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PubMed2006

Nonlinear relations between house dust mite allergen levels and mite sensitization in farm and nonfarm children.

BACKGROUND: Low sensitization rates to common allergens have been observed in farm children, which might be due to high exposure to microbial agents. It is not known how microbial agents modify the association between specific allergen exposure and sensitization. OBJECTIVE: To examine the relations between house dust mite allergen exposure and mite sensitization in farm and nonfarm children and to assess the effects of microbial agents levels on this association. METHODS: Major mite allergens of Dermatophagoides pteronyssinus (Der p 1) and Dermatophagoides farinae (Der f 1), endotoxin, beta(1,3)-glucans and fungal extracellular polysaccharides were measured in mattress dust of 402 children participating in a cross-sectional study in five European countries. Mite allergen (Der p 1 + Der f 1) levels were divided into tertiles with cut-offs 1.4 and 10.4 microg/g. Sensitization was assessed by measurement of allergen-specific immunoglobulin E against house dust mite. RESULTS: Prevalence ratios of mite sensitization for medium and high when compared with low mite allergen levels were 3.1 [1.7-5.7] and 1.4 [0.7-2.8] respectively. Highest mite sensitization rates at intermediate exposure levels were consistently observed across country (except for Sweden) and in both farm and nonfarm children. The shape of the dose-response curve was similar for above and below median mattress microbial agent levels, but the 'sensitization peak' appeared to be lower for above median levels. CONCLUSIONS: Our data suggest a bell-shaped dose-response relationship between mite allergen exposure and sensitization to mite allergens. In populations with high microbial agent levels and low sensitization rates, the curve is shifted down.

Adolescent↗
PubMed2006

Working towards healthy air in dwellings in Europe.

Poor indoor air quality has been implicated in the increase in allergic and respiratory diseases seen in industrialized countries in recent decades. Although air pollution in the workplace is well studied, much less is known about the consequences of poor air quality in homes. In an attempt to halt or slow down the increase in allergic and respiratory diseases, the European Federation of Allergy and Airways Diseases Patients Associations (EFA) carried out the EU-funded project entitled 'Towards Healthy Air in Dwellings in Europe' (THADE). The aims were to: compile an overview of evidence-based data about exposure to indoor air pollution and its health effects, particularly in relation to allergies, asthma and other respiratory diseases such as chronic obstructive pulmonary disease; review cost-effective measures and technology to improve indoor air quality; review legislation and guidelines on indoor air pollution; produce maps of pollutants in dwellings; and recommend an integrated strategy that defines appropriate indoor air quality policies for implementation in Europe. This paper summarizes the information about air quality in dwellings and indoor environment-related diseases collected by expert consultants within the framework of THADE and terminates with recommendations for actions aimed at improving air quality in homes. The results of this project confirmed that air pollution in dwellings is a relevant health problem. It is a complex problem that must be addressed at European and international levels, and it involves the medical profession, scientific societies, patients' organizations, lawmakers, architects and the building industry. The complete THADE report is available at http://www.efanet.org/activities/documents/THADEReport.pdf.

Air Pollutants↗
PubMed2005

HLA antigens in Greek children with allergic bronchial asthma.

The aim of our study was to investigate the genetic linkage between mite allergic bronchial asthma and HLA class I and II antigens and haplotypes. Sixty Greek children with allergic bronchial asthma due to mite sensitivity (Dermatophagoides pteronyssinus and Dermatophagoides farinae) and their family members were typed for HLA class I and II antigens (total 263 subjects). One hundred and twenty-five healthy, unrelated Greek children without medical history of atopy were also typed as control group. Major histocompatibility complex class I and II gene analysis revealed that only HLA-DRB1*04 and HLA-DQA1*0301 alleles are possibly important factors in the development of atopic asthma in Greek children with sensitivity to mites. No significant differences among the HLA-DRB1*04 subtypes have been established. Transmission disequilibrium test revealed that no specific HLA-A, -B, -DRB1, -DQA1 and -DQB1 alleles were transmitted preferentially to the affected children. HLA-DQB1*0301-4 alleles were associated with high levels of total serum immunoglobulin E in affected children. The study of the HLA haplotypes failed to demonstrate any significant association between any extended or natural selection haplotype and mite allergic bronchial asthma in Greek children.

Adolescent↗
PubMed2004

Aeroallergen sensitization in pediatric allergic rhinitis in Singapore: is air-conditioning a factor in the tropics?

Singapore is a unique blend of a tropical environment with a high standard of hygiene and public health care. The objective was to define the prevalence, clinical characteristics, and environmental risk factors of specific aeroallergen sensitization in pediatric allergic rhinitis patients in this unique environment. The method adopted was a retrospective analysis of allergic rhinitis patients, undergoing aeroallergen skin prick testing (SPT), in the outpatient specialty clinic of the KK Children's hospital, from July 2001 to June 2002. A total of 202 patients were included, 161 (80%) males, 167 (83%) Chinese, age mean 7.6 yr (range 2-14 yr). The most prevalent clinical symptoms were: watery rhinorrhea 61%, blocked nose 61%, sneezing 52%, snoring 17%, and epistaxis 12%. SPT results were positive for house dust mites in 97% of children, pets (20%), molds (19%), pollens (15%), and kapok (10%). Mold sensitization was significantly more prevalent in households without air-conditioning (aircon), 49% vs. 10% with aircon (odds ratio 9.4, 95% CI 3.8-22.9). Polysensitization (sensitization to three or more allergens) was similarly more prevalent in households without aircon, 51% vs. 14% with aircon (odds ratio 6.4, 95% CI 2.8-14.7). It was concluded that indoor aeroallergen sensitization is the major associated factor with clinical allergic rhinitis in children in Singapore. Patients living in households without air-conditioning are at increased risk of mold sensitization and polysensitization.

Adolescent↗
PubMed2004

Dermatophagoides-induced interleukin-10 production by peripheral blood lymphocytes from patients with asthma in remission.

Interleukin (IL)-10 is a cytokine that regulates inflammatory responses. We studied the role of IL-10 in the development of tolerance to Dermatophagoides farinae in asthma patients in remission, since asthma improves in most children during adolescence. The spontaneous production of IL-10 by cultured peripheral blood mononuclear cells (PBMC) was higher in patients with active asthma than in normal subjects. IL-10 production decreased when 1 microg/ml D. farinae was added to cultures, but increased again in a dose-dependent manner when higher concentrations of D. farinae were added. In patients with remission of asthma, IL-10 production was lower than in patients with active asthma. However, production of IL-10 showed a reciprocal increase in the presence of 1 microg/ml D. farinae, and decreased again at 10 and 50 microg/ml D. farinae. Such alterations were not observed in normal subjects. Cell lines established from patients asthma in remission showed higher IL-10 production when compared with that by cell lines from normal subjects or patients with active asthma when the cells were stimulated by D. farinae at 1 or 10 microg/ml. Neutralization of IL-10 led to revival of the D. farinae-specific proliferative response of PBMC from patients in remission, which was otherwise decreased. The increase of IL-10 production stimulated by D. farinae was inhibited by addition of an anti-IL-10 antibody. In contrast, antigen-induced interferon (IFN)-gamma production, which was increased by D. farinae stimulation when patients were in remission, did not increase after treatment with anti-IL-10, although spontaneous IFN-gamma production increased to the level seen after D. farinae stimulation. The reduced IL-4 production by cells from patients in remission after stimulation with D. farinae antigen, which was significantly higher in active patients, was not reversed by neutralization of IL-10. The D. farinae-induced IL-10/IL-4 production ratio, but not the IL-10/IL-5 production ratio, may be a significant indicator for evaluation of whether a patient has been in remission. In conclusion, D. farinae-specific anergy of T cells is likely to be induced by increased levels of IL-10 and IFN-gamma that are initially produced by specific T cells after exposure to relevant mite allergen in patients in remission.

Adolescent↗
PubMed2005

Building characteristics affect the risk of allergy development.

Damp dwellings increase the risk for house dust mite (HDM) infestation in temperate climate zones and may be associated with an increased risk for allergic disease. The aim of the study was to assess possible relationships between allergen levels in house dust, characteristics of residence buildings and allergic diseases in children. A subsample of 12-yr-old children, having the same address in 1991 and 1996, was selected from a population-based sample of children from the Göteborg area. Health inspectors examined the residences of all the 109 children and several different building characteristics including humidity and indoor temperature were collected. Dust samples for analysis of HDM allergens were collected from the children's beds, and for analysis of cat and dog allergens from the living room. Current health status was assessed by questionnaires, interviews and skin prick tests (SPT). Dog or cat allergens were found in all houses, even in houses without such animals. HDM allergens were found in 60% of the houses, but only six of them had levels exceeding 2 microg/g dust. There was a strong association between HDM-infestation and wheeze, but not with specific sensitization to HDM. The type of building (houses when compared with flats), the ventilation system and the presence of a basement had all major implications on respiratory symptoms, atopy and HDM infestation. We can conclude that dog or cat allergens were found in all houses, and a strong association between HDM infestation and indoor environment. Building construction affected both respiratory morbidity and sensitisation independently, suggesting not only worsening of symptoms but also a causative relationship with disease development.

Air Pollution, Indoor↗
PubMed2005

Prenatal exposure to mite and pet allergens and total serum IgE at birth in high-risk children.

To examine the relationship between prenatal exposure to mite, cat and dog allergens and total serum IgE at birth in newborns at high risk of asthma. In the homes of 221 newborns with at least one first-degree relative with asthma, concentrations (ng/g dust) of allergens of house dust mite (mite), cat and dog were measured at the fourth to sixth month of pregnancy in dust samples from the maternal mattress and living room. At day 3-5 after birth, total IgE was measured in capillary heel blood. A total number of 174 blood samples were available (11 mothers refused newborn's blood sampling, and in 36 cases the blood sample was too small for analysis). In 24% of the newborns, total IgE was elevated (cut-off value 0.5 IU/ml). A significant dose response relationship was found between increasing mite allergen levels [divided in quartiles ng/g dust (qrt)] and the percentage of elevated IgE: first qrt (0-85 ng/g) 13%; second qrt (86-381) 19%; third qrt (382-2371) 26%; fourth qrt (> or =2372) 42%, respectively, p=0.01. This relationship remained significant after adjusting for passive smoking, maternal and paternal mite allergy, socio-demographic factors, birth characteristics and (breast) feeding practice in the first week of life. In high-risk newborns, prenatal exposure to mite allergens, but not to cat and dog allergens from dust of the living room and of the maternal mattress was associated with total serum IgE at birth.

Allergens↗
PubMed2005

The primary prevention of asthma in children study: design of a multifaceted prevention program.

The PREVASC study addresses the primary prevention of asthma in infants and small children. The objective of this study is to investigate whether a multifaceted prenatally started intervention strategy in high-risk infants leads to a decrease in the occurrence of (severe) asthma and whether a refinement of the prevention strategy leads to an increase in the adherence to the prevention program. The primary prevention program includes house dust mite impermeable bed coverings, education on breast feeding, hypoallergenic feeding, timing of introduction of solid food and smoking cessation. A total of 888 infants were prenatally included. By the time of inclusion the mothers were 3-7 months pregnant. About 27 infants were excluded from the study and 18 dropped out. Of the remaining 843 infants 535 had a first-degree familial predisposition of asthma (high-risk group), whereas a reference group of 308 (162 boys) infants was not predisposed for asthma in the first-degree (low-risk group). To evaluate the (cost-)effectiveness of the preventive intervention, 222 (118 boys) infants of the high-risk group allocated to the intervention group and 221 (112 boys) allocated to a control group are followed up. The low-risk infants served as controls to evaluate the predictive value of high risk (first-degree familial predisposition of asthma). The infants are followed from the prenatal stage until they reach the age of 6 yr. The remaining 92 high-risk infants were included in an optimized randomized-clinical adherence trial (RCAT). Of these 92 infants, 45 (20 boys) were allocated to an intervention group and 47 (24 boys) to a control group. Until now all infants have been followed for at least 1 yr.

Allergens↗
PubMed2005

The efficacy and safety of heat-killed Lactobacillus paracasei for treatment of perennial allergic rhinitis induced by house-dust mite.

Live Lactobacillus paracasi 33 (LP33) may effectively improve the quality of life for patients with perennial allergic rhinitis. It has been demonstrated that heat-killed lactic acid bacteria (LAB) suppress specific immunoglobulin E synthesis and stimulate interleukin-12 production in animals. The aim of this study was, therefore, to evaluate the efficacy of heat-killed LP33 in the treatment of allergic rhinitis induced by house-dust-mite in human subjects. A total of 90 patients were enrolled in a randomized, double blind, placebo-controlled trial and assigned to three treatment groups. Patients in groups A and B received two capsules per day of live or heat-killed LAB (5 x 10(9) colony-forming units/capsule), respectively, over a period of 30 days while those in Group C received placebo capsules. A modified questionnaire on pediatric rhinoconjunctivitis-related quality of life was administered to all subjects or their parents during each clinical visit. The overall quality of life score decreased for groups A and B, as compared with the placebo group, in terms of both frequency (9.47 +/- 2.89, 6.30 +/- 2.19, vs. -3.47 +/- 1.53, respectively; p < 0.0001) and level of bother (5.91 +/- 3.21, 6.04 +/- 2.44, vs. -2.80 +/- 1.64, respectively; p = 0.004) after the 30-day treatment. The efficacy of the heat-killed LP33 was not inferior to the live variant. No obvious side effects were reported for either active treatment group during the study period. Our results suggest that heat-killed LP33 can effectively improve the overall quality of life for patients with allergic rhinitis, and that it may be efficacious as an alternative treatment.

Adolescent↗
PubMed2005

Three-year follow-up of clinical and inflammation parameters in children monosensitized to mites undergoing sub-lingual immunotherapy.

Parallel follow-up of clinical and inflammatory markers during sub-lingual immunotherapy (SLIT) is highly beneficial. Twenty-four children (age 4-16) monosensitized to house dust mite were randomized to receive either active or placebo SLIT for 1 yr in a double-blind placebo controlled design (Marcucci et al., Allergy 2003: 58: 657-62). Thereafter, for 2 yr they all received active treatment. Symptom scores for rhinitis, asthma, and drug usage were daily recorded. Eosinophil cationic protein (ECP) and tryptase in sputum and nasal secretions, serum and nasal mite-specific immunoglobulin E (IgE) were recorded before treatment and at 10-12 months intervals. Nasal ECP and nasal tryptase after specific nasal provocation tests were significantly reduced as compared to baseline values (p = 0.0043 and 0.0195, respectively) in the third year of active treatment. None of the other inflammatory parameters was increased. In placebo treated patients all these parameters tended to decrease only after switching to active treatment. Clinical scores did not improve in treated vs. placebo patients in the double-blind placebo-controlled phase of the study. In both cohorts a clinical benefit was observed as intra-group score reduction as compared to baseline. A significant difference was reached in patients treated for 2 yr for rhinitis and asthma (p = 0.0009 and 0.0019, respectively) but not for drug usage and in patients treated for 3 yr for rhinitis, asthma, and drug usage (p = 0.0105, 0.0048, and 0.02, respectively). SLIT in children monosensitized to mites reverted the spontaneous increase in nasal IgE and in local parameters of allergic inflammation. These outcomes were followed by a consolidated clinical improvement in the second and third year of treatment.

Administration, Sublingual↗
PubMed2006

Cytokine production, activation marker, and skin homing receptor in children with atopic dermatitis and bronchial asthma.

T cells are known to develop a critical role in the pathogenesis of atopic dermatitis (AD) and bronchial asthma. T cells involved in AD express the skin homing receptor CLA, but no lung homing receptor has been identified in bronchial asthma. We compared different cell markers and the cytokine production in T cells from children with AD or bronchial asthma. We studied the involvement of CLA+ and CLA- T-cell subpopulations in these diseases. We studied 20 children with acute AD lesions, 15 with mild persistent asthma, and 15 non-atopic controls. All patients were sensitized to house dust mite (DP) and evaluated during the acute phase. Total and specific IgE were measured by immunoassay and the expression of different cell markers and the cytokine production was analyzed by flow cytometry in peripheral blood mononuclear cells. Total IgE was significantly higher in AD children and IgE to DP in the asthmatic children. There was a significant increase in CD25+ CD4+ cells in asthmatic children and in HLA-DR+ CD4+ and HLA-DR+ CD8+ cells in AD. In the CD4+ subsets, there was an increase in IL-13, IL-5 and TNF-alpha in AD compared to controls, a decrease in IFN-gamma in asthmatic children compared to controls, and an increase in IL-13, IL5, IL2, TNF-alpha, and IFN-gamma in the AD compared to asthmatic children. Changes in cytokine production were mainly detected in CLA+ cells in AD and in CLA- cells in asthma. Differences exist in total and specific IgE, activation markers, and cytokine patterns between AD children and children with asthma, with the former expressing a Th2 pattern whereas in asthmatic children we only detected a decrease in IFN-gamma. Moreover, the subpopulations (CLA+ vs. CLA-) expressing these changes were different, indicating that the underlying mechanisms in the two diseases are not exactly the same.

Adolescent↗
PubMed2006

Skin test reactivity to molds in pre-school children with newly diagnosed asthma.

BACKGROUND: The aim of the present study was to evaluate the prevalence of sensitization to molds and to house dust mites (HDM) in pre-school children with newly-diagnosed asthma. METHODS: From 1996 to 2000, 122 children 1 to 6 years of age with fresh asthma treated in the Kuopio University Hospital, Kuopio, Finland, were recruited in the study; 94% attended. Skin prick tests were performed to common inhalant allergens and to 10 molds. The homes were surveyed for moisture damage. RESULTS: A majority of the houses had signs of dampness and moisture. One-third of the children reacted to inhalant allergens. There were 11 positive reactions to molds in five children who all reacted to at least one animal dander or seasonal pollen. Aspergillus fumigatus, Botrytis cinerea, and Cladosporium herbarum were the most common mold allergens. There were only two children with positive reactions to HDM, and none of them reacted to molds. No associations were found between the presence or degree of moisture problems at home and mold or HDM allergy. CONCLUSION: Sensitization to molds seems to play only a minor role in pre-school children with newly-diagnosed asthma in a northern climate where the incidences of mold and HDM allergies are rather low.

Age Factors↗
PubMed2007

Suspension-cultured BY-2 tobacco cells produce and mature immunologically active house dust mite allergens.

The replacement of crude allergen extracts by selected allergens currently represents a major goal for the improvement of allergy diagnosis and immunotherapy. Indeed, the development of molecularly defined vaccines would facilitate both standardization and enhance batch-to-batch reproducibility as well as treatment specificity. In this study, we have investigated the potential of tobacco plant cells to produce biologically active forms of the two major allergens from the house dust mite. A detailed characterization of these plant-made allergens has shown similar proteolytic maturation and folding as well as comparable immunoreactivity to their natural counterparts. Altogether, our results exemplify that suspension-cultured BY-2 tobacco cells represent a low cost and environmentally safe expression system suitable to produce recombinant allergens from Dermatophagoides pteronyssinus under a form appropriate for diagnostic and therapeutic purposes.

Allergens↗
PubMed2007

Staphylococcus aureus-derived enterotoxins enhance house dust mite-induced patch test reactions in atopic dermatitis.

BACKGROUND: Up to 65% of Staphylococcus aureus strains isolated from the skin of patients with atopic dermatitis (AD) produce exotoxins with superantigenic properties that may also act as allergens leading to an induction of exotoxin-specific IgE antibodies. Staphylococcal enterotoxin B (SEB) applied epicutaneously in a concentration of 10 micro g/cm(2), i.e. 200 micro g/ml, under occlusion induces cutaneous inflammation in patients with AD and healthy individuals. METHODS: We performed patch tests in 32 adult patients with AD using different concentrations (i.e. 2-200 micro g/ml) of SEA, SEB and house dust mite (HDM) extract (500 micro g/ml). Furthermore, the respective enterotoxins and HDM extract were applied simultaneously to the same patch test site. Specific IgE levels to SEA, SEB and HDM were measured with the CAP FEIA. RESULTS: The rates of patch test reactions to SEA and SEB increased with rising enterotoxin concentrations. There were no differences in the rates of patch test reactions to SEA and SEB between patients sensitized to the corresponding enterotoxin and non-IgE-sensitized patients. The number of patch test reactions to the mixture of enterotoxin and HDM extract was higher than the number of patch test reactions to either the enterotoxins or HDM extract. We identified 11 patients with AD who reacted neither to the enterotoxins nor to HDM extract, but who showed patch test reactions to the mixture. These reactions were not predicted by the presence of enterotoxin- or HDM-specific IgE. CONCLUSIONS: Colonization with exotoxin-producing S. aureus may influence the outcome of patch tests in patients with AD.

Adolescent↗
PubMed2005

Allergens and endotoxin in settled dust from day-care centers and schools in Oslo, Norway.

UNLABELLED: Allergy to indoor allergens can cause frequent and severe health problems in children. Because little is known about the content of allergens in the indoor environments in Norway, we wanted to assess the levels of cat, dog and mite allergens in schools and day-care centers in Oslo. Allergen levels in dust samples from 155 classrooms and 81 day-care units were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Additionally, we measured the levels of endotoxin in 31 day-care units, using the limulus amebocyte lysate test. Most of the dust samples contained detectable amounts of cat and dog allergens. In mattress and floor dust (day-care centers), and curtain and floor dust (schools) the median Fel d 1 levels were 0.17, 0.002, 0.02 and 0.079 microg/m2, while the median Can f 1 levels were 1.7, 0.03, 0.1 and 0.69 microg/m2, respectively. Levels of cat and dog allergens in school floor dust were associated with the number of pupils with animals at home. In contrast, <1% of the samples had measurable levels of the mite allergen Der p 1. Moreover, the levels of endotoxin tended to be higher in dust from floors (1.4 ng/m2) compared with that from mattresses (0.9 ng/m2). PRACTICAL IMPLICATIONS: To reduce allergen exposure, allergic individuals should be placed in the classes/rooms with the fewest pet owners. Moreover, mattresses in day-care centers are major reservoirs of cat and dog allergens and should be cleaned frequently.

Air Pollution, Indoor↗
PubMed2006

Allergens in school settings: results of environmental assessments in 3 city school systems.

Environmental allergens are major triggers for pediatric asthma. While children's greatest exposure to indoor allergens is in the home, other public places where children spend a large amount of time, such as school and day care centers, may also be sources of significant allergen encounters. The purpose of this article is to describe schoolroom allergen levels from 3 different geographic sites obtained from dust samples collected in the fall and in spring. Environmental dust samples were collected from elementary schools in Birmingham (AL), Detroit (MI), and Houston (TX), from 4 room locations, including the cafeteria, library, upper grades, and lower grades. Samples were assayed for dust mite (Dermatophagoides pteronyssinus and Dermatophagoides farinae), cat (Felis domesticus), and cockroach (Blatella germanica 2) allergen levels. Allergen levels varied by geographic location and type of schoolroom. Schoolroom settings differed by the type of flooring (hard and carpet), room characteristics and use (food service, library shelves with books, and general classroom with multiple types of materials [individual desks and different types of furniture]), and the average age of the schoolroom dwellers (younger vs. older children). Dust mite, cat, and cockroach allergens were present in all schoolrooms and all sites at varying levels by season and by type of room. Schools may be important sources of direct allergen exposure and reservoirs that could potentially contribute to allergic sensitization and disease exacerbation in children. Further studies are needed to carefully examine the environmental allergen load in schools and its effect on children.

Air Pollutants↗
PubMed2006

Total serum IgE and IgE antibodies specific to house dust mite found in two aged-matched cohorts of children with and without otitis media with effusion.

OBJECTIVES: To determine whether otitis media with effusion (OME) is associated with elevated serum immunoglobulin E (IgE) and IgE specific for house dust mite. DESIGN: Forty-seven children who had evidence of bilateral OME, both otoscopically and on tympanometry, on two separate occasions, 3 months apart were admitted for ventilation tubes. Forty-eight children admitted for minor eye surgery who had otoscopically normal ears and no history of middle ear problems were used as controls. Bloods samples were taken under anaesthesia. Total IgE and IgE radioallergosorbent test (RAST) to house dust mite was measured by the Pharmacia Unicap 100 system. The results from the two groups were compared. SETTING: Birmingham Children's Hospital. PARTICIPANTS: Children between the ages of 3 and 10. Children with Down's syndrome, cleft lip and palate, ciliary abnormalities, known immunodeficiencies and cardiac abnormalities were excluded. MAIN OUTCOME MEASURES: Total IgE and RAST to house dust mite. A RAST of >0.35 was taken to be positive. RESULTS: There was no statistical difference between the control and study groups for the total IgE. Six children from both study and control groups had a raised house dust mite RAST. There was no difference in the levels between either group. CONCLUSIONS: Our findings indicate that there is no direct relationship between OME and biochemical evidence of allergy, specifically to house dust mite.

Allergens↗