Anaphylaxis in practice: A guide to the 2023 Practice Parameter Update.

This review will summarize new research developments and clinical practice recommendations for the diagnosis and management of anaphylaxis presented in the Joint Task Force on Practice Parameters' 2023 Anaphylaxis Practice Parameter Update. It is intended to serve as a high-level summary of the 2023 practice parameter, which makes clinically impactful recommendations based on new evidence that has emerged since the 2015 practice parameter. We invite clinicians to explore the full 2023 practice parameter to better understand the research methods and underlying evidence that have informed the recommendations summarized here. There are new and evolving diagnostic criteria for anaphylaxis, rules for defining elevated tryptase levels, and recognition of signs and symptoms particular to infants and toddlers. The administration of epinephrine should not be used as a surrogate to diagnose anaphylaxis. Risk factors for anaphylaxis should be assessed on a case-by-case basis. Patient counseling and shared decision making (SDM) are essential for supporting patients' treatment decisions and capacity to manage the risk of anaphylaxis at home and in other community settings. Activation of emergency medical services following home epinephrine administration may not be required in all cases, and patients should be engaged in SDM to determine when home management may be appropriate.

Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.

A systematic review and expert Delphi Consensus recommendation on the use of vaccines in patients receiving dupilumab: A position paper of the American College of Allergy, Asthma and Immunology.

BACKGROUND: Dupilumab is a monoclonal antibody that targets the interleukin (IL)-4 receptor alpha subunit, thus blocking the effects of IL-4 and IL-13, and has shown efficacy in treating various conditions including asthma, atopic dermatitis, eosinophilic esophagitis, and others. Because of its immune modulatory effects, clinical trials that studied dupilumab did not allow patients to receive live vaccines during the clinical trials because of an abundance of caution, and thus package inserts recommend that patients who are being treated with dupilumab should avoid live vaccines. Because dupilumab is now approved for use in patients from 6 months of age for the treatment of atopic dermatitis, this reported contraindication is now posing a clinical dilemma for patients and clinicians. OBJECTIVE: To perform a systematic review of literature on the safety and efficacy of vaccinations in patients who are receiving dupilumab and to provide expert guidance on the use of vaccines in patients who are receiving dupilumab. METHODS: A systematic review of the literature was performed, and an expert Delphi Panel was assembled. RESULTS: The available literature on patients who received vaccinations while using dupilumab overall suggests that live vaccines are safe and that the vaccine efficacy, in general, is not affected by dupilumab. The expert Delphi panel agreed that the use of vaccines in patients receiving dupilumab was likely safe and effective. CONCLUSION: Vaccines (including live vaccines) can be administered to patients receiving dupilumab in a shared decision-making capacity.

Saliva antibody profiles are associated with reaction threshold and severity of peanut allergic reactions.

BACKGROUND: Reaction threshold and severity in food allergy are difficult to predict, and noninvasive predictors are lacking. OBJECTIVE: We sought to determine the relationships between pre-challenge levels of peanut (PN)-specific antibodies in saliva and reaction threshold, severity, and organ-specific symptoms during PN allergic reactions. METHODS: We measured PN-specific antibody levels in saliva collected from 127 children with suspected PN allergy before double-blind, placebo-controlled PN challenges in which reaction threshold, severity, and symptoms were rigorously characterized. Low threshold (LT) PN allergy was defined as reaction to <300 mg of PN protein cumulatively consumed. A consensus severity grading system was used to grade severity. We analyzed associations between antibody levels and reaction threshold, severity, and organ-specific symptoms. RESULTS: Among the 127 children, those with high pre-challenge saliva PN IgE had higher odds of LT PN allergy (odds ratio [OR] 3.9, 95% CI 1.6-9.5), while those with high saliva PN IgA:PN IgE ratio or PN IgG4:PN IgE ratio had lower odds of LT PN allergy (OR 0.3, 95% CI 0.1-0.8; OR 0.4, 95% CI 0.2-0.9). Children with high pre-challenge saliva PN IgG4 had lower odds of severe PN reactions (OR 0.4, 95% CI 0.2-0.9). Children with high saliva PN IgE had higher odds of respiratory symptoms (OR 8.0, 95% CI 2.2-26.8). Saliva PN IgE modestly correlated with serum PN IgE levels (Pearson r = 0.31, P = .0004). High and low saliva PN IgE levels further distinguished reaction threshold and severity in participants stratified by serum PN IgE, suggesting endotypes. CONCLUSIONS: Saliva PN antibodies could aid in noninvasive risk stratification of PN allergy threshold, severity, and organ-specific symptoms.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. METHODS: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. FINDINGS: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. INTERPRETATION: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. FUNDING: AstraZeneca.

Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models.

Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.

Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent.

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.

miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

Overall haemostatic potential assay for prediction of outcomes in venous and arterial thrombosis and thrombo-inflammatory diseases.

Thromboembolic diseases including arterial and venous thrombosis are common causes of morbidity and mortality globally. Thrombosis frequently recurs and can also complicate many inflammatory conditions through the process of 'thrombo-inflammation,' as evidenced during the COVID-19 pandemic. Current candidate biomarkers for thrombosis prediction, such as D-dimer, have poor predictive efficacy. This limits our capacity to tailor anticoagulation duration individually and may expose lower risk individuals to undue bleeding risk. Global coagulation assays, such as the Overall Haemostatic Potential (OHP) assay, that investigate fibrin generation and fibrinolysis, may provide a more accurate and functional assessment of hypercoagulability. We present a review of fibrin's critical role as a central modulator of thrombotic risk. The results of our studies demonstrating the OHP assay as a predictive biomarker in venous thromboembolism, chronic renal disease, diabetes mellitus, post-thrombotic syndrome, and COVID-19 are discussed. As a comprehensive and global measurement of fibrin generation and fibrinolytic capacity, the OHP assay may be a valuable addition to future multi-modal predictive tools in thrombosis.

Coptisine inhibits neointimal hyperplasia through attenuating Pak1/Pak2 signaling in vascular smooth muscle cells without retardation of re-endothelialization.

BACKGROUND AND AIMS: Vascular injury-induced endothelium-denudation and profound vascular smooth muscle cells (VSMCs) proliferation and dis-regulated apoptosis lead to post-angioplasty restenosis. Coptisine (CTS), an isoquinoline alkaloid, has multiple beneficial effects on the cardiovascular system. Recent studies identified it selectively inhibits VSMCs proliferation. However, its effects on neointimal hyperplasia, re-endothelialization, and the underlying mechanisms are still unclear. METHODS: Cell viability was assayed by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and cell counting kit-8 (CCK-8). Cell proliferation and apoptosis were measured by flow cytometry and immunofluorescence of Ki67 and TUNEL. Quantitative phosphoproteomics (QPP) was employed to screen CTS-responsive phosphor-sites in the key regulators of cell proliferation and apoptosis. Neointimal hyperplasia was induced by balloon injury of rat left carotid artery (LCA). Adenoviral gene transfer was conducted in both cultured cells and LCA. Re-endothelialization was evaluated by Evan's blue staining of LCA. RESULTS: 1) CTS had strong anti-proliferative and pro-apoptotic effects in cultured rat VSMCs, with the EC50 4∼10-folds lower than that in endothelial cells (ECs). 2) Rats administered with CTS, either locally to LCA's periadventitial space or orally, demonstrated a potently inhibited balloon injury-induced neointimal hyperplasia, but had no delaying effect on re-endothelialization. 3) The QPP results revealed that the phosphorylation levels of Pak1S144/S203, Pak2S20/S197, Erk1T202/Y204, Erk2T185/Y187, and BadS136 were significantly decreased in VSMCs by CTS. 4) Adenoviral expression of phosphomimetic mutants Pak1D144/D203/Pak2D20/D197 enhanced Pak1/2 activities, stimulated the downstream pErk1T202/Y204/pErk2T185/Y187/pErk3S189/pBadS136, attenuated CTS-mediated inhibition of VSMCs proliferation and promotion of apoptosis in vitro, and potentiated neointimal hyperplasia in vivo. 5) Adenoviral expression of phosphoresistant mutants Pak1A144/A203/Pak2A20/A197 inactivated Pak1/2 and totally simulated the inhibitory effects of CTS on platelet-derived growth factor (PDGF)-stimulated VSMCs proliferation and PDGF-inhibited apoptosis in vitro and neointimal hyperplasia in vivo. 6) LCA injury significantly enhanced the endogenous phosphorylation levels of all but pBadS136. CTS markedly attenuated all the enhanced levels. CONCLUSIONS: These results indicate that CTS is a promising medicine for prevention of post-angioplasty restenosis without adverse impact on re-endothelialization. CTS-directed suppression of pPak1S144/S203/pPak2S20/S197 and the subsequent effects on downstream pErk1T202/Y204/pErk2T185/Y187/pErk3S189 and pBadS136 underline its mechanisms of inhibition of VSMCs proliferation and stimulation of apoptosis. Therefore, the phosphor-sites of Pak1S144/S203/Pak2S20/S197 constitute a potential drug-screening target for fighting neointimal hyperplasia restenosis.

Plasmid DNA ionisable lipid nanoparticles as non-inert carriers and potent immune activators for cancer immunotherapy.

Immunotherapy is currently a standard of care in the treatment of many malignancies. However, predictable side effects caused by systemic administration of highly immunostimulatory molecules have been a serious concern within this field. Intratumoural expression or silencing of immunogenic and immunoinhibitory molecules using nucleic acid-based approaches such as plasmid DNA (pDNA) and small interfering RNA (siRNA), respectively, could represent a next generation of cancer immunotherapy. Here, we employed lipid nanoparticles (LNPs) to deliver either non-specific pDNA and siRNA, or constructs targeting two prominent immunotherapeutic targets OX40L and indoleamine 2,3-dioxygenase-1 (IDO), to tumours in vivo. In the B16F10 mouse model, intratumoural delivery of LNP-formulated non-specific pDNA and siRNA led to strong local immune activation and tumour growth inhibition even at low doses due to the pDNA immunogenic nature. Replacement of these non-specific constructs by pOX40L and siIDO resulted in more prominent immune activation as evidenced by increased immune cell infiltration in tumours and tumour-draining lymph nodes. Consistently, pOX40L alone or in combination with siIDO could prolong overall survival, resulting in complete tumour regression and the formation of immunological memory in tumour rechallenge models. Our results suggest that intratumoural administration of LNP-formulated pDNA and siRNA offers a promising approach for cancer immunotherapy.

Annual mpMRI surveillance: PI-RADS upgrading and increasing trend correlated with patients who harbor clinically significant disease.

INTRODUCTION: Prostate cancer screening has routinely identified men with very low- or low-risk disease, per the National Comprehensive Cancer Network guidelines. Current literature has demonstrated that the most appropriate management strategy for these patients is active surveillance (AS). The mainstay of AS includes periodic biopsies and biannual prostate-specific antigen tests. However, multiparametric magnetic resonance imaging (mpMRI) is uniquely posed to improve patient surveillance. This study aimed to evaluate the utility of an annual mpMRI in patients on AS, focusing on radiologic upgrading and Prostate Imaging-Reporting and Data System (PI-RADS) trends as indicators of clinically significant disease. METHODS: This prospective, single intuition, study enrolled 208 patients on AS who had at least two biopsies and 1 mpMRI with a median follow-up of 5.03 years. The main outcome variable was time to Gleason grade (GG) reclassification. RESULTS: After delineating patients on their initial PI-RADS score, men with score 3 and 5 lesions at first MRI had comparable GG reclassification-free survival to their counterparts. Conversely, men with initial PI-RADS 4 lesions showed a lower 5-year GG reclassification-free survival compared to those with PI-RADS score 1-2. The cohort was then subset to 70 patients who obtained ≥2 mpMRIs on protocol. Men experiencing uptrending mpMRI scores had an increased risk of GG reclassification, with a 35.4% difference in 5 year GG reclassification-free survival probability on the Kaplan-Meier curve analysis. CONCLUSION: In conclusion, this study demonstrates that for men on AS with stable recapitulated disease, an annual MRI may replace repeat biopsies after confirmatory sampling has been obtained. On the other hand, men who initiate AS with PI-RADS 4 and/or who display uptrending mpMRI scores require periodic biopsies along with repeat imaging. This study highlights the utility of integrating an annual MRI into AS protocols, thus promising a more effective approach to management.

Cellular uptake and in vivo distribution of mesenchymal-stem-cell-derived extracellular vesicles are protein corona dependent.

Extracellular vesicles (EVs) derived from mesenchymal stem cells are promising nanotherapeutics in liver diseases due to their regenerative and immunomodulatory properties. Nevertheless, a concern has been raised regarding the rapid clearance of exogenous EVs by phagocytic cells. Here we explore the impact of protein corona on EVs derived from two culturing conditions in which specific proteins acquired from media were simultaneously adsorbed on the EV surface. Additionally, by incubating EVs with serum, simulating protein corona formation upon systemic delivery, further resolved protein corona-EV complex patterns were investigated. Our findings reveal the potential influences of corona composition on EVs under in vitro conditions and their in vivo kinetics. Our data suggest that bound albumin creates an EV signature that can retarget EVs from hepatic macrophages. This results in markedly improved cellular uptake by hepatocytes, liver sinusoidal endothelial cells and hepatic stellate cells. This phenomenon can be applied as a camouflage strategy by precoating EVs with albumin to fabricate the albumin-enriched protein corona-EV complex, enhancing non-phagocytic uptake in the liver. This work addresses a critical challenge facing intravenously administered EVs for liver therapy by tailoring the protein corona-EV complex for liver cell targeting and immune evasion.

Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

The Natural History and Risk Factors for the Development of Food Allergies in Children and Adults.

PURPOSE OF REVIEW: This narrative review explores food allergy prevalence and natural history stratified by life stages, especially in context of evolving knowledge over the last few decades. RECENT FINDINGS: The prevalence of food allergy remains highest in early childhood with common food triggers being cow's milk, soy, hen's egg, wheat, peanut, tree nuts, sesame, fish, and shellfish. This correlates with certain risk factors especially pertinent in the postnatal period which appear to predispose an individual to developing a food allergy. Some allergies (such as milk and egg) were previously thought to be easily outgrown in early life; however, recent studies suggest increasing rates of persistence of these allergies into young adulthood; the reason behind this is unknown. Despite this, there is also evidence demonstrating that food allergies can be outgrown in adolescents and adults. An understanding of the paradigm shifts in the natural history of food allergy allows clinicians to provide updated, age-appropriate, and tailored advice for patients on the management and prognosis of food allergy.

Effects of MDMA-assisted therapy for PTSD on self-experience.

INTRODUCTION: There is a resurgence of interest in the therapeutic potential of psychedelic substances such as 3,4-methylenedioxymethamphetamine (MDMA). Primary findings from our randomized, double-blind, placebo-controlled, multi-site Phase 3 clinical trial of participants with severe PTSD (NCT03537014) showed that MDMA-assisted therapy induced significant attenuation in the Clinician-Administered PTSD Scale for DSM-5 compared to Therapy with placebo. Deficits in emotional coping skills and altered self-capacities constitute major obstacles to successful completion of available treatments. The current analysis evaluated the differential effects of MDMA-assisted therapy and Therapy with placebo on 3 transdiagnostic outcome measures and explored the contribution of changes in self-experience to improvement in PTSD scores. METHODS: Participants were randomized to receive manualized therapy with either MDMA or placebo during 3 experimental sessions in combination with 3 preparation and 9 integration therapy visits. Symptoms were measured at baseline and 2 months after the last experimental session using the 20-item Toronto Alexithymia Scale (TAS-20), the 26-item Self Compassion Scale (SCS), and the 63-item Inventory of Altered Self-Capacities (IASC). RESULTS: 90 participants were randomized and dosed (MDMA-assisted therapy, n = 46; Therapy with placebo, n = 44); 84.4% (76/90) had histories of developmental trauma, and 87.8% (79/90) had suffered multiple traumas. MDMA-assisted therapy facilitated statistically significant greater improvement on the TAS-20, the SCS, and most IASC factors of interpersonal conflicts; idealization disillusionment; abandonment concerns; identity impairment; self-awareness; susceptibility to influence; affect dysregulation; affect instability; affect skill deficit; tension reduction activities; the only exception was identity diffusion. CONCLUSION: Compared with Therapy with placebo, MDMA-assisted therapy had significant positive effects on transdiagnostic mental processes of self-experience which are often associated with poor treatment outcome. This provides a possible window into understanding the psychological capacities facilitated by psychedelic agents that may result in significant improvements in PTSD symptomatology.

The lateral habenula integrates age and experience to promote social transitions in developing rats.

Social behavior deficits are an early-emerging marker of psychopathology and are linked with early caregiving quality. However, the infant neural substrates linking early care to social development are poorly understood. Here, we focused on the infant lateral habenula (LHb), a highly-conserved brain region at the nexus between forebrain and monoaminergic circuits. Despite its consistent links to adult psychopathology, this brain region has been understudied in development when the brain is most vulnerable to environmental impacts. In a task combining social and threat cues, suppressing LHb principal neurons had opposing effects in infants versus juveniles, suggesting the LHb promotes a developmental switch in social approach behavior under threat. We observed that early caregiving adversity (ECA) disrupts typical growth curves of LHb baseline structure and function, including volume, firing patterns, neuromodulatory receptor expression, and functional connectivity with cortical regions. Further, we observed that suppressing cortical projections to the LHb rescued social approach deficits following ECA, identifying this microcircuit as a substrate for disrupted social behavior. Together, these results identify immediate biomarkers of ECA in the LHb and highlight this region as a site of early social processing and behavior control.

Joint transcriptomic and cytometric study of children with peanut allergy reveals molecular and cellular cross talk in reaction thresholds.

BACKGROUND: Reaction thresholds in peanut allergy are highly variable. Elucidating causal relationships between molecular and cellular processes associated with variable thresholds could point to therapeutic pathways for raising thresholds. OBJECTIVE: The aim of this study was to characterize molecular and cellular systemic processes associated with reaction threshold in peanut allergy and causal relationships between them. METHODS: A total of 105 children aged 4 to 14 years with suspected peanut allergy underwent double-blind, placebo-controlled food challenge to peanut. The cumulative peanut protein quantity eliciting allergic symptoms was considered the reaction threshold for each child. Peripheral blood samples collected at 0, 2, and 4 hours after challenge start were used for RNA sequencing, whole blood staining, and cytometry. Statistical and network analyses were performed to identify associations and causal mediation between the molecular and cellular profiles and peanut reaction threshold. RESULTS: Within the cohort (N = 105), 81 children (77%) experienced allergic reactions after ingesting varying quantities of peanut, ranging from 43 to 9043 mg of cumulative peanut protein. Peripheral blood expression of transcripts (eg, IGF1R [false discovery rate (FDR) = 5.4e-5] and PADI4 [FDR = 5.4e-5]) and neutrophil abundance (FDR = 9.5e-4) were associated with peanut threshold. Coexpression network analyses revealed that the threshold-associated transcripts were enriched in modules for FcγR-mediated phagocytosis (FDR = 3.2e-3) and Toll-like receptor (FDR = 1.4e-3) signaling. Bayesian network, key driver, and causal mediation analyses identified key drivers (AP5B1, KLHL21, VASP, TPD52L2, and IGF2R) within these modules that are involved in bidirectional causal mediation relationships with neutrophil abundance. CONCLUSION: Key driver transcripts in FcγR-mediated phagocytosis and Toll-like receptor signaling interact bidirectionally with neutrophils in peripheral blood and are associated with reaction threshold in peanut allergy.

Identifying Children at Risk of Growth and Nutrient Deficiencies in the Food Allergy Clinic.

BACKGROUND: Food allergies affect growth in children by decreasing the availability of nutrients through decreased dietary intake, increased dietary needs, food-medication interactions, and psychosocial burden. Guidelines on food allergy management frequently recommend nutrition counseling and growth monitoring of children with food allergies. OBJECTIVE: To provide clear guidance for clinicians to identify children with food allergies who are at nutritional risk and ensure prompt intervention. METHODS: We provide a narrative review summarizing information from national and international guidelines, retrospective studies, population studies, review articles, case reports, and case series to identify those with food allergy at greatest nutritional risk, determine the impact of nutritional interventions on growth, and develop guidance for risk reduction in children with food allergies. RESULTS: Children with food allergies are at increased risk of nutritional deficiencies and poor growth. Nutritional assessment and intervention can improve outcomes. Identifying poor growth is an important step in the nutrition assessment. Therefore, growth should be assessed at each allergy evaluation. Interventions to ensure adequate dietary intake for growth include appropriately prescribed elimination diets, breast-feeding support and assessment, supplemental formula, vitamin and/or mineral supplementation, appropriate milk substitutes, and timely introduction of nutrient-dense complementary foods. Access to foods of appropriate nutritional value is an ongoing concern. CONCLUSION: Nutrition intervention or referral to registered dietitian nutritionists with additional training and/or experience in food allergy may result in improved growth and nutrition outcomes.