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1.
Proc Natl Acad Sci U S A ; 121(14): e2314918121, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38527192

RESUMEN

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.


Asunto(s)
Estimulación Encefálica Profunda , Sustancia Blanca , Humanos , Estimulación Encefálica Profunda/métodos , Giro del Cíngulo/fisiología , Cuerpo Calloso , Potenciales Evocados
2.
Differentiation ; 138: 100790, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38908344

RESUMEN

Mutation of the GABRA1 gene is associated with neurodevelopmental defects and epilepsy. GABRA1 encodes for the α1 subunit of the γ-aminobutyric acid type A receptor (GABAAR), which regulates the fast inhibitory impulses of the nervous system. Multiple model systems have been developed to understand the function of GABRA1, but these models have produced complex and, at times, incongruent data. Thus, additional model systems are required to validate and substantiate previous results. We sought to provide initial phenotypic analysis of a novel germline mutant allele. Our analysis provides a solid foundation for the future use of this allele to characterize gabra1 functionally and pharmacologically using zebrafish. We investigated the behavioral swim patterns associated with a nonsense mutation of the zebrafish gabra1 (sa43718 allele) gene. The sa43718 allele causes a decrease in gabra1 mRNA expression, which is associated with light induced hypermotility, one phenotype previously associated with seizure like behavior in zebrafish. Mutation of gabra1 was accompanied by decreased mRNA expression of gabra2, gabra3, and gabra5, indicating a reduction in the expression of additional α sub-units of the GABAAR. Although multiple sub-units were decreased, larvae continued to respond to pentylenetetrazole (PTZ), indicating that a residual GABAAR exists in the sa43718 allele. Proteomics analysis demonstrated that mutation of gabra1 is associated with abnormal expression of proteins that regulate synaptic vesicle fusion, vesicle transport, synapse development, and mitochondrial protein complexes. These data support previous studies performed in a zebrafish nonsense allele created by CRISPR/Cas9 and validate that loss of function mutations in the gabra1 gene result in seizure-like phenotypes with abnormal development of the GABA synapse. Our results add to the existing body of knowledge as to the function of GABRA1 during development and validate that zebrafish can be used to provide complete functional characterization of the gene.


Asunto(s)
Alelos , Receptores de GABA-A , Proteínas de Pez Cebra , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Mutación con Pérdida de Función , Codón sin Sentido/genética , Mutación de Línea Germinal , Fenotipo , Convulsiones/genética , Convulsiones/patología
3.
Biochemistry ; 63(2): 194-201, 2024 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-38154792

RESUMEN

The protein tau misfolds into disease-specific fibrillar structures in more than 20 neurodegenerative diseases collectively referred to as tauopathies. To understand and prevent disease-specific mechanisms of filament formation, in vitro models for aggregation that robustly yield these different end point structures will be necessary. Here, we used cryo-electron microscopy (cryo-EM) to reconstruct fibril polymorphs taken on by residues 297-391 of tau under conditions previously shown to give rise to the core structure found in Alzheimer's disease (AD). While we were able to reconstitute the AD tau core fold, the proportion of these paired helical filaments (PHFs) was highly variable, and a majority of filaments were composed of PHFs with an additional identical C-shaped protofilament attached near the PHF interface, termed triple helical filaments (THFs). Since the impact of filament layer quaternary structure on the biological properties of tau and other amyloid filaments is not known, the applications for samples of this morphology are presently uncertain. We further demonstrate the variation in the proportion of PHFs and PHF-like fibrils compared to other morphologies as a function of shaking time and AD polymorph-favoring cofactor concentration. This variation in polymorph abundance, even under identical experimental conditions, highlights the variation that can arise both within a lab and in different laboratory settings when reconstituting specific fibril polymorphs in vitro.


Asunto(s)
Enfermedad de Alzheimer , Proteínas tau , Humanos , Enfermedad de Alzheimer/metabolismo , Microscopía por Crioelectrón , Ovillos Neurofibrilares/química , Proteínas tau/química , Proteínas tau/genética , Estructura Cuaternaria de Proteína
4.
J Biol Chem ; 299(6): 104715, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37061002

RESUMEN

Trypanosomatids are a diverse group of uniflagellate protozoan parasites that include globally relevant pathogens such as Trypanosoma cruzi, the causative agent of Chagas disease. Trypanosomes lack the fatty acid synthase system typically used for de novo fatty acid (FA) synthesis in other eukaryotes. Instead, these microbes have evolved a modular FA elongase (ELO) system comprised of individual ELO enzymes (ELO1-4) that can operate processively to generate long chain- and very long chain-FAs. The importance of ELO's for maintaining lipid homeostasis in trypanosomatids is currently unclear, given their ability to take up and utilize exogenous FAs for lipid synthesis. To assess ELO function in T. cruzi, we generated individual KO lines, Δelo1, Δelo2, and Δelo3, in which the genes encoding ELO1-3 were functionally disrupted in the parasite insect stage (epimastigote). Using unbiased lipidomic and metabolomic analyses, in combination with metabolic tracing and biochemical approaches, we demonstrate that ELO2 and ELO3 are required for global lipid homeostasis, whereas ELO1 is dispensable for this function. Instead, ELO1 activity is needed to sustain mitochondrial activity and normal growth in T. cruzi epimastigotes. The cross-talk between microsomal ELO1 and the mitochondrion is a novel finding that, we propose, merits further examination of the trypanosomatid ELO pathway as critical for central metabolism.


Asunto(s)
Enfermedad de Chagas , Trypanosoma cruzi , Humanos , Trypanosoma cruzi/genética , Trypanosoma cruzi/metabolismo , Elongasas de Ácidos Grasos/metabolismo , Enfermedad de Chagas/genética , Enfermedad de Chagas/metabolismo , Homeostasis , Mitocondrias/genética , Mitocondrias/metabolismo , Lípidos
5.
Clin Infect Dis ; 2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38465976

RESUMEN

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

6.
J Neurophysiol ; 132(1): 136-146, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38863430

RESUMEN

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease, but its mechanisms of action remain unclear. Detailed multicompartment computational models of STN neurons are often used to study how DBS electric fields modulate the neurons. However, currently available STN neuron models have some limitations in their biophysical realism. In turn, the goal of this study was to update a detailed rodent STN neuron model originally developed by Gillies and Willshaw in 2006. Our design requirements consisted of explicitly representing an axon connected to the neuron and updating the ion channel distributions based on the experimental literature to match established electrophysiological features of rodent STN neurons. We found that adding an axon to the STN neuron model substantially altered its firing characteristics. We then used a genetic algorithm to optimize biophysical parameters of the model. The updated model exhibited spontaneous firing, action potential shape, hyperpolarization response, and frequency-current curve that aligned well with experimental recordings from STN neurons. Subsequently, we evaluated the general compatibility of the updated biophysics by applying them to 26 different STN neuron morphologies derived from three-dimensional anatomical reconstructions. The different morphologies affected the firing behavior of the model, but the updated biophysics were robustly capable of maintaining the desired electrophysiological features. The new STN neuron model developed in this work offers a valuable tool for studying STN neuron firing properties and may find application in simulating STN local field potentials and analyzing the effects of STN DBS.NEW & NOTEWORTHY This study presents an anatomically and biophysically realistic rodent STN neuron model. The work showcases the use of a genetic algorithm to optimize the model parameters. We noted a substantial influence of the axon on the electrophysiological characteristics of STN neurons. The updated model offers a valuable tool to investigate the firing of STN neurons and their modulation by intrinsic and/or extrinsic factors.


Asunto(s)
Potenciales de Acción , Modelos Neurológicos , Neuronas , Núcleo Subtalámico , Núcleo Subtalámico/fisiología , Núcleo Subtalámico/citología , Animales , Neuronas/fisiología , Potenciales de Acción/fisiología , Ratas , Axones/fisiología , Estimulación Encefálica Profunda
7.
N Engl J Med ; 385(1): 23-34, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34133855

RESUMEN

BACKGROUND: The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. METHODS: We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. RESULTS: A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis. CONCLUSIONS: Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Glucocorticoides/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Disfunción Ventricular Izquierda/prevención & control , Adolescente , COVID-19/complicaciones , COVID-19/inmunología , COVID-19/mortalidad , Niño , Preescolar , Estudios de Cohortes , Terapia Combinada , Quimioterapia Combinada , Femenino , Hospitalización , Humanos , Inmunomodulación , Lactante , Modelos Logísticos , Masculino , Puntaje de Propensión , Vigilancia en Salud Pública , Choque/etiología , Choque/prevención & control , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/mortalidad , Resultado del Tratamiento , Disfunción Ventricular Izquierda/etiología , Adulto Joven
8.
Mov Disord ; 39(3): 539-545, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38321526

RESUMEN

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or ventral intermediate nucleus (VIM) are established targets for the treatment of Parkinson's disease (PD) or essential tremor (ET), respectively. However, DBS of the zona incerta (ZI) can be effective for both disorders. VIM DBS is assumed to achieve its therapeutic effect via activation of the cerebellothalamic (CBT) pathway, whereas the activation of the hyperdirect (HD) pathway likely plays a role in the mechanisms of STN DBS. Interestingly, HD pathway axons also emit collaterals to the ZI and red nucleus (RN) and the CBT pathway courses nearby to the ZI. OBJECTIVE: The aim was to examine the ability of ZI DBS to mutually activate the HD and CBT pathways in a detailed computational model of human DBS. METHODS: We extended a previous model of the human HD pathway to incorporate axon collaterals to the ZI and RN. The anatomical framework of the model system also included representations of the CBT pathway and internal capsule (IC) fibers of passage. We then performed detailed biophysical simulations to quantify DBS activation of the HD, CBT, and IC pathways with electrodes located in either the STN or ZI. RESULTS: STN DBS and ZI DBS both robustly activated the HD pathway. However, STN DBS was limited by IC activation at higher stimulus amplitudes. Alternatively, ZI DBS avoided IC activation while simultaneously activating the HD and CBT pathways. CONCLUSIONS: From both neuroanatomical and biophysical perspectives, ZI DBS represents an advantageous target for coupled activation of the HD and CBT pathways. © 2024 International Parkinson and Movement Disorder Society.


Asunto(s)
Estimulación Encefálica Profunda , Temblor Esencial , Enfermedad de Parkinson , Núcleo Subtalámico , Zona Incerta , Humanos , Núcleo Subtalámico/fisiología , Enfermedad de Parkinson/terapia , Temblor Esencial/terapia
9.
Cerebellum ; 23(2): 554-569, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37308757

RESUMEN

Perception of our linear motion - heading - is critical for postural control, gait, and locomotion, and it is impaired in Parkinson's disease (PD). Deep brain stimulation (DBS) has variable effects on vestibular heading perception, depending on the location of the electrodes within the subthalamic nucleus (STN). Here, we aimed to find the anatomical correlates of heading perception in PD. Fourteen PD participants with bilateral STN DBS performed a two-alternative forced-choice discrimination task where a motion platform delivered translational forward movements with a heading angle varying between 0 and 30° to the left or to the right with respect to the straight-ahead direction. Using psychometric curves, we derived the heading discrimination threshold angle of each patient from the response data. We created patient-specific DBS models and calculated the percentages of stimulated axonal pathways that are anatomically adjacent to the STN and known to play a major role in vestibular information processing. We performed correlation analyses to investigate the extent of these white matter tracts' involvement in heading perception. Significant positive correlations were identified between improved heading discrimination for rightward heading and the percentage of activated streamlines of the contralateral hyperdirect, pallido-subthalamic, and subthalamo-pallidal pathways. The hyperdirect pathways are thought to provide top-down control over STN connections to the cerebellum. In addition, STN may also antidromically activate collaterals of hyperdirect pathway that projects to the precerebellar pontine nuclei. In select cases, there was strong activation of the cerebello-thalamic projections, but it was not consistently present in all participants. Large volumetric overlap between the volume of tissue activation and the STN in the left hemisphere positively impacted rightward heading perception. Altogether, the results suggest heavy involvement of basal ganglia cerebellar network in STN-induced modulation of vestibular heading perception in PD.


Asunto(s)
Estimulación Encefálica Profunda , Percepción de Movimiento , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/terapia , Estimulación Encefálica Profunda/métodos , Núcleo Subtalámico/fisiología , Tálamo
10.
Org Biomol Chem ; 22(2): 202-227, 2024 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-38018443

RESUMEN

Imines are a versatile class of chemicals with applications in pharmaceuticals and as synthetic intermediates. While imines are conventionally synthesized via aldehyde-amine condensation, their direct preparation from amines can avoid the need for the independent preparation of the aldehyde coupling partner and associated constraints with regard to aldehyde storage and purification. The direct preparation of imines from amines typically utilizes transition metal catalysis and is often well-aligned with green chemistry principles. This review provides a comprehensive overview of transition metal catalysed imine synthesis, with a particular focus on the copper-catalyzed oxidative coupling of amines. The emerging application of micellar catalysis for imine synthesis is also surveyed due to its potential to avoid the use of hazardous solvents and intensify these reactions through reduced catalyst loadings and locally increased reactant concentrations. Future directions relating to the confluence of these two areas are proposed towards the more sustainable preparation of imines.

11.
Surg Endosc ; 38(2): 964-974, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37964093

RESUMEN

OBJECTIVE: With the increased adoption of robotic pancreaticoduodenectomy, the effects of unplanned conversions to an 'open' operation are ill-defined. This study aims to describe the impact of unplanned conversions of robotic pancreaticoduodenectomy on short-term outcomes and suggest a stepwise approach for safe unplanned conversions during robotic pancreaticoduodenectomy. METHODS: This is an analysis of 400 consecutive patients undergoing robotic pancreaticoduodenectomy in a single high-volume institution. Data are presented as median (mean ± SD), and significance is accepted with 95% probability. RESULTS: Between November 2012 and February 2023, 184 (46%) women and 216 (54%) men, aged 70 (68 ± 11.0) years, underwent a robotic pancreaticoduodenectomy. Unplanned conversions occurred in 42 (10.5%) patients; 18 (5%) were converted due to unanticipated vascular involvement, 13 (3%) due to failure to obtain definitive control of bleeding, and 11 (3%) due to visceral obesity. Men were more likely to require a conversion than women (29 vs. 13, p = 0.05). Conversions were associated with shorter operative time (376 (323 ± 182.2) vs. 434 (441 ± 98.7) min, p < 0.0001) but higher estimated blood loss (675 (1010 ± 1168.1) vs. 150 (196 ± 176.8) mL, p < 0.0001). Patients that required an unplanned conversion had higher rates of complications with Clavien-Dindo scores of III-V (31% vs. 12%, p = 0.003), longer length of stay (8 (11 ± 11.6) vs. 5 (7 ± 6.2), p = 0.0005), longer ICU length of stay (1 (2 ± 5.1) vs. 0 (0 ± 1.3), p < 0.0001) and higher mortality rates (21% vs. 4%, p = 0.0001). The conversion rate significantly decreased over time (p < 0.0001). CONCLUSIONS: Unplanned conversions of robotic pancreaticoduodenectomy significantly and negatively affect short-term outcomes, including postoperative mortality. Men were more likely to require a conversion than women. The unplanned conversions rates significantly decreased over time, implying that increased proficiency and patient selection may prevent unplanned conversions. An unplanned conversion should be undertaken in an organized stepwise approach to maximize patient safety.


Asunto(s)
Laparoscopía , Procedimientos Quirúrgicos Robotizados , Robótica , Masculino , Humanos , Femenino , Procedimientos Quirúrgicos Robotizados/efectos adversos , Pancreaticoduodenectomía/efectos adversos , Estudios Retrospectivos , Tempo Operativo , Tiempo de Internación , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Laparoscopía/efectos adversos
12.
Tetrahedron Lett ; 1452024 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-39036418

RESUMEN

The synthesis of a new homogeneous reductant based on 4,4'-tBu2-2,2'-bipyridine, tBu-OED4, is reported. tBu-OED4 was prepared on a multigram scale in two steps from inexpensive and commercially available starting materials, with no chromatography required for purification. tBu-OED4 has a reduction potential of -1.33 V (vs Ferrocenium/Ferrocene) and is soluble in a range of common organic solvents. We demonstrate that tBu-OED4 can facilitate Ni/Co dual-catalyzed C(sp2)-C(sp3) cross-electrophile coupling reactions and is highly functional group tolerant. tBu-OED4 is expected to be a valuable addition to the set of homogeneous reductants available for organic transformations.

13.
Artículo en Inglés | MEDLINE | ID: mdl-38965736

RESUMEN

AIM: This study aimed to determine adherence with follow-up from the New Zealand pre-school vision screening programme. The study also examined associations between pre-school vision screening outcomes and cognitive measures assessed at the 54-month follow-up in the Growing Up in New Zealand study cohort. METHODS: A cross-sectional retrospective record review of pre-school vision screening outcomes and hospital ophthalmology records with linkage to Growing Up in New Zealand cohort study data. RESULTS: Of 176 children referred from vision screening, 21.6% did not attend a referral appointment. Of 138 children who attended a referral appointment, 21.0% did not attend one or more follow-up appointments. Ethnic differences were observed in attendance at referral appointments (attended Maori 13%, Pacific 22.5%, European/Other 64.5%; not attended Maori 26.3%, Pacific 28.9%, European/Other 44.7%; P = 0.04) and follow-up appointments (attended Maori 11.9%, Pacific 15.6%, European/Other 72.5%; not attended Maori 17.2%, Pacific 48.3%, European/Other 34.5%; P = 0.001). Vision screening outcome was significantly associated with letter naming fluency scores (P = 0.01) but not name and numbers scores (P = 0.05). CONCLUSIONS: Non-attendance at referral and follow-up appointments limits the efficacy of vision screening, particularly for children of Maori and Pacific ethnicity. Children referred from vision screening achieve lower scores on letter naming fluency, a key predictor of reading ability in later childhood. Equity-based improvements are required to ensure that all children referred from vision screening receive appropriate follow-up eye care.

14.
J Oral Maxillofac Surg ; 82(5): 554-562, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38403271

RESUMEN

BACKGROUND: There is a lack of consensus on the optimal triage pathway for emergency department (ED) patients with mandibular fractures. It remains unclear if patient insurance payers predict hospital admission given potentially competing logistical and health system incentives. PURPOSE: To generate nationally representative estimates of the frequency of hospital admission and its association with primary insurance payers for ED patients with mandible fractures. METHODS: This retrospective cohort study used the 2018 Nationwide Emergency Department Sample, the largest all-payer database in the United States, to identify patients with mandible fractures. The database includes a stratified sample with discharge weights to generate nationally representative estimates. Patients with other facial fractures and/or concomitant injuries that independently warranted admission were excluded. PREDICTOR: The primary predictor variable was primary payer (public, private, self-pay, and other/no charge). OUTCOME VARIABLE: The primary outcome variable was hospital admission (yes/no). COVARIATES: Covariates included patient-, medical/injury-, and hospital-related variables. ANALYSES: Descriptive statistics, along with bivariate and multivariate logistic regression with Bonferroni correction, were used to produce national estimates and identify predictors of admission. P < .01 was considered significant. RESULTS: The cohort included 27,238 weighted encounters involving isolated mandible fractures, of which 5,345(20%) were admitted. The payers for admitted patients were 46% public, 25% private, 22% self-pay, and 7% no charge/other. In bivariate analyses, public insurance was associated with a higher likelihood of admission than private insurance (RR 1.24, 95% CI 1.06 to 1.45), though there was no association in the multivariate model (OR 1.03, 95% CI 0.83 to 1.28). In multivariate analysis, higher Charlson Comorbidity Index (OR 1.32, 95% CI 1.18 to 1.48), alcohol-related disorder (OR 3.47, 95% CI 2.74 to 4.39), substance-related disorder (OR 1.43, 95% CI 1.20 to 1.71), and more mandible fractures (OR 3.08, 95% CI 2.65 to 3.59) were associated with admission. Compared to body fractures, subcondylar (OR 3.83, 95% CI 2.39 to 6.14), angle (OR 3.53, 95% CI 2.84 to 6.09), and symphysis (OR 4.14, 95% CI 2.84 to 6.09) fractures had higher odds of admission. Finally, level I (OR 4.11, 95% CI 2.41 to 6.98) and level II (OR 3.16, 95% CI 1.85 to 5.39) trauma centers had higher odds of admission. CONCLUSIONS: In 2018, 20% of ED patients with isolated mandible fractures were admitted. Several patient and hospital characteristics were predictors of admission. Insurance status was not associated with admission.


Asunto(s)
Servicio de Urgencia en Hospital , Fracturas Mandibulares , Humanos , Fracturas Mandibulares/economía , Fracturas Mandibulares/epidemiología , Fracturas Mandibulares/terapia , Servicio de Urgencia en Hospital/estadística & datos numéricos , Estudios Retrospectivos , Femenino , Masculino , Estados Unidos , Adulto , Persona de Mediana Edad , Seguro de Salud/estadística & datos numéricos , Admisión del Paciente/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Hospitalización/economía , Anciano , Adolescente , Adulto Joven , Cobertura del Seguro/estadística & datos numéricos
15.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-34521756

RESUMEN

Viscoelastic flows through porous media become unstable and chaotic beyond critical flow conditions, impacting widespread industrial and biological processes such as enhanced oil recovery and drug delivery. Understanding the influence of the pore structure or geometry on the onset of flow instability can lead to fundamental insights into these processes and, potentially, to their optimization. Recently, for viscoelastic flows through porous media modeled by arrays of microscopic posts, Walkama et al. [D. M. Walkama, N. Waisbord, J. S. Guasto, Phys. Rev. Lett 124, 164501 (2020)] demonstrated that geometric disorder greatly suppressed the strength of the chaotic fluctuations that arose as the flow rate was increased. However, in that work, disorder was only applied to one originally ordered configuration of posts. Here, we demonstrate experimentally that, given a slightly modified ordered array of posts, introducing disorder can also promote chaotic fluctuations. We provide a unifying explanation for these contrasting results by considering the effect of disorder on the occurrence of stagnation points exposed to the flow field, which depends on the nature of the originally ordered post array. This work provides a general understanding of how pore geometry affects the stability of viscoelastic porous media flows.

16.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33468674

RESUMEN

The global incidence of tuberculosis remains unacceptably high, with new preventative strategies needed to reduce the burden of disease. We describe here a method for the generation of synthetic self-adjuvanted protein vaccines and demonstrate application in vaccination against Mycobacterium tuberculosis Two vaccine constructs were designed, consisting of full-length ESAT6 protein fused to the TLR2-targeting adjuvants Pam2Cys-SK4 or Pam3Cys-SK4 These were produced by chemical synthesis using a peptide ligation strategy. The synthetic self-adjuvanting vaccines generated powerful local CD4+ T cell responses against ESAT6 and provided significant protection in the lungs from virulent M. tuberculosis aerosol challenge when administered to the pulmonary mucosa of mice. The flexible synthetic platform we describe, which allows incorporation of adjuvants to multiantigenic vaccines, represents a general approach that can be applied to rapidly assess vaccination strategies in preclinical models for a range of diseases, including against novel pandemic pathogens such as SARS-CoV-2.


Asunto(s)
Mycobacterium tuberculosis/inmunología , Vacunas contra la Tuberculosis/farmacología , Tuberculosis/inmunología , Tuberculosis/prevención & control , Vacunas Conjugadas/farmacología , Adyuvantes Inmunológicos/farmacología , Animales , Antígenos Bacterianos/inmunología , Vacuna BCG/inmunología , Vacuna BCG/farmacología , Proteínas Bacterianas , Linfocitos T CD4-Positivos/inmunología , COVID-19/prevención & control , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , SARS-CoV-2/inmunología , Receptor Toll-Like 2/inmunología , Vacunas contra la Tuberculosis/inmunología , Vacunas Conjugadas/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/farmacología
17.
Proc Natl Acad Sci U S A ; 118(34)2021 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-34417313

RESUMEN

When displayed on erythrocytes, peptides and proteins can drive antigen-specific immune tolerance. Here, we investigated a straightforward approach based on erythrocyte binding to promote antigen-specific tolerance to both peptides and proteins. We first identified a robust erythrocyte-binding ligand. A pool of one million fully d-chiral peptides was injected into mice, blood cells were isolated, and ligands enriched on these cells were identified using nano-liquid chromatography-tandem mass spectrometry. One round of selection yielded a murine erythrocyte-binding ligand with an 80 nM apparent dissociation constant, Kd We modified an 83-kDa bacterial protein and a peptide antigen derived from ovalbumin (OVA) with the identified erythrocyte-binding ligand. An administration of the engineered bacterial protein led to decreased protein-specific antibodies in mice. Similarly, mice given the engineered OVA-derived peptide had decreased inflammatory anti-OVA CD8+ T cell responses. These findings suggest that our tolerance-induction strategy is applicable to both peptide and protein antigens and that our in vivo selection strategy can be used for de novo discovery of robust erythrocyte-binding ligands.


Asunto(s)
Antígenos/genética , Antígenos/metabolismo , Eritrocitos/metabolismo , Ingeniería de Proteínas/métodos , Animales , Antígenos/química , Línea Celular , Bases de Datos Factuales , Femenino , Tolerancia Inmunológica , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Unión Proteica
18.
Neuromodulation ; 27(3): 422-439, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37204360

RESUMEN

BACKGROUND: Deep brain stimulation (DBS) has revolutionized the treatment of neurological disorders, yet the mechanisms of DBS are still under investigation. Computational models are important in silico tools for elucidating these underlying principles and potentially for personalizing DBS therapy to individual patients. The basic principles underlying neurostimulation computational models, however, are not well known in the clinical neuromodulation community. OBJECTIVE: In this study, we present a tutorial on the derivation of computational models of DBS and outline the biophysical contributions of electrodes, stimulation parameters, and tissue substrates to the effects of DBS. RESULTS: Given that many aspects of DBS are difficult to characterize experimentally, computational models have played an important role in understanding how material, size, shape, and contact segmentation influence device biocompatibility, energy efficiency, the spatial spread of the electric field, and the specificity of neural activation. Neural activation is dictated by stimulation parameters including frequency, current vs voltage control, amplitude, pulse width, polarity configurations, and waveform. These parameters also affect the potential for tissue damage, energy efficiency, the spatial spread of the electric field, and the specificity of neural activation. Activation of the neural substrate also is influenced by the encapsulation layer surrounding the electrode, the conductivity of the surrounding tissue, and the size and orientation of white matter fibers. These properties modulate the effects of the electric field and determine the ultimate therapeutic response. CONCLUSION: This article describes biophysical principles that are useful for understanding the mechanisms of neurostimulation.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedades del Sistema Nervioso , Humanos , Modelos Neurológicos , Simulación por Computador , Electrodos , Encéfalo/fisiología
19.
Neuromodulation ; 27(3): 455-463, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37097269

RESUMEN

BACKGROUND: Subthalamic deep brain stimulation (DBS) is an established clinical therapy, but an anatomically clear definition of the underlying neural target(s) of the stimulation remains elusive. Patient-specific models of DBS are commonly used tools in the search for stimulation targets, and recent iterations of those models are focused on characterizing the brain connections that are activated by DBS. OBJECTIVE: The goal of this study was to quantify axonal pathway activation in the subthalamic region from DBS at different electrode locations and stimulation settings. MATERIALS AND METHODS: We used an anatomically and electrically detailed computational model of subthalamic DBS to generate recruitment curves for eight different axonal pathways of interest, at three generalized DBS electrode locations in the subthalamic nucleus (STN) (ie, central STN, dorsal STN, posterior STN). These simulations were performed with three levels of DBS electrode localization uncertainty (ie, 0.5 mm, 1.0 mm, 1.5 mm). RESULTS: The recruitment curves highlight the diversity of pathways that are theoretically activated with subthalamic DBS, in addition to the dependence of the stimulation location and parameter settings on the pathway activation estimates. The three generalized DBS locations exhibited distinct pathway recruitment curve profiles, suggesting that each stimulation location would have a different effect on network activity patterns. We also found that the use of anodic stimuli could help limit activation of the internal capsule relative to other pathways. However, incorporating realistic levels of DBS electrode localization uncertainty in the models substantially limits their predictive capabilities. CONCLUSIONS: Subtle differences in stimulation location and/or parameter settings can impact the collection of pathways that are activated during subthalamic DBS.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Axones , Electrodos
20.
Int J Mol Sci ; 25(9)2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38731959

RESUMEN

Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.


Asunto(s)
Biomarcadores , Hemangioma Cavernoso del Sistema Nervioso Central , Hemangioma Cavernoso del Sistema Nervioso Central/sangre , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico , Humanos , Animales , Ratones , Pronóstico , Biomarcadores/sangre , Proteómica/métodos , Hemorragia Cerebral/sangre , Hemorragia Cerebral/diagnóstico , Proteína KRIT1/sangre , Modelos Animales de Enfermedad , Femenino , Masculino
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