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BACKGROUND: Nucleos(t)ide analogues, with a proven record of safety and efficacy, have been the therapy of choice for over a decade for the treatment of chronic hepatitis B. The approval of tenofovir alafenamide (TAF) in 2016 provided an additional treatment option. AIMS: The aim of this study was to evaluate the characteristics and clinical outcomes of patients treated with TAF in usual clinical practice. METHODS: Retrospective data from electronic health records was obtained from those enrolled in TARGET-HBV, a longitudinal observational cohort study of patients with chronic hepatitis B managed according to local practice standards at community and academic medical centers throughout the U.S. RESULTS: Of 500 patients enrolled, most were male (66%) and of Asian race (66%) with median age of 55 years. Cirrhosis was evident in 15%. Most patients (82%) had switched to TAF after treatment with other antivirals. The perceived safety profile of TAF was cited as the primary reason for changing therapy (32%). TAF was well tolerated and only 4 patients discontinued therapy due to adverse event during a median duration of TAF dosing of 74 weeks. Among those with paired laboratory data 12-18 months after switching to TAF, biochemical response and HBV DNA suppression was maintained. Most patients had normal renal function which was essentially unchanged throughout follow-up. CONCLUSIONS: TAF is frequently utilized in routine clinical practice due to the perception of its improved safety profile. The current study supports the growing body of evidence regarding the safety and effectiveness of TAF. Trial Registration ClinicalTrials.gov identifier: NCT03692897, https://clinicaltrials.gov/ct2/show/NCT03692897 .
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Hepatite B Crônica , Adenina/uso terapêutico , Alanina/uso terapêutico , Antivirais/efeitos adversos , Feminino , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tenofovir/efeitos adversos , Tenofovir/análogos & derivados , Resultado do TratamentoRESUMO
BACKGROUND: As coronavirus disease 2019 (COVID-19) disseminates throughout the United States, a better understanding of the patient characteristics associated with hospitalization, morbidity, and mortality in diverse geographic regions is essential. METHODS: Hospital chargemaster data on adult patients with COVID-19 admitted to 245 hospitals across 38 states between 15 February and 20 April 2020 were assessed. The clinical course from admission, through hospitalization, and to discharge or death was analyzed. RESULTS: A total of 11 721 patients were included (majority were >60 years of age [59.9%] and male [53.4%]). Comorbidities included hypertension (46.7%), diabetes (27.8%), cardiovascular disease (18.6%), obesity (16.1%), and chronic kidney disease (12.2%). Mechanical ventilation was required by 1967 patients (16.8%). Mortality among hospitalized patients was 21.4% and increased to 70.5% among those on mechanical ventilation. Male sex, older age, obesity, geographic region, and the presence of chronic kidney disease or a preexisting cardiovascular disease were associated with increased odds of mechanical ventilation. All aforementioned risk factors, with the exception of obesity, were associated with increased odds of death (all P values < .001). Many patients received investigational medications for treatment of COVID-19, including 48 patients on remdesivir and 4232 on hydroxychloroquine. CONCLUSIONS: This large observational cohort describes the clinical course and identifies factors associated with the outcomes of hospitalized patients with COVID-19 across the United States. These data can inform strategies to prioritize prevention and treatment for this disease.
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COVID-19 , Adulto , Idoso , Comorbidade , Hospitalização , Humanos , Hidroxicloroquina , Masculino , Respiração Artificial , Estudos Retrospectivos , SARS-CoV-2 , Estados Unidos/epidemiologiaRESUMO
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is typically associated with obesity. Little is known about the prevalence of cirrhosis in patients with NAFLD and a normal body mass index (BMI). METHODS: We determined prevalence of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities among participants in all BMI categories in the TARGET-NASH study. A total of 3386 patients with NAFLD were enrolled from August 2016 through March 2019. The odds ratios of cirrhosis, CVD, and metabolic abnormalities were estimated by age and race, adjusting for sex and center type. RESULTS: Based on standard BMI cutoff values, 12.8% of study subjects were lean, 27.1% were overweight, 26.5% had class 1 obesity, and 33.7% had class 2 or 3 obesity. Asians accounted for 48.7% of lean participants, and proportions decreased as BMI categories increased (P < .0001). Lower proportions of lean participants had cirrhosis (22.6% vs 40.2% of non-lean participants), CVD history (9.0% vs 14.8% of nonlean participants), diabetes (32.6% vs 53.5% of non-lean participants), hypertension (47.8% vs 67.4% of non-lean participants), or dyslipidemia (54.0% vs 64.1% of non-lean participants). Asian participants had a lower prevalence of cirrhosis, history of CVD, cardiovascular events, and diabetes compared with non-Asians, independent of BMI category. After we adjusted for age, sex, and center type and site, the odds of NAFLD-associated cirrhosis in Asians who were lean was almost half the odds of NAFLD-associated cirrhosis in non-Asians who were lean (odds ratio, 0.47; 95% CI, 0.29-0.77). CONCLUSIONS: More than 10% participants in a cohort of persons with NAFLD in the United States are lean; Asians account for almost half of the lean persons with NAFLD. Lean participants had a lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-lean persons with NAFLD. Asian participants had a significantly lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-Asians in all BMI categories. ClinicalTrials.gov, Number: NCT02815891.
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Diabetes Mellitus , Hepatopatia Gordurosa não Alcoólica , Humanos , Cirrose Hepática/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Sobrepeso , Prevalência , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Entire populations of edible dormice (Glis glis) can skip reproduction in years without mast seeding of deciduous trees (particularly beech or oak seed), because juveniles require high-calorie seeds for growth and fattening prior to hibernation. We hypothesized that, in mast failure years, female dormice may be forced to spend larger amounts of time foraging for low-quality food, which would increase their exposure to predators, mainly owls. This may lead to chronic stress, i.e. long-term increased secretion of glucocorticoids (GC), which can have inhibitory effects on reproductive function in both female and male mammals. We monitored reproduction in free-living female dormice over 3 years with varying levels of food availability, and performed a supplemental feeding experiment. To measure stress hormone levels, we determined fecal GC metabolite (GCM) concentrations collected during the day, which reflect hormone secretion rates in the previous nocturnal activity phase. We found that year-to-year differences in beech mast significantly affected fecal GCM levels and reproduction. However, contrary to our hypothesis, GCM levels were lowest in a non-mast year without reproduction, and significantly elevated in full-mast and intermediate years, as well as under supplemental feeding. Variation in owl density in our study area had no influence on GCM levels. Consequently, we conclude that down-regulation of gonads and reproduction skipping in mast failure years in this species is not caused by chronic stress. Thus, in edible dormice, delayed reproduction apparently is profitable in response to the absence of energy-rich food in non-mast years, but not in response to chronic stress.
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Corticosterona/metabolismo , Dieta/veterinária , Glucocorticoides/metabolismo , Myoxidae/fisiologia , Reprodução , Estresse Fisiológico , Animais , Áustria , Suplementos Nutricionais/análise , FemininoRESUMO
BACKGROUND: Red foxes (Vulpes vulpes L.) have become successful inhabitants of urban areas in recent years. However, our knowledge about the occurrence, distribution and association with land uses of these urban foxes is poor, partly because many favoured habitats are on private properties and therefore hardly accessible to scientists. We assumed that citizen science, i.e. the involvement of the public, could enable researchers to bridge this information gap. We analysed 1179 fox sightings in the city of Vienna, Austria reported via citizen science projects to examine relationships between foxes and the surrounding land use classes as well as sociodemographic parameters. RESULTS: Conditional probabilities of encountering foxes were substantially higher in gardens, areas with a low building density, parks or squares as compared to agricultural areas, industrial areas or forests. Generalized linear model analyses showed that sociodemographic parameters such as education levels, district area, population density and average household income additionally improved the predictability of fox sightings. CONCLUSIONS: Reports of fox sightings by citizen scientists might help to support the establishment of wildlife management in cities. Additionally, these data could be used to address public health issues in relation with red foxes as they can carry zoonoses that are also dangerous to humans.
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Distribuição Animal , Ecossistema , Raposas , Animais , Áustria , Cidades , Participação da Comunidade , Humanos , Classe SocialRESUMO
Mahalanobis distance is often recommended to identify patients or clinical sites that are considered unusual in clinical trials. Patients extreme in one or more covariates may be considered outliers in that they reside some distance from the multivariate mean, which can be thought of as the center of the data cloud. Less often discussed, patients whose data are believed to be "too good to be true" are located near the centroid as inliers. In order to efficiently investigate these anomalies for potential lapses in data quality, it is important to understand how the individual variables contribute to each multivariate outlier. There is a lack of literature describing a reasonable workflow for identification of outliers and their subsequent investigation to understand how each variable contributes to an observation being considered extreme. We describe how to identify multivariate inliers and outliers, classify outliers according to varying levels of severity, and summarize the contributions of variables using principal components in a manner that is accessible to a wide audience with straightforward interpretation. We illustrate how numerous data visualizations, including Pareto plots, can facilitate further review even in studies containing numerous observations and variables. We illustrate these methodologies using data from a multicenter clinical trial.
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Ensaios Clínicos como Assunto , Confiabilidade dos Dados , HumanosRESUMO
A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, ß and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARß. The potent and selective RARγ antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARα-mediated adverse effects.
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Desenho de Fármacos , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Piperazinas/farmacologia , Pirazóis/farmacologia , Receptores do Ácido Retinoico/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Receptor gama de Ácido RetinoicoRESUMO
The Ural owl (Strix uralensis) is the biggest forest-living owl in Austria; however, it became extinct in Austria through poaching and habitat loss more than half a century ago. The birds examined in the present study were breeding pairs from the reintroduction project with the aim of determining exploratory plasma biochemistry reference intervals in Ural owls and evaluating the amount of biological variation between seasons, sexes, and ages. A total of 45 birds were sampled, including 13 adult males, 14 adult females, and 18 juvenile birds. Remarkably, almost all of the analytes showed significant differences between the subgroups, primarily between seasons, followed by age and sex. Only creatinkinase, glucose, lactatdehydrogenase, and triglycerides did not show any significant variations. Despite partitioning of reference values into subgroups according to biological variation diminishing the number of reference individuals in the respective groups, the resulting smaller reference intervals will improve medical assessment. The results of the present study once again demonstrate that significant seasonal fluctuations must be expected and considered in the interpretation. It can be assumed that these differences are probably even greater in free-range birds with considerable changes in food quantity and quality during and between years.
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Análise Química do Sangue/veterinária , Conservação dos Recursos Naturais , Estrigiformes/sangue , Animais , Proteínas de Arabidopsis/sangue , Áustria , Ácidos e Sais Biliares/sangue , Glicemia , Proteínas Sanguíneas , Cálcio/sangue , Eletrólitos , Espécies em Perigo de Extinção , Enzimas/sangue , Feminino , Lipídeos/sangue , Masculino , Valores de Referência , Especificidade da Espécie , Ureia/sangue , Ácido Úrico/sangueRESUMO
The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor ß (TRß) agonists is described. Compounds with >50× binding selectivity for TRß over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.
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Acetatos/farmacologia , Desenho de Fármacos , Indóis/farmacologia , Receptores beta dos Hormônios Tireóideos/agonistas , Acetatos/síntese química , Acetatos/química , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The United States (US) Food and Drug Administration (FDA) Investigational New Drug (IND) Final Rule (US FDA, Final rule: Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 2010) applies to all human drugs and biological products being studied under an IND. The Final Rule specifies that a sponsor must file an IND safety report for any Suspected Unexpected Serious Adverse Reaction (SUSAR) of a medicinal product being investigated. To make a proper SUSAR classification, sponsors need to go beyond conventional Data Monitoring Committees (DMCs) with an interdisciplinary effort, using all relevant data (including data outside clinical trials), to make judgments on the possibility of serious adverse events being caused by the study drug-rather than the underlying condition of the patient or a concomitant therapy. Ball et al. (Ball et al. in Ther Innov Regul Sci 55:705-716, 2021) have reported on how the Final Rule has been implemented by large pharmaceutical companies. This paper explores the experiences of small sponsor companies regarding the Final Rule, to understand the current challenges that they have been facing to meet aggregate IND safety reporting requirements.
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Produtos Biológicos , Drogas em Investigação , Humanos , Estados Unidos , Drogas em Investigação/efeitos adversos , Equivalência Terapêutica , United States Food and Drug AdministrationRESUMO
BACKGROUND: Adverse event incidence analyses are a critical component for describing the safety profile of any new intervention. The results typically are presented in lengthy summary tables. For therapeutic areas where patients have frequent adverse events, analysis and interpretation are made more difficult by the sheer number and variety of events that occur. Understanding the risk in these instances becomes even more crucial. PURPOSE: We describe a space-saving graphical summary that overcomes the limitations of traditional presentations of adverse events and improves interpretability of the safety profile. METHODS: We present incidence analyses of adverse events graphically using volcano plots to highlight treatment differences. Data from a clinical trial of patients experiencing an aneurysmal subarachnoid hemorrhage are used for illustration. Adjustments for multiplicity are illustrated. RESULTS: Color is used to indicate the treatment with higher incidence; bubble size represents the total number of events that occur in the treatment arms combined. Adjustments for multiple comparisons are displayed in a manner to indicate clearly those events for which the difference between treatment arms is statistically significant. Furthermore, adverse events can be displayed by time intervals, with multiple volcano plots or animation to appreciate changes in adverse event risk over time. Such presentations can emphasize early differences across treatments that may resolve later or highlight events for which treatment differences may become more substantial with longer follow-up. LIMITATIONS: Treatment arms are compared in a pairwise fashion. CONCLUSIONS: Volcano plots are space-saving tools that emphasize important differences between the adverse event profiles of two treatment arms. They can incorporate multiplicity adjustments in a manner that is straightforward to interpret and, by using time intervals, can illustrate how adverse event risk changes over the course of a clinical trial.
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Ensaios Clínicos como Assunto , Gráficos por Computador , Interpretação Estatística de Dados , Medição de Risco , Terapêutica/efeitos adversos , Humanos , Incidência , Hemorragia Subaracnóidea/terapia , Terapêutica/estatística & dados numéricosRESUMO
Purpose: Validation of the novel Lexitas modified NEI scale for use in assessment of corneal fluorescein staining. Patients and Methods: A series of 18 illustrations and 14 clinical photographs depicting varying severity levels of corneal fluorescein staining were assessed by 3 independent examiners. Regions of the cornea were graded for staining severity based on 3 different grading scales: the original NEI staining scale (density-based scoring; 0-3 scale), a structured version of the NEI scale (dot-count scoring; 0-3 scale), and the Lexitas modified NEI staining scale (0-4 scale with half-point increments). Kappa statistics (simple and weighted) were computed to determine intra-examiner image grading repeatability for each examiner over 2 separate assessments. Inter-examiner assessment reliability utilized the scores from the first read of each examiner, and pairs of examiners to compute kappa statistics. Results: Data was analyzed from the scores provided by the examiners from each gradable corneal region on 32 images (18 illustrations and 14 photographs) for a total of 154 corneal regions across the 3 grading scales for each validation run. The mean intra-examiner simple/weighted kappa values using the NEI density, NEI dot count, and the Lexitas modified NEI staining scales were 0.67/0.72, 0.91/0.94, 0.80/0.92 for the graded illustrations, and 0.83/0.88, 0.76/0.85, 0.77/0.88 for the graded photographs, respectively. The mean inter-examiner simple/weighted kappa values using the NEI density, NEI dot count, and the Lexitas modified NEI staining scales were 0.59/0.65, 0.86/0.90, and 0.78/0.91 for the graded illustrations, and 0.80/0.88, 0.84/0.89, 0.69/0.88 for the graded photographs, respectively. Conclusion: The expanded scale of the Lexitas modified NEI staining scale demonstrated a high degree of reliability and repeatability of grading assessments within and across individual examiners, comparing favorably with the original NEI staining scale. A future investigation into the in-office utility of the Lexitas modified NEI staining scale is warranted.
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PURPOSE: The purpose of this pilot study was to evaluate the safety and efficacy of azithromycin ophthalmic solution 1% in patients with contact lens-related dry eye (CLDE). METHODS: This was a 4-week, single-center, open-label clinical trial in patients diagnosed with CLDE using the Contact Lens Dry Eye Questionnaire (CLDEQ). Fifty patients were enrolled in this study. The patients were randomized to 1 of 2 treatment groups: azithromycin ophthalmic solution administered bid on days 1 and 2 and on days 3 to 29±1 or Visine for Contacts rewetting drops administered qid on days 1 to 29±1. The patient diaries were used daily to collect data on comfortable and total contact lens wear time and ocular dryness throughout the treatment period. Tear osmolarity, fluorescein corneal staining, and visual acuity were also assessed during clinic visits. RESULTS: Fifty patients were enrolled, and 44 completed the study. One patient discontinued in the azithromycin group, and five patients discontinued in the rewetting drops group because of adverse events. A statistically significant increase in mean comfortable contact lens wear time from baseline was observed for the subjects treated with azithromycin ophthalmic solution as compared with the subjects treated with rewetting drops at week 4 (P=0.004; primary endpoint), in addition to weeks 2 and 3. The improvement in the mean comfortable wear time for the patients in the azithromycin treatment group exceeded 2 hrs throughout the treatment period (weeks 1-4). No significant differences were observed between the groups for total wear time, low contrast visual acuity, or tear osmolarity. Subject-rated ocular dryness (PM time assessments) was significantly improved from baseline in the subjects treated with azithromycin ophthalmic solution as compared with those treated with rewetting drops at weeks 2 and 3 endpoints (P=0.015 for each week). Additionally, a statistical difference was observed in favor of the azithromycin treatment group at week 2 for the subjects reclassifying as nondry eye as determined by the CLDEQ (P=0.05). CONCLUSIONS: Treatment with topical azithromycin ophthalmic solution was well tolerated and resulted in a significant improvement in comfortable contact lens wear time in the patients with CLDE.
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Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Lentes de Contato/efeitos adversos , Síndromes do Olho Seco/tratamento farmacológico , Soluções Oftálmicas/administração & dosagem , Administração Tópica , Adolescente , Adulto , Idoso , Antibacterianos/efeitos adversos , Azitromicina/efeitos adversos , Córnea/metabolismo , Síndromes do Olho Seco/etiologia , Síndromes do Olho Seco/fisiopatologia , Feminino , Fluoresceína/metabolismo , Humanos , Imidazóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Projetos Piloto , Lágrimas/química , Acuidade Visual/fisiologia , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Generalized estimating equations (GEE) provide population-averaged model inference for longitudinal and clustered outcomes via a generalized linear model for the effect of explanatory variables on the marginal mean, while intra-cluster correlations are ordinarily treated as nuisance parameters. Software to richly parameterize and conduct inference for complex correlation structures in the marginal modeling framework is scarce. METHODS: A SAS macro, GEECORR, has been developed for the analysis of clustered binary data based on GEE to include additional estimating equations for modeling pairwise correlation between binary variates as a function of covariates. RESULTS: We illustrate the macro in a surveillance study with repeated measures, a longitudinal study, and a study with biological clustering. CONCLUSIONS: This article provides an overview of the GEE method consisting of a pair of estimating equations, describes the features and capabilities of the GEECORR macro including regression diagnostics and finite-sample bias-corrected covariance estimators, and demonstrates the macro usage for three studies.
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Modelos Estatísticos , Viés , Análise por Conglomerados , Simulação por Computador , Humanos , Modelos Lineares , Estudos LongitudinaisRESUMO
This study describes the design of the TARGET-hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET-HCC is a 5-year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice. Patients can complete patient-reported outcome measures and provide biological specimens for future translational studies. The TARGET-HCC study includes adults with histologic, cytologic, or radiologic diagnosis of HCC from academic and community centers in both the United States and Europe. A total of 1,841 participants were enrolled between January 9, 2017, and July 23, 2019, at 67 sites in the United States and Europe. To date, the most common liver disease etiology in the cohort continues to be hepatitis C, although nearly half had a nonviral etiology, including alcohol-related liver disease or nonalcoholic steatohepatitis. Most included patients were diagnosed at an early stage (Barcelona Clinic Liver Cancer Stage [BCLC] 0/A), but only approximately one third underwent curative treatment. Systemic therapy has been used in 7.3% of enrolled patients, including 45.7% of those with BCLC stage C tumors. Conclusion: Overall, the TARGET-HCC cohort allows for the assessment of patient characteristics and investigation of new treatment paradigms and sequencing with existing agents as well as novel regimens for HCC.
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Carcinoma Hepatocelular/terapia , Pesquisa sobre Serviços de Saúde/métodos , Neoplasias Hepáticas/terapia , Avaliação de Resultados em Cuidados de Saúde/métodos , Adulto , Idoso , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Europa (Continente) , Feminino , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Projetos de Pesquisa , Estados UnidosRESUMO
The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH2 to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH2. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over ß-arrestin recruitment. Ex vivo experiments show that the combination of GLP-1(9-36)NH2 and LSN3318839 produces glucose-dependent insulin secretion similar to that of GLP-1(7-36)NH2. Under nutrient-stimulated conditions that release GLP-1, LSN3318839 demonstrates robust glucose lowering in animal models alone or in treatment combination with sitagliptin. From a therapeutic perspective, the biological properties of LSN3318839 support the concept that GLP-1R potentiation is sufficient for reducing hyperglycemia.
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Regulação Alostérica/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Administração Oral , Animais , Glicemia/análise , Descoberta de Drogas , Receptor do Peptídeo Semelhante ao Glucagon 1/química , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Camundongos , Modelos Moleculares , Ratos Sprague-DawleyRESUMO
BACKGROUND: Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. METHODS: In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis). RESULTS: Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70 percent), as compared with 174 of 287 such patients in the lamivudine group (61 percent, P=0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerase-chain-reaction assay (90 percent vs. 72 percent, P<0.001) and normalization of alanine aminotransferase levels (78 percent vs. 71 percent, P=0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a base-10 scale] copies per milliliter, P<0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups. CONCLUSIONS: Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.).
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Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Adulto , Antivirais/efeitos adversos , DNA Viral/sangue , Método Duplo-Cego , Farmacorresistência Viral , Feminino , Guanina/efeitos adversos , Guanina/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/sangue , Hepatite B Crônica/patologia , Humanos , Lamivudina/efeitos adversos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Resultado do TratamentoRESUMO
BACKGROUND: The Institute for Safe Medication Practices (ISMP) describes high alert medications (HAM) as medications that represent a heightened risk of patient harm when used in error. IV smart pumps with dose error reduction systems (DERS) were created to help address medication administration errors. Compliance with DERS provides a measure of how accurately a hospital uses smart pump technology to reduce IV medication error. OBJECTIVE: The primary purpose of this research was to use the REMEDI dataset, an aggregate, multi-hospital database inclusive of smart pump analytics, to improve the current understanding of clinical practices for IV HAM administration. METHODS: Descriptive analyses and analysis of variance (ANOVA) were used to test for differences in the mean DERS alert override rate, and mean DERS alert override to reprogram ratio between non-HAM and HAM overall, by hospital system, and by pump type. RESULTS: High mean override rates for non-HAM (73.8%) and HAM (75.8%) and high override to reprogram ratios for both non-HAM (7.30) and HAM (9.92) were seen. No significant differences were found in override rates (pâ¯=â¯0.23) and override to reprogram ratios (pâ¯=â¯0.06) between non-HAM and HAM. By hospital system, significant variability in override rates and override to reprogram ratios were seen. By pump type, there were no significant differences in the mean override rates (Baxter: pâ¯=â¯0.09; BD pâ¯=â¯0.34; ICU Medical pâ¯=â¯0.18) and the mean override to reprogram ratios (Baxter pâ¯=â¯0.84; BD pâ¯=â¯0.03; ICU Medical pâ¯=â¯0.63) between non-HAM and HAM. CONCLUSIONS: These findings indicate that the majority of alerts generated are bypassed by clinicians at the point of care, a symptom of alert fatigue. Given the potential for significant patient harm with HAM and the high DERS alert override rates that routinely occur during IV medication administration, this study provides further support for clinician-driven IV smart pump innovation to improve alert fatigue.