APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology.

Background: Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.

The San Francisco Health Systems Collaborative: Public Health and Health Care Delivery Systems' Response to the Covid-19 Pandemic.

The Covid-19 pandemic challenged health care delivery systems worldwide. Many acute care hospitals in communities that experienced surges in cases and hospitalizations had to make decisions such as rationing scarce resources. Hospitals serving low-income communities, communities of color, and those in other historically marginalized or vulnerable groups reported the greatest operational impacts of surges.

C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. The complement pathway has been proposed as a therapeutic target. C5aR1 inhibition reduces plaque load, gliosis, and memory deficits in animal models, however, the cellular bases underlying this neuroprotection were unclear.

C5aR1 inhibition alleviates cranial radiation-induced cognitive decline.

Unlabelled: Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are a particularly pressing problem for the survivors of pediatric and low grade glioma (LGG) cancers who often live long post-RT lives. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss.

APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology.

Background: Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimer's Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects.

Sex-specific associations between AD genotype and the microbiome of human amyloid beta knock-in (hAβ-KI) mice.

Introduction: Emerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.

Methods: We used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).

Results: Eighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA).

The Abca7 variant reduces Aβ generation, plaque load, and neuronal damage.

Background: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).

Methods: CRISPR-Cas9 was used to generate an Abca7 variant in mice, modeling the homologous human ABCA7 variant, and extensive characterization was performed.

Results: Abca7 microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity.

BIN1 suppresses glial response to plaques in mouse model of Alzheimer's disease.

Introduction: The BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.

Methods: To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1 knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.

C5aR1 signaling promotes region- and age-dependent synaptic pruning in models of Alzheimer's disease.

Introduction: Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD.

C5aR1 signaling promotes region and age dependent synaptic pruning in models of Alzheimer's Disease.

Introduction: Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD.

C5aR1 antagonism suppresses inflammatory glial gene expression and alters cellular signaling in an aggressive Alzheimer's model.

Alzheimer's disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. Pharmacologic inhibition of C5aR1 reduces plaque load, gliosis and memory deficits in animal models. However, the cellular basis underlying this neuroprotection and which processes were the consequence of amyloid reduction vs alteration of the response to amyloid were unclear.

San Francisco's Citywide COVID-19 Response: Strategies to Reduce COVID-19 Severity and Health Disparities, March 2020 Through May 2022.

San Francisco implemented one of the most intensive, comprehensive, multipronged COVID-19 pandemic responses in the United States using 4 core strategies: (1) aggressive mitigation measures to protect populations at risk for severe disease, (2) prioritization of resources in neighborhoods highly affected by COVID-19, (3) timely and adaptive data-driven policy making, and (4) leveraging of partnerships and public trust. We collected data to describe programmatic and population-level outcomes. The excess all-cause mortality rate in 2020 in San Francisco was half that seen in 2019 in California as a whole (8% vs 16%).

FEASIBILITY AND SAFETY OF A FIELD CARE CLINIC AS AN ALTERNATIVE AMBULANCE DESTINATION DURING THE COVID-19 PANDEMIC.

Background: Anticipating an increased utilization of healthcare facilities during the COVID-19 surge, the San Francisco Department of Public Health developed a plan to deploy neighborhood-based Field Care Clinics (FCCs) that would decompress emergency departments by serving patients with low acuity complaints. These clinics would receive patients directly from the Emergency Medical Services (EMS) system. Transports were initiated by a paramedic-driven protocol, originally by EMS crews and later by the Centralized Ambulance Destination Determination (CADDiE) System.

A Trem2 mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques.

Background: The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current Trem2 mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2 (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products.

Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation.

The complement system is an ancient collection of proteolytic cascades with well-described roles in regulation of innate and adaptive immunity. With the convergence of a revolution in complement-directed clinical therapeutics, the discovery of specific complement-associated targetable pathways in the central nervous system, and the development of integrated multi-omic technologies that have all emerged over the last 15 years, precision therapeutic targeting in Alzheimer disease and other neurodegenerative diseases and processes appears to be within reach. As a sensor of tissue distress, the complement system protects the brain from microbial challenge as well as the accumulation of dead and/or damaged molecules and cells.

Basic emergency care course and longitudinal mentorship completed in a rural Neno District, Malawi: A feasibility, acceptability, and impact study.

Background: Frontline providers mostly outside specific emergency areas deliver emergency care around the world, yet often they do not receive dedicated training in managing emergency conditions. When designed for low-resource settings, emergency care training has been shown to improve provider skills, facilitate efficient use of available resources, and reduce death and disability by ensuring timely access to life-saving care.

Methods: The WHO/ICRC Basic Emergency Care (BEC) Course with follow up longitudinal mentorship for 6 months was implemented in rural Neno District Malawi from September 2019-April 2020.

Degenerate mapping of environmental location presages deficits in object-location encoding and memory in the 5xFAD mouse model for Alzheimer's disease.

A key challenge in developing diagnosis and treatments for Alzheimer's disease (AD) is to detect abnormal network activity at as early a stage as possible. To date, behavioral and neurophysiological investigations in AD model mice have yet to conduct a longitudinal assessment of cellular pathology, memory deficits, and neurophysiological correlates of neuronal activity. We therefore examined the temporal relationships between pathology, neuronal activities and spatial representation of environments, as well as object location memory deficits across multiple stages of development in the 5xFAD mice model and compared these results to those observed in wild-type mice.

C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimer's disease.

Multiple studies have recognized the involvement of the complement cascade during Alzheimer's disease pathogenesis. However, the specific role of C5a-C5aR1 signaling in the progression of this neurodegenerative disease is still not clear. Furthermore, its potential as a therapeutic target to treat AD still remains to be elucidated.

Modulation of C5a-C5aR1 signaling alters the dynamics of AD progression.

Background: The complement system is part of the innate immune system that clears pathogens and cellular debris. In the healthy brain, complement influences neurodevelopment and neurogenesis, synaptic pruning, clearance of neuronal blebs, recruitment of phagocytes, and protects from pathogens. However, excessive downstream complement activation that leads to generation of C5a, and C5a engagement with its receptor C5aR1, instigates a feed-forward loop of inflammation, injury, and neuronal death, making C5aR1 a potential therapeutic target for neuroinflammatory disorders.

Mobile application adjunct to the WHO basic emergency care course: a mixed methods study.

Objectives: The WHO developed a 5-day basic emergency care (BEC) course using the traditional lecture format. However, adult learning theory suggests that lecture-based courses alone may not promote long-term knowledge retention. We assessed whether a mobile application adjunct (BEC app) can have positive impact on knowledge acquisition and retention compared with the BEC course alone and evaluated perceptions, acceptability and barriers to adoption of such a tool.

Pre-course online cases for the world health organization's basic emergency care course in Uganda: A mixed methods analysis.

Introduction: The Ministry of Health - Uganda implemented the World Health Organization's Basic Emergency Care course (BEC) to improve formal emergency care training and address its high burden of acute illness and injury. The BEC is an open-access, in-person, short course that provides comprehensive basic emergency training in low-resource settings. A free, open-access series of pre-course online cases available as downloadable offline files were developed to improve knowledge acquisition and retention.