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1.
Blood ; 144(1): 35-45, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38643510

RESUMO

ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Receptores CXCR4 , Verrugas , Humanos , Feminino , Receptores CXCR4/antagonistas & inibidores , Masculino , Doenças da Imunodeficiência Primária/tratamento farmacológico , Verrugas/tratamento farmacológico , Método Duplo-Cego , Adulto , Pessoa de Meia-Idade , Síndromes de Imunodeficiência/tratamento farmacológico , Quinolinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Adolescente , Adulto Jovem , Criança , Contagem de Linfócitos , Aminoquinolinas , Benzimidazóis , Butilaminas
2.
Blood ; 136(26): 2994-3003, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-32870250

RESUMO

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327.


Assuntos
Aminoquinolinas/administração & dosagem , Benzimidazóis/administração & dosagem , Butilaminas/administração & dosagem , Doenças da Imunodeficiência Primária/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Verrugas/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Aminoquinolinas/efeitos adversos , Benzimidazóis/efeitos adversos , Butilaminas/efeitos adversos , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos , Doenças da Imunodeficiência Primária/sangue , Doenças da Imunodeficiência Primária/genética , Estudos Prospectivos , Receptores CXCR4/genética , Verrugas/sangue , Verrugas/genética
3.
Sensors (Basel) ; 22(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36080994

RESUMO

Pork accounts for an important proportion of livestock products. For pig farming, a lot of manpower, material resources and time are required to monitor pig health and welfare. As the number of pigs in farming increases, the continued use of traditional monitoring methods may cause stress and harm to pigs and farmers and affect pig health and welfare as well as farming economic output. In addition, the application of artificial intelligence has become a core part of smart pig farming. The precision pig farming system uses sensors such as cameras and radio frequency identification to monitor biometric information such as pig sound and pig behavior in real-time and convert them into key indicators of pig health and welfare. By analyzing the key indicators, problems in pig health and welfare can be detected early, and timely intervention and treatment can be provided, which helps to improve the production and economic efficiency of pig farming. This paper studies more than 150 papers on precision pig farming and summarizes and evaluates the application of artificial intelligence technologies to pig detection, tracking, behavior recognition and sound recognition. Finally, we summarize and discuss the opportunities and challenges of precision pig farming.


Assuntos
Criação de Animais Domésticos , Bem-Estar do Animal , Criação de Animais Domésticos/métodos , Animais , Inteligência Artificial , Fazendas , Gado , Suínos
4.
Mediators Inflamm ; 2020: 2453537, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32322162

RESUMO

L-arginine (Arg) is a semiessential amino acid with several physiological functions. N-Carbamylglutamate (NCG) can promote the synthesis of endogenous Arg in mammals. However, the roles of Arg or NCG on hepatic inflammation and apoptosis in suckling lambs suffering from intrauterine growth restriction (IUGR) are still unclear. The current work is aimed at examining the effects of dietary Arg and NCG on inflammatory and hepatocyte apoptosis in IUGR suckling lambs. On day 7 after birth, 48 newborn Hu lambs were selected from a cohort of 432 twin lambs. Normal-birthweight and IUGR Hu lambs were allocated randomly (n = 12/group) to control (CON), IUGR, IUGR+1% Arg, or IUGR+0.1% NCG groups. Lambs were fed for 21 days from 7 to 28 days old. Compared with CON lambs, relative protein 53 (P53), apoptosis antigen 1 (Fas), Bcl-2-associated X protein (Bax), caspase-3, cytochrome C, tumor necrosis factor alpha (TNF-α), nuclear factor kappa-B (NF-κB) p65, and NF-κB pp65 protein levels were higher (P < 0.05) in liver from IUGR lambs, whereas those in liver from IUGR lambs under Arg or NCG treatment were lower than those in IUGR lambs. These findings indicated that supplementing Arg or NCG reduced the contents of proinflammatory cytokines at the same time when the apoptosis-related pathway was being suppressed, thus suppressing the IUGR-induced apoptosis of hepatic cells.


Assuntos
Arginina/uso terapêutico , Retardo do Crescimento Fetal/tratamento farmacológico , Retardo do Crescimento Fetal/metabolismo , Glutamatos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Peso Corporal/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Citocromos c/metabolismo , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Marcação In Situ das Extremidades Cortadas , Fígado/efeitos dos fármacos , Fígado/metabolismo , NF-kappa B/metabolismo , Gravidez , Radioimunoensaio , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ovinos , Fator de Necrose Tumoral alfa/metabolismo
5.
Diabetes Obes Metab ; 19(7): 1024-1031, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28294499

RESUMO

AIM: To compare the addition of weekly dulaglutide vs the addition of placebo to titrated glargine in patients with type 2 diabetes (T2D) with sub-optimum glycated haemoglobin (HbA1c) concentration. MATERIALS AND METHODS: Patients (N = 300) from this phase III, double-blind, parallel-arm, placebo-controlled study were randomized to weekly subcutaneous injections of dulaglutide 1.5 mg or placebo with titrated daily glargine (mean ± standard deviation baseline dose: 39 ± 22 U), with or without metformin (≥1500 mg/d). The primary endpoint was superiority of dulaglutide/glargine to placebo/glargine with regard to change from baseline in HbA1c level at 28 weeks. RESULTS: Least squares (LS) mean ± standard error (s.e.) HbA1c changes from baseline were -1.44 ± 0.09% (-15.74 ± 0.98 mmol/mol) with dulaglutide/glargine and -0.67 ± 0.09% (-7.32 ± 0.98 mmol/mol) with placebo/glargine at 28 weeks (LS mean difference [95% confidence interval] -0.77% [-0.97, -0.56]; P < .001). Body weight decreased with dulaglutide/glargine and increased with placebo/glargine (LS mean difference: -2.41 ± 0.39 kg; P < .001). Increases from baseline in mean glargine dose were significantly smaller with dulaglutide/glargine vs placebo/glargine (13 ± 2 U [0.1 ± 0.02 U/kg] vs 26 ± 2 U [0.3 ± 0.02 U/kg], respectively; P < .001; LS mean ± s.e. final dose: dulaglutide/glargine, 51 ± 2 U; placebo/glargine, 65 ± 2 U). The hypoglycaemia rate (≤3.9 mmol/L threshold) was 7.69 ± 15.15 and 8.56 ± 16.13 events/patient/year, respectively (P = .488). One episode of severe hypoglycaemia occurred in the dulaglutide/glargine group. Common gastrointestinal adverse events with dulaglutide were nausea (12.0%), diarrhoea (11.3%) and vomiting (6.0%). CONCLUSIONS: Weekly dulaglutide 1.5 mg added to basal insulin is an efficacious and well tolerated treatment option for patients with T2D.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Incretinas/uso terapêutico , Insulina Glargina/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Esquema de Medicação , Monitoramento de Medicamentos , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Incretinas/administração & dosagem , Incretinas/efeitos adversos , Injeções Subcutâneas , Insulina Glargina/administração & dosagem , Insulina Glargina/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos
6.
Lancet ; 385(9982): 2057-66, 2015 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-26009229

RESUMO

BACKGROUND: For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal-bolus insulin regimen is often recommended. We aimed to compare the efficacy and safety of long-acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes. METHODS: We did this 52 week, randomised, open-label, phase 3, non-inferiority trial at 105 study sites in 15 countries. Patients (aged ≥18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1:1:1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1·5 mg, dulaglutide 0·75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A1c (HbA1c) from baseline to week 26, with a 0·4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01191268. FINDINGS: Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1·5 mg (n=295), dulaglutide 0·75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1·5 mg (-1·64% [95% CI -1·78 to -1·50], -17·93 mmol/mol [-19·44 to -16·42]) and dulaglutide 0·75 mg (-1·59% [-1·73 to -1·45], -17·38 mmol/mol [-18·89 to -15·87]) than in those receiving glargine (-1·41% [-1·55 to -1·27], -15·41 mmol/mol [-16·92 to -13·90]). The adjusted mean difference versus glargine was -0·22% (95% CI -0·38 to -0·07, -2·40 mmol/mol [-4·15 to -0·77]; p=0·005) for dulaglutide 1·5 mg and -0·17% (-0·33 to -0·02, -1·86 mmol/mol [-3·61 to -0·22]; p=0·015) for dulaglutide 0·75 mg. Five (<1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1·5 mg group); pneumonia (n=1 in the dulaglutide 0·75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1·5 mg group, 44 (15%) patients in the dulaglutide 0·75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting. INTERPRETATION: Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment. FUNDING: Eli Lilly and Company.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina Lispro/administração & dosagem , Insulina de Ação Prolongada/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Adolescente , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Esquema de Medicação , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Insulina Glargina , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Resultado do Tratamento , Adulto Jovem
7.
Diabetes Obes Metab ; 18(10): 999-1005, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27279266

RESUMO

AIM: To conduct a substudy, using 24-hour continuous glucose monitoring (CGM), of the AWARD-4 trial, which was designed to compare insulin + glucagon-like peptide-1 receptor agonist treatment with an insulin-only regimen. METHODS: The AWARD-4 trial randomized 884 conventional insulin regimen-treated patients to dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, all in combination with prandial insulin lispro. The CGM substudy included 144 patients inserted with a Medtronic CGMS iPro CGM device to enable 3-day glucose monitoring. CGM sessions were completed at weeks 0, 13, 26 and 52. CGM measures included mean 24-hour glucose, percentage time in target glucose ranges, hyper- and hypoglycaemia and glucose variability. The primary objective was treatment comparison for percentage time spent with CGM glucose values in the 3.9-7.8 mmol/L range after 26 weeks. RESULTS: At week 26, mean CGM values decreased in all treatment groups (change from baseline -2.8 ± 0.3, -2.4 ± 0.3 and -2.5 ± 0.3 mmol/L for dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, respectively); between-group differences were not statistically significant. Treatment groups were similar for percentage time in the 3.9-7.8 mmol/L range. Percentage time in the 3.9-10.0 mmol/L range was greater for dulaglutide 1.5 mg than for glargine (p < 0.05). Dulaglutide and glargine were associated with decreased glucose variability for all CGM variability indices. The overall within-patient standard deviation (s.d.) was significantly reduced with dulaglutide 1.5 mg versus glargine (p < 0.05). At week 52, there were no significant differences among the groups with regard to measures of normoglycaemia or near-normoglycaemia and for the overall within-patient s.d. Treatment with glargine was associated with greater increases in percentage time spent with glucose values ≤3.9 mmol/L, with statistically significant differences between the groups at 52 weeks (p < 0.05). CONCLUSIONS: In combination with prandial lispro, treatment with dulaglutide and glargine resulted in similar proportions of glucose values in the normoglycaemic range, but dulaglutide provided an improved balance between the proportion of values within the near-normoglycaemia range and values within the hypoglycaemic range.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Insulina Lispro/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Automonitorização da Glicemia/métodos , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Insulina Glargina/administração & dosagem , Insulina Glargina/efeitos adversos , Insulina Lispro/efeitos adversos , Masculino , Refeições , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos
8.
Pharm Stat ; 15(1): 46-53, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26610282

RESUMO

In randomized clinical trials with time-to-event outcomes, the hazard ratio is commonly used to quantify the treatment effect relative to a control. The Cox regression model is commonly used to adjust for relevant covariates to obtain more accurate estimates of the hazard ratio between treatment groups. However, it is well known that the treatment hazard ratio based on a covariate-adjusted Cox regression model is conditional on the specific covariates and differs from the unconditional hazard ratio that is an average across the population. Therefore, covariate-adjusted Cox models cannot be used when the unconditional inference is desired. In addition, the covariate-adjusted Cox model requires the relatively strong assumption of proportional hazards for each covariate. To overcome these challenges, a nonparametric randomization-based analysis of covariance method was proposed to estimate the covariate-adjusted hazard ratios for multivariate time-to-event outcomes. However, empirical evaluations of the performance (power and type I error rate) of the method have not been studied. Although the method is derived for multivariate situations, for most registration trials, the primary endpoint is a univariate outcome. Therefore, this approach is applied to univariate outcomes, and performance is evaluated through a simulation study in this paper. Stratified analysis is also investigated. As an illustration of the method, we also apply the covariate-adjusted and unadjusted analyses to an oncology trial.


Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Simulação por Computador/estatística & dados numéricos , Estatísticas não Paramétricas , Humanos
9.
J Biopharm Stat ; 25(1): 54-65, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24905704

RESUMO

Hypoglycemia has long been recognized as a major barrier to achieving normoglycemia with intensive diabetic therapies. It is a common safety concern for the diabetes patients. Therefore, it is important to apply appropriate statistical methods when analyzing hypoglycemia data. Here, we carried out bootstrap simulations to investigate the performance of the four commonly used statistical models (Poisson, negative binomial, analysis of covariance [ANCOVA], and rank ANCOVA) based on the data from a diabetes clinical trial. Zero-inflated Poisson (ZIP) model and zero-inflated negative binomial (ZINB) model were also evaluated. Simulation results showed that Poisson model inflated type I error, while negative binomial model was overly conservative. However, after adjusting for dispersion, both Poisson and negative binomial models yielded slightly inflated type I errors, which were close to the nominal level and reasonable power. Reasonable control of type I error was associated with ANCOVA model. Rank ANCOVA model was associated with the greatest power and with reasonable control of type I error. Inflated type I error was observed with ZIP and ZINB models.


Assuntos
Glicemia/efeitos dos fármacos , Simulação por Computador , Diabetes Mellitus/tratamento farmacológico , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Análise de Variância , Distribuição Binomial , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Humanos , Hipoglicemia/sangue , Hipoglicemia/diagnóstico , Insulina Glargina , Insulina Lispro/efeitos adversos , Insulina de Ação Prolongada/efeitos adversos , Distribuição de Poisson , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Tempo , Resultado do Tratamento
10.
Pharm Stat ; 14(3): 262-71, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25866149

RESUMO

The benefits of adjusting for baseline covariates are not as straightforward with repeated binary responses as with continuous response variables. Therefore, in this study, we compared different methods for analyzing repeated binary data through simulations when the outcome at the study endpoint is of interest. Methods compared included chi-square, Fisher's exact test, covariate adjusted/unadjusted logistic regression (Adj.logit/Unadj.logit), covariate adjusted/unadjusted generalized estimating equations (Adj.GEE/Unadj.GEE), covariate adjusted/unadjusted generalized linear mixed model (Adj.GLMM/Unadj.GLMM). All these methods preserved the type I error close to the nominal level. Covariate adjusted methods improved power compared with the unadjusted methods because of the increased treatment effect estimates, especially when the correlation between the baseline and outcome was strong, even though there was an apparent increase in standard errors. Results of the Chi-squared test were identical to those for the unadjusted logistic regression. Fisher's exact test was the most conservative test regarding the type I error rate and also with the lowest power. Without missing data, there was no gain in using a repeated measures approach over a simple logistic regression at the final time point. Analysis of results from five phase III diabetes trials of the same compound was consistent with the simulation findings. Therefore, covariate adjusted analysis is recommended for repeated binary data when the study endpoint is of interest.


Assuntos
Interpretação Estatística de Dados , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do Tratamento , Viés , Distribuição de Qui-Quadrado , Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/normas , Diabetes Mellitus/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Modelos Lineares , Modelos Logísticos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas
11.
Endocr Pract ; 20(5): 389-98, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24325997

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of insulin lispro in the treatment of patients with type 2 diabetes (T2DM) who had a body mass index (BMI) ≥30 kg/m2 (obese) compared with patients with BMIs <30 kg/m2 (nonobese). METHODS: A retrospective analysis of predefined end-points from 7 randomized clinical trials of T2DM patients treated with insulin lispro was performed. The primary efficacy measure was to assess the noninferiority of insulin lispro in obese patients versus nonobese patients as measured by the change in hemoglobin A1C (HbA1c) from baseline to Month 3 (n = 1,518), using a noninferiority margin of 0.4%. The secondary measures included overall hypoglycemia incidence and event rates and relative change in body weight. RESULTS: Mean changes in HbA1c from baseline (9.06% for obese and 8.92% for nonobese) to Month 3 were similar for obese patients (-1.03%) and nonobese (-1.02%), with a least squares (LS) mean difference (95% confidence interval [CI]) of -0.05% (-0.17%, 0.07%; P = .384). The overall incidence of hypoglycemia (53% vs. 63%; P<.001) and rate of hypoglycemia (0.93 vs. 1.76 events per 30 days; P<.001) was significantly lower in obese patients compared with nonobese patients. The 2 BMI cohorts did not demonstrate a significant difference in mean percent changes in body weights (LS mean difference = 0.4% [-0.2%, 0.9%]; P = .202). CONCLUSION: Obese patients with T2DM treated with insulin lispro were able to achieve the same level of glycemic control as their nonobese counterparts, with some evidence supporting a reduced risk of hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Lispro/uso terapêutico , Idoso , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/análise , Humanos , Insulina Lispro/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos
12.
Aging Clin Exp Res ; 26(2): 115-21, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24092662

RESUMO

BACKGROUND AND AIMS: Few studies have evaluated long-term durability of glycemic control in older patients. The aim of this study was to compare durability of glycemic control of twice-daily insulin lispro mix 75/25 (LM75/25; 75 % insulin lispro protamine suspension, 25 % insulin lispro) and once-daily insulin glargine (GL) added to oral antihyperglycemic medications in older patients (≥65 years of age). METHODS: Patients were participants in the maintenance phase of the DURABLE trial. During the initiation phase, patients with type 2 diabetes were randomized to LM75/25 or GL. After 6 months, patients with hemoglobin A1c (HbA1c) ≤7.0 % advanced to the 24-month maintenance phase. The primary objective was between-group comparison of duration of maintaining the HbA1c goal in older patients (≥65 years of age). A similar analysis was conducted for older patients achieving HbA1c ≤6.5 % in the initiation phase. RESULTS: Median time of maintaining HbA1c goal was longer in LM75/25 versus GL (19.6 versus 15.4 months, p = 0.007) and more LM75/25 patients maintained goal versus GL (49.2 versus 30.4 %; p = 0.003). HbA1c reduction from baseline was greater in LM75/25 versus GL (-1.56 ± 0.10 versus -1.24 ± 0.11 %; p = 0.003). Post-meal glucose was significantly lower in LM75/25 versus GL (158.86 ± 3.42 versus 171.67 ± 4.51 mg/dL; p = 0.017). No differences were observed in overall and severe hypoglycemia. LM75/25 patients had higher daily insulin doses (0.41 ± 0.02 versus 0.32 ± 0.02 units/kg/day; p < 0.001) and more weight gain (5.47 ± 0.49 versus 3.10 ± 0.53 kg; p = 0.001). Similar results were generally obtained in older patients with HbA1c ≤6.5 %. CONCLUSIONS: In our evaluation of older patients from a larger trial, LM75/25 appeared to provide longer durability of glycemic control, as well as a greater number of patients maintaining HbA1c goal versus GL.


Assuntos
Insulinas Bifásicas/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina Lispro/uso terapêutico , Insulina Isófana/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico , Idoso , Envelhecimento/sangue , Insulinas Bifásicas/administração & dosagem , Insulinas Bifásicas/efeitos adversos , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/etiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina Glargina , Insulina Lispro/administração & dosagem , Insulina Lispro/efeitos adversos , Insulina Isófana/administração & dosagem , Insulina Isófana/efeitos adversos , Insulina de Ação Prolongada/administração & dosagem , Insulina de Ação Prolongada/efeitos adversos , Quimioterapia de Manutenção , Masculino
13.
Aging Clin Exp Res ; 26(1): 77-88, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23959960

RESUMO

BACKGROUND AND AIMS: Glycemic control in geriatric patients with type 2 diabetes (T2DM) remains clinically challenging. The objective of this study was to compare the safety and efficacy of insulin lispro in patients C65 years (geriatric) to those\65 years (non-geriatric), using a metaanalysis of randomized controlled clinical trials (RCT). METHODS: This is a retrospective analysis of predefined endpoints from an integrated database of seven RCTs of T2DM patients treated with insulin lispro. The primary efficacy measure tested the non-inferiority of insulin lispro (geriatric vs. non-geriatric; non-inferiority margin 0.4 %) in terms of hemoglobin A1c (HbA1c) change from baseline to Month 3 (N = 1,525), with change from baseline to Month 6 as a supportive analysis (N = 885). Changes in HbA1c from baseline were evaluated with an analysis of covariance model. Secondary measures included incidence and rate of hypoglycemia, and incidence of cardiovascular events. RESULTS: Mean change in HbA1c from baseline to Month 3 was similar for geriatric (-0.97 %) and non-geriatric patients (-1.05 %); least-square (LS) mean difference (95 % CI) was 0.02 % (-0.11, 0.15 %; p = 0.756). Similar results were observed in patients treated up to Month 6; LS mean difference (95 % CI) was 0.07 % (-0.12, 0.26 %; p = 0.490). Decrease in HbA1c from baseline to Months 3 and 6 was non-inferior in geriatric compared with non-geriatric patients. There were no significant differences in the incidence and the rate of hypoglycemia, incidence of cardiovascular events, or other serious adverse events including malignancy, post-baseline between the two cohorts. CONCLUSION: Key measures of efficacy and safety in geriatric patients with T2DM were not significantly different from non-geriatric patients when utilizing insulin lispro. Insulin lispro may be considered a safe and efficacious therapeutic option for the management of T2DM in geriatric patients.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina Lispro/efeitos adversos , Insulina Lispro/uso terapêutico , Fatores Etários , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do Tratamento
14.
Cureus ; 16(3): e55620, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38586639

RESUMO

Hepatoid adenocarcinoma (HAC) of the colon is a rare type of tumor with hepatocellular differentiation. HAC often produces alpha-fetoprotein (AFP) and metastasizes to lymph nodes and the liver. HAC is usually aggressive with a poor prognosis and has a propensity for intravascular growth and frequent distant metastasis. Because the biology of HAC is not fully understood, there are very limited therapeutic options known to reduce recurrence and improve survival. In addition, because HAC is so rare, it is difficult to acquire data from large randomized clinical trials to guide practice; therefore, case reports can provide valuable information for the treatment of HAC. In this report, we present a case of a 30-year-old male patient with HAC with high AFP levels and liver metastases. The patient underwent hepatic arterial infusion chemotherapy (HAIC) with doxorubicin/oxaliplatin to treat the liver metastasis, and three weeks later, he received radical sigmoid and rectal resection, left liver resection, and ileostomy. Then, the patient received eight cycles of chemotherapy with epirubicin plus folinic acid, fluorouracil, and oxaliplatin (FOLFOX) every three weeks, followed by maintained therapy with capecitabine for 2.5 years without relapse. This case report indicates that, although HAC is usually an aggressive disease with frequent distant metastasis, patients with HAC may still have a good prognosis if treated with appropriate strategy.

15.
Oncoimmunology ; 13(1): 2290790, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38169917

RESUMO

Background: Immunotherapy has shown intracranial efficacy in non-small cell lung cancer (NSCLC) patients with brain metastases. However, predictive biomarkers for intracranial response to immunotherapy are lacking. This post-hoc analysis aimed to explore the potential of immunological cytokines in cerebrospinal fluid (CSF) to predict intracranial tumor response to immunotherapy in patients with brain metastases. Methods: Treatment-naive NSCLC patients with brain metastases who received camrelizumab plus chemotherapy were enrolled. Paired plasma and CSF samples were prospectively collected at baseline and the first treatment assessment. All samples were analyzed for 92 immuno-oncology cytokines using Olink's panels. Results: A total of 28 patients were included in this analysis. At baseline, most immunological cytokines were significantly lower in CSF than in plasma, whereas a subset comprising CD83, PTN, TNFRSF21, TWEAK, ICOSLG, DCN, IL-8, and MCP-1, was increased in CSF. Baseline CSF levels of LAMP3 were significantly higher in patients with intracranial tumor response, while the levels of CXCL10, IL-12, CXCL11, IL-18, TIE2, HGF, and PDCD1 were significantly lower. Furthermore, the CXCL10, CXCL11, TIE2, PDCD1, IL-18, HGF, and LAMP3 in CSF were also significantly associated with intracranial progression-free survival for immunotherapy. The identified cytokines in CSF were decreased at the first treatment evaluation in patients with intracranial tumor response. The logistic CSF immuno-cytokine model yielded an AUC of 0.91, as compared to PD-L1 expression (AUC of 0.72). Conclusions: Immunological cytokines in CSF could predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases, and the findings warrant validation in a larger prospective cohort study. Trial registration: ClinicalTrials.gov identifier: NCT04211090.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Interleucina-18/uso terapêutico , Citocinas , Estudos Prospectivos , Imunoterapia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/secundário
16.
Ethn Dis ; 23(4): 393-400, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24392599

RESUMO

OBJECTIVE: To explore the impact of race/ethnicity on efficacy and safety of twice-daily insulin lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% insulin lispro) and once daily insulin glargine (GL). DESIGN, SETTING, PATIENTS: More than 2,000 Patients with type 2 diabetes enrolled in the 24-week initiation phase of the DURABLE Trial. MAIN OUTCOME MEASURES: Efficacy and safety variables at endpoint, including hemoglobin A1c (HbA1c), self-monitored plasma glucose (SMPG), and hypoglycemia, in each racial/ethnic group were compared to Caucasians within treatment groups. RESULTS: Asian patients had less (LM75/25: -1.46%, P < .01; GL: -1.25%, P < .01) and Hispanic patients had greater (LM75/25: -2.17%) HbA1c reduction from baseline vs Caucasian patients (LM75/25: -1.84%; GL: -1.78%). Fewer Asian (LM75/25: 20%, P < .001; GL: 22%, P < .001) and Hispanic patients (LM75/25: 40%, P < .01) reached HbA1c target (< 7%) vs Caucasian patients (LM75/25: 53%; GL: 44%). Fasting plasma glucose was similar among groups, postprandial glucose (PPG) with GL was lower for African patients post-breakfast and post-dinner and higher for Asian patients post-lunch. Only PPG with LM75/25 was lower for Hispanic patients post-breakfast. Weight gain was lower in Asian patients (LM75/ 25). Insulin dose was higher for Asian (LM75/25 and GL) and lower for African patients (GL). Hypoglycemia rate was lower for Asian (LM75/25 and GL) and Hispanic patients (LM75/25). CONCLUSIONS: There were significant efficacy and safety differences among racial/ethnic groups in the DURABLE trial. These differences may be important in designing insulin based treatment plans.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etnologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Automonitorização da Glicemia , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Animals (Basel) ; 13(15)2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37570282

RESUMO

This paper proposes a method for automatic pig detection and segmentation using RGB-D data for precision livestock farming. The proposed method combines the enhanced YOLOv5s model with the Res2Net bottleneck structure, resulting in improved fine-grained feature extraction and ultimately enhancing the precision of pig detection and segmentation in 2D images. Additionally, the method facilitates the acquisition of 3D point cloud data of pigs in a simpler and more efficient way by using the pig mask obtained in 2D detection and segmentation and combining it with depth information. To evaluate the effectiveness of the proposed method, two datasets were constructed. The first dataset consists of 5400 images captured in various pig pens under diverse lighting conditions, while the second dataset was obtained from the UK. The experimental results demonstrated that the improved YOLOv5s_Res2Net achieved a mAP@0.5:0.95 of 89.6% and 84.8% for both pig detection and segmentation tasks on our dataset, while achieving a mAP@0.5:0.95 of 93.4% and 89.4% on the Edinburgh pig behaviour dataset. This approach provides valuable insights for improving pig management, conducting welfare assessments, and estimating weight accurately.

18.
Turk J Pediatr ; 65(6): 919-930, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38204306

RESUMO

BACKGROUND: An assessment of functional gastrointestinal disorders (FGIDs) in premature infants in their first year of life and neonatal factors influencing the progression of FGIDs was conducted in this research. METHODS: Subjects selected for the retrospective study involved preterm infants being hospitalized in the neonatal department of Northern Jiangsu People`s Hospital from September 2018 to September 2021. Data on neonatal risk factors such as gestational age, gender, birth weight, mode of delivery, feeding pattern, antibiotic administration and addition of probiotics, duration of hospitalization, maternal history of smoking, and mental health status, were all collected and analyzed. FGIDs were diagnosed according to Rome IV criteria. RESULTS: This study included 988 preterm infants, with 725 (73.4%) having at least one FGID, 449 (45.4%) with infant colic, 411 (41.6%) with infant regurgitation, 237 (24.0%) with infant dyschezia, 190 (19.2%) with functional constipation, and 34 (3.4%) with functional diarrhea throughout the first year of life. In total, 263 infants (26.6%) without FGID symptoms were included in the control group. Further, a higher prevalence of FGIDs was observed in preterm infants with infant colic as well as infant regurgitation in particular as being characterized by a low gestational age ( < 32 w), low birth weight ( < 1.5 kg), Cesarean section, formula feeding, neonatal antibiotics use, hospitalization longer than 7 days, and maternal history of smoking. It was found from association analyses that infants exclusively breastfed in their first month of life were at lower risk for regurgitation than those in the control group. CONCLUSIONS: Unnecessary antibiotic use in the neonatal period, Cesarean delivery, passive smoking, lack of breastfeeding along with inappropriate probiotics usage are major risk factors for FGIDs, and their systematic control may be effective in reducing the susceptibility to and prevalence of FGIDs in preterm infants in the first year of life.


Assuntos
Cólica , Gastroenteropatias , Gravidez , Lactente , Recém-Nascido , Humanos , Feminino , Recém-Nascido Prematuro , Cesárea , Estudos Retrospectivos , Gastroenteropatias/epidemiologia , Fatores de Risco , Antibacterianos/uso terapêutico
19.
J Anim Sci Biotechnol ; 14(1): 117, 2023 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-37691111

RESUMO

BACKGROUND: Exposure to bisphenol A (BPA), an environmental pollutant known for its endocrine-disrupting properties, during gestation has been reported to increase the risk of fetal growth restriction (FGR) in an ovine model of pregnancy. We hypothesized that the FGR results from the BPA-induced insufficiency and barrier dysfunction of the placenta, oxidative stress, inflammatory responses, autophagy and endoplasmic reticulum stress (ERS). However, precise mechanisms underlying the BPA-induced placental dysfunction, and subsequently, FGR, as well as the potential involvement of placental ERS in these complications, remain to be investigated. METHODS: In vivo experiment, 16 twin-pregnant (from d 40 to 130 of gestation) Hu ewes were randomly distributed into two groups (8 ewes each). One group served as a control and received corn oil once a day, whereas the other group received BPA (5 mg/kg/d as a subcutaneous injection). In vitro study, ovine trophoblast cells (OTCs) were exposed to 4 treatments, 6 replicates each. The OTCs were treated with 400 µmol/L BPA, 400 µmol/L BPA + 0.5 µg/mL tunicamycin (Tm; ERS activator), 400 µmol/L BPA + 1 µmol/L 4-phenyl butyric acid (4-PBA; ERS antagonist) and DMEM/F12 complete medium (control), for 24 h. RESULTS: In vivo experiments, pregnant Hu ewes receiving the BPA from 40 to 130 days of pregnancy experienced a decrease in placental efficiency, progesterone (P4) level and fetal weight, and an increase in placental estrogen (E2) level, together with barrier dysfunctions, OS, inflammatory responses, autophagy and ERS in type A cotyledons. In vitro experiment, the OTCs exposed to BPA for 24 h showed an increase in the E2 level and related protein and gene expressions of autophagy, ERS, pro-apoptosis and inflammatory response, and a decrease in the P4 level and the related protein and gene expressions of antioxidant, anti-apoptosis and barrier function. Moreover, treating the OTCs with Tm aggravated BPA-induced dysfunction of barrier and endocrine (the increased E2 level and decreased P4 level), OS, inflammatory responses, autophagy, and ERS. However, treating the OTCs with 4-PBA reversed the counteracted effects of Tm mentioned above. CONCLUSIONS: In general, the results reveal that BPA exposure can cause ERS in the ovine placenta and OTCs, and ERS induction might aggravate BPA-induced dysfunction of the placental barrier and endocrine, OS, inflammatory responses, and autophagy. These data offer novel mechanistic insights into whether ERS is involved in BPA-mediated placental dysfunction and fetal development.

20.
JAMA Netw Open ; 6(2): e2255050, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36753281

RESUMO

Importance: Use of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear. Objective: To investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases. Design, Setting, and Participants: This open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled. Interventions: The eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone. Main Outcomes and Measures: The primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed. Results: A total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P < .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3; 95% CI, 14.4-18.2 months vs 9.5; 95% CI, 8.3-10.8 months; P < .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0%; 95% CI, 77.0%-93.0% vs 63.0%; 95% CI, 52.2%-73.7%; P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable. Conclusions and Relevance: In this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT01951469.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Gefitinibe , Neoplasias Pulmonares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Gefitinibe/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Prospectivos , Inibidores de Proteínas Quinases , Adulto , Idoso , Idoso de 80 Anos ou mais
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