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Background Despite a better understanding of the epidemiology, pathogenesis, and management of patients with anaphylaxis, there remain knowledge gaps. Enumerating and prioritizing these gaps would allow limited scientific resources to be directed more effectively. Objective We sought to systematically describe and appraise anaphylaxis knowledge gaps and future research priorities based on their potential impact and feasibility. Methods We convened a 25-member multidisciplinary panel of anaphylaxis experts. Panelists formulated knowledge gaps/research priority statements in an anonymous electronic survey. Four anaphylaxis themed writing groups were formed to refine statements: (1) Population Science, (2) Basic and Translational Sciences, (3) Emergency Department Care/Acute Management, and (4) Long-Term Management Strategies and Prevention. Revised statements were incorporated into an anonymous electronic survey, and panelists were asked to rate the impact and feasibility of addressing statements on a continuous 0 to 100 scale. Results The panel generated 98 statements across the 4 anaphylaxis themes: Population Science (29), Basic and Translational Sciences (27), Emergency Department Care/Acute Management (24), and Long-Term Management Strategies and Prevention (18). Median scores for impact and feasibility ranged from 50.0 to 95.0 and from 40.0 to 90.0, respectively. Key statements based on median rating for impact/feasibility included the need to refine anaphylaxis diagnostic criteria, identify reliable diagnostic, predictive, and prognostic anaphylaxis bioassays, develop clinical prediction models to standardize postanaphylaxis observation periods and hospitalization criteria, and determine immunotherapy best practices. Conclusions We identified and systematically appraised anaphylaxis knowledge gaps and future research priorities. This study reinforces the need to harmonize scientific pursuits to optimize the outcomes of patients with and at risk of anaphylaxis.

Anaphylaxis is a systemic allergic reaction that can be caused by food, drugs, insect bites, or unknown triggers in infants and toddlers. Anaphylaxis rates are increasing. Infants and toddlers may have increased exposure to known and unknown allergens, decreased ability to describe their symptoms, and an expanded differential diagnosis for consideration on presentation. The most common symptoms in these age groups are cutaneous and gastrointestinal. Age-specific language may be helpful for caregivers to identify and describe the symptoms of anaphylaxis in infants and toddlers. Long-term management of anaphylaxis includes allergy evaluation to guide avoidance and assess prognosis and education on allergic reaction management; this incorporates the prescription of epinephrine autoinjector and provision of an allergy emergency plan.

Health disparities are health differences linked with economic, social, and environmental disadvantage. They adversely affect groups that have systematically experienced greater social or economic obstacles to health. Renewed efforts are needed to reduced health disparities in the United States, highlighted by the disparate impact on racial minorities during the coronavirus pandemic. Institutional or systemic patterns of racism are promoted and legitimated through accepted societal standards, and organizational processes within the field of medicine, and contribute to health disparities. Herein, we review current evidence regarding health disparities in allergic rhinitis, asthma, atopic dermatitis, food allergy, drug allergy, and primary immune deficiency disease in racial and ethnic underserved populations. Best practices to address these disparities involve addressing social determinants of health and adopting policies to improve access to specialty care and treatment for the underserved through telemedicine and community partnerships, cross-cultural provider training to reduce implicit bias, inclusion of underserved patients in research, implementation of culturally competent patient education, and recruitment and training of health care providers from underserved communities. Addressing health disparities requires a multilevel approach involving patients, health providers, local agencies, professional societies, and national governmental agencies.

Food allergy management in child care centers and schools is a controversial topic, for which evidence-based guidance is needed. Following the Grading of Recommendations Assessment, Development, and Evaluation approach, we conducted systematic literature reviews of the anticipated health effects of selected interventions for managing food allergy in child care centers and schools; we compiled data about the costs, feasibility, acceptability, and effects on health equity of the selected interventions; and we developed the following conditional recommendations: we suggest that child care centers and schools implement allergy training and action plans; we suggest that they use epinephrine (adrenaline) to treat suspected anaphylaxis; we suggest that they stock unassigned epinephrine autoinjectors, instead of requiring students to supply their own personal autoinjectors to be stored on site for designated at-school use; and we suggest that they do not implement site-wide food prohibitions (eg, "nut-free" schools) or allergen-restricted zones (eg, "milk-free" tables), except in the special circumstances identified in this document. The recommendations are labeled "conditional" due to the low quality of available evidence. More research is needed to determine with greater certainty which interventions are likely to be the most beneficial. Policymakers might need to adapt the recommendations to fit local circumstances.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality and is associated with high recurrence rates. The introduction of direct oral anticoagulants (DOACs) in the 2010s has changed the landscape of VTE management. DOACs have become the preferred anticoagulant therapy for their ease of use, predictable pharmacokinetics, and improved safety profile. Increasingly, guidelines have recommended long term anticoagulation for some indications such as following first unprovoked major VTE, although an objective individualised risk assessment for VTE recurrence remains elusive. The balance of preventing VTE recurrence needs to be weighed against the not insignificant bleeding risk, which is cumulative with prolonged use. Hence, there is a need for an individualised, targeted approach for assessing the risk of VTE recurrence, especially in those patients in whom the balance between benefit and risk of long-term anticoagulation is not clear. Clinical factors alone do not provide the level of discrimination required on an individual level. Laboratory data from global coagulation assays and biomarkers may provide enhanced risk assessment ability and are an active area of research. A review of the prediction models and biomarkers for assessing VTE recurrence risk is provided, with an emphasis on contemporary developments in the era of DOACs and global coagulation assays.

Previous guidance on infant anaphylaxis largely relied on data from older children and adults. Infants are a unique subgroup, which presents specific challenges because infants are unable to verbalize symptoms, although the magnitude of underrecognition is not well studied. Data show that strict avoidance of allergens is difficult to achieve in the infant age group and a source of stress and anxiety for their caregivers. Recent studies suggest that infant anaphylaxis is less severe than in older children, which could greatly assist with implementation of food allergy prevention and treatment. New evidence from clinical trials and observational and real-world studies show that infant anaphylaxis is rare on first ingestion of a new food and typically not severe when it occurs, which parents may not be aware of when preparing to introduce peanut or other common food allergens to infants for the purpose of prevention. The better safety and efficacy of oral immunotherapy in infants and preschoolers could help prevent undesired psychosocial consequences of longstanding food allergy such as anxiety, bullying, and poor quality of life. Evidence from recent years on the lower risk of infant anaphylaxis and its severity could move allergy practice toward the confidence that regular, long-term ingestion provides.

This comprehensive practice parameter for allergic rhinitis (AR) and nonallergic rhinitis (NAR) provides updated guidance on diagnosis, assessment, selection of monotherapy and combination pharmacologic options, and allergen immunotherapy for AR. Newer information about local AR is reviewed. Cough is emphasized as a common symptom in both AR and NAR. Food allergy testing is not recommended in the routine evaluation of rhinitis. Intranasal corticosteroids (INCS) remain the preferred monotherapy for persistent AR, but additional studies support the additive benefit of combination treatment with INCS and intranasal antihistamines in both AR and NAR. Either intranasal antihistamines or INCS may be offered as first-line monotherapy for NAR. Montelukast should only be used for AR if there has been an inadequate response or intolerance to alternative therapies. Depot parenteral corticosteroids are not recommended for treatment of AR due to potential risks. While intranasal decongestants generally should be limited to short-term use to prevent rebound congestion, in limited circumstances, patients receiving regimens that include an INCS may be offered, in addition, an intranasal decongestant for up to 4 weeks. Neither acupuncture nor herbal products have adequate studies to support their use for AR. Oral decongestants should be avoided during the first trimester of pregnancy. Recommendations for use of subcutaneous and sublingual tablet allergen immunotherapy in AR are provided. Algorithms based on a combination of evidence and expert opinion are provided to guide in the selection of pharmacologic options for intermittent and persistent AR and NAR.

Purpose: To evaluate neurotoxicity in testicular cancer survivors (TCSs) years after treatment and secondly the influence of neurotoxicity on quality-of-life (QoL). Methods: We identified 2234 TCSs who completed the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire. QoL was evaluated with the European Organization for Research and Treatment of Cancer QLQ-C30. Patients were grouped according to treatment strategy: surveillance (N = 1113), infradiaphragmatic radiotherapy (N = 301), cisplatin-etoposide-bleomycin (BEP) (N = 759), and more than one line of treatment (MTOL) (N = 61). Association of treatment modality with long-term neurotoxicity was analyzed with ordinal logistic regression. Secondly, associations between neurotoxicity and QoL were analyzed in BEP-treated patients. Analyses were age-adjusted and repeated with additional adjustment for comorbidity, smoking, and alcohol consumption. Results: After a median follow-up of 18.4 years, treatment with BEP and MTOL was associated with overall increased risk of neurotoxicity (odds ratio 2.4–4.7 depending on treatment intensity, P < 0.001) as well as subscales (peripheral neuropathy, ototoxicity, and dysfunction associated with neuropathy, all P < 0.001). Radiotherapy and surveillance were not associated with neurotoxicity. In patients treated with BEP, neurotoxicity was highly associated with all indicators of worse QoL outcomes (P-trend: 1.5 × 10−17 to 1.1 × 10−28) after almost 20 years of follow-up. Conclusions: Treatment with BEP was associated with long-term neurotoxicity, which was highly associated with decreased QoL. Strategies to ameliorate or prevent neurotoxicity should be investigated. Implications for Cancer Survivors: Treatment with chemotherapy for testicular cancer induces long-term neuro- and ototoxicity which may have severe influence on quality-of-life years after treatment cessation.

Background: Sexual function and quality of life remain unexplored among long-term survivors of bilateral testicular cancer (TC). Objective: To investigate sexual function, fatigue, anxiety, and depression among long-term survivors of bilateral TC (unilateral TC with contralateral germ cell neoplasia in situ [TC + GCNIS] or bilateral TC [BTC]). Design, setting, and participants: This was a cross-sectional study of 2479 long-term TC survivors, of whom 126 were treated with contralateral radiotherapy for GCNIS, 93 were treated with bilateral orchiectomy for BTC, and 2260 had unilateral TC (reference group). Outcome measurements and statistical analysis: Outcomes were assessed using validated questionnaires at a median time since diagnosis of 17 yr (interquartile range 12–23). Results for survivors of TC + GCNIS and of BTC were compared with those for the reference group. Adjustment was made for age and treatment for disseminated disease. Results and limitations: The age-adjusted risk of anxiety was significantly higher among BTC survivors (odds ratio 1.7, 95% confidence interval [CI] 1.1–2.8; p = 0.002) than in the reference group. Apart from a higher risk of reduced motivation among survivors of TC + GCNIS (β = 0.067, 95% CI 0.0013–0.13; p = 0.046) there were no significant differences between the groups. Limitations include the low number of cases with symptoms of depression. Conclusions: Survivors of BTC had a higher risk of anxiety but did not experience impairment of other aspects of quality of life when compared to survivors of unilateral TC. These results are of importance for evidence-based information on late effects for bilateral TC patients. Patient summary: We evaluated quality of life and sexual function among long-term survivors of bilateral testicular cancer. Reassuringly, we did not find impaired quality of life apart from a higher risk of anxiety when comparing survivors of bilateral testicular cancer with survivors of unilateral testicular cancer. Long-term survivors of bilateral testicular cancer had a higher risk of anxiety but not of sexual dysfunction when compared to long-term survivors of unilateral testicular cancer.

Background Peanut allergy is a potentially severe and lifelong allergy, with few effective treatments or preventive measures. Objective To convene an expert panel of allergists, pediatricians, and advocates to discuss and highlight unmet needs in the prevention and management of peanut allergies. Methods Literature searches of PubMed were performed. The panel evaluated published data on the prevention of peanut allergy, treatment of existing peanut allergy, and management of reactions after unintentional peanut exposures. Results The following key unmet needs in the prevention and management of peanut allergy were identified: (1) enhancing and optimizing implementation of early peanut introduction as a means of preventing the development of peanut allergy, (2) developing knowledge translation strategies regarding the safety and efficacy data for current and emerging immunotherapies for peanut-allergic children to support their use in clinical practice, and (3) promoting understanding of true exposure risk in allergic individuals and ensuring access to epinephrine for unintentional exposures that provoke severe reactions. Practitioners should help educate caregivers about the actual risks associated with peanut allergy and its prevention and management so that treatment decisions can be evidence based rather than fear based. Support tools are needed to help address caregiver goals, expectations, and psychological barriers, as well as identify facilitators for prevention and treatment strategies. Conclusion There are significant unmet needs in our understanding of peanut allergy; addressing these needs will help to enhance understanding of how to most effectively prevent and treat peanut allergy, as well as educate the food-allergic and nonallergic community regarding current evidence-based practices.

Predicting the risk of recurrence after venous thromboembolism (VTE) remains an important clinical challenge. Post-anticoagulation cessation d-dimer has previously been shown to be associated with increased VTE recurrence in unprovoked major VTE, however this is not routinely used clinically and has not been validated in provoked VTE and isolated distal DVT (IDDVT). We aimed to retrospectively evaluate this practice in the real-world setting including examining its use in provoked VTE and IDDVT. Consecutive patients diagnosed with DVT or PE between January 2013 and December 2016 were retrospectively evaluated. Clinical features, VTE risk factors, recurrence and bleeding rates were evaluated for patients with normal and abnormal post-anticoagulation d-dimer, as well as those patients who did not undergo D-dimer testing. Patients with active malignancy, superficial vein thrombosis and inadequate follow-up were excluded. Of the 1033 patients with a diagnosis of VTE in the study period, 173 were included in the “d-dimer tested” group, and 254 in the “d-dimer un-tested” comparison group. Abnormal post-anticoagulation d-dimer was significantly associated with VTE recurrence (HR 5.96, 95% CI 2.15–14.57, p

Individuals with food allergy are at risk for accidental exposures, potentially resulting in allergic reactions that may cause significant morbidity and mortality. Dining out, including restaurants or take-out, account for a large proportion of severe reactions. Errors due to gaps in knowledge or miscommunication can easily occur on behalf of food-allergic individuals or restaurant staff, resulting in accidental exposures and allergic reactions. Improved legislation, training of restaurant staff, and practitioner-guided education are recommended to reinforce patient safety and prevent severe allergic reactions. This Work Group Report provides guidance with specific practices that practitioners may recommend, and that patients and restaurant staff may employ, for prevention and treatment of food-allergic reactions in restaurants.

ObjectiveTo examine the cardiovascular, cerebrovascular, and peripheral vascular safety of erenumab across migraine prevention studies.MethodsVascular adverse events (AEs) and blood pressure data were integrated across 4 double-blind, placebo-controlled studies of erenumab and their open-label extensions in patients with chronic or episodic migraine. Subgroup analyses were conducted by acute migraine-specific medication use and number of vascular risk factors at baseline. Standardized search terms were used to identify vascular AEs (cardiovascular, cerebrovascular, or peripheral). An independent committee adjudicated whether targeted events were vascular in origin.ResultsIn placebo-controlled studies, 2,443 patients received placebo (n = 1,043), erenumab 70 mg (n = 893), or erenumab 140 mg (n = 507) subcutaneously once monthly. Regardless of acute migraine-specific medication use or vascular risk factors at baseline, AE incidence was similar across the placebo and erenumab treatment groups. Hypertension AEs were reported for 0.9% (placebo), 0.8% (erenumab 70 mg), and 0.2% (erenumab 140 mg) of patients. Vascular AEs, which were similar across double-blind and open-label treatment, generally were confounded, with plausible alternative etiologies. In 18 patients with events reviewed by the independent committee, 4 events were positively adjudicated as cardiovascular in origin: 2 deaths and 2 vascular events. All 4 positively adjudicated cardiovascular events occurred during open-label erenumab treatment.ConclusionSelective blockade of the canonical calcitonin gene-related peptide receptor with erenumab for migraine prevention had a vascular safety profile comparable to that of placebo over 12 weeks, with no increased emergence of events over time. Further study of long-term safety of erenumab in patients with migraine is needed.Clinicaltrials.gov identifiersNCT02066415, NCT02456740, NCT01952574, NCT02483585, NCT02174861, and NCT01723514.Classification of evidenceThis analysis provides Class II evidence that for patients with migraine, erenumab does not increase the risk of vascular AEs.

Purpose: Long-term cancer survivors may develop psychological late effects. The aim of the present study was to determine prevalence of high level of stress in testicular cancer survivors (TCS) compared with the general population and prevalence of high level of stress among TCS stratified by type of treatment (surveillance, bleomycin, etoposide and cisplatin (BEP), or abdominal radiotherapy (RT)). Methods: In this large, nationwide and population-based, cross-sectional study, a total of 2252 TCS filled in a questionnaire between 2014–2016 covering psychological stress (Perceived Stress Scale (PSS)), sociodemographic factors, and physical health variables. Results were compared with a reference population. The reference population consisted of 61,927 men without prior or present cancer and sampled at random from the central population. High level of stress was defined as a PSS score ≥ 16, equivalent to the highest scoring quintile in the reference population. Logistic regression models adjusted for relevant covariates were used to estimate prevalence ratios of high level of stress. Results: Distribution of TCS was: surveillance, n = 1134; BEP, n = 807; and RT, n = 311 (median time since diagnosis was 19 years). TCS were more likely to have high level of stress compared to the reference population with a prevalence ratio of 1.56 (95% CI, 1.40–1.73). Individually, surveillance, BEP and RT groups had higher level of stress compared to the reference population. Conclusions: TCS are more likely to have high level of stress. Screening programs for psychological stress should be considered as part of the follow-up program. Implications for cancer survivors: A higher level of stress is observed in TCS irrespective of treatment.

Food allergy is an immune-mediated disease and must be differentiated from other adverse effects related to food that are non-immune mediated. Symptoms of immunoglobulin (Ig) E-mediated allergy can range from mild to severe, and life-threatening anaphylaxis may occur. Current recommended strategies for diagnosis include the use of skin prick tests, allergen-specific serum IgE, and/or oral food challenges. Management entails allergen avoidance and appropriate treatment of allergic reactions should accidental ingestions occur. Treatment approaches under investigation include immunotherapy as well as biologics and novel vaccines. Attention has also recently focused on implementing strategies for prevention of food allergy.

Hepatocellular carcinoma (HCC) is a malignancy with one of the worst prognoses. Long noncoding RNA (lncRNA) are emerging as an important regulator of gene expression and function, leading to the development of cancer. The aim of this study was to determine the relationship between lncRNA and HCC and to further guide clinical therapy. lncRNA in HCC and adjacent tissues were screened, and the correlation between lncRNA‐PDPK2P expression in liver tissues and the pathological characteristics and severity of HCC was assessed. The effects of PDPK2P on HCC proliferation, apoptosis, metastasis, and invasion were also systematically investigated via CCK‐8 assay, flow cytometry, scratch wound healing, and transwell assay, respectively. The relationship between PDPK2P and PDK1 was verified by RNA pull‐down, rescue experiments and western blot. lncRNA‐PDPK2P was highly expressed in HCC tissues with a distinct positive correlation between PDPK2P and PDK1, and the upregulation was clinically associated with a larger tumor embolus, low differentiation, and poor survival. Mechanistically, lncRNA‐PDPK2P interacted with PDK1 and promoted HCC progression through the PDK1/AKT/caspase 3 signaling pathway. lncRNA‐PDPK2P can promote HCC progression, suggesting it may be a clinically valuable biomarker and serve as a molecular target for the diagnosis, prognosis, and therapy of hepatocellular carcinoma.

Many patients with systemic lupus erythematosus (SLE) have lupus nephritis, one of the severe complications of SLE. We previously reported that CD8+CD103+ T regulatory cells induced ex vivo with transforming growth factor β (TGF-β) (iTregs) inhibited immune cells responses to ameliorate excessive autoimmune inflammation. However, the molecular mechanism(s) underlying the role of these CD8+ iTregs is still unclear. Here we identified that CD39, which is highly expressed on CD8+ iTregs, crucially contributes to the immunosuppressive role of the CD8+CD103+ iTregs. We showed that adoptive transfer of CD8+CD103+ iTregs significantly relieves the chronic graft-versus-host disease with lupus nephritis and CD39 inhibitor mostly abolished the functional activities of these CD8+ iTregs in vitro and in vivo. CD39+ cells sorted from CD8+CD103+ iTregs were more effective in treating lupus nephritis than CD39− partner cells in vivo. Furthermore, human CD8+ iTregs displayed increased CD103 and CD39 expressions, and CD39 was involved in the suppressive function of human CD8+ iTregs. Thus, our data implicated a crucial role of CD39 in CD8+CD103+ iTregs in treating lupus nephritis, and CD39 could be a new phenotypic biomarker for the identification of highly qualified CD8+ Tregs. This subpopulation may have therapeutic potential in patients with SLE nephritis and other autoimmune diseases., This work demonstrates that CD39 plays a key role on CD8+CD103+ induced T regulatory cells in treating lupus nephritis. Using a chronic graft-versus-host disease lupus nephritis model and a series of in vitro experiments, Zhang et al. showed that CD39 is an excellent marker to identify the suppressive activity of CD8+CD103+ cells.

BACKGROUND: Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. METHODS: In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×10(6), 150×10(6), 450×10(6), or 800×10(6) CAR-positive (CAR+) T cells in the dose-escalation phase and 150×10(6) to 450×10(6) CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety. RESULTS: Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10(−4) nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion. CONCLUSIONS: We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.)

Background/aims Rheumatoid arthritis (RA) is a progressive, chronic, even disabling systemic autoimmune disease. Imbalance between pathogenic immune cells and immunosuppressive cells is associated with the pathogenesis and development of RA and other autoimmune diseases. As Foxp3 is also expressed on activated CD4+ cells in the presence of inflammation, the identification of Treg cells in patients with RA remains a challenge. Methods Comprehensive analyses were carried out by Flow cytometry. Expression of Helios, CD226, T cell immunoreceptor with Ig and ITIM domains clinical samples and healthy controls. Results We have systemically examined three potential markers, Helios, CD226 and TIGIT, that are possibly related to Treg identification, and found that Helios expression on CD4+Foxp3+cells was decreased and negatively correlated with the disease activity of RA patients, while CD226 and TIGIT both showed elevated expression levels in CD4+Foxp3+cells in RA patients and they were not associated with disease activity of RA patients. Conclusion Taken together, our findings indicate that CD4+CD25hiCD127low/-Foxp3+Helios+ may represent the real Treg cell population in patients with RA.

Dabigatran is a direct thrombin inhibitor, the sole agent of its class. It is an effective anticoagulant1 with a specific antidote, idarucizumab.2 It is, however, renally cleared such that should patients prescribed dabigatran develop an acute kidney injury (AKI), a coagulopathic state can be anticipated. We describe a multimodal approach involving the use of hemodialysis and 3 doses of idarucizumab to manage coagulopathy and major hemorrhage in a patient prescribed dabiagatran with severe AKI. We also illustrate that dabiagatran can be implicated as a cause of acute interstitial nephritis.

Background Compensated Leydig cell (LC) dysfunction, defined by elevated serum levels of luteinizing hormone (LH) in combination with normal total testosterone levels, is common in testicular cancer (TC) survivors. The association between this condition and quality of life is unknown. We aimed to clarify if TC survivors with compensated LC dysfunction have impaired quality of life. Patients and Methods In total, 147 long-term TC survivors were included. On the basis of a single measurement of testosterone and LH, compensated LC dysfunction was defined by age-adjusted levels of LH above normal range combined with testosterone levels within the normal range. Quality-of-life outcomes including sexual function, anxiety and depression, fatigue, and overall self-evaluated quality of life were compared between patients with and without compensated LC dysfunction with adjustment for age. Results In total, 60 TC survivors had compensated LC dysfunction and 87 TC survivors had normal LC function. TC survivors with compensated LC dysfunction had lower serum levels of total testosterone (11 vs. 13 nmol/L, P = .016). There were no significant differences in the investigated quality-of-life outcomes (anxiety, depression, sexual function, fatigue) between the 2 groups. Conclusion Compensated LC dysfunction in TC survivors was not associated with symptoms of depression, anxiety, sexual dysfunction, fatigue, or impaired overall self-evaluated quality of life. Limitations include the few cases of symptoms of depression (n = 7). Our findings do not suggest that testosterone substitution is indicated in TC survivors with compensated LC dysfunction.

Background: As there is limited data on the sustainability of desensitization of multifood-oral immunotherapy (multifood-OIT), we conducted a multisite multifood-OIT study to compare the efficacy of successful desensitization with sustained dosing vs discontinued dosing after multifood-OIT. Methods: We enrolled 70 participants, aged 5–22 years with multiple food allergies confirmed by double-blind placebo-controlled food challenges (DBPCFCs). In the open-label phase of the study, all participants received omalizumab (weeks 1–16) and multi-OIT (2–5 allergens; weeks 8–30) and eligible participants (on maintenance dose of each allergen by weeks 28–29) were randomized 1:1:1 to 1 g, 300 mg, or 0 mg arms (blinded, weeks 30–36) and then tested by food challenge at week 36. Success was defined as passing 2 g food challenge to at least 2 foods in week 36. Findings: Most participants were able to reach a dose of 2 g or higher of each of 2, 3, 4, and 5 food allergens (as applicable to the participant's food allergens in OIT) in week 36 food challenges. Using an intent-to-treat analysis, we did not find evidence that a 300 mg dose was effectively different than a 1 g dose in maintaining desensitization, and both together were more effective than OIT discontinuation (0 mg dose) (85% vs 55%, P = 0.03). Fifty-five percent of the intent-to-treat participants and 69% of per protocol participants randomized to the 0 mg arm showed no objective reactivity after 6 weeks of discontinuation. Cross-desensitization was found between cashew/pistachio and walnut/pecan when only one of the foods was part of OIT. No statistically significant safety differences were found between the three arms. Interpretation: These results suggest that sustained desensitization after omalizumab-facilitated multi-OIT best occurs through continued maintenance OIT dosing of either 300 mg or 1 g of each food allergen as opposed to discontinuation of multi-OIT. Funding: Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Jeff and MacKenzie Bezos, NIAID AADCRC U19AI104209. Trial Registration Number: ClinicalTrials.gov number, NCT02626611. Keywords: Food allergy, Oral immunotherapy, Omalizumab, Sustained unresponsiveness, Food allergen

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions.METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms.RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; PCONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

The spleen is one of the most frequently injured organs in blunt abdominal trauma. Computed tomography (CT) is the imaging modality of choice to assess patients with blunt spleen trauma, which may include lacerations, subcapsular or parenchymal hematomas, active hemorrhage, and vascular injuries. While computer-assisted diagnosis systems exist for other conditions assessed using CT scans, the current method to detect spleen injuries involves the manual review of scans by radiologists, which is a time-consuming and repetitive process. In this study, we propose an automated spleen injury detection method using machine learning. CT scans from patients experiencing traumatic injuries were collected from Michigan Medicine and the Crash Injury Research Engineering Network (CIREN) dataset. Ninety-nine scans of healthy and lacerated spleens were split into disjoint training and test sets, with random forest (RF), naive Bayes, SVM, k-nearest neighbors (k-NN) ensemble, and subspace discriminant ensemble models trained via 5-fold cross validation. Of these models, random forest performed the best, achieving an Area Under the receiver operating characteristic Curve (AUC) of 0.91 and an F1 score of 0.80 on the test set. These results suggest that an automated, quantitative assessment of traumatic spleen injury has the potential to enable faster triage and improve patient outcomes.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Background Anaphylaxis remains difficult to diagnose and epinephrine underused. Objective To better understand the thoughts of pediatricians regarding when acute allergic reactions constitute anaphylaxis and when epinephrine should be given by conducting an anonymous online survey. Methods The survey consisted of 8 case-based scenarios of allergic reactions with the following 2 questions on each case: (1) does this case represent anaphylaxis? and (2) if this patient immediately presented to you, would you treat the patient with epinephrine during the reaction? Results A total of 1001 responses were analyzed. When assessing all cases combined, there was discordance in whether a case represented anaphylaxis and administration of epinephrine was warranted in 8% of the cases. An average of 5% of all the respondents suggested that the case represented anaphylaxis but would not warrant epinephrine, whereas an average of 3% suggested that the case did not represent anaphylaxis but that epinephrine was warranted. Conclusion The results of this survey reveal that there is discordance among pediatricians on when an allergic reaction is considered anaphylaxis and when epinephrine is warranted. These data highlight the need for continued improvement of the definition of anaphylaxis and continued need for education regarding the diagnosis and management of anaphylaxis.

Background There is no widely adopted severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions, thus limiting the ability to optimize and standardize management practices and advance research. Objective The aim of this study was to develop a severity grading system for acute allergic reactions for use in clinical care and research. Methods From May to September 2020, we convened a 21-member multidisciplinary panel of allergy and emergency care experts; 9 members formed a writing group to critically appraise and assess the strengths and limitations of prior severity grading systems and develop the structure and content for an optimal severity grading system. The entire study panel then revised the grading system and sought consensus by utilizing Delphi methodology. Results The writing group recommended that an optimal grading system encompass the severity of acute allergic reactions on a continuum from mild allergic reactions to anaphylactic shock. Additionally, the severity grading system must be able to discriminate between clinically important differences in reaction severity to be relevant in research while also being intuitive and straightforward to apply in clinical care. Consensus was reached for all elements of the proposed severity grading system. Conclusion We developed a consensus severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions. Successful international validation, refinement, dissemination, and application of the grading system will improve communication among providers and patients about the severity of allergic reactions and will help advance future research.

Background Epinephrine autoinjectors (EAs) are the standard of care for severe food allergic reactions, although they are frequently underused or misused. Objective To understand the factors associated with underuse of EA by caregivers of pediatric patients with food allergy. Methods A survey was administered to 200 caregivers of pediatric patients with food allergies to assess most severe lifetime allergic reaction, EA education, and use and factors associated with incorrect use or underutilization. Results A total of 164 surveys were completed; of which 118 (72%) of lifetime most severe reactions warranted EA use, but the EA was used in only 45 (38.1%). Reasons caregivers indicated for not administering the EA included the following: reactions did not seem severe enough; it was the patient’s first allergic reaction; use of other medication; and fear of using EA. Conclusion Multiple factors contribute to underuse of EA in the treatment of severe allergic reactions. Results from this study highlight the need for continuous EA education in caregivers of and pediatric patients with food allergies, using a multipronged approach targeting clear symptom recognition and alleviation of fear of EA use.

Background The use of inconsistent definitions for anaphylaxis outcomes limits our understanding of the natural history and epidemiology of anaphylaxis, hindering clinical practice and research efforts. Objective Our aim was to develop consensus definitions for clinically relevant anaphylaxis outcomes by utilizing a multidisciplinary group of clinical and research experts in anaphylaxis. Methods Using Delphi methodology, we developed agenda topics and drafted questions to review during monthly conference calls. Through online surveys, a 19-member panel consisting of experts in allergy and/or immunology and emergency medicine rated their level of agreement with the appropriateness of statements on a scale of 1 to 9. A median value of 1.0 to 3.4 was considered inappropriate, a median value of 3.5 to 6.9 was considered uncertain, and a median value of 7.0 to 9.0 was considered appropriate. A disagreement index was then calculated, with values less than 1.0 categorized as “consensus reached.” If consensus was not reached after the initial survey, subsequent surveys incorporating the aggregate de-identified responses from prior surveys were sent to panel members. This process was repeated until consensus was reached or 4 survey rounds had been completed, after which the question was categorized as “no consensus reached.” Results The panel developed outcome definitions for persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. There was also consensus among panel members regarding the need to develop an anaphylaxis severity grading system. Conclusion Dissemination and application of these definitions in clinical care and research will help standardize the terminology used to describe anaphylaxis outcomes and serve as the foundation for future research, including research aimed at development of an anaphylaxis severity grading system.

Purpose of review Epinephrine is the agreed-upon first line treatment for anaphylaxis, yet it continues to be underused by patients/caregivers and providers alike. Recent findings There are unfortunately limited data on how epinephrine can best be utilized in anaphylaxis, which hinders how best to inform patients and providers. Studies reporting underuse suggest various barriers and themes on why this may happen. Summary Continued education of patients, caregivers, and providers is needed; however, is not likely to be enough to close the gap. Thus, novel studies on how to increase use; increase availability in a cost-effective manner; and newer, effective delivery routes are still needed.

Recognizing anaphylaxis in infants and toddlers can be challenging for health care providers and caregivers, and current diagnostic criteria and anaphylaxis action plans do not specifically address this younger population.To describe symptoms and signs observed by primary caregivers of infants and toddlers during severe food-induced allergic reactions.We conducted a national online survey among primary caregivers of children who experienced a severe food-induced allergic reaction when less than 36 months of age. Respondents who were present during the child's most severe reaction were asked to report symptoms and signs observed. The survey asked about infant- and toddler-specific symptoms and signs in lay language for caregivers. Data were compared with patient-reported data from past studies to identify distinct patterns among the younger population.The survey was completed for 374 children (193 infants, 181 toddlers). The most common symptoms and signs reported were skin reactions (90%), facial and extremity swelling (59%), gastrointestinal issues (51%), and coughing/wheezing (45%). Infants (aged12 months) more frequently experienced skin reactions, skin mottling, and ear pulling/scratching or putting fingers in ears, as compared with toddlers (aged 12-35 months). Toddlers experienced throat itching and coughing/wheezing more frequently than infants.Anaphylaxis presentation demonstrates similarities and differences in infants and toddlers. Modifying the terminology used in the current criteria allowed for reporting of symptoms and signs of anaphylaxis that are more common in infants and toddlers. Diagnostic criteria, clinical guidelines, and anaphylaxis action plans may be enhanced to address this young, often nonverbal, population.

In 2020, the first food allergy treatment, an oral immunotherapy (OIT) product for peanut allergy, was approved by the Food and Drug Administration, and a peanut epicutaneous immunotherapy patch was under review. As food allergy therapies become available and widespread, allergy offices will need to adjust practices to be able to offer their patients these new treatments. OIT is an intensive therapy that requires commitment from patients and their families, and open communication with the practice is paramount. OIT may not be the right therapy for every patient, and although identifying good candidates is still an area rich for research opportunity, experience from cohorts and clinical trials provides some insight. It is important to understand the scope of practice for each member of the OIT team based on state regulations for a particular location. Staffing and space will likely dictate how many patients at an individual office could be on active OIT at one time. Emergency medications, supplies, and protocols must be in place. Screening, scheduling, visit procedures, monitoring, home dosing, dose modifications, safety precautions, adverse reactions, and maintenance will be addressed in this article. Finally, adjunct therapies under investigation will be reviewed.

The SARS-CoV2 pandemic has prompted a re-evaluation of our current practice of medicine. The seemingly abrupt worldwide spread of this disease resulted in immediate changes and a reduction in many allergy-focussed services and procedures. The reality of the long-term circulation of this virus in our communities requires us to evolve as a specialty. In this article, we outline current and future challenges in the management of food allergy in light of coronavirus disease 2019 (COVID-19). We focus on infant food allergy prevention, management of anaphylaxis, accurate diagnosis with oral food challenges, and active management of food allergy with oral immunotherapy. This article identifies the challenges of conflicting guidelines, shortcomings of acute management approaches, and inherent system deficiencies. We offer perspectives and strategies that can be implemented now, including an evaluation of virtual care and telemedicine for the management of food allergy. The use of a shared decision-making model results in novel approaches that can benefit our patients and our specialty for years to come. COVID-19 has forced us to re-evaluate our current way of thinking about food allergy management to better treat our patients.

Background Food allergic reactions of varying severity occur in restaurants. Studies to date have shown that there are gaps in knowledge of and communication between restaurant staff and food allergic individuals. Objective We sought to characterize allergic reactions in restaurants to better inform the restaurant industry, food allergic individual, and allergist so that mitigation strategies can be implemented. Methods Data collected over a 2-year period from 2822 individuals in the Food Allergy Research & Education registry were analyzed using descriptive statistics. Results Dining out accounted for the second most common location for a food allergic reaction, after one's home, and many were severe with 28.0% requiring 1 dose and 6.2% requiring 2 doses of epinephrine. Cafes, fast food establishments, and Asian restaurants were frequently implicated sites. Peanut, tree nuts, and milk were the most common inciting allergens, and tree nuts resulted in the most common use of epinephrine. Of the allergic reactions, 53.9% occurred despite conveyance of food allergy to restaurant staff, 26.6% occurred when allergens were declared on the menu, and 13.7% occurred when allergens were declared on the menu and restaurant staff were informed of a food allergy. Conclusions Allergic reactions in restaurants are common and can be severe. Findings presented here underscore the need for restaurant staff training and mandatory declaration of allergenic ingredients in meals. This updated knowledge will help support advocacy efforts and inform patients, allergists, and the restaurant industry on best practices for dining out to improve the quality of life for food allergic individuals.

In the wake of the COVID-19 pandemic and massive disruptions to daily life in the spring of 2020, in May 2020, the Centers for Disease Control (CDC) released guidance recommendations for schools regarding how to have students attend while adhering to principles of how to reduce the risk of contracting SARS-CoV-2. As part of physical distancing measures, the CDC is recommending that schools who traditionally have had students eat in a cafeteria or common large space instead have children eat their lunch or other meals in the classroom at already physically distanced desks. This has sparked concern for the safety of food-allergic children attending school, and some question of how the new CDC recommendations can coexist with recommendations in the 2013 CDC Voluntary Guidelines on Managing Food Allergy in Schools as well as accommodations that students may be afforded through disability law that may have previously prohibited eating in the classroom. This expert consensus explores the issues related to evidence-based management of food allergy at school, the issues of managing the health of children attending school that are acutely posed by the constraints of an infectious pandemic, and how to harmonize these needs so that all children can attend school with minimal risk from both an infectious and allergic standpoint.

Given the burden of disease and the consequences of a diagnosis of peanut allergy, it is important that peanut allergy be accurately diagnosed so that an appropriate treatment plan can be developed. However, a test that indicates there is peanut sensitization present (eg, a "positive" test) is not always associated with clinical reactivity. This practice parameter addresses the diagnosis of IgE-mediated peanut allergy, both in children and adults, as pertaining to 3 fundamental questions, and based on the systematic reviews and meta-analyses, makes recommendations for the clinician who is evaluating a patient for peanut allergy. These questions relate to when diagnostic tests should be completed, which diagnostic tests to utilize, and the utility (or lack thereof) of diagnostic testing to predict the severity of a future allergic reaction to peanut.

The increased incidence of systemic lupus erythematosus (SLE) in recent decades might be related to changes in modern dietary habits. Since sodium chloride (NaCl) promotes pathogenic T cell responses, we hypothesize that excessive salt intake contributes to the increased incidence of autoimmune diseases, including SLE. Given the importance of dendritic cells (DCs) in the pathogenesis of SLE, we explored the influence of an excessive sodium chloride diet on DCs in a murine SLE model. We used an induced lupus model in which bone marrow-derived dendritic cells (BMDCs) were incubated with activated lymphocyte-derived DNA (ALD-DNA) and transferred into C57BL/6 recipient mice. We observed that a high-salt diet (HSD) markedly exacerbated lupus progression, which was accompanied by increased DC activation. NaCl treatment also stimulated the maturation, activation and antigen-presenting ability of DCs in vitro. Pretreatment of BMDCs with NaCl also exacerbated BMDC-ALD-DNA-induced lupus. These mice had increased production of autoantibodies and proinflammatory cytokines, more pronounced splenomegaly and lymphadenopathy, and enhanced pathological renal lesions. The p38 MAPK–STAT1 pathway played an important role in NaCl-induced DC immune activities. Taken together, our results demonstrate that HSD intake promotes immune activation of DCs through the p38 MAPK–STAT1 signaling pathway and exacerbates the features of SLE. Thus, changes in diet may provide a novel strategy for the prevention or amelioration of lupus or other autoimmune diseases.

Background Ustekinumab is approved for Crohn’s disease and Ulcerative colitis with acute infusion reactions reported at a rate of 0.9%–4.5%. Methods A retrospective chart review was conducted on inflammatory bowel disease (IBD) patients experiencing an acute infusion reaction to ustekinumab at 2 large institutions. Results Acute ustekinumab infusion reactions occurred in 16 patients with Crohn’s disease (CD) and Ulcerative colitis (UC), at a rate of 0.8%–3%. Patients were all naïve to ustekinumab, receiving their initial IV induction. Ninety-three percent subsequently tolerated the injection without issues. Conclusions In this large, real-world study of acute infusion reactions to ustekinumab, the rate was similar to that seen in clinical trials—0.8%–3%.

PURPOSE To analyze the risk of cardiovascular disease (CVD) after treatment of male germ cell cancer (GCC). METHODS Clinical data were extracted from the Danish Testicular Cancer database. For each patient, 10 men matched on date of birth were identified in the Danish normal population by risk-set sampling. Cardiovascular risk factors, CVD, and associated deaths were identified in Danish registries. The association between treatment and outcomes was analyzed by separate Cox models for each outcome. Cancer treatment was included as a time-varying covariate. RESULTS We included 5,185 patients with GCC and 51,850 men in the normal population. Median follow-up was 15.8 years. Treatment with bleomycin-etoposide-cisplatin (BEP; n = 1,819) was associated with increased risks of hypertension and hypercholesterolemia. Hazard ratios (HRs) of CVD < 1 year after initiation of BEP treatment were as follows: myocardial infarction (HR, 6.3; 95% CI, 2.9 to 13.9), cerebrovascular accident (HR, 6.0; 95% CI, 2.6 to 14.1), and venous thromboembolism (HR, 24.7; 95% CI, 14.0 to 43.6). One year after BEP treatment, the risk of CVD decreased to normal levels, but after 10 years, increasing risks were found for myocardial infarction (HR, 1.4; 95% CI, 1.0 to 2.0) and cardiovascular death (HR, 1.6; 95% CI, 1.0 to 2.5). Radiotherapy (n = 780) increased the risk of diabetes at long-term follow-up (HR, 1.4; 95% CI, 1.0 to 2.0) but not that of other outcomes. With surveillance (n = 3,332), cardiovascular risk factors, CVD, and cardiovascular death data were comparable to that of the normal population. CONCLUSION Treatment with BEP was associated with highly increased risks of CVD < 1 year after treatment start and mildly increased risks after 10 years of follow-up. Radiotherapy increased the risk of diabetes but not incident CVD. The risk of CVD in patients followed in a surveillance program was comparable to that of the normal population.