Positive allosteric modulation as a potential therapeutic strategy in anti-NMDA receptor encephalitis

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENTAnti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.</jats:p

Uncertainty as a Key Influence in the Decision To Admit Patients with Transient Ischemic Attack

Background Patients with transient ischemic attacks (TIA) are at high risk of subsequent vascular events. Hospitalization improves quality of care, yet admission rates for TIA patients vary considerably. Objectives We sought to identify factors associated with the decision to admit patents with TIA. Design We conducted a secondary analysis of a prior study’s data including semi-structured interviews, administrative data, and chart review. Participants We interviewed multidisciplinary clinical staff involved with TIA care. Administrative data included information for TIA patients in emergency departments or inpatient settings at VA medical centers (VAMCs) for fiscal years (FY) 2011 and 2014. Chart reviews were conducted on a subset of patients from 12 VAMCs in FY 2011. Approach For the qualitative data, we focused on interviewees’ responses to the prompt: “Tell me what influences you in the decision to or not to admit TIA patients.” We used administrative data to identify admission rates and chart review data to identify ABCD2 scores (a tool to classify stroke risk after TIA). Key Results Providers’ decisions to admit TIA patients were related to uncertainty in several domains: lack of a facility TIA-specific policy, inconsistent use of ABCD2 score, and concerns about facilities’ ability to complete a timely workup. There was a disconnect between staff perceptions about TIA admission and facility admission rates. According to chart review data, staff at facilities with higher admission rates in FY 2011 reported consistent reliance on ABCD2 scores and related guidelines in admission decision-making. Conclusions Many factors contributed to decisions regarding admitting a patient with TIA; however, clinicians’ uncertainty appeared to be a key driver. Further quality improvement interventions for TIA care should focus on facility adoption of TIA protocols to address uncertainty in TIA admission decision-making and to standardize timely evaluation of TIA patients and delivery of secondary prevention strategies

Safety Assessment of Biotechnology Products for Potential Risk of Food Allergy: Implications of New Research

Food allergy is a potential risk associated with use of transgenic proteins in crops. Currently, safety assessment involves consideration of the source of the introduced protein, in silico amino acid sequence homology comparisons to known allergens, physicochemical properties, protein abundance in the crop, and, when appropriate, specific immunoglobulin E binding studies. Recently conducted research presented at an International Life Sciences Institute/Health and Environmental Sciences Institute–hosted workshop adds to the scientific foundation for safety assessment of transgenic proteins in five areas: structure/activity, serum screening, animal models, quantitative proteomics, and basic mechanisms. A web-based tool is now available that integrates a database of allergenic proteins with a variety of computational tools which could be used to improve our ability to predict allergenicity based on structural analysis. A comprehensive strategy and model protocols have been developed for conducting meaningful serum screening, an extremely challenging process. Several animal models using oral sensitization with adjuvant and one dermal sensitization model have been developed and appear to distinguish allergenic from nonallergenic food extracts. Data presented using a mouse model suggest that pepsin resistance is indicative of allergenicity. Certain questions remain to be addressed before considering animal model validation. Gel-free mass spectrometry is a viable alternative to more labor-intensive approaches to quantitative proteomics. Proteomic data presented on four nontransgenic varieties of soy suggested that if known allergen expression in genetically modified crops falls within the range of natural variability among commercial varieties, there appears to be no need to test further. Finally, basic research continues to elucidate the etiology of food allergy

Strategic Activity and Financial Performance of U.S. Rural Hospitals: A National Study, 1983 to 1988

This study examines the effect of 13 strategic management activities on the financial performance of a national sample of 797 U.S. rural hospitals during the period of 1983-1988. Controlled for environment-market, geographic-region, and hospital-related variables, the results show almost no measurable effect of strategic adoption on rural hospital profitability and liquidity. Where statistically significant relationships existed, they were more often negative than positive. These findings were not expected; it was hypothesized that positive effects across a broad range of strategies would emerge, other things being equal. Discussed are possible explanations for these findings as well as their implication for a rural health policy relying on individual rural hospital strategic adaptation to environmental change.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72301/1/j.1748-0361.1994.tb00225.x.pd

Show me the numbers: what data currently exist for non‐native species in the USA?

Non‐native species continue to be introduced to the United States from other countries via trade and transportation, creating a growing need for early detection and rapid response to new invaders. It is therefore increasingly important to synthesize existing data on non‐native species abundance and distributions. However, no comprehensive analysis of existing data has been undertaken for non‐native species, and there have been few efforts to improve collaboration. We therefore conducted a survey to determine what datasets currently exist for non‐native species in the US from county, state, multi‐state region, national, and global scales. We identified 319 datasets and collected metadata for 79% of these. Through this study, we provide a better understanding of extant non‐native species datasets and identify data gaps (ie taxonomic, spatial, and temporal) to help guide future survey, research, and predictive modeling efforts

An efficacy trial of an electronic health record-based strategy to inform patients on safe medication use: The role of written and spoken communication

We tested the feasibility and efficacy of an electronic health record (EHR) strategy that automated the delivery of print medication information at the time of prescribing

Electrical Stimulation Modulates High γ Activity and Human Memory Performance.

Direct electrical stimulation of the brain has emerged as a powerful treatment for multiple neurological diseases, and as a potential technique to enhance human cognition. Despite its application in a range of brain disorders, it remains unclear how stimulation of discrete brain areas affects memory performance and the underlying electrophysiological activities. Here, we investigated the effect of direct electrical stimulation in four brain regions known to support declarative memory: hippocampus (HP), parahippocampal region (PH) neocortex, prefrontal cortex (PF), and lateral temporal cortex (TC). Intracranial EEG recordings with stimulation were collected from 22 patients during performance of verbal memory tasks. We found that high γ (62-118 Hz) activity induced by word presentation was modulated by electrical stimulation. This modulatory effect was greatest for trials with poor memory encoding. The high γ modulation correlated with the behavioral effect of stimulation in a given brain region: it was negative, i.e., the induced high γ activity was decreased, in the regions where stimulation decreased memory performance, and positive in the lateral TC where memory enhancement was observed. Our results suggest that the effect of electrical stimulation on high γ activity induced by word presentation may be a useful biomarker for mapping memory networks and guiding therapeutic brain stimulation

Mental Health Over Time in a Military Sample: The Impact of Alcohol Use Disorder on Trajectories of Psychopathology After Deployment

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116086/1/jts22055.pd

Global governance for improved human, animal, and planetary health : the essential role of schools and programs of public health

Since March 2021, the world’s leaders have expressed a desire to “build back better,” reflecting a desire to see an enhanced post-pandemic world and the need to improve and protect health by being better prepared to respond to future pandemics. On March 30, 2021, 25 of the world’s leaders signed an accord calling for a new pandemic preparedness treaty. There is great complexity in achieving an international health treaty. The Independent Panel for Pandemic Preparedness and Response, appointed by the World Health Organization (WHO), reported on May 14, 2021. They called for better funding for WHO, a Global Council for Health threats to work collaboratively with the WHO, and the delivery of the global vaccine program. They called for “21st century health data surveillance” and transparency in data sharing across countries. The Rome Declaration of the Global Health Summit of the G20, called for better preparedness, for support to low- and middle-income countries and for better global financing and governance for public health and health care. The Carbis Bay Declarations of the G7 governments set out proposals for a better planet, economy, and health. The European Union has set out plans to strengthen its capabilities through a Health Emergency Responsiveness Agency (HERA). The vision for HERA may be an example of how other supra-national, continental, or WHO regional health response agencies could be organized and resourced. A Special Session of the World Health Assembly which took place in November 2021 has agreed to set up an Intergovernmental negotiating body to move forward the process of establishing a new Global Pandemic Preparedness Treaty