Objective.-To summarize available literature regarding headache as a manifestation of coronaviruses and to describe potential underlying mechanisms. Review Methods.-References for this review were identified by searches within PubMed without any date restrictions. The search terms used were coronavirus disease 2019 (COVID-19) clinical manifestation, COVID-19 epidemiology, neurologic findings in COVID-19, headache in COVID-19, neurologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and headache in SARS-CoV-2. Results.-Headache is one of the most common neurologic complaints in patients with SARS-CoV-2. While the pathophysiological connection between headache and SARS-CoV-2 is unclear, inflammatory mechanisms may play a key role. One of the mechanisms cited in the literature of migraine and other headache disorders is the activation of nociceptive sensory neurons by cytokines and chemokines. A similar mechanism has been reported in SARS-CoV-2 with the release of cytokines and chemokines by macrophages throughout the course of infection. Other mechanisms for headache in SARS-CoV-2 include (1) viral neuroinvasion as seen with viral encephalitis; (2) hypoxemia due to the well-described pulmonary manifestations of the disease; and (3) thrombosis secondary to COVID-19 induced hypercoagulable states. Conclusion.-According to the Centers for Disease Control, common symptoms of human coronavirus include fever, cough, runny nose, sore throat, and headache. In the case of SARS-CoV-2, there are limited reports about headaches, one of the most common clinical manifestations. There are currently no studies that focus specifically on headache among patients with SARS-CoV-2 infection.

Objective: To characterize patient-reported ideas and concerns about cluster headache, treatment options, and management strategies. Background: Cluster headache patients experience severe pain and often suffer additional consequences from their disease. Patients have identified methods to cope with and combat cluster headache that are not widely known. Methods: Secondary analysis was performed using deidentified data from the online Clusterbusters Medication Use survey, wherein 10 questions allowed for freely written comments. Using mixed-methods techniques, neurologists with expertise in headache medicine identified themes from these comments. Subgroup analysis sought to identify variables associated with specific themes. Results: Among 2274 free-text responses from 493 adult participants, 23 themes were identified. Themes commonly discussed in the literature included such topics as "nothing worked" (24.7%, 122/493), "side effects" (12.8%, 63/493), and difficulties with "access/cost" (2.4%, 12/493). Less widely recognized themes included the use of "illicit substances" (35.5%, 175/493) and "vitamins/supplements" (12.2%, 60/493) in disease management. Lesser-known themes included "coffee" (5.3%, 26/493) and "exercise/physical activity" (4.7%, 23/493). Using strict significance criteria, no subgroup was associated with any theme. Several poignant quotes highlighted patient thoughts and experiences. Conclusions: This mixed-methods analysis identified challenges endured by cluster headache patients, as well as a variety of patient-directed disease management approaches. The volunteered information spotlights pharmacological, physiological, and psychological aspects of cluster headache that warrant further exploratory and interventional investigation.

A nonparametric method for analyzing quantal response data from an indirect bioassay experiment is proposed. Kernel estimates of the dose-response curve are used to develop approximate confidence intervals for (i) the optimal combination dose of a drug with therapeutic effects at low doses and toxic effects at high doses, and (ii) the lethal dose levels of a toxic chemical. This nonparametric procedure was implemented on real and simulated data. The confidence interval for problem (i) has high coverage probabilities when the dose-response curve is symmetric about the optima. However, the coverage probabilities are adversely affected by asymmetry about the optima and consequently are not reliable unless the sample sizes are large. The use of kernel estimators with higher-order kernels may alleviate this sensitivity to asymmetry. The confidence interval for problem (ii) has high coverage probabilities robust with respect to the shape or symmetry of the underlying dose-response curve.

The follicular histoarchitecture of the thyroid forms the anatomical basis for thyroid physiology and is commonly disturbed in diseases of the thyroid. We have used cultured porcine thyroid cells to study thyroid epithelial morphogenesis and its regulation. When cultured in the presence of TSH, freshly isolated thyroid cells reorganize to form follicles within three-dimensional cell aggregates. However, when established follicles are washed into TSH-free medium, thyroid cells spread and migrate to convert follicles into confluent epithelioid monolayers, activating morphogenetic mechanisms, such as cell locomotility, that may be relevant to thyroid inflammation and tumor invasiveness. The phenomenon of follicle to monolayer conversion, therefore, provides an opportunity to identify morphogenetic mechanisms that 1) must be tonically inhibited to maintain follicular organization and 2) may contribute to pathogenetic disturbances of follicular architecture when functioning aberrantly. In this study we found that follicle to monolayer conversion is associated with an increase in cellular phosphotyrosine. This was particularly evident at nascent focal adhesions (cell-substrate adhesive junctions) and later at cell-cell junctions. Focal adhesion assembly was accompanied by reorganization of the actin cytoskeleton, with the appearance of prominent stress fibers. Genistein, a potent inhibitor of protein tyrosine kinases, inhibited the accumulation of phosphotyrosine, focal adhesion assembly, and follicle to monolayer conversion. We conclude that tyrosine phosphorylation exerts an important influence on thyroid epithelial organization in culture, at least partly mediated through regulation of focal adhesion assembly.