RESUMO
BACKGROUND: Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and health professionals to inform a core outcome set to be reported in all kidney transplant clinical trials. METHODS: In an international online survey, participants rated the absolute importance of 16 infections and eight severity dimensions on 9-point Likert Scales, with 7-9 being critically important. Relative importance was determined using a best-worst scale. Means and proportions of the Likert-scale ratings and best-worst preference scores were calculated. RESULTS: 353 healthcare professionals (19 who identified as both patients/caregiver and healthcare professionals) and 220 patients/caregivers (190 patients, 22 caregivers, eight who identified as both) from 55 countries completed the survey. Both healthcare professionals and patients/caregivers rated bloodstream (mean 8.4 and 8.5, respectively; aggregate 8.5), kidney/bladder (mean 7.9 and 8.4; aggregate 8.1), and BK virus (mean 8.1 and 8.6; aggregate 8.3) as the top three most critically important infection outcomes, whilst infectious death (mean 8.8 and 8.6; aggregate 8.7), impaired graft function (mean 8.4 and 8.7; aggregate 8.5) and admission to the intensive care unit (mean 8.2 and 8.3; aggregate 8.2) were the top three severity dimensions. Relative importance (best-worst) scores were consistent. CONCLUSIONS: Healthcare professionals and patients/caregivers consistently identified bloodstream infection, kidney/bladder infections, and BK virus as the three most important infection outcomes, and infectious death, admission to intensive care unit and infection impairing graft function as the three most important infection severity outcomes.
Assuntos
Cuidadores , Transplante de Rim , Técnica Delphi , Pessoal de Saúde , Humanos , Transplante de Rim/efeitos adversos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: In the perioperative context, benzodiazepines are widely used as anxiolytics. They affect cognition in general, but it is unclear whether the effects of a small dose of the short-acting benzodiazepine midazolam can be assessed objectively. To address this scientific question, we conducted a prospective observational study in adults 55-73 years of age. Using both validated psychometric and functional imaging techniques, we determined whether a 2-mg intravenous (IV) dose of midazolam affects cognitive function. METHODS: We measured the effect of 2 mg IV of midazolam with both the well-established Repeatable Battery for the Assessment of Neuropsychological Status test and resting-state functional magnetic imaging (rs-fMRI) in older adults. RESULTS: Midazolam reduces immediate and delayed memory and has a profound and robust effect on rs-fMRI. Baseline resting-state connectivity predicts memory decline after midazolam administration. CONCLUSIONS: Observed effects of midazolam on brain networks were statistically significant even in a small group of volunteers. If validated by other investigators, resting-state brain connectivity may have utility as a measure to predict sensitivity to midazolam in older adults.
Assuntos
Ansiolíticos/administração & dosagem , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Midazolam/administração & dosagem , Fatores Etários , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Feminino , Humanos , Infusões Intravenosas , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Repressão PsicológicaRESUMO
BACKGROUND: Cortical thickness (CT) and gyrification are complementary indices that assess different aspects of gray matter structural integrity. Both neurodevelopment insults and acute tissue response to antipsychotic medication could underlie the known heterogeneity of treatment response and are well-suited for interrogation into the relationship between gray matter morphometry and clinical outcomes in schizophrenia (SZ). METHODS: Using a prospective design, we enrolled 34 unmedicated patients with SZ and 23 healthy controls. Patients were scanned at baseline and after a 6-week trial with risperidone. CT and local gyrification index (LGI) values were quantified from structural MRI scans using FreeSurfer 5.3. RESULTS: We found reduced CT and LGI in patients compared to controls. Vertex-wise analyses demonstrated that hypogyrification was most prominent in the inferior frontal cortex, temporal cortex, insula, pre/postcentral gyri, temporoparietal junction, and the supramarginal gyrus. Baseline CT was predictive of subsequent response to antipsychotic treatment, and increase in CT after 6 weeks was correlated with greater symptom reductions. CONCLUSIONS: In summary, we report evidence of reduced CT and LGI in unmedicated patients compared to controls, suggesting involvement of different aspects of gray matter morphometry in the pathophysiology of SZ. Importantly, we found that lower CT at baseline and greater increase of CT following 6 weeks of treatment with risperidone were associated with better clinical response. Our results suggest that cortical thinning may normalize as a result of a good response to antipsychotic medication, possibly by alleviating potential neurotoxic processes underlying gray matter deterioration.
Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/farmacologia , Córtex Cerebral/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Estudos Prospectivos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológicoRESUMO
Acquisition of multimodal brain imaging data for the same subject has become more common leading to a growing interest in determining the intermodal relationships between imaging modalities to further elucidate the pathophysiology of schizophrenia. Multimodal data have previously been individually analyzed and subsequently integrated; however, these analysis techniques lack the ability to examine true modality inter-relationships. The utilization of a multiset canonical correlation and joint independent component analysis (mCCA + jICA) model for data fusion allows shared or distinct abnormalities between modalities to be examined. In this study, first-episode schizophrenia patients (nSZ =19) and matched controls (nHC =21) completed a resting-state functional magnetic resonance imaging (fMRI) scan at 7 T. Grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), and amplitude of low frequency fluctuation (ALFF) maps were used as features in a mCCA + jICA model. Results of the mCCA + jICA model indicated three joint group-discriminating components (GM-CSF, WM-ALFF, GM-ALFF) and two modality-unique group-discriminating components (GM, WM). The joint component findings are highlighted by GM basal ganglia, somatosensory, parietal lobe, and thalamus abnormalities associated with ventricular CSF volume; WM occipital and frontal lobe abnormalities associated with temporal lobe function; and GM frontal, temporal, parietal, and occipital lobe abnormalities associated with caudate function. These results support and extend major findings throughout the literature using independent single modality analyses. The multimodal fusion of 7 T data in this study provides a more comprehensive illustration of the relationships between underlying neuronal abnormalities associated with schizophrenia than examination of imaging data independently.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Imageamento por Ressonância Magnética , Imagem Multimodal , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Mapeamento Encefálico/métodos , Líquido Cefalorraquidiano/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/instrumentação , Masculino , Modelos Estatísticos , Imagem Multimodal/métodos , Descanso , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto-temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto-temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. METHODS: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1-week of antipsychotic treatment. RESULTS: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto-temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1-week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. CONCLUSIONS: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto-temporal dysconnectivity. Patterns of fronto-temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits.
Assuntos
Antipsicóticos/uso terapêutico , Encéfalo/fisiopatologia , Memória Episódica , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico/métodos , Causalidade , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/tratamento farmacológico , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Processamento de Sinais Assistido por Computador , Resultado do TratamentoRESUMO
The HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis (HOPE Trial) is a multicenter randomized trial addressing chronic pain among patients receiving maintenance hemodialysis for end-stage kidney disease. The trial uses a sequential, multiple assignment design with a randomized component for all participants (Phase 1) and a non-randomized component for a subset of participants (Phase 2). During Phase 1, participants are randomized to Pain Coping Skills Training (PCST), an intervention designed to increase self-efficacy for managing pain, or Usual Care. PCST consists of weekly, live, coach-led cognitive behavioral therapy sessions delivered by video- or tele-conferencing for 12 weeks followed by daily interactive voice response sessions delivered by telephone for an additional 12 weeks. At 24 weeks (Phase 2), participants in both the PCST and Usual Care groups taking prescription opioid medications at an average dose of ≥20 morphine milligram equivalents per day are offered buprenorphine, a partial opioid agonist with a more favorable safety profile than full-agonist opioids. All participants are followed for 36 weeks. The primary outcome is pain interference ascertained, for the primary analysis, at 12 weeks. Secondary outcomes include additional patient-reported measures and clinical outcomes including falls, hospitalizations, and death. Exploratory outcomes include acceptability, tolerability, and efficacy of buprenorphine. The enrollment target of 640 participants was met 27 months after trial initiation. The findings of the trial will inform the management of chronic pain, a common and challenging issue for patients treated with maintenance hemodialysis. NCT04571619.
Assuntos
Buprenorfina , Dor Crônica , Humanos , Analgésicos Opioides/uso terapêutico , Buprenorfina/uso terapêutico , Dor Crônica/tratamento farmacológico , Dor Crônica/epidemiologia , Estudos Multicêntricos como Assunto , Manejo da Dor , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal/efeitos adversosRESUMO
The Arenaviridae are a diverse and globally distributed collection of viruses that are maintained primarily by rodent reservoirs. Junin virus (JUNV) and Lassa virus (LASV) can both cause significant outbreaks of severe and often fatal human disease throughout their respective areas of endemicity. In an effort to improve upon the existing live attenuated JUNV Candid1 vaccine, we generated a genetically homogenous stock of this virus from cDNA copies of the virus S and L segments by using a reverse genetics system. Further, these cDNAs were used in combination with LASV cDNAs to successfully generate two recombinant Candid1 JUNV/LASV chimeric viruses (via envelope glycoprotein [GPC] exchange). It was found that while the GPC extravirion domains were readily exchangeable, homologous stable signal peptide (SSP) and G2 transmembrane and cytoplasmic tail domains were essential for correct GPC maturation and production of infectious chimeric viruses. The switching of the JUNV and LASV G1/G2 ectodomains within the Candid1 vaccine background did not alter the attenuated phenotype of the vaccine strain in a lethal mouse model. These recombinant chimeric viruses shed light on the fundamental requirements of arenavirus GPC maturation and may serve as a strategy for the development of bivalent JUNV and LASV vaccine candidates.
Assuntos
Glicoproteínas/genética , Vírus Junin/genética , Vírus Lassa/genética , Recombinação Genética , Proteínas do Envelope Viral/genética , Vacinas Virais , Animais , Infecções por Arenaviridae/mortalidade , Infecções por Arenaviridae/prevenção & controle , Infecções por Arenaviridae/virologia , Chlorocebus aethiops , Glicoproteínas/química , Glicoproteínas/metabolismo , Humanos , Vírus Junin/metabolismo , Vírus Junin/patogenicidade , Vírus Lassa/metabolismo , Vírus Lassa/patogenicidade , Camundongos , Sinais Direcionadores de Proteínas/genética , Sinais Direcionadores de Proteínas/fisiologia , Estrutura Terciária de Proteína/genética , Estrutura Terciária de Proteína/fisiologia , Células Vero , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo , Vacinas Virais/administração & dosagem , Vacinas Virais/genéticaRESUMO
Candid1, a live-attenuated Junin virus vaccine strain, was developed during the early 1980s to control Argentine hemorrhagic fever, a severe and frequently fatal human disease. Six amino acid substitutions were found to be unique to this vaccine strain, and their role in virulence attenuation in mice was analyzed using a series of recombinant viruses. Our results indicate that Candid1 is attenuated in mice through a single amino acid substitution in the transmembrane domain of the G2 glycoprotein. This work provides insight into the molecular mechanisms of attenuation of the only arenavirus vaccine currently available.
Assuntos
Vírus Junin/imunologia , Vírus Junin/patogenicidade , Mutação de Sentido Incorreto , Proteínas do Envelope Viral/genética , Vacinas Virais/genética , Fatores de Virulência/genética , Substituição de Aminoácidos/genética , Animais , Infecções por Arenaviridae/patologia , Infecções por Arenaviridae/virologia , Análise Mutacional de DNA , Modelos Animais de Doenças , Camundongos , Dados de Sequência Molecular , Mutação Puntual , Doenças dos Roedores/patologia , Doenças dos Roedores/virologia , Análise de Sequência de DNA , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Proteínas do Envelope Viral/metabolismo , Vacinas Virais/imunologia , Fatores de Virulência/metabolismoRESUMO
Background: Recent innovations have the potential to disrupt the current paradigm for kidney failure treatment. The US Food and Drug Administration is committed to incorporating valid scientific evidence about how patients weigh the benefits and risks of new devices into their decision making, but to date, premarket submission of patient preference information (PPI) has been limited for kidney devices. With input from stakeholders, we developed a survey intended to yield valid PPI, capturing how patients trade off the potential benefits and risks of wearable dialysis devices and in-center hemodialysis. Methods: We conducted concept elicitation interviews with individuals receiving dialysis to inform instrument content. After instrument drafting, we conducted two rounds of pretest interviews to evaluate survey face validity, comprehensibility, and perceived relevance. We pilot tested the survey with in-center hemodialysis patients to assess comprehensibility and usability further. Throughout, we used participant input to guide survey refinements. Results: Thirty-six individuals receiving in-center or home dialysis participated in concept elicitation (N=20) and pretest (N=16) interviews. Participants identified reduced fatigue, lower treatment burden, and enhanced freedom as important benefits of a wearable device, and many expressed concerns about risks related to device disconnection-specifically bleeding and infection. We drafted a survey that included descriptions of the risks of serious bleeding and serious infection and an assessment of respondent willingness to wait for a safer device. Input from pretest interviewees led to various instrument modifications, including treatment descriptions, item wording, and risk-level explanations. Pilot testing of the updated survey among 24 in-center hemodialysis patients demonstrated acceptable survey comprehensibility and usability, although 50% of patients required some assistance. Conclusions: The final survey is a 54-item web-based instrument that will yield estimates of the maximal acceptable risk for the described wearable device and willingness to wait for wearable devices with lower risk.
Assuntos
Falência Renal Crônica , Dispositivos Eletrônicos Vestíveis , Humanos , Falência Renal Crônica/terapia , Preferência do Paciente , Diálise Renal , Terapia de Substituição Renal , Inquéritos e QuestionáriosRESUMO
The clostridial botulinum neurotoxins (BoNTs) are the most potent protein toxins known. The carboxyl-terminal fragment of the toxin heavy chain (Hc) has been intensively investigated as a BoNT vaccine immunogen. We sought to determine whether targeting Hc to antigen-presenting cells (APCs) could accelerate the immune responses to vaccination with BoNT serotype A (BoNT/A) Hc. To test this hypothesis, we targeted Hc to the Fc receptors for IgG (FcγRs) expressed by dendritic cells (DCs) and other APCs. Hc was expressed as a fusion protein with a recombinant ligand for human FcγRs (R4) to produce HcR4 or a similar ligand for murine FcγRs to produce HcmR4. HcR4, HcmR4, and Hc were produced as secreted proteins using baculovirus-mediated expression in SF9 insect cells. In vitro receptor binding assays showed that HcR4 effectively targets Hc to all classes of FcγRs. APCs loaded with HcR4 or HcmR4 are substantially more effective at stimulating Hc-reactive T cells than APCs loaded with nontargeted Hc. Mice immunized with a single dose of HcmR4 or HcR4 had earlier and markedly higher Hc-reactive antibody titers than mice immunized with nontargeted Hc. These results extend to BoNT neutralizing antibody titers, which are substantially higher in mice immunized with HcmR4 than in mice immunized with Hc. Our results demonstrate that targeting Hc to FcγRs augments the pace and magnitude of immune responses to Hc.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Vacinas Bacterianas/imunologia , Toxinas Botulínicas Tipo A/imunologia , Botulismo/prevenção & controle , Receptores Fc/metabolismo , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Neutralizantes , Células Apresentadoras de Antígenos/metabolismo , Antitoxinas/sangue , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/metabolismo , Baculoviridae/genética , Linhagem Celular , Feminino , Vetores Genéticos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Spodoptera , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/metabolismo , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/metabolismoRESUMO
Cold pre-conditioning reduces subsequent brain injury in small animals but the underlying mechanisms remain undefined. As hypothermia triggers systemic macrophage tumor necrosis factor alpha (TNF-α) production and other neural pre-conditioning stimuli depend on this cytokine, we reasoned that microglia and TNF-α would be similarly involved with cold pre-conditioning neuroprotection. Also, as slice cultures closely approximate their in vivo counterpart and include quiescent microglia, we used rat hippocampal slice cultures to confirm this hypothesis. Furthermore, inflammatory cytokine gene screening with subsequent PCR and immunostaining confirmation of targeted mRNA and related protein changes showed that cold pre-conditioning triggered a significant rise in TNF-α that localized to microglia and a significant rise in interleukin (IL)-11 that localized mainly to hippocampal pyramidal neurons and, more rarely, astrocytes. Importantly, co-stimulation with cold and IL-11, an anti-inflammatory cytokine that inhibits TNF-α expression, abrogated the otherwise evident protection. Instead, cold pre-conditioning coupled with blockade of IL-11 signaling further enhanced neuroprotection from that seen with cold pre-conditioning alone. Thus, physiological activation of brain pro-inflammatory cytokine signaling, and its amplification by inhibition of coincident anti-inflammatory cytokine signaling, may be opportune targets for the development of novel therapeutics that can mimic the protection seen in cold pre-conditioning.
Assuntos
Temperatura Baixa , Interleucina-11/antagonistas & inibidores , Interleucina-11/metabolismo , Neurônios/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Região CA1 Hipocampal/citologia , Meios de Cultura Livres de Soro/farmacologia , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Agonistas de Aminoácidos Excitatórios/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , N-Metilaspartato/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfopiruvato Hidratase/metabolismo , RNA Mensageiro/metabolismo , Ratos , Receptores Tipo I de Fatores de Necrose Tumoral/farmacologia , Transdução de Sinais/efeitos dos fármacos , Temperatura , Fatores de Tempo , Técnicas de Cultura de Tecidos , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Infection remains a leading cause of death in kidney transplant recipients. This study aimed to assess the scope and consistency of infection outcomes reported in contemporary trials conducted in kidney transplant recipients. METHODS: A literature review of all randomized trials and trial protocols reporting infection outcomes in adult kidney transplant recipients was identified in the Cochrane Kidney and Transplant Specialized Register from January 2014 to July 2019. Characteristics and infection outcomes from the trials were analyzed. RESULTS: From 102 included trials, 772 outcome measures were extracted and categorized into 216 unique measures with a median of 3.2 outcome measures per trial (range: 1-9). Measures were further grouped into 32 outcomes based on site of infection (14 outcomes) and organism (18 outcomes). The most commonly reported site-specific outcome and organism-specific outcome were systemic infection (71% trials) and cytomegalovirus infection (62% trials), respectively. Outcome metric and methods of aggregation included mean, median, proportion, proportional change, and number of patients with at least 1 episode. Across all trials, measures were assessed at 55 different time points with a range of 1-11 time points per trial. CONCLUSIONS: Infection outcomes in kidney transplant recipients were frequently reported by site and organism but varied widely in terms of outcome, metrics, method of aggregation, and time point of measurement. Establishment of core outcomes for infection based on the shared priorities of patients/caregivers and health professionals may improve the consistency, comparability, and usefulness of trial evidence.
Assuntos
Transplante de Rim , Adulto , Humanos , Transplante de Rim/efeitos adversos , TransplantadosRESUMO
Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3(+)CD14(+) monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p < 0.009); (2) stable interferon beta-treated relapsing-remitting multiple sclerosis (p < 0.001) and; (3) healthy controls (p < 0.009). Glatiramer acetate-stimulated CD4( +) T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p = 0.0017 for multiple sclerosis; p = 0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon beta is beneficial in multiple sclerosis; why so remains unclear. Interferon beta-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon beta and a new target for therapeutic intervention in relapsing-remitting multiple sclerosis.
Assuntos
Interferon beta/efeitos adversos , Monócitos/metabolismo , Esclerose Múltipla Recidivante-Remitente/metabolismo , Receptores de Superfície Celular/sangue , Linfócitos T/metabolismo , Adulto , Antígeno B7-1/sangue , Antígeno B7-2/sangue , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Separação Celular , Feminino , Citometria de Fluxo , Imunofluorescência , Acetato de Glatiramer , Humanos , Imunossupressores/farmacologia , Interferon beta-1b , Interferon beta/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/fisiologia , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Peptídeos/farmacologia , Receptores de Superfície Celular/biossíntese , Receptores Imunológicos/sangue , Recidiva , Linfócitos T/imunologiaRESUMO
INTRODUCTION: Understanding who heeds the driving-related COVID-19 restrictions is critical for assisting public health professionals improve response to this and future pandemic events. The purpose of the current study was to characterize driving behavior changes among adolescents as a function of COVID-19 restrictions. It was hypothesized that adolescent driving would be reduced by COVID-19 restrictions, especially for younger teens, non-minorities, females, non-working teens, and those with higher prosocial tendencies. METHODS: Participants were licensed drivers in "REACT," a longitudinal study of adolescent driving attention. Upon enrollment in REACT, drivers were required to be age 16 or 18, have been issued a driver's license within the last two weeks, and be fluent in written/spoken English. The current observational cohort study was of drivers reporting driving exposure between February 8 and April 22, 2020. Linear mixed-effects models estimated differences in driving changes between COVID-19 periods. RESULTS: Results indicated a decrease across pre-COVID-19 period (February 8 - March 13, 2020) in days driven per week and vehicle miles driven (VMD) was explained by the change of slope post-COVID-19 restrictions (March 14 - April 22, 2020). Post-COVID-19, driving days per week decreased by 37 % and VMD decreased by 35 %. This decrease was lower in ethnic minorities, older adolescents, and employed adolescents. Those with greater dire prosocial tendencies showed greater post-COVID-19 driving decline. DISCUSSION: Findings provide early evidence of COVID-19 restriction-related adolescent driving changes suggesting older, employed, minority teens and teens with lower prosocial tendencies are less likely to reduce driving behavior. These observations provide a foundation for more extensive studies of adolescent drivers during various driving and contact restrictions and inform future public health campaigns for social distancing.
Assuntos
Comportamento do Adolescente , Condução de Veículo , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Acidentes de Trânsito , Adolescente , Atenção , Betacoronavirus , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Licenciamento , Estudos Longitudinais , Masculino , Distanciamento Físico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , SARS-CoV-2 , Isolamento SocialRESUMO
BACKGROUND AND OBJECTIVES: The language used to communicate important aspects of kidney health is inconsistent and may be conceptualized differently by patients and health professionals. These problems may impair the quality of communication, care, and patient outcomes. We aimed to describe the perspectives of patients on terms used to describe kidney health. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with CKD (n=54) and caregivers (n=13) from the United States, United Kingdom, and Australia participated in ten focus groups to discuss terms for kidney health (including kidney, renal, CKD, ESKD, kidney failure, and descriptors for kidney function). We analyzed the data using thematic analysis. RESULTS: We identified four themes: provoking and exacerbating undue trauma (fear of the unknown, denoting impending death, despair in having incurable or untreatable disease, premature labeling and assumptions, judgment, stigma, and failure of self); frustrated by ambiguity (confused by medicalized language, lacking personal relevance, baffled by imprecision in meaning, and/or opposed to obsolete terms); making sense of the prognostic enigma (conceptualizing level of kidney function, correlating with symptoms and effect on life, predicting progression, and need for intervention); and mobilizing self-management (confronting reality, enabling planning and preparation, taking ownership for change, learning medical terms for self-advocacy, and educating others). CONCLUSIONS: The obscurity and imprecision of terms in CKD can be unduly distressing and traumatizing for patients, which can impair decision making and self-management. Consistent and meaningful patient-centered terminology may improve patient autonomy, satisfaction, and outcomes.
Assuntos
Cuidadores/psicologia , Pacientes/psicologia , Insuficiência Renal Crônica/psicologia , Terminologia como Assunto , Adolescente , Adulto , Idoso , Comunicação , Compreensão , Tomada de Decisões , Progressão da Doença , Medo , Feminino , Grupos Focais , Frustração , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Autogestão , Adulto JovemRESUMO
In brain, monomeric immunoglobin G (IgG) is regarded as quiescent and only poised to initiate potentially injurious inflammatory reactions via immune complex formation associated with phagocytosis and tumor necrosis factor alpha (TNF-alpha) production in response to disease. Using rat hippocampal slice and microglial cultures, here we show instead that physiological levels (i.e., 0.2-20 microg/ml) of monomeric IgG unassociated with disease triggered benign low-level proinflammatory signaling that was neuroprotective against CA1 area excitotoxicity and followed a U-shaped or hormetic dose-response. The data indicate that physiological IgG levels activated microglia by enhancing recycling endocytosis plus TNF-alpha release from these cells to produce the neuroprotection. Minocycline, known for its anti-inflammatory and neuroprotective effects when given after disease onset, abrogated IgG-mediated neuroprotection and related microglial effects when given before injury. In contrast, E-prostanoid receptor subtype 2 (EP2) activation, which served as an exemplary paracrine stimulus like the one expected from neuronal activity, amplified IgG-mediated increased microglial recycling endocytosis and TNF-alpha production. Furthermore, like monomeric IgG these EP2 related effects took days to be effective, suggesting both were adaptive anabolic effects consistent with those seen from other long-term preconditioning stimuli requiring de novo protein synthesis. The data provide the first evidence that brain monomeric IgG at physiological levels can have signaling function via enhanced recycling endocytosis/TNF-alpha production from microglia unassociated with disease and that these IgG-mediated changes may be a means by which paracrine signaling from neuronal activity influences microglia to evoke neuroprotection. The data provide further support that low-level proinflammatory neural immune signaling unassociated with disease enhances brain function.
Assuntos
Endocitose/fisiologia , Imunoglobulina G/farmacologia , Microglia/efeitos dos fármacos , Microglia/fisiologia , Fármacos Neuroprotetores/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células Cultivadas , Dinoprostona/farmacologia , Relação Dose-Resposta a Droga , Ectodisplasinas/metabolismo , Endocitose/efeitos dos fármacos , Glucose/deficiência , Hipocampo , Hipóxia , Imunoglobulina G/líquido cefalorraquidiano , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Minociclina/farmacologia , N-Metilaspartato/toxicidade , Neurotoxinas/toxicidade , Técnicas de Cultura de Órgãos , Fosfopiruvato Hidratase/metabolismo , Ratos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologia , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
To better understand cognitive control impairment in schizophrenia, it is vital to determine the extent of dysfunctional connectivity in the associated fronto-striatal brain network, with a focus on the connections with the anterior cingulate cortex (ACC), prior to the potential confounding effect of medication. It is also essential to determine the effects following antipsychotic medication and the relationship of those effects on psychosis improvement. Twenty-two patients with schizophrenia, initially unmedicated and after a 6-week course of risperidone, and 20 matched healthy controls (HC) performed a fMRI task twice, six weeks apart. We investigated group and longitudinal differences in ACC-related functional connectivity during performance of a Stroop color task as well as connectivity patterns associated with improvement in psychosis symptoms. Unmedicated patients with schizophrenia showed greater functional connectivity between ACC and bilateral caudate and midbrain and lower connectivity with left putamen compared to healthy controls. At baseline, greater functional connectivity between ACC and bilateral putamen predicted subsequent better treatment response. Change in functional connectivity between ACC and left putamen positively correlated with better treatment response. These results suggest that patterns of functional connectivity in fronto-striatal networks can be utilized to predict potential response to antipsychotic medication. Prior to treatment, brain function may be structured with a predisposition that favors or not treatment response.
Assuntos
Antipsicóticos/farmacologia , Disfunção Cognitiva/fisiopatologia , Conectoma , Função Executiva/fisiologia , Giro do Cíngulo/fisiopatologia , Rede Nervosa/fisiopatologia , Putamen/fisiopatologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Resultado do Tratamento , Adulto , Disfunção Cognitiva/etiologia , Feminino , Seguimentos , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Putamen/diagnóstico por imagem , Risperidona/farmacologia , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Teste de Stroop , Adulto JovemRESUMO
Recent magnetic resonance spectroscopy (MRS) studies suggest that abnormalities of the glutamatergic system in schizophrenia may be dependent on illness stage, medication status, and symptomatology. Glutamatergic metabolites appear to be elevated in the prodromal and early stages of schizophrenia but unchanged or reduced below normal in chronic, medicated patients. However, few of these studies have measured metabolites with high-field 7T MR scanners, which offer higher signal-to-noise ratio and better spectral resolution than 3T scanners and facilitate separation of glutamate and glutamine into distinct signals. In this study, we examined glutamate and other metabolites in the dorsal anterior cingulate cortex (ACC) of first-episode schizophrenia patients. Glutamate and N-acetylaspartate (NAA) were significantly lower in schizophrenia patients vs controls. No differences were observed in levels of glutamine, GABA, or other metabolites. In schizophrenia patients but not controls, GABA was negatively correlated with the total score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as well as the immediate memory and language subscales. Our findings suggest that glutamate and NAA reductions in the ACC may be present early in the illness, but additional large-scale studies are needed to confirm these results as well as longitudinal studies to determine the effect of illness progression and treatment. The correlation between GABA and cognitive function suggests that MRS may be an important technique for investigating the neurobiology underlying cognitive deficits in schizophrenia.
Assuntos
Ácido Aspártico/análogos & derivados , Disfunção Cognitiva/metabolismo , Ácido Glutâmico/metabolismo , Giro do Cíngulo/metabolismo , Transtornos Psicóticos/metabolismo , Esquizofrenia/metabolismo , Ácido gama-Aminobutírico/metabolismo , Adulto , Ácido Aspártico/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Humanos , Masculino , Espectroscopia de Prótons por Ressonância Magnética , Transtornos Psicóticos/complicações , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Schizophrenia is thought to be a disorder of brain dysconnectivity. An imbalance between cortical excitation/inhibition is also implicated, but the link between these abnormalities remains unclear. The present study used magnetic resonance spectroscopy and functional magnetic resonance imaging at 7T to investigate how measurements of glutamate and gamma-aminobutyric acid (GABA) relate to the blood oxygen level-dependent (BOLD) response during a cognitive task, and how these relationships are altered in schizophrenia. METHODS: Usable functional magnetic resonance imaging data from 17 first-episode psychosis (FEP) patients (4 women, 13 men) and 21 matched healthy control subjects (HCs) (5 women, 16 men) were acquired during a Stroop task. Within- and between-group comparisons of the BOLD response were performed. Neurometabolite levels were measured in the dorsal anterior cingulate cortex. Two multiple regressions investigated how glutamate, glutamine, and GABA related to the BOLD response in HCs and FEP patients separately. A third investigated between-group differences in the relationships between the BOLD response and each of these neurometabolites. RESULTS: Compared with HCs, FEP patients showed an increased BOLD response within regions of the executive and default mode networks. In FEP patients, the relationship between anterior cingulate cortex glutamate levels and the BOLD response in regions of the posterior default mode network was opposite to that of HCs. In FEP patients but not HCs, anterior cingulate cortex GABA levels correlated with the local BOLD response and with the Stroop reaction time. CONCLUSION: These results suggest a mechanism whereby alterations in the relationship between cortical glutamate/GABA and BOLD response is disrupting the dynamic of major neural networks, possibly affecting cognition.
Assuntos
Encéfalo/fisiopatologia , Excitabilidade Cortical , Ácido Glutâmico/metabolismo , Inibição Neural , Transtornos Psicóticos/fisiopatologia , Ácido gama-Aminobutírico/metabolismo , Adulto , Encéfalo/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/psicologia , Teste de Stroop , Adulto JovemRESUMO
Magnetic Resonance Spectroscopy is a popular approach to probe brain chemistry in schizophrenia (SZ), but no consensus exists as to the extent of alterations. This may be attributable to differential effects of populations studied, brain regions examined, or antipsychotic medication effects. Here, we measured neurometabolites in the anterior cingulate cortex (ACC) and hippocampus, two structurally dissimilar brain regions implicated in the SZ pathophysiology. We enrolled 61 SZ with the goal to scan them before and after six weeks of treatment with risperidone. We also scanned 31 matched healthy controls twice, six weeks apart. Using mixed effect repeated measures linear models to examine the effect of group and time on metabolite levels in each voxel, we report an increase in hippocampal glutamateâ¯+â¯glutamine (Glx) in SZ compared to controls (pâ¯=â¯0.043), but no effect of antipsychotic medication (pâ¯=â¯0.330). In the ACC, we did not find metabolite alterations or antipsychotic medication related changes after six weeks of treatment with risperidone. The coefficients for the discriminant function (differentiating SZ from HC) in the ACC were greatest for NAA (-0.83), and in the hippocampus for Glx (0.76), the same metabolites were associated with greater treatment response in patients at trend level. Taken together, our data extends the existing literature by demonstrating regionally distinct metabolite alterations in the same patient group and suggests that antipsychotic medications may have limited effects on metabolite levels in these regions.