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Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1ß and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.
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Proteínas Adaptadoras de Sinalização CARD/imunologia , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/mortalidade , Inflamassomos/imunologia , Animais , Encéfalo/imunologia , Células Cultivadas , Quimiocinas CC/imunologia , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/imunologia , Interleucina-1beta/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Células VeroRESUMO
BACKGROUND: Electronic health records (EHRs) with large sample sizes and rich information offer great potential for dementia research, but current methods of phenotyping cognitive status are not scalable. OBJECTIVE: The aim of this study was to evaluate whether natural language processing (NLP)-powered semiautomated annotation can improve the speed and interrater reliability of chart reviews for phenotyping cognitive status. METHODS: In this diagnostic study, we developed and evaluated a semiautomated NLP-powered annotation tool (NAT) to facilitate phenotyping of cognitive status. Clinical experts adjudicated the cognitive status of 627 patients at Mass General Brigham (MGB) health care, using NAT or traditional chart reviews. Patient charts contained EHR data from two data sets: (1) records from January 1, 2017, to December 31, 2018, for 100 Medicare beneficiaries from the MGB Accountable Care Organization and (2) records from 2 years prior to COVID-19 diagnosis to the date of COVID-19 diagnosis for 527 MGB patients. All EHR data from the relevant period were extracted; diagnosis codes, medications, and laboratory test values were processed and summarized; clinical notes were processed through an NLP pipeline; and a web tool was developed to present an integrated view of all data. Cognitive status was rated as cognitively normal, cognitively impaired, or undetermined. Assessment time and interrater agreement of NAT compared to manual chart reviews for cognitive status phenotyping was evaluated. RESULTS: NAT adjudication provided higher interrater agreement (Cohen κ=0.89 vs κ=0.80) and significant speed up (time difference mean 1.4, SD 1.3 minutes; P<.001; ratio median 2.2, min-max 0.4-20) over manual chart reviews. There was moderate agreement with manual chart reviews (Cohen κ=0.67). In the cases that exhibited disagreement with manual chart reviews, NAT adjudication was able to produce assessments that had broader clinical consensus due to its integrated view of highlighted relevant information and semiautomated NLP features. CONCLUSIONS: NAT adjudication improves the speed and interrater reliability for phenotyping cognitive status compared to manual chart reviews. This study underscores the potential of an NLP-based clinically adjudicated method to build large-scale dementia research cohorts from EHRs.
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COVID-19 , Demência , Idoso , Algoritmos , Teste para COVID-19 , Cognição , Demência/diagnóstico , Registros Eletrônicos de Saúde , Humanos , Medicare , Processamento de Linguagem Natural , Reprodutibilidade dos Testes , Estados UnidosRESUMO
BACKGROUND: Psychiatric illness can mimic a comatose state. The most common is a conversion reaction resulting in a functional coma, which poses a unique diagnostic challenge to the clinician. Little is known about this condition, and the literature is limited by inconsistent terminology and by a lack of high-quality evidence. OBJECTIVE: To provide a conceptual definition of functional coma, describe case examples, summarize management, and increase recognition of this often underacknowledged entity. METHODS: We present two cases and provide a comprehensive review of the literature on the differential diagnosis, pathophysiology, workup, and management. RESULTS: Functional coma is defined as an involuntary coma-like state that occurs in the absence of structural or metabolic damage to the brain and that is distinct from catatonia. This term should supplant the previous phrase of "psychogenic coma." Psychiatric disorders are frequently present premorbidly, but are not required for the diagnosis. About half of the cases occur in the perioperative setting. Physical exam can provide helpful clues, including passive resistance to eye opening or avoidance of the face with arm drop. Additional work-up, including laboratory studies, brain imaging, and electroencephalography, should be obtained but are unremarkable in functional coma. Case studies suggest that the episodes last for several hours, with a range of 45 minutes to 4 days. Treatment includes supportive management and careful psychoeducation. CONCLUSIONS: Functional coma should be conceptualized as a distinct condition from catatonia and psychogenic non-epileptic seizures. Additional clinical and translation research is needed to further explore the etiology of this condition.
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Coma/diagnóstico , Transtorno Conversivo/diagnóstico , Adulto , Encéfalo/fisiologia , Coma/fisiopatologia , Transtorno Conversivo/fisiopatologia , Diagnóstico Diferencial , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Traditionally, ecosystem monitoring, conservation, and restoration have been conducted in a piecemeal manner at the local scale without regional landscape context. However, scientifically driven conservation and restoration decisions benefit greatly when they are based on regionally determined benchmarks and goals. Unfortunately, required data sets rarely exist for regionally important ecosystems. Because of early recognition of the extreme ecological importance of Laurentian Great Lakes coastal wetlands, and the extensive degradation that had already occurred, significant investments in coastal wetland research, protection, and restoration have been made in recent decades and continue today. Continued and refined assessment of wetland condition and trends, and the evaluation of restoration practices are all essential to ensuring the success of these investments. To provide wetland managers and decision makers throughout the Laurentian Great Lakes basin with the optimal tools and data needed to make scientifically-based decisions, our regional team of Great Lakes wetland scientists developed standardized methods and indicators used for assessing wetland condition. From a landscape perspective, at the Laurentian Great Lakes ecosystem scale, we established a stratified random-site-selection process to monitor birds, anurans, fish, macroinvertebrates, vegetation, and physicochemical conditions of coastal wetlands in the US and Canada. Monitoring of approximately 200 wetlands per year began in 2011 as the Great Lakes Coastal Wetland Monitoring Program. In this paper, we describe the development, delivery, and expected results of this ongoing international, multi-disciplinary, multi-stakeholder, landscape-scale monitoring program as a case example of successful application of landscape conservation design.
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Astrócitos/imunologia , Encefalite por Herpes Simples/imunologia , Interferon Tipo I/imunologia , Animais , Astrócitos/virologia , Encéfalo/imunologia , Encéfalo/virologia , Modelos Animais de Doenças , Encefalite por Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Estimativa de Kaplan-Meier , Camundongos , Camundongos Knockout , Microglia/imunologia , Microglia/virologia , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais , Carga ViralRESUMO
Newborns are significantly more susceptible to severe disease after infection with herpes simplex virus (HSV) compared with adults, with differences in the host response implicated as a major factor. To understand host response differences between these age groups, we investigated the shutoff of protein synthesis by the host and the retargeting of host phosphatase PP1α by the HSV-1 protein γ34.5 for reversal of translational arrest. In a murine newborn model of viral dissemination, infection with the HSV-1 mutant for PP1α binding resulted in complete absence of disease. PP1α-binding mutant HSV-1 replicated in visceral organs early after inoculation, demonstrating that HSV-1 replication requires PP1α-targeting only later in infection. Newborn mice deficient in type I IFN signaling partially rescued the virulence of the PP1α-binding mutant virus, suggesting an IFN-independent role for eIF2α kinases during infection. When we investigated the contribution of PP1α targeting to pathogenesis in the brain, we found that the inability of HSV-1 to bind PP1α increased survival time in both newborn and adult mice. Unlike disseminated disease, type I IFN signaling in the brain was required to attenuate disease following PP1α-mutant virus infection. Furthermore, pharmacologic inhibition of eIF2α dephosphorylation reduced HSV-1 replication in a brain slice culture model of encephalitis. Our findings reveal age-dependent differences in γ34.5 function and tissue-specific reliance on the type I IFN response for protection from HSV disease. These results define an important role for γ34.5 in neonatal infections in contrast to other studies indicating that the autophagy-inhibiting function of γ34.5 is dispensable for pathogenesis in the newborn brain.
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Encefalopatias/patologia , Herpes Simples/patologia , Fosfoproteínas Fosfatases/metabolismo , Simplexvirus/fisiologia , Animais , Animais Recém-Nascidos , Fator de Iniciação 2 em Eucariotos/metabolismo , Técnicas In Vitro , Camundongos , Fosforilação , Simplexvirus/patogenicidade , VirulênciaRESUMO
Biotic indicators are useful for assessing ecosystem health because the structure of resident communities generally reflects abiotic conditions integrated over time. We used fish data collected over 5 years for 470 Great Lakes coastal wetlands to develop multi-metric indices of biotic integrity (IBI). Sampling and IBI development were stratified by vegetation type within each wetland to account for differences in physical habitat. Metrics were evaluated against numerous indices of anthropogenic disturbance derived from water quality and surrounding land-cover variables. Separate datasets were used for IBI development and testing. IBIs were composed of 10-11 metrics for each of four vegetation types (bulrush, cattail, water lily, and submersed aquatic vegetation). Scores of all IBIs correlated well with disturbance indices using the development data, and the accuracy of our IBIs was validated using the testing data. Our fish IBIs can be used to prioritize wetland protection and restoration efforts across the Great Lakes basin. The IBIs will also be useful in monitoring programs mandated by the Agreement between Canada and the United States of America on Great Lakes Water Quality, such as for assessing Beneficial Use Impairments (BUIs) in Great Lakes Areas of Concern, and in other ecosystem management programs in Canada and the USA.
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Monitoramento Ambiental , Peixes , Áreas Alagadas , Animais , Biodiversidade , Aves , Canadá , Ecologia , Ecossistema , Lagos , Estados Unidos , Qualidade da ÁguaRESUMO
Newborns are more susceptible to severe disease from infection than adults, with maturation of immune responses implicated as a major factor. The type I interferon response delays mortality and limits viral replication in adult mice in a model of herpes simplex virus (HSV) encephalitis. We found that intact type I interferon signaling did not control HSV disease in the neonatal brain. However, the multifunctional HSV protein γ34.5 involved in countering type I interferon responses was important for virulence in the brain in both age groups. To investigate this observation further, we studied a specific function of γ34.5 which contributes to HSV pathogenesis in the adult brain, inhibition of the cellular process of autophagy. Surprisingly, we found that the beclin binding domain of γ34.5 responsible for inhibiting autophagy was dispensable for HSV disease in the neonatal brain, as infection of newborns with the deletion mutant decreased time to mortality compared to the rescue virus. Additionally, a functional beclin binding domain in HSV γ34.5 did not effectively inhibit autophagy in the neonate, unlike in the adult. Type I IFN responses promote autophagy in adult, a finding we confirmed in the adult brain after HSV infection; however, in the newborn brain we observed that autophagy was activated through a type I IFN-independent mechanism. Furthermore, autophagy in the wild-type neonatal mouse was associated with increased apoptosis in infected regions of the brain. Observations in the mouse model were consistent with those in a human case of neonatal HSV encephalitis. Our findings reveal age-dependent differences in autophagy for protection from HSV encephalitis, indicating developmental differences in induction and regulation of this innate defense mechanism after HSV infection in the neonatal brain.
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Autofagia/fisiologia , Encefalite por Herpes Simples/patologia , Encefalite por Herpes Simples/fisiopatologia , Herpes Simples/patologia , Herpes Simples/fisiopatologia , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/fisiopatologia , Animais , Animais Recém-Nascidos , Apoptose/fisiologia , Autopsia , Encefalite por Herpes Simples/congênito , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos KnockoutRESUMO
A computational fluid dynamics model is used to predict the oscillatory flow through tapered cylindrical tube sections (jet pumps). The asymmetric shape of jet pumps results in a time-averaged pressure drop that can be used to suppress Gedeon streaming in closed-loop thermoacoustic devices. However, previous work has shown that flow separation in the diverging flow direction counteracts the time-averaged pressure drop. In this work, the characteristics of flow separation in jet pumps are identified and coupled with the observed jet pump performance. Furthermore, it is shown that the onset of flow separation can be shifted to larger displacement amplitudes by designs that have a smoother transition between the small opening and the tapered surface of the jet pump. These design alterations also reduce the duration of separated flow, resulting in more effective and robust jet pumps. To make the proposed jet pump designs more compact without reducing their performance, the minimum big opening radius that can be implemented before the local minor losses have an influence on the jet pump performance is investigated. To validate the numerical results, they are compared with experimental results for one of the proposed jet pump designs.
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The design of compact thermoacoustic devices requires compact jet pump geometries, which can be realized by employing jet pumps with multiple orifices. The oscillatory flow through the orifice(s) of a jet pump generates asymmetric hydrodynamic end effects, which result in a time-averaged pressure drop that can counteract Gedeon streaming in traveling wave thermoacoustic devices. In this study, the performance of jet pumps having 1-16 orifices is characterized experimentally in terms of the time-averaged pressure drop and acoustic power dissipation. Upon increasing the number of orifices, a significant decay in the jet pump performance is observed. Further analysis shows a relation between this performance decay and the diameter of the individual holes. Possible causes of this phenomenon are discussed. Flow visualization is used to study the differences in vortex ring interaction from adjacent jet pump orifices. The mutual orifice spacing is varied and the corresponding jet pump performance is measured. The orifice spacing is shown to have less effect on the jet pump performance compared to increasing the number of orifices.
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A two-dimensional computational fluid dynamics model is used to predict the oscillatory flow through a tapered cylindrical tube section (jet pump) placed in a larger outer tube. Due to the shape of the jet pump, an asymmetry in the hydrodynamic end effects will exist which will cause a time-averaged pressure drop to occur that can be used to cancel Gedeon streaming in a closed-loop thermoacoustic device. The performance of two jet pump geometries with different taper angles is investigated. A specific time-domain impedance boundary condition is implemented in order to simulate traveling acoustic wave conditions. It is shown that by scaling the acoustic displacement amplitude to the jet pump dimensions, similar minor losses are observed independent of the jet pump geometry. Four different flow regimes are distinguished and the observed flow phenomena are related to the jet pump performance. The simulated jet pump performance is compared to an existing quasi-steady approximation which is shown to only be valid for small displacement amplitudes compared to the jet pump length.
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The oscillatory flow through tapered cylindrical tube sections (jet pumps) is characterized by a numerical parameter study. The shape of a jet pump results in asymmetric hydrodynamic end effects which cause a time-averaged pressure drop to occur under oscillatory flow conditions. Hence, jet pumps are used as streaming suppressors in closed-loop thermoacoustic devices. A two-dimensional axisymmetric computational fluid dynamics model is used to calculate the performance of a large number of conical jet pump geometries in terms of time-averaged pressure drop and acoustic power dissipation. The investigated geometrical parameters include the jet pump length, taper angle, waist diameter, and waist curvature. In correspondence with previous work, four flow regimes are observed which characterize the jet pump performance and dimensionless parameters are introduced to scale the performance of the various jet pump geometries. The simulation results are compared to an existing quasi-steady theory and it is shown that this theory is only applicable in a small operation region. Based on the scaling parameters, an optimum operation region is defined and design guidelines are proposed which can be directly used for future jet pump design.
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Deciphering the contribution of genetic instability in somatic cells is critical to our understanding of many human disorders. Myotonic dystrophy type 1 (DM1) is one such disorder that is caused by the expansion of a CTG repeat that shows extremely high levels of somatic instability. This somatic instability has compromised attempts to measure intergenerational repeat dynamics and infer genotype-phenotype relationships. Using single-molecule PCR, we have characterized more than 17 000 de novo somatic mutations from a large cohort of DM1 patients. These data reveal that the estimated progenitor allele length is the major modifier of age of onset. We find no evidence for a threshold above which repeat length does not contribute toward age at onset, suggesting pathogenesis is not constrained to a simple molecular switch such as nuclear retention of the DMPK transcript or haploinsufficiency for DMPK and/or SIX5. Importantly, we also show that age at onset is further modified by the level of somatic instability; patients in whom the repeat expands more rapidly, develop the symptoms earlier. These data establish a primary role for somatic instability in DM1 severity, further highlighting it as a therapeutic target. In addition, we show that the level of instability is highly heritable, implying a role for individual-specific trans-acting genetic modifiers. Identifying these trans-acting genetic modifiers will facilitate the formulation of novel therapies that curtail the accumulation of somatic expansions and may provide clues to the role these factors play in the development of cancer, aging and inherited disease in the general population.
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Distrofia Miotônica/etiologia , Distrofia Miotônica/genética , Característica Quantitativa Herdável , Expansão das Repetições de Trinucleotídeos , Idade de Início , Idoso , Alelos , Estudos de Associação Genética , Instabilidade Genômica , Haploinsuficiência/genética , Proteínas de Homeodomínio/genética , Humanos , Pessoa de Meia-Idade , Distrofia Miotônica/epidemiologia , Miotonina Proteína Quinase , Proteínas Serina-Treonina Quinases/genéticaRESUMO
BACKGROUND: Outcomes of neonates with herpes simplex virus (HSV) encephalitis are worse after infection with HSV-2 when compared with HSV-1. The proteins herpes virus entry mediator (HVEM) and nectin-1 mediate HSV entry into susceptible cells. Prior studies have shown receptor-dependent differences in pathogenesis that depend on route of inoculation and host developmental age. METHODS: We investigated serotype-related differences in HSV disease and their relationship to entry receptor availability in a mouse model of encephalitis. RESULTS: Mortality was attenuated in 7-d-old, wild-type (WT) mice inoculated with HSV-1(F) when compared with HSV-2(333). No serotype-specific differences were seen after inoculation of adult mice. HSV-1 pathogenesis was also attenuated relative to HSV-2 in newborn but not adult mice lacking HVEM or nectin-1. HSV-2 requires nectin-1 for encephalitis in adult but not newborn mice; in contrast, nectin-1 was important for HSV-1 pathogenesis in both age groups. Early viral replication was independent of age, viral serotype, or mouse genotype, suggesting host responses influence outcomes. In this regard, significantly greater amounts of inflammatory mediators were detected in brain homogenates from WT newborns 2 d after infection compared with adults and receptor-knockout newborns. CONCLUSION: Dysregulation of inflammatory responses induced by infection may influence the severity of HSV encephalitis.
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Moléculas de Adesão Celular/metabolismo , Encefalite por Herpes Simples/virologia , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Complicações Infecciosas na Gravidez/virologia , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Internalização do Vírus , Animais , Animais Recém-Nascidos , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Modelos Animais de Doenças , Encefalite por Herpes Simples/genética , Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/metabolismo , Genótipo , Herpes Simples/genética , Herpes Simples/imunologia , Herpes Simples/metabolismo , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 2/metabolismo , Interações Hospedeiro-Patógeno , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nectinas , Fenótipo , Complicações Infecciosas na Gravidez/genética , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/deficiência , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Sorogrupo , Fatores de Tempo , Replicação ViralRESUMO
BACKGROUND AND OBJECTIVES: Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is most common, accounting for â¼15%-40% of adult encephalitis diagnoses. We aim to investigate the association between immune status and HSV encephalitis (HSVE). Using a US Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. METHODS: We used the US Medicaid Analytic eXtract data between 2007 and 2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age and sex-matched adult cases of HSVE with a sufficient enrollment period (12 months before HSVE diagnosis) to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson Comorbidity Index, and non-autoimmune comorbidities. RESULTS: Incidence of HSVE was â¼3.01 per 105 person-years among adults. A total of 951 HSVE cases and 95,100 age and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong (adjusted odds ratio (OR) 2.6; 95% CI 2.2-3.2). The association of HSVE and immunomodulating medications had an OR of 2.2 (CI 1.9-2.6), also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: OR 2.3 (CI 1.9-2.7) for autoimmune disease and 2.0 (CI 1.7-2.3) for immunosuppressive and immunomodulatory medications. DISCUSSION: In a large, national population, HSVE is strongly associated with preexisting autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date.
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Doenças Autoimunes , Encefalite por Herpes Simples , Agentes de Imunomodulação , Humanos , Feminino , Masculino , Encefalite por Herpes Simples/epidemiologia , Encefalite por Herpes Simples/imunologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Adulto , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Agentes de Imunomodulação/uso terapêutico , Agentes de Imunomodulação/efeitos adversos , Estudos de Casos e Controles , Incidência , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Adulto Jovem , Medicaid , Idoso , Adolescente , ComorbidadeAssuntos
Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Interações Hospedeiro-Patógeno , Proteínas Virais/genética , Autofagia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/fisiologia , Humanos , Mutação , Terapia Viral Oncolítica , Inibidores da Síntese de Proteínas , Proteínas Virais/química , Proteínas Virais/metabolismoRESUMO
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as 'cascade screening'. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer-held DMD register. Over the period, 1971-2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks.
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Triagem de Portadores Genéticos/métodos , Distrofia Muscular de Duchenne/genética , Sistema de Registros , Adulto , Distrofina/genética , Feminino , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Estudos Retrospectivos , Reino UnidoRESUMO
BACKGROUND: Data supporting dementia as a risk factor for coronavirus disease 2019 (COVID-19) mortality relied on ICD-10 codes, yet nearly 40% of individuals with probable dementia lack a formal diagnosis. Dementia coding is not well established for people with HIV (PWH), and its reliance may affect risk assessment. METHODS: This retrospective cohort analysis of PWH with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR positivity includes comparisons to people without HIV (PWoH), matched by age, sex, race, and zipcode. Primary exposures were dementia diagnosis, by International Classification of Diseases (ICD)-10 codes, and cognitive concerns, defined as possible cognitive impairment up to 12âmonths before COVID-19 diagnosis after clinical review of notes from the electronic health record. Logistic regression models assessed the effect of dementia and cognitive concerns on odds of death [odds ratio (OR); 95% CI (95% confidence interval)]; models adjusted for VACS Index 2.0. RESULTS: Sixty-four PWH were identified out of 14â129 patients with SARS-CoV-2 infection and matched to 463 PWoH. Compared with PWoH, PWH had a higher prevalence of dementia (15.6% vs. 6%, P â=â0.01) and cognitive concerns (21.9% vs. 15.8%, P â=â0.04). Death was more frequent in PWH ( P â<â0.01). Adjusted for VACS Index 2.0, dementia [2.4 (1.0-5.8), P â=â0.05] and cognitive concerns [2.4 (1.1-5.3), P â=â0.03] were associated with increased odds of death. In PWH, the association between cognitive concern and death trended towards statistical significance [3.92 (0.81-20.19), P â=â0.09]; there was no association with dementia. CONCLUSION: Cognitive status assessments are important for care in COVID-19, especially among PWH. Larger studies should validate findings and determine long-term COVID-19 consequences in PWH with preexisting cognitive deficits.
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COVID-19 , Demência , Infecções por HIV , Humanos , COVID-19/complicações , SARS-CoV-2 , Teste para COVID-19 , Estudos Retrospectivos , Infecções por HIV/complicações , Fatores de Risco , CogniçãoRESUMO
We describe an acute, postoperative dysarthria-facial paresis. While the rare stroke syndrome has been described previously, we present an under-described clinical nuance to its presentation with a particularly clear imaging correlation. A 78-year-old, right-handed man with a past medical history of aortic stenosis presented after a transcatheter aortic valve replacement. Immediately postoperatively, no neurological deficits were noted. That evening, he described his speech as "drunken." He was later noted to have a right lower facial droop in addition to the speech change. His speech exhibited labial, lingual, and (to a lesser degree) guttural dysarthria. At the patient's request due to claustrophobia, he received 2 mg of oral lorazepam prior to cranial imaging. Afterwards, he was sleepy but arousable, yet was unable to put pen to paper when asked to write. Right lower facial paresis persisted, but he now demonstrated a right pronator drift, which resolved after 14 h without other evolution to his clinical examination. Brainstem lesions above the level of the pontine facial nucleus may present with central facial paresis contralateral to the lesion. An associated dysarthria may have both labial and lingual features in the absence of tongue or pharyngeal weakness. Our review of reported cases of dysarthria in isolation, dysarthria in combination with facial paresis, and facial paresis finds that all presentations may result from cortical, subcortical, or brainstem involvement. Stroke mechanisms are most commonly thromboembolic or small-vessel-ischemic in either the anterior or posterior circulations.
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OBJECTIVE: To determine the clinical presentation and patient outcomes after treatment with IV immunoglobulin (IVIG), high-dose steroids, or standard of care alone in Eastern equine encephalitis (EEE), a mosquito-borne viral infection with significant neurologic morbidity and mortality. METHODS: A retrospective observational study of patients admitted to 2 tertiary academic medical centers in Boston, Massachusetts, with EEE from 2005 to 2019. RESULTS: Of 17 patients (median [IQR] age, 63 [36-70] years; 10 (59%) male, and 16 (94%) White race), 17 patients had fever (100%), 15 had encephalopathy (88%), and 12 had headache (71%). Eleven of 14 patients with CSF cell count differential had a neutrophil predominance (mean = 60.6% of white blood cells) with an elevated protein level (median [IQR], 100 mg/dL [75-145]). Affected neuroanatomic regions included the basal ganglia (n = 9/17), thalamus (n = 7/17), and mesial temporal lobe (n = 7/17). A total of 11 patients (65%) received IVIG; 8 (47%) received steroids. Of the patients who received IVIG, increased time from hospital admission to IVIG administration correlated with worse long-term disability as assessed by the modified Rankin Scale (mRS) (r = 0.72, p = 0.02); steroid use was not associated with the mRS score. The mortality was 12%. CONCLUSIONS: Clinicians should suspect EEE in immunocompetent patients with early subcortical neuroimaging abnormalities and CSF neutrophilic predominance. This study suggests a lower mortality than previously reported, but a high morbidity rate in EEE. IVIG as an adjunctive to standard of care may be considered early during hospitalization.