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Risk stratification based on prediction models has become increasingly important in preventing and managing chronic diseases. However, due to cost- and time-limitations, not every population can have resources for collecting enough detailed individual-level information on a large number of people to develop risk prediction models. A more practical approach is to use prediction models developed from existing studies and calibrate them with relevant summary-level information of the target population. Many existing studies were conducted under the population-based case-control design. Gail et al. (J Natl Cancer Inst 81:1879-1886, 1989) proposed to combine the odds ratio estimates obtained from case-control data and the disease incidence rates from the target population to obtain the baseline hazard function, and thereby the pure risk for developing diseases. However, the approach requires the risk factor distribution of cases from the case-control studies be same as the target population, which, if violated, may yield biased risk estimation. In this article, we propose two novel weighted estimating equation approaches to calibrate the baseline risk by leveraging the summary information of (some) risk factors in addition to disease-free probabilities from the targeted population. We establish the consistency and asymptotic normality of the proposed estimators. Extensive simulation studies and an application to colorectal cancer studies demonstrate the proposed estimators perform well for bias reduction in finite samples.
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Simulação por Computador , Humanos , Estudos de Casos e Controles , Medição de Risco/métodos , Fatores de Risco , Modelos Estatísticos , Neoplasias Colorretais , Modelos de Riscos ProporcionaisRESUMO
Lanthanide-based upconversion molecular complexes have potential application in diverse fields and attracted considerable research interest in recent years. However, the similar coordination reactivity of lanthanide ions has constrained the designability of target molecule with well-defined structure, and many attempts obtained statistical mixtures. Herein, an ion-paired Yb-Eu heteronuclear complex [Eu(TpPy)2][Yb(ND)4] (TpPy = tris[3-(2-pyridyl)pyrazolyl]hydroborate, ND = 3-cyano-2-methyl-1,5-naphthyridin-4-olate) was designed and synthesized. Thanks to the radius difference between Eu3+ (1.07 Å) and Yb3+ (0.98 Å) ions, the hexadentate TpPy ligand was selected to coordinate with Eu3+ and the Yb3+ with a smaller radius was chelated by bidentate ND ligand. As a result, the sites of Eu3+ and Yb3+ in the complex can be clarified by high-resolution mass spectrometry and single-crystal structure analysis. Upon the excitation of Yb3+ at 980 nm, the upconversion emission of Eu3+ was realized through a cooperative sensitization process. Furthermore, [Eu(TpPy)2][Yb(ND)4] demonstrated excellent photostability during continuous high-power density 980 nm laser irradiation, with a LT95 (the time to 95% of the initial emission intensity) of 420 minutes. This work provides the first example of a pure ion-paired Yb-Eu heteronuclear complex upconversion system and may bring insights into rational design of lanthanide-based upconversion molecular complexes.
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BACKGROUND & AIMS: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. METHODS: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. RESULTS: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. CONCLUSIONS: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.
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Neoplasias Colorretais , Análise de Custo-Efetividade , Humanos , Pessoa de Meia-Idade , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Custo-Benefício , Detecção Precoce de Câncer/métodos , Colonoscopia , Neoplasias Colorretais/epidemiologia , Programas de Rastreamento/métodosRESUMO
Ischemic stroke, which accounts for nearly 80% of all strokes, leads to white matter injury and neurobehavioral dysfunction, but relevant therapies to inhibit demyelination or promote remyelination after white matter injury are still unavailable. In this study, the middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro were used to establish the ischemic models. We found that Eph receptor A4 (EphA4) had no effect on the apoptosis of oligodendrocytes using TUNEL staining. In contrast, EphA4 promoted proliferation of oligodendrocyte precursor cells (OPCs), but reduced the numbers of mature oligodendrocytes and the levels of myelin-associated proteins (MAG, MOG, and MBP) in the process of remyelination in ischemic models in vivo and in vitro as determined using PDGFRα-EphA4-shRNA and LV-EphA4 treatments. Notably, conditional knockout of EphA4 in OPCs (EphA4fl/fl + AAV-PDGFRα-Cre) improved the levels of myelin-associated proteins and functional recovery following ischemic stroke. In addition, regulation of remyelination by EphA4 was mediated by the Ephexin-1/RhoA/ROCK signaling pathway. Therefore, EphA4 did not affect oligodendrocyte (OL) apoptosis but regulated white matter remyelination after ischemic stroke through the Ephexin-1/RhoA/ROCK signaling pathway. EphA4 may provide a novel and effective therapeutic target in clinical practice of ischemic stroke.
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AVC Isquêmico , Remielinização , Acidente Vascular Cerebral , Substância Branca , Apoptose , Humanos , Oligodendroglia , Receptor EphA4 , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Remielinização/fisiologia , Transdução de Sinais , Proteína rhoA de Ligação ao GTPRESUMO
Accurate risk assessment is critical in clinical decision-making. It entails the projected risk based on a risk prediction model agreeing with the observed risk in the target cohort. However, the model often over- or under-estimates the risk. Building a new model for the target cohort would be ideal but costly. It is therefore of great interest to recalibrate an existing model for the target cohort. Existing methods have been proposed to recalibrate the model by leveraging the disease incidence rates from the target cohort. However, they assume the same covariate distribution across cohorts and when the assumption is violated, the recalibrated model can be substantially biased. Further, recalibration is also complicated by the two-phase sampling design that is commonly used for developing risk prediction models. In this paper, we develop a weighted estimating-equation approach accounting for the two-phase design and combine it with a weighted empirical likelihood that leverages the summary information on both disease incidence rates and covariates from the target cohort. We provide a resampling-based inference procedure. Our extensive simulation results show that using the summary information from the target population, the proposed recalibration method yields nearly unbiased risk estimates under a wide range of scenarios. An application to a colorectal cancer study also illustrates that the proposed method yields a well-calibrated model in the target cohort.
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Simulação por Computador , Humanos , Medição de Risco/métodos , IncidênciaRESUMO
We previously reported that astrocytes are the main sources of interleukin (IL)-17A production that could aggravate neuronal injuries in ischemic stroke. However, the effects of IL-17A on ischemic astrocytes themselves and the underlying molecular mechanism are still unclear. In this study, we found that recombinant mouse (rm) IL-17A could significantly (P < 0.05 or <0.001) alleviate 1-hour oxygen-glucose deprivation (OGD)/reoxygenation (R) 24-hour-induced ischemic injuries in cortical astrocytes with a dose-dependent manner (n = 6 per group). The Western blot and cell cycle analysis results revealed that rmIL-17A significantly ( P < 0.05) inhibited procaspase-3 cleavage without affecting cell proliferation in 1-hour OGD/R 24-hour-treated cortical astrocytes (n = 6 per group). Among the five IL-17 receptor subunits (IL-RA, -RB, -RC, -RD, and -RE), only IL-17RA ( P < 0.01) and -17RC ( P < 0.05) membrane translocation (not messenger RNA and protein) levels were downregulated in cortical astrocytes following 1-hour OGD/reperfusion 24 hours, and rmIL-17A could significantly ( P < 0.05 or <0.001) inhibit this downregulation (n = 6 per group). To further verify the impact of IL-17A on the neurological outcome of ischemic stroke, we found that the intracerebroventricular injection of IL-17A neutralizing monoclonal antibody remarkably ( P < 0.001) reduced the astrocyte activation and improve neurological function ( P < 0.05 or <0.01) of mice following 1-hour middle cerebral artery occlusion/reperfusion (R) 3 to 7 days (n = 6 or 8 per group). These results suggested that IL-17A-mediated alleviation of cortical astrocyte ischemic injuries could affect the neurological outcome of mice with ischemic stroke, which might be mainly dependent on the cell apoptosis pathway through inhibiting the downregulation of IL-17RA and -17RC membrane translocations.
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In pharmaceutical/clinical development, two-stage seamless adaptive designs are commonly considered. Such designs include a two-stage phase I/II or phase II/III adaptive trial that combines one phase IIb study for dose-finding or treatment selection and one phase III study for efficacy confirmation into a single study. At the end of stage 1, promising dose(s) will be selected based on pre-specified selection criteria. In practice, since there is little power with limited subjects available at interim, commonly considered selection criteria for critical decision-making include (i) conditional power, (ii) precision analysis, (iii) predictive probability of success, and (iv) probability of being the best dose or treatment. The selected promising dose(s) will then proceed to the next stage for efficacy confirmation. In this article, we introduce, compare, and evaluate these criteria. Simulation studies and a numeric example are given to illustrate those criteria. Besides, we attempt to address some concerns for the two-stage seamless adaptive clinical trial.
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Fármacos Cardiovasculares/administração & dosagem , Determinação de Ponto Final/estatística & dados numéricos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Probabilidade , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Vasoespasmo Coronário/tratamento farmacológico , Vasoespasmo Coronário/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Determinação de Ponto Final/métodos , Humanos , Estudos Multicêntricos como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
For review and approval of drug products, a 95% confidence interval approach for evaluation of new drugs is commonly used, while a 90% confidence interval approach is considered for assessment of generic drugs and biosimilar products. In the past decade, FDA has been challenged for adopting different standards (i.e., 5% type-I error rate for new drugs and 10% type-I error rate for generics/biosimilars) for regulatory submissions of drugs and biologics. This note intends to clarify the confusion by pointing out the fundamental differences between (i) the concepts of point hypotheses and interval hypotheses, and (ii) the concepts of interval hypotheses testing and confidence interval approach. In general, the method of interval hypotheses testing is not equivalent to the confidence interval approach although they may be operationally equivalent under certain conditions.
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Medicamentos Biossimilares , Desenvolvimento de Medicamentos/estatística & dados numéricos , Medicamentos Biossimilares/química , Medicamentos Biossimilares/uso terapêutico , Intervalos de Confiança , Desenvolvimento de Medicamentos/métodos , Humanos , Tamanho da Amostra , Equivalência TerapêuticaRESUMO
In analytical similarity assessment of a biosimilar product, key quality attributes of the test and reference products need to be shown statistically similar. When there were multiple references, similarity among the reference products is also required. We proposed a simultaneous confidence approach based on the fiducial inference theory as an alternative to the pairwise comparison method. Three versions with two types of simultaneous confidence intervals for each version were proposed based on different assumptions of the population variance. We conducted extensive simulation studies to compare the performance of our proposed method and the pairwise method, and provided examples to illustrate the concern of using pairwise method.
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Medicamentos Biossimilares , Simulação por Computador/estatística & dados numéricos , Equivalência Terapêutica , Intervalos de Confiança , Humanos , Distribuição AleatóriaRESUMO
OBJECTIVES: Accurate localization of a colonic lesion is crucial to successful resection. Although colonic tattooing is a widely accepted technique to mark lesions for future identification surgery or repeat colonoscopy, no consensus guidelines exist. The objective of this study was to determine whether the current tattooing practice at a tertiary medical center differs from recommendations in the literature and self-reported provider practice. METHODS: The study consisted of an observational retrospective chart review of patients who received colonic tattoos, as well as a provider survey of reported tattooing practices at a tertiary academic medical center. A total of 747 patients older than 18 years of age who underwent colonoscopy with tattoo were included. Forty-four gastroenterologists performing endoscopy were surveyed on tattooing techniques. RESULTS: In the majority of cases, neither the number of tattoos, location of the tattoo nor the distance from the lesion was specified within the report. Following the index procedure, a tattoo was detected in 75% of surgical resections and 73% of endoscopies. At the time of surgery, however, the tattoo and/or the lesion was detected approximately 94% of the time. Twenty-five endoscopists (56.8%) completed the survey. Differences were seen the between the chart review and reported practice. Most providers report placing ≥2 marks (87.2%); however, chart review revealed that only 56.2 % were tattooed with ≥2 marks. CONCLUSIONS: Variation exists between the reported tattooing practice and actual practice. Despite this, most tattoos are identified at the time of surgery or repeat endoscopy. Further research is needed to determine whether a standardized approach to tattooing and reporting could improve localization at repeat endoscopy.
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Pólipos do Colo/cirurgia , Colonoscopia/métodos , Neoplasias Colorretais/cirurgia , Documentação/estatística & dados numéricos , Gastroenterologistas , Padrões de Prática Médica/estatística & dados numéricos , Tatuagem/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Pólipos do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tatuagem/métodos , Centros de Atenção Terciária , Adulto JovemRESUMO
Human leukocyte antigen (HLA) serotyping is not considered to have significant impact on liver graft survival and does not factor into U.S. organ allocation. Immune-related liver diseases such as primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and primary biliary cholangitis (PBC) have been speculated to represent a disease subgroup that may have significantly different graft outcomes depending on HLA donor/recipient characterization. The aim of this study was to investigate whether HLA serotyping/matching influenced post-transplant graft failure for immune-related liver diseases using the United Network for Organ Sharing database. From 1994 to 2015, 5665 patients underwent first-time liver-only transplants for PSC, AIH, and PBC with complete graft survival and donor/recipient HLA data. Graft failure was noted in 38.6% (2188/5665), and all groups had comparable 5-year graft survival (75.1%-78.8%, P = 0.069). The overall degree of, and loci-specific mismatch level, did not influence outcomes. Multivariable Cox proportional hazards regression noted increased graft failure risk for recipient HLA-B7, HLA-B57, HLA-B75, HLA-DR13 and donor HLA-B55, HLA-B58, and HLA-DR8 for PSC patients, protective effects for recipient HLA-DR1 and HLA-DR3 for AIH patients, and increased risk for HLA-DR7 for AIH patients. These findings warrant further investigation to evaluate the impact of HLA serotyping on post-transplant outcomes.
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Colangite Esclerosante/imunologia , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Hepatite Autoimune/imunologia , Histocompatibilidade/imunologia , Cirrose Hepática Biliar/imunologia , Transplante de Fígado , Estudos de Casos e Controles , Colangite Esclerosante/cirurgia , Feminino , Seguimentos , Sobrevivência de Enxerto , Hepatite Autoimune/cirurgia , Humanos , Cirrose Hepática Biliar/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Sorotipagem , Doadores de Tecidos/provisão & distribuição , Obtenção de Tecidos e ÓrgãosRESUMO
BACKGROUND & AIMS: Guidelines recommend that patients with Helicobacter pylori (H. pylori)-associated peptic ulcer disease (PUD) receive H. pylori eradication therapy followed by post-treatment testing to prove eradication; however, post-treatment testing rates are suboptimal and barriers to testing are poorly understood. Our aim was to identify factors that predicted receipt of post-treatment testing. METHODS: We performed a retrospective cohort study of 152 patients with H. pylori-associated PUD diagnosed between 2007 and 2015 at a large tertiary medical center in the United States, who received standard eradication therapy and ambulatory follow-up within one year. The primary outcome of interest was receipt of post-treatment testing. Logistic regression models compared post-treatment testing rates in those diagnosed while outpatient vs inpatient, patients with vs without repeat endoscopy, and patients with vs without gastroenterology (GI) clinic follow-up. Propensity scores controlled for age, sex, race, ulcer location, and symptom persistence. RESULTS: Among 152 patients, 67 (44%) patients received post-treatment testing. There were significant differences in post-treatment testing rates in those diagnosed as outpatients vs inpatients (57% vs 33%; OR 3.87, P = 0.001) and in patients with vs without GI follow-up (62% vs 11%; OR 9.85, P < 0.0001). CONCLUSIONS: The rate of testing for eradication after treatment in patients with H. pylori- associated PUD was low. However, this was significantly improved in patients who have GI follow-up and whose diagnosis was made in the outpatient setting. Our study demonstrates a clear opportunity for quality improvement initiatives.
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Infecções por Helicobacter/microbiologia , Úlcera Péptica/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Helicobacter pylori/patogenicidade , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
In recent years, multi-regional clinical trials (MRCT) that conduct clinical trials simultaneously in Asian Pacific region, Europe, and the United States have become very popular for global pharmaceutical development. The main purpose of multi-regional clinical trials is to shorten the time for pharmaceutical development and regulatory submission, and approval around the world. In practice, however, clinical results observed from some regions (sub-population) may not be consistent with the results from other regions and/or all regions combined (entire population). The inconsistency observed may be due to ethnic differences in different regions, differences in medical practice, time points of assessment, or by random chance due to small sample size for the region. Some regional regulatory agencies require consistency evaluation between local country results and overall results. However, the challenge is there is no detailed guidance on the definition of 'consistency' and methodology to evaluate it. Therefore, the questions are: how to evaluate consistency and what statistical methods are appropriate to be used for consistency evaluation? In this article, several statistical tests for consistency (similarity) between clinical results observed from a specific sub-population and the entire population are proposed. These methods are compared through extensive simulation. As most published articles discussed consistency evaluation for superiority situations, we have discussed consistency evaluation for non-inferiority situation in this article through a simulated example concerning consistency in some countries. Recommendations of the statistical methods to be used for consistency evaluation are given. Other aspects that should be considered for consistency evaluation are also provided.
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Simulação por Computador/estatística & dados numéricos , Demografia/estatística & dados numéricos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Vigilância da População , Demografia/métodos , Humanos , Estudos Multicêntricos como Assunto/métodos , Vigilância da População/métodosRESUMO
Importance: The left atrial appendage is a key site of thrombus formation in atrial fibrillation (AF) and can be occluded or removed at the time of cardiac surgery. There is limited evidence regarding the effectiveness of surgical left atrial appendage occlusion (S-LAAO) for reducing the risk of thromboembolism. Objective: To evaluate the association of S-LAAO vs no receipt of S-LAAO with the risk of thromboembolism among older patients undergoing cardiac surgery. Design, Setting, and Participants: Retrospective cohort study of a nationally representative Medicare-linked cohort from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (2011-2012). Patients aged 65 years and older with AF undergoing cardiac surgery (coronary artery bypass grafting [CABG], mitral valve surgery with or without CABG, or aortic valve surgery with or without CABG) with and without concomitant S-LAAO were followed up until December 31, 2014. Exposures: S-LAAO vs no S-LAAO. Main Outcomes and Measures: The primary outcome was readmission for thromboembolism (stroke, transient ischemic attack, or systemic embolism) at up to 3 years of follow-up, as defined by Medicare claims data. Secondary end points included hemorrhagic stroke, all-cause mortality, and a composite end point (thromboembolism, hemorrhagic stroke, or all-cause mortality). Results: Among 10â¯524 patients undergoing surgery (median age, 76 years; 39% female; median CHA2DS2-VASc score, 4), 3892 (37%) underwent S-LAAO. Overall, at a mean follow-up of 2.6 years, thromboembolism occurred in 5.4%, hemorrhagic stroke in 0.9%, all-cause mortality in 21.5%, and the composite end point in 25.7%. S-LAAO, compared with no S-LAAO, was associated with lower unadjusted rates of thromboembolism (4.2% vs 6.2%), all-cause mortality (17.3% vs 23.9%), and the composite end point (20.5% vs 28.7%) but no significant difference in rates of hemorrhagic stroke (0.9% vs 0.9%). After inverse probability-weighted adjustment, S-LAAO was associated with a significantly lower rate of thromboembolism (subdistribution hazard ratio [HR], 0.67; 95% CI, 0.56-0.81; P < .001), all-cause mortality (HR, 0.88; 95% CI, 0.79-0.97; P = .001), and the composite end point (HR, 0.83; 95% CI, 0.76-0.91; P < .001) but not hemorrhagic stroke (subdistribution HR, 0.84; 95% CI, 0.53-1.32; P = .44). S-LAAO, compared with no S-LAAO, was associated with a lower risk of thromboembolism among patients discharged without anticoagulation (unadjusted rate, 4.2% vs 6.0%; adjusted subdistribution HR, 0.26; 95% CI, 0.17-0.40; P < .001), but not among patients discharged with anticoagulation (unadjusted rate, 4.1% vs 6.3%; adjusted subdistribution HR, 0.88; 95% CI, 0.56-1.39; P = .59). Conclusions and Relevance: Among older patients with AF undergoing concomitant cardiac surgery, S-LAAO, compared with no S-LAAO, was associated with a lower risk of readmission for thromboembolism over 3 years. These findings support the use of S-LAAO, but randomized trials are necessary to provide definitive evidence.
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Apêndice Atrial/cirurgia , Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Readmissão do Paciente/estatística & dados numéricos , Tromboembolia/prevenção & controle , Idoso , Valva Aórtica/cirurgia , Ponte de Artéria Coronária/efeitos adversos , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Valva Mitral/cirurgia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Dispositivo para Oclusão Septal , Tromboembolia/epidemiologia , Tromboembolia/etiologiaRESUMO
Liver retransplantation in patients with primary sclerosing cholangitis (PSC) has not been well studied. The aims of this study were to characterize patients with PSC listed for and undergoing retransplantation and to describe the outcomes in these patients. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database was used to identify all primary liver transplantations and subsequent relistings and first retransplantations in adults with PSC between 1987 and 2015. A total of 5080 adults underwent primary transplantation for PSC during this period, and of the 1803 who experienced graft failure (GF), 762 were relisted, and 636 underwent retransplantation. Younger patients and patients with GF due to vascular thrombosis or biliary complications were more likely to be relisted, whereas those with Medicaid insurance or GF due to infection were less likely. Both 5-year graft and patient survival after retransplantation were inferior to primary transplantation (P < 0.001). Five-year survival after retransplantation for disease recurrence (REC), however, was similar to primary transplantation (graft survival, P = 0.45; patient survival, P = 0.09) and superior to other indications for retransplantation (graft and patient survival, P < 0.001). On multivariate analysis, mechanical ventilation, creatinine, bilirubin, albumin, advanced donor age, and a living donor were associated with poorer outcomes after retransplantation. In conclusion, although survival after liver retransplantation in patients with PSC was overall inferior to primary transplantation, outcomes after retransplantation for PSC REC were similar to primary transplantation at 5 years. Retransplantation may therefore represent a treatment option with the potential for excellent outcomes in patients with REC of PSC in the appropriate clinical circumstances. Liver Transplantation 23 769-780 2017 AASLD.
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Colangite Esclerosante/cirurgia , Sobrevivência de Enxerto , Transplante de Fígado/métodos , Fígado/cirurgia , Reoperação/métodos , Adulto , Colangite Esclerosante/mortalidade , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva , Reoperação/efeitos adversos , Respiração Artificial , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Listas de EsperaRESUMO
As more and more generics become available in the market place, the safety/efficacy concerns may arise as the result of interchangeably use of approved generics. However, bioequivalence assessment for regulatory approval among generics of the innovative drug product is not required. In practice, approved generics are often used interchangeably without any mechanism of safety monitoring. In this article, based on indirect comparisons, we proposed several methods to assessing bioequivalence and interchangeability between generics. The applicability of the methods and the similarity assumptions were discussed, as well as the inappropriateness of directly adopting adjusted indirect comparison to the field of generics' comparison. Besides, some extensions were given to take into consideration the important topics in clinical trials for bioequivalence assessments, for example, multiple comparisons and simultaneously testing bioequivalence among three generics. Extensive simulation studies were conducted to investigate the performances of the proposed methods. The studies of malaria generics and HIV/AIDS generics prequalified by the WHO were used as real examples to demonstrate the use of the methods. Copyright © 2017 John Wiley & Sons, Ltd.
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Medicamentos Genéricos/farmacocinética , Modelos Estatísticos , Equivalência Terapêutica , Fármacos Anti-HIV/farmacocinética , Antimaláricos/farmacocinética , Artemeter , Artemisininas/farmacocinética , Simulação por Computador , Intervalos de Confiança , Etanolaminas/farmacocinética , Fluorenos/farmacocinética , Infecções por HIV/tratamento farmacológico , Humanos , Lamivudina/farmacocinética , Lumefantrina , Malária/tratamento farmacológico , Zidovudina/farmacocinéticaRESUMO
BACKGROUND: Framingham Stroke Risk Score (FSRS) is the most well-regarded risk appraisal tools for evaluating an individual's absolute risk on stroke onset. However, several widely accepted risk factors for stroke were not included in the original Framingham model. This study proposed a new model which combines an existing risk models with new risk factors using synthesis analysis, and applied it to the longitudinal Atherosclerosis Risk in Communities (ARIC) data set. METHODS: Risk factors in original prediction models and new risk factors in proposed model had been discussed. Three measures, like discrimination, calibration and reclassification, were used to evaluate the performance of the original Framingham model and new risk prediction model. RESULTS: Modified C-statistics, Hosmer-Lemeshow Test and classless NRI, class NRI were the statistical indices which, respectively, denoted the performance of discrimination, calibration and reclassification for evaluating the newly developed risk prediction model on stroke onset. It showed that the NEW-STROKE (new stroke risk score prediction model) model had higher modified C-statistics, smaller Hosmer-Lemeshow chi-square values after recalibration than original FSRS model, and the classless NRI and class NRI of the NEW-STROKE model over the original FSRS model were all significantly positive in overall group. CONCLUSION: The NEW-STROKE integrated with seven literature-derived risk factors outperformed the original FSRS model in predicting the risk score of stroke. It illustrated that seven literature-derived risk factors contributed significantly to stroke risk prediction.
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Modelos Estatísticos , Medição de Risco , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Aterosclerose , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de SobrevidaRESUMO
BACKGROUND: There is increasing evidence for a heterogeneity of phenotypes in primary sclerosing cholangitis (PSC), but differences across the age spectrum in adults with PSC have not been well characterized. AIMS: To characterize phenotypic variations and liver transplantation outcomes by age group in adults with PSC. METHODS: The United Network for Organ Sharing database was used to identify waitlist registrations for primary liver transplantation in adults with PSC. Patients were split into three age groups: 18-39 (young), 40-59 (middle-aged), and ≥60 (older). Their clinical characteristics and outcomes on the waitlist and post-transplant were compared. RESULTS: Overall, 8272 adults with PSC were listed for liver transplantation during the study period, of which 28.9% were young, 52.0% were middle-aged, and 19.1% were older. The young age group had the greatest male predominance (70.0 vs. 66.2 vs. 65.1%, p = 0.001), the highest proportion of black individuals (20.0 vs. 11.0 vs. 5.5%, p < 0.001), and the most patients listed with concomitant autoimmune hepatitis (2.2 vs. 1.0 vs. 0.8%, p < 0.001). Older patients experienced the greatest waitlist and post-transplant mortality. Graft survival was greatest in the middle-aged group. Young patients were most likely to experience acute rejection (31 vs. 22.8 vs. 18.0%, p < 0.001) and have graft failure due to chronic rejection or PSC recurrence (47.8 vs. 42.3 vs. 17.9%, p < 0.001). CONCLUSIONS: Age-related differences exist among adults with PSC and are associated with outcomes pre- and post-transplant. Young patients may have a more robust immune-related phenotype that is associated with poorer graft survival. Future studies are needed to further investigate these findings.
Assuntos
Colangite Esclerosante/cirurgia , Transplante de Fígado , Adolescente , Adulto , Distribuição por Idade , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/etnologia , Colangite Esclerosante/mortalidade , Bases de Dados Factuais , Feminino , Rejeição de Enxerto/etnologia , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Fenótipo , Recidiva , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Fatores de Tempo , Obtenção de Tecidos e Órgãos , Resultado do Tratamento , Estados Unidos/epidemiologia , Listas de Espera/mortalidade , Adulto JovemRESUMO
As more and more generic (or biosimilar) drug products become available in the market place, it is a concern whether the approved generic (or biosimilar) drug products are safe and efficacious and hence can be used interchangeably. According to current regulation, most regulatory agencies such as the United States Food and Drug Administration (FDA) indicate an approved generic (or biosimilar) drug product can serve as a substitute for the innovative drug product. Bioequivalence (biosimilarity) assessment for regulatory approval among generic copies (or biosimilars) of the innovative drug product are not required. In practice, approved generic (or biosimilar) drugs are commonly used interchangeably without any mechanism of safety monitoring. In this article, current bioequivalence (or biosimilarity) limit is adjusted according to the observed geometric mean ratio and corresponding variability for development of safety margins for monitoring of drug interchangeability by minimizing the relative change in response with and without the switching.
Assuntos
Medicamentos Biossimilares/normas , Medicamentos Genéricos/normas , Equivalência Terapêutica , Aprovação de Drogas , Humanos , Estatística como Assunto , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: Intra-operative cell salvage (CS) was reported to have no impairment on blood coagulation in low-bleeding-risk cardiac surgery with cardiopulmonary bypass (CPB), but studies in high-bleeding-risk cardiac surgery are limited. The objective of this study is to evaluate the impact of CS on blood coagulation in high-bleeding-risk cardiac surgery with CPB. METHODS: One hundred and ten patients were randomly assigned to either with intra-operative CS group (Group CS) or without intra-operative CS group (Group C). Study endpoints included the incidence of impairment of blood coagulation during perioperative period (peri-op) and the incidence of adverse events during postoperative period (post-op). Peri-op was defined as the period from beginning of anesthesia (anesthesia induction) to 24 h after end of surgery. Post-op was defined as the period from the end of surgery to 24 h after end of surgery. The types of impairment of blood coagulation included heparin residual, coagulopathy due to low PLT, coagulopathy due to low FIB, coagulopathy due to low coagulation factors, hyperfibrinolytic. The sum of above five types was total impairment of blood coagulation. Adverse events included excessive bleeding, resternotomy, etc. RESULTS: The incidence of heparin residual measured both at the end of surgery and during post-op were significantly higher in Group CS than in Group C (15.09 vs 4.00, 13.21 vs 2.00 %; p = 0.024, 0.010, respectively). Similarly, the incidence of total impairment of blood coagulation at the end of surgery and during post-op were significantly higher in Group CS than in Group C (32.08 vs 18.00, 26.42 vs 12.00 %; p = 0.043, 0.040, respectively). The incidence of excessive bleeding during post-op was 32.08 % in Group CS compared with 16.00 % in Group C (p = 0.038). Intriguingly, CS was associated with a significantly increase in the relative risk ratios for heparin residual and excessive bleeding (p = 0.034, 0.049, respectively). CONCLUSIONS: Intra-operative CS could impair blood coagulation in the scenario of high-risk-bleeding cardiac surgery with CPB.