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Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (pwCF) aged 2 years and older with at least one F508del-CFTR allele or more. After U.S. approval in 2019, reports emerged of depression-related adverse events in pwCF treated with ELX/TEZ/IVA. Objectives: To review available evidence on depression-related events in pwCF treated with ELX/TEZ/IVA in the context of background epidemiology in pwCF. Methods: Safety data from 14 ELX/TEZ/IVA clinical trials and 10 trials of CF transmembrane conductance regulator (CFTR) modulators in which placebo was administered, along with data from CF registries in the United States and Germany and cumulative postmarketing adverse event data from 61,499 pwCF who initiated ELX/TEZ/IVA after initial approval in the United States (October 2019) through October 2022, were reviewed and used to calculate exposure-adjusted rates of depression-related adverse events and prevalence of depression. In addition, a scientific literature review was conducted to identify ELX/TEZ/IVA publications reporting depression-related events or changes in depressive symptoms after treatment initiation. Measurements and Main Results: In clinical trials, the exposure-adjusted rate of any depression-related adverse event was 3.32/100 person years (PY) in the pooled ELX/TEZ/IVA group (n = 1,711) and 3.24/100 PY in the pooled placebo group (n = 1,369). The exposure-adjusted rates of suicidal ideation and suicide attempt were also similar between the pooled ELX/TEZ/IVA group and pooled placebo group (ideation: 0.23/100 PY vs. 0.28/100 PY; attempt: 0.08/100 PY vs. 0.14/100 PY). In the postmarketing setting, the exposure-adjusted reporting rates of depression-related events were low in context of the background prevalence in pwCF (all depression-related events: 1.29/PY; suicidal ideation: 0.12/100 PY; and suicide attempt: 0.05/100 PY). Assessments of individual case reports were confounded by preexisting mental health conditions, intercurrent psychosocial stressors (including coronavirus disease [COVID-19] lockdowns), and the heterogeneous and fluctuating nature of depression. Data from CF registries in the United States and Germany showed that patterns of depression prevalence in pwCF exposed to ELX/TEZ/IVA did not change after treatment initiation. Published studies utilizing the nine-item Patient Health Questionnaire did not show evidence of worsening depression symptoms in pwCF treated with ELX/TEZ/IVA. Conclusions: Our review of data from clinical trials, postmarketing reports, an ongoing registry-based ELX/TEZ/IVA postauthorization safety study, and peer-reviewed literature suggests that depression symptoms and depression-related events reported in pwCF treated with ELX/TEZ/IVA are generally consistent with background epidemiology of these events in the CF population and do not suggest a causal relationship with ELX/TEZ/IVA treatment.
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Aminofenoles , Benzodioxoles , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Indoles , Pirazoles , Piridinas , Pirrolidinas , Quinolonas , Humanos , Depresión/tratamiento farmacológico , Fibrosis Quística/tratamiento farmacológicoRESUMEN
For multiple rare diseases as defined by a common biomarker signature, or a disease with multiple disease subtypes of low frequency, it is often possible to provide confirmatory evidence for these disease or subtypes (baskets) as a combined group. A novel drug, as a second generation, may have marginal improvement in efficacy overall but superior efficacy in some baskets. In this situation, it is appealing to test hypotheses of both non-inferiority overall and superiority on certain baskets. The challenge is designing a confirmatory study efficient to address multiple questions in one trial. A two-stage adaptive design is proposed to test the non-inferiority hypothesis at the interim stage, followed by pruning and pooling before testing a superiority hypothesis at the final stage. Such a design enables an efficient and novel registration pathway, including an early claim of non-inferiority followed by a potential label extension with superiority on certain baskets and an improved benefit-risk profile demonstrated by longer term efficacy and safety data. Operating characteristics of this design are examined by simulation studies, and its appealing features make it ready for use in a confirmatory setting, especially in emerging markets, where both the need and the possibility for efficient use of resources may be the greatest.
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Proyectos de Investigación , Humanos , Simulación por ComputadorRESUMEN
BACKGROUND: The TP53 gene is estimated to be mutated in over 50% of tumors, with the majority of tumors exhibiting abnormal TP53 signaling pathways. However, the exploration of TP53 mutation-related LncRNAs in Hepatocellular carcinoma (HCC) remains incomplete. This study aims to identify such LncRNAs and enhance the prognostic accuracy for Hepatoma patients. MATERIAL AND METHODS: Differential gene expression was identified using the "limma" package in R. Prognosis-related LncRNAs were identified via univariate Cox regression analysis, while a prognostic model was crafted using multivariate Cox regression analysis. Survival analysis was conducted using Kaplan-Meier curves. The precision of the prognostic model was assessed through ROC analysis. Subsequently, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm were executed on the TCGA dataset via the TIDE database. Fractions of 24 types of immune cell infiltration were obtained from NCI Cancer Research Data Commons using deconvolution techniques. The protein expression levels encoded by specific genes were obtained through the TPCA database. RESULTS: In this research, we have identified 85 LncRNAs associated with TP53 mutations and developed a corresponding signature referred to as TP53MLncSig. Kaplan-Meier analysis revealed a lower 3-year survival rate in high-risk patients (46.9%) compared to low-risk patients (74.2%). The accuracy of the prognostic TP53MLncSig was further evaluated by calculating the area under the ROC curve. The analysis yielded a 5-year ROC score of 0.793, confirming its effectiveness. Furthermore, a higher score for TP53MLncSig was found to be associated with an increased response rate to immune checkpoint blocker (ICB) therapy (p = .005). Patients possessing high-risk classification exhibited lower levels of P53 protein expression and higher levels of genomic instability. CONCLUSION: The present study aimed to identify and validate LncRNAs associated with TP53 mutations. We constructed a prognostic model that can predict chemosensitivity and response to ICB therapy in HCC patients. This novel approach sheds light on the role of LncRNAs in TP53 mutation and provides valuable resources for analyzing patient prognosis and treatment selection.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Proteína p53 Supresora de Tumor/genética , ARN Largo no Codificante/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Pronóstico , Mutación/genéticaRESUMEN
Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here. Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, the mean percent predicted FEV1 increased (11.2 [95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI, -65.9 to -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (-2.00 [95% CI, -2.45 to -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, -0.73 to 1.75) percentage points per year. Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ⩾6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registered with www.clinicaltrials.gov (NCT04183790).
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Fibrosis Quística , Adulto , Niño , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Fibrosis Quística/diagnóstico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/uso terapéutico , Alelos , Agonistas de los Canales de Cloruro/uso terapéutico , Aminofenoles/efectos adversos , Benzodioxoles/efectos adversos , MutaciónRESUMEN
Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and effective in people with cystic fibrosis (CF) aged ⩾6 years with at least one F508del-CFTR allele but has not been studied in younger children. Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2-5 years. Methods: In this phase 3, open-label, two-part study (parts A and B), children weighing <14 kg (on Day 1) received ELX 80 mg once daily (qd), TEZ 40 mg qd, and IVA 60 mg each morning and 59.5 mg each evening; children weighing ⩾14 kg received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours. Measurements and Main Results: The primary endpoints for part A (15-d treatment period) were pharmacokinetics and safety and tolerability. For part B (24-wk treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5, defined as the number of lung turnovers required to reduce the end tidal N2 concentration to 2.5% of its starting value) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in part A confirmed the appropriateness of the part B dosing regimen. In part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events, which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L; 95% confidence interval [CI], -61.3 to -54.6; n = 69) and LCI2.5 (-0.83 U; 95% CI, -1.01 to -0.66; n = 50) were observed from baseline through Week 24. Mean body mass index was within the normal range at baseline and remained stable at Week 24. Conclusions: In this open-label study in children 2-5 years of age, ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and LCI2.5. Clinical trial registered with www.clinicaltrials.gov (NCT04537793).
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Fibrosis Quística , Humanos , Niño , Anciano , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/uso terapéutico , Cloruros , Alelos , Agonistas de los Canales de Cloruro/uso terapéutico , Aminofenoles , Benzodioxoles , MutaciónRESUMEN
BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. METHODS: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor-tezacaftor-deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor-tezacaftor-deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor-deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)-tezacaftor-deutivacaftor or tezacaftor-ivacaftor active control for 4 weeks, following a 4-week tezacaftor-ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. FINDINGS: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI -0·8 to 7·0) and 2·7 percentage points (-1·0 to 6·5) from baseline at week 12, respectively, versus -0·8 percentage points (-6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)-tezacaftor-deutivacaftor (n=9), vanzacaftor (10 mg)-tezacaftor-deutivacaftor (n=19), vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (-1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (-4·1 to 8·0), respectively, in sweat chloride concentration of -42·8 mmol/L (-51·7 to -34·0), -45·8 mmol/L (95% CI -51·9 to -39·7), -49·5 mmol/L (-55·9 to -43·1), and 2·3 mmol/L (-7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (-10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=18) and tezacaftor-ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor-ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and -0·1 percentage points (-6·4 to 6·1), respectively, in sweat chloride concentration of -45·5 mmol/L (-49·7 to -41·3) and -2·6 mmol/L (-8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and -5·0 points (-16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor-tezacaftor-deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. INTERPRETATION: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor-tezacaftor-deutivacaftor in phase 3 clinical trials compared with elexacaftor-tezacaftor-ivacaftor. FUNDING: Vertex Pharmaceuticals.
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Fibrosis Quística , Humanos , Adulto , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Cloruros , Volumen Espiratorio Forzado , Aminofenoles/efectos adversos , Benzodioxoles/uso terapéutico , Mutación , Método Doble Ciego , Agonistas de los Canales de Cloruro/uso terapéuticoRESUMEN
Carrier transport was studied both numerically and experimentally using scanning photocurrent microscopy (SPCM) in two-dimensional (2D) transport structures, where the structure size in the third dimension is much smaller than the diffusion length and electrodes cover the whole terminal on both sides. Originally, one would expect that with increasing width in 2D transport structures, scanning photocurrent profiles will gradually deviate from those of the ideal one-dimensional (1D) transport structure. However, the scanning photocurrent simulation results surprisingly showed almost identical profiles from structures with different widths. In order to clarify this phenomenon, we observed the spatial distribution of carriers. The simulation results indicate that the integrated carrier distribution in the 2D transport structures with finite width can be well described by a simple-exponential-decay function with the carrier decay length as the fitting parameter, just like in the 1D transport structures. For ohmic-contact 2D transport structures, the feasibility of the fitting formula from our previous 1D analytical model was confirmed. On the other hand, the application of a simple-exponential-decay function in scanning photocurrent profiles for the diffusion length extraction in Schottky-contact 2D transport structures was also justified. Furthermore, our simulation results demonstrate that the scanning photocurrent profiles in the ohmic- or Schottky-contact three-dimensional (3D) transport structures with electrodes covering the whole terminal on both sides will reduce to those described by the corresponding 1D fitting formulae. Finally, experimental SPCM on a p-type InGaAs air-bridge two-terminal thin-film device was carried out. The measured photocurrent profiles can be well fitted by the specific fitting formula derived from our previous 1D analytical model and the extracted electron mobility-lifetime product of this thin-film device is 6.6 × 10-7 cm2·V-1. This study allows us to extract the minority carrier decay length and to obtain the mobility-lifetime product which can be used to evaluate the performance of 2D carrier transport devices.
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Two-dimensional metal-organic frameworks (2D-MOFs) and their derivatives are promising for catalysis, energy storage, gas separation, etc. due to their unique microstructure and physicochemical properties. Many efforts have been devoted to fabricating 2D-MOFs with challenges remaining in yield and fine control of their thickness and lateral size. Here a versatile strategy has been used involving epitaxial, anisotropic, and confined growth of CoNi-MOF-71 nanosheet arrays, giving rise to excellent quantity and controllability of the 2D-MOFs. Electromagnetic (EM) wave absorption performance has been investigated for the resultant 2D Co/Ni/C derivatives. Compared with the bulk counterpart, significantly increased surface area, conductivity, and shape anisotropy for the 2D derivatives result in enhanced interfacial polarization, conductive loss, and magnetic resonance. As such, optimum EM wave absorption of minimum reflection loss RLmin = -49.8 dB and an ultrawide effective adsorption bandwidth EAB = 7.6 GHz can be achieved at a thickness of 2.6 mm. This work not only sheds light on the performance enhancement for 2D absorbers via synergistic effects of multiple attenuation mechanisms but also provides an effective fabrication route of ultrathin MOFs with high yield and uniform size for extended applications in catalysis, electrochemistry, and optoelectronics fields.
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Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes. Methods: In this 24-week open-label phase 3 study, children (N = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h). Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period when compared with the pretreatment baseline. Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).
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Agonistas de los Canales de Cloruro/uso terapéutico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/efectos de los fármacos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Indoles/uso terapéutico , Pirazoles/uso terapéutico , Quinolonas/uso terapéutico , Alelos , Niño , Agonistas de los Canales de Cloruro/farmacocinética , Combinación de Medicamentos , Femenino , Variación Genética , Genotipo , Humanos , Indoles/farmacocinética , Masculino , Pirazoles/farmacocinética , Quinolonas/farmacocinéticaRESUMEN
A new simple method is proposed to extract the ambipolar diffusion length for two-dimensional (2D) electronic transport in thin film structures using a scanning photoluminescence microscopy (SPLM) setup. No spatially-resolved photoluminescence detection methods are required. By measuring the excitation-position-dependent PL intensity across the edge of a semiconductor, ambipolar diffusion length can be extracted from the SPLM profile through a simple analytic fitting function. Numerical simulation was first used to verify the fitting method. Then the fitting method was applied to extract the ambipolar diffusion length from the measured SPLM profile of a GaAs thin film structure. Carrier lifetime was obtained in an accompanying time-resolved photoluminescence measurement under the same excitation condition, and thus the ambipolar diffusion coefficient can be determined simultaneously. The new fitting method provides a simple way to evaluate carrier transport properties in 2D electronic transport structures such as thin films or quantum wells.
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In the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. Such a study design may not be suitable for immunotherapy cancer trials, when both long-term survivors (or even cured patients from the disease) and delayed treatment effect are present, because exponential distribution is not appropriate to describe such data and consequently could lead to severely underpowered trial. In this research, we proposed a piecewise proportional hazards cure rate model with random delayed treatment effect to design single-arm phase II immunotherapy cancer trials. To improve test power, we proposed a new weighted one-sample log-rank test and provided a sample size calculation formula for designing trials. Our simulation study showed that the proposed log-rank test performs well and is robust of misspecified weight and the sample size calculation formula also performs well.
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Ensayos Clínicos Fase II como Asunto/métodos , Neoplasias/tratamiento farmacológico , Proyectos de Investigación , Tiempo de Tratamiento , Supervivientes de Cáncer , Simulación por Computador , Humanos , Inmunoterapia , Modelos de Riesgos Proporcionales , Tamaño de la MuestraRESUMEN
Timelines of longitudinal studies are often anchored by specific events. In the absence of fully observed the anchoring event times, the study timeline becomes undefined, and the traditional longitudinal analysis loses its temporal reference. In this paper, we considered an analytical situation where the anchoring events are interval-censored. We demonstrated that by expressing the regression parameter estimators as stochastic functionals of a plug-in estimate of the unknown anchoring event time distribution, the standard longitudinal models could be extended to accommodate the situation of less well-defined timelines. We showed that for a broad class of longitudinal models, the functional parameter estimates are consistent and asymptotically normally distributed with a n convergence rate under mild regularity conditions. Applying the developed theory to linear mixed-effects models, we further proposed a hybrid computational procedure that combines the strengths of the Fisher's scoring method and the expectation-expectation (EM) algorithm, for model parameter estimation. We conducted a simulation study to validate the asymptotic properties and to assess the finite sample performance of the proposed method. A real data analysis was used to illustrate the proposed method. The method fills in a gap in the existing longitudinal analysis methodology for data with less well defined timelines.
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@#Objective To investigate the role of preoperative peripheral blood CD4/CD8 ratio in predicting the prognosis of patients with coronary atherosclerotic heart disease (CAD) after off-pump coronary artery bypass grafting (OPCABG). Methods A total of 118 patients with CAD who underwent OPCABG in our hospital from September 2016 to April 2017 were included in the study, including 82 males and 36 females aged 62.74±4.50 years. The primary end point was the incidence of major adverse cardiovascular events (MACE). Patients were divided into a high CD4/CD8 group (≥1.40, 62 patients) and a low CD4/CD8 group (<1.40, 56 patients) according to the results of flow cytometry. The correlation between CD4/CD8 ratio and prognosis of patients after OPCABG and the value of CD4/CD8 ratio for predicting postoperative MACE were evaluated. Results Median duration of follow-up was 23.25 (20.91, 24.70) months, during which 21 patients (17.80%) experienced MACE and 4 patients (3.39%) were lost to follow-up. Kaplan-Meier analysis revealed that high CD4/CD8 group had a significantly higher MACE rate than the low CD4/CD8 group did (log-rank χ2=5.797, P=0.02). The results of adjusted Cox proportional hazards model showed that CD4/CD8 ratio (HR=3.103, 95%CI 1.557-6.187, P<0.01) was an independent risk factor of MACE in patients with CAD after OPCABG. The receiver operating characteristic curve showed that area under curve was 0.778 (95%CI 0.661-0.894, P<0.01), the optimal cut off value was 2.24, the sensitivity was 57.1%, and the specificity was 87.6%. Conclusion Preoperative peripheral blood CD4/CD8 ratio is an independent predictor of MACE after OPCABG in patients with CAD.
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We conducted a randomized controlled trial of an individually tailored, virtual perspective-taking intervention to reduce race and socioeconomic status (SES) disparities in providers' pain treatment decisions. Physician residents and fellows (n = 436) were recruited from across the United States for this two-part online study. Providers first completed a bias assessment task in which they made treatment decisions for virtual patients with chronic pain who varied by race (black/white) and SES (low/high). Providers who demonstrated a treatment bias were randomized to the intervention or control group. The intervention consisted of personalized feedback about their bias, real-time dynamic interactions with virtual patients, and videos depicting how pain impacts the patients' lives. Treatment bias was re-assessed 1 week later. Compared with the control group, providers who received the tailored intervention had 85% lower odds of demonstrating a treatment bias against black patients and 76% lower odds of demonstrating a treatment bias against low SES patients at follow-up. Providers who received the intervention for racial bias also showed increased compassion for patients compared with providers in the control condition. Group differences did not emerge for provider comfort in treating patients. Results suggest an online intervention that is tailored to providers according to their individual treatment biases, delivers feedback about these biases, and provides opportunities for increased contact with black and low SES patients, can produce substantial changes in providers' treatment decisions, resulting in more equitable pain care. Future studies should examine how these effects translate to real-world patient care and the optimal timing/dose of the intervention.
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Dolor Crónico/psicología , Disparidades en Atención de Salud , Manejo del Dolor/psicología , Médicos/psicología , Grupos Raciales/psicología , Clase Social , Adulto , Población Negra/psicología , Dolor Crónico/economía , Dolor Crónico/terapia , Toma de Decisiones Clínicas/métodos , Femenino , Disparidades en Atención de Salud/economía , Humanos , Masculino , Manejo del Dolor/economía , Médicos/economía , Médicos/normas , Interfaz Usuario-Computador , Población Blanca/psicologíaRESUMEN
Spatially resolved current measurements such as scanning photocurrent microscopy (SPCM) have been extensively applied to investigate carrier transport properties in semiconductor nanowires. A traditional simple-exponential-decay formula based on the assumption of carrier diffusion dominance in the scanning photocurrent profiles can be applied for carrier diffusion length extraction using SPCM in Schottky-contact-based or p-n junction-based devices where large built-in electric fields exist. However, it is also important to study the electric-field dependent transport properties in widely used ohmic-contact nanowire devices where the assumption of carrier diffusion dominance is invalid. Here we derive an analytic formula for scanning photocurrent profiles in such ohmic-contact nanowire devices under uniform applied electric fields and weak optical excitation. Under these operation conditions and the influence of photo-carrier-induced electric field, the scanning photocurrent profile and the carrier spatial distribution strikingly do not share the same functional form. Instead, a surprising new analytic relation between the scanning photocurrent profile and the minority carrier decay length was established. Then the derived analytic formula was validated numerically and experimentally. This analytic formula provides a new fitting method for SPCM profiles to correctly determine the minority carrier decay length, which allows us to quantitatively evaluate the performance of nanowire-based devices.
RESUMEN
Biological processes are usually defined on timelines that are anchored by specific events. For example, cancer growth is typically measured by the change in tumor size from the time of oncogenesis. In the absence of such anchoring events, longitudinal assessments of the outcome lose their temporal reference. In this paper, we considered the estimation of local change rates in the outcomes when the anchoring events are interval-censored. Viewing the subject-specific anchoring event times as random variables from an unspecified distribution, we proposed a distribution-free estimation method for the local growth rates around the unobserved anchoring events. We expressed the rate parameters as stochastic functionals of the anchoring time distribution and showed that under mild regularity conditions, consistent and asymptotically normal estimates of the rate parameters could be achieved, with a n convergence rate. We conducted a carefully designed simulation study to evaluate the finite sample performance of the method. To motivate and illustrate the use of the proposed method, we estimated the skeletal growth rates of male and female adolescents, before and after the unobserved pubertal growth spurt (PGS) times.
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Biometría/métodos , Modelos Estadísticos , Adolescente , Desarrollo Óseo/fisiología , Simulación por Computador , Femenino , Crecimiento/fisiología , Humanos , Cinética , Masculino , Pubertad/fisiología , Factores de TiempoRESUMEN
A cancer clinical trial with an immunotherapy often has 2 special features, which are patients being potentially cured from the cancer and the immunotherapy starting to take clinical effect after a certain delay time. Existing testing methods may be inadequate for immunotherapy clinical trials, because they do not appropriately take the 2 features into consideration at the same time, hence have low power to detect the true treatment effect. In this paper, we proposed a piece-wise proportional hazards cure rate model with a random delay time to fit data, and a new weighted log-rank test to detect the treatment effect of an immunotherapy over a chemotherapy control. We showed that the proposed weight was nearly optimal under mild conditions. Our simulation study showed a substantial gain of power in the proposed test over the existing tests and robustness of the test with misspecified weight. We also introduced a sample size calculation formula to design the immunotherapy clinical trials using the proposed weighted log-rank test.
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Ensayos Clínicos como Asunto/métodos , Inmunoterapia/métodos , Neoplasias/terapia , Simulación por Computador , Humanos , Modelos de Riesgos Proporcionales , Tamaño de la Muestra , Factores de Tiempo , Resultado del TratamientoRESUMEN
Fetal exposure to gestational diabetes mellitus (GDM) predisposes children to future health complications including hypertension and cardiovascular disease. A key mechanism by which these complications occur is through the functional impairment of vascular progenitor cells, including endothelial colony-forming cells (ECFCs). Previously, we showed that fetal ECFCs exposed to GDM have decreased vasculogenic potential and altered gene expression. In this study, we evaluate whether transgelin (TAGLN), which is increased in GDM-exposed ECFCs, contributes to vasculogenic dysfunction. TAGLN is an actin-binding protein involved in the regulation of cytoskeletal rearrangement. We hypothesized that increased TAGLN expression in GDM-exposed fetal ECFCs decreases network formation by impairing cytoskeletal rearrangement resulting in reduced cell migration. To determine if TAGLN is required and/or sufficient to impair ECFC network formation, TAGLN was reduced and overexpressed in ECFCs from GDM and uncomplicated pregnancies, respectively. Decreasing TAGLN expression in GDM-exposed ECFCs improved network formation and stability as well as increased migration. In contrast, overexpressing TAGLN in ECFCs from uncomplicated pregnancies decreased network formation, network stability, migration, and alignment to laminar flow. Overall, these data suggest that increased TAGLN likely contributes to the vasculogenic dysfunction observed in GDM-exposed ECFCs, as it impairs ECFC migration, cell alignment, and network formation. Identifying the molecular mechanisms underlying fetal ECFC dysfunction following GDM exposure is key to ascertain mechanistically the basis for cardiovascular disease predisposition later in life.
Asunto(s)
Diabetes Gestacional/metabolismo , Células Endoteliales/metabolismo , Feto/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Neovascularización Fisiológica/fisiología , Células Madre/metabolismo , Adulto , Movimiento Celular/fisiología , Células Cultivadas , Femenino , Humanos , Embarazo , Adulto JovenRESUMEN
Polymorphic variants of genes involved in folate metabolism are implicated in the susceptibility to meningioma and glioma, but the results from published articles are controversial and inconclusive. Therefore, we performed this meta-analysis including all studies available to evaluate the relationship between folate metabolism genetic polymorphisms and the susceptibility to meningioma and glioma in adults. We searched the literature in PubMed, EMBASE and Cochrane Central Library for relevant articles published up to August 2016. The odds ratios (ORs) and the corresponding 95% confidence intervals (95%Cls) were used to evaluate the associations of two folate metabolism genetic variants MTRR A66G (rs1801394) and MTHFR A1298C (rs1801131) with the risk of meningioma and glioma in adults. We found significant association of MTHFR A1298C (rs1801131) variant genotypes with increased incidence of meningioma and glioma in this study population (CA vs. AA: OR=1.22, P<0.001; CA+CC vs. AA: OR=1.18, P=0.002). Moreover, we found that MTRR A66G (rs1801394) variant genotypes was associated with increased risk of meningioma and glioma (G vs. A: OR=1.11, P=0.020; GG vs. AA+AG: OR=1.17, P=0.043; GG vs. AA: OR=1.22, P=0.023). In conclusion, our meta-analysis suggests that two folate metabolism genetic variants MTRR A66G (rs1801394) and MTHFR A1298C (rs1801131) contribute to genetic susceptibility to meningioma and glioma in adults.
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Vasculogenesis is a complex process by which endothelial stem and progenitor cells undergo de novo vessel formation. Quantitative assessment of vasculogenesis is a central readout of endothelial progenitor cell functionality. However, current assays lack kinetic measurements. To address this issue, new approaches were developed to quantitatively assess in vitro endothelial colony-forming cell (ECFC) network formation in real time. Eight parameters of network structure were quantified using novel Kinetic Analysis of Vasculogenesis (KAV) software. KAV assessment of structure complexity identified two phases of network formation. This observation guided the development of additional vasculogenic readouts. A tissue cytometry approach was established to quantify the frequency and localization of dividing ECFCs. Additionally, Fiji TrackMate was used to quantify ECFC displacement and speed at the single-cell level during network formation. These novel approaches were then implemented to identify how intrauterine exposure to maternal diabetes mellitus (DM) impairs fetal ECFC vasculogenesis. Fetal ECFCs exposed to maternal DM form fewer initial network structures, which are not stable over time. Correlation analyses demonstrated that ECFC samples with greater division in branches form fewer closed network structures. Additionally, reductions in average ECFC movement over time decrease structural connectivity. Identification of these novel phenotypes utilizing the newly established methodologies provides evidence for the cellular mechanisms contributing to aberrant ECFC vasculogenesis.