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1.
Qual Life Res ; 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-39103575

RESUMEN

PURPOSE: We applied a previously established common T-score metric for patient-reported and performance-based physical function (PF), offering the unique opportunity to directly compare measurement type-specific patterns of associations with potential laboratory-based, psychosocial, sociodemographic, and health-related determinants in hemodialysis patients. METHODS: We analyzed baseline data from the CONVINCE trial (N = 1,360), a multinational randomized controlled trial comparing high-flux hemodialysis with high-dose hemodiafiltration. To explore the associations of potential determinants with performance-based versus patient-reported PF, we conducted multiple linear regression (backward elimination with cross-validation and Lasso regression). We used standardized T-scores as estimated from the PROMIS PF short-form 4a (patient-reported PF) and the Physical Performance Test (performance-based PF) as dependent variables. RESULTS: Performance-based and patient-reported PF were both significantly associated with a laboratory marker-based indicator of muscle mass (simplified creatinine index), although the effects were relatively small (partial f2 = 0.04). Age was negatively associated with PF; the effect size was larger for performance-based (partial f2 = 0.12) than for patient-reported PF (partial f2 = 0.08). Compared to performance-based PF, patient-reported PF showed a stronger association with self-reported health domains, particularly pain interference and fatigue. When using the individual difference between patient-reported and performance-based T-scores as outcome, we found that younger age and more fatigue were associated with lower patient-reported PF compared to performance-based PF (small effect size). CONCLUSION: Patient-reported and performance-based assessments were similarly associated with an objective marker of physical impairment in hemodialysis patients. Age and fatigue may result in discrepancies when comparing performance-based and patient-reported scores on the common PF scale. Trial Registration CONVINCE is registered in the Dutch Trial Register (Register ID: NL64750.041.18). The registration can be accessed at: https://onderzoekmetmensen.nl/en/trial/52958 .

2.
ACS Appl Mater Interfaces ; 16(33): 44236-44248, 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39121451

RESUMEN

Hybrid battery cells that combine a garnet-type Li7La3Zr2O12 (LLZO) solid electrolyte with other solid, polymer or liquid electrolytes are increasingly investigated. In such cells with layered electrolytes, ensuring a low-resistive heteroionic interface between neighboring electrolytes is crucial for preventing major additional overpotentials during operation. Electrochemical impedance spectroscopy is frequently used to extract such parameters, usually on multilayer symmetrical model cells that contain the different electrolytes stacked in series. Unfortunately, the impedance contributions of the heteroionic interfaces often overlap with those of the electrolyte|electrode interfaces, necessitating the use of sophisticated four-point cells that probe the electrochemical potential away from the polarization source. In this work, an alternative solution to this problem is demonstrated by taking advantage of the inherent fast charge transfer kinetics of LLZO with its parent metal electrode. The "resistance-free" nature of a reversible Li|LLZO interface enables a precise evaluation of the heteroionic interface impedance in symmetric two-point cells of the type Li|LLZO|electrolyte|LLZO|Li with negligible electrode contribution. This is exemplified for symmetric multilayer cells containing tantalum-doped LLZO and a poly(ethylene oxide) (PEO)-based dry polymer electrolyte. Validation and comparison of impedance data with results from symmetric four-point cells and two-point cells with ion-blocking electrodes demonstrate the advantage of the proposed method. Overall, this study presents a simple and reliable method for studying heteroionic interface impedances in LLZO-containing multilayer cells.

3.
Kidney Int ; 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39089577

RESUMEN

In the CONVINCE trial, the primary analysis demonstrated a survival benefit for patients receiving high-dose hemodiafiltration (HDF) as compared with high-flux hemodialysis (HD). A secondary objective was to evaluate effects on health-related quality of life (HRQoL); assessed in eight domains (physical function, cognitive function, fatigue, sleep disturbance, anxiety, depression, pain interference, social participation) applying instruments from the Patient-Reported Outcome Measurement Information System (PROMIS) before randomization and every three months thereafter. In total 1360 adults with dialysis-dependent chronic kidney disease, eligible to receive high-flux HDF (23 liters or more), were randomized (1:1); 84% response rate to all questionnaires. Both groups reported a continuous deterioration in all HRQoL domains. Overall, raw score changes from baseline were more favorable in the HDF group, resulting in a significant omnibus test after a median observation period of 30 months. Most relevant single raw score differences were reported for cognitive function. Patients receiving HDF reported a decline of -0.95 units (95% confidence interval - 2.23 to +0.34) whereas HD treated patients declined by -3.90 units (-5.28 to - 2.52). A joint model, adjusted for mortality differences, utilizing all quarterly assessments, identified a significantly slower HRQoL decline in physical function, cognitive function, pain interference, and social participation for the HDF group. Their physical health summary score declined -0.46 units/year slower compared to the HD group. Thus, the CONVINCE trial showed a beneficial effect of high-dose hemodiafiltration for survival as well as a moderate positive effect on patients' quality of life, most pronounced with respect to their cognitive function. REGISTRATION: NTR7138 on the International Clinical Trials Registry Platform.

4.
Soft Matter ; 20(31): 6231-6246, 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39051502

RESUMEN

Biomedical applications such as drug delivery, tissue engineering, and functional surface coating rely on switchable adsorption and desorption of specialized guest molecules. Poly(dehydroalanine), a polyzwitterion containing pH-dependent positive and negative charges, shows promise for such reversible loading, especially when integrated into a gel network. Herein, we present the fabrication of poly(dehydroalanine)-derived gels of different size scales and evaluate them with respect to their practical use in biomedicine. Already existing protocols for bulk gelation were remodeled to derive suitable reaction conditions for droplet-based microfluidic synthesis. Depending on the layout of the microfluidic chip, microgels with a size of approximately 30 µm or 200 µm were obtained, whose crosslinking density can be increased by implementing a multi-arm crosslinker. We analyzed the effects of the crosslinker species on composition, permeability, and softness and show that the microgels exhibit advantageous properties inherent to zwitterionic polymer systems, including high hydrophilicity as well as pH- and ionic strength-sensitivity. We demonstrate pH-regulated uptake and release of fluorescent model dyes before testing the adsorption of a small antimicrobial peptide, LL-37. Quantification of the peptide accommodated within the microgels reveals the impact of size and crosslinking density of the microgels. Biocompatibility of the microgels was validated by cell tests.


Asunto(s)
Microesferas , Concentración de Iones de Hidrógeno , Microgeles/química , Péptidos/química , Geles/química , Microfluídica , Humanos , Péptidos Catiónicos Antimicrobianos/química
5.
J Vasc Surg Cases Innov Tech ; 10(5): 101551, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39069990

RESUMEN

Polymer ring stent grafts from Endologix are reliable to treat challenging abdominal aortic aneurysm anatomy (hostile neck and tortuous or narrow iliac arteries). Rare cases of anaphylactoid reactions have been reported during the filing time of the graft rings due to polymer leakage. Management with amines, an antihistamine drug, and supportive care quickly stabilized both of our patients, which permitted the continuation and completion of their surgery. In our experience, there was no death-related events nor negative impact on patients surgical and clinical outcomes. We report on polymer leakage using the Ovation IX and ALTO stent grafts resulting in an anaphylactoid reaction.

6.
Microsurgery ; 44(6): e31212, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39046178

RESUMEN

INTRODUCTION: A reconstructive option for extensive chest wall reconstruction is the free myocutaneous vastus lateralis muscle (VL) flap which can be performed in isolation or in conjunction with a fasciocutaneus anterolateral thigh (cVLALT) and/or myofasciocutaneous tensor fascia lata flap (cVLTFL). We aimed to directly compare the outcomes of these reconstructive options. METHODS: Patients who underwent oncological chest wall reconstruction with a free VL, cVLALT, or cVLTFL flap between February 2010 and 2022 were included in this retrospective study. Patient demographics, surgical characteristics, as well as medical and reconstructive outcomes, were evaluated. The operative outcomes between myocutaneous VL, cVLALT, and cVLTFL flap reconstructions were compared. RESULTS: A total of 41 patients underwent chest wall reconstruction with a free myocutaneous VL (n = 25; 61%), cVLALT (n = 14; 34%), or cVLTFL Three acute flap thromboses occurred in the entire cohort (3/41, 7%), with one myocutaneous VL flap failing because of recurrent venous thrombosis during the salvage procedure. Total flap necrosis was seen in two cases (5%; VL flap: n = 1; cVLALT flap: n = 1), and partial flap necrosis in one VL flap (1/25, 4%) and in the distal ALT portion of three cVLALT flaps (3/14, 21%). No significant difference was seen between isolated VL and conjoined VL flaps regarding the partial (p = .28) or total flap necrosis rate (p = .9). CONCLUSION: The free (conjoined) VL flap provides reliable outcomes for obliterating dead space achieving durable reconstruction of complex chest wall defects.


Asunto(s)
Fascia Lata , Colgajos Tisulares Libres , Procedimientos de Cirugía Plástica , Músculo Cuádriceps , Muslo , Pared Torácica , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Procedimientos de Cirugía Plástica/métodos , Pared Torácica/cirugía , Fascia Lata/trasplante , Colgajos Tisulares Libres/trasplante , Anciano , Adulto , Muslo/cirugía , Músculo Cuádriceps/trasplante , Músculo Cuádriceps/cirugía , Colgajo Miocutáneo/trasplante , Neoplasias Torácicas/cirugía , Resultado del Tratamiento
7.
Angew Chem Int Ed Engl ; 63(36): e202411010, 2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-38895894

RESUMEN

Elemental sulfur has shown to be a promising alternative feedstock for development of novel polymeric materials with high sulfur content. However, the utilization of inverse vulcanized polymers is restricted by the limitation of functional comonomers suitable for an inverse vulcanization. Control over properties and structure of inverse vulcanized polymers still poses a challenge to current research due to the dynamic nature of sulfur-sulfur bonds and high temperature of inverse vulcanization reactions. In here, we report for the first time the inverse vulcanization of norbornenyl pentafluorophenyl ester (NB-PFPE), allowing for post-modification of inverse vulcanized polymers via amidation of reactive PFP esters to yield high sulfur content polymers under mild conditions. Amidation of the precursor material with three functional primary amines (α-amino-ω-methoxy polyethylene glycol, aminopropyl trimethoxy silane, allylamine) was investigated. The resulting materials were applicable as sulfur containing poly(ethylene glycol) nanoparticles in aqueous environment. Cross-linked mercury adsorbents, sulfur surface coatings, and high-sulfur content networks with predictable thermal properties were achievable using aminopropyl trimethoxy silane and allylamine for post-polymerization modification, respectively. With the broad range of different amines available and applicable for post-polymerization modification, the versatility of poly(sulfur-random-NB-PFPE) as a platform precursor polymer for novel specialized sulfur containing materials was showcased.

8.
J Burn Care Res ; 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38837360

RESUMEN

Effective burn surgery is based on two fundamental principles: prompt excision of necrotic tissue and definitive coverage preserving functional dermis and body contour. There is often compromise, either prioritizing the urgency of excision or opting for patient stability and optimal conditions prior to autografting. We propose a surgical concept that addresses this critical treatment gap. In 2022 we implemented a new three-phase protocol, EDM: (Excision phase, E) Immediate excision of the burn wound preserving body contour; (Dermis phase, D) definitive temporization of the wound bed, using Biodegradable Temporizing Matrix (BTM), to prepare it for successful grafting. (Meek phase, M): Upon complete dermal temporization, full autologous coverage in a single micrografting procedure. We performed a retrospective single-center cohort study to characterize the EDM protocol compared to the prior standard of care (>40%TBSA, n=5 in EDM vs. n=10 matched controls). Primary outcomes were total surgeries required, total surgeries to achieve>90% healing, uninterrupted recovery time without surgery, and time on mechanical ventilation. The EDM group required fewer surgeries in total (5 vs. 9.5 ; p=0.01) and to achieve>90% healing (3 vs. 6.5; p=0.001). EDM patients experienced longer uninterrupted recovery (24 vs. 14 days, p=0.001). Additionally, EDM patients spent less time on mechanical ventilation (210 vs. 1136 hours, p=0.005). The EDM protocol could improve surgical efficiency, ultimately having the potential to expedite rehabilitation in severely burned patients. The study underscores the potential of combining fundamentals of burn surgery, with innovative surgical techniques and materials, in order to bridge the gap between excision and grafting.

9.
Neuron ; 112(14): 2289-2303, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-38729151

RESUMEN

The property of mixed selectivity has been discussed at a computational level and offers a strategy to maximize computational power by adding versatility to the functional role of each neuron. Here, we offer a biologically grounded implementational-level mechanistic explanation for mixed selectivity in neural circuits. We define pure, linear, and nonlinear mixed selectivity and discuss how these response properties can be obtained in simple neural circuits. Neurons that respond to multiple, statistically independent variables display mixed selectivity. If their activity can be expressed as a weighted sum, then they exhibit linear mixed selectivity; otherwise, they exhibit nonlinear mixed selectivity. Neural representations based on diverse nonlinear mixed selectivity are high dimensional; hence, they confer enormous flexibility to a simple downstream readout neural circuit. However, a simple neural circuit cannot possibly encode all possible mixtures of variables simultaneously, as this would require a combinatorially large number of mixed selectivity neurons. Gating mechanisms like oscillations and neuromodulation can solve this problem by dynamically selecting which variables are mixed and transmitted to the readout.


Asunto(s)
Modelos Neurológicos , Neuronas , Neuronas/fisiología , Animales , Red Nerviosa/fisiología , Humanos , Dinámicas no Lineales
10.
Chemistry ; 30(38): e202401047, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38699878

RESUMEN

The ability of light to change the properties of light-responsive polymers opens avenues for targeted release of cargo with a high degree of spatial and temporal control. Recently, we established photoacid polymers as light-switchable macromolecular amphiphiles. In these systems, light-induced excited-state proton transfer (ESPT) causes changes in amphilicity. However, as the intermolecular process itself critically depends on the local environment of the photoacid unit within the polymer, the overall amphiphilicity directly influences ESPT. Thus, understanding the impact of the local environment on the photophysics of photoacidic side chains is key to material design. In this contribution we address both thermodynamic and kinetic aspects of ESPT in oxazoline-based amphiphilic polymers with pyrenol-based photoacid side chains. We will compare the effect of polymer design, i. e. statistical and block arrangements, i. e. in poly[(2-ethyl-2-oxazoline)-co-(1-(6/8-hydroxyperene)sulphonylaziridine)] and poly(2-ethyl-2-oxazoline)-block-poly[(2-ethyl-2-oxazoline)-co-(2-(3-(6-hydroxypyrene)sulphonamide)propyl-2-oxazoline), on the intermolecular proton transfer reaction by combining steady-state and time-resolved absorption and emission spectroscopy. ESPT appears more prominent in the statistical copolymer compared to a block copolymer with overall similar pyrenol loading. We hypothesize that the difference is due to different local chain arrangements adopted by the polymers in the two cases.

11.
ACS Appl Mater Interfaces ; 16(19): 24796-24805, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38700504

RESUMEN

Future technologies to harness solar energy and to convert this into chemical energy strongly rely on straightforward approaches to prepare versatile soft matter scaffolds for the immobilization of catalysts and sensitizers in a defined environment. In addition, particularly for light-driven hydrogen evolution, a transition to noble metal-free photosensitizers and catalysts is urgently required. Herein, we report a fully organic light-harvesting soft matter network based on a polyampholyte hydrogel where both photosensitizer (a perylene monoimide derivative) and a H2 evolution catalyst ([Mo3S13]2-) are electrostatically incorporated. The resulting material exhibits sustained visible-light-driven H2 evolution in aqueous ascorbic acid solution, even at rather low loadings of photosensitizer (0.4%) and catalyst (120 ppm). In addition, we provide initial insights into the long-term stability of the hybrid hydrogel. We believe that these results pave the way for a generalized route toward the incorporation of noble metal-free light-driven catalysis in soft matter networks.

12.
Aesthetic Plast Surg ; 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38777929

RESUMEN

BACKGROUND: The increasing demand and changing trends in rhinoplasty surgery emphasize the need for effective doctor-patient communication, for which Artificial Intelligence (AI) could be a valuable tool in managing patient expectations during pre-operative consultations. OBJECTIVE: To develop an AI-based model to simulate realistic postoperative rhinoplasty outcomes. METHODS: We trained a Generative Adversarial Network (GAN) using 3,030 rhinoplasty patients' pre- and postoperative images. One-hundred-one study participants were presented with 30 pre-rhinoplasty patient photographs followed by an image set consisting of the real postoperative versus the GAN-generated image and asked to identify the GAN-generated image. RESULTS: The study sample (48 males, 53 females, mean age of 31.6 ± 9.0 years) correctly identified the GAN-generated images with an accuracy of 52.5 ± 14.3%. Male study participants were more likely to identify the AI-generated images compared with female study participants (55.4% versus 49.6%; p = 0.042). CONCLUSION: We presented a GAN-based simulator for rhinoplasty outcomes which used pre-operative patient images to predict accurate representations that were not perceived as different from real postoperative outcomes. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

13.
J Clin Med ; 13(9)2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38731190

RESUMEN

Objectives: Addressing extensive and deep burn wounds poses considerable challenges for both patients and surgeons. The NovoSorb® Biodegradable Temporizing Matrix (BTM) emerged as a novel dermal substitute and has been subjected to evaluation in large burn wound cases, with a specific focus on identifying risk factors associated with suboptimal take rates. Methods: All patients with burn wounds greater than 10% body surface that underwent BTM treatment between March 2020 and November 2023 were eligible for inclusion. Univariate analyses and linear regression models were employed to discern risk factors and predictors influencing the take rates of both the BTM and split-thickness skin grafts (STSGs). Results: A total of 175 patients (mean age 56.2 ± 19.8 years, 70.3% male) were evaluated. The mean take rates of the BTM and STSGs were 82.0 ± 24.7% and 87.3 ± 19.0%, respectively. There were significant negative correlations between BTM take and the number of surgeries before BTM application (r = -0.19, p = 0.01), %TBSA and STSG take (r = -0.36, p = <0.001) and significant positive correlations between BTM and STSG take (r = 0.41, p ≤ 0.001) in addition to NPWT and STSG take (r = 0.21, p = 0.01). Multivariate regression analyses showed that a larger number of surgeries prior to BTM application (OR -3.41, 95% CI -6.82, -0.03, p = 0.04) was associated with poorer BTM take. Allograft treatment before BTM application (OR -14.7, 95% CI -23.0, -6.43,p = 0.01) and failed treatment with STSG before BTM application (OR -20.8, 95% CI -36.3, -5.23, p ≤ 0.01) were associated with poorer STSG take, whereas higher BTM take rates were associated with overall higher STSG take (OR -0.15, 95% 0.05, 0.26, p = 0.01). The Meek technique was used in 24 patients and showed similar take rates (BTM: 76.3 ± 28.0%, p = 0.22; STSG: 80.7 ± 21.1, p = 0.07). Conclusions: This study summarizes our findings on the application of a BTM in the context of large burn wounds. The results demonstrate that successful treatment can be achieved even in patients with extensive burns, resulting in satisfying take rates for both the BTM and STSG. The data underscore the importance of promptly applying a BTM to debrided wounds and indicate good results when using Meek.

14.
Artículo en Inglés | MEDLINE | ID: mdl-38753578

RESUMEN

BACKGROUND: Substance use is strongly associated with suicide attempts throughout life. We aimed to investigate the prevalence of suicide attempts (SA) and associated factors in life in patients with Alcohol Use Disorder (AUD). METHODS: The sample consisted of 424 men with AUD who underwent treatment at the Addiction Psychiatry Unit of the Hospital de Clínicas de Porto Alegre. The clinical evaluation included the Addiction Severity Index, the Childhood Trauma Questionnaire, the Barratt Impulsiveness Scale, and the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders. Variables that showed p-value < 0.05 in the bivariate analyses were included in a hierarchical regression model with robust variance to investigate associations with SA in life via estimation of adjusted Prevalence Ratios (PR). RESULTS: The lifetime prevalence of SA among alcohol users was 36.6%. Patients with childhood maltreatment, borderline personality disorder, and higher impulsivity scores had a higher lifetime prevalence of SA. CONCLUSION: Our findings indicate that male inpatient alcoholics present an important prevalence of SA. The study also corroborates the relationship between maltreatment, impulsivity, and borderline personality disorder with SA among inpatients in treatment for AUD.

15.
Commun Biol ; 7(1): 576, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38755409

RESUMEN

Avoidance, a hallmark of anxiety-related psychopathology, often comes at a cost; avoiding threat may forgo the possibility of a reward. Theories predict that optimal approach-avoidance arbitration depends on threat-induced psychophysiological states, like freezing-related bradycardia. Here we used model-based fMRI analyses to investigate whether and how bradycardia states are linked to the neurocomputational underpinnings of approach-avoidance arbitration under varying reward and threat magnitudes. We show that bradycardia states are associated with increased threat-induced avoidance and more pronounced reward-threat value comparison (i.e., a stronger tendency to approach vs. avoid when expected reward outweighs threat). An amygdala-striatal-prefrontal circuit supports approach-avoidance arbitration under threat, with specific involvement of the amygdala and dorsal anterior cingulate (dACC) in integrating reward-threat value and bradycardia states. These findings highlight the role of human freezing states in value-based decision making, relevant for optimal threat coping. They point to a specific role for amygdala/dACC in state-value integration under threat.


Asunto(s)
Imagen por Resonancia Magnética , Humanos , Masculino , Adulto , Femenino , Adulto Joven , Bradicardia/fisiopatología , Reacción de Prevención/fisiología , Amígdala del Cerebelo/fisiología , Recompensa , Giro del Cíngulo/fisiología , Miedo/fisiología , Ansiedad/fisiopatología , Frecuencia Cardíaca/fisiología , Toma de Decisiones/fisiología
16.
Res Sq ; 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38562728

RESUMEN

How do social factors impact the brain and contribute to increased alcohol drinking? We found that social rank predicts alcohol drinking, where subordinates drink more than dominants. Furthermore, social isolation escalates alcohol drinking, particularly impacting subordinates who display a greater increase in alcohol drinking compared to dominants. Using cellular resolution calcium imaging, we show that the basolateral amygdala-medial prefrontal cortex (BLA-mPFC) circuit predicts alcohol drinking in a rank-dependent manner, unlike non-specific BLA activity. The BLA-mPFC circuit becomes hyperexcitable during social isolation, detecting social isolation states. Mimicking the observed increases in BLA-mPFC activity using optogenetics was sufficient to increase alcohol drinking, suggesting the BLA-mPFC circuit may be a neural substrate for the negative impact of social isolation. To test the hypothesis that the BLA-mPFC circuit conveys a signal induced by social isolation to motivate alcohol consumption, we first determined if this circuit detects social information. Leveraging optogenetics in combination with calcium imaging and computer vision pose tracking, we found that BLA-mPFC circuitry governs social behavior and neural representation of social contact. We further show that BLA-mPFC stimulation mimics social isolation-induced mPFC encoding of sucrose and alcohol, and inhibition of the BLA-mPFC circuit decreases alcohol drinking following social isolation. Collectively, these data suggest the amygdala-cortical circuit mirrors a neural encoding state similar to social isolation and underlies social isolation-associated alcohol drinking.

17.
Cancer Discov ; 14(8): 1440-1456, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-38564707

RESUMEN

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.


Asunto(s)
Neoplasias Pulmonares , Mutación Puntual , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-met , Humanos , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Ratones , Línea Celular Tumoral
18.
Alcohol ; 119: 1-5, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38621495

RESUMEN

BACKGROUND: Shortening telomere length (TL) is an important ageing marker associated with substance use disorder (SUD). However, the influence of psychiatric and clinical comorbidities and alcohol-related outcomes has not been much explored in the context of TL in individuals with alcohol use disorder (AUD) and may be a source of heterogeneity in AUD studies. Therefore, our aim was to investigate the influence of AUD, alcohol-related outcomes, and common psychiatric comorbidities on TL in men with AUD and healthy controls (HC). METHODS: Men with AUD (n = 108, mean age = 52.4, SD = 8.6) were recruited in a detoxification unit, and HC (n = 80, mean age = 50.04, SD = 9.1) from the blood bank, both located in Brazil. HC had no current or lifetime diagnosis of any substance use disorder. Psychiatric comorbidities were assessed using SCID-I. TL ratio was measured in triplicates using quantitative multiplex PCR. RESULTS: Telomere length did not differ between individuals with AUD and HC (p = 0.073) or was associated with AUD-related outcomes, trauma, or clinical comorbidities. Individuals with externalizing disorders had longer TL when comparing with those with internalizing disorders (p = 0.018) or without comorbidity (p = 0.018). CONCLUSION: Our findings indicate that TL was influenced by the presence of psychiatric comorbidity rather than case or control status. These results were adjusted for potential confounders, such as age.


Asunto(s)
Alcoholismo , Comorbilidad , Acortamiento del Telómero , Humanos , Masculino , Brasil/epidemiología , Alcoholismo/epidemiología , Alcoholismo/genética , Persona de Mediana Edad , Adulto , Estudios de Casos y Controles , Trastornos Mentales/epidemiología , Trastornos Mentales/genética , Telómero
19.
Vet Clin Pathol ; 53(2): 280-284, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38684480

RESUMEN

BACKGROUND: The current bone marrow (BM) reference intervals (RI) are based on a limited number of cats. Age-related changes in BM variables might be important,possibly affecting the interpretation of the results. OBJECTIVES: Establish BM cytologic reference intervals (RIs) and association of age and sex on these findings, in healthy juvenile and young adult cats. METHODS: BM aspirates of cats deemed healthy based on history and clinical, CBC, serum chemistry findings, and negative retrovirus serology were obtained and examined cytologically. The examination included a 1000-nucleated differential cell count and cell morphologic assessment. RIs were calculated using parametric, robust, and nonparametric methods. The cytologic findings were examined for associations with sex and age. RESULTS: The study included 40 cats (females, 22 [55%]; males, 18 [45%]) with a median age of 1.5 years (range 0.5-5). Most calculated RIs were similar to those previously reported. BM plasma cell and monocyte counts were weakly and positively correlated with age (rs, .312 and .373, respectively; P < .05). Metarubricytes were higher infemales (mean, 25.1%; SD, 6.0%) than males (mean, 21.2%; SD, 6.0%; P < .05). CONCLUSIONS: The BM differential cell counts determined in this study can serve as RIs for cats aged 0.5-5 years.


Asunto(s)
Células de la Médula Ósea , Animales , Gatos , Masculino , Femenino , Valores de Referencia , Células de la Médula Ósea/citología , Factores de Edad , Médula Ósea , Citología
20.
Burns ; 50(6): 1494-1503, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38627164

RESUMEN

BACKGROUND: Burn injuries pose a significant burden on both patients and healthcare systems. Yet, costs arising from the consumption of resources by these patients are rarely examined in Canada. OBJECTIVE: The objective of this study was to assess real-world costs resulting from the initial hospitalization of patients admitted to a major burn unit in Quebec, Canada. METHODS: A cost study based on a retrospective cohort was undertaken using in-hospital economic data matched to hospital chart data. Our cohort included all burn-injured patients admitted between April 1, 2017, and March 31, 2021, to the hospital's major burn unit during their initial hospitalization. Descriptive statistics were tabulated for sociodemographic and economic data. Costing data were analyzed unstratified and stratified according to burn severity (i.e., ≥ 20% of total body surface area [TBSA] vs. < 20%). Costs were presented in CAD 2021. RESULTS: Our cohort included 362 patients, including 65 (18%) with TBSA ≥ 20%. The average initial hospitalization cost was $32,360 ($22,783 for < 20% TBSA and $76,121 for ≥ 20% TBSA). CONCLUSION: Findings reveal that the total cost of the initial hospitalization, from a public hospital perspective, was $11,714,348. Our study underlines the substantial burden associated with burns and highlights the need for long-term cost evaluations.


Asunto(s)
Quemaduras , Costo de Enfermedad , Costos de Hospital , Hospitalización , Humanos , Quemaduras/economía , Quemaduras/terapia , Masculino , Femenino , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Costos de Hospital/estadística & datos numéricos , Anciano , Quebec , Superficie Corporal , Adulto Joven , Unidades de Quemados/economía , Unidades de Quemados/estadística & datos numéricos , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricos , Costos de la Atención en Salud/estadística & datos numéricos , Estudios de Cohortes , Adolescente , Canadá
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