) has been reported in recent years, especially in persons on non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to their low genetic barrier to mutations. However, there is a paucity of epidemiological data quantifying HIVDR in the era of new drugs like dolutegravir (DTG) in sub-Saharan Africa. We, therefore, sought to determine the prevalence and correlates of viral load (VL) suppression in adult people with HIV (PWH) on a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) or tenofovir alafenamide/emtricitabine/dolutegravir (TAFED) and describe patterns of mutations in individuals failing treatment. METHODS: We conducted a cross-sectional study among 384 adults living with HIV aged ≥15 years between 5th June 2023 and 10th August 2023. Demographic, laboratory and clinical data were collected from electronic health records using a data collection form. Viral load suppression was defined as plasma HIV-1 RNA VL of <1000 copies/ml after being on ART for ≥ 6 months. SPSS version 22 to analyze the data. Descriptive statistics and logistic regression were the statistical methods used. RESULTS: The median (interquartile range (IQR)) age was 22 (IQR 18, 38) years, and 66.1% (n = 254) were females. VL suppression was 90.4% (n = 347); (95% confidence interval (CI) 87.6%-93.6%) after switching to TLD/TAFED. Among the virally suppressed, the majority (67.1%, n = 233) were female. Those who missed ≥2 doses in the last 30 days prior to the most recent review were less likely to attain viral suppression compared to those who did not miss any dose (adjusted odds ratio (AOR) 0.047; 95% CI 0.016-0.136; p<0.001). Four participants had resistance mutations to lamivudine and tenofovir. The most common NRTI mutations were M184MV and K65R while K101E was the most common NNRTI mutation. CONCLUSION: Our findings show that viral suppression was high after switching to TLD/TAFED; but lower than the last 95% target of the UNAIDS. Adherence to antiretroviral therapy was a significant correlate of VL suppression. We, therefore, recommend prompt switching of PWH to TLD/TAFED regimen and close monitoring to enhance adherence to therapy.
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Fármacos Anti-VIH , Farmacorresistencia Viral , Infecciones por VIH , VIH-1 , Lamivudine , Mutación , Piperazinas , Piridonas , Tenofovir , Carga Viral , Humanos , Femenino , Adulto , VIH-1/genética , VIH-1/efectos de los fármacos , Masculino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Farmacorresistencia Viral/genética , Carga Viral/efectos de los fármacos , Zambia/epidemiología , Estudios Transversales , Tenofovir/uso terapéutico , Tenofovir/farmacología , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacología , Piperazinas/uso terapéutico , Lamivudine/uso terapéutico , Lamivudine/farmacología , Piridonas/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/farmacología , Emtricitabina/uso terapéutico , Persona de Mediana Edad , Adulto Joven , Adolescente , Combinación de MedicamentosRESUMEN
INTRODUCTION: CARISEL is an implementation-effectiveness "hybrid" study examining the perspectives of people living with HIV-1 (patient study participants [PSPs]) on cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) dosed every 2 months (Q2M) across 5 European countries. METHODS: PSPs completed questionnaires on acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure), and feasibility (Feasibility of Intervention Measure) at their first (Month [M] 1), third (M4), and seventh (M12) injection visits. Semistructured qualitative interviews were also conducted. RESULTS: Overall, 437 PSPs were enrolled, of whom 430 received treatment. Median (interquartile range) age was 44 (37-51) years, 25.3% (n = 109/430) were female (sex at birth), and 21.9% (n = 94/430) were persons of color. Across time points, PSPs found CAB + RPV LA highly acceptable, appropriate, and feasible (mean scores ≥4.47/5). Qualitative data supported these observations. CONCLUSIONS: PSPs found CAB + RPV LA Q2M to be an acceptable, appropriate, and feasible treatment option.
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Fármacos Anti-VIH , Infecciones por VIH , Piridonas , Rilpivirina , Humanos , Rilpivirina/uso terapéutico , Rilpivirina/administración & dosificación , Femenino , Masculino , Adulto , Infecciones por VIH/tratamiento farmacológico , Persona de Mediana Edad , Europa (Continente) , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Piridonas/uso terapéutico , Piridonas/administración & dosificación , VIH-1/efectos de los fármacos , Encuestas y Cuestionarios , DicetopiperazinasRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and an overall survival of 80% after 4 years. See related article by Stieglitz et al., p. 1590 (4) .
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Leucemia Mielomonocítica Juvenil , Piridonas , Pirimidinonas , Humanos , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Leucemia Mielomonocítica Juvenil/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Resultado del Tratamiento , Enfermedades Raras/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
This systematic review and meta-analysis evaluates the effects of dabrafenib and/or trametinib in treating BRAF V600-mutant gliomas. The study analyzed eight trials involving both high-grade and low-grade glioma patients, assessing outcomes such as progression-free survival (PFS), overall survival (OS), adverse events (AEs), and disease response. The pooled results showed a median PFS of 6.10 months and OS of 22.73 months, with notable improvement in disease response rates when using combination therapy. However, the high incidence of AEs (50%) and death events (43%) necessitates caution in interpreting these results. The study's limitations include a lack of randomized controlled trials and high heterogeneity in AE data. Future research should focus on larger, controlled studies, standardized AE assessments, and exploration of neurocognitive outcomes to better understand and optimize treatment strategies for BRAF V600-mutant gliomas.
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Neoplasias Encefálicas , Glioma , Imidazoles , Mutación , Oximas , Proteínas Proto-Oncogénicas B-raf , Piridonas , Pirimidinonas , Humanos , Oximas/uso terapéutico , Pirimidinonas/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Piridonas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Imidazoles/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Resultado del TratamientoRESUMEN
BACKGROUND: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk. METHODS: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years. CONCLUSION: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter. TRIAL REGISTRATION: ClinicalTrials.gov NCT05757869.
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Fibrilación Atrial , Inhibidores del Factor Xa , Pirazoles , Piridonas , Accidente Cerebrovascular , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirazoles/administración & dosificación , Piridonas/uso terapéutico , Piridonas/administración & dosificación , Piridonas/efectos adversos , Método Doble Ciego , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/etiología , Masculino , Femenino , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/administración & dosificación , Aleteo Atrial/complicaciones , Hemorragia/inducido químicamente , Persona de Mediana Edad , Anciano , Factor XIa/antagonistas & inhibidores , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversosRESUMEN
Importance: Approximately 10% to 15% of ischemic strokes are associated with cancer; cancer-associated stroke, particularly when cryptogenic, is associated with high rates of recurrent stroke and major bleeding. Limited data exist on the safety and efficacy of different antithrombotic strategies in patients with cancer and cryptogenic stroke. Objective: To compare apixaban vs aspirin for the prevention of adverse clinical outcomes in patients with history of cancer and cryptogenic stroke. Design, Setting, and Participants: Post hoc analysis of data from 1015 patients with a recent cryptogenic stroke and biomarker evidence of atrial cardiopathy in the Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial, a multicenter, randomized, double-blind clinical trial conducted from 2018 to 2023 at 185 stroke centers in North America. Data analysis was performed from October 15, 2023, to May 23, 2024. Exposures: Oral apixaban, 5 mg (or 2.5 mg if criteria met), twice daily vs oral aspirin, 81 mg, once daily. Subgroups of patients with and without cancer at baseline were examined. Main Outcomes and Measures: The primary outcome for this post hoc analysis was a composite of major ischemic or major hemorrhagic events. Major ischemic events were recurrent ischemic stroke, myocardial infarction, systemic embolism, and symptomatic deep vein thrombosis or pulmonary embolism. Major hemorrhagic events included symptomatic intracranial hemorrhage and any major extracranial hemorrhage. Results: Among 1015 participants (median [IQR] age, 68 [60-76] years; 551 [54.3%] female), 137 (13.5%) had a history of cancer. The median (IQR) follow-up was 1.5 (0.6-2.5) years for patients with history of cancer and 1.5 (0.6-3.0) years for those without history of cancer. Participants with history of cancer, compared with those without history of cancer, had a higher risk of major ischemic or major hemorrhagic events (hazard ratio [HR], 1.73; 95% CI, 1.10-2.71). Among those with history of cancer, 8 of 61 participants (13.1%) randomized to apixaban and 16 of 76 participants (21.1%) randomized to aspirin had a major ischemic or major hemorrhagic event; however, the risk was not significantly different between groups (HR, 0.61; 95% CI, 0.26-1.43). Comparing participants randomized to apixaban vs aspirin among those with cancer, events included recurrent stroke (5 [8.2%] vs 9 [11.8%]), major ischemic events (7 [11.5%] vs 14 [18.4%]), and major hemorrhagic events (1 [1.6%] vs 2 [2.6%]). Conclusions and Relevance: Among participants in the ARCADIA trial with history of cancer, the risk of major ischemic and hemorrhagic events did not differ significantly with apixaban compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.
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Aspirina , Inhibidores del Factor Xa , Accidente Cerebrovascular Isquémico , Neoplasias , Pirazoles , Piridonas , Humanos , Piridonas/uso terapéutico , Piridonas/efectos adversos , Masculino , Femenino , Aspirina/uso terapéutico , Aspirina/efectos adversos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Anciano , Persona de Mediana Edad , Método Doble Ciego , Accidente Cerebrovascular Isquémico/prevención & control , Accidente Cerebrovascular Isquémico/etiología , Accidente Cerebrovascular Isquémico/epidemiología , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Fibrinolíticos/uso terapéutico , Fibrinolíticos/efectos adversos , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/etiología , Hemorragia/inducido químicamenteRESUMEN
Cardiac arrhythmias are often linked to the overactivity of cardiac fibroblasts (CFs). Investigating the impact of poly (ADP-ribose) polymerase 9 (PARP9) on Angiotensin II (Ang II)-induced fibroblast activation and the therapeutic effects of pirfenidone (PFD) offers valuable insights into cardiac arrhythmias. This study utilized weighted gene co-expression network analysis (WGCNA), differential gene expression (DEG) analysis, protein-protein interaction (PPI), and receiver operating characteristic (ROC) analysis on the GSE42955 dataset to identify the hub gene with a significant diagnostic value. The ImmuCellAI tool revealed an association between PARP9 and immune cell infiltration. Our in vitro assessments focused on the influence of PFD on myofibroblast differentiation, transforming growth factor-beta (TGF-ß) expression, and Ang II-induced proliferation and migration in CFs. Additionally, we explored the impact on fibrosis markers and the TGF-ß/Smad signaling pathway in the context of PARP9 overexpression. Analysis of the GSE42955 dataset revealed PARP9 as a central gene with high clinical diagnostic value, linked to seven types of immune cells. The in vitro studies demonstrated that PFD significantly mitigates Ang II-induced CF proliferation, migration, and fibrosis. It also reduces Ang II-induced PARP9 expression and decreases fibrosis markers, including TGF-ß, collagen I, collagen III, and α-SMA. Notably, PARP9 overexpression can partially counteract PFD's inhibitory effects on CFs and modify the expression of fibronectin, CTGF, α-SMA, collagen I, collagen III, MMP2, MMP9, TGF-ß, and p-Smad2/3 in the TGF-ß/Smad signaling pathway. In summary, our findings suggest that PFD effectively counteracts the adverse effects of Ang II-induced CF proliferation and fibrosis, and modulates the TGF-ß/Smad signaling pathway and PARP9 expression. This identifies a potential therapeutic approach for managing myocardial fibrosis.
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Angiotensina II , Miocardio , Piridonas , Transducción de Señal , Proteínas Smad , Factor de Crecimiento Transformador beta , Piridonas/farmacología , Piridonas/uso terapéutico , Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Miocardio/metabolismo , Miocardio/patología , Angiotensina II/farmacología , Angiotensina II/metabolismo , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Poli(ADP-Ribosa) Polimerasas/genética , Fibrosis/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Movimiento Celular/efectos de los fármacos , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Diferenciación Celular/efectos de los fármacos , RatasRESUMEN
Non-vitamin K oral anticoagulants (NOACs) have revolutionized anticoagulant therapy, offering improved safety and efficacy over traditional agents like warfarin. This review comprehensively examines the dual roles of NOACs-apixaban, rivaroxaban, edoxaban, and dabigatran-not only as anticoagulants, but also as modulators of inflammation via protease-activated receptor (PAR) signaling. We highlight the unique pharmacotherapeutic properties of each NOAC, supported by key clinical trials demonstrating their effectiveness in preventing thromboembolic events. Beyond their established anticoagulant roles, emerging research suggests that NOACs influence inflammation through PAR signaling pathways, implicating factors such as factor Xa (FXa) and thrombin in the modulation of inflammatory responses. This review synthesizes current evidence on the anti-inflammatory potential of NOACs, exploring their impact on inflammatory markers and conditions like atherosclerosis and diabetes. By delineating the mechanisms by which NOACs mediate anti-inflammatory effects, this work aims to expand their therapeutic utility, offering new perspectives for managing inflammatory diseases. Our findings underscore the broader clinical implications of NOACs, advocating for their consideration in therapeutic strategies aimed at addressing inflammation-related pathologies. This comprehensive synthesis not only enhances understanding of NOACs' multifaceted roles, but also paves the way for future research and clinical applications in inflammation and cardiovascular health.
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Anticoagulantes , Inflamación , Receptores Proteinasa-Activados , Transducción de Señal , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Anticoagulantes/uso terapéutico , Anticoagulantes/farmacología , Anticoagulantes/administración & dosificación , Receptores Proteinasa-Activados/metabolismo , Transducción de Señal/efectos de los fármacos , Administración Oral , Animales , Rivaroxabán/uso terapéutico , Rivaroxabán/farmacología , Rivaroxabán/administración & dosificación , Piridonas/farmacología , Piridonas/uso terapéutico , Piridonas/administración & dosificaciónRESUMEN
This retrospective cohort study analyzed data from a Japanese health insurance database to assess the effectiveness of baloxavir (n = 4822) for preventing severe events compared with oseltamivir (n = 10,523) in patients with influenza B. The primary endpoint was hospitalization incidence (Days 2-14). The secondary endpoints included intravenous antibacterial drug use, pneumonia hospitalization, heart failure hospitalization, inhalational oxygen requirement, and use of other anti-influenza drugs. The hospitalization incidence was significantly lower with baloxavir (0.15% vs. 0.37%; risk ratio: 2.48, 95% confidence interval: 1.13-5.43). Pneumonia and additional anti-influenza therapy were also less frequent with baloxavir, thus supporting its use. Trial Registration: UMIN Clinical Trials Registry Study ID: UMIN000051382.
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Antivirales , Dibenzotiepinas , Virus de la Influenza B , Gripe Humana , Morfolinas , Oseltamivir , Pacientes Ambulatorios , Piridonas , Triazinas , Humanos , Gripe Humana/tratamiento farmacológico , Dibenzotiepinas/uso terapéutico , Oseltamivir/uso terapéutico , Antivirales/uso terapéutico , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Adulto , Piridonas/uso terapéutico , Morfolinas/uso terapéutico , Triazinas/uso terapéutico , Anciano , Virus de la Influenza B/efectos de los fármacos , Adulto Joven , Adolescente , Hospitalización/estadística & datos numéricos , Niño , Piridinas/uso terapéutico , Japón/epidemiología , Preescolar , Resultado del Tratamiento , Lactante , Anciano de 80 o más AñosRESUMEN
Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.
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Apoptosis , Proliferación Celular , Modelos Animales de Enfermedad , Piridonas , Pirimidinonas , Rosiglitazona , Neoplasias de la Vejiga Urinaria , Animales , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Piridonas/farmacología , Piridonas/uso terapéutico , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Ratones , Apoptosis/efectos de los fármacos , Humanos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Invasividad Neoplásica , Femenino , PPAR gamma/metabolismo , PPAR gamma/agonistas , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Retinoides/farmacología , Retinoides/uso terapéuticoRESUMEN
INTRODUCTION: Millions of people living with HIV (PLWH) take oral antiretroviral therapy (ART), which requires a lifetime of consistent medication adherence. The relationship between adherence and poor HIV outcomes is well documented. Newer ART regimens that include dolutegravir (DTG) could be more forgiving, but empirical evidence on the relationship between adherence and viral suppression under DTG is only emerging. METHODS: In this observational cohort study (secondary analysis of data from a randomized trial), we used data from 313 ART clients from a large HIV clinic in Kampala, Uganda. Over the 4-year study period (January 2018-January 2022), 91% switched from non-DTG regimens to DTG regimens. We measured adherence using Medication Event Monitoring Systems-caps and extracted prescription information and viral load measures from electronic health records. We estimated unadjusted linear regressions and adjusted models that included individual and time fixed-effects. RESULTS: Under non-DTG regimens, 96% of participants were virally suppressed (defined as viral load < 200 copies/ml) when adherence was 90% or higher in the 3 months before viral load measurement. Viral suppression was 32 percentage points lower when adherence was between 0% and 49% (95% CI -0.44, -0.20, p < 0.01), 12 percentage points lower when adherence was between 50% and 79% (95% CI -0.23, -0.02, p < 0.01), and not significantly different when adherence was between 80% and 89% (effect of 0.00, 95% CI -0.06, 0.07, p = 0.81). In contrast, for participants taking DTG, there was no statistically significant difference in viral suppression among any of the four adherence levels; more than 95% were virally suppressed at each adherence level. On average, switching to DTG increased viral suppression by 6 percentage points in our adjusted models (95% CI 0.00, 0.13, p = 0.03). CONCLUSIONS: There was no significant association between adherence levels and viral suppression among PLWH taking DTG regimens, suggesting a high degree of forgiveness for missed doses. The use of DTG should be prioritized over older regimens, particularly for those with low adherence. CLINICAL TRIAL NUMBER: NCT03494777.
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Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Cumplimiento de la Medicación , Oxazinas , Piperazinas , Piridonas , Carga Viral , Humanos , Uganda , Piridonas/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Femenino , Cumplimiento de la Medicación/estadística & datos numéricos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Adulto , Carga Viral/efectos de los fármacos , Oxazinas/uso terapéutico , Piperazinas/uso terapéutico , Estudios de Cohortes , Persona de Mediana Edad , Fármacos Anti-VIH/uso terapéuticoRESUMEN
ABSTRACT: Long-acting injectable cabotegravir (CAB-LA) was US Food and Drug Administration-approved in 2021. However, little is known about providers' CAB-LA knowledge, attitudes, challenges, and prescribing preferences for transgender women patients. Understanding this is critical to developing new pre-exposure prophylaxis (PrEP) interventions tailored to transgender women. We conducted 45-min, in-depth Zoom interviews (IDIs) with United States-based health care providers who prescribe PrEP to transgender women. IDIs focused on providers' CAB-LA knowledge/acceptability, willingness to prescribe CAB-LA to transgender women, potential challenges, and solutions to mitigate challenges. Providers ( N = 17) had a mean age of 43 years, and 35.4% ( n = 6) identified as people of color. Most ( n = 12) had basic knowledge of CAB-LA but wanted additional training. All participants found CAB-LA acceptable and were willing to prescribe. Most ( n = 11) anticipated minimal challenges to implementation. Others ( n = 4) reported potential issues, including logistical/scheduling concerns that impede CAB-LA integration and staffing concerns. Many providers expressed support for self-injection ( n = 13) and injections at "drop-in" clinics ( n = 8) to overcome challenges.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Personal de Salud , Profilaxis Pre-Exposición , Piridonas , Investigación Cualitativa , Personas Transgénero , Humanos , Personas Transgénero/psicología , Personas Transgénero/estadística & datos numéricos , Femenino , Adulto , Estados Unidos , Masculino , Profilaxis Pre-Exposición/métodos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Personal de Salud/psicología , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Piridonas/administración & dosificación , Piridonas/uso terapéutico , Persona de Mediana Edad , Conocimientos, Actitudes y Práctica en Salud , Inyecciones , Accesibilidad a los Servicios de Salud , Preparaciones de Acción Retardada , Actitud del Personal de Salud , Entrevistas como Asunto , DicetopiperazinasRESUMEN
INTRODUCTION: Venous thromboembolism (VTE) is a major concern following total knee arthroplasty (TKA). The optimal pharmacological prophylaxis remains, however, controversial. The present investigation compared several non-vitamin K antagonist oral anticoagulants commonly employed as VTE prophylaxis following TKA. A Bayesian network meta-analysis was conducted to compare apixaban, aspirin, dabigatran, edoxaban, enoxaparin, fondaparinux, and rivaroxaban. The outcomes of interest were to compare the rate of deep venous thrombosis (DVT), pulmonary embolism (PE), and major and minor haemorrhages. METHODS: This study was conducted according to the PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-Analyses of Health Care Interventions. In March 2024, PubMed, Web of Science, and Google Scholar were accessed with no time constraints. All randomised controlled trials (RCTs) comparing two or more drugs for the prevention of VTE following TKA were considered for inclusion. RESULTS: Data from 29,678 patients were collected. Of them, 67% (19,884 of 29,678 patients) were women. The mean age of the patients was 66.8 ± 2.8 years, and the mean BMI was 29.2 ± 1.5 kg/m2. There was comparability in age, sex, and BMI at baseline. Apixaban 5 mg, dabigatran 220 mg, and rivaroxaban 10 mg were the most effective in reducing the rate of DVT. Apixaban 5 mg, enoxaparin 60 mg, and rivaroxaban 40 mg were the most effective in reducing the rate of PE. Apixaban 5 mg, rivaroxaban 10 mg, and apixaban 10 mg were associated with the lowest rate of major haemorrhages. Apixaban 5 mg and 20 mg, and dabigatran 220 mg were associated with the lowest rate of minor haemorrhages. CONCLUSION: Administration of apixaban 5 mg demonstrated the best balance between VTE prevention and haemorrhage control following TKA. LEVEL OF EVIDENCE: Level I, network meta-analysis of RCTs.
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Artroplastia de Reemplazo de Rodilla , Teorema de Bayes , Metaanálisis en Red , Tromboembolia Venosa , Humanos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Tromboembolia Venosa/prevención & control , Tromboembolia Venosa/etiología , Rivaroxabán/uso terapéutico , Rivaroxabán/administración & dosificación , Piridonas/administración & dosificación , Piridonas/uso terapéutico , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Dabigatrán/uso terapéutico , Dabigatrán/administración & dosificación , Pirazoles/uso terapéutico , Aspirina/uso terapéutico , Aspirina/administración & dosificación , Fibrinolíticos/uso terapéutico , Fibrinolíticos/administración & dosificación , Embolia Pulmonar/prevención & control , Embolia Pulmonar/etiología , Enoxaparina/administración & dosificación , Enoxaparina/uso terapéutico , Hemorragia/inducido químicamente , Femenino , Fondaparinux/uso terapéutico , Piridinas , TiazolesRESUMEN
Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.
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Tumores del Estroma Gastrointestinal , Neurofibromatosis 1 , Piridonas , Pirimidinonas , Humanos , Piridonas/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Pirimidinonas/uso terapéutico , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Patients with atrial fibrillation and severe chronic kidney disease have higher risks of bleeding, thromboembolism, and mortality. However, optimal anticoagulant choice in these high-risk patients remains unclear. METHODS AND RESULTS: Using deidentified electronic health records from the Optum Labs Data Warehouse, adults with atrial fibrillation and severe chronic kidney disease (estimated glomerular filtration rate <30 mL/min per 1.73 m2) initiating warfarin, apixaban, or rivaroxaban between 2011 and 2021 were included. Using inverse probability of treatment weighting, adjusted risks of major bleeding, stroke/systemic embolism, and death were compared among agents. A total of 6794 patients were included (mean age, 78.5 years; mean estimated glomerular filtration rate, 24.7 mL/min per 1.73 m2; 51% women). Apixaban versus warfarin was associated with a lower risk of major bleeding (incidence rate, 1.5 versus 2.9 per 100 person-years; subdistribution hazard ratio [sub-HR], 0.53 [95% CI, 0.39-0.70]), and similar risks for stroke/systemic embolism (incidence rate, 1.9 versus 2.4 per 100 person-years; sub-HR, 0.80 [95% CI, 0.59-1.09]) and death (incidence rate, 4.6 versus 4.5 per 100 person-years; HR, 1.03 [95% CI, 0.82-1.29]). Rivaroxaban versus warfarin was associated with a higher risk of major bleeding (incidence rate, 4.9 versus 2.9 per 100 person-years; sub-HR, 1.65 [95% CI, 1.10-2.48]), with no difference in risks for stroke/systemic embolism and death. Apixaban versus rivaroxaban was associated with a lower risk of major bleeding (sub-HR, 0.53 [95% CI, 0.36-0.78]). CONCLUSIONS: These real-world findings are consistent with potential safety advantages of apixaban over warfarin and rivaroxaban for patients with atrial fibrillation and severe chronic kidney disease. Further randomized trials comparing individual oral anticoagulants are warranted.
Asunto(s)
Anticoagulantes , Fibrilación Atrial , Embolia , Hemorragia , Pirazoles , Piridonas , Insuficiencia Renal Crónica , Rivaroxabán , Accidente Cerebrovascular , Warfarina , Humanos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/complicaciones , Fibrilación Atrial/mortalidad , Femenino , Masculino , Anciano , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/mortalidad , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Anticoagulantes/administración & dosificación , Warfarina/efectos adversos , Warfarina/uso terapéutico , Rivaroxabán/efectos adversos , Rivaroxabán/uso terapéutico , Rivaroxabán/administración & dosificación , Embolia/prevención & control , Embolia/epidemiología , Embolia/etiología , Pirazoles/efectos adversos , Pirazoles/uso terapéutico , Piridonas/efectos adversos , Piridonas/uso terapéutico , Piridonas/administración & dosificación , Administración Oral , Medición de Riesgo , Anciano de 80 o más Años , Factores de Riesgo , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Incidencia , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/administración & dosificaciónAsunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Humanos , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/economía , Fármacos Anti-VIH/economía , Fármacos Anti-VIH/uso terapéutico , Costos de los Medicamentos , Piridonas/economía , Piridonas/uso terapéutico , Profilaxis Pre-Exposición/economía , Profilaxis Pre-Exposición/métodos , Compuestos Heterocíclicos con 3 Anillos/economía , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/uso terapéutico , PiperazinasRESUMEN
Chronic kidney disease (CKD) remains a significant global health issue and is a leading cause of mortality worldwide. Patients with CKD have an increased risk of developing atrial fibrillation (AF) and venous thromboembolism (VTE). While direct oral anticoagulants (DOACs) have become a standard of care for anticoagulation (AC) in patients with AF and VTE, the appropriate use of these agents in comorbid kidney impairment warrants detailed discussion. This scientific narrative review summarizes the effectiveness and safety of apixaban use in patients with renal dysfunction by assessing the current published pharmacokinetic, interventional, observational, and guideline data. Apixaban is a highly selective, orally active, direct inhibitor of factor Xa, with well-established pharmacokinetics and consistent clinical outcomes across a broad range of patient populations, including those with kidney impairment. Overall, the scientific literature has shown that apixaban has a favorable clinical efficacy and safety profile compared with vitamin K antagonists for patients with AF or VTE and comorbid kidney impairment. These data support the approved label dosing strategy of apixaban in reducing the risk of stroke/systemic embolism in patients with nonvalvular AF and in treating VTE across all ranges of kidney function. Both clinician experience and knowledge of patient-specific factors may be required in the management of comorbid patients with advanced CKD or those requiring dialysis, as data on these patients are limited.