Background: Given the good prognosis of low-risk papillary thyroid microcarcinomas (lrPTMCs) accurate risk stratification is valuable to optimize management: active surveillance vs. surgery. BRAFV600E testing was associated with increased recurrence risk, hence AS seems reasonable for mutation-negative lrPTMC. However, when considering AS, patient perception is highly important as adherence and emotional aspects are challenging. In this study, we aimed to model the contribution of BRAFV600E testing for the management of PTMCs when tailored to the patient perspective. Methods: We developed a Markovian model to predict the role of BRAFV600E in prioritizing between hemithyroidectomy (HT) and active surveillance (AS) for lrPTMCs. We used a simulated cohort of lrPTMCs, with probabilities of each strategy driven from previous literature. Outcomes were measured as quality-of-life years (QALYs). One- and two-way sensitivity analyses were conducted to ascertain model robustness. Results: We found that the optimal strategy (e.g., that would maximize QALYs) varies according to BRAFV600E status for patients without a preset predilection between AS to HT. Using one-way sensitivity analysis, we found that the two main variables that have the strongest impact on the decision are the utility of AS and the utility of a disease-free state after HT. Two-way sensitivity analysis demonstrated that BRAFV600E status can define the optimal strategy for patients in the middle zone of the utility range (e.g., patients without clear preference). Conclusions: Our model suggests that BRAFV600E status can facilitate decision-making regarding AS vs. HT for patients without preset predilection. Our model supports further real-life studies of BRAFV600E testing for PTMCs.

Background The safe consumption of foods depends on their allergen content in relation to patient Low Observed Adverse Effect Level (LOAEL) and No Observed Adverse Effect Level (NOAEL), and other factors. In the case of milk, data on LOAEL and NOAEL is limited and conflicting. Objective To determine the threshold dose distribution and the lowest individual ED for milk in a large group of milk allergic patients Methods Individuals with confirmed cow’s milk allergy who underwent either a diagnostic or pre-oral immunotherapy (OIT) open milk oral food challenge in The Institute of Allergy, Immunology, and Pediatric Pulmonology at Shamir Medical Center, between 2010 and 2015 were included. A subgroup of patients with severe milk allergy underwent a modified challenge with 90-120 minute-interval following a dose of 0.3 mg cow’s milk protein. Results A total of 866 participants (193 with diagnostic challenges and 673 with pre-OIT challenges) were included in the study. The discrete ED 01 and ED 05, or values derived where 1% or 5% of the respective allergic population would be predicted to experience an allergic reaction, were 1.1-1.9 and 4.7-5.6 mg milk protein, respectively, and the values for cumulative doses for ED 01 and ED 05 were 0.9-1.8 and 5.2-6.2 mg milk protein, respectively. None of the patients, including the most severe milk allergic individuals who underwent the modified challenge, reacted to the first 0.3 mg protein dose. Discussion This report provides valuable information on milk NOAELs, LOAELs and EDs which might assist regulators in their decisions on food labeling in general, and for milk in particular. CLINICAL IMPLICATIONS The current study, using the largest studied population, demonstrates that milk NOAELs and LOAELs are higher than previously described. No patient reacted to <1mg milk protein. CAPSULE SUMMARY The finding of higher LOAEL and NOAEL and of a “safe dose” is important for mainly for regulators but as well as milk allergic patients and families in their decisions on milk labeling.