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Purpose of ReviewIgE-mediated food allergies are an increasing health concern, and current management includes food avoidance and use of emergency medications. Effective treatment of food allergy is highly desirable. Next generation approaches for the treatment of food allergy aim to improve both safety and efficacy, potentially including long-term tolerance.Recent FindingsOral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) will likely be integrated into clinical practice as part of food allergy management in the near future. Newer approaches, such as sublingual immunotherapy (SLIT), modified proteins, lysosomal-associated membrane protein DNA (LAMP DNA) vaccines, and the use of immunomodulatory agents, are early in development and depending on results, could also become important treatment options.SummaryThis is a review of novel approaches to the treatment of food allergy that are currently under investigation, including the use of SLIT, modified proteins, probiotics, Chinese herbal supplements, biologic therapies, and DNA vaccines, as well as a summary of the current status of OIT and EPIT.

BACKGROUNDCow's milk (CM) allergy is the most common food allergy in young children. Treatment with oral immunotherapy (OIT) has shown efficacy, but high rates of adverse reactions. The aim of this study was to determine whether baked milk OIT (BMOIT) could reduce adverse reactions while still inducing desensitization, and to identify immunological correlates of successful BMOIT.METHODSThis phase II, randomized trial evaluated the safety and efficacy of BMOIT in milk-allergic children 3-18 years old. After the initial placebo-controlled first year of treatment, placebo-treated participants crossed over to active BMOIT. Double-blind, placebo-controlled oral food challenges (OFCs) were conducted with BM after year 1 and to both BM and unheated milk (UM) after year 2. IgG and IgE antibodies were measured along with CM-specific (CM+) CD4+ memory T cell populations, profiled using flow cytometry and scRNA-Seq.RESULTSTwenty-one of 30 (70%) reached the primary endpoint of tolerating 4044 mg of BM protein at month 24, and 11 of 30 tolerated 2000 mg or more of UM protein. Dosing symptoms were common, but more than 98% were mild, with no severe reactions. Immunological changes associated with desensitization included increased CM IgG4, CM+ FOXP3+ cells, and Tregs and corresponding decreases in CM IgE, CM+ Th2A cells, and CD154+ cells. T cell and antibody measurements were combined to build a model that predicted UM OFC outcomes.CONCLUSIONBMOIT was well tolerated and induced desensitization to BM and UM. This desensitization corresponded to redistribution within antigen-specific antibody and T cell compartments that provided insight into the mechanistic changes that occur with OIT treatment.TRIAL REGISTRATIONClinicalTrials.gov NCT03462030.FUNDING: Myra Reinhardt Family Foundation (grant number 128388), NIH/NIAID (U19AI135731, T32AI125179, S10OD025052).

MIRAGE syndrome is a multi‐organ disease caused by gain‐of‐function (GOF) mutations in the viral restriction factor SAMD9. Herein, we present the case of a 32‐week pre‐term female neonate with severe intrauterine growth restriction, primary adrenal insufficiency, and persistent thrombocytopenia. A rapid trio‐whole exome sequencing at 23‐days of age found a de novo SAMD9 G1048R mutation, consistent with a diagnosis of MIRAGE syndrome, and at this time was not found to have evidence of immune abnormalities or hematologic malignancy. Analysis of predicted tertiary structures from our patient’s SAMD9 G1048R mutation demonstrated structural similarities to known SAMD9 GOF variants. Absence of immunologic and oncologic manifestations in this patient may relate to early identification and reflect low SAMD9 expression during the neonatal window. Risk for developing immune deficiency and malignancy may continue to increase as this patient grows older, thus requiring close outpatient surveillance to mitigate future risk of these complications. A de novo SAMD9 variant G1048R is associated with MIRAGE syndrome symptoms in a neonate. SAMD9 G1048R's predicted tertiary structure has similarity to known MIRAGE variants. SAMD9 expression is increased in pediatric viral infection. Neonatal MIRAGE may lack immune deficiency and myelodysplastic syndrome.

Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. 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. 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. 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.).

Inflammation and depression are closely inter-related; inflammation induces symptoms of depression and, conversely, depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites. By acting on glutamatergic neurotransmission, these neuroactive metabolites play a key role in the development of depression-like behaviors. An important outcome of the preclinical research on inflammation-induced depression is the identification of potential novel targets for antidepressant treatments, which include targeting the kynurenine system and production of downstream metabolites, altering transport of kynurenine into the brain, and modulating glutamatergic transmission.

Background Activation of the tryptophan degrading enzyme indoleamine-2,3-dioxygenase 1 (IDO1) is associated with the development of behavioral signs of depression. Systemic immune challenge induces IDO1 in both the periphery and the brain, leading to increased circulating and brain concentrations of kynurenines. However, whether IDO1 activity within the brain is necessary for the manifestation of depression-like behavior of mice following a central immune challenge remains to be elucidated. Methods We investigated the role of brain IDO1 in mediating depression-like behavior of mice in response to intracerebroventricular injection of saline or lipopolysaccharide (LPS, 10 ng). Results LPS increased the duration of immobility in the tail suspension test and decreased preference for a sucrose solution. These effects were associated with an activation of central but not peripheral IDO1, as LPS increased brain kynurenine but had no effect on plasma concentrations of kynurenine. Interestingly, genetic deletion or pharmacological inhibition of IDO1, using 1-methyl-tryptophan, abrogated the reduction in sucrose preference induced by intracerebroventricular LPS. 1-Methyl-tryptophan also blocked the LPS-induced increase in duration of immobility during the tail suspension test. Conclusions These data indicate that activation of brain IDO1 is sufficient to induce depression-like behaviors of mice in response to central LPS.

Forest-going populations are key to malaria transmission in the Greater Mekong Sub-region (GMS) and are therefore targeted for elimination efforts. Estimating the size of this population is essential for programs to assess, track and achieve their elimination goals. Leveraging data from three cross-sectional household surveys and one survey among forest-goers, the size of this high-risk population in a southern province of Lao PDR between December 2017 and November 2018 was estimated by two methods: population-based household surveys and capture–recapture. During the first month of the dry season, the first month of the rainy season, and the last month of the rainy season, respectively, 16.2% [14.7; 17.7], 9.3% [7.2; 11.3], and 5.3% [4.4; 6.1] of the adult population were estimated to have engaged in forest-going activities. The capture–recapture method estimated a total population size of 18,426 [16,529; 20,669] forest-goers, meaning 61.0% [54.2; 67.9] of the adult population had engaged in forest-going activities over the 12-month study period. This study demonstrates two methods for population size estimation to inform malaria research and programming. The seasonality and turnover within this forest-going population provide unique opportunities and challenges for control programs across the GMS as they work towards malaria elimination.

Lao People’s Democratic Republic (Lao PDR) has made significant progress in reducing malaria in recent years. In the Greater Mekong Subregion, forest-going is often a risk factor contributing to continuing malaria transmission. This study assessed forest-going and other potential risk factors for malaria cases in Champasak Province, Lao PDR. Routine passive surveillance data from August 2017 to December 2018 were extracted from health facilities in three districts for a case-control study; at the time of presentation, all fever cases were asked to report any recent forest travel. Multivariable logistic regression was used to assess the relationship between forest-going and malaria infection while controlling for other covariates. Of 2933 fever cases with data available on forest-sleeping and malaria diagnosis from 25 health facilities, 244 (8%) tested positive (cases), and 2689 (92%) tested negative (controls). Compared with spending 0–2 nights in the forest, spending 3–7 nights in the forest was associated with 9.7 times the odds of having a malaria infection (95% CI: 4.67–20.31, p < 0.001) when adjusting for gender, occupation, and season. Forest-going, especially longer trips, is associated with increased risk for confirmed symptomatic malaria in southern Lao PDR, and appropriate and targeted intervention efforts are needed to protect this high-risk population.

Introduction: Novel interventions are needed to accelerate malaria elimination, especially in areas where asymptomatic parasitemia is common, and where transmission generally occurs outside of village-based settings. Testing of community members linked to a person with clinical illness (reactive case detection, RACD) has not shown effectiveness in prior studies due to the limited sensitivity of current point-of-care tests. This study aims to assess the effectiveness of active case finding in village-based and forested-based settings using novel high-sensitivity rapid diagnostic tests in Lao People’s Democratic Republic (Lao PDR). Methods and analysis: This study is a cluster-randomized split-plot design trial. The interventions include village-based mass test and treat (MTAT), focal test and treat in high-risk populations (FTAT), and the combination of these approaches, using high-sensitivity rapid diagnostic tests (HS-RDTs) to asses P. falciparum infection status. Within four districts in Champasak province, Lao PDR fourteen health center-catchment areas will be randomized to either FTAT or control; and within these HCCAs, 56 villages will be randomized to either MTAT or control. In intervention areas, FTAT will be conducted by community-based peer navigators on a routine basis, and three separate rounds of MTAT are planned. The primary study outcome will be PCR-based Plasmodium falciparum prevalence after one year of implementation. Secondary outcomes include malaria incidence; interventional coverage; operational feasibility and acceptability; and cost and cost- effectiveness. Ethics and dissemination: Findings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with Ministry of Health and community leaders in Lao PDR and throughout the Greater Mekong Subregion. Trial registration: clinicaltrials.gov NCT03783299 (21/12/2018)