RESUMO
Neuroinflammation is a hallmark of neurodegenerative disorders including Alzheimer's disease (AD). Microglia, the brain's immune cells, express many of the AD-risk loci identified in genome wide association studies and present a promising target for anti-inflammatory RNA therapeutics but are difficult to transfect with current methods. Here, several lipid nanoparticle (LNP) formulations are examined, and a lead candidate that supports efficient RNA delivery in cultures of human stem cell-derived microglia-like cells (iMGLs) and animal models of neuroinflammation is identified. The lead microglia LNP (MG-LNP) formulation shows minimal toxicity and improves delivery efficiency to inflammatory iMGLs, suggesting a preference for delivery into activated microglia. Intraperitoneal injection of the MG-LNP formulation generates widespread expression of the delivered reporter construct in all organs, whereas local intracisternal injection directly into the cerebrospinal fluid leads to preferential expression in the brain. It is shown that LNP-mediated delivery of siRNA targeting the PU.1 transcription factor, a known AD-risk locus, successfully reduces PU.1 levels in iMGLs and reduces neuroinflammation in mice injected with LPS and in CK-p25 mice that mimic the chronic neuroinflammation seen in AD patients. The LNP formulation represents an effective RNA delivery vehicle when applied intrathecally and can be broadly utilized to test potential neuroinflammation-directed gene therapies.
Assuntos
Doença de Alzheimer , Nanopartículas , Humanos , Animais , Camundongos , RNA Interferente Pequeno/genética , Doenças Neuroinflamatórias , Estudo de Associação Genômica Ampla , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismoRESUMO
BACKGROUND: The operating room (OR) remains a challenging and hierarchical work environment within healthcare, where the attending surgeon functions as a team captain. Unprofessional behavior or disconnects in this environment can lead to breakdowns in teamwork and reports within the safety event reporting system (SERS).1 Interventions focused on remediating adverse behaviors and team interactions should optimize team function and potentially enhance patient outcomes. The aim of the present study focused on decreasing the SERS reports regarding behavior and communication disconnects from 11/2019 to 03/2023. METHODS: A multidisciplinary team designed a novel reporting system to separate mechanical and procedural safety events from communication and behavior-related disconnects in the OR. The following plan-do-study-act cycles were performed by the multidisciplinary team: (1) developed the role of the Peer Advocate (PA) to mediate conversations amongst team members when behavior and communication disconnects occur, (2) redirect behavior and communication disconnects reported in the SERS to the PA Program, and (3) develop and discuss interpersonal skills to prevent disconnects from occurring. RESULTS: Thirty-nine disconnects were reported through the PA Program during the two-year trial. The most common initiating team member were nurses, and the most common identifying team member were surgeons. The number of monthly SERS reports regarding behavior and communication disconnects decreased with the described interventions. CONCLUSION: The multidisciplinary task force developed and adapted a process to address communication and behavioral concerns in an efficient and supportive manner, with the objective of restoring relationships amongst team members in the perioperative environment and de-weaponizing the SERS.
RESUMO
Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer's disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders.
Assuntos
Doença de Alzheimer , Doenças Neuroinflamatórias , Animais , Camundongos , Humanos , Oncogenes , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Linhagem Celular , Modelos Animais de Doenças , Camundongos TransgênicosRESUMO
PROBLEM/CONDITION: Autism spectrum disorder (ASD). PERIOD COVERED: 2016. DESCRIPTION OF SYSTEM: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance program that provides estimates of the prevalence of ASD among children aged 8 years whose parents or guardians live in 11 ADDM Network sites in the United States (Arizona, Arkansas, Colorado, Georgia, Maryland, Minnesota, Missouri, New Jersey, North Carolina, Tennessee, and Wisconsin). Surveillance is conducted in two phases. The first phase involves review and abstraction of comprehensive evaluations that were completed by medical and educational service providers in the community. In the second phase, experienced clinicians who systematically review all abstracted information determine ASD case status. The case definition is based on ASD criteria described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. RESULTS: For 2016, across all 11 sites, ASD prevalence was 18.5 per 1,000 (one in 54) children aged 8 years, and ASD was 4.3 times as prevalent among boys as among girls. ASD prevalence varied by site, ranging from 13.1 (Colorado) to 31.4 (New Jersey). Prevalence estimates were approximately identical for non-Hispanic white (white), non-Hispanic black (black), and Asian/Pacific Islander children (18.5, 18.3, and 17.9, respectively) but lower for Hispanic children (15.4). Among children with ASD for whom data on intellectual or cognitive functioning were available, 33% were classified as having intellectual disability (intelligence quotient [IQ] ≤70); this percentage was higher among girls than boys (39% versus 32%) and among black and Hispanic than white children (47%, 36%, and 27%, respectively) [corrected]. Black children with ASD were less likely to have a first evaluation by age 36 months than were white children with ASD (40% versus 45%). The overall median age at earliest known ASD diagnosis (51 months) was similar by sex and racial and ethnic groups; however, black children with IQ ≤70 had a later median age at ASD diagnosis than white children with IQ ≤70 (48 months versus 42 months). INTERPRETATION: The prevalence of ASD varied considerably across sites and was higher than previous estimates since 2014. Although no overall difference in ASD prevalence between black and white children aged 8 years was observed, the disparities for black children persisted in early evaluation and diagnosis of ASD. Hispanic children also continue to be identified as having ASD less frequently than white or black children. PUBLIC HEALTH ACTION: These findings highlight the variability in the evaluation and detection of ASD across communities and between sociodemographic groups. Continued efforts are needed for early and equitable identification of ASD and timely enrollment in services.