RESUMO
To build a just, equitable, and diverse academy, scientists and institutions must address systemic barriers that sex and gender minorities face. This Commentary summarizes (1) critical context informing the contemporary oppression of transgender people, (2) how this shapes extant research on sex and gender, and (3) actions to build an inclusive and rigorous academy for all.
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Minorias Sexuais e de Gênero , Pessoas Transgênero , Masculino , Feminino , Humanos , Identidade de GêneroRESUMO
Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed â¼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
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Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Potenciação de Longa Duração/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/metabolismo , Potenciais de Ação/fisiologia , Processamento Alternativo/genética , Processamento Alternativo/fisiologia , Animais , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Feminino , Células HEK293 , Homeostase/fisiologia , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/fisiologia , Antígeno Neuro-Oncológico Ventral , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Proteínas de Ligação a RNA/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sinapses/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
The socially monogamous prairie vole (Microtus ochrogaster) and promiscuous meadow vole (Microtus pennsylvanicus) are closely related, but only prairie voles display long-lasting pair bonds, biparental care, and selective aggression towards unfamiliar individuals after pair bonding. These social behaviors in mammals are largely mediated by steroid hormone signaling in the social behavior network (SBN) of the brain. Hormone receptors are reproducible markers of sex differences that can provide more information than anatomy alone and can even be at odds with anatomical dimorphisms. We reasoned that behaviors associated with social monogamy in prairie voles may emerge in part from unique expression patterns of steroid hormone receptors in this species, and that these expression patterns would be more similar across males and females in prairie than in meadow voles or the laboratory mouse. To obtain insight into steroid hormone signaling in the developing prairie vole brain, we assessed expression of estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), and androgen receptor (Ar) within the SBN, using in situ hybridization at postnatal day 14 in mice, meadow, and prairie voles. We found species-specific patterns of hormone receptor expression in the hippocampus and ventromedial hypothalamus, as well as species differences in the sex bias of these markers in the principal nucleus of the bed nucleus of the stria terminalis. These findings suggest the observed differences in gonadal hormone receptor expression may underlie species differences in the display of social behaviors.
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Encéfalo , Pradaria , Feminino , Animais , Masculino , Camundongos , Encéfalo/metabolismo , Comportamento Social , Arvicolinae/metabolismo , Hormônios/metabolismo , Hormônios Gonadais/metabolismo , Esteroides/metabolismoRESUMO
Sex is ubiquitous and variable throughout the animal kingdom. Historically, scientists have used reductionist methodologies that rely on a priori sex categorizations, in which two discrete sexes are inextricably linked with gamete type. However, this binarized operationalization does not adequately reflect the diversity of sex observed in nature. This is due, in part, to the fact that sex exists across many levels of biological analysis, including genetic, molecular, cellular, morphological, behavioral, and population levels. Furthermore, the biological mechanisms governing sex are embedded in complex networks that dynamically interact with other systems. To produce the most accurate and scientifically rigorous work examining sex in neuroendocrinology and to capture the full range of sex variability and diversity present in animal systems, we must critically assess the frameworks, experimental designs, and analytical methods used in our research. In this perspective piece, we first propose a new conceptual framework to guide the integrative study of sex. Then, we provide practical guidance on research approaches for studying sex-associated variables, including factors to consider in study design, selection of model organisms, experimental methodologies, and statistical analyses. We invite fellow scientists to conscientiously apply these modernized approaches to advance our biological understanding of sex and to encourage academically and socially responsible outcomes of our work. By expanding our conceptual frameworks and methodological approaches to the study of sex, we will gain insight into the unique ways that sex exists across levels of biological organization to produce the vast array of variability and diversity observed in nature.
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Neuroendocrinologia , Sexo , Animais , Neuroendocrinologia/métodosRESUMO
BACKGROUND AND PURPOSE: Three-dimensional (3D) imaging of the spine, augmented with AI-enabled image enhancement and denoising, has the potential to reduce imaging times without compromising image quality or diagnostic performance. This work evaluates the time savings afforded by a novel, rapid lumbar spine MRI protocol as well as image quality and diagnostic differences stemming from the use of an AI-enhanced 3D T2 sequence combined with a single Dixon acquisition. MATERIALS AND METHODS: Thirty-five subjects underwent MRI using standard 2D lumbar imaging in addition to a "rapid protocol" consisting of 3D imaging, enhanced and denoised using a prototype DL reconstruction algorithm as well as a two-point Dixon sequence. Images were graded by subspecialized radiologists and imaging times were collected. Comparison was made between 2D sagittal T1 and Dixon fat images for neural foraminal stenosis, intraosseous lesions, and fracture detection. RESULTS: This study demonstrated a 54% reduction in total acquisition time of a 3D AI-enhanced imaging lumbar spine MRI rapid protocol combined with a sagittal 2D Dixon sequence, compared to a 2D standard-of-care protocol. The rapid protocol also demonstrated strong agreement with the standard-of-care protocol with respect to osseous lesions (κ = 0.88), fracture detection (κ = 0.96), and neural foraminal stenosis (ICC > 0.9 at all levels). CONCLUSION: 3D imaging of the lumbar spine with AI-enhanced DL reconstruction and Dixon imaging demonstrated a significant reduction in imaging time with similar performance for common diagnostic metrics. Although previously limited by long postprocessing times, this technique has the potential to enhance patient throughput in busy radiology practices while providing similar or improved image quality.
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Aprendizado Profundo , Imageamento Tridimensional , Humanos , Imageamento Tridimensional/métodos , Constrição Patológica , Imageamento por Ressonância Magnética/métodos , Aumento da Imagem/métodosRESUMO
OBJECTIVES: To compare interobserver agreement and image quality of 3D T2-weighted fast spin echo (T2w-FSE) L-spine MRI images processed with a deep learning reconstruction (DLRecon) against standard-of-care (SOC) reconstruction, as well as against 2D T2w-FSE images. The hypothesis was that DLRecon 3D T2w-FSE would afford improved image quality and similar interobserver agreement compared to both SOC 3D and 2D T2w-FSE. METHODS: Under IRB approval, patients who underwent routine 3-T lumbar spine (L-spine) MRI from August 17 to September 17, 2020, with both isotropic 3D and 2D T2w-FSE sequences, were retrospectively included. A DLRecon algorithm, with denoising and sharpening properties was applied to SOC 3D k-space to generate 3D DLRecon images. Four musculoskeletal radiologists blinded to reconstruction status evaluated randomized images for motion artifact, image quality, central/foraminal stenosis, disc degeneration, annular fissure, disc herniation, and presence of facet joint cysts. Inter-rater agreement for each graded variable was evaluated using Conger's kappa (κ). RESULTS: Thirty-five patients (mean age 58 ± 19, 26 female) were evaluated. 3D DLRecon demonstrated statistically significant higher median image quality score (2.0/2) when compared to SOC 3D (1.0/2, p < 0.001), 2D axial (1.0/2, p < 0.001), and 2D sagittal sequences (1.0/2, p value < 0.001). κ ranges (and 95% CI) for foraminal stenosis were 0.55-0.76 (0.32-0.86) for 3D DLRecon, 0.56-0.73 (0.35-0.84) for SOC 3D, and 0.58-0.71 (0.33-0.84) for 2D. Mean κ (and 95% CI) for central stenosis at L4-5 were 0.98 (0.96-0.99), 0.97 (0.95-0.99), and 0.98 (0.96-0.99) for 3D DLRecon, 3D SOC and 2D, respectively. CONCLUSIONS: DLRecon 3D T2w-FSE L-spine MRI demonstrated higher image quality and similar interobserver agreement for graded variables of interest when compared to 3D SOC and 2D imaging. KEY POINTS: ⢠3D DLRecon T2w-FSE isotropic lumbar spine MRI provides improved image quality when compared to 2D MRI, with similar interobserver agreement for clinical evaluation of pathology. ⢠3D DLRecon images demonstrated better image quality score (2.0/2) when compared to standard-of-care (SOC) 3D (1.0/2), p value < 0.001; 2D axial (1.0/2), p value < 0.001; and 2D sagittal sequences (1.0/2), p value < 0.001. ⢠Interobserver agreement for major variables of interest was similar among all sequences and reconstruction types. For foraminal stenosis, κ ranged from 0.55 to 0.76 (95% CI 0.32-0.86) for 3D DLRecon, 0.56-0.73 (95% CI 0.35-0.84) for standard-of-care (SOC) 3D, and 0.58-0.71 (95% CI 0.33-0.84) for 2D.
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Aprendizado Profundo , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Adulto , Idoso , Constrição Patológica , Feminino , Humanos , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: Describe tendon injuries and their structural causes seen on ultrasound in wrists with distal radius fractures and estimate the accuracy of ultrasound and its impact on clinical management. MATERIALS AND METHODS: Ultrasounds of 226 wrists (221 patients) with distal radius fractures were retrospectively reviewed. Ultrasound findings of tendon injuries and their structural causes were correlated with surgery and clinical outcome. Accuracy and inter- and intra-observer reproducibilities were calculated. RESULTS: Twenty-five wrists were treated non-operatively while 201 underwent surgery. Ultrasound demonstrated hardware contact with flexor pollicis longus (FPL) in 76 wrists, extensor pollicis longus (EPL) in 21, and other tendons in 94. Ultrasound identified tendon ruptures in 23 wrists (13 EPL/8 FPL/2 extensor indicis proprius (EIP)), most of which were surgically confirmed. Among 12 wrists with confirmed EPL ruptures, distal radius fracture had been treated with volar plating in 6 and non-operatively in 6, and ultrasound showed osseous irregularity at the rupture site in 8. All FPL ruptures occurred in wrists with volar plating. Ultrasound findings were concordant with subsequent clinical management in most. In 2, ultrasound findings led to the decision to remove hardware despite lack of symptoms. Ultrasound had sensitivity/specificity/accuracy of 88/99/98% for identifying a specific tendon as ruptured and 88/87/88% for tendon abnormalities in general. Inter- and intra-observer reproducibilities were excellent (kappa = 0.85 ~ 1.0). CONCLUSION: Certain wrist tendons, particularly EPL and FPL, are vulnerable after distal radius fractures. Ultrasound is accurate and useful for detecting tendon injury and sources of tendon irritation and can guide clinical management.
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Fraturas do Rádio , Traumatismos dos Tendões , Placas Ósseas/efeitos adversos , Fixação Interna de Fraturas/efeitos adversos , Humanos , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/cirurgia , Estudos Retrospectivos , Ruptura/diagnóstico por imagem , Ruptura/etiologia , Traumatismos dos Tendões/diagnóstico por imagem , Traumatismos dos Tendões/etiologia , UltrassonografiaRESUMO
PURPOSE OF REVIEW: Uterine sarcomas are rare and are often challenging to differentiate on imaging from benign mimics, such as leiomyoma. As functional MRI techniques have improved and new adjuncts, such as machine learning and texture analysis, are now being investigated, it is helpful to be aware of the current literature on imaging features that may sometimes allow for preoperative distinction. RECENT FINDINGS: MRI, with both conventional and functional imaging, is the modality of choice for evaluating uterine mesenchymal tumors, especially in differentiating uterine leiomyosarcoma from leiomyoma through validated diagnostic algorithms. MRI is sometimes helpful in differentiating high-grade stromal sarcoma from low-grade stromal sarcoma or differentiating endometrial stromal sarcoma from endometrial carcinoma. However, imaging remains nonspecific for evaluating rarer neoplasms, such as uterine tumor resembling ovarian sex cord tumor or perivascular epithelioid cell tumor, primarily because of the small number and power of relevant studies. SUMMARY: Through advances in MRI techniques and novel investigational imaging adjuncts, such as machine learning and texture analysis, imaging differentiation of malignant from benign uterine mesenchymal tumors has improved and could help reduce morbidity relating to misdiagnosis or diagnostic delays.
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Neoplasias do Endométrio , Sarcoma do Estroma Endometrial , Sarcoma , Neoplasias Uterinas , Feminino , Humanos , Imageamento por Ressonância Magnética , Sarcoma/diagnóstico por imagem , Neoplasias Uterinas/diagnóstico por imagemRESUMO
PURPOSE: Verify whether there is a difference in likelihood of developing pulmonary embolism (PE) between pregnant women, nonpregnant women of reproductive age, and postpartum (up to 6 weeks) women, by comparing their outcomes on computed tomography pulmonary angiography (CTPA) done for suspicion of PE. MATERIALS AND METHODS: Retrospective cohort study of 1463 CTPA done for suspicion of PE in females of reproductive age (18-40 years), nonpregnant, pregnant (antepartum), and postpartum, from 2 tertiary-care academic hospitals between October 2006 and September 2015. Primary outcome was diagnosis of PE on imaging. Additional assessment was made of technical adequacy of the studies and method of delivery for the postpartum cohort (vaginal vs caesarean birth). Twenty-nine technically nondiagnostic studies were excluded. The effect of any potential variable on PE status was tested using univariate logistic regression. Subgroup analysis was performed after excluding patients with independent risk factors for PE. RESULTS: The rate of CTPA positive for PE was less among pregnant patients compared to early postpartum and nonpregnant women of similar age, 2.9% vs 11.5% and 10.3%, respectively. Pregnancy was associated with statistically significant decreased odds ratio of developing a PE on CTPA, 0.23 (0.09-0.89), P value = .004. After excluding patients with additional independent risk factors for PE, there was no statistically significant odds ratio association between presence of PE on CTPA and pregnancy 0.41 (0.13-1.34), P value = .14. CONCLUSION: Rate of CTPA positive for PE in pregnant women was lower than in nonpregnant and early postpartum women. Pregnancy was statistically significantly less likely to be associated with positive PE on a CTPA study. The common perception that pregnancy (antepartum state) is associated with an increased risk of PE may require a thorough critical reappraisal.
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Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/epidemiologia , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/epidemiologia , Adolescente , Adulto , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Tomografia Computadorizada Multidetectores/métodos , Período Pós-Parto , Gravidez , Prevalência , Fatores de Proteção , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Surveillance of venous thromboembolisms (VTEs) is necessary for improving patient safety in acute care hospitals, but current detection methods are inaccurate and inefficient. With the growing availability of clinical narratives in an electronic format, automated surveillance using natural language processing (NLP) techniques may represent a better method. OBJECTIVE: We assessed the accuracy of using symbolic NLP for identifying the 2 clinical manifestations of VTE, deep vein thrombosis (DVT) and pulmonary embolism (PE), from narrative radiology reports. METHODS: A random sample of 4000 narrative reports was selected among imaging studies that could diagnose DVT or PE, and that were performed between 2008 and 2012 in a university health network of 5 adult-care hospitals in Montreal (Canada). The reports were coded by clinical experts to identify positive and negative cases of DVT and PE, which served as the reference standard. Using data from the largest hospital (n=2788), 2 symbolic NLP classifiers were trained; one for DVT, the other for PE. The accuracy of these classifiers was tested on data from the other 4 hospitals (n=1212). RESULTS: On manual review, 663 DVT-positive and 272 PE-positive reports were identified. In the testing dataset, the DVT classifier achieved 94% sensitivity (95% CI, 88%-97%), 96% specificity (95% CI, 94%-97%), and 73% positive predictive value (95% CI, 65%-80%), whereas the PE classifier achieved 94% sensitivity (95% CI, 89%-97%), 96% specificity (95% CI, 95%-97%), and 80% positive predictive value (95% CI, 73%-85%). CONCLUSIONS: Symbolic NLP can accurately identify VTEs from narrative radiology reports. This method could facilitate VTE surveillance and the evaluation of preventive measures.
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Registros Eletrônicos de Saúde/estatística & dados numéricos , Processamento de Linguagem Natural , Embolia Pulmonar/diagnóstico , Tromboembolia Venosa/diagnóstico , Trombose Venosa/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Canadá , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Embolia Pulmonar/etiologia , Fatores de Risco , Tromboembolia Venosa/complicações , Trombose Venosa/etiologiaRESUMO
BACKGROUND: A fundamental feature of early nervous system development is the guidance of axonal projections to their targets in order to assemble neural circuits that control behavior. Spinal commissural neurons are an attractive model to investigate the multiple guidance cues that control growth cone navigation both pre- and post-midline crossing, as well as along both the dorsal-ventral (D-V) and anterior-posterior (A-P) axes. Accumulating evidence suggests that guidance of spinal commissural axons along the A-P axis is dependent on components of the planar cell polarity (PCP) signaling pathway. In the zebrafish, the earliest born spinal commissural neuron to navigate the midline and turn rostrally is termed commissural primary ascending (CoPA). Unlike mammalian systems, CoPA axons cross the midline as a single axon and allow an analysis of the role of PCP components in anterior pathfinding in single pioneering axons. RESULTS: Here, we establish CoPA cells in the zebrafish spinal cord as a model system for investigating the molecular function of planar cell polarity signaling in axon guidance. Using mutant analysis, we show that the functions of Fzd3a and Vangl2 in the anterior turning of commissural axons are evolutionarily conserved in teleosts. We extend our findings to reveal a role for the PCP gene scribble in the anterior guidance of CoPA axons. Analysis of single CoPA axons reveals that these commissural axons become responsive to PCP-dependent anterior guidance cues even prior to midline crossing. When midline crossing is prevented by dcc gene knockdown, ipsilateral CoPA axons still extend axons anteriorly in response to A-P guidance cues. We show that this ipsilateral anterior pathfinding that occurs in the absence of midline crossing is dependent on PCP signaling. CONCLUSION: Our results demonstrate that anterior guidance decisions by CoPA axons are dependent on the function of planar cell polarity genes both prior to and after midline crossing.
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Orientação de Axônios/fisiologia , Proteínas de Membrana/metabolismo , Medula Espinal/embriologia , Medula Espinal/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Animais Geneticamente Modificados , Axônios/metabolismo , Evolução Biológica , Polaridade Celular/genética , Imunofluorescência , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Proteínas de Membrana/genética , Microscopia Confocal , Modelos Animais , Morfolinos , Mutação , Receptores de Neurotransmissores , Transdução de Sinais , Medula Espinal/citologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
Thiamine deficiency (TD) leads to Wernicke's encephalopathy (WE), in which focal histological lesions occur in periventricular areas of the brain. Recently, impaired neurogenesis has been reported in the hippocampus during the dietary form of TD, and in pyrithiamine-induced TD (PTD), a well-characterized model of WE. To further characterize the consequences of PTD on neural stem/progenitor cell (NSPC) activity, we have examined the effect of this treatment in the rat on both the subventricular zone (SVZ) of the rostral lateral ventricle and subgranular layer (SGL) of the hippocampus, and in the thalamus and inferior colliculus, two vulnerable brain regions in this disorder. In both the SVZ and SGL, PTD led to a decrease in the numbers of bromodeoxyuridine-stained cells, indicating that proliferation of NSPCs destined for neurogenesis in these areas was reduced. Doublecortin (DCX) immunostaining in the SGL was decreased, indicating a reduction in neuroblast formation, consistent with impaired NSPC activity. DCX labeling was not apparent in focal areas of vulnerability. In the thalamus, proliferation of cells was absent while in the inferior colliculus, numerous actively dividing cells were apparent, indicative of a differential response between these two brain regions. Exposure of cultured neurospheres to PTD resulted in decreased proliferation of NSPCs, consistent with our in vivo findings. Together, these results indicate that PTD considerably affects cell proliferation and neurogenesis activity in both neurogenic areas and parts of the brain known to display structural and functional vulnerability, confirming and extending recent findings on the effects of TD on neurogenesis. Future use of NSPCs in vitro may allow a closer and more detailed examination of the mechanism(s) underlying inhibition of these cells during TD.
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Encéfalo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Piritiamina/toxicidade , Encefalopatia de Wernicke/patologia , Animais , Encéfalo/patologia , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Replicação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Colículos Inferiores/efeitos dos fármacos , Colículos Inferiores/patologia , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/patologia , Masculino , Proteínas Associadas aos Microtúbulos/análise , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Neuropeptídeos/análise , Ratos , Ratos Sprague-Dawley , Tálamo/efeitos dos fármacos , Tálamo/patologia , Encefalopatia de Wernicke/induzido quimicamenteRESUMO
We report the case of a 39-year-old woman complaining of painless unilateral nipple enlargement for 3 weeks. She had no family history of breast cancer. Clinical examination revealed left nipple enlargement without pain, erythema, or skin changes m no associated palpable breast or axillary masses. Ultrasound showed several bright foci in the left nipple suggestive of microcalcifications. Neither solid nor cystic masses were detected. The mammogram performed subsequently confirmed the presence of multiple pleomorphic microcalcifications within the nipple. Wedge biopsy showed a syringomatous adenoma. Wide local excision of the nipple was performed. The postoperative course was uneventful.
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Mamografia/métodos , Mamilos , Siringoma/diagnóstico por imagem , Adulto , Biópsia , Diagnóstico Diferencial , Feminino , Humanos , Siringoma/patologia , UltrassonografiaRESUMO
We report the case of a patient who underwent a vacuum-assisted biopsy of amorphous clustered microcalcifications complicated by a large compression-refractory hematoma secondary to pseudoaneurysm formation. Breast sonography was used to identify an actively bleeding vessel and guide compression. However, due to its unresponsiveness to conventional management and rapid progression, the hematoma required surgical evacuation and ligation of the bleeding vessel. This suggests that, in the face of significant intractable bleeding, a heightened awareness of the possible need for surgical intervention should be maintained.
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Falso Aneurisma/diagnóstico , Doenças Mamárias/diagnóstico , Drenagem/métodos , Hematoma/diagnóstico , Biópsia Guiada por Imagem/métodos , Artéria Torácica Interna , Ultrassonografia Doppler em Cores/métodos , Falso Aneurisma/complicações , Doenças Mamárias/etiologia , Doenças Mamárias/cirurgia , Emergências , Feminino , Hematoma/etiologia , Hematoma/cirurgia , Humanos , Imageamento Tridimensional/métodos , Pessoa de Meia-Idade , VácuoRESUMO
Homeostatic regulation of synapses is vital for nervous system function and key to understanding a range of neurological conditions. Synaptic homeostasis is proposed to operate over hours to counteract the destabilizing influence of long-term potentiation (LTP) and long-term depression (LTD). The prevailing view holds that synaptic scaling is a slow first-order process that regulates postsynaptic glutamate receptors and fundamentally differs from LTP or LTD. Surprisingly, we find that the dynamics of scaling induced by neuronal inactivity are not exponential or monotonic, and the mechanism requires calcineurin and CaMKII, molecules dominant in LTD and LTP. Our quantitative model of these enzymes reconstructs the unexpected dynamics of homeostatic scaling and reveals how synapses can efficiently safeguard future capacity for synaptic plasticity. This mechanism of synaptic adaptation supports a broader set of homeostatic changes, including action potential autoregulation, and invites further inquiry into how such a mechanism varies in health and disease.
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Calcineurina , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Homeostase , Sinapses , Animais , Sinapses/metabolismo , Sinapses/fisiologia , Calcineurina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , CamundongosRESUMO
We have recently proposed experimental design guidelines and areas of study for preclinical rodent models of gender-affirming hormone therapy in neuroscience. These guidelines also apply to any field subject to the influences of gonadal steroid hormones, including metabolism and growth, cancer, and physiology. This perspective briefly describes our suggestions for these fields. Studying the effects of exogenous steroid hormones will have translational benefits for the community. We also discuss the need for equitable practices for cisgender scientists who wish to implement these guidelines and engage with the community. It is necessary that community-informed practices are implemented in preclinical research to maximize the benefit to transgender, nonbinary, and/or gender diverse (TNG) healthcare, which is currently in jeopardy in the United States, Europe, and across the globe.
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Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI's pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI's synaptic effects and dampening hyperexcitability.
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Canabidiol , Camundongos , Animais , Canabidiol/farmacologia , Hipocampo/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Sinapses/fisiologia , Transdução de Sinais , Receptores de Canabinoides/metabolismoRESUMO
Most studies attempting to address the health care needs of the millions of transgender, nonbinary, and/or gender-diverse (TNG) individuals rely on human subjects, overlooking the benefits of translational research in animal models. Researchers have identified many ways in which gonadal steroid hormones regulate neuronal gene expression, connectivity, activity, and function across the brain to control behavior. However, these discoveries primarily benefit cisgender populations. Research into the effects of exogenous hormones such as estradiol, testosterone, and progesterone has a direct translational benefit for TNG individuals on gender-affirming hormone therapies (GAHTs). Despite this potential, endocrinological health care for TNG individuals remains largely unimproved. Here, we outline important areas of translational research that could address the unique health care needs of TNG individuals on GAHT. We highlight key biomedical questions regarding GAHT that can be investigated using animal models. We discuss how contemporary research fails to address the needs of GAHT users and identify equitable practices for cisgender scientists engaging with this work. We conclude that if necessary and important steps are taken to address these issues, translational research on GAHTs will greatly benefit the health care outcomes of TNG people.
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Hormônios , Pesquisa Translacional Biomédica , HumanosRESUMO
PURPOSE: To assess the accuracy of a natural language processing (NLP) model in extracting splenomegaly described in patients with cancer in structured computed tomography radiology reports. METHODS: In this retrospective study between July 2009 and April 2019, 3,87,359 consecutive structured radiology reports for computed tomography scans of the chest, abdomen, and pelvis from 91,665 patients spanning 30 types of cancer were included. A randomized sample of 2,022 reports from patients with colorectal cancer, hepatobiliary cancer (HB), leukemia, Hodgkin lymphoma (HL), and non-HL patients was manually annotated as positive or negative for splenomegaly. NLP model training/testing was performed on 1,617/405 reports, and a new validation set of 400 reports from all cancer subtypes was used to test NLP model accuracy, precision, and recall. Overall survival was compared between the patient groups (with and without splenomegaly) using Kaplan-Meier curves. RESULTS: The final cohort included 3,87,359 reports from 91,665 patients (mean age 60.8 years; 51.2% women). In the testing set, the model achieved accuracy of 92.1%, precision of 92.2%, and recall of 92.1% for splenomegaly. In the validation set, accuracy, precision, and recall were 93.8%, 92.9%, and 86.7%, respectively. In the entire cohort, splenomegaly was most frequent in patients with leukemia (32.5%), HB (17.4%), non-HL (9.1%), colorectal cancer (8.5%), and HL (5.6%). A splenomegaly label was associated with an increased risk of mortality in the entire cohort (hazard ratio 2.10; 95% CI, 1.98 to 2.22; P < .001). CONCLUSION: Automated splenomegaly labeling by NLP of radiology report demonstrates good accuracy, precision, and recall. Splenomegaly is most frequently reported in patients with leukemia, followed by patients with HB.
Assuntos
Neoplasias Colorretais , Leucemia , Radiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Processamento de Linguagem Natural , Estudos Retrospectivos , Esplenomegalia/diagnóstico por imagem , Esplenomegalia/etiologiaRESUMO
There are over 1 million transgender people living in the United States, and 33% report negative experiences with a healthcare provider, many of which are connected to data representation in electronic health records (EHRs). We present recommendations and common pitfalls involving sex- and gender-related data collection in EHRs. Our recommendations leverage the needs of patients, medical providers, and researchers to optimize both individual patient experiences and the efficacy and reproducibility of EHR population-based studies. We also briefly discuss adequate additions to the EHR considering name and pronoun usage. We add the disclaimer that these questions are more complex than commonly assumed. We conclude that collaborations between local transgender and gender-diverse persons and medical providers as well as open inclusion of transgender and gender-diverse individuals on terminology and standards boards is crucial to shifting the paradigm in transgender and gender-diverse health.