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1.
N Am Spine Soc J ; 18: 100323, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38746017

RESUMO

Background: Postoperative infection is a complication of spinal fusion surgery resulting in increased patient morbidity. Strategies including intraoperative application of powdered vancomycin have been proposed to reduce the incidence of infection; however, such antimicrobial effects are short-lived. Methods: Instrumentation of the L4-L5 vertebrae was performed mimicking pedicle screw and rod fixation in 30 rats. Titanium instrumentation inoculated with either PBS or 1×105 CFU bioluminescent MRSA, along with biomimetic bone grafts infused with varying concentrations of vancomycin and 125 µg of rhBMP-2 (BioMim-rhBMP-2-VCM) were implanted prior to closure. Infection was quantified during the six-week postoperative period using bioluminescent imaging. Arthrodesis was evaluated using micro-CT. Results: Infected animals receiving a bone graft infused with low-dose (0.18 mg/g) or high-dose vancomycin (0.89 mg/g) both exhibited significantly lower bioluminescent signal over the six-week postoperative period than control animals inoculated with MRSA and implanted with bone grafts lacking vancomycin (p=.019 and p=.007, respectively). Both low and high-dose vancomycin-infused grafts also resulted in a statistically significant reduction in average bioluminescence when compared to control animals (p=.027 and p=.047, respectively), independent of time. MicroCT analysis of animals from each group revealed pseudoarthrosis only in the control group, suggesting a correlation between infection and pseudoarthrosis. MRSA-inoculated control animals also had significantly less bone volume formation on micro-CT than the PBS-inoculated control cohort (p<.001), the MRSA+low-dose vancomycin-infused bone graft cohort (p<.001), and the MRSA+high-dose vancomycin-infused bone graft cohort (p<.001). Conclusion: BioMim-rhBMP-2-VCM presents a novel tissue engineering approach to simultaneously promoting arthrodesis and antimicrobial prophylaxis in spinal fusion. Despite mixed evidence of potential osteotoxicity of vancomycin reported in literature, BioMim-rhBMP-2-VCM preserved arthrodesis and osteogenesis with increasing vancomycin loading doses due to the graft's osteoinductive composition.

2.
Plast Reconstr Surg Glob Open ; 12(4): e5741, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38645631

RESUMO

Background: Venous thromboembolism (VTE) is a dangerous postoperative complication after abdominal wall reconstruction (AWR). Intraoperative core body temperature has been associated with thrombotic events in other surgical contexts. This study examines the effects of intraoperative temperature on VTE rate after AWR. Methods: A retrospective study was performed on AWR patients. Cohorts were defined by postoperative 30-day VTE. Intraoperative core body temperature was recorded as the minimum, maximum, and mean intraoperative temperatures. Study variables were analyzed with logistic regression and cutoff analysis to assess for association with VTE. Results: In total, 344 patients met inclusion criteria. Fourteen patients were diagnosed with 30-day VTE for an incidence of 4.1%. The VTE cohort had a longer median inpatient stay (8 days versus 5 days, P < 0.001) and greater intraoperative change in peak inspiratory pressure (3 mm H2O versus 1 mm H2O, P = 0.01) than the non-VTE cohort. Operative duration [odds ratio (OR) = 1.32, P = 0.01], length of stay (OR = 1.07, P = 0.001), and intraoperative PIP difference (OR = 1.18, P = 0.045) were significantly associated with 30-day VTE on univariable regression. Immunocompromised status (OR = 4.1, P = 0.023; OR = 4.0, P = 0.025) and length of stay (OR = 1.1, P < 0.001; OR = 1.1, P < 0.001) were significant predictors of 30-day VTE on two multivariable regression models. No significant associations were found between temperature metrics and 30-day VTE on cutoff point or regression analysis. Conclusions: Intraoperative core body temperature did not associate with 30-day VTE after AWR, though operative duration, length of stay, immunocompromised status, and intraoperative PIP difference did. Surgeons should remain mindful of VTE risk after AWR, and future research is warranted to elucidate all contributing factors.

3.
PLoS Comput Biol ; 20(4): e1012015, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38620017

RESUMO

Recent advances in single-cell sequencing technology have provided opportunities for mathematical modeling of dynamic developmental processes at the single-cell level, such as inferring developmental trajectories. Optimal transport has emerged as a promising theoretical framework for this task by computing pairings between cells from different time points. However, optimal transport methods have limitations in capturing nonlinear trajectories, as they are static and can only infer linear paths between endpoints. In contrast, stochastic differential equations (SDEs) offer a dynamic and flexible approach that can model non-linear trajectories, including the shape of the path. Nevertheless, existing SDE methods often rely on numerical approximations that can lead to inaccurate inferences, deviating from true trajectories. To address this challenge, we propose a novel approach combining forward-backward stochastic differential equations (FBSDE) with a refined approximation procedure. Our FBSDE model integrates the forward and backward movements of two SDEs in time, aiming to capture the underlying dynamics of single-cell developmental trajectories. Through comprehensive benchmarking on multiple scRNA-seq datasets, we demonstrate the superior performance of FBSDE compared to other methods, highlighting its efficacy in accurately inferring developmental trajectories.


Assuntos
Modelos Teóricos , Processos Estocásticos
4.
Am J Kidney Dis ; 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38636649

RESUMO

RATIONALE & OBJECTIVE: The US Kidney Allocation System (KAS) prioritizes candidates with ≤20% Estimated Post-Transplant Survival (EPTS) for high longevity kidneys defined by a ≤20% Kidney Donor Profile Index (KDPI). Use of EPTS in the KAS deprioritizes candidates with older age, diabetes, and longer dialysis durations. We assessed whether this use also disadvantages racial-ethnic minority candidates, who are younger but more likely to have diabetes and longer durations of kidney failure requiring dialysis. STUDY DESIGN: Observational cohort study. SETTING: & Participants: Adult candidates for and recipients of kidney transplantation represented in the Scientific Registry of Transplant Recipients from January 2015 through December 2020. EXPOSURE: Race and ethnicity. OUTCOMES: Age-adjusted assignment to ≤20% EPTS, transplantation of a ≤20% KDPI kidney, and post-transplant survival in longevity matched recipients by racial-ethnicity. ANALYTIC APPROACH: Multivariable logistic regression, Fine-Gray competing risks survival analysis, and Kaplan-Meier and Cox Proportional Hazards methods. RESULTS: The cohort included 199,444 candidates (7% Asian, 29% Black, 19% Hispanic/Latino, 43% White) listed for deceased donor kidney transplantation. Non-White candidates had significantly higher rates of diabetes, longer dialysis duration, and were younger than White candidates. Adjusted for age, Asian, Black, and Hispanic/Latino candidates had significantly lower odds of having a ETPS score ≤20% (OR 0.86, [0.81, 0.91], 0.52 [0.50, 0.54], and 0.49, [0.47, 0.51]), and were less likely to receive a ≤20% KDPI kidney (subHR 0.70 [0.66, 0.75], 0.89 [0.87, 0.92], and 0.73 [0.71, 0.76]), compared to White candidates. Among recipients with ≤20% EPTS scores transplanted with a ≤20% KDPI deceased donor kidney, Asian and Hispanic recipients had lower post-transplant mortality (HR 0.45 [0.27, 0.77], and 0.63 [0.47, 0.86]) and Black recipients had higher but not statistically significant post-transplant mortality (HR 1.22 [0.99, 1.52]) compared to White recipients. LIMITATIONS: Provider reported race-ethnicity data and 5-year post transplant follow-up period. CONCLUSIONS: The US kidney allocation system is less likely to identify racial-ethnic minority candidates as having a ≤20% EPTS score which triggers allocation of high longevity deceased donor kidneys. These findings should inform the OPTN about how to remedy racial/ethnic disparities introduced through KAS's current approach of allocating allografts with longer predicted longevity to recipients with longer estimated post-transplant survival.

5.
Sci Rep ; 14(1): 8684, 2024 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622246

RESUMO

Ciliates are powerful unicellular model organisms that have been used to elucidate fundamental biological processes. However, the high motility of ciliates presents a major challenge in studies using live-cell microscopy and microsurgery. While various immobilization methods have been developed, they are physiologically disruptive to the cell and incompatible with microscopy and/or microsurgery. Here, we describe a Simple Microfluidic Operating Room for the Examination and Surgery of Stentor coeruleus (SMORES). SMORES uses Quake valve-based microfluidics to trap, compress, and perform surgery on Stentor as our model ciliate. Compared with previous methods, immobilization by physical compression in SMORES is more effective and uniform. The mean velocity of compressed cells is 24 times less than that of uncompressed cells. The compression is minimally disruptive to the cell and is easily applied or removed using a 3D-printed pressure rig. We demonstrate cell immobilization for up to 2 h without sacrificing cell viability. SMORES is compatible with confocal microscopy and is capable of media exchange for pharmacokinetic studies. Finally, the modular design of SMORES allows laser ablation or mechanical dissection of a cell into many cell fragments at once. These capabilities are expected to enable biological studies previously impossible in ciliates and other motile species.


Assuntos
Cilióforos , Microfluídica , Salas Cirúrgicas , Cilióforos/fisiologia
6.
J Struct Biol ; 216(2): 108073, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38432598

RESUMO

Cryo-electron microscopy has become a powerful tool to determine three-dimensional (3D) structures of rigid biological macromolecules from noisy micrographs with single-particle reconstruction. Recently, deep neural networks, e.g., CryoDRGN, have demonstrated conformational and compositional heterogeneity of complexes. However, the lack of ground-truth conformations poses a challenge to assess the performance of heterogeneity analysis methods. In this work, variational autoencoders (VAE) with three types of deep generative priors were learned for latent variable inference and heterogeneous 3D reconstruction via Bayesian inference. More specifically, VAEs with "Variational Mixture of Posteriors" priors (VampPrior-SPR), non-parametric exemplar-based priors (ExemplarPrior-SPR) and priors from latent score-based generative models (LSGM-SPR) were quantitatively compared with CryoDRGN. We built four simulated datasets composed of hypothetical continuous conformation or discrete states of the hERG K + channel. Empirical and quantitative comparisons of inferred latent representations were performed with affine-transformation-based metrics. These models with more informative priors gave better regularized, interpretable factorized latent representations with better conserved pairwise distances, less deformed latent distributions and lower within-cluster variances. They were also tested on experimental datasets to resolve compositional and conformational heterogeneity (50S ribosome assembly, cowpea chlorotic mottle virus, and pre-catalytic spliceosome) with comparable high resolution. Codes and data are available: https://github.com/benjamin3344/DGP-SPR.

7.
JAMA ; 331(6): 500-509, 2024 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-38349372

RESUMO

Importance: The US heart allocation system prioritizes medically urgent candidates with a high risk of dying without transplant. The current therapy-based 6-status system is susceptible to manipulation and has limited rank ordering ability. Objective: To develop and validate a candidate risk score that incorporates current clinical, laboratory, and hemodynamic data. Design, Setting, and Participants: A registry-based observational study of adult heart transplant candidates (aged ≥18 years) from the US heart allocation system listed between January 1, 2019, and December 31, 2022, split by center into training (70%) and test (30%) datasets. Adult candidates were listed between January 1, 2019, and December 31, 2022. Main Outcomes and Measures: A US candidate risk score (US-CRS) model was developed by adding a predefined set of predictors to the current French Candidate Risk Score (French-CRS) model. Sensitivity analyses were performed, which included intra-aortic balloon pumps (IABP) and percutaneous ventricular assist devices (VAD) in the definition of short-term mechanical circulatory support (MCS) for the US-CRS. Performance of the US-CRS model, French-CRS model, and 6-status model in the test dataset was evaluated by time-dependent area under the receiver operating characteristic curve (AUC) for death without transplant within 6 weeks and overall survival concordance (c-index) with integrated AUC. Results: A total of 16 905 adult heart transplant candidates were listed (mean [SD] age, 53 [13] years; 73% male; 58% White); 796 patients (4.7%) died without a transplant. The final US-CRS contained time-varying short-term MCS (ventricular assist-extracorporeal membrane oxygenation or temporary surgical VAD), the log of bilirubin, estimated glomerular filtration rate, the log of B-type natriuretic peptide, albumin, sodium, and durable left ventricular assist device. In the test dataset, the AUC for death within 6 weeks of listing for the US-CRS model was 0.79 (95% CI, 0.75-0.83), for the French-CRS model was 0.72 (95% CI, 0.67-0.76), and 6-status model was 0.68 (95% CI, 0.62-0.73). Overall c-index for the US-CRS model was 0.76 (95% CI, 0.73-0.80), for the French-CRS model was 0.69 (95% CI, 0.65-0.73), and 6-status model was 0.67 (95% CI, 0.63-0.71). Classifying IABP and percutaneous VAD as short-term MCS reduced the effect size by 54%. Conclusions and Relevance: In this registry-based study of US heart transplant candidates, a continuous multivariable allocation score outperformed the 6-status system in rank ordering heart transplant candidates by medical urgency and may be useful for the medical urgency component of heart allocation.


Assuntos
Insuficiência Cardíaca , Transplante de Coração , Obtenção de Tecidos e Órgãos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bilirrubina , Serviços de Laboratório Clínico , Coração , Fatores de Risco , Medição de Risco , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/cirurgia , Estados Unidos , Alocação de Recursos para a Atenção à Saúde/métodos , Valor Preditivo dos Testes , Obtenção de Tecidos e Órgãos/métodos , Obtenção de Tecidos e Órgãos/organização & administração
8.
Res Pract Thromb Haemost ; 8(1): 102315, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38404943

RESUMO

Background: The majority of randomized controlled trials (RCTs) investigating venous thromboembolism (VTE) prophylaxis in patients with cancer involve commercial sponsorship. Commercial sponsorship overcomes feasibility limitations inherent in RCTs, such as recruitment and funding, but has attracted scrutiny for its potential for bias. Objectives: In RCTs of VTE prophylaxis in patients with cancer, how do trial characteristics compare between commercially sponsored RCTs and noncommercially sponsored RCTs? Methods: Medline, Embase, and Cochrane Central Register of Controlled Trials were searched for RCTs that investigated at least 1 pharmacologic intervention for VTE prophylaxis in adult patients with cancer. Screening and data extraction were conducted by independent reviewers. Outcomes included trial characteristics, reporting of favorable outcomes, protocol-manuscript discrepancies, and appraisal of spin. Outcomes were compared using the independent t-test, Mann-Whitney U-test, Pearson chi-squared test, and Fisher's exact test. Logistic regression was performed to identify factors associated with possible bias. Results: Of the 54 trials analyzed, 34 (63%) reported commercial sponsorship. Commercial sponsorship was not associated with the reporting of favorable outcomes, presence of spin, retrospective registration, or protocol-manuscript discrepancy. Spin was most prevalent in the abstract conclusions (9 out of 17 [53.3%]) and manuscript conclusions (8 out of 17 [46.7%]).Commercially sponsored trials had a higher rate of intention-to-treat analysis. Noncommercially sponsored trials were more likely to report retrospective registration of trial protocol and the use of composite primary outcomes. Conclusion: There were few significant differences between trial characteristics, suggesting that the evidence from commercially sponsored trials investigating VTE prophylaxis in patients with cancer is unlikely to be subject to bias attributable to commercial sponsorship.

9.
Ann Surg Oncol ; 31(6): 3684-3693, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38388930

RESUMO

BACKGROUND: Recent data suggest disparities in receipt of regional anesthesia prior to breast reconstruction. We aimed to understand factors associated with block receipt for mastectomy with immediate tissue expander (TE) reconstruction in a high-volume ambulatory surgery practice with standardized regional anesthesia pathways. PATIENTS AND METHODS: Patients who underwent mastectomy with immediate TE reconstruction from 2017 to 2022 were included. All patients were considered eligible for and were offered preoperative nerve blocks as part of routine anesthesia care. Interpreters were used for non-English speaking patients. Patients who declined a block were compared with those who opted for the procedure. RESULTS: Of 4213 patients who underwent mastectomy with immediate TE reconstruction, 91% accepted and 9% declined a nerve block. On univariate analyses, patients with the lowest rate of block refusal were white, non-Hispanic, English speakers, patients with commercial insurance, and patients undergoing bilateral reconstruction. The rate of block refusal went down from 12 in 2017 to 6% in 2022. Multivariable logistic regression demonstrated that older age (p = 0.011), Hispanic ethnicity (versus non-Hispanic; p = 0.049), Medicaid status (versus commercial insurance; p < 0.001), unilateral surgery (versus bilateral; p = 0.045), and reconstruction in earlier study years (versus 2022; 2017, p < 0.001; 2018, p < 0.001; 2019, p = 0.001; 2020, p = 0.006) were associated with block refusal. CONCLUSIONS: An established preoperative regional anesthesia program with blocks offered to all patients undergoing mastectomy with TE reconstruction can result in decreased racial disparities. However, continued differences in age, ethnicity, and insurance status justify future efforts to enhance preoperative educational efforts that address patient hesitancies in these subpopulations.


Assuntos
Anestesia por Condução , Neoplasias da Mama , Disparidades em Assistência à Saúde , Mamoplastia , Mastectomia , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias da Mama/cirurgia , Anestesia por Condução/métodos , Mamoplastia/métodos , Seguimentos , Adulto , Bloqueio Nervoso/métodos , Prognóstico , Idoso , Dispositivos para Expansão de Tecidos
10.
bioRxiv ; 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38370688

RESUMO

Ciliates are powerful unicellular model organisms that have been used to elucidate fundamental biological processes. However, the high motility of ciliates presents a major challenge in studies using live-cell microscopy and microsurgery. While various immobilization methods have been developed, they are physiologically disruptive to the cell and incompatible with microscopy and/or microsurgery. Here, we describe a Simple Microfluidic Operating Room for the Examination and Surgery of Stentor coeruleus (SMORES). SMORES uses Quake valve-based microfluidics to trap, compress, and perform surgery on Stentor as our model ciliate. Compared with previous methods, immobilization by physical compression in SMORES is more effective and uniform. The mean velocity of compressed cells is 24 times less than that of uncompressed cells. The compression is minimally disruptive to the cell and is easily applied or removed using a 3D-printed pressure rig. We demonstrate cell immobilization for up to 2 hours without sacrificing cell viability. SMORES is compatible with confocal microscopy and is capable of media exchange for pharmacokinetic studies. Finally, the modular design of SMORES allows laser ablation or mechanical dissection of a cell into many cell fragments at once. These capabilities are expected to enable biological studies previously impossible in ciliates and other motile species.

11.
J Heart Lung Transplant ; 43(6): 954-962, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38423416

RESUMO

BACKGROUND: Since 2019, the annual transplantation rate of hearts donated following circulatory death (DCD) has increased significantly in the United States. The 2 major heart procurement techniques following circulatory death are direct procurement and perfusion (DPP) and normothermic regional perfusion (NRP). Post-transplant survival for heart recipients has not been compared between these 2 techniques. METHODS: This observational study uses data on adult heart transplants from donors after circulatory death from January 1, 2019 to December 31, 2021 in the Scientific Registry of Transplant Recipients. We identified comparable transplant cases across procurement types using propensity-score matching and measured the association between procurement technique and 1-year post-transplant survival using Kaplan-Meier and Cox proportional hazards model stratefied by matching pairs. RESULTS: Among 318 DCD heart transplants, 216 (68%) were procured via DPP, and 102 (32%) via NRP. Among 22 transplant centers that accepted circulatory-death donors, 3 used NRP exclusively, and 5 used both procurement techniques. After propensity-score matching on recipient and donor factors, there was no significant difference in 1-year post-transplant survival (93.1% for NRP vs 91.1% for DPP, p = 0.79) between procurement techniques. CONCLUSIONS: NRP and DPP procurements are associated with similar 1-year post-transplant survival. If NRP is ethically permissible and improves outcomes for abdominal organs, it should be the preferred procurement technique for DCD hearts.


Assuntos
Sobrevivência de Enxerto , Transplante de Coração , Preservação de Órgãos , Perfusão , Obtenção de Tecidos e Órgãos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Obtenção de Tecidos e Órgãos/métodos , Perfusão/métodos , Sobrevivência de Enxerto/fisiologia , Preservação de Órgãos/métodos , Adulto , Estudos Retrospectivos , Doadores de Tecidos , Estados Unidos/epidemiologia , Taxa de Sobrevida/tendências , Morte , Seguimentos , Sistema de Registros
12.
J Reconstr Microsurg ; 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38267009

RESUMO

BACKGROUND: A comprehensive understanding of changes in health-related quality of life after head and neck cancer surgery is necessary for effective preoperative counseling. The goal of this study was to perform a longitudinal analysis of postoperative quality of life outcomes after fibula free flap (FFF) mandible reconstruction. METHODS: A retrospective review was performed for all patients who underwent oncologic mandible reconstruction with an FFF between 2000 and 2021. Completion of at least one postoperative FACE-Q questionnaire was necessary for inclusion. FACE-Q scores were divided into five time periods for analysis. Functional outcomes measured with speech language pathology (SLP) assessments and tracheostomy and gastrostomy tube status were analyzed at three time points. RESULTS: One hundred and nine patients were included. Of these, 68 patients also had at least one SLP assessment. All outcomes as measured by the various FACE-Q scales did not improve significantly from the immediate postoperative time point to the last evaluated time point (p > 0.05). SLP functional outcomes showed some deterioration over time, but these were not significant (p > 0.05). The percentage of patients who required a tracheostomy (18 to 2%, p = 0.002) or gastrostomy tube (25 to 11%, p = 0.035) decreased significantly from the immediate postoperative time point to the last evaluated time point. CONCLUSION: Subjective quality of life outcomes do not change significantly with time after oncologic FFF mandible reconstruction. Reconstructive surgeons can use these results to help patients establish appropriate and achievable quality of life goals after surgery. Further studies are warranted to elucidate the impact of specific relevant clinical variables on postoperative quality of life.

13.
ACS Biomater Sci Eng ; 10(2): 814-824, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38226596

RESUMO

Cultivated meat production is a promising technology to generate meat while reducing the reliance on traditional animal farming. Biomaterial scaffolds are critical components in cultivated meat production, enabling cell adhesion, proliferation, differentiation, and orientation. In the present work, naturally derived glutenin was fabricated into films with and without surface patterning and in the absence of toxic cross-linking or stabilizing agents for cell culture related to cultivated meat goals. The films were stable in culture media for at least 28 days, and the surface patterns induced cell alignment and guided myoblast organization (C2C12s) and served as a substrate for 3T3-L1 adipose cells. The films supported adhesion, proliferation, and differentiation with mass balance considerations (films, cells, and matrix production). Freeze-thaw cycles were applied to remove cells from glutenin films and monitor changes in glutenin mass with respect to culture duration. Extracellular matrix (ECM) extraction was utilized to quantify matrix deposition and changes in the original biomaterial mass over time during cell cultivation. Glutenin films with C2C12s showed mass increases with time due to cell growth and new collagen-based ECM expression during proliferation and differentiation. All mass balances were compared among cell and noncell systems as controls, along with gelatin control films, with time-dependent changes in the relative content of film, matrix deposition, and cell biomass. These data provide a foundation for cell/biomaterial/matrix ratios related to time in culture as well as nutritional and textural features.


Assuntos
Materiais Biocompatíveis , Carne in vitro , Animais , Glutens/química , Músculos
14.
bioRxiv ; 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38293057

RESUMO

The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: α 2 γ 2 ) to adult hemoglobin (HbA: α 2 ß 2 ) during development. BCL11A binds at a cognate recognition site (TGACCA) in the γ-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a special role in DNA binding and γ-globin gene repression. Our findings help account for some rare γ-globin gene promoter mutations that perturb BCL11A binding and lead to increased HbF in adults (hereditary persistence of fetal hemoglobin). Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and ß-thalassemia.

15.
J Surg Oncol ; 129(1): 183-193, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37990858

RESUMO

BACKGROUND: Using real working examples, we provide strategies and address challenges in linear and logistic regression to demonstrate best practice guidelines and pitfalls of regression modeling in surgical oncology research. METHODS: To demonstrate our best practices, we reviewed patients who underwent tissue expander breast reconstruction between 2019 and 2021. We assessed predictive factors that affect BREAST-Q Physical Well-Being of the Chest (PWB-C) scores at 2 weeks with linear regression modeling and overall complications and malrotation with logistic regression modeling. Model fit and performance were assessed. RESULTS: The 1986 patients were included in the analysis. In linear regression, age [ß = 0.18 (95% CI: 0.09, 0.28); p < 0.001], single marital status [ß = 2.6 (0.31, 5.0); p = 0.026], and prepectoral pocket dissection [ß = 4.6 (2.7, 6.5); p < 0.001] were significantly associated with PWB-C at 2 weeks. For logistic regression, BMI [OR = 1.06 (95% CI: 1.04, 1.08); p < 0.001], age [OR = 1.02 (1.01, 1.03); p = 0.002], bilateral reconstruction [OR = 1.39 (1.09, 1.79); p = 0.009], and prepectoral dissection [OR = 1.53 (1.21, 1.94); p < 0.001] were associated with increased likelihood of a complication. CONCLUSION: We provide focused directives for successful application of regression techniques in surgical oncology research. We encourage researchers to select variables with clinical judgment, confirm appropriate model fitting, and consider clinical plausibility for interpretation when utilizing regression models in their research.


Assuntos
Implante Mamário , Implantes de Mama , Neoplasias da Mama , Mamoplastia , Oncologia Cirúrgica , Feminino , Humanos , Implante Mamário/efeitos adversos , Implantes de Mama/efeitos adversos , Neoplasias da Mama/cirurgia , Neoplasias da Mama/complicações , Mamoplastia/métodos , Complicações Pós-Operatórias/etiologia , Análise de Regressão , Estudos Retrospectivos
16.
J Surg Oncol ; 129(4): 681-690, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38073188

RESUMO

BACKGROUND: There is a lack of literature of health-related quality of life endpoints for radial forearm (RF) versus anterolateral thigh (ALT) free flap reconstruction for glossectomy defects. Our goal was to perform a comprehensive evaluation of clinical, functional, and quality of life outcomes after glossectomy reconstruction using a RF or ALT flap. METHODS: A retrospective review was performed on patients who underwent glossectomy and immediate reconstruction with RF or ALT flaps between 2016 and 2021. Outcomes of interest included readmission and reoperation rates, functional assessments, tracheostomy and gastrostomy tube status, and FACE-Q Head and Neck Cancer scores. RESULTS: Seventy-eight patients consisting of 54 RF and 24 ALT free flaps were included. ALT patients had a larger median flap size (72 vs. 48 cm2 , p = 0.021) and underwent mandibulotomy (50% vs. 7.4%, p < 0.0001) and base of tongue resection (58.3% vs. 24.1%, p = 0.005) at higher rates. No significant differences were found with respect to other outcomes. CONCLUSION: The RF and ALT flaps are suitable for glossectomy reconstruction, with minimal differences seen in postoperative outcomes. Our study suggests that ALT can be used in patients with base of tongue and larger defect sizes, while providing similar functional and clinical outcomes to RF reconstruction.


Assuntos
Retalhos de Tecido Biológico , Neoplasias da Língua , Humanos , Glossectomia/métodos , Coxa da Perna/cirurgia , Antebraço/cirurgia , Qualidade de Vida , Neoplasias da Língua/cirurgia , Estudos Retrospectivos , Medidas de Resultados Relatados pelo Paciente
17.
Rofo ; 196(4): 354-362, 2024 Apr.
Artigo em Inglês, Alemão | MEDLINE | ID: mdl-37944934

RESUMO

BACKGROUND: Imaging biomarkers are quantitative parameters from imaging modalities, which are collected noninvasively, allow conclusions about physiological and pathophysiological processes, and may consist of single (monoparametric) or multiple parameters (bi- or multiparametric). METHOD: This review aims to present the state of the art for the quantification of multimodal and multiparametric imaging biomarkers. Here, the use of biomarkers using artificial intelligence will be addressed and the clinical application of imaging biomarkers in breast and prostate cancers will be explained. For the preparation of the review article, an extensive literature search was performed based on Pubmed, Web of Science and Google Scholar. The results were evaluated and discussed for consistency and generality. RESULTS AND CONCLUSION: Different imaging biomarkers (multiparametric) are quantified based on the use of complementary imaging modalities (multimodal) from radiology, nuclear medicine, or hybrid imaging. From these techniques, parameters are determined at the morphological (e. g., size), functional (e. g., vascularization or diffusion), metabolic (e. g., glucose metabolism), or molecular (e. g., expression of prostate specific membrane antigen, PSMA) level. The integration and weighting of imaging biomarkers are increasingly being performed with artificial intelligence, using machine learning algorithms. In this way, the clinical application of imaging biomarkers is increasing, as illustrated by the diagnosis of breast and prostate cancers. KEY POINTS: · Imaging biomarkers are quantitative parameters to detect physiological and pathophysiological processes.. · Imaging biomarkers from multimodality and multiparametric imaging are integrated using artificial intelligence algorithms.. · Quantitative imaging parameters are a fundamental component of diagnostics for all tumor entities, such as for mammary and prostate carcinomas.. CITATION FORMAT: · Bäuerle T, Dietzel M, Pinker K et al. Identification of impactful imaging biomarker: Clinical applications for breast and prostate carcinoma. Fortschr Röntgenstr 2024; 196: 354 - 362.


Assuntos
Carcinoma , Medicina Nuclear , Neoplasias da Próstata , Humanos , Masculino , Inteligência Artificial , Biomarcadores , Imageamento por Ressonância Magnética/métodos , Próstata/diagnóstico por imagem , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Feminino
19.
J Surg Oncol ; 129(3): 617-628, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37985365

RESUMO

BACKGROUND: The choice of tissue type for free flap reconstruction of posterolateral mandible resections is dependent on patient and defect characteristics. We compared clinical and patient-reported outcomes following reconstruction of these defects with a soft tissue or bony free flap. METHODS: A retrospective review was performed on patients who underwent posterolateral segmental mandibulectomy with immediate free flap reconstruction at MSKCC from 2006 to 2021. Outcomes of interest were patient-reported outcome measures (PROMs) assessed by FACE-Q surveys and complications at the flap recipient site. RESULTS: Ninety patients received a bony flap and 24 patients received a soft tissue flap. Patients reconstructed with soft tissue flaps had greater rates of composite soft tissue defects (p < 0.0001), condyle resection (p = 0.001), and peripheral vascular disease (p = 0.035). Complication rates were similar between the cohorts (p > 0.05). Bony flaps scored higher on multiple FACE-Q scales: Facial Appearance (p = 0.023) Eating/Drinking (p = 0.029), Smiling (p = 0.012), Speaking (p < 0.001), Swallowing (p = 0.012), Smiling Distress (p = 0.037), and Speaking Distress (p = 0.001). CONCLUSION: Reconstruction of posterolateral mandibular defects has a similar complication profile when utilizing a bony or soft tissue free flap. Bony flaps may perform better with respect to PROMs. Reconstructive surgeons should consider using bony flap reconstruction to achieve higher patient satisfaction and quality of life.


Assuntos
Retalhos de Tecido Biológico , Procedimentos de Cirurgia Plástica , Humanos , Qualidade de Vida , Mandíbula/cirurgia , Retalhos de Tecido Biológico/cirurgia , Medidas de Resultados Relatados pelo Paciente , Estudos Retrospectivos
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