SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms that determine such variable outcomes remain unresolved. Here we investigated CD4+ T cells that are reactive against the spike glycoprotein of SARS-CoV-2 in the peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors. We detected spike-reactive CD4+ T cells not only in 83% of patients with COVID-19 but also in 35% of healthy donors. Spike-reactive CD4+ T cells in healthy donors were primarily active against C-terminal epitopes in the spike protein, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared with N-terminal epitopes. Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. This results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses. The effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined in larger cohorts. However, the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming trials investigating COVID-19 vaccines.

An integrated molecular risk score early in life for subsequent childhood asthma risk.

BACKGROUND: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). METHODS: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). RESULTS: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). CONCLUSION: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.

Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition.

Examining the role of social relationships on health and health behaviors in African American men with prostate cancer: a qualitative analysis.

PURPOSE: Cancer survivor cohort studies document the positive impact of health behaviors on cancer survivorship by influencing quality of life, comorbidity burden, and cancer recurrence. Social networks can be instrumental in supporting health behavior changes. This study used qualitative interviews to explore how social networks may impact health and health behaviors of African American Prostate Cancer Survivors (AAPCS) enrolled in Men Moving Forward (MMF), a lifestyle intervention designed with and for AAPCS. Specifically, we sought to understand how different relationships within social networks influence health and health behaviors, and to identify potential mechanisms for this influence. METHODS: Eighteen men who completed the MMF intervention participated in a semi-structured interview which explored social connections, health and health behaviors, stress, and the cancer experience. Interviews were recorded and transcribed, and thematic analysis was performed by two coders. RESULTS: Participants described robust social networks of friends and family. Four distinct yet overlapping themes were identified that described how relationships influence health and health behaviors among AAPCS: (1) provision of knowledge, (2) health and behavior history, (3) encouragement and support, and (4) shared behavior. CONCLUSIONS: These results provide initial insight into the types of relationships that influence health, and the intersecting and multifaceted mechanisms through which this influence occurs.

Correlates of intention to screen for cervical cancer among adult women in Kyotera District, Central Uganda: a community based cross-sectional study.

INTRODUCTION: Cervical cancer continues to pose a major public health challenge in low-income countries. Cervical cancer screening programs enable early detection and effectively reduce the incidence of cervical cancer as well as late-stage diagnosis and mortality. However, screening uptake remains suboptimal in Uganda. This study assessed correlates of intention to screen for cervical cancer among women in the Kyotera district of Central Uganda. METHODS: We analyzed cross-sectional data collected to determine the effectiveness of community audio towers (CATs) as a modality of health communication to support cervical cancer prevention. Women (n = 430) aged 21-60 years without a prior history of cervical cancer screening were surveyed about demographics, sources of health information and cervical cancer screening intentions in 2020. We used generalized linear modelling with modified Poisson regression and backwards variable elimination to identify adjusted prevalence ratios and 95% confidence intervals (CI) to determine factors associated with intention to screen for cervical cancer. RESULTS: Half (50.2%) of the participants had intentions to screen for cervical cancer within twelve months and 26.5% had moderate knowledge about cervical cancer. Nearly half (46.0%) considered themselves at risk of cervical cancer. Compared to residents who primarily received their health information from social media and radio, participants who received health information primarily from CATs (aPR:0.64, 95% CI:0.52-0.80, p < 0.001) and TV (aPR:0.52, 95% CI:0.34-0.82, p = 0.005) had a lower prevalence of intention to screen for cervical cancer. The prevalence of intentions to screen for cervical cancer in twelve months was higher among those resided in town councils (aPR:1.44, 95% CI:1.12-1.86, p = 0.004) compared to rural areas, and higher among those who considered themselves to be at risk of cervical cancer (aPR:1.74, 95% CI:1.28-2.36, p < 0.001) compared to those who did not. CONCLUSIONS: We found suboptimal prevalence of intentions to screen for cervical cancer among women in central Uganda. Additional research and implementation projects are needed to increase cervical cancer screening. Targeting risk perceptions and behavioral approaches to increase intentions could be effective in future intervention work. Based on urban-rural differences, additional work is needed to support equitable sharing of information to support cancer prevention messaging; CATs and TV may best help reach those with lower intentions to screen based on our research.

Impact of using less objective symptoms to define tolerated dose during food challenges: A data-driven approach.

BACKGROUND: Food challenges (FCs) form the basis for assessing efficacy outcomes in interventional studies of food allergy; however, different studies have used a variety of similar but not identical criteria to define a challenge reaction, including subjective (nonobjective) symptoms occurring in a single-organ system as dose limiting. OBJECTIVE: Our aim was to undertake a secondary analysis of 4 interventional studies to assess the impact of using less objective criteria to determine challenge-stop on reaction thresholds and their reproducibility. METHODS: We analyzed individual participant data, including individual participant data meta-analysis, by using 3 different published challenge-stop criteria: (1) PRACTALL consesus criteria; (2) Consortium for Food Allergy Research version 3 (CoFAR v3) with at least 1 moderate- or severe-grade symptom; or (3) CoFAR v3 with at least 2 mild symptoms occurring in different organ systems. Reproducibility of challenge threshold was also assessed in participants undergoing subsequent repeat FCs. RESULTS: Four studies, with detailed challenge data from a total of 592 participants, were included. Applying CoFAR v3 definitions for dose-limiting symptoms resulted in an underestimate of reaction thresholds compared with those in PRACTALL (P < .001) that is equivalent to almost a single dosing increment when using a semi-log dosing regimen. Reproducibility was also reduced when applying CoFAR v3 (P < .001 [n = 223]). Using the least conservative interpretation of CoFAR v3 (≥2 mild symptoms occurring in different systems) resulted in a significant overestimate of 15% when assessing oral immunotherapy efficacy. Applying a data-driven minor modification to CoFAR v3 resulted in a new set of challenge-stop criteria with validity similar to that of PRACTALL but one that is simpler to implement and in which significant gastrointestinal discomfort with observable decreased activity remains a dose-limiting symptom. CONCLUSION: The use of less objective symptoms to define challenge-stop compromises the reproducibility of the FC as a tool to assess efficacy outcomes in interventional studies, and potentially overestimates the efficacy of the intervention tested.

Disparities in Cardiovascular Disease-Related Outcomes Among Cancer Survivors in the United States: A Systematic Review of the Literature.

BACKGROUND: Cancer and cardiovascular disease (CVD) are major causes of morbidity and mortality in the United States (US). Cancer survivors have increased risks for CVD and CVD-related mortality due to multiple factors including cancer treatment-related cardiotoxicity. Disparities are rooted in differential exposure to risk factors and social determinants of health (SDOH), including systemic racism. This review aimed to assess SDOH's role in disparities, document CVD-related disparities among US cancer survivors, and identify literature gaps for future research. METHODS: Following the Peer Review of Electronic Search Strategies (PRESS) guidelines, MEDLINE, PsycINFO, and Scopus were searched on March 15, 2021, with an update conducted on September 26, 2023. Articles screening was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, a pre-defined Population, Exposure, Comparison, Outcomes, and Settings (PECOS) framework, and the Rayyan platform. A modified version of the Newcastle-Ottawa Scale was used to assess the risk of bias, and RAW Graphs for alluvial charts. This review is registered with PROSPERO under ID #CRD42021236460. RESULTS: Out of 7,719 retrieved articles, 24 were included, and discussed diverse SDOH that contribute to CVD-related disparities among cancer survivors. The 24 included studies had a large combined total sample size (n=7,704,645; median=19,707). While various disparities have been investigated, including rural-urban, sex, socioeconomic status, and age, a notable observation is that non-Hispanic Black cancer survivors experience disproportionately adverse CVD outcomes when compared to non-Hispanic White survivors. This underscores historical racism and discrimination against non-Hispanic Black individuals as fundamental drivers of CVD-related disparities. CONCLUSIONS: Stakeholders should work to eliminate the root causes of disparities. Clinicians should increase screening for risk factors that exacerbate CVD-related disparities among cancer survivors. Researchers should prioritise the investigation of systemic factors driving disparities in cancer and CVD and develop innovative interventions to mitigate risk in cancer survivors.

Early introduction of peanut reduces peanut allergy across risk groups in pooled and causal inference analyses.

BACKGROUND: The Learning Early About Peanut allergy (LEAP) study has shown the effectiveness of early peanut introduction in prevention of peanut allergy (PA). In the Enquiring About Tolerance (EAT) study, a statistically significant reduction in PA was present only in per-protocol (PP) analyses, which can be subject to bias. OBJECTIVE: The aim of this study was to combine individual-level data from the LEAP and EAT trials and provide robust evidence on the bias-corrected, causal effect of early peanut introduction. METHOD: As part of the European Union-funded iFAAM project, this pooled analysis of individual pediatric patient data combines and compares effectiveness and efficacy estimates of oral tolerance induction among different risk strata and analysis methods. RESULTS: An intention-to-treat (ITT) analysis of pooled data showed a 75% reduction in PA (p < .0001) among children randomized to consume peanut from early infancy. A protective effect was present across all eczema severity groups, irrespective of enrollment sensitization to peanut, and across different ethnicities. Earlier age of introduction was associated with improved effectiveness of the intervention. In the pooled PP analysis, peanut consumption reduced the risk of PA by 98% (p < .0001). A causal inference analysis confirmed the strong PP effect (89% average treatment effect relative risk reduction p < .0001). A multivariable causal inference analysis approach estimated a large (100%) reduction in PA in children without eczema (p = .004). CONCLUSION: We demonstrate a significant reduction in PA with early peanut introduction in a large group of pooled, randomized participants. This significant reduction was demonstrated across all risk subgroups, including children with no eczema. Furthermore, our results point to increased efficacy of the intervention with earlier age of introduction.

EAACI guidelines on the diagnosis of IgE-mediated food allergy.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

EAACI Molecular Allergology User's Guide 2.0.

Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE-mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE-mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well-defined, highly pure molecules for component-resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the "EAACI Molecular Allergology User's Guide" (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state-of-the-art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.

Spatial accessibility to health facilities among pregnant women with and without exposure to intimate partner violence in Uganda.

BACKGROUND: Poor physical access to health facilities could increase the likelihood of undetected intimate partner violence (IPV) during pregnancy. We aimed to determine sub-regional differences and associations between spatial accessibility to health facilities and IPV among pregnant women in Uganda. METHOD: Weighted cross-sectional analyses were conducted using merged 2016 Uganda Demographic and Health Survey and 2014 Uganda Bureau of Statistics health facility datasets. Our study population were 986 women who self-reported being currently pregnant and responded to IPV items. Outcome was spatial accessibility computed as the near point linear distance [< 5 km (optimal) vs. ≥ 5 km (low)] between women's enumeration area and health facility according to government reference cutoffs. Primary independent variable (any IPV) was defined as exposure to at least one of physical, emotional, and sexual IPV forms. Logistic regression models were sequentially adjusted for covariates in blocks based on Andersen's behavioral model of healthcare utilization. Covariates included predisposing (maternal age, parity, residence, partner controlling behavior), enabling (wealth index, occupation, education, economic empowerment, ANC visit frequency), and need (wanted current pregnancy, difficulty getting treatment money, afraid of partner, and accepted partner abuse) factors. RESULTS: Respondents' mean age was 26.1 years with ± 9.4 standard deviations (SD), mean number of ANC visits was 3.8 (± 1.5 SD) and 492/986 (49.9%) pregnant women experienced IPV. Median spatial accessibility to the nearest health facility was 4.1 km with interquartile range (IQR) from 0.2 to 329.1 km. Southwestern, and Teso subregions had the highest average percentage of pregnant women experiencing IPV (63.8-66.6%) while Karamoja subregion had the highest median spatial accessibility (7.0 to 9.3 km). In the adjusted analysis, pregnant women exposed to IPV had significantly higher odds of low spatial accessibility to nearest health facilities when compared to pregnant women without IPV exposure after controlling for enabling factors in Model 2 (aOR 1.6; 95%CI 1.2, 2.3) and need factors in Model 3 (aOR 1.5; 95%CI 1.1, 3.8). CONCLUSIONS: Spatial accessibility to health facilities were significantly lower among pregnant women with IPV exposure when compared to those no IPV exposure. Improving proximity to the nearest health facilities with ANC presents an opportunity to intervene among pregnant women experiencing IPV. Focused response and prevention interventions for violence against pregnant women should target enabling and need factors.

Healthcare provider experiences interacting with survivors of intimate partner violence: a qualitative study to inform survivor-centered approaches.

BACKGROUND: Intimate partner violence (IPV) remains a pervasive form of gender-based violence (GBV) that is largely undisclosed, especially among women seeking healthcare services in Uganda. Prioritizing survivor needs may improve IPV disclosure. This study explores healthcare worker experiences from provider-patient interactions with survivors seeking antenatal care services (ANC) in Uganda. METHODS: In-depth interviews were conducted among twenty-eight experienced healthcare providers in a rural and an urban-based ANC clinic in Eastern and Central Uganda. Providers were asked what they viewed as the needs and fears of women identified as having experienced any form of IPV. Iterative, inductive/deductive thematic analysis was conducted to discover themes regarding perceived needs, fears, and normalizing violence experienced by IPV survivors. RESULTS: According to healthcare providers, IPV survivors are unaware of available support services, and have need for support services. Providers reported that some survivors were afraid of the consequences of IPV disclosure namely, community stigma, worries about personal and their children's safety, retaliatory abuse, fear of losing their marriage, and partners' financial support. Women survivors also blamed themselves for IPV. Contextual factors underlying survivor concerns included the socio-economic environment that 'normalizes' violence, namely, some cultural norms condoning violence, and survivors' unawareness of their human rights due to self-blame and shame for abuse. CONCLUSIONS: We underscore a need to empower IPV survivors by prioritizing their needs. Results highlight opportunities to create a responsive healthcare environment that fosters IPV disclosure while addressing survivors' immediate medical and psychosocial needs, and safety concerns. Our findings will inform GBV prevention and response strategies that integrate survivor-centered approaches in Uganda.

Intimate partner violence and antenatal care utilization predictors in Uganda: an analysis applying Andersen's behavioral model of healthcare utilization.

BACKGROUND: Optimal utilization of antenatal care (ANC) services improves positive pregnancy experiences and birth outcomes. However, paucity of evidence exists on which factors should be targeted to increase ANC utilization among women experiencing intimate partner violence (IPV) in Uganda. OBJECTIVE: To determine the independent association between IPV exposure and ANC utilization as well as the predictors of ANC utilization informed by Andersen's Behavioral Model of Healthcare Utilization. METHODS: We analyzed 2016 Uganda Demographic and Health Survey data that included a sample of 1,768 women with children aged 12 to 18 months and responded to both ANC utilization and IPV items. Our outcome was ANC utilization, a count variable assessed as the number of ANC visits in the last 12 months preceding the survey. The key independent variable was exposure to any IPV form defined as self-report of having experienced physical, sexual and/or emotional IPV. Covariates were grouped into predisposing (age, formal education, religion, problem paying treatment costs), enabling (women's autonomy, mass media exposure), need (unintended pregnancy, parity, history of pregnancy termination), and healthcare system/environmental factors (rural/urban residence, spatial accessibility to health facility). Poisson regression models tested the independent association between IPV and ANC utilization, and the predictors of ANC utilization after controlling for potential confounders. RESULTS: Mean number of ANC visits (ANC utilization) was 3.71 visits with standard deviation (SD) of ± 1.5 respectively. Overall, 60.8% of our sample reported experiencing any form of IPV. Any IPV exposure was associated with lower number of ANC visits (3.64, SD ± 1.41) when compared to women without IPV exposure (3.82, SD ± 1.64) at p = 0.013. In the adjusted models, any IPV exposure was negatively associated with ANC utilization when compared to women with no IPV exposure after controlling for enabling factors (Coef. -0.03; 95%CI -0.06,-0.01), and healthcare system/environmental factors (Coef. -0.06; 95%CI -0.11,-0.04). Predictors of ANC utilization were higher education (Coef. 0.27; 95%CI 0.15,0.39) compared with no education, high autonomy (Coef. 0.12; 95%CI 0.02,0.23) compared to low autonomy, and partial media exposure (Coef. 0.06; 95%CI 0.01,0.12) compared to low media exposure. CONCLUSION: Addressing enabling and healthcare system/environmental factors may increase ANC utilization among Ugandan women experiencing IPV. Prevention and response interventions for IPV should include strategies to increase girls' higher education completion rates, improve women's financial autonomy, and mass media exposure to improve ANC utilization in similar populations in Uganda.

Filaggrin loss-of-function mutations are associated with persistence of egg and milk allergy.

BACKGROUND: A genetic defect in the epidermal barrier protein filaggrin (FLG) plays a major role in the etiology of eczema and associated allergic airways diseases. However, it is still controversial to what extend loss-of-function (LOF) mutations in FLG contribute to the development and persistence of food allergies. OBJECTIVES: This study tested association of FLG LOF mutations with allergic reactions to diverse foods and investigated their potential effect on the persistence of early food allergies. METHODS: This study recruited 890 children with challenge-proven food allergy for the German Genetics of Food Allergy Study (GOFA). Longitudinal data were available for 684 children. All children were clinically characterized, including their allergic responses to specific foods, and genotyped for the 4 most common LOF mutations in FLG; R501X, 2282del4, R2447X, and S3247X. Associations between FLG mutations and food allergies were analyzed by logistic regression using the German Multicenter Allergy Study cohort as the control population. RESULTS: FLG mutations were associated with allergies to diverse foods including hen's egg (HE), cow's milk (CM), peanut, hazelnut, fish, soy, cashew, walnut, and sesame with similar risk estimates. Effects remained significant after adjusting for the eczema status. Interestingly, FLG mutations increased the risk of a persistent course of HE and CM allergy. CONCLUSIONS: Using the gold standard for food allergy diagnosis, this study demonstrates that FLG LOF mutations confer a risk of any food allergy independent of eczema. These mutations predispose to the persistence of HE and CM allergy and should be considered in the assessment of tolerance development.

Safety of peanut (Arachis hypogaea) allergen powder-dnfp in children and teenagers with peanut allergy: Pooled summary of phase 3 and extension trials.

BACKGROUND: Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; previously known as AR101) is a daily oral immunotherapy approved to mitigate allergic reactions after accidental peanut exposure in peanut-allergic individuals aged 4-17 years. OBJECTIVE: We sought to comprehensively summarize the PTAH safety profile for up to ∼2 years of treatment. METHODS: Safety and adverse event (AE) data from participants aged 4-17 years from 3 controlled, phase 3 and 2 open-label extension trials were pooled and assessed. RESULTS: Of the 944 individuals receiving ≥1 PTAH dose, median exposure was ∼49 weeks; most participants experienced ≥1 treatment-related AE (TRAE; n = 853; 90.4%). A total of 829 participants experienced TRAEs with a maximum severity of mild (497, 52.6%) or moderate (332, 35.2%); 24 participants (2.5%) experienced TRAEs graded as severe. Overall, 80 participants (9.5%) discontinued as a result of AEs; most experienced gastrointestinal symptoms and discontinued during the first 6 months. When adjusted for exposure, AEs and TRAEs occurred at a rate of 76.4 and 58.7 events per participant-year of exposure (PYE), respectively, during updosing; AEs and TRAEs decreased to 23.0 and 14.2, respectively, during 300 mg maintenance. Overall, exposure-adjusted rates of systemic allergic reactions were 0.12 events/PYE (mild), 0.11 events/PYE (moderate), and 0.01 events/PYE (severe [anaphylaxis]). CONCLUSION: The safety profile of PTAH was consistent across trials, manageable, and improved over time. AEs were predominantly mild to moderate, and all grades declined in frequency with continued treatment. These data can be used to facilitate shared decision-making discussions with patients and families considering treatment with PTAH.

Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.

BACKGROUND: Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE: This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS: Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS: At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS: After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.

Home mortgage discrimination and incidence of triple-negative and Luminal A breast cancer among non-Hispanic Black and non-Hispanic White females in California, 2006-2015.

PURPOSE: In the United States, Black females are burdened by more aggressive subtypes and increased mortality from breast cancer compared to non-Hispanic (NH) White females. Institutional racism may contribute to these inequities. We aimed to characterize the association between home mortgage discrimination, a novel measure of institutional racism, and incidence of Luminal A and triple-negative breast cancer (TNBC) subtypes among NH Black and NH White females in California metropolitan areas. METHODS: We merged data from the California Cancer Registry on females aged 20 + diagnosed with primary invasive breast cancer between 2006 and 2015 with a census tract-level index of home mortgage lending bias measuring the odds of mortgage loan denial for Black versus White applicants, generated from the 2007-2013 Home Mortgage Disclosure Act database. Poisson regression estimated cross-sectional associations of census tract-level racial bias in mortgage lending with race/ethnicity- and Luminal A and TNBC-specific incidence rate ratios, adjusting for neighborhood confounders. RESULTS: We identified n = 102,853 cases of Luminal A and n = 15,528 cases of TNBC over the study period. Compared to NH Whites, NH Black females had higher rates of TNBC, lower rates of Luminal A breast cancer, and lived in census tracts with less racial bias in home mortgage lending. There was no evidence of association between neighborhood racial bias in mortgage lending at the time of diagnosis and either subtype among either racial/ethnic group. CONCLUSION: Future research should incorporate residential history data with measures of institutional racism to improve estimation and inform policy interventions.

Open-label follow-on study evaluating the efficacy, safety, and quality of life with extended daily oral immunotherapy in children with peanut allergy.

BACKGROUND: The benefit of daily administration of Peanut (Arachis hypogaea) Allergen Powder-dnfp (PTAH)-formerly AR101-has been established in clinical trials, but limited data past the first year of treatment are available. This longitudinal analysis aimed to explore the impact of continued PTAH therapeutic maintenance dosing (300 mg/day) on efficacy, safety/tolerability, and food allergy-related quality of life. METHODS: We present a subset analysis of PALISADE-ARC004 participants (aged 4-17 years) who received 300 mg PTAH daily for a total of ~1.5 (Group A, n = 110) or ~2 years (Group B, n = 32). Safety assessments included monitoring the incidence of adverse events (AEs), accidental exposures to food allergens, and adrenaline use. Efficacy was assessed by double-blind, placebo-controlled food challenge (DBPCFC); skin prick testing; peanut-specific antibody assays; and Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) scores. RESULTS: Continued maintenance with PTAH increased participants' ability to tolerate peanut protein: 48.1% of completers in Group A (n = 50/104) and 80.8% in Group B (n = 21/26) tolerated 2000 mg peanut protein at exit DBPCFC without dose-limiting symptoms. Immune biomarkers showed a pattern consistent with treatment-induced desensitization. Among PTAH-continuing participants, the overall and treatment-related exposure-adjusted AE rate decreased throughout the intervention period in both groups. Clinically meaningful improvements in FAQLQ and FAIM scores over time suggest a potential link between increased desensitization as determined by the DBPCFC and improved quality of life. CONCLUSIONS: These results demonstrate that daily PTAH treatment for peanut allergy beyond 1 year leads to an improved safety/tolerability profile and continued clinical and immunological response.

Allergen immunotherapy and/or biologicals for IgE-mediated food allergy: A systematic review and meta-analysis.

BACKGROUND: There is substantial interest in immunotherapy and biologicals in IgE-mediated food allergy. METHODS: We searched six databases for randomized controlled trials about immunotherapy alone or with biologicals (to April 2021) or biological monotherapy (to September 2021) in food allergy confirmed by oral food challenge. We pooled the data using random-effects meta-analysis. RESULTS: We included 36 trials about immunotherapy with 2126 mainly child participants. Oral immunotherapy increased tolerance whilst on therapy for peanut (RR 9.9, 95% CI 4.5.-21.4, high certainty); cow's milk (RR 5.7, 1.9-16.7, moderate certainty) and hen's egg allergy (RR 8.9, 4.4-18, moderate certainty). The number needed to treat to increase tolerance to a single dose of 300 mg or 1000 mg peanut protein was 2. Oral immunotherapy did not increase adverse reactions (RR 1.1, 1.0-1.2, low certainty) or severe reactions in peanut allergy (RR 1,6, 0.7-3.5, low certainty), but may increase (mild) adverse reactions in cow's milk (RR 3.9, 2.1-7.5, low certainty) and hen's egg allergy (RR 7.0, 2.4-19.8, moderate certainty). Epicutaneous immunotherapy increased tolerance whilst on therapy for peanut (RR 2.6, 1.8-3.8, moderate certainty). Results were unclear for other allergies and administration routes. There were too few trials of biologicals alone (3) or with immunotherapy (1) to draw conclusions. CONCLUSIONS: Oral immunotherapy improves tolerance whilst on therapy and is probably safe in peanut, cow's milk and hen's egg allergy. More research is needed about quality of life, cost and biologicals.

EAACI guidelines: Anaphylaxis (2021 update).

Anaphylaxis is a clinical emergency which all healthcare professionals need to be able to recognize and manage. The European Academy of Allergy and Clinical Immunology Anaphylaxis multidisciplinary Task Force has updated the 2014 guideline. The guideline was developed using the AGREE II framework and the GRADE approach. The evidence was systematically reviewed and recommendations were created by weighing up benefits and harms. The guideline was peer-reviewed by external experts and reviewed in a public consultation. The use of clinical criteria to identify anaphylaxis is suggested with blood sampling for the later measurement of tryptase. The prompt use of intramuscular adrenaline as first-line management is recommended with the availability of adrenaline autoinjectors to patients in the community. Pharmacokinetic data should be provided for adrenaline autoinjector devices. Structured, comprehensive training for people at risk of anaphylaxis is recommended. Simulation training and visual prompts for healthcare professionals are suggested to improve the management of anaphylaxis. It is suggested that school policies reflect anaphylaxis guidelines. The evidence for the management of anaphylaxis remains mostly at a very low level. There is an urgent need to prioritize clinical trials with the potential to improve the management of patients at risk of anaphylaxis.