The prevalence of food allergy is steadily increasing, and the burden of food allergy has become significant. However, treatments for food allergy remain experimental.
To review advances in the past ...18 months for the prevention and treatment of food allergies, with a particular focus on peanut allergy.
Recently published trials on the use of oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) as well as updates on the implementation of the early introduction of peanut guidelines were identified.
To address the slow implementation of the early introduction of peanut guidelines, addendum guidelines were published by the National Institute of Allergy and Infectious Diseases, which provide broader and more practical guidelines across a wider range of patients. Well-known studies of OIT have supported its efficacy. Recent studies have shown the potential for sustained unresponsiveness (SU) in up to 50% of subjects after peanut OIT and an even higher proportion in toddlers who received peanut OIT. Adjustments in the protocol to address practicality and safety have shown potential for lower maintenance doses and faster buildups. Longer durations of peanut SLIT have shown successful desensitization to moderate amounts of peanut and may also show the potential for SU. EPIT has maintained an excellent safety profile with statistically significant response rates in children <11 years of age.
Advances in food immunotherapy have continued to push the field forward and provided a better understanding of the safety and efficacy of OIT, SLIT, and EPIT. These treatments remain experimental, although phase III studies are currently underway.
Background Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head ...circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. Methods We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. Results Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. Conclusions Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.
Peanut allergy is a generally persistent, sometimes life-threatening food allergy. With no treatments demonstrating the ability to cure a food allergy, the focus of drugs in development has been on ...providing a level of protection against accidental exposure reactions. However, no study has estimated the relative risk reduction of a food-allergic population receiving a specific immunotherapeutic treatment for their allergies.
To estimate the relative risk reduction when consuming peanut-contaminated packaged food products in a double-blind, placebo-controlled Phase 3 study population of children treated with epicutaneous immunotherapy (EPIT) for 12 months with either a patch containing 250 μg peanut protein (250-μg patch) or a placebo patch.
The probability of an allergic reaction due to the unintended presence of peanut protein in packaged food products was modeled per study group and food category combination using Monte Carlo simulations. Risks per eating occasion of a contaminated packaged food product and the number of individuals per study population predicted to react on a yearly basis were investigated.
The population treated with the 250-μg patch demonstrated a significantly increased dose-response distribution after 12 months of treatment, which resulted in a relative risk reduction of 73.2% to 78.4% when consuming peanut-contaminated packaged food products. In contrast, no statistically significant change was observed for the placebo group at the 12-month point.
Our study estimates a substantial relative risk reduction for allergic reactions among peanut-allergic children after 12 months of EPIT with the 250-μg patch, supporting the potential real-world clinical relevance of this investigational immunotherapy and its possible role as a future therapy for peanut-allergic children. ClinicalTrials.gov Identifier: NCT02636699
Results The revised protocol not only eliminated the need for a two-arm trial and hence, the associated administrative burden, but also reduced the overall length of the clinical trial by almost ...fifteen months, potentially reducing non-compliance and drop-outs. The model is sufficiently powered for small sample sizes to detect risk factors associated with time to loss of SU.
The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common ...breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.
There are limited treatments available for autism spectrum disorder (ASD). Studies have reported significant associations between the receptor genes of oxytocin (OT) and vasopressin (AVP) and ASD ...diagnosis, as well as ASD-related phenotypes. Researchers have also found the manipulation of these systems affects social and repetitive behaviors, core characteristics of ASD. Consequently, research involving the oxytocin/vasopressin pathways as intervention targets has increased. Therefore, further examination into the relationship between these neuropeptides and ASD was undertaken. In this study, we examined associations between variants in the receptor genes of vasopressin (
), oxytocin (
), and ASD diagnosis along with related subphenotypes.
Probands were assessed using Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and clinical DSM-IV-TR criteria. Single nucleotide polymorphisms (SNPs) in
and
, and microsatellites in
were genotyped in ~200 families with a proband with ASD. Family-based association testing (FBAT) was utilized to determine associations between variants and ASD. Haplotypes composed of
SNPs (i.e., rs53576-rs2254298-rs2268493) were also analyzed due to previously published associations.
Using the additive inheritance model in FBAT we found associations between
SNPs (rs28632197,
= 0.005, rs35369693,
= 0.025) and diagnosis. As in other studies,
rs2268493 (
= 0.050) was associated with diagnosis. rs2268493 was also associated with ASD subphenotypes of social withdrawal (
= 0.013) and Insistence on Sameness (
= 0.039). Further analyses demonstrated that the haplotype, rs2254298-rs2268493 was found to be significantly associated with diagnosis (A-T;
= 0.026). FBAT was also used to analyze
microsatellites (RS1 and RS3). Both length variants were found to be associated with restrictive, repetitive behaviors, but not overall diagnosis. Correction for multiple comparisons was performed for SNPs tested in each gene region, only
SNPs remained significantly associated with ASD diagnosis.
Autism is a heterogeneous disorder with many genes and pathways that contribute to its development. SNPs and microsatellites in the receptor genes of OT and AVP are associated with ASD diagnosis and measures of social behavior as well as restricted repetitive behaviors. We reported a novel association with ASD and
SNPs. Understanding of genotype-phenotype relationships may be helpful in the development of pharmacological interventions for the OT/AVP system.
Aim
The study investigated psychiatrists' views towards the issue of medication discontinuation for patients in remission from first‐episode psychosis in four countries (Hong Kong, Korea, Singapore ...and Japan) that are part of the Asian Network for Early Psychosis, focusing on whether the views of these countries differ with one another.
Methods
A questionnaire was distributed to psychiatrists for completion. The questionnaire contained three sections: direct questions probing at views on medication discontinuation, case vignettes to assess applied decision‐making and a checklist of criteria psychiatrists may view as necessary for the patient to satisfy before discontinuation. Total of 484 psychiatrists (97 from Hong Kong, 88 from Korea, 64 from Singapore and 233 from Japan) completed the questionnaire.
Results
We found that (a) Asian psychiatrists believed that 1% to 19% of remitted patients can discontinue medication, an estimation that was lower than Western psychiatrists; (b) in agreement with clinical guidelines, Asian psychiatrists believed that patients should remain on medication for at least 1 to 2 years following the absence of psychotic symptoms; (c) “Absence of any relapsing episode following first episode” was considered the most important criterion when making a decision; and (d) there were significant differences in clinicians' perceptions across the four countries: for instance, Korean psychiatrists were more conservative with the duration of antipsychotics maintenance, while Singaporean psychiatrists were more open‐minded towards clinical trials.
Conclusions
Culture and social norms appear to determine the relative importance of factors that psychiatrists might consider during the decision‐making process, thereby producing variations in the views held in different countries.
To present the current status of knowledge in the field of patellofemoral (PF) osteoarthritis (OA) and formulate a research agenda in order to guide future research on this topic.
A 1-day meeting was ...organized with the aim to bring together international experts in the field to discuss the current state of knowledge on PF OA. Experts from multiple disciplines were invited based on their scientific publications in the field of PF OA and interest in the subject. Topics discussed include the diagnosis, impact, prognosis, and treatment of PF OA.
Following context-setting presentations, an interactive discussion was held in order to achieve consensus on the PF OA topics of interest: (1) diagnosis and definition; (2) burden; (3) outcome measures; (4) prognosis; (5) risk factors, and (6) treatment. Groups of meeting attendees reviewed the literature on these topics and narratively summarized the current state of knowledge, and each group formulated research agenda items relevant to the specific topics of interest. Each consortium member consequently ranked the importance of all items on a 0–10 Numerical Rating Scale (NRS) (10 = extremely important, to 0 = not at all important).
After ranking all formulated items on importance, 6 of the 28 research agenda items formulated received an average of 7.5 points on the NRS. The most highly ranked items covered the fields of treatment, diagnosis, and definition of PF OA.
We recommend to develop clear clinical criteria for PF OA and to reach consensus on the definition of PF OA by both radiographs and MRI. Additionally, more understanding is necessary to be able to distinguish PF symptoms from those arising from the tibiofemoral joint. More insight is needed on effective treatment strategies for PF OA; specifically, tailoring nonpharmacological treatments to individuals with PF OA, and determining whether isolated PF OA requires different treatment strategies than combined PF and tibiofemoral OA.
Oral immunotherapy (OIT) leads to suppression of mast cell and basophil degranulation along with changes in the adaptive immune response.
This study aimed to determine how rapidly these effects occur ...during OIT and more broadly, the kinetics of basophil and mast cell suppression throughout the course of therapy.
Twenty participants, age 4 to 12 years, were enrolled in a peanut OIT trial and assessed for desensitization and sustained unresponsiveness after 9 months of therapy. Blood was collected 5 times in the first month and then intermittently throughout to quantify immunoglobulins and assess basophil activation by CD63, CD203c, and phosphorylated SYK (pSYK).
Twelve of 16 participants that completed the trial were desensitized after OIT, with 9 achieving sustained unresponsiveness after discontinuing OIT for 4 weeks. Basophil hyporesponsiveness, defined by lower CD63 expression, was detected as early as day 90. pSYK was correlated with CD63 expression, and there was a significant decrease in pSYK by day 250. CD203c expression remained unchanged throughout therapy. Interestingly, although basophil activation was decreased across the cohort during OIT, basophil activation did not correlate with individual clinical outcomes. Serum peanut-specific IgG4 and IgA increased throughout therapy, whereas IgE remained unchanged.
Suppression of basophil activation occurs within the first 90 days of peanut OIT, ultimately leading to suppression of signaling through pSYK.
Opinion statement
Purpose of review
The recent approval of the first commercial peanut oral immunotherapy formulation ushered a new era of clinical food allergy treatment. With different options for ...peanut immunotherapy available, it is important review the evidence of efficacy, risks, and unique considerations for the individual modalities.
Recent findings
Oral immunotherapy (OIT), epicutaneous immunotherapy (EPIT), and sublingual immunotherapy (SLIT) for peanut allergy have risen as possible treatments for peanut allergy. Numerous studies indicate that OIT effectively desensitizes by increasing the amount of peanut protein than can be consumed without symptoms. While this desensitization is to increased amounts of peanut protein when compared to SLIT or EPIT, OIT appears to have greater risk for anaphylaxis and other adverse events. EPIT has the unique benefit of a single-dose patch without the need for in-clinic visits for dose escalation, and it bypasses the oral route which may be advantageous in certain patients. The impact of peanut immunotherapy on health-related quality of life is not well studied and current data is conflicting, but suggests that improvement in certain domains of QOL, especially for caregivers of children with peanut allergy, may be an important target for immunotherapy.
Summary
This review focuses on the data for efficacy, safety, and tolerability of OIT, SLIT, and EPIT with the aim of presenting information that will assist allergy practitioners in choosing an immunotherapy modality when indicated.
PDF
