Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19 (preprint)

The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 donor lungs with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage (DAD). We identify changes in cellular composition across progressive DAD, including waves of molecularly distinct macrophages and depleted epithelial and endothelial populations throughout different types of tissue damage. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early DAD, and fibrosis-related collagens in organised DAD. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early DAD. These results provide the first comprehensive, spatially resolved atlas of DAD stages, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways across alveolar damage progression.

A Feasibility Study of LORETA Z-Score Neurofeedback Training in Adults with Schizophrenia-Spectrum Disorder Experiencing Treatment-Resistant Auditory Verbal Hallucinations

Introduction: The incomplete effectiveness of interventions demands new ways to help people diagnosed with schizophrenia who experience auditory verbal hallucinations (SZ-AVH). We aimed to perform a feasibility study of low-resolution electromagnetic tomography analysis (LORETA) neurofeedback with people exhibiting treatment-resistant SZ-AVH. Methods: We examined changes in resting-state quantitative electroencephalogram (qEEG) in four people with SZ-AVH (three male, one female) after LORETA Z-score neurofeedback training. Results: The study design had to be amended due to a national COVID-19 lockdown. Neurofeedback was well tolerated and no participants dropped out. Recruitment was the main feasibility issue. Barriers included a lack of knowledge of neurofeedback by patients and mental health teams, as well as the travel and time commitment involved. For the only patient who completed all 20 sessions, elevated frontal, central, and temporal theta absolute power measured at baseline normalized after treatment, but decreased temporal delta and an increase in coherence for all frequency bands were also found. Conclusions: Two key lessons were drawn for the feasibility of trials of EEG neurofeedback in this population. First, significant effort is needed to educate mental health professionals and patients about neurofeedback. Second, the equipment employed for neurofeedback training needs to be physically based at a site where patients routinely attend.

An Initiative to Improve Follow-up of Patients with Glaucoma

Purpose This study describes the implementation of an electronic medical record (EMR)-based initiative aimed at reducing the number of patients with glaucoma-related diagnoses lost to follow-up (LTF) and reviews its short-term outcomes. Design Retrospective, comparative case series. Participants Patients with glaucoma-related diagnoses seen 1 year prior at the Lahey Medical Center and who had not returned within the 6-month period between January 1, 2020, and June 30, 2020, which spanned the outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic in the United States. Methods An EMR-based tool was designed to identify patients suspected of being LTF with glaucoma-related diagnoses. Providers were enlisted to review the EMR for each of these patients and re-engage them, as appropriate. One month later, the initiative was evaluated by means of a retrospective chart review. Binary logistic regression analysis was used to identify demographic, clinical, and sociomedical factors associated with being LTF. Main Outcome Measures Patients who completed a telemedicine or in-person appointment, or had a future scheduled or ordered return appointment, were considered re-engaged. Results Of the 3551 patients seen during the study period, 384 patients were identified as LTF (11%), with 60 identifying COVID-19 as the reason for canceling their visit (16%). Patients who lived farther from the eye clinic (P < 0.001) or who had a history of canceling or missing an appointment (P < 0.001) were more likely to be LTF. Patients with open-angle glaucoma (P = 0.042) or who had completed a visual field (P < 0.001) or ophthalmic imaging (P < 0.001) within the past year were less likely to be LTF. One month after the re-engagement initiative, 124 LTF patients (32%) had been re-engaged (40% through telemedicine), 238 patients (62%) had future scheduling orders in place, and 22 patients (6%) had no active plan for future follow-up. Conclusions An EMR-based tool is an effective method for identifying patients at risk of being LTF and provides an opportunity for providers to recall and re-engage patients. Use of telemedicine to recontact LTF patients shows promise of improving the management of glaucoma, enhancing clinical productivity, and documenting treatment plans, thereby potentially reducing medicolegal liability.

Palmitoylethanolamide (PEA) Inhibits SARS-CoV-2 Entry by Interacting with S Protein and ACE-2 Receptor.

Lipids play a crucial role in the entry and egress of viruses, regardless of whether they are naked or enveloped. Recent evidence shows that lipid involvement in viral infection goes much further. During replication, many viruses rearrange internal lipid membranes to create niches where they replicate and assemble. Because of the close connection between lipids and inflammation, the derangement of lipid metabolism also results in the production of inflammatory stimuli. Due to its pivotal function in the viral life cycle, lipid metabolism has become an area of intense research to understand how viruses seize lipids and to design antiviral drugs targeting lipid pathways. Palmitoylethanolamide (PEA) is a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that also counteracts SARS-CoV-2 entry and its replication. Our work highlights for the first time the antiviral potency of PEA against SARS-CoV-2, exerting its activity by two different mechanisms. First, its binding to the SARS-CoV-2 S protein causes a drop in viral infection of ~70%. We show that this activity is specific for SARS-CoV-2, as it does not prevent infection by VSV or HSV-2, other enveloped viruses that use different glycoproteins and entry receptors to mediate their entry. Second, we show that in infected Huh-7 cells, treatment with PEA dismantles lipid droplets, preventing the usage of these vesicular bodies by SARS-CoV-2 as a source of energy and protection against innate cellular defenses. This is not surprising since PEA activates PPAR-α, a transcription factor that, once activated, generates a cascade of events that leads to the disruption of fatty acid droplets, thereby bringing about lipid droplet degradation through ß-oxidation. In conclusion, the present work demonstrates a novel mechanism of action for PEA as a direct and indirect antiviral agent against SARS-CoV-2. This evidence reinforces the notion that treatment with this compound might significantly impact the course of COVID-19. Indeed, considering that the protective effects of PEA in COVID-19 are the current objectives of two clinical trials (NCT04619706 and NCT04568876) and given the relative lack of toxicity of PEA in humans, further preclinical and clinical tests will be needed to fully consider PEA as a promising adjuvant therapy in the current COVID-19 pandemic or against emerging RNA viruses that share the same route of replication as coronaviruses.

Preparing for a Pandemic: Accelerating Vaccine Availability

Vaccinating the world’s population quickly in a pandemic has enormous health and economic benefits. We analyze the problem faced by governments in determining the scale and structure of procurement for vaccines. We analyze alternative approaches to procurement. We find that if the goal is to accelerate the vaccine delivery timetable, buyers should directly fund manufacturing capacity and shoulder most of the risk of failure, while maintaining some direct incentives for speed. We analyzed the optimal portfolio of vaccine investments for countries with different characteristics as well as the implications for international cooperation. Our analysis, considered in light of the experience of 2020, suggests lessons for future pandemics.

An Initiative to Improve Follow-up of Patients with Glaucoma.

Purpose: This study describes the implementation of an electronic medical record (EMR)-based initiative aimed at reducing the number of patients with glaucoma-related diagnoses lost to follow-up (LTF) and reviews its short-term outcomes. Design: Retrospective, comparative case series. Participants: Patients with glaucoma-related diagnoses seen 1 year prior at the Lahey Medical Center and who had not returned within the 6-month period between January 1, 2020, and June 30, 2020, which spanned the outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic in the United States. Methods: An EMR-based tool was designed to identify patients suspected of being LTF with glaucoma-related diagnoses. Providers were enlisted to review the EMR for each of these patients and re-engage them, as appropriate. One month later, the initiative was evaluated by means of a retrospective chart review. Binary logistic regression analysis was used to identify demographic, clinical, and sociomedical factors associated with being LTF. Main Outcome Measures: Patients who completed a telemedicine or in-person appointment, or had a future scheduled or ordered return appointment, were considered re-engaged. Results: Of the 3551 patients seen during the study period, 384 patients were identified as LTF (11%), with 60 identifying COVID-19 as the reason for canceling their visit (16%). Patients who lived farther from the eye clinic (P < 0.001) or who had a history of canceling or missing an appointment (P < 0.001) were more likely to be LTF. Patients with open-angle glaucoma (P = 0.042) or who had completed a visual field (P < 0.001) or ophthalmic imaging (P < 0.001) within the past year were less likely to be LTF. One month after the re-engagement initiative, 124 LTF patients (32%) had been re-engaged (40% through telemedicine), 238 patients (62%) had future scheduling orders in place, and 22 patients (6%) had no active plan for future follow-up. Conclusions: An EMR-based tool is an effective method for identifying patients at risk of being LTF and provides an opportunity for providers to recall and re-engage patients. Use of telemedicine to recontact LTF patients shows promise of improving the management of glaucoma, enhancing clinical productivity, and documenting treatment plans, thereby potentially reducing medicolegal liability.

New perspectives in office-based otoendoscopy and endoscopic ear surgery

Otoendoscopy describes the use of Hopkins rod telescopes to examine the ear. Over the past two decades, the role of endoscopes has evolved from a diagnostic tool in the office to the operating room, where Hopkins rod and distal chip scopes are being used to perform routine and complex middle ear and mastoid surgery. Advancements in endoscopic ear surgery techniques have increased interest in endoscopes for in-office otologic procedures. Compared with binocular microscopy, the endoscope provides enhanced depth of field and visualization of the hidden recesses of the middle ear (and mastoid) using small surgical corridors. These advantages are leveraged in the office setting for diagnosing, documenting and managing otologic pathology, even more now during the COVID-19 pandemic. In this review, we describe the indications, techniques and potential complications of office-based otoendoscopy and endoscopic ear surgery.

Contact Area Detector using Cross View Projection Consistency for COVID-19 Projects (preprint)

The ability to determine what parts of objects and surfaces people touch as they go about their daily lives would be useful in understanding how the COVID-19 virus spreads. To determine whether a person has touched an object or surface using visual data, images, or videos, is a hard problem. Computer vision 3D reconstruction approaches project objects and the human body from the 2D image domain to 3D and perform 3D space intersection directly. However, this solution would not meet the accuracy requirement in applications due to projection error. Another standard approach is to train a neural network to infer touch actions from the collected visual data. This strategy would require significant amounts of training data to generalize over scale and viewpoint variations. A different approach to this problem is to identify whether a person has touched a defined object. In this work, we show that the solution to this problem can be straightforward. Specifically, we show that the contact between an object and a static surface can be identified by projecting the object onto the static surface through two different viewpoints and analyzing their 2D intersection. The object contacts the surface when the projected points are close to each other; we call this cross view projection consistency. Instead of doing 3D scene reconstruction or transfer learning from deep networks, a mapping from the surface in the two camera views to the surface space is the only requirement. For planar space, this mapping is the Homography transformation. This simple method can be easily adapted to real-life applications. In this paper, we apply our method to do office occupancy detection for studying the COVID-19 transmission pattern from an office desk in a meeting room using the contact information.