Differential Effects of Astrocyte Manipulations on Learned Motor Behavior and Neuronal Ensembles in the Motor Cortex.

Although motor cortex is crucial for learning precise and reliable movements, whether and how astrocytes contribute to its plasticity and function during motor learning is unknown. Here, we report that astrocyte-specific manipulations in primary motor cortex (M1) during a lever push task alter motor learning and execution, as well as the underlying neuronal population coding. Mice that express decreased levels of the astrocyte glutamate transporter 1 (GLT1) show impaired and variable movement trajectories, whereas mice with increased astrocyte Gq signaling show decreased performance rates, delayed response times, and impaired trajectories. In both groups, which include male and female mice, M1 neurons have altered interneuronal correlations and impaired population representations of task parameters, including response time and movement trajectories. RNA sequencing further supports a role for M1 astrocytes in motor learning and shows changes in astrocytic expression of glutamate transporter genes, GABA transporter genes, and extracellular matrix protein genes in mice that have acquired this learned behavior. Thus, astrocytes coordinate M1 neuronal activity during motor learning, and our results suggest that this contributes to learned movement execution and dexterity through mechanisms that include regulation of neurotransmitter transport and calcium signaling.SIGNIFICANCE STATEMENT We demonstrate for the first time that in the M1 of mice, astrocyte function is critical for coordinating neuronal population activity during motor learning. We demonstrate that knockdown of astrocyte glutamate transporter GLT1 affects specific components of learning, such as smooth trajectory formation. Altering astrocyte calcium signaling by activation of Gq-DREADD upregulates GLT1 and affects other components of learning, such as response rates and reaction times as well as trajectory smoothness. In both manipulations, neuronal activity in motor cortex is dysregulated, but in different ways. Thus, astrocytes have a crucial role in motor learning via their influence on motor cortex neurons, and they do so by mechanisms that include regulation of glutamate transport and calcium signals.

Fragile X Syndrome Patient-Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes.

BACKGROUND: Fragile X syndrome (FXS) is characterized by physical abnormalities, anxiety, intellectual disability, hyperactivity, autistic behaviors, and seizures. Abnormal neuronal development in FXS is poorly understood. Data on patients with FXS remain scarce, and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. METHODS: To mimic human neuron development in vivo, we coinjected neural precursor cells derived from FXS patient-derived induced pluripotent stem cells and neural precursor cells derived from corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. RESULTS: The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Immunofluorescence and single and bulk RNA sequencing analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, we found increased percentages of Arc- and Egr-1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons. CONCLUSIONS: This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3-dimensional context.

The Future of Telehealth for Allergic Disease.

The COVID-19 pandemic created an explosion in the use of telehealth. However, telehealth consists of much more than a video discussion between doctor and patient. Since the onset of the COVID-19 pandemic, allergists have demonstrated a high level of synchronous telemedicine adoption with existing patients but have not taken full advantage of other virtual care modalities that have the potential to facilitate the efficient delivery of allergy care to the broader population. This is partially due to a lack of awareness about the various remote care services and how to implement and bill for them appropriately. This rostrum describes the spectrum of telehealth services, reviews existing literature on the use of telehealth in allergy, and provides suggestions about how allergists and immunologists can optimize the use of telehealth to optimize patient access and outcomes as well as receive appropriate compensation for specialty clinical services provided by themselves and their staff.

Immediate Reactions After the First Dose of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Messenger RNA Vaccines Do Not Preclude Second-Dose Administration.

Addressing coronavirus disease 2019 (COVID-19) vaccine hesitancy and minimizing potential vaccine contraindications are critical to combatting the pandemic. We describe a practical approach to immediate adverse events after the first dose of messenger RNA vaccines for severe acute respiratory syndrome coronavirus 2, focusing on diagnosis and management of allergic reactions.

Reflecting on prediction strategies for epidemics: Preparedness and public health response.

OBJECTIVE: To provide an overview of the literature on respiratory infectious disease epidemic prediction, preparedness, and response (including pharmaceutical and nonpharmaceutical interventions) and their impact on public health, with a focus on respiratory conditions such as asthma. DATA SOURCES: Published literature obtained through PubMed database searches. STUDY SELECTIONS: Studies relevant to infectious epidemics, asthma, modeling approaches, health care access, and data analytics related to intervention strategies. RESULTS: Prediction, prevention, and response strategies for infectious disease epidemics use extensive data sources and analytics, addressing many areas including testing and early diagnosis, identifying populations at risk of severe outcomes such as hospitalizations or deaths, monitoring and understanding transmission and spread patterns by age group, social interactions geographically and over time, evaluating the effectiveness of pharmaceutical and nonpharmaceutical interventions, and understanding prioritization of and access to treatment or preventive measures (eg, vaccination, masks), given limited resources and system constraints. CONCLUSION: Previous epidemics and pandemics have revealed the importance of effective preparedness and response. Further research and implementation need to be performed to emphasize timely and actionable strategies, including for populations with particular health conditions (eg, chronic respiratory diseases) at risk for severe outcomes.

Work Group Report: COVID-19: Unmasking Telemedicine.

Telemedicine adoption has rapidly accelerated since the onset of the COVID-19 pandemic. Telemedicine provides increased access to medical care and helps to mitigate risk by conserving personal protective equipment and providing for social/physical distancing to continue to treat patients with a variety of allergic and immunologic conditions. During this time, many allergy and immunology clinicians have needed to adopt telemedicine expeditiously in their practices while studying the complex and variable issues surrounding its regulation and reimbursement. Some concerns have been temporarily alleviated since March 2020 to aid with patient care in the setting of COVID-19. Other changes are ongoing at the time of this publication. Members of the Telemedicine Work Group in the American Academy of Allergy, Asthma & Immunology (AAAAI) completed a telemedicine literature review of online and Pub Med resources through May 9, 2020, to detail Pre-COVID-19 telemedicine knowledge and outline up-to-date telemedicine material. This work group report was developed to provide guidance to allergy/immunology clinicians as they navigate the swiftly evolving telemedicine landscape.

Peanut Oral Immunotherapy: a Current Perspective.

PURPOSE OF THE REVIEW: Peanut oral immunotherapy (OIT) is one of the most studied experimental therapies for food allergy. With the recently FDA-approved peanut product, Palforzia, the goal of this article is to review the most recent data from clinical trials, discuss recent trends, and anticipate future developments. RECENT FINDINGS: The latest research suggests that peanut OIT could be a promising option for peanut-allergic patients, with the majority of participants in research studies achieving the primary efficacy endpoint of desensitization, as well as sustained unresponsiveness in select populations. Some studies also showed improvements in food allergy-related quality of life. However, peanut OIT is not without risk or side effects, including potentially serious allergic reactions. Future research will need to evaluate the short- and long-term effectiveness of the therapy in the real-world setting, predictors of important treatment outcomes, and the use of adjunctive therapies that may mitigate some of these allergic reactions.

The role of mobile health technologies in allergy care: An EAACI position paper.

Mobile health (mHealth) uses mobile communication devices such as smartphones and tablet computers to support and improve health-related services, data and information flow, patient self-management, surveillance, and disease management from the moment of first diagnosis to an optimized treatment. The European Academy of Allergy and Clinical Immunology created a task force to assess the state of the art and future potential of mHealth in allergology. The task force endorsed the "Be He@lthy, Be Mobile" WHO initiative and debated the quality, usability, efficiency, advantages, limitations, and risks of mobile solutions for allergic diseases. The results are summarized in this position paper, analyzing also the regulatory background with regard to the "General Data Protection Regulation" and Medical Directives of the European Community. The task force assessed the design, user engagement, content, potential of inducing behavioral change, credibility/accountability, and privacy policies of mHealth products. The perspectives of healthcare professionals and allergic patients are discussed, underlining the need of thorough investigation for an effective design of mHealth technologies as auxiliary tools to improve quality of care. Within the context of precision medicine, these could facilitate the change in perspective from clinician- to patient-centered care. The current and future potential of mHealth is then examined for specific areas of allergology, including allergic rhinitis, aerobiology, allergen immunotherapy, asthma, dermatological diseases, food allergies, anaphylaxis, insect venom, and drug allergy. The impact of mobile technologies and associated big data sets are outlined. Facts and recommendations for future mHealth initiatives within EAACI are listed.

Exploring the Utility of Noninvasive Type 2 Inflammatory Markers for Prediction of Severe Asthma Exacerbations in Children and Adolescents.

BACKGROUND: Noninvasive markers of type 2 inflammation are needed to identify children and adolescents who might benefit from personalized biologic therapy. OBJECTIVE: We hypothesized that blood eosinophil counts would predict 1 or more acute visits for asthma and that prediction could be improved with the addition of a second, noninvasive type 2 inflammatory biomarker. METHODS: Children and adolescents 5 to 21 years (N = 589) with an asthma exacerbation necessitating systemic corticosteroid treatment in the previous year completed a characterization visit and telephone calls at 6 and 12 months. The primary outcome was an acute visit for asthma with receipt of systemic corticosteroids. Acute visits were verified by medical record review. Exploratory outcomes included time to first acute visit and hospitalization. RESULTS: Acute visits occurred in 106 (35.5%) children and 72 (24.8%) adolescents. Elevated blood eosinophils were associated with increased odds and shorter time to first acute visit, but optimal cut-points differed by age (≥150 vs ≥300 cells/µL for children vs adolescents, respectively). The addition of a second marker of type 2 inflammation did not improve prediction in children, but increased the odds and hazard of an acute visit up to 16.2% and 11.9%, respectively, in adolescents. Similar trends were noted for hospitalizations. CONCLUSIONS: Blood eosinophils and other noninvasive markers of type 2 inflammation may be useful in the clinical assessment of children and adolescents with asthma. However, features of type 2 inflammation vary by age. Whether children and adolescents also respond differently to management of type 2 inflammation is unclear and warrants further evaluation.

Direct to Consumer Telemedicine.

PURPOSE OF REVIEW: Telemedicine uses technology to connect patients and data with providers at a distance. Direct to consumer telemedicine is a rapidly growing segment of the industry. RECENT FINDINGS: The telehealth market has skyrocketed in recent years, making it a multi-billion dollar industry. Direct to consumer telehealth, dominated by the for-profit private sector, is the most popular form. Direct to consumer telemedicine is a subset of telehealth that shows promise in increasing access to and engagement in medical care. Quality assurance, reimbursement, and regulatory oversight are important factors in assuring appropriate widespread adoption.

Direct oral amoxicillin challenge without preliminary skin testing in adult patients with allergy and at low risk with reported penicillin allergy.

Introduction: Ten percent of hospitalized patients report penicillin allergy; however, recent studies indicate that ∼98% of these patients are not acutely hypersensitive. Unconfirmed penicillin allergy poses public health risks, and an evaluation of penicillin allergy labels is recommended to improve antibiotic stewardship. Although the most widely accepted protocol is penicillin skin testing, followed by oral amoxicillin challenge, time constraints and resources may preclude this. Recent literature supports the safety and efficacy of direct oral amoxicillin challenge in individuals at low risk. Methods: We retrospectively evaluated direct oral challenge acceptance and outcomes in eligible adult outpatients with allergy and with a penicillin allergy label over a 6-month period. Direct oral amoxicillin challenge was recommended in patients with a history of benign rash, benign somatic symptoms, or unknown history associated with the last penicillin exposure >12 months ago. Those with severe reactions or reactions within 12 months of evaluation were not challenged. The patients were monitored for 60 minutes after challenge and were discharged with instructions to call in the event of a delayed reaction. Results: There were 50 of 355 adults (14%) with a penicillin allergy label seen by a single allergist; of these patients, 38 (76%) met our criteria for a direct oral challenge. The index penicillin associated reactions were mostly remote, and 44 subjects (88%) reported reactions >10 years earlier. Four patients (8%) were de-labeled based on history alone. Twenty subjects (40%) consented to challenge in the clinic, and none developed immediate, or to our knowledge, delayed hypersensitivity reactions. Three of 20 patients (15%) developed self-limited subjective symptoms that were not deemed to constitute true immunoglobulin E mediated hypersensitivity. A total of 24 patients (48%) had the penicillin allergy label removed from their medical record. Conclusion: This study added to the accumulating body of evidence that supports the safety and efficacy of direct provocative challenge without preliminary skin testing to exclude penicillin allergy in individuals at low risk. Larger prospective studies are necessary to confirm these observations.

A Good Case of Recurrent Pneumonia.

Bordetella bronchiseptica infection is a common cause of pneumonia in animals but rarely causes disease in humans. Additionally, coinfection with Pneumocystis jirovecii is very uncommon and is occasionally seen in patients with acquired immunodeficiency syndrome (AIDS). We report a case of a 61-year-old HIV-negative man, who presented with hypoxic respiratory failure 2 days after completion of systemic intravenous antibiotic treatment for B bronchiseptica. His past medical history was significant for a benign thymoma. The patient was found to be coinfected with B bronchiseptica and P jirovecii. Laboratory results showed panhypogammaglobulinemia and low absolute B- and CD4 T-cells. Therefore, the patient was diagnosed with Good's syndrome. However, despite treatment with intravenous antibiotics and intravenous immunoglobulin, the patient continued to deteriorate and expired. This patient demonstrates the importance of recognizing this rare immunodeficiency early in order to improve morbidity and mortality. Furthermore, this case highlights the importance of early immunoglobulin screening in the presence of asymptomatic thymoma.

Tips for Seeing Patients via Telemedicine.

PURPOSE OF REVIEW: Telemedicine is a technology that permits patients to be seen at a distance. This review describes different types of telemedicine, why they might be useful for a practice, what equipment is needed, and how to select and schedule patients. RECENT FINDINGS: The use of synchronous telemedicine is increasing rapidly and has surpassed 50% of ambulatory encounters in some instances. Management of patients is particularly germane for an allergy practice since it is an outpatient specialty with patients who live in widely distributed locations with limited access to allergists. With utilization of digital exam equipment, in vitro tests for diagnosis, and spirometry at the patient location, there are few clear advantages of seeing patients in-person over virtual visits. Telemedicine is here today. As its use increases, it is critical that allergy specialists embrace this new technology.

The THIK and Thin of Microglia Dynamics.

Madry et al. (2018) show that the two-pore potassium channel THIK-1 is tonically active in microglia and promotes microglial ramification and surveillance of the brain parenchyma. Interestingly, THIK-1 is not essential to damage-induced outgrowth of microglial processes but is critical to microglial IL-1ß release.