BACKGROUND:The optimal timing of oral anticoagulation for prevention of early ischaemic stroke recurrence in people with acute ischaemic stroke and atrial fibrillation remains uncertain. We aimed to estimate the effects of starting a direct oral anticoagulant (DOAC) early (≤4 days) versus later (≥5 days) after onset of ischaemic stroke. METHODS:For this systematic review and meta-analysis we searched the electronic databases PubMed, Cochrane Central Register of Controlled Trials, and Embase for randomised controlled trials published from inception until March 16, 2025. We included clinical trials if they were pre-registered, randomised, investigated clinical outcomes, and included participants with acute ischaemic stroke and atrial fibrillation who were assigned to either early or later initiation (≤4 days vs ≥5 days) of a DOAC in approved doses. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassified stroke within 30 days of randomisation. Secondary outcomes included components of the primary composite within 30 days and 90 days. We did a one-stage individual patient data meta-analysis with the use of a generalised linear mixed-effects model, accounting for between-trial differences, to generate treatment effects, which are presented as odds ratios (ORs) and 95% CIs. This study is registered with PROSPERO, CRD42024522634. FINDINGS:We identified four eligible trials: TIMING (NCT02961348), ELAN (NCT03148457), OPTIMAS (NCT03759938), and START (NCT03021928). After excluding participants who opted out of data sharing or were not randomly assigned to DOAC initiation within 4 days or at day 5 or later, we included 5441 participants (mean age 77·7 years [SD 10·0], 2472 [45·4%] women, median National Institutes of Health Stroke Scale 5 [IQR 3-10]) in the individual patient data meta-analysis. We obtained primary outcome data for 5429 participants. The primary outcome occurred in 57 (2·1%) of 2683 participants who started DOAC early versus 83 (3·0%) of 2746 participants who started later (OR 0·70, 95% CI 0·50-0·98, p=0·039). Early DOAC reduced the risk of recurrent ischaemic stroke (45 [1·7%] of 2683 vs 70 [2·6%] of 2746, OR 0·66, 0·45-0·96, p=0·029). There was no evidence of an increase in symptomatic intracerebral haemorrhage with early DOAC initiation (10 [0·4%] of 2683 vs 10 [0·4%] of 2746, OR 1·02, 0·43-2·46, p=0·96). INTERPRETATION:For people with acute ischaemic stroke and atrial fibrillation, early DOAC initiation (within 4 days) reduced the risk of the composite outcome of recurrent ischaemic stroke, symptomatic intracerebral haemorrhage, or unclassified stroke within 30 days. These findings support early DOAC initiation in clinical practice. FUNDING:The CATALYST collaboration was facilitated by a British Heart Foundation grant for OPTIMAS (grant reference number CS/17/6/33361), with support from researchers at the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and a Swiss National Science Foundation grant for ELAN (32003B_197009; 32003B_169975).

Importance:Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke with atrial fibrillation. It is unknown whether there is an optimal starting day within the 14-day period that balances the risks of recurrent embolic events against serious hemorrhagic events. Objective:To determine if there is an optimal delay time to initiate treatment with a direct oral anticoagulant after atrial fibrillation-related stroke that minimizes the risk of a composite outcome of ischemic or hemorrhagic events. Design, Setting, and Participants:This phase 2, pragmatic, response-adaptive randomized clinical trial was conducted between June 2017 and June 2023 at acute care hospitals in Texas and included patients who had a mild to moderate ischemic stroke (minimum lesion diameter of 1.5 cm) with atrial fibrillation and were prescribed a direct oral anticoagulant within 2 weeks from stroke onset. Intervention:Within 3 to 4 days after atrial fibrillation-associated ischemic stroke, patients were randomized to a group for treatment start date (group 1 was day 3 or 4 after stoke onset; group 2 was day 6; group 3 was day 10; and group 4 was day 14) with a direct oral anticoagulant for secondary stroke prevention. Main Outcomes and Measures:The composite primary outcome was an ischemic (stroke or systemic embolism) or hemorrhagic (symptomatic intracranial hemorrhage or major systemic hemorrhage) event observed within 30 days from the index stroke time of onset. Posterior probabilities were used to estimate which timing groups were optimal for treatment initiation and were recalculated at predefined intervals. The randomization allocations were adjusted to favor the groups with higher probabilities. Results:The trial enrolled and randomized 200 patients (50% were female; the median age was 75 years [IQR, 65-81 years]; 17.5% were Asian, Black, or >1 race; 16.5% were Hispanic; the median National Institutes of Health Stroke Scale score was 6.5 [IQR, 4-14]; and the median lesion diameter was 3.1 cm [IQR, 2.0-4.4 cm]). No ischemic events were observed for group 1, 3 events were observed for group 2, 2 events were observed for group 3, and 2 events were observed for group 4. One hemorrhagic event was observed for group 1, 1 event was observed for group 2, 1 event was observed for group 3, and 0 events were observed for group 4. Group 1 had a posterior probability of 0.41 for being the optimal day for treatment initiation and it was 0.26 for group 2, 0.17 for group 3, and 0.15 for group 4. The use of response-adaptive randomization was feasible and favored groups with earlier initiation times for use of a direct oral anticoagulant. Conclusions and Relevance:A clearly superior day to initiate use of a direct oral anticoagulant for secondary stroke prevention in patients with atrial fibrillation was not identified, but the evidence suggests that initiating use of a direct oral anticoagulant earlier is better than at later times within the first 2 weeks after stroke onset. Trial Registration:ClinicalTrials.gov Identifier: NCT03021928.

Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke with atrial fibrillation. It is unknown whether there is an optimal starting day within the 14-day period that balances the risks of recurrent embolic events against serious hemorrhagic events. To determine if there is an optimal delay time to initiate treatment with a direct oral anticoagulant after atrial fibrillation–related stroke that minimizes the risk of a composite outcome of ischemic or hemorrhagic events. This phase 2, pragmatic, response-adaptive randomized clinical trial was conducted between June 2017 and June 2023 at acute care hospitals in Texas and included patients who had a mild to moderate ischemic stroke (minimum lesion diameter of 1.5 cm) with atrial fibrillation and were prescribed a direct oral anticoagulant within 2 weeks from stroke onset. Within 3 to 4 days after atrial fibrillation–associated ischemic stroke, patients were randomized to a group for treatment start date (group 1 was day 3 or 4 after stoke onset; group 2 was day 6; group 3 was day 10; and group 4 was day 14) with a direct oral anticoagulant for secondary stroke prevention. The composite primary outcome was an ischemic (stroke or systemic embolism) or hemorrhagic (symptomatic intracranial hemorrhage or major systemic hemorrhage) event observed within 30 days from the index stroke time of onset. Posterior probabilities were used to estimate which timing groups were optimal for treatment initiation and were recalculated at predefined intervals. The randomization allocations were adjusted to favor the groups with higher probabilities. The trial enrolled and randomized 200 patients (50% were female; the median age was 75 years [IQR, 65-81 years]; 17.5% were Asian, Black, or >1 race; 16.5% were Hispanic; the median National Institutes of Health Stroke Scale score was 6.5 [IQR, 4-14]; and the median lesion diameter was 3.1 cm [IQR, 2.0-4.4 cm]). No ischemic events were observed for group 1, 3 events were observed for group 2, 2 events were observed for group 3, and 2 events were observed for group 4. One hemorrhagic event was observed for group 1, 1 event was observed for group 2, 1 event was observed for group 3, and 0 events were observed for group 4. Group 1 had a posterior probability of 0.41 for being the optimal day for treatment initiation and it was 0.26 for group 2, 0.17 for group 3, and 0.15 for group 4. The use of response-adaptive randomization was feasible and favored groups with earlier initiation times for use of a direct oral anticoagulant. A clearly superior day to initiate use of a direct oral anticoagulant for secondary stroke prevention in patients with atrial fibrillation was not identified, but the evidence suggests that initiating use of a direct oral anticoagulant earlier is better than at later times within the first 2 weeks after stroke onset. ClinicalTrials.gov Identifier: NCT03021928

Introduction: Ischemic stroke is a leading cause of death and disability in the US, with 20-40% of cases, classified as cryptogenic or with an unexplained cause. Detection of one cause, paroxysmal atrial fibrillation (AF), is critical to ensuring optimal treatment with direct oral anticoagulant (DOAC). Currently, the most reliable AF detection strategy is use of an insertable cardiac monitor (ICM). However, earlier detection of occult cardioembolic patterns using MRI may promote earlier decisions for DOAC use. The overall goal of this study is to determine if MRI lesion patterns are predictive of AF detection by ICM. Methodology: Cases of consecutive patients (1/1/2015 - 12/31/2017) with MRI-confirmed stroke performed 48h from time last known well and prior to endovascular treatment were retrospectively analyzed. The primary outcome, presence of occult atrial fibrillation, was detected by ICM placement within 90 days and follow-up within 180 days from stroke. Four imaging patterns were tested as predictors of AF: i) acute stroke lesion involving multiple vascular territories (MVT, i.e. right or left carotid and/or posterior circulation), ii) MVT plus wedge-shaped cortical infarct or chronic stroke on FLAIR, iii) MVT involving 3 territories, and iv) MVT in 3 territories plus chronic FLAIR lesion. Adjustment variables were based on univariate logistic regression predictors of AF at P ≤0.1000. Results: Of the 101 cases in this analysis, the median age was 63 years and 49.5% male. Stroke in multiple vascular territories MVT was present in 22/101 (22%) at baseline. The total AF 6-month detection rate was 36/101 (36%). The imaging pattern most predictive of AF was pattern ii, MVT plus chronic FLAIR with an unadjusted odds ratio (OR) of 3.47, 95% CI of 0.3442-2.1731, P=.0073. The adjusted OR (age ≥ 55, history of stroke, and history of TIA,) was 3.26, 95% CI: 1.0358-11.1860, P =.0480. Conclusion: The presence of acute lesions in MVT and a chronic FLAIR lesion may be a biomarker of occult cardioembolic source that could be used early after the onset of stroke to determine optimal DOAC use for secondary prevention and potential risk reduction of stroke recurrence from suspected but unproven cardioembolic source. Funding: Lone Star Stroke Research Consortium

Introduction: Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke due to atrial fibrillation (AF). It is unknown whether there is an optimal day within that 14-day period that balances the risks of recurrent embolic vs serious hemorrhagic events. Methodology: The Lone Start Stroke START trial is a pragmatic, prospective, multi-center, response-adaptive randomized Phase 2 study of 200 patients prescribed a direct oral anticoagulant (DOAC) for secondary prevention of stroke due to AF. Patients were randomized into one of 4 Arms: Day 3-4 from stroke onset, Day 6, Day 10, or Day 14. The primary outcome was an ischemic (stroke or systemic embolus) or hemorrhagic (ICH or major systemic hemorrhage) event observed within 30 days from the index stroke time of onset. Posterior probabilities that each arm was the best were calculated at predefined intervals and randomization allocations were adjusted to favor the Arms with higher probabilities. Results: The median age was 75 (IQR 65-81), median NIHSS at presentation was 7 (IQR 4-14), median lesion diameter was 3.1 cm (IQR 2.0-4.4) at the time of randomization. The sample was 50% female, 17.5% non-white, and 16.5% Hispanic. Apixaban was the prescribed DOAC in 89% of the patients. No ischemic events were observed for Arm 1, and no hemorrhage events were observed for Arm 4. Arm 1 (3-4 days) had a posterior 41.1% probability of being the best among the four, with probabilities of 26.4%, 17.1%, and 15.4 % respectively, for the other arms. Response adapted randomization was feasible and favored the earlier two arms. Expected event rates for each arm are presented in the Table. The timing and severity of the outcome events will be presented at the conference. Conclusion: Although the START trial did not identify a clearly superior day to initiate DOAC for secondary stroke prevention in AF, the evidence suggests that initiating DOAC early is better than at later times within the first 2 weeks after stroke onset.

ABSTRACTBackground and PurposeA 10-hospital regional network transitioned to tenecteplase as the standard of care stroke thrombolytic in September 2019 because of its workflow advantages and reported non-inferior clinical outcomes relative to alteplase in meta-analyses of randomized trials. We assessed whether tenecteplase use in routine clinical practice reduces thrombolytic workflow times with non-inferior clinical outcomes.MethodsWe designed a prospective registry-based observational, sequential cohort comparison tenecteplase (n=234) to alteplase (n=354) treated stroke patients. We hypothesized: (1) an increase in the proportion of patients meeting target times for target door to needle (DTN) and transfer door-in-door-out (DIDO), and (2) non-inferior favorable (discharge to home with independent ambulation) and unfavorable (symptomatic intracranial hemorrhage, in-hospital mortality or discharge to hospice) in the tenecteplase group. Total hospital cost associated with each treatment was also compared.ResultsTarget DTN within 45 minutes was superior for tenecteplase, 41% versus 29%; aOR 1.76 (95% CI 1.24, 2.52), P = 0.002. Target DIDO within 90 minutes was superior for tenecteplase 37% (15/43) versus 14% (9/65); OR 3.69 (95% CI 1.47, 9.7), P =0.006, overall, and 67% (12/18) versus 14% (2/14) for those transferred for thrombectomy after thrombolytic treatment (P =0.009). Favorable outcome for tenecteplase fell within the 6.5% non-inferiority margin; aOR 1.28 (95% CI 0.92, 1.77). Unfavorable outcome was less for tenecteplase 7.7% versus 11.9%, aOR 0.79 (95% CI 0.46, 1.32), but did not fall within the pre-specified 1% non-inferior boundary. Net benefit (%favorable – %unfavorable) was greater for the tenecteplase sample: 36% v 27%. P =0.022. Median cost per hospital encounter was less for tenecteplase cases ($13,382 vs $15,841; P <0.001).ConclusionsSwitching to tenecteplase in routine clinical practice in a 10-hospital network was associated with shorter DTN and DIDO times, non-inferior favorable clinical outcomes at discharge, and reduced hospital costs. Evaluation in larger, multicenter cohorts is recommended to determine if these observations generalize.

We present an exploratory study for identification of sex differences in imaging biomarkers that could further refine selection of patients for acute reperfusion therapy and trials based on sex and imaging targets.

Introduction: The decline in the probability of a therapeutic target over time from stroke onset may underlie the declining efficacy of stroke therapies over time. The persistence of a therapeutic target in some patients supports the use of imaging to identify candidates for treatments at later time windows. In light of the known sex differences in stroke subtype, severity and outcomes, we investigated sex differences in the probability of endovascular targets and its relationship of time from stroke onset. Hypothesis: The rate of endovascular targets is different in women than men and sex interacts with endovascular target timing. Methods: A prospective consecutive cohort of 1,092 ischemic stroke patients, with NIHSS > 3, in whom MRI performed within 24 hours of last known well (LKW), was evaluated for potential endovascular therapeutic (EVT) target: intracranial ICA or MCA-M1 occlusion on MRA. Time from LKW, sex, age and the presence of perfusion-diffusion mismatch were modeled as predictors of EVT target. Results: Overall, women had a significantly higher probability of presenting with endovascular targets with an adjusted odds ratio, OR, of 1.450, p=0.013. The probability of target detection decreased over time for both sexes, but the rates of decline differed significantly (p=0.034) in multivariate models, with targets consistently present at later times in women. A multivariate model of endovascular target adjusted for the presence of mismatch and the interaction between sex and mismatch resulted in a sex difference of 230% (odds ratio of 2.32, p=0.010), independent of time from onset. Conclusions: Women demonstrated prolonged presence of endovascular targets. In light of recent endovascular trial results, this identification of disparities in imaging biomarkers represents a step toward further refining the imaging selection of patients for acute reperfusion therapy and trials. The results implicate the need to stratify considerations of treatment intervention based on sex due to the potentially extended therapeutic time window for women.

Sex differences exist in stroke epidemiology, acute presentation, treatment, and post-stroke clinical outcome. Neuroimaging can objectively identify potential pathological therapeutic targets and is reflective clinical observations. MCA occlusion (MCAO) is measurable by angiography and the presence of penumbra by diffusion-perfusion mismatch. We present evaluation of sex differences in the Lesion Evolution in Stroke and Ischemia On Neuroimaging (LESION) Project to determine if the probability of MCAO and penumbra depend on sex. We hypothesize imaging-based evidence is consistent with clinical observations of sex differences in severity and interactions with age and race. Methods: Patients included in the LESION study were diagnosed with acute ischemic cerebrovascular syndrome, had a brain MRI obtained within 24 hours from last known well and NIHSS>3 or were treated with acute intervention with a pre-treatment MRI. MR imaging included DWI, FLAIR, MRA and PWI, which were co-localized over the entire brain. Patients with M1 or M2 abnormalities were graded as MCAO. The probability of having an MCAO or measurable pathological target was qualitatively evaluated as a function of sex with adjustment for age and race. Results: Women were more likely than men (all p<0.05) to have a measurable of MCAO (OR [CI’s]) = (1.43 [1.08-1.89]), perfusion defect (1.42 [1.02-2.0]), or a diffusion-perfusion mismatch (1.35 [1.02-1.80]) (Table). This sex difference remained after adjusting for time from onset, NIHSS and age. Women over 70 years are most likely to have a measurable therapeutic target and white women are more likely to have a penumbral pattern than men or non-white women (p<0.05). Conclusion: This preliminary imaging-based evidence is encouraging that sex differences in imaging biomarkers exist in a representative sample of acute stroke patients. This study shows that sex differences exist not only in the clinical phenotype, but in presence of a biological target.

BACKGROUND. A contributing factor in the decreased efficacy of thrombolysis over time may be a decrease in the probability of the therapeutic target, but this has not been well studied. Detection of therapeutic targets beyond 4.5 hr is the premise for reperfusion trials at extended time windows. We quantified the relationship of time from onset to the probability of detection of therapeutic targets. METHODS. We analyzed a consecutive series of 1103 ischemic stroke patients with NIHSS > 3 and an MRI within 24 hr from last known well. Potential therapeutic targets were occlusion on MRA (ARTERY), M1 or M2 occlusion (MCAO), focal ischemia on perfusion MRI (PERFUSION), and diffusion-perfusion mismatch (MISMATCH). Logistic regression models evaluated hours from onset, NIHSS, age, and sex as predictors of target. RESULTS. ARTERY, PERFUSION, and MISMATCH probabilities decreased over time (p < 0.0001) at approximately 1% per hour. More severe strokes increased the probability of detection by about 1% per NIHSS point. Logistic regression model found significant relationships of MISMATCH to hours, NIHSS, MCAO, and the interaction of NIHSS X MCAO (Table). MCAO patients had higher probabilities of MISMATCH, which decreased more rapidly over time (Graph). The probability of MISMATCH can be estimated by the logistic regression model: e.g., MCAO and NIHSS 12 at 9 hr = 78%; MCAO and NIHSS 14 at 20 hr = 47%. CONCLUSION. The probability of potential targets of reperfusion therapy declines over the first 24 hours from stroke onset. A substantial proportion of patients have a target beyond the proven time window for thrombolytic therapy, and the proportion can be estimated by the logistic regression model.

Background: Some patients seen by a stroke team do not have cerebrovascular disease but a condition that mimics stroke. The purpose of this study was to determine the rate and predictors of stroke mimics in a large sample. Methods: This is an analysis of data from consecutive patients seen by the National Institutes of Health Stroke Program over 10 years. Data were collected prospectively as a quality improvement initiative. Patients with a cerebrovascular event or a stroke mimic were compared with the Student t or Pearson chi-square test as appropriate, and logistic regression was done to identify independent predictors. Results: The analysis included 8187 patients: 30% had a stroke mimic. Patients with a stroke mimic were younger, and the proportion of patients with a stroke mimic was higher among women, patients without any risk factors, those seen as a code stroke or who arrived to the emergency department via personal vehicle, and those who had the onset of symptoms while inpatients. The proportion of patients with a stroke mimic was marginally higher among African-Americans than Caucasians. Factors associated with the greatest odds of having a stroke mimic in the logistic regression were lack of a history of hypertension, atrial fibrillation or hyperlipidemia. Conclusions: One third of the patients seen by a stroke team over 10 years had a stroke mimic. Factors associated with a stroke mimic may be ascertained by an emergency physician before calling the stroke team.

Background and Purpose— The STAIR (Stroke Treatment Academic Industry Roundtable) meeting aims to advance acute stroke therapy development through collaboration between academia, industry, and regulatory institutions. In pursuit of this goal and building on recently available level I evidence of benefit from endovascular therapy (ET) in large vessel occlusion stroke, STAIR IX consensus recommendations were developed that outline priorities for future research in ET. Methods— Three key directions for advancing the field were identified: (1) development of systems of care for ET in large vessel occlusion stroke, (2) development of therapeutic approaches adjunctive to ET, and (3) exploring clinical benefit of ET in patient population insufficiently studied in recent trials. Methodological issues such as optimal trial design and outcome measures have also been addressed. Results— Development of systems of care strategies should be geared both toward ensuring broad access to ET for eligible patients and toward shortening time to reperfusion to the minimum possible. Adjunctive therapy development includes neuroprotective approaches, adjuvant microcirculatory/collateral enhancing strategies, and periprocedural management. Future research priorities seeking to expand the eligible patient population are to determine benefit of ET in patients presenting beyond conventional time windows, in patients with large baseline ischemic core lesions, and in other important subgroups. Conclusions— Research priorities in ET for large vessel occlusion stroke are to improve systems of care, investigate effective adjuvant therapies, and explore whether patient eligibility could be expanded.

To shed light on brain complications occurring after heart surgery, the authors assessed BBB disruption and DWI findings in half of their patients by imaging at 24 hours after surgery and 24-48 hours later. Additionally, postcontrast T1 images were obtained postoperatively at 2-4 days in the other half of the patients. Almost half the patients undergoing cardiac surgery had evidence of BBB abnormalities and three-quarters showed acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MR can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery.BACKGROUND AND PURPOSE: CNS complications are often seen after heart surgery, and postsurgical disruption of the BBB may play an etiologic role. The objective of this study was to determine the prevalence of MR imaging-detected BBB disruption (HARM) and DWI lesions after cardiac surgery.MATERIALS AND METHODS: All patients had an MRI after cardiac surgery. For half the patients (group 1), we administered gadolinium 24 hours after surgery and obtained high-resolution DWI and FLAIR images 24-48 hours later. We administered gadolinium to the other half (group 2) at the time of the postoperative scan, 2-4 days after surgery. Two stroke neurologists evaluated the images.RESULTS: Of the 19 patients we studied, none had clinical evidence of a stroke or delirium at the time of the gadolinium administration or the scan, but 9 patients (47%) had HARM (67% in group 1; 30% in group 2; P = .18) and 14 patients (74%) had DWI lesions (70% in group 1; 78% in group 2; P = 1.0). Not all patients with DWI lesions had HARM, and not all patients with HARM had DWI lesions (P = .56).CONCLUSIONS: Almost half the patients undergoing cardiac surgery have evidence of HARM, and three-quarters have acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MR imaging can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery.

The art and science of diagnosing endocrinology diseases requires a practitioner to consistently think outside the “assay.” Autoimmune thyroid disease (AITD) is a common diagnosis and may be synergistic with Epstein-Barr virus (EBV) in its presentation. Four female adolescents with ages 14–17 years presented for consultation regarding abnormal thyroid function. The symptomatology presented includes fatigue, appetite changes, irritability, restlessness, headaches, facial/peripheral edema, sleep disturbances, and weight changes. All reported thyroid enlargement; small to moderate glands palpated nontender and nonnodular. Each female's past medical history considered unremarkable, and two of the four reported a positive family history of thyroid disease. Laboratory data collected included thyroid stimulating hormone, free thyroxine (FT4), thyroid peroxidase (TPO), thyrotropin-stimulating immunoglobulin (TSI), EBV (VCA [viral capsid antigen]) IgM, and EBV (VCA) IgG. All presented with + TPO values, two with + TSI values. Three females had positive EBV (VCA) IgG values representing chronic disease with infection in the past 3-12 months. One noted a positive EBV (VCA) IgM value representing an acute infection within the past 3 months (Gilbert-Barness & Barness, 2003). The two presented with Hashimoto's; they responded well and were biochemically euthyroid within 3 months. The two diagnosed with Grave's were both initially placed on antithyroidal medication, methimazole. The response was variable. One responded well and began weaning the dose within 6 months, and the other required a thyroidectomy 5 months into diagnosis because of a suspected allergic reaction to methimazole. Although thyroid function had improved, symptoms such as fatigue remained. All four unique cases presented with AITD with EBV, requiring additional education and reassurance through anticipatory guidance. AITD affects approximately 10% of the population (Davies, 2008), with EBV infecting 98% of world's population (Toussirot & Roudier, 2008). The correlation between EBV and other autoimmune disease processes such as systemic lupus and multiple sclerosis have been well documented. In an exhaustive literature search, very little is known or has been documented in the relationship of EBV and AITD. Therefore, as a practitioner, one must never discount a thorough health history and think beyond the master gland, the thyroid.

Beginning in 1949, the U.S. Justice Department put the leadership of the American Communist Party (CPUSA) on trial for conspiracy to advocate the overthrow of the U.S. government by force and violence. Convictions in the first trial (Dennis v. United States) were secured largely on the testimony of paid FBI informants. An appeal was rejected by the Supreme Court in 1951, during the Korean War, opening the door for more trials, convictions, and imprisonments of American Communists. The previously undocumented career of Angela Calomiris (1916-95), a prosecution witness at the 1949 trial, gives unusual insight into one informant/informer's ambitions and meteoric rise to celebrity. A rather notorious Greenwich Village lesbian, Calomiris was nevertheless no stranger to crew-cut FBI agents, and published one of the first books by Red Scare informant-witnesses, Red Masquerade: Undercover for the F.B.I. At the height of her celebrity, she appeared on Eleanor Roosevelt's radio show.