How T cells become restricted to binding antigenic peptides within class I or class II major histocompatibility complex molecules (pMHCI or pMHCII, respectively) via clonotypic T-cell receptors (TCRs) remains debated. During development, if TCR-pMHC interactions exceed an affinity threshold, a signal is generated that positively selects the thymocyte to become a mature CD4 + or CD8 + T cell that can recognize foreign peptides within MHCII or MHCI, respectively. But whether TCRs possess an intrinsic, subthreshold specificity for MHC that facilitates sampling of the peptides within MHC during positive selection or T-cell activation is undefined. Here we asked if increasing the frequency of lymphocyte-specific protein tyrosine kinase (Lck)-associated CD4 molecules in T-cell hybridomas would allow for the detection of subthreshold TCR-MHC interactions. The reactivity of 10 distinct TCRs was assessed in response to selecting and nonselecting MHCII bearing cognate, null, or "shaved" peptides with alanine substitutions at known TCR contact residues: Three of the TCRs were selected on MHCII and have defined peptide specificity, two were selected on MHCI and have a known pMHC specificity, and five were generated in vitro without defined selecting or cognate pMHC. Our central finding is that IL-2 was made when each TCR interacted with selecting or nonselecting MHCII presenting shaved peptides. These responses were abrogated by anti-CD4 antibodies and mutagenesis of CD4. They were also inhibited by anti-MHC antibodies that block TCR-MHCII interactions. We interpret these data as functional evidence for TCR-intrinsic specificity for MHCII.TCR | MHC | restriction | CD4 | Lck P ositive and negative selection limit the αβT-cell repertoire to cells expressing clonotypic T-cell receptors (TCRs) that distinguish the antigenicity of peptides embedded within class I and class II major histocompatibility complex molecules (pMHCI or pMHCII, respectively) based on their source of origin (i.e., self or foreign) (1-4). Approximately 7.5% of CD4 + CD8+ doublepositive (DP) thymocytes express TCRs that interact with selfpMHC above an affinity threshold required for positive selection, whereas 7.5% cross a higher affinity threshold that mediates negative selection and the remaining TCRs fail to direct positive selection (5). The rules that restrict TCR recognition of antigenic peptides within MHCI or MHCII are unresolved.Two models have been proposed to explain MHC restriction. One posits that restriction is imposed by CD4 or CD8 during thymocyte development to eliminate TCRs that recognize non-MHC ligands (2, 6). Here, the CD4-and CD8-associated Src kinase, p56Lck [lymphocyte-specific protein tyrosine kinase (Lck)], is sequestered away from the immunoreceptor tyrosine-based activation motifs (ITAMs) of the TCR-associated CD3δe, CD3γe, and CD3ζζ signaling modules. Positively selecting signals are then generated in thymocytes expressing TCRs that bind MHCII or MHCI together with CD4 or CD8, respectively, as this localizes Lck to the ITAMs. T...

IMPORTANCE Although various treatments have been found in clinical trials to be effective in treating actinic keratosis (AK), researchers often report different outcomes. Heterogeneous outcome reporting precludes the comparison of results across studies and impedes the synthesis of treatment effectiveness in systematic reviews.OBJECTIVE To establish an international core outcome set for all clinical studies on AK treatment using systematic literature review and a Delphi consensus process.EVIDENCE REVIEW Survey study with a formal consensus process. The keywords actinic keratosis and treatment were searched in PubMed, Embase, CINAHL, and the Cochrane Library to identify English-language studies investigating AK treatments published between January 1, 1980, and July 13, 2015. Physician and patient stakeholders were nominated to participate in Delphi surveys by the Measurement of Priority Outcome Variables in Dermatologic Surgery Steering Committee members. All participants from the first round were invited to participate in the second round. Outcomes reported in randomized controlled clinical trials on AK treatment were rated via web-based e-Delphi consensus surveys.Stakeholders were asked to assess the relative importance of each outcome in 2 Delphi survey rounds. Outcomes were provisionally included, pending the final consensus conference, if at least 70% of patient or physician stakeholders rated the outcome as critically important in 1 or both Delphi rounds and the outcome received a mean score of 7.5 from either stakeholder group. Data analysis was performed from November 5, 2018, to February 27, 2019.FINDINGS A total of 516 outcomes were identified by reviewing the literature and surveying key stakeholder groups. After deduplication and combination of similar outcomes, 137 of the 516 outcomes were included in the Delphi surveys. Twenty-one physicians and 12 patients participated in round 1 of the eDelphi survey, with 17 physicians (81%) retained and 12 patients (100%) retained in round 2. Of the 137 candidate outcomes, 9 met a priori Delphi consensus criteria, and 6 were included in the final outcomes set after a consensus meeting: complete clearance of AKs, percentage of AKs cleared, severity of adverse events, patient perspective on effectiveness, patient-reported future treatment preference, and recurrence rate. It was recommended that treatment response be assessed at 2 to 4 months and recurrence at 6 to 12 months, with the AK rate of progression to cutaneous squamous cell carcinoma reported whenever long-term follow-up was possible.CONCLUSIONS AND RELEVANCE Consensus was reached regarding a core outcome set for AK trials. Further research may help determine the specific outcome measures used to assess each of these outcomes.

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Background and Objectives To date, there are no well‐established guidelines regarding laser therapy for the treatment of cutaneous lesions in pediatric patients. We aim to ascertain the types of lasers commonly used, types of lesions treated, and factors that affect the selection of specific laser modalities in pediatric patients. Study Design/Materials and Methods An anonymous online survey was distributed to healthcare providers who treat children with lasers through listservs of four major national and international dermatology and laser organizations. Results Outpatient office‐based procedure rooms are the most common clinical setting for laser procedures (74.4%), and pulsed dye laser is the most commonly used laser (95.4%). Conditions routinely treated with lasers included port wine stains (95.4%), infantile hemangiomas (81.5%), other vascular lesions (81.5%), scars (77.7%), and hair (60.8%). 84.4% of respondents expressed concern about general anesthesia in patients <2 years old. Nevi of Ota is treated with laser more frequently (52.3%) than other pigmented lesions. Limitations Limited generalizability of case examples to general conditions. Conclusions Vascular lesions are the most common lesions treated with lasers in pediatric dermatology patients, and most providers are using these devices in the outpatient setting. Many providers are concerned about the effects of repeated general anesthesia in infants, and there appears to be a trend toward providing laser therapy in the outpatient setting without general anesthesia. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

3. A small subset of patients who prioritize high titer immunity over potential skin flare may consider biologic discontinuation prior to receiving an inactive vaccine. We believe that regions with high rates of COVID-19 infection, hospitalization, or mortality may justify this unique approach. Detailed guidance will be required in order to safely vaccinate biologic-maintained patients. When faced with the possibility of interrupting immunosuppressive treatments dermatologists may fear the development of antidrug antibodies (ADAs) that diminish the efficacy of biologic therapy. Recent studies of newer biologics, those targeting the IL-23/IL-17 immunological pathways such as guselkumab, tildrakizumab, and ustekinumab, reveal less than 6.7% of patients developing ADAs. 5 The lower occurrence of immunogenicity seen with IL-23/IL-17 biologics and the growing arsenal of available treatments make restarting or switching biologic therapy after a pause for vaccination a more plausible therapeutic option. We believe early anticipation of vaccine scenarios is essential to ensure safe management of patients on biologic therapies throughout all phases of the COVID-19 pandemic. DISCLOSURES Dr. Krase has done consulting for AbbVie and has received an honorarium. Ms. Hauptman and Dr. Vasic have no potential perceived conflicts of interest to disclose.