Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 37
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
J Virol ; 97(10): e0095923, 2023 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-37772825

RESUMEN

IMPORTANCE: Viral encephalomyelitis outcome is dependent on host responses to neuronal infection. Interferon (IFN) is an important component of the innate response, and IFN regulatory factor (IRF) 7 is an inducible transcription factor for the synthesis of IFN-α. IRF7-deficient mice develop fatal paralysis after CNS infection with Sindbis virus, while wild-type mice recover. Irf7 -/- mice produce low levels of IFN-α but high levels of IFN-ß with induction of IFN-stimulated genes, so the reason for this difference is not understood. The current study shows that Irf7 -/- mice developed inflammation earlier but failed to clear virus from motor neuron-rich regions of the brainstem and spinal cord. Levels of IFN-γ and virus-specific antibody were comparable, indicating that IRF7 deficiency does not impair expression of these known viral clearance factors. Therefore, IRF7 is either necessary for the neuronal response to currently identified mediators of clearance or enables the production of additional antiviral factor(s) needed for clearance.


Asunto(s)
Infecciones por Alphavirus , Encefalomielitis , Factor 7 Regulador del Interferón , Virus Sindbis , Animales , Ratones , Infecciones por Alphavirus/inmunología , Infecciones por Alphavirus/virología , Tronco Encefálico/virología , Encefalomielitis/inmunología , Encefalomielitis/virología , Inflamación/virología , Factor 7 Regulador del Interferón/deficiencia , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/metabolismo , Interferón beta/inmunología , Interferón beta/metabolismo , Neuronas Motoras/virología , Virus Sindbis/inmunología , Médula Espinal/virología
2.
PLoS Pathog ; 18(5): e1010556, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35576231

RESUMEN

Antibiotic tolerance is typically associated with a phenotypic change within a bacterial population, resulting in a transient decrease in antibiotic susceptibility that can contribute to treatment failure and recurrent infections. Although tolerant cells may emerge prior to treatment, the stress of prolonged antibiotic exposure can also promote tolerance. Here, we sought to determine how Yersinia pseudotuberculosis responds to doxycycline exposure, to then verify if these gene expression changes could promote doxycycline tolerance in culture and in our mouse model of infection. Only four genes were differentially regulated in response to a physiologically-relevant dose of doxycycline: osmB and ompF were upregulated, tusB and cnfy were downregulated; differential expression also occurred during doxycycline treatment in the mouse. ompF, tusB and cnfy were also differentially regulated in response to chloramphenicol, indicating these could be general responses to ribosomal inhibition. cnfy has previously been associated with persistence and was not a major focus here. We found deletion of the OmpF porin resulted in increased antibiotic accumulation, suggesting expression may promote diffusion of doxycycline out of the cell, while OsmB lipoprotein had a minor impact on antibiotic permeability. Overexpression of tusB significantly impaired bacterial survival in culture and in the mouse, suggesting that tRNA modification by tusB, and the resulting impacts on translational machinery, promotes survival during treatment with an antibiotic classically viewed as bacteriostatic. We believe this may be the first observation of bactericidal activity of doxycycline under physiological conditions, which was revealed by reversing tusB downregulation.


Asunto(s)
Yersinia pseudotuberculosis , Animales , Antibacterianos/metabolismo , Antibacterianos/farmacología , Doxiciclina/metabolismo , Doxiciclina/farmacología , Ratones , Permeabilidad , ARN de Transferencia/metabolismo , Yersinia pseudotuberculosis/genética , Yersinia pseudotuberculosis/metabolismo
3.
Arch Sex Behav ; 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38956001

RESUMEN

Feminist considerations have influenced how women and men view sex, affecting not only women's perspectives but also men's feelings about sexual desire with regard to gender equity. This might be especially the case among men who self-identify as feminist. However, how men should manage their sexual desire or communicate about it within relationships with women is not always clear in this evolving social climate. Thus, the current study aimed to explore the successes and/or struggles feminist heterosexual men experience while navigating their desires alongside feminist considerations. To explore this, we recruited feminist-identified heterosexual men in long-term relationships. We asked participants (N = 30) a series of questions regarding their sexual desire, considering the context of their long-term relationships and evolving gender norms, during a one-on-one interview via Zoom. Using thematic analysis, we identified 11 themes from the interview data. We found that, though the feminist men in this study were all aware of negative societal perceptions of heterosexual men's sexual desire, most men in this study did not feel conflicts between their feminist principles and their own sexual desires. This is because they reported already following feminist principles; those who felt ambivalent navigated this by communicating with their partners. Findings demonstrate the usefulness and positive impact men report feminism having on them, their sexuality, and their long-term relationships, by allowing them to better engage with their sexuality and partners.

4.
J Digit Imaging ; 35(3): 534-537, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35169963

RESUMEN

We are among the many that believe that artificial intelligence will not replace practitioners and is most valuable as an adjunct in diagnostic radiology. We suggest a different approach to utilizing the technology, which may help even radiologists who may be averse to adopting AI. A novel method of leveraging AI combines computer vision and natural language processing to ambiently function in the background, monitoring for critical care gaps. This AI Quality workflow uses a visual classifier to predict the likelihood of a finding of interest, such as a lung nodule, and then leverages natural language processing to review a radiologist's report, identifying discrepancies between imaging and documentation. Comparing artificial intelligence predictions with natural language processing report extractions with artificial intelligence in the background of computer-aided detection decisions may offer numerous potential benefits, including streamlined workflow, improved detection quality, an alternative approach to thinking of AI, and possibly even indemnity against malpractice. Here we consider early indications of the potential of artificial intelligence as the ultimate quality assurance for radiologists.


Asunto(s)
Inteligencia Artificial , Radiología , Diagnóstico por Imagen , Humanos , Radiografía , Radiólogos , Radiología/métodos
5.
Intern Med J ; 51(5): 660-665, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-34047037

RESUMEN

BACKGROUND: Oxygen is commonly used in the acute care setting. However, used inappropriately, oxygen therapy can result in adverse consequences, including progressive respiratory failure and death. AIM: To investigate the effectiveness of a targeted intervention to improve prescribing practice and therapeutic application of supplemental oxygen. METHODS: Respiratory, Oncology and Surgery wards were targeted for the intervention. Nursing and junior medical staff from these wards undertook an education programme about safe use of oxygen. Cross-sectional data about oxygen prescribing, administration and monitoring were collected on inpatients in these wards at baseline, and at 3 and 6 months post-intervention, using a modified version of the British Thoracic Society Oxygen Audit Tool. RESULTS: At baseline, there was a written prescription for oxygen in 56% of patients (n = 43) using oxygen and this increased to 75% (n = 44) at 3 months, and remained at 65% (n = 48) at 6 months. However, the increased prescription rates were not statistically significant when compared to baseline (χ2 = 3.54, df = 1, P = 0.06 and χ2 = 0.73, df = 1, P = 0.40, respectively). The observed increase in oxygen prescriptions was driven by the medical wards: Oncology ward at 3 months (χ2 = 8.24, df = 1, P = 0.004); and Respiratory ward at 3 months (χ2 = 3.31, df = 1, P = 0.069) and 6 months (χ2 = 4.98, df = 1, P = 0.026). CONCLUSION: The education programme intervention to improve oxygen prescription showed promise in the medical wards but did not impact outcomes in the surgical ward setting, where different strategies may be needed.


Asunto(s)
Oxígeno , Insuficiencia Respiratoria , Estudios Transversales , Humanos , Terapia por Inhalación de Oxígeno , Estudios Prospectivos , Insuficiencia Respiratoria/terapia
6.
J Labelled Comp Radiopharm ; 64(3): 140-146, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33067810

RESUMEN

Prostate-specific membrane antigen (PSMA)-targeted imaging and therapy of prostate cancer using theranostic pairs is rapidly changing clinical practice. To facilitate clinical trials, fully automated procedures for the radiosyntheses of [68 Ga]Ga-PSMA-11 and [177 Lu]Lu-PSMA-617 were developed from commercially available precursors using the cassette based iPHASE MultiSyn module. Formulated and sterile radiopharmaceuticals were obtained in 76 ± 3% (n = 20) and 91 ± 4% (n = 15) radiochemical yields after 17 and 20 min, respectively. Radiochemical purity was always >95% and molar activities exceeded 792 ± 100 and 88 ± 6 GBq/µmol, respectively. Quality control showed conformity with all relevant release criteria and radiopharmaceuticals were used in the clinic.


Asunto(s)
Dipéptidos , Compuestos Heterocíclicos con 1 Anillo , Antígeno Prostático Específico
7.
J Neuroinflammation ; 17(1): 103, 2020 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-32252790

RESUMEN

BACKGROUND: Mural cells synthesize and deposit laminin to the basement membrane. To investigate the function of mural cell-derived laminin, we generated a mutant mouse line lacking mural cell-derived laminin (termed PKO). In a previous study, we showed that the PKO mice were grossly normal under homeostatic condition, but developed blood-brain barrier (BBB) breakdown with advanced age (> 8 months), suggesting that these mutants are intrinsically weak. Based on these findings, we hypothesized that PKO mice have exacerbated injuries in pathological conditions. METHODS: Using collagenase-induced intracerebral hemorrhage (ICH) as an injury model, we examined various stroke outcomes, including hematoma volume, neurological function, neuronal death, BBB integrity, paracellular/transcellular transport, inflammatory cell infiltration, and brain water content, in PKO mice and their wildtype littermates at young age (6-8 weeks). In addition, transmission electron microscopy (TEM) analysis and an in vitro ICH model were used to investigate the underlying molecular mechanisms. RESULTS: Compared to age-matched wildtype littermates, PKO mice display aggravated stroke outcomes, including larger hematoma size, worse neurological function, increased neuronal cell death, enhanced BBB permeability, increased transcytosis, and elevated inflammatory cell infiltration. These mutants also exhibit high baseline brain water content independent of aquaporin-4 (AQP4). In addition, mural cell-derived laminin significantly reduced caveolin-1 without affecting tight junction proteins in the in vitro ICH model. CONCLUSIONS: These results suggest that mural cell-derived laminin attenuates BBB damage in ICH via decreasing caveolin-1 and thus transcytosis, regulates brain water homeostasis, and plays a beneficial role in ICH.


Asunto(s)
Membrana Basal/metabolismo , Barrera Hematoencefálica/metabolismo , Hemorragia Cerebral/patología , Laminina/metabolismo , Animales , Barrera Hematoencefálica/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transcitosis/fisiología
8.
Tob Control ; 29(2): 183-190, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-30770436

RESUMEN

BACKGROUND: Previous secondhand smoke (SHS) reduction interventions have provided only delayed feedback on reported smoking behaviour, such as coaching, or presenting results from child cotinine assays or air particle counters. DESIGN: This SHS reduction trial assigned families at random to brief coaching and continuous real-time feedback (intervention) or measurement-only (control) groups. PARTICIPANTS: We enrolled 298 families with a resident tobacco smoker and a child under age 14. INTERVENTION: We installed air particle monitors in all homes. For the intervention homes, immediate light and sound feedback was contingent on elevated indoor particle levels, and up to four coaching sessions used prompts and praise contingent on smoking outdoors. Mean intervention duration was 64 days. MEASURES: The primary outcome was 'particle events' (PEs) which were patterns of air particle concentrations indicative of the occurrence of particle-generating behaviours such as smoking cigarettes or burning candles. Other measures included indoor air nicotine concentrations and participant reports of particle-generating behaviour. RESULTS: PEs were significantly correlated with air nicotine levels (r=0.60) and reported indoor cigarette smoking (r=0.51). Interrupted time-series analyses showed an immediate intervention effect, with reduced PEs the day following intervention initiation. The trajectory of daily PEs over the intervention period declined significantly faster in intervention homes than in control homes. Pretest to post-test, air nicotine levels, cigarette smoking and e-cigarette use decreased more in intervention homes than in control homes. CONCLUSIONS: Results suggest that real-time particle feedback and coaching contingencies reduced PEs generated by cigarette smoking and other sources. TRIAL REGISTRATION NUMBER: NCT01634334; Post-results.


Asunto(s)
Contaminación del Aire Interior/análisis , Prevención del Hábito de Fumar/métodos , Contaminación por Humo de Tabaco/análisis , Fumar Tabaco/prevención & control , Adulto , Niño , Preescolar , Retroalimentación , Femenino , Humanos , Lactante , Análisis de Series de Tiempo Interrumpido , Masculino , Tutoría/métodos , Nicotina/análisis , Vapeo/prevención & control , Adulto Joven
9.
J Surg Res ; 235: 131-140, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30691786

RESUMEN

BACKGROUND: Socioeconomic status (SES) and race have been shown to increase the incidence of being afflicted by a traumatic brain injury (TBI) resulting in worse posthospitalization outcomes. The goal of this study was to determine the effect disparities have on in-hospital mortality, discharge to inpatient rehabilitation, hospital length of stay (LOS), and TBI procedures performed stratified by severity of TBI. METHODS: This was a retrospective cohort study of patients with closed head injuries using the National Trauma Data Bank (2012-2015). Multivariate logistic/linear regression models were created to determine the impact of race and insurance status in groups graded by head Abbreviated Injury Scale (AIS). RESULTS: We analyzed 131,461 TBI patients from NTDB. Uninsured patients experienced greater mortality at an AIS of 5 (odds ratio [OR] = 1.052, P = 0.001). Uninsured patients had a decreased likelihood of being discharged to inpatient rehabilitation with an increasing AIS beginning from an AIS of 2 (OR = 0.987, P = 0.008) to an AIS of 5 (OR = 0.879, P < 0.001). Black patients had an increased LOS as their AIS increased from an AIS of 2 (0.153 d, P < 0.001) to 5 (0.984 d, P < 0.001) with the largest discrepancy in LOS occurring at an AIS of 5. CONCLUSIONS: Disparities in race and SES are associated with differences in mortality, LOS, and discharge to inpatient rehabilitation. Patients with more severe TBI have the greatest divergence in treatment and outcome when stratified by race and ethnicity as well as SES.


Asunto(s)
Lesiones Traumáticas del Encéfalo/mortalidad , Disparidades en Atención de Salud , Clase Social , Índices de Gravedad del Trauma , Adulto , Anciano , Anciano de 80 o más Años , Lesiones Traumáticas del Encéfalo/etnología , Femenino , Mortalidad Hospitalaria , Humanos , Cobertura del Seguro , Tiempo de Internación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
11.
Arch Insect Biochem Physiol ; 93(4): 210-221, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27696504

RESUMEN

Green tea has been found to increase the lifespan of various experimental animal models including the fruit fly, Drosophila melanogaster. High in polyphenolic content, green tea has been shown to reduce oxidative stress in part by its ability to bind free iron, a micronutrient that is both essential for and toxic to all living organisms. Due to green tea's iron-binding properties, we questioned whether green tea acts to increase the lifespan of the fruit fly by modulating iron regulators, specifically, mitoferrin, a mitochondrial iron transporter, and transferrin, found in the hemolymph of flies. Publicly available hypomorph mutants for these iron regulators were utilized to investigate the effect of green tea on lifespan and fertility. We identified that green tea could not increase the lifespan of mitoferrin mutants but did rescue the reduced male fertility phenotype. The effect of green tea on transferrin mutant lifespan and fertility were comparable to w1118 flies, as observed in our previous studies, in which green tea increased male fly lifespan and reduced male fertility. Expression levels in both w1118 flies and mutant flies, supplemented with green tea, showed an upregulation of mitoferrin but not transferrin. Total body and mitochondrial iron levels were significantly reduced by green tea supplementation in w1118 and mitoferrin mutants but not transferrin mutant flies. Our results demonstrate that green tea may act to increase the lifespan of Drosophila in part by the regulation of mitoferrin and reduction of mitochondrial iron.


Asunto(s)
Camellia sinensis/química , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiología , Hierro/metabolismo , Polifenoles/metabolismo , Transferrina/genética , Animales , Antioxidantes/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Femenino , Fertilidad/efectos de los fármacos , Longevidad/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Polifenoles/farmacología , Transferrina/metabolismo
13.
mBio ; 15(6): e0073624, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38695564

RESUMEN

Sindbis virus (SINV) infection of mice provides a model system for studying the pathogenesis of alphaviruses that infect the central nervous system (CNS) to cause encephalomyelitis. While studies of human viral infections typically focus on accessible cells from the blood, this compartment is rarely evaluated in mice. To bridge this gap, single-cell RNA sequencing (scRNAseq) was combined with flow cytometry to characterize the transcriptional and phenotypic changes of peripheral blood mononuclear cells (PBMCs) from SINV-infected mice. Twenty-one clusters were identified by scRNAseq at 7 days after infection, with a unique cluster and overall increase in naive B cells for infected mice. Uninfected mice had fewer immature T cells and CCR9+ CD4 T cells and a unique immature T cell cluster. Gene expression was most altered in the Ki67+ CD8 T cell cluster, with chemotaxis and proliferation-related genes upregulated. Global analysis indicated metabolic changes in myeloid cells and increased expression of Ccl5 by NK cells. Phenotypes of PBMCs and cells infiltrating the CNS were analyzed by flow cytometry over 14 days after infection. In PBMCs, CD8 and Th1 CD4 T cells increased in representation, while B cells showed a transient decrease at day 5 in total, Ly6a+, and naive cells, and an increase in activated B cells. In the brain, CD8 T cells increased for the first 7 days, while Th1 CD4 T cells and naive and Ly6a+ B cells continued to accumulate for 14 days. Therefore, dynamic immune cell changes can be identified in the blood as well as the CNS during viral encephalomyelitis. IMPORTANCE: The outcome of viral encephalomyelitis is dependent on the host immune response, with clearance and resolution of infection mediated by the adaptive immune response. These processes are frequently studied in mouse models of infection, where infected tissues are examined to understand the mechanisms of clearance and recovery. However, studies of human infection typically focus on the analysis of cells from the blood, a compartment rarely examined in mice, rather than inaccessible tissue. To close this gap, we used single-cell RNA sequencing and flow cytometry to profile the transcriptomic and phenotypic changes of peripheral blood mononuclear cells (PBMCs) before and after central nervous system (CNS) infection in mice. Changes to T and B cell gene expression and cell composition occurred in PBMC and during entry into the CNS, with CCL5 being a differentially expressed chemokine. Therefore, dynamic changes occur in the blood as well as the CNS during the response of mice to virus infection, which will inform the analysis of human studies.


Asunto(s)
Infecciones por Alphavirus , Leucocitos Mononucleares , Animales , Ratones , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Infecciones por Alphavirus/virología , Infecciones por Alphavirus/inmunología , Infecciones por Alphavirus/genética , Virus Sindbis/genética , Virus Sindbis/inmunología , Ratones Endogámicos C57BL , Fenotipo , Femenino , Modelos Animales de Enfermedad , Encefalitis Viral/inmunología , Encefalitis Viral/virología , Encefalitis Viral/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Análisis de la Célula Individual
14.
Cureus ; 16(5): e61388, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38947652

RESUMEN

Blunt abdominal trauma patients who have had prior bariatric procedures may present a diagnostic and therapeutic challenge. The single anastomosis duodenal-ileal bypass with sleeve (SADI-S) is a modified duodenal switch procedure that is relatively uncommon. This case report describes a patient who previously underwent a SADI-S for the management of obesity and subsequently sustained a seat belt injury in a motor vehicle collision resulting in a laceration of the efferent loop. The patient presented with symptoms of acute abdominal pain and was diagnosed through imaging studies. Prompt surgical intervention was performed with resection and primary anastomosis of the damaged section of the jejunum, and repair of a large mesenteric laceration. We discuss the importance of early recognition and intraoperative decision-making in the case of this patient concerning her SADI-S.

15.
Cureus ; 16(3): e56626, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38646226

RESUMEN

Motor vehicle collisions are a leading cause of morbidity and mortality within the United States. Safety devices such as seatbelts and airbags have significantly reduced mortality rates for drivers. Some drivers personalize their vehicles with inexpensive items that may cause significant injury during vehicular collisions. We present a case of a face and neck penetrating injury from a metal aftermarket rhinestone emblem attached to the steering wheel during a motor vehicle collision. A 43-year-old female was involved in an accident where the airbag had deployed and projected two pieces of the metal emblem at her face and neck. The fragment in the neck was removed at the bedside, while that in the face required removal in the operating room. She recovered well postoperatively and was discharged the same day. This case highlights the potential for the dangers caused by aftermarket rhinestone emblems on steering wheels. We recommend that increased national advisories and legislative actions be considered to limit the use of these emblems.

16.
Respir Med ; 224: 107533, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38355019

RESUMEN

BACKGROUND AND OBJECTIVE: The interstitial lung diseases (ILD) are a heterogenous group of disorders with similar clinical presentation, but widely varying prognoses. The use of a pragmatic disease behaviour classification (DBC), first proposed in international guidelines in 2013, categorises diseases into five behavioural classes based on their predicted clinical course. This study aimed to determine the prognostic utility of the DBC in an ILD cohort. METHODS: Consecutive patients presented at the weekly multidisciplinary meeting (MDM) of a specialist ILD centre were included. MDM consensus was obtained for diagnosis and DBC category (1-5). Baseline and serial clinical and physiological data were collected over the study period (median 3.9 years, range 0-5.4 years). The relationship between DBC and prognostic outcomes was explored. RESULTS: 137 ILD patients, [64 (47%) female] were included with mean age 67.0 ± 1.1 years, baseline FVC% 72.7 ± 1.7, and baseline DLco% 57.8 ± 1.6%. Patients were stratified into DBC by consensus at MDM: DBC1 n = 0 (0%), DBC2 n = 16 (12%), DBC3 n = 10 (7.3%), DBC4 n = 55 (40%), and DBC5 n = 56 (41%). On univariable Cox regression, increasing DBC class was associated with poorer progression-free survival (HR 1.6, 95% CI 1.2-2.0, p < 0.001). On multivariable Cox regression, DBC remained predictive of PFS when combined with age and gender (HR 1.4, 95% CI 1.1-1.9, p = 0.011), baseline FVC% (HR 1.5, 95% CI 1.1-1.8, p = 0.003) and ILD diagnosis (HR 1.6, 95% CI 1.2-2.2, p < 0.0001). CONCLUSION: DBC as determined at ILD multidisciplinary meeting may be a useful prognostic tool for the management of ILD patients.


Asunto(s)
Enfermedades Pulmonares Intersticiales , Humanos , Femenino , Anciano , Masculino , Enfermedades Pulmonares Intersticiales/diagnóstico , Pronóstico , Capacidad Vital , Supervivencia sin Progresión , Pruebas de Función Respiratoria , Pulmón , Estudios Retrospectivos
17.
Cell Death Dis ; 15(4): 246, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38575601

RESUMEN

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF-challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.


Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Sinucleinopatías , Animales , Humanos , Ratones , Ratas , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Neuronas Dopaminérgicas/metabolismo , Mesencéfalo/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Sinucleinopatías/metabolismo , Sinucleinopatías/patología
18.
Am Surg ; 89(1): 88-97, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33877932

RESUMEN

INTRODUCTION: Advanced directives (ADs) provide a framework from which families may understand patient's wishes. However, end-of-life planning may not be prioritized by everyone. This analysis aimed to determine what populations have ADs and how they affected trauma outcomes. METHODS: Adult trauma patients recorded in the American College of Surgeons Trauma Quality Improvement Program (TQIP) from 2013-2015 were included. The primary outcome was presence of an AD. Secondary outcomes included mortality, length of stay (LOS), mechanical ventilation, ICU admission/LOS, withdrawal of life-sustaining measures, and discharge disposition. Multivariable logistic regression models were developed for outcomes. RESULTS: 44 705 patients were included in the analyses. Advanced directives were present in 1.79% of patients. The average age for patients with ADs was 77.8 ± 10.7. African American (odds ratio (OR) .53, confidence intervals [CI] .36-.79) and Asian (OR .22, CI .05-.91) patients were less likely to have ADs. Conversely, Medicaid (OR 1.70, CI 1.06-2.73) and Medicare (OR 1.65, CI 1.25-2.17) patients were more likely to have ADs as compared to those with private insurance. The presence of ADs was associated with increased hospital mortality (OR 2.84, CI 2.19-3.70), increased transition to comfort measures (OR 2.87, CI 2.08-3.95), and shorter LOS (CO -.74, CI -1.26-.22). Patients with ADs had an increased odds of hospice care (OR 4.24, CI 3.18-5.64). CONCLUSION: Advanced directives at admission are uncommon, particularly among African Americans and Asians. The presence of ADs was associated with increased mortality, use of mechanical ventilation, admission to the ICU, withdrawal of life-sustaining measures, and hospice. Future research should target expansion of ADs among minority populations to alleviate disparities in end-of-life treatment.


Asunto(s)
Cuidado Terminal , Adulto , Humanos , Anciano , Estados Unidos , Medicare , Directivas Anticipadas , Cobertura del Seguro , Muerte
19.
JAMA Health Forum ; 3(11): e224149, 2022 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-36399352

RESUMEN

Importance: Buprenorphine is an approved medication for opioid use disorder (MOUD); however, prescribing buprenorphine is limited by a requirement to obtain a waiver to prescribe it (hereinafter, "DATA [Drug Abuse Treatment Act]-waiver") and a lack of knowledge of the best practices among clinicians. Objective: To examine how Project ECHO (Extension for Community Healthcare Outcomes) telementoring is associated with changes in DATA-waiver attainment and buprenorphine prescribing among primary care clinicians in Minnesota. Design, Setting, and Participants: In this retrospective matched-cohort study of 918 clinicians, ECHO-trained clinicians were enrolled on the date they first attended ECHO (January 3, 2018, to June 11, 2020); comparison clinicians were assigned an enrollment date from the distribution of the first ECHO sessions. The baseline period was 12 months preceding enrollment, with follow-up for 18 months or until June 30, 2020. The ECHO-trained clinicians were a population-based sample of primary care clinicians who treated Medicaid patients in Minnesota 12 months prior to the initiation of ECHO training. This analysis used propensity score matching to select comparison clinicians who were similar across demographic and clinical practice characteristics at baseline in a 2:1 ratio. Follow-up was available for 167 ECHO-trained clinicians (54.6%) and 330 comparison clinicians (53.9%) at 18 months. Exposures: ECHO-trained clinicians attended at least 1 weekly, hour-long ECHO session. Comparison clinicians never participated in any ECHO sessions. Main Outcomes and Measures: DATA-waiver attainment, any buprenorphine prescribing, and the percentage of patients with opioid use disorder (OUD) who were prescribed buprenorphine. Results: The final sample included 918 clinicians (ECHO-trained [306]; comparison [612]), of whom 620 (67.5%) practiced outside the metropolitan Twin Cities (Minneapolis-St Paul) region. The mean (SD) age of the ECHO-trained clinicians was 46.0 (12.1) years and that of the comparison clinicians was 45.7 (12.3) years. Relative to the changes among the matched comparison clinicians, the ECHO-trained clinicians were more likely to obtain a DATA-waiver (difference-in-differences, 22.7 percentage points; 95% CI, 15.5-29.9 percentage points; P < .001) and prescribe any buprenorphine (16.5 percentage points; 95% CI, 10.4-22.5 percentage points; P < .001) after 6 quarters of follow-up. ECHO-trained clinicians prescribed buprenorphine to a greater share of patients with OUD (a difference of 7.6 percentage points per month; 95% CI, 4.6-10.6 percentage points per month; P < .001), relative to that prescribed by the comparison clinicians. Conclusions and Relevance: According to the findings of this matched-cohort study, ECHO telementoring may be associated with greater prescribing of buprenorphine by primary care clinicians. These findings suggest that Project ECHO training could be a useful tool for expanding access to MOUD.


Asunto(s)
Buprenorfina , Trastornos Relacionados con Opioides , Humanos , Estados Unidos , Persona de Mediana Edad , Buprenorfina/uso terapéutico , Tratamiento de Sustitución de Opiáceos , Minnesota/epidemiología , Estudios de Cohortes , Estudios Retrospectivos , Pautas de la Práctica en Medicina , Trastornos Relacionados con Opioides/diagnóstico por imagen , Atención Primaria de Salud
20.
Addict Behav ; 125: 107130, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34674905

RESUMEN

PURPOSE OF THE RESEARCH: Early evidence from studies of home smoking policies suggests that in-home cannabis smoking is more often allowed than in-home tobacco smoking, but there are not yet data on whether cannabis is more often smoked in the home compared to tobacco, or whether in-home cannabis and tobacco smoking differs by usage status. Using cross-sectional data from over 100,000 sentinel drug users from 17 countries, we compared cannabis and tobacco smoking in the homes of Global Drug Survey 2019 respondents who currently used cannabis only, tobacco only, both tobacco and cannabis, or neither. PRINCIPAL RESULTS: Complete data on cannabis and tobacco use and in-home smoking were available for 107,272 adults (average age = 30 ± 12, 34% women, countries with the three highest response rates; Germany = 32%, USA = 10%, New Zealand = 9%). In total, 53.6% and 50.6% of respondents reported past-year cannabis and tobacco smoking in their home respectively. Stratifying respondents into current cannabis-only users, tobacco-only users, dual users, and non-users, past-year in-home cannabis smoking was more prevalent (78.8%) among cannabis-only users than was in-home tobacco smoking (67.9%) among tobacco-only users. Among dual users, past-year in-home cannabis smoking (82.8%; 95%CI = 80%-86%) was higher than in-home tobacco smoking (75.9%; 95%CI = 69%-81%; p < 0.001). In-home cannabis and tobacco smoking was similar among non-users (20.2% and 20.5%, respectively). MAJOR CONCLUSIONS: Past-year in-home cannabis smoking was more prevalent than tobacco smoking in the homes of participants who used cannabis and/or tobacco, supporting our speculation that in-home cannabis smoking might be more socially acceptable than in-home tobacco smoking.


Asunto(s)
Fumar Marihuana , Preparaciones Farmacéuticas , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Fumar Marihuana/epidemiología , Encuestas y Cuestionarios , Fumar Tabaco , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA