Search Results (41)

Background/Objectives: Asthma, a chronic airway inflammatory disease characterized by bronchial narrowing and caused by an inflammatory response, results in airway obstruction and hyperresponsiveness. Stachydrine (STA), an abundant metabolite found in plants and humans, is recognized for its bioactivity in treating fibrosis, cancer, and inflammation. However, its effects on asthma have not been fully elucidated. We aimed to investigate the ameliorating effects of STA on chronic airway inflammation caused by Dermatophagoides pteronyssinus (house dust mite, HDM). Methods: We used a murine model of HDM-induced airway inflammation to assess the change in metabolite profile by chronic airway inflammation. The mice were challenged with HDM (35 challenges in total) for up to 12 weeks. Serum metabolites were analyzed using capillary electrophoresis time-of-flight mass spectrometry. Results: HDM exposure increased airway hypersensitivity, immune cell infiltration, cytokine production, goblet cell hyperplasia, collagen deposition, and alpha smooth muscle actin and fibronectin expression. Serum metabolite analysis revealed that STA levels were lower in the mice with HDM-induced chronic inflammation than in the controls. In vitro analyses demonstrated that HDM sensitization increased cytokine production (interleukin [IL]-6 and IL-8) and extracellular signal-regulated kinase (ERK) activity. However, STA treatment reduced HDM-induced IL-6 and IL-8 production and ERK activity. Co-treatment with a mitogen-activated protein kinase (MAPK) inhibitor and STA resulted in a more pronounced reduction in cytokine production and MAPK activity. Conclusions: These findings suggest that STA, particularly when used in combination with a MAPK inhibitor, effectively suppresses airway inflammation through ERK pathway inhibition, making it a potential therapeutic agent for asthma treatment. Full article

House dust mites (HDMs) are a major source of indoor allergens, significantly contributing to allergic rhinitis, asthma and atopic dermatitis. This review examines the epidemiology, microbiological classification and pathophysiology of HDM allergy, highlighting key allergens such as Der p 1, Der p 2 and Der p 23. Furthermore, we discuss the pivotal role of allergen-specific immunotherapy (AIT), the only disease-modifying treatment for immunoglobulin (Ig)-E disease. Recent studies have identified predictive biomarkers for allergen-specific immunotherapy (AIT) efficacy, including the specific IgE to total IgE (sIgE/tIgE) ratio and regulatory follicular T cell profiles, supporting a more personalized approach to therapy. Additionally, emerging immunotherapy strategies, such as recombinant allergens and peptide-based formulations, aim to improve safety and clinical outcomes. As HDM allergy prevalence rises globally, further research into optimizing diagnostics and treatment strategies remains crucial for enhancing patient care. Full article

The diagnosis of allergic reactions to Anisakis remains challenging due to the lack of specific allergens available for routine clinical use. However, the latest version of the multiplex macroarray ALEX-2 now allows the detection of specific IgE against Ani s 1, the major species-specific allergen, as well as Ani s 3 (tropomyosin), a highly cross-reactive molecule with homologs in other allergenic sources. This study aimed to evaluate the potential role of ALEX-2 in diagnosing Anisakis sensitization by comparing it with a previously validated diagnostic algorithm. Serum samples from patients with suspected Anisakis sensitization were consecutively collected at an Italian allergy centre. Diagnosis was based on a history of allergic reactions following seafood consumption, along with negative test results for fish allergy. All patients underwent skin prick testing and specific IgE measurement for Anisakis (p4), Ascaris (p1), shrimp (f24), and Dermatophagoides pteronyssinus (d1), as well as tropomyosins from house dust mites (d205) and shrimp (f351). Additionally, the basophil activation test (BAT) using crude Anisakis extract was performed. Patients were also tested using the ALEX-2 allergy macroarray. Correlation analyses and multiple logistic regression models were applied to assess associations between conventional singleplex tests and the severity of clinical manifestations. A total of 33 eligible subjects were recruited, including 20 females (60.6%). Seven (21.2%) were aged 0–29 years, eleven (33.3%) were 30–60 years old, and fifteen (45.5%) were over 60 years old. ALEX-2 showed positivity for Ani s 1 or Ani s 3 in 39.39% (95% CI: 22.90–57.86%) of subjects with confirmed Anisakis sensitization. A significant correlation was observed between Ani s 3 (r = 0.31 [95% CI: 0.04–0.56], p = 0.01) and Ascaris (r = 0.35 [95% CI: 0.129–0.55], p = 0.004) levels and the severity of clinical reactions. Despite the limitations of this cross-sectional study, including a small sample size, our preliminary findings suggest that the ALEX-2 macroarray may not be sufficiently sensitive for the first-line diagnosis of Anisakis allergy. However, it could provide valuable additional information, as Ani s 1 positivity indicates primary sensitization to the nematode, while Ani s 3 positivity appears to correlate with clinical severity. Larger prospective longitudinal studies are needed to confirm these findings and further assess the predictive value of ALEX-2 in diagnosing Anisakis allergy. Full article

Chronic Rhinosinusitis (CR) is a common inflammatory condition with complex pathophysiology involving multiple interleukins. In times of precision medicine, it is mandatory to cluster our patients to offer the best tailored treatment with the lowest cost possible. Therefore, some triage markers can be used towards this goal, without raising much financial burden. The aim of this study was to identify the association of staphylococcal enterotoxin (SE)-specific IgE of types A, B, C, and TSST-1 (toxic shock syndrome toxin-1); and total IgE (tIgE) and specific IgE for Dermatophagoides pteronyssinus (DP), Dermatophagoides farinae (DF), and Blomia tropicalis (BT) in Brazilian patients with CRSwNP. Thirty-six patients with CSRwNP were analyzed for serum IgE levels: tIgE and specific IgE for: DP, DF, BT, and SE types A, B, C, TSST-1 by ImmunoCAP^®. The mean value of tIgE in SE-specific IgE-positive patients was 767 IU/mL and in house-dust-mite (HDM)-positive patients, the mean tIgE was 319 IU/mL (p < 0.005). A total of 86% of patients who had high tIgE levels but were SE-specific IgE-negative had positive specific IgE for at least one of the HDMs tested. The Fisher exact test statistic value for this association was significant (p < 0.05/p = 0.014). We found an association between high levels of tIgE and SE-specific IgE in patients with CRSwNP, possibly related to local and peripheric polyclonal IgE production. The mean value of tIgE—with a suggested cutoff point of tIgE levels of 767 IU/mL—can be used as a triage biomarker for positive SE-specific IgE in CRSwNP patients. Full article

The aim of this study was to optimize a basophil activation test in the detection of allergy to the house dust mite Dermatophagoides pteronyssinus in children with allergic respiratory diseases. This study involved 32 cases, 13 girls and 19 boys aged 4–17 years, with perennial asthma or allergic rhinitis caused by D. pteronyssinus. The control group consisted of 13 girls and 19 boys aged 4–17 years with seasonal allergic asthma or rhinitis provoked by Timothy or birch pollen. House dust mite (HDM) allergy was excluded in the controls based on their medical history, skin prick test (SPT) results and sIgE determination. In all patients, a basophil activation test (BAT) was performed with five dilutions of D. pteronyssinus allergen (the dilution series ranged from 22.5 to 0.00225 ng/mL). The results were analyzed by using the receiver operating characteristics (ROC) to determine the optimal allergen concentrations, outcome measures and cut-off points that would differentiate most accurately between HDM-allergic and non-allergic patients. As a “gold standard”, criteria for allergen-specific immunotherapy with D. pteronyssinus or respective pollens were applied by an experienced pediatric allergist following the guidelines of the European Academy of Allergy and Clinical Immunology. The highest diagnostic efficiency was yielded by the protocol assuming a cut-off value of 9.76% activated basophils after activation with a single allergen concentration of 2.25 ng/mL (sensitivity 90.6%, specificity 100%). This protocol yielded 3 (4.7%) misclassifications, all false negative, when compared with the “gold standard”. There was a strong correlation with the BAT results at 22.5, 2.25 and 0.225 ng/mL (respectively r = 0.90 and r = 0.78, p < 0.001), as well as between the BAT at 2.25 ng/mL and SPT (r = 0.82, p < 0.001) and between the SPT and sIgE levels (r = 0.78, p < 0.001). High cross-reactivity between D. pteronyssinus and D. farinae was confirmed based on the BAT at 22.5 ng/mL (r = 0.82, p < 0.001). In conclusion, the BAT showed very good concordance with the result of a meticulous process of decision-making that combined validated allergy tests (SPT, sIgE) with expert guidelines, specialist knowledge and experience. Facing the risk of the incorrect qualification of patients for costly, long-lasting and potentially risky allergen-specific immunotherapy, the inclusion of a basophil activation test into diagnostic process seems fully justified. Full article

Allergic rhinitis (AR) is a common chronic disease that significantly impacts the quality of life. Lidocaine is known to have anti-inflammatory and immunomodulatory effects. This study evaluated the effect of lidocaine analogs in a Dermatophagoides pteronyssinus (DP)-induced AR mouse model. An AR model was developed using BALB/c mice via intraperitoneal sensitization with DP and intranasal challenge with DP. One hour before stimulation with DP, lidocaine analogs, EI137 and EI341 (at a dose of 0.5 or 5 ug/g), were administered intranasally. Nasal symptoms and serum total IgE, interleukin (IL)-4, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α levels were evaluated. Reverse-transcription polymerase chain reaction was used to determine IL-4, IL-10, and IFN-γ, as well as the expression of their mRNA transcription factors in the sinonasal mucosa. Histologic changes were evaluated using hematoxylin and eosin and periodic acid–Schiff staining. The DP-induced AR mouse model had increased serum levels of total IgE and cytokines. EI137 and EI341 significantly suppressed the levels of total IgE, IL-4, and TNF-α. Intranasal instillation of EI137 and EI341 significantly inhibited IL-4, IL-10, and IFN-γ mRNA expression, as well as inflammatory cells and mucus-producing goblet cells. Lidocaine analogs also suppressed DP-stimulated IL-4, IFN-γ, and IFN-γ production by splenocytes. Intranasal instillation of EI137 and EI341 exhibited anti-allergic and anti-inflammatory effects, influenced by Th1 and Th2 inflammatory cytokines. These lidocaine analogs suppressed DP-induced sinonasal mucosal inflammation, inflammatory cell infiltration, and mucus hypersecretion. Full article

Updated notions about the so-called hygiene hypothesis consider now that helminths may have influence in the training of the immune system during childhood. Considering the similar type of immune response between helminth infections and allergic illnesses, the objective of this study was to evaluate how structural and functional conservation between house-dust mite allergens and their helminth orthologs might contribute to the cross-induction of IgE responses in allergies and helminthiasis. Amino acid sequences from group-1, -2, -5, -9, -10, -18, -21, and -23 allergens of the house dust mite Dermatophagoides pteronyssinus were retrieved from curated databases, and orthologs were identified in other mite species and different helminth parasites. We also assessed structural, conservational, functional, and immunologic relationships between these major mite allergens and their helminth counterparts. De novo 3D-modelling, B-cell epitopes prediction, structural conservation, and docking analyses were analyzed by Robetta platform, ElliPro and CBTope, RaptorX, and Z-Dock, respectively. Our results extend previous findings on structural conservations between major allergens and parasite proteins and show that these conservations go beyond the well-known conservations and may account for the observed immunological cross-reactions. This understanding can contribute in the near future to the development of more specific serological testing for mite-induced allergies and helminthiasis. Full article

Background: Severe asthma often remains uncontrolled despite optimized inhaled treatment. The rise of biologic therapy in severe asthma represented a major advance for the disease management. However, correct phenotyping and monitoring of severe asthma patients is key to the success of targeted biologic therapy. Materials and Methods: We present the case of a 63-year-old female, never a smoker, diagnosed with asthma at the age of 45 and associated persistent mild rhinitis, without other notable comorbidities. She was prescribed medium-dose ICS/LABA, administered inconstantly in the first years after the diagnosis, with poor overall control of the disease. After several exacerbation episodes, treatment compliance improved, but the control of the disease remained poor despite adding an antileukotriene. In January 2019, she presented an exacerbation episode requiring treatment with oral corticosteroids (OCS) and she was afterwards put on high-dose ICS/LABA and continued the antileukotriene. She was referred for a skin allergy test, which revealed mild sensitization to Dermatophagoides pteronyssinus and farinae, with a total IgE level of 48.3 IU/mL. The blood eosinophil level was 270 cells/mm³. The lung function was variable, going from mild impairment to severe fixed obstruction during exacerbations. Despite optimized inhaled treatment, good adherence and inhaler technique, and allergen avoidance strategies, asthma control was not achieved, and she continued to experience severe episodes of exacerbation requiring OCS. Results: In October 2019, she was initiated on biologic therapy with omalizumab, which allowed asthma control to be achieved and maintained for 18 months, with preserved lung function, good symptom control, no exacerbations and slightly elevated blood eosinophil level (340–360 cells/mm³). In April 2021, she started experiencing exacerbation episodes requiring OCS (three episodes within 6 months), with a progressive increase in blood eosinophil level (up to 710 cells/mm³), and progressive deterioration of asthma control and lung function, despite continuation of previous therapy. A specific IgE test against Aspergillus was negative, and total IgE level was 122.4 IU/mL. In December 2021, the patient was switched from omalizumab to benralizumab. Asthma control was again achieved, lung function improved significantly and the patient did not experience any other exacerbation episodes up until today, which allowed for a reduction in ICS dose. Intriguingly, a relapsing eosinophilia was also noted under anti-IL5-R treatment prior to the dose administration, but with preserved asthma control. Conclusions: This case underscores the pivotal role of meticulous phenotyping in severe asthma management on one side, and careful monitoring of patient evolution and possible side effects of treatment on the other side. By showcasing how diverse inflammatory pathways can coexist within a single patient and impact treatment outcomes, it highlights the necessity of tailored biologic therapy for sustained control. Full article

In distinguishing the allergic asthma (AA) phenotype, it has been identified that specific biomarkers could assist; however, none of them are considered ideal. This study aimed to analyze three groups of biologically active substances in the serum. Twenty steroid-free AA patients, sensitized to Dermatophagoides pteronyssinus, and sixteen healthy subjects (HSs) were enrolled in this study. Blood samples were collected from all patients. Additionally, all AA patients underwent a bronchial allergen challenge (BAC) with Dermatophagoides pteronyssinus, all of which were positive, and blood samples were collected again 24 h later. The concentrations of ten biologically active substances were measured in the serum samples, using enzyme-linked immunosorbent assay (ELISA) and the Luminex^® 100/200™ System technology for bead-based multiplex and singleplex immunoassays. Descriptive and analytical statistical methods were used. A p-value of 0.05 or lower was considered statistically significant. The soluble interleukin 5 receptor subunit alpha (sIL-5Rα) and thioredoxin 1 (TRX1) concentrations were significantly increased, whereas those of tyrosine-protein kinase Met (MET), pentraxin 3 (PTX3), and I C-telopeptide of type I collagen (ICTP) were decreased in the AA group compared with the HS group. A significant positive correlation was noted for sIL-5Rα with fractional exhaled nitric oxide (Fe_NO), blood eosinophil (EOS) count, and total immunoglobulin E (IgE) levels, and a negative correlation was noted with forced expiratory volume in 1 s (FEV₁). Moreover, PTX3 showed negative correlations with blood EOS count and total IgE levels, whereas ICTP exhibited a negative correlation with the blood EOS count. In conclusion, this study demonstrated that the serum concentrations of MET, PTX3, TRX1, ICTP, and particularly sIL-5Rα could potentially serve as biomarkers of the AA phenotype. Full article

Most fungal species are commensals and non-pathogenic to plants, humans, or animals. However, several species of the Alternaria, Aspergillus, Trichophyton, and Microsporum genera are common causes of disease, even for immunocompetent individuals. Besides mucosal damage, fungi may contribute to a skin barrier impairment, favoring sensitization and allergy development. A total of 68 allergic dogs were selected from a veterinary dermatology and allergy outpatient consultation for conditions related to both Malassezia overgrowth and other fungal complications. The allergy diagnosis was made through anamnesis and current clinical criteria, with the involved allergenic species being identified by intradermal tests (IDTs) and allergen-specific immunoglobulin E (sIgE) determination in serum. Dermatophagoides farinae, Dactylis glomerata, and Malassezia pachydermatis showed as the higher sensitization species from house dust mites, grass pollen, and fungi, respectively. Significant correlations at p < 0.05 were found between sensitization to Dactylis glomerata and Phleum pratense grass pollens, Dermatophagoides farinae and Dermatophagoides pteronyssinus, Acarus siro, Tyrophagus putrescentiae, and Lepidoglyphus destructor dust/storage mites, and between fungi like Aspergillus mix and Penicillium or Alternaria alternata. A significant correlation was also found between sensitization to the Aspergillus mix and D. farinae, D. pteronyssinus, or A. siro. Rather severe dermatitis was observed when a positive IDT to Malassezia pachydermatis was found, regardless of the detection of circulating sIgE, allowing us to consider the usefulness of both the IDT and the sIgE for a systematic diagnosis of allergy to fungi. Full article

(1) Background: Modification of the structural elements of allergens is widely used in the field of allergies. The goal of the present research was to express, purify, and characterize the shortened recombinant group 5 allergen of Dermatophagoides pteronyssinus (rDer p 5). (2) Methods: rDer p 5 storage stability and aggregation capacity were explored through in silico analysis, dynamic light scattering (DLS), and SDS-PAGE. Serum IgE reactivity and cytokine amount were investigated in sera or cell culture supernatants through ELISA, MULTIPLEX^®, and Western blot analysis using sera from sensitized humans from Brazil, Colombia, and Ecuador. (3) Results: Dimeric rDer p 5 was detected through native PAGE, and this result was confirmed by data from DLS. The protein was thermically stable, as it did not degrade at 4 °C for 21 days. The shortened rDer p 5 was classified as a major IgE allergen in Brazil and Colombia, but minor in Ecuador. IL-13, IL-10, IL-1β, and IL-6 were significantly elevated in the sera of rDer p 5-reactive patients. The same cytokines plus IL-5 were more secreted by human cells upon rDer p 5 stimulation. (4) Conclusions: N-terminal peptide deletion led to a higher rDer p 5 folding stability, which, even though dimeric, was an IgE-reactive protein. Therefore, rDer p 5 could be used for molecular diagnostic applications or as backbone for hypoallergen design. Full article

Background: Patients with Kawasaki disease (KD) are at a significantly increased risk of allergic diseases. Immunoglobulin E (IgE) is an immunoglobulin that mediates allergic sensitization to various allergens and is related to various allergic diseases. However, few studies have analyzed specific IgE on allergy biomarkers after KD is diagnosed. Objective: This study aimed to investigate the pattern of specific IgE levels against food and inhalant allergens. Methods: This retrospective study was conducted in Taiwan to identify patients admitted with KD. A subset of 453 admitted KD children younger than or equal to five years of age with intravenous immunoglobulin (IVIG) was followed up at our clinic with available specific IgE data. Results: The most common allergens were Dermatophagoides farina or pteronyssinus, house-dust, and cockroach mix. Positive specific IgE for Dermatophagoides farina or pteronyssinus was less common in children diagnosed with KD who were two years old or younger (p = 0.028). KD patients with higher basophils before IVIG (p = 0.010 and 0.018 for two different mites) and higher C-reactive protein (CRP, p = 0.030 and 0.028) after IVIG were at higher risk of mite sensitization. Integrated mite sensitization demonstrated higher basophils before IVIG, age at KD diagnosis, and the male sex to be clinically meaningful after logistic regression models. Conclusions: This study is the first to suggest that specific IgE in KD patients may be correlated with age at KD diagnosis, as well as basophils. Further longitudinal prospective studies are warranted to clarify the unique profile of specific IgE in KD patients. Full article

At present, there are no effective, non-invasive, and objective indicators to evaluate the efficacy of pediatric house dust mite (HDM)-specific allergen immunotherapy (AIT). A prospective, observational study was performed in children with Dermatophagoides pteronyssinus (Der p) asthma and/or allergic rhinitis (AR). Forty-four patients received subcutaneous Der p-AIT for 2 years, and eleven patients received only symptomatic treatment. The patients needed to finish their questionnaires at each visit. Serum and salivary Der p-specific IgE, IgG4, and IgE-blocking factors (IgE-BFs) were measured at 0, 4, 12, and 24 months during AIT. A correlation between them was also evaluated. Subcutaneous Der p-specific AIT improved the clinical symptoms of children with asthma and/or AR. The Der p-specific IgE-BF significantly increased at 4, 12, and 24 months after AIT treatment. Serum and salivary Der p-specific IgG4 significantly increased with the time of the AIT treatment, and significant correlations between them at different time points were observed (p < 0.05). Furthermore, there were significant correlations (R = 0.31–0.62) between the serum Der p-specific IgE-BF and Der p-specific IgG4 at the baseline, 4, 12, and 24 months after the AIT (p < 0.01). The salivary Der p-specific IgG4 levels also demonstrated a certain correlation with the Der p-specific IgE-BF. Der p-specific AIT is an effective treatment for children with asthma and/or AR. Its effect was associated with increased serum and salivary-specific IgG4 levels, as well as an increased IgE-BF. Non-invasive salivary-specific IgG4 may be useful for monitoring the efficacy of AIT in children. Full article

Blood eosinophils can be described as inflammatory-like (iEOS-like) and lung-resident-like (rEOS-like) eosinophils. This study is based on the hypothesis that eosinophilopoetins such as interleukin (IL)-3 and IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) alter the proliferative properties of eosinophil subtypes and may be associated with the expression of their receptors on eosinophils. We investigated 8 individuals with severe nonallergic eosinophilic asthma (SNEA), 17 nonsevere allergic asthma (AA), and 11 healthy subjects (HS). For AA patients, a bronchial allergen challenge with Dermatophagoides pteronyssinus was performed. Eosinophils were isolated from peripheral blood using high-density centrifugation and magnetic separation methods. The subtyping of eosinophils was based on magnetic bead-conjugated antibodies against L-selectin. Preactivation by eosinophilopoetins was performed by incubating eosinophil subtypes with IL-3, IL-5, and GM-CSF, and individual combined cell cultures were prepared with airway smooth muscle (ASM) cells. ASM cell proliferation was assessed using an Alamar blue assay. The gene expression of eosinophilopoetin receptors was analyzed with a qPCR. IL-5 and GM-CSF significantly enhanced the proliferative properties of iEOS-like and rEOS-like cells on ASM cells in both SNEA and AA groups compared with eosinophils not activated by cytokines (p < 0.05). Moreover, rEOS-like cells demonstrated a higher gene expression of the IL-3 and IL-5 receptors compared with iEOS-like cells in the SNEA and AA groups (p < 0.05). In conclusion: IL-5 and GM-CSF promote the proliferative properties of iEOS-like and rEOS-like eosinophils; however, the effect of only IL-5 may be related to the expression of its receptors in asthma patients. Full article

Background: To determine medication adherence to intranasal corticosteroid spray (INCS) among allergic rhinitis (AR) patients with comorbid medical conditions. Methods: A cross-sectional study was conducted. Adults above 18 years old with persistent symptoms of AR and comorbid physician-diagnosed asthma, eczema, diabetes mellitus (DM) and hypertension (HPT) were included. The severity of symptoms was assessed by the total nasal symptom score (TNSS), medication adherence was based on the patients’ diaries and barriers to adherence were analyzed by the Brief Medication Questionnaire. Results: 185 participants were enrolled. The medication adherence was 58.9%. Medication adherence was significantly superior in participants with elevated total serum immunoglobulin E (IgE) (χ2 = 8.371, p < 0.05), house dust mite (HDM) allergy to Dermatophagoides pteronyssinus (DP) type (χ2 = 5.149, p < 0.05) and severe TNSS at the first visit (χ2 = 37.016, p < 0.05). Adherence was twice more likely in DP allergy, 2.7 times more likely in elevated total IgE and 15 times more likely in severe TNSS at the first visit. Among the barriers to adherence was lack of symptoms, taking medication only when necessary, fear of adverse effects, running out of medication, experiencing bothersome effects, ineffective response, forgetfulness and taking too many medications. Only lack of symptoms, taking medication when symptomatic, fear of adverse effects and running out of medication were significant. No significant association was found between asthma/eczema (χ2 = 0.418, p > 0.05), HPT/DM (χ2 = 0.759, p > 0.05) and multi-medicine use (χ2 = 1.027, p > 0.05) with medication adherence. Conclusions: Patients having AR with severe nasal symptoms at first presentation, who are sensitized to DP HDM and who have elevated total serum IgE levels have a higher adherence to INCS use. The use of multiple medicines had no impact on the adherence to INCS. As a lack of symptoms was a barrier towards adherence, the benefits of using INCS according to the prescribed dose and frequency must be emphasized to patients with mild and moderate AR at each medical visit. A good rapport between patients and their health care providers is needed to build trust and overcome the barriers, particularly to allay the fears of adverse effects of INCS. The other barriers, such as running out of supply, can be overcome by posting medications directly to patients by the healthcare providers. Full article