Spatial proteomics of hippocampal subfield-specific pathology in Alzheimer's disease and primary age-related tauopathy.

INTRODUCTION: Alzheimer's disease (AD) and primary age-related tauopathy (PART) both harbor 3R/4R hyperphosphorylated-tau (p-tau)-positive neurofibrillary tangles (NFTs) but differ in the spatial p-tau development in the hippocampus. METHODS: Using Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT-bearing and non-NFT-bearing neurons in AD (n = 7) and PART (n = 7) subjects. RESULTS: Proteomic measures of synaptic health were inversely correlated with the subregional p-tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aß) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART. DISCUSSION: These results suggest subfield-specific proteome differences that may explain some of the differences in Aß and p-tau distribution and apparent pathogenicity. In addition, hippocampal neurons in possible PART may have more in common with AD than with definite PART, highlighting the importance of Aß in the pathologic process. HIGHLIGHTS: Synaptic health is inversely correlated with local p-tau burden. The proteome of NFT- and non-NFT-bearing neurons is influenced by the presence of Aß in the hippocampus. Neurons in possible PART cases share more proteomic similarities with neurons in ADNC than they do with neurons in definite PART cases.

Why Do Haul Truck Fatal Accidents Keep Occurring?

Powered haulage continues to be a large safety concern for the mining industry, accounting for approximately 50% of the mining fatal accidents every year. Among these fatal accidents, haul-truck-related accidents are the most common, with 6 of 28 and 6 of 27 fatal accidents occurring in 2017 and 2018, respectively. To better understand why these accidents continue to occur and what can be done to prevent them, researchers reviewed the 91 haul-truck-related fatal accidents that occurred in the USA from 2005 to 2018 and performed bow-tie analyses using the final reports published by the Mine Safety and Health Administration. The analyses explore the context of the accidents with a focus on the initiating event, event outcome, hazards present, and possible preventative and mitigative controls. Overall, the vast majority of the accidents resulted in a haul truck colliding with the environment, and the majority of these events were initiated by loss of situational awareness or loss of control. The majority of the hazards were related to design and organizational controls. The results of this study suggest a need to investigate operator decision-making and organizational controls and to focus on improving design and operation controls such as mine design and operational procedures.

Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology.

Senescent cells contribute to pathology and dysfunction in animal models1. Their sparse distribution and heterogenous phenotype have presented challenges for detecting them in human tissues. We developed a senescence eigengene approach to identify these rare cells within large, diverse populations of postmortem human brain cells. Eigengenes are useful when no single gene reliably captures a phenotype, like senescence; they also help to reduce noise, which is important in large transcriptomic datasets where subtle signals from low-expressing genes can be lost. Each of our eigengenes detected ~2% senescent cells from a population of ~140,000 single nuclei derived from 76 postmortem human brains with various levels of Alzheimer's disease (AD) pathology. More than 97% of the senescent cells were excitatory neurons and overlapped with tau-containing neurofibrillary tangles (NFTs). Cyclin dependent kinase inhibitor 2D (CDKN2D/p19) was predicted as the most significant contributor to the primary senescence eigengene. RNAscope and immunofluorescence confirmed its elevated expression in AD brain tissue whereby p19-expressing neurons had 1.8-fold larger nuclei and significantly more cells with lipofuscin than p19-negative neurons. These hallmark senescence phenotypes were further elevated in the presence of NFTs. Collectively, CDKN2D/p19-expressing neurons with NFTs represent a unique cellular population in human AD with a senescence phenotype. The eigengenes developed may be useful in future senescence profiling studies as they accurately identified senescent cells in snRNASeq datasets and predicted biomarkers for histological investigation.

Developing a Virtual Reality Environment for Mining Research.

Recent advances in computing, rendering, and display technologies have generated increased accessibility for virtual reality (VR). VR allows the creation of dynamic, high-fidelity environments to simulate dangerous situations, test conditions, and visualize concepts. Consequently, numerous products have been developed, but many of these are limited in scope. Therefore, the National Institute for Occupational Safety and Health researchers developed a VR framework, called VR Mine, to rapidly create an underground mine for human data collection, simulation, visualization, and training. This paper describes the features of VR Mine using self-escape and proximity detection as case studies. Features include mine generation, simulated networks, proximity detection systems, and the integration and visualization of real-time ventilation models.

Pulseless Ventricular Tachycardia During Office-Based Anesthetic in a Four-Year-Old Child.

A 4-year-old 16-kg boy presented for full mouth dental rehabilitation in a private pediatric dental office. The patient had no significant previous medical history. Upon sevoflurane induction by a dentist anesthesiologist, the patient converted from normal sinus rhythm to pulseless ventricular tachycardia. Advanced cardiac life support protocol was initiated. After 2 automatic external defibrillator shocks were delivered in conjunction with epinephrine administration, the patient returned to normal sinus rhythm. The patient was transported via emergency medical service paramedics to a local children's hospital emergency room where he was observed uneventfully for 24 hours prior to discharge.

A case of intra-operative ventricular fibrillation: Electro-cauterization, undiagnosed Takotsubo cardiomyopathy or long QT syndrome?

INTRODUCTION: Cardiac arrest in the perioperative setting is an extremely serious event that is estimated to occur between 4.6 and 19.7 per 10,000 anesthetics.(1-5) While risk factors for cardiac complications can be identified pre- operatively, in many cases workup of risk factors are not indicated by standard pre-operative testing guidelines. PRESENTATION OF CASE: We present a case of a 47-year-old female undergoing an elective bilateral mastectomy who suddenly converted to ventricular fibrillation. While ventricular fibrillation is not a unique finding, our search for its etiology revealed two previously undiagnosed cardiac conditions, and possible electro- cautery induced ventricular fibrillation. DISCUSSION: In this case study, we discuss the possible etiology of ventricular fibrillation in our patient and highlight the importance pre-operative patient investigation and history provide. CONCLUSION: Searching for the potential causes that may have contributed to the cardiac arrest is an extremely useful exercise as it allows us to better prepare patients pre-operatively, improve intra-operative care, and prevent future cardiac events.

Methemoglobinemia secondary to over-the-counter Anbesol.

BACKGROUND: Methemoglobinemia is a potentially lethal condition which may result from exposure to benzocaine. It must be treated promptly, because it may cause a significant decrease in oxygen delivery to tissues and organs. CASE DESCRIPTION: A 39-year-old caucasian man presented to the emergency department (ED) with dental pain. After a review of systems and a dental exam, an oxygen saturation of 90% was noted. The patient reported no previous cardiac or pulmonary pathology, but did report using a large amount of over-the-counter Anbesol. A second oxygen saturation measurement had fallen to 87%. An arterial blood gas sample was taken, and the patient was found to have high levels of methemoglobin. He was transferred to the critical care ED and treated with 2 mg/kg intravenous methylene blue. CLINICAL IMPLICATIONS: Dentists must be aware of the possible lethal effects of benzocaine toxicity, including methemoglobinemia. It is important to recognize the signs and symptoms and act in a judicious manner.

Development of a composite material phantom mimicking the magnetic resonance parameters of the neonatal brain at 3.0 Tesla.

OBJECTIVE: Development of a composite material phantom, comprised of polyvinyl alcohol cryogel (PVA-C) and an agarose additive, to effectively mimic the magnetic resonance relaxation times (T1 and T2) of neonatal white matter (WM) and gray matter (GM) at 3.0 T. MATERIALS AND METHODS: Samples of PVA-C with and without agarose were prepared with 1 cycle of freezing/thawing. Measurements of T1 and T2, at 3.0 T, were performed on the samples at temperatures ranging from 20 degrees C to 40 degrees C. RESULTS: A sample temperature of 40 degrees C was required to achieve a T1 value sufficiently long to represent neonatal WM. At this temperature, neonatal WM relaxation times required 3% PVA-C with 0.3% agarose, whereas gray matter relaxation times required 8% PVA-C with 1.4% agarose. CONCLUSIONS: By adjusting the sample temperature, polyvinyl alcohol concentration, and agarose concentration, the relaxation times of neonatal brain tissues can be obtained using this composite material.

Optimization of 3D MP-RAGE for neonatal brain imaging at 3.0 T.

Three-dimensional (3D) magnetic resonance imaging (MRI) has shown great potential for studying the impact of prematurity and pathology on brain development. We have investigated the potential of optimized T1-weighted 3D magnetization-prepared rapid gradient-echo imaging (MP-RAGE) for obtaining contrast between white matter (WM) and gray matter (GM) in neonates at 3 T. Using numerical simulations, we predicted that the inversion time (TI) for obtaining strongest contrast at 3 T is approximately 2 s for neonates, whereas for adults, this value is approximately 1.3 s. The optimal neonatal TI value was found to be insensitive to reasonable variations of the assumed T1 relaxation times. The maximum theoretical contrast for neonates was found to be approximately one third of that for adults. Using the optimized TI values, MP-RAGE images were obtained from seven neonates and seven adults at 3 T, and the contrast-to-noise ratio (CNR) was measured for WM versus five GM regions. Compared to adults, neonates exhibited lower CNR between cortical GM and WM and showed a different pattern of regional variation in CNR. These results emphasize the importance of sequence optimization specifically for neonates and demonstrate the challenge in obtaining strong contrast in neonatal brain with T1-weighted 3D imaging.