Glycolysis: An early marker for vancomycin-specific T-cell activation.

BACKGROUND: Vancomycin, a glycopeptide antibiotic used for Gram-positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA-A*32:01-expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug-reactive T-cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug-specific T-cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug-reactive T-cell clones (TCCs) generated from healthy donors and vancomycin-hypersensitive patients. METHODS: CD4+ and CD8+ vancomycin-responsive TCCs were generated by serial dilution. The Seahorse XFe96 Analyzer was used to measure the extracellular acidification rate (ECAR) as an indicator of glycolytic function. Additionally, T-cell proliferation and cytokine release (IFN-γ) assay were utilised to correlate the bioenergetic characteristics of T-cell activation with in vitro assays. RESULTS: Model T-cell stimulants induced non-specific T-cell activation, characterised by immediate augmentation of ECAR and rate of ATP production (JATPglyc). There was a dose-dependent and drug-specific glycolytic shift when vancomycin-reactive TCCs were exposed to the drug. Vancomycin-reactive TCCs did not exhibit T-cell cross-reactivity with structurally similar compounds within proliferative and cytokine readouts. However, cross-reactivity was observed when analysing energetic responses; TCCs with prior specificity for vancomycin were also found to exhibit glycolytic switching after exposure to teicoplanin. Glycolytic activation of TCC was HLA restricted, as exposure to HLA blockade attenuated the glycolytic induction. CONCLUSION: These studies describe the glycolytic shift of CD4+ and CD8+ T cells following vancomycin exposure. Since similar glycolytic switching is observed with teicoplanin, which did not activate T cells, it is possible the master switch for T-cell activation is located upstream of metabolic signalling.

The dynamic nature of student discipline and discipline disparities.

Researchers have long used end-of-year discipline rates to identify punitive schools, explore sources of inequitable treatment, and evaluate interventions designed to stem both discipline and racial disparities in discipline. Yet, this approach leaves us with a "static view"-with no sense of how disciplinary responses fluctuate throughout the year. What if daily discipline rates, and daily discipline disparities, shift over the school year in ways that could inform when and where to intervene? This research takes a "dynamic view" of discipline. It leverages 4 years of atypically detailed data regarding the daily disciplinary experiences of 46,964 students from 61 middle schools in one of the nation's largest school districts. Reviewing these data, we find that discipline rates are indeed dynamic. For all student groups, the daily discipline rate grows from the beginning of the school year to the weeks leading up to the Thanksgiving break, falls before major breaks, and grows following major breaks. During periods of escalation, the daily discipline rate for Black students grows significantly faster than the rate for White students-widening racial disparities. Given this, districts hoping to stem discipline and disparities may benefit from timing interventions to precede these disciplinary spikes. In addition, early-year Black-White disparities can be used to identify the schools in which Black-White disparities are most likely to emerge by the end of the school year. Thus, the results reported here provide insights regarding not only when to intervene, but where to intervene to reduce discipline rates and disparities.

Characterization of Drug-Specific CD4+ T-Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions.

Carbamazepine (CBZ) is an aromatic anticonvulsant known to cause drug hypersensitivity reactions, which range in severity from relatively mild maculopapular exanthema to potentially fatal Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). These reactions are known to be associated with human leukocyte antigen (HLA) class I alleles, and CBZ interacts preferentially with the related HLA proteins to activate CD8+ T-cells. This study aimed to evaluate the contribution of HLA class II in the effector mechanism(s) of CBZ hypersensitivity. CBZ-specific T-cells clones were generated from two healthy donors and two hypersensitive patients with high-risk HLA class I markers. Phenotype, function, HLA allele restriction, response pathways, and cross-reactivity of CBZ-specific T-cells were assessed using flow cytometry, proliferation analysis, enzyme-linked immunosorbent spot, and enzyme-linked immunosorbent assay. The association between HLA class II allele restriction and CBZ hypersensitivity was reviewed using Allele Frequency Net Database. Forty-four polyclonal CD4+ CBZ-specific T-cell clones were generated and found to be restricted to HLA-DR, particularly HLA-DRB1*07:01. This CD4+-mediated response proceeded through a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the CD8+ response, CBZ-stimulated CD4+ clones secreted granulysin, a key mediator of SJS-TEN. Our database review revealed an association between HLA-DRB1*07:01 and CBZ-induced SJS-TEN. These findings implicate HLA class II antigen presentation as an additional pathogenic factor for CBZ hypersensitivity reactions. Both HLA class II molecules and drug-responsive CD4+ T-cells should be evaluated further to gain better insights into the pathogenesis of drug hypersensitivity reactions.

Detection of Hepatic Drug Metabolite-Specific T-Cell Responses Using a Human Hepatocyte, Immune Cell Coculture System.

Drug-responsive T-cells are activated with the parent compound or metabolites, often via different pathways (pharmacological interaction and hapten). An obstacle to the investigation of drug hypersensitivity is the scarcity of reactive metabolites for functional studies and the absence of coculture systems to generate metabolites in situ. Thus, the aim of this study was to utilize dapsone metabolite-responsive T-cells from hypersensitive patients, alongside primary human hepatocytes to drive metabolite formation, and subsequent drug-specific T-cell responses. Nitroso dapsone-responsive T-cell clones were generated from hypersensitive patients and characterized in terms of cross-reactivity and pathways of T-cell activation. Primary human hepatocytes, antigen-presenting cells, and T-cell cocultures were established in various formats with the liver and immune cells separated to avoid cell contact. Cultures were exposed to dapsone, and metabolite formation and T-cell activation were measured by LC-MS and proliferation assessment, respectively. Nitroso dapsone-responsive CD4+ T-cell clones from hypersensitive patients were found to proliferate and secrete cytokines in a dose-dependent manner when exposed to the drug metabolite. Clones were activated with nitroso dapsone-pulsed antigen-presenting cells, while fixation of antigen-presenting cells or omission of antigen-presenting cells from the assay abrogated the nitroso dapsone-specific T-cell response. Importantly, clones displayed no cross-reactivity with the parent drug. Nitroso dapsone glutathione conjugates were detected in the supernatant of hepatocyte immune cell cocultures, indicating that hepatocyte-derived metabolites are formed and transferred to the immune cell compartment. Similarly, nitroso dapsone-responsive clones were stimulated to proliferate with dapsone, when hepatocytes were added to the coculture system. Collectively, our study demonstrates the use of hepatocyte immune cell coculture systems to detect in situ metabolite formation and metabolite-specific T-cell responses. Similar systems should be used in future diagnostic and predictive assays to detect metabolite-specific T-cell responses when synthetic metabolites are not available.

Activation of tolvaptan-responsive T-cell clones with the structurally-related mozavaptan.

Tolvaptan is an effective drug for the treatment of autosomal dominant polycystic kidney disease, but its use is associated with a significant risk of T-cell-mediated liver injury in a small number of patients. An important clinical conundrum following the contraindication of tolvaptan is whether administration of agents of similar pharmacological action and structure will be tolerated. Herein, we addressed this question through the exposure of tolvaptan-responsive T-cell clones to similar pharmaceutical agents. Whilst lixivaptan and conivaptan did not activate tolvaptan-responsive T-cells, mozavaptan evoked proliferative responses comparable with tolvaptan itself, indicating that there may be collateral immunological intolerance to this compound as a product of sensitization to tolvaptan.

Pathology of drug hypersensitivity reactions and mechanisms of immune tolerance.

Immune-mediated type IV adverse drug reactions are idiosyncratic in nature, generally not related to the primary or secondary pharmacology of the drug. Due to their complex nature and rarity, these iatrogenic reactions are seldom predicted or encountered during preclinical/early clinical development stages, and often precipitate upon exposure to wider populations (i.e. phase III onwards). They confer a burden on the healthcare sector in both a clinical and financial sense presenting a severe impediment to the drug discovery and development process. Research over the past 50 years has improved our understanding of these reactions markedly as both in vitro and in vivo studies have placed the role of the immune system, in particular; drug-responsive T cells, firmly in the spotlight as the mediators of these reactions. Indeed, the role of different populations of T cells in adverse events and the interaction of drug molecules with HLA proteins expressed on the surface of antigen-presenting cells is of considerable interest. Herein, this review examines the pathways of immune-mediated adverse events including the various T cell subtypes implicated and the mechanisms of T cell activation. Additionally, we address the enigma of immunological tolerance and explore the role tolerance plays in determination of susceptibility to such adverse events even in individuals carrying immunogenic liabilities.

Checkpoint Inhibition Reduces the Threshold for Drug-Specific T-Cell Priming and Increases the Incidence of Sulfasalazine Hypersensitivity.

An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors (ICIs) and sulfasalazine (SLZ). Thus, the aim of this study was to characterize the T cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in vitro platforms. A regulatory competent human dendritic cell/T-cell coculture assay was used to model the effects of ICIs on de novo nitroso sulfamethoxazole- and sulfapyridine (SP) (the sulfonamide component of SLZ) hydroxylamine-specific priming responses. The role of T cells in the pathogenesis of the observed reactions was explored in 3 patients through phenotypic characterization of SP/sulfapyridine hydroxylamine (SPHA)-responsive T-cell clones (TCC), and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T cells and intensity of the T-cell response was observed with PD-1/PD-L1 blockade. Monoclonal populations of SP- and SPHA-responsive T cells were isolated from all 3 patients. A core secretory effector molecule profile (IFN-γ, IL-13, granzyme B, and perforin) was identified for SP and SPHA-responsive TCC, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T cells are effectors of hypersensitivity reactions observed in oncology patients administered ICIs and SLZ. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring.

A Low-Cost, Autonomous Gait Detection and Estimation System for Analyzing Gait Impairments in Mice.

With the advancement in imaging technology, many commercial systems have been developed for performing motion analysis in mice. However, available commercial systems are expensive and use proprietary software. In this paper, we describe a low-cost, camera-based design of an autonomous gait acquisition and analysis system for inspecting gait deficits in C57BL/6 mice. Our system includes video acquisition, autonomous gait-event detection, gait-parameter extraction, and result visualization. We provide a simple, user-friendly, step-by-step detailed methodology to apply well-known image processing techniques for detecting mice footfalls and calculating various gait parameters for analyzing gait abnormalities in healthy and neurotraumatic mice. The system was used in a live animal study for assessing recovery in a mouse model of Parkinson's disease. Using the videos acquired in the study, we validate the performance of our system with receiver operating characteristic (ROC) and Hit : Miss : False (H : M : F) detection analyses. Our system correctly detected the mice footfalls with an average H : M : F score of 92.1 : 2.3 : 5.6. The values for the area under an ROC curve for all the ROC plots are above 0.95, which indicates an almost perfect detection model. The ROC and H : M : F analyses show that our system produces accurate gait detection. The results observed from the gait assessment study are in agreement with the known literature. This demonstrates the practical viability of our system as a gait analysis tool.

T cell mediated hypersensitivity to previously tolerated iodinated contrast media precipitated by introduction of atezolizumab.

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coadministration of atezolizumab. Causality was confirmed by a positive re-challenge with amidotrizoate and laboratory investigations that implicated T cells. Importantly, the introduction of atezolizumab appears to have altered the immunologic response to amidotrizoate in terms of the tolerance-elicitation continuum. Proof of concept studies demonstrated enhancement of recall responses to a surrogate antigen panel following in-vitro (healthy donors) and in-vivo (ICI patients) administrations of ICIs. Our findings highlight the importance of considering all concomitant medications in patients on ICIs who develop immune-mediated adverse reactions. In the event of some immune-related adverse reactions, it may be critical to identify the culprit antigen-forming entity that the ICIs have altered the perception of rather than simply attribute causality to the ICI itself in order to optimize both patient safety and treatment of malignancies.

In-Vitro Approaches to Predict and Study T-Cell Mediated Hypersensitivity to Drugs.

Mitigating the risk of drug hypersensitivity reactions is an important facet of a given pharmaceutical, with poor performance in this area of safety often leading to warnings, restrictions and withdrawals. In the last 50 years, efforts to diagnose, manage, and circumvent these obscure, iatrogenic diseases have resulted in the development of assays at all stages of a drugs lifespan. Indeed, this begins with intelligent lead compound selection/design to minimize the existence of deleterious chemical reactivity through exclusion of ominous structural moieties. Preclinical studies then investigate how compounds interact with biological systems, with emphasis placed on modeling immunological/toxicological liabilities. During clinical use, competent and accurate diagnoses are sought to effectively manage patients with such ailments, and pharmacovigilance datasets can be used for stratification of patient populations in order to optimise safety profiles. Herein, an overview of some of the in-vitro approaches to predict intrinsic immunogenicity of drugs and diagnose culprit drugs in allergic patients after exposure is detailed, with current perspectives and opportunities provided.

Shedding Light on Drug-Induced Liver Injury: Activation of T Cells From Drug Naive Human Donors With Tolvaptan and a Hydroxybutyric Acid Metabolite.

Exposure to tolvaptan is associated with a significant risk of liver injury in a small fraction of patients with autosomal dominant polycystic kidney disease. The observed delayed onset of liver injury of between 3 and 18 months after commencing tolvaptan treatment, along with rapid recurrence of symptoms following re-challenge is indicative of an adaptive immune attack. This study set out to assess the intrinsic immunogenicity of tolvaptan and pathways of drug-specific T-cell activation using in vitro cell culture platforms. Tolvaptan (n = 7), as well as oxybutyric (DM-4103, n = 1) and hydroxybutyric acid (DM-4107, n = 18) metabolite-specific T-cell clones were generated from tolvaptan naive healthy donor peripheral blood mononuclear cells. Tolvaptan and DM-4103 T-cell clones could also be activated with DM-4107, whereas T-cell clones originally primed with DM-4107 were highly specific to this compound. A signature cytokine profile (IFN-γ, IL-13, granzyme B, and perforin) for almost all T-cell clones was identified. Mechanistically, compound-specific T-cell clone activation was dependent on the presence of soluble drug and could occur within 4 h of drug exposure, ruling out a classical hapten mechanism. However, antigen processing dependence drug presentation was indicated in many T-cell clones. Collectively these data show that tolvaptan-associated liver injury may be attributable to an adaptive immune attack upon the liver, with tolvaptan- and metabolite-specific T cells identified as candidate effector cells in such etiology.

Whites' County-Level Racial Bias, COVID-19 Rates, and Racial Inequities in the United States.

Mounting evidence reveals considerable racial inequities in coronavirus disease 2019 (COVID-19) outcomes in the United States (US). Area-level racial bias has been associated with multiple adverse health outcomes, but its association with COVID-19 is yet unexplored. Combining county-level data from Project Implicit on implicit and explicit anti-Black bias among non-Hispanic Whites, Johns Hopkins Coronavirus Resource Center, and The New York Times, we used adjusted linear regressions to estimate overall COVID-19 incidence and mortality rates through 01 July 2020, Black and White incidence rates through 28 May 2020, and Black-White incidence rate gaps on average area-level implicit and explicit racial bias. Across 2994 counties, the average COVID-19 mortality rate (standard deviation) was 1.7/10,000 people (3.3) and average cumulative COVID-19 incidence rate was 52.1/10,000 (77.2). Higher racial bias was associated with higher overall mortality rates (per 1 standard deviation higher implicit bias b = 0.65/10,000 (95% confidence interval: 0.39, 0.91); explicit bias b = 0.49/10,000 (0.27, 0.70)) and higher overall incidence (implicit bias b = 8.42/10,000 (4.64, 12.20); explicit bias b = 8.83/10,000 (5.32, 12.35)). In 957 counties with race-specific data, higher racial bias predicted higher White and Black incidence rates, and larger Black-White incidence rate gaps. Anti-Black bias among Whites predicts worse COVID-19 outcomes and greater inequities. Area-level interventions may ameliorate health inequities.

Tolvaptan- and Tolvaptan-Metabolite-Responsive T Cells in Patients with Drug-Induced Liver Injury.

Tolvaptan is an effective drug for the treatment of autosomal dominant polycystic kidney disease, but its use is associated with a significant risk of liver injury in a small number of patients. Herein we describe the presence of tolvaptan- and tolvaptan-metabolite-responsive T cell clones within the peripheral circulation of patients with liver injury. Drug treatment of the clones resulted in a proliferative response and secretion of IFN-γ, IL-13, and the cytolytic molecule granzyme B. Future work should explore pathways of tolvaptan driven T cell activation and the role of T cells in the disease pathogenesis.

When policy and psychology meet: Mitigating the consequences of bias in schools.

Harsh exclusionary discipline predicts major negative life outcomes, including adult incarceration and unemployment. This breeds racial inequality because Black students are disproportionately at risk for this type of discipline. Can a combination of policy and psychological interventions reduce this kind of discipline and mitigate this inequality? Two preregistered experiments (N experiment1 = 246 teachers; N experiment2 = 243 teachers) used an established paradigm to systematically test integration of two and then three policy and psychological interventions to mitigate the consequences of bias (troublemaker labeling and pattern perception) on discipline (discipline severity). Results indicate that the integrated interventions can curb teachers' troublemaker labeling and pattern prediction toward Black students who misbehave in a hypothetical paradigm. In turn, integration of the three components reduced racial inequality in teachers' discipline decisions. This research informs scientific theory, public policy, and interventions.

After "The China Virus" Went Viral: Racially Charged Coronavirus Coverage and Trends in Bias Against Asian Americans.

On March 8, 2020, there was a 650% increase in Twitter retweets using the term "Chinese virus" and related terms. On March 9, there was an 800% increase in the use of these terms in conservative news media articles. Using data from non-Asian respondents of the Project Implicit "Asian Implicit Association Test" from 2007-2020 (n = 339,063), we sought to ascertain if this change in media tone increased bias against Asian Americans. Local polynomial regression and interrupted time-series analyses revealed that Implicit Americanness Bias-or the subconscious belief that European American individuals are more "American" than Asian American individuals-declined steadily from 2007 through early 2020 but reversed trend and began to increase on March 8, following the increase in stigmatizing language in conservative media outlets. The trend reversal in bias was more pronounced among conservative individuals. This research provides evidence that the use of stigmatizing language increased subconscious beliefs that Asian Americans are "perpetual foreigners." Given research that perpetual foreigner bias can beget discriminatory behavior and that experiencing discrimination is associated with adverse mental and physical health outcomes, this research sounds an alarm about the effects of stigmatizing media on the health and welfare of Asian Americans.

NF-κB Signaling in Astrocytes Modulates Brain Inflammation and Neuronal Injury Following Sequential Exposure to Manganese and MPTP During Development and Aging.

Chronic exposure to manganese (Mn) is associated with neuroinflammation and extrapyramidal motor deficits resembling features of Parkinson's disease. Activation of astrocytes and microglia is implicated in neuronal injury from Mn but it is not known whether early life exposure to Mn may predispose glia to more severe inflammatory responses during aging. We therefore examined astrocyte nuclear factor kappa B (NF-κB) signaling in mediating innate immune inflammatory responses during multiple neurotoxic exposures spanning juvenile development into adulthood. MnCl2 was given in drinking water for 30-day postweaning to both wildtype mice and astrocyte-specific knockout (KO) mice lacking I kappa B kinase 2, the central upstream activator of NF-κB. Following juvenile exposure to Mn, mice were subsequently administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 4 months of age. Animals were evaluated for behavioral alterations and brain tissue was analyzed for catecholamine neurotransmitters. Stereological analysis of neuronal and glial cell counts from multiple brain regions indicated that juvenile exposure to Mn amplified glial activation and neuronal loss from MPTP exposure in the caudate-putamen and globus pallidus, as well as increased the severity of neurobehavioral deficits in open field activity assays. These alterations were prevented in astrocyte-specific I kappa B kinase 2 KO mice. Juvenile exposure to Mn increased the number of neurotoxic A1 astrocytes expressing C3 as well as the number of activated microglia in adult mice following MPTP challenge, both of which were inhibited in KO mice. These results demonstrate that exposure to Mn during juvenile development heightens the innate immune inflammatory response in glia during a subsequent neurotoxic challenge through NF-κB signaling in astrocytes.

Strategies for Enhancing Resilience in Medical Students: a Group Concept Mapping Analysis.

OBJECTIVE: Research has consistently shown that medical students have greater rates of stress and mental-ill health in comparison with non-medical students. The objective of this study was to investigate the resilience strategies employed by medical students in an Irish medical school to inoculate themselves against the deleterious effects of stress on health and wellbeing. METHODS: Group concept mapping was utilized incorporating qualitative and quantitative methodologies. The stages undertaken by year 3 students at an Irish medical school involved brainstorming/idea generation, categorization, and rating of resilience strategies students employed to manage stress during medical school. The data was analyzed utilizing The Concept System® software through multidimensional scaling and hierarchical clustering. RESULTS: Categories of resilience strategies employed included "friends and family," "de-stress through exercise/sport," "extra-curricular non-medical activities," "self-enabled distraction," "organization," and "enhancing emotional and mental wellbeing." Students rated spending time with "friends and family" to be most effective when seeking to relieve stress, whereas students rated "de-stressing through exercise/sport" as being of greatest importance in relation to inclusion in a resilience-based intervention. Students recognized the value of incorporating strategies to enhance emotional and mental wellbeing into a resilience-promoting program. "Self-enabled distraction" rated poorly on both scales. CONCLUSIONS: Strategies rated by students to be important to incorporate in a stress reduction management program are accessible, are feasible, and can be implemented into the medical curriculum.

T-Cell Activation by Low Molecular Weight Drugs and Factors That Influence Susceptibility to Drug Hypersensitivity.

Drug hypersensitivity reactions adversely affect treatment outcome, increase the length of patients' hospitalization, and limit the prescription options available to physicians. In addition, late stage drug attrition and the withdrawal of licensed drugs cost the pharmaceutical industry billions of dollars. This significantly increases the overall cost of drug development and by extension the price of licensed drugs. Drug hypersensitivity reactions are characterized by a delayed onset, and reactions tend to be more serious upon re-exposure. The role of drug-specific T-cells in the pathogenesis of drug hypersensitivity reactions and definition of the nature of the binding interaction of drugs with HLA and T-cell receptors continues to be the focus of intensive research, primarily because susceptibility is associated with expression of one or a small number of HLA alleles. This review critically examines the mechanisms of T-cell activation by drugs. Specific examples of drugs that activate T-cells via the hapten, the pharmacological interaction with immune receptors and the altered self-peptide repertoire pathways, are discussed. Furthermore, the impacts of drug metabolism, drug-protein adduct formation, and immune regulation on the development of drug antigen-responsive T-cells are highlighted. The knowledge gained from understanding the pathways of T-cell activation and susceptibility factors for drug hypersensitivity will provide the building blocks for the development of predictive in vitro assays that will prevent or help to minimize the incidence of these reactions in clinic.

Dyslexia Augusti: Does Suetonius describe a pattern of signs consistent with dyslexia?

It is generally agreed that Morgan was the first to reliably describe dyslexia with the case of Percy F. However, Suetonius, in "The lives of the twelve Caesars" describes the Emperor Augustus as having a range of language and literacy difficulties that could be consistent with this diagnosis. Using the framework of cognitive psychology, which rarely comments on the historical record, this article argues that Suetonius describes both signs and compensating strategies typical of an adult with remediated developmental dyslexia. If accepted, this analysis would locate a possible coherent description of the condition back to the second century CE.