Transcriptome analysis of adenomyosis eutopic endometrium reveals molecular mechanisms involved in adenomyosis-related implantation failure and pregnancy disorders.

BACKGROUND: Women with adenomyosis are characterized by having defective decidualization, impaired endometrial receptivity and/or embryo-maternal communication, and implantation failure. However, the molecular mechanisms underlying adenomyosis-related infertility remain unknown, mainly because of the restricted accessibility and the difficult preservation of endometrial tissue in vitro. We have recently shown that adenomyosis patient-derived endometrial organoids, maintain disease-specific features while differentiated into mid-secretory and gestational endometrial phase, overcoming these research barriers and providing a robust platform to study adenomyosis pathogenesis and the associated molecular dysregulation related to implantation and pregnancy disorders. For this reason, we aim to characterize the dysregulated mechanisms in the mid-secretory and gestational endometrium of patients with adenomyosis by RNA-sequencing. METHODS: Endometrial organoids were derived from endometrial biopsies collected in the proliferative phase of women with adenomyosis (ADENO) or healthy oocyte donors (CONTROL) (n = 15/group) and differentiated into mid-secretory (-SECorg) and gestational (-GESTorg) phases in vitro. Following RNA-sequencing, the significantly differentially expressed genes (DEGs) (FDR < 0.05) were identified and selected for subsequent functional enrichment analysis and QIAGEN Ingenuity Pathway Analysis (IPA). Statistical differences in gene expression were evaluated with the Student's t-test or Wilcoxon test. RESULTS: We identified 1,430 DEGs in ADENO-SECorg and 1,999 DEGs in ADENO-GESTorg. In ADENO-SECorg, upregulated genes included OLFM1, FXYD5, and RUNX2, which are involved in impaired endometrial receptivity and implantation failure, while downregulated genes included RRM2, SOSTDC1, and CHAC2 implicated in recurrent implantation failure. In ADENO-GESTorg, upregulated CXCL14 and CYP24A1 and downregulated PGR were related to pregnancy loss. IPA predicted a significant inhibition of ID1 signaling, histamine degradation, and activation of HMGB1 and Senescence pathways, which are related to implantation failure. Alternatively, IPA predicted an inhibition of D-myo-inositol biosynthesis and VEGF signaling, and upregulation of Rho pathway, which are related to pregnancy loss and preeclampsia. CONCLUSIONS: Identifying dysregulated molecular mechanisms in mid-secretory and gestational endometrium of adenomyosis women contributes to the understanding of adenomyosis-related implantation failure and/or pregnancy disorders revealing potential therapeutic targets. Following experimental validation of our transcriptomic and in silico findings, our differentiated adenomyosis patient-derived organoids have the potential to provide a reliable platform for drug discovery, development, and personalized drug screening for affected patients.

Evaluation of the Cytokine Response Induced by Specific Allergen Immunotherapy in Patients with Vespa velutina Anaphylaxis.

INTRODUCTION: Changes in the cytokine profile from type 2 to type 1 together with the induction of regulatory cells are expected during hymenoptera venom immunotherapy (VIT). The present study was aimed to investigate the changes in type 1, type 2, and regulatory cytokines induced by a Vespula spp. VIT in patients with anaphylaxis to Vespa velutina. METHODS: Twenty consecutive patients with anaphylaxis due to Vespa velutina were treated with Vespula spp. VIT. Serum cytokines (IL-4, IL-5, IL-10, IL-13, and IFN-É£) were measured at baseline, 6, and 12 months after starting VIT. RESULTS: A significant increase in serum IFN-y was detected after 6 and 12 months of VIT. An increase in serum IL-10 and a decrease in IL-5 were observed after 12 months. IL-4 was undetectable all along the study, and an unexpected increase of IL-13 was present at 12 months of treatment. CONCLUSION: Vespula spp. VIT seems to be able to induce a shift to type 1 cytokine production measured through IFN-y levels and IL-10 production after, at least, 6 and 12 months of VIT, respectively.

Peeking into the Stingers: A Comprehensive SWATH-MS Study of the European Hornet Vespa crabro (Linnaeus, 1758) (Hymenoptera: Vespidae) Venom Sac Extracts.

This study aimed to investigate the venom sac extracts (VSEs) of the European hornet (EH) Vespa crabro (Linnaeus, 1758) (Hymenoptera: Vespidae), focusing on the differences between stinging females, gynes (G), and workers (W), at the protein level. Using a quantitative "Sequential Window Acquisition of all Theoretical Fragment Ion Mass Spectra" (SWATH-MS) analysis, we identified and quantified a total of 240 proteins. Notably, within the group, 45.8% (n = 110) showed significant differential expression between VSE-G and VSE-W. In this set, 57.3% (n = 63) were upregulated and 42.7% (n = 47) downregulated in the G. Additionally, the two-hundred quantified proteins from the class Insecta belong to sixteen different species, six of them to the Hymenoptera/Apidae lineage, comprising seven proteins with known potential allergenicity. Thus, phospholipase A1 (Vesp v 1), phospholipase A1 verutoxin 2b (VT-2b), hyaluronidase A (Vesp v 2A), hyaluronidase B (Vesp v 2B), and venom allergen 5 (Vesp v 5) were significantly downregulated in the G, and vitellogenin (Vesp v 6) was upregulated. Overall, 46% of the VSE proteins showed differential expression, with a majority being upregulated in G. Data are available via ProteomeXchange with identifier PXD047955. These findings shed light on the proteomic differences in VSE between EH castes, potentially contributing to our understanding of their behavior and offering insights for allergy research.

RNA viruses alter house dust mite physiology and allergen production with no detected consequences for allergenicity.

RNA viruses have recently been detected in association with house dust mites, including laboratory cultures, dust samples, and mite-derived pharmaceuticals used for allergy diagnosis. This study aimed to assess the incidence of viral infection on Dermatophagoides pteronyssinus physiology and on the allergenic performance of extracts derived from its culture. Transcriptional changes between genetically identical control and virus-infected mite colonies were analysed by RNAseq with the support of a new D. pteronyssinus high-quality annotated genome (56.8 Mb, 108 scaffolds, N50 = 2.73 Mb, 96.7% BUSCO-completeness). Extracts of cultures and bodies from both colonies were compared by inspecting major allergen accumulation by enzyme-linked immunosorbent assay (ELISA), allergen-related enzymatic activities by specific assays, airway inflammation in a mouse model of allergic asthma, and binding to allergic patient's sera IgE by ImmunoCAP. Viral infection induced a significant transcriptional response, including several immunity and stress-response genes, and affected the expression of seven allergens, putative isoallergens and allergen orthologs. Major allergens were unaffected except for Der p 23 that was upregulated, increasing ELISA titers up to 29% in infected-mite extracts. By contrast, serine protease allergens Der p 3, 6 and 9 were downregulated, being trypsin and chymotrypsin enzymatic activities reduced up to 21% in extracts. None of the parameters analysed in our mouse model, nor binding to human IgE were significantly different when comparing control and infected-mite extracts. Despite the described physiological impact of viral infection on the mites, no significant consequences for the allergenicity of derived extracts or their practical use in allergy diagnosis have been detected.

Medroxyprogesterone acetate: an alternative to GnRH-antagonist in oocyte vitrification for social fertility preservation and preimplantation genetic testing for aneuploidy.

RESEARCH QUESTION: Can medroxyprogesterone acetate (MPA) be used as a pituitary suppressor instead of a gonadotrophin releasing hormone (GnRH) antagonist during ovarian stimulation in elective fertility preservation and preimplantation genetic testing for aneuploidy (PGT-A) cycles? DESIGN: A multicentre, retrospective, observational, cohort study conducted in 11 IVIRMA centres affiliated to private universities. Of a total of 1652 cycles of social fertility preservation, 267 patients were stimulated using a progestin-primed ovarian stimulation protocol (PPOS), and 1385 patients received a GnRH antagonist. In the PGT-A cycles, 5661 treatments were analysed: 635 patients received MPA and 5026 patients received GnRH antagonist. A further 66 fertility preservation and 1299 PGT-A cycles were cancelled. All cycles took place between June 2019 and December 2021. RESULTS: In the social fertility preservation cycles, the number of mature oocytes vitrified in MPA was similar to the number of those treated with an antagonist, a trend that was seen regardless of age (≤35 or >35 years). In the PGT-A cycles, no differences were found in number of metaphase II, two pronuclei, number of biopsied embryos (4.4 ± 3.1 versus 4.5 ± 3.1), rate of euploidy (57.9% versus 56.4%) or ongoing pregnancy rate (50.4% versus 47.1%, P = 0.119) between the group receiving MPA versus a GnRH antagonist, whereas the clinical miscarriage rate was higher in the antagonist group (10.4% versus 14.8%, P = 0.019). CONCLUSIONS: Administration of PPOS yields similar results to GnRH antagonists in oocytes retrieved, rate of euploid embryos and clinical outcome. Hence, PPOS can be recommended for ovarian stimulation in social fertility preservation and PGT-A cycles, as it allows greater patient comfort.

Extracellular vesicles secreted by adenomyosis endometrial organoids contain miRNAs involved in embryo implantation and pregnancy.

RESEARCH QUESTION: Do extracellular vesicles secreted by the endometrium of women with adenomyosis contain miRNAs involved in adenomyosis-related infertility? DESIGN: A descriptive study using organoids from eutopic endometrium of women with adenomyosis (n = 4) generated and differentiated to secretory and gestational phases, in which miRNA cargo from extracellular vesicles secreted by these differentiated organoids in each phase was analysed by next-generation sequencing. miRNAs in secretory-extracellular vesicles and gestational-extracellular vesicles were selected based on the counts per million. miRNAs target genes in each phase were obtained from miRNet and gene ontology was used for enrichment analysis. RESULTS: miRNA sequencing identified 80 miRNAs in secretory-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-24-3p, hsa-miR-26a-5p, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-200c-3p and hsa-miR-423a-5p, related to adenomyosis pathogenesis and implantation failure. Further, 60 miRNAs were identified in gestational-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-26a-5p, hsa-miR-30a-5p, hsa-miR-30c-5p, hsa-miR-222-3p and hsa-miR-423a-5p were associated with preeclampsia and miscarriage. Among the target genes of these miRNAs, PTEN, MDM4, PLAGL2 and CELF1, whose downregulation (P = 0.0003, P < 0.0001, P = 0.0002 and P = 0.0003, respectively) contributes to adenomyosis pathogenesis, and impaired early embryo development, leading to implantation failure and miscarriage, are highlihghted. Further, functional enrichment analyses of the target genes revealed their involvement in cell differentiation, proliferation, apoptosis, cell cycle regulation and response to extracellular stimuli. CONCLUSIONS: Eutopic endometrium in secretory and gestational phase from women with adenomyosis releases extracellular vesicles containing miRNAs involved in adenomyosis progression, impaired embryo implantation and pregnancy complications.

Association of blood cadmium and lead levels with self-reported reproductive lifespan and pregnancy loss: The national health and nutrition examination survey 1999-2018.

Cadmium and lead are known to interfere with the endocrine function. Thus, hormonally regulated processes such as menarche, menopause and pregnancy are likely influenced by chronic exposure to these metals. In US post-menopausal women, who already completed their reproductive lifespan, we evaluated the association between blood cadmium and lead levels with self-reported reproductive lifespan and personal history of pregnancy loss. We selected 5317 post-menopausal women participating in the National Health and Nutrition Examination Survey (NHANES), 1999-2018. Blood cadmium and lead levels were measured by inductively coupled plasma mass spectrometry. Reproductive lifespan was defined as the number of years between self-reported age at menarche and menopause. Personal history of pregnancy loss was defined as number of self-reported pregnancy losses out of the self-reported number of pregnancies. The fully adjusted mean difference in reproductive lifespan (95% confidence interval [CI]) comparing the 80th to the 20th percentiles of blood cadmium and lead distributions was, respectively, 0.50 (0.10, 0.91) and 0.72 (0.41, 1.03) years. Ever smoker showed stronger association of blood lead with reproductive lifespan. For self-reported pregnancy loss, the corresponding fully adjusted relative prevalence (95% CI) was 1.10 (0.93, 1.31) for cadmium and 1.10 (1.00, 1.21) for lead, and remained similar after additional adjustment for reproductive lifespan. In never smokers, the relative prevalence was 1.07 (1.04, 1.11) and 1.16 (1.05, 1.28) for blood cadmium and lead, respectively. These findings suggest that blood cadmium and lead exposures increase reproductive lifespan and prevalence of pregnancy loss in the general population. Additional studies are needed to improve the understanding of mechanisms and prevention potential of metals-related pregnancy outcomes.

Differences in breast cancer-risk factors between screen-detected and non-screen-detected cases (MCC-Spain study).

PURPOSE: The variation in breast cancer (BC)-risk factor associations between screen-detected (SD) and non-screen-detected (NSD) tumors has been poorly studied, despite the interest of this aspect in risk assessment and prevention. This study analyzes the differences in breast cancer-risk factor associations according to detection method and tumor phenotype in Spanish women aged between 50 and 69. METHODS: We examined 900 BC cases and 896 controls aged between 50 and 69, recruited in the multicase-control MCC-Spain study. With regard to the cases, 460 were detected by screening mammography, whereas 144 were diagnosed by other means. By tumor phenotype, 591 were HR+, 153 were HER2+, and 58 were TN. Lifestyle, reproductive factors, family history of BC, and tumor characteristics were analyzed. Logistic regression models were used to compare cases vs. controls and SD vs. NSD cases. Multinomial regression models (controls used as a reference) were adjusted for case analysis according to phenotype and detection method. RESULTS: TN was associated with a lower risk of SD BC (OR 0.30 IC 0.10-0.89), as were intermediate (OR 0.18 IC 0.07-0.44) and advanced stages at diagnosis (OR 0.11 IC 0.03-0.34). Nulliparity in postmenopausal women and age at menopause were related to an increased risk of SD BC (OR 1.60 IC 1.08-2.36; OR 1.48 IC 1.09-2.00, respectively). Nulliparity in postmenopausal women was associated with a higher risk of HR+ (OR 1.66 IC 1.15-2.40). Age at menopause was related to a greater risk of HR+ (OR 1.60 IC 1.22-2.11) and HER2+ (OR 1.59 IC 1.03-2.45) tumors. CONCLUSION: Reproductive risk factors are associated with SD BC, as are HR+ tumors. Differences in BC-risk factor associations according to detection method may be related to prevailing phenotypes among categories.

The Asian wasp Vespa velutina nigrithorax: Entomological and allergological characteristics.

The yellow-legged or Asian wasp (Vespa velutina nigrithorax) has spread rapidly across Europe since its first introduction in France, in 2004. Originally from South-East Asia, it is considered an invasive species outside its native region. Apart from the ecological and economic implications of its presence, it may cause health problems to humans due to the toxic and allergenic components of its venom. Vespa velutina nigrithorax has become the most prevalent cause of anaphylaxis due to Hymenoptera venom in some regions of Spain. Although sIgE against both antigen 5 (Vesp v 5) and A1-phospholipase (Vesp v 1) has been detected in these patients, only Vesp v 5 may be considered a dominant allergen. Interestingly, Vesp v 1 appears to be a glycosylated allergen different from A1-phospholipases from other species. Inhibition studies suggest that Vespula spp venom could behave as primary sensitizer. Besides, changes in sIgE and sIgG4 during Vespula venom immunotherapy in patients with anaphylaxis due to V. velutina support the use of Vespula venom extracts to treat these patients. The purpose of this review is to explore the biological behaviour of V. velutina and to summarize the current knowledge of the allergic reactions provoked by this wasp.

Mammographic features of benign breast lesions and risk of subsequent breast cancer in women attending breast cancer screening.

OBJECTIVES: To evaluate the mammographic features in women with benign breast disease (BBD) and the risk of subsequent breast cancer according to their mammographic findings. METHODS: We analyzed data from a Spanish cohort of women screened from 1995 to 2015 and followed up until December 2017 (median follow-up, 5.9 years). We included 10,650 women who had both histologically confirmed BBD and mammographic findings. We evaluated proliferative and nonproliferative BBD subtypes, and their mammographic features: architectural distortion, asymmetries, calcifications, masses, and multiple findings. The adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for breast cancer were estimated using a Cox proportional hazards model. We plotted the adjusted cumulative incidence curves. RESULTS: Calcifications were more frequent in proliferative disease with atypia (43.9%) than without atypia (36.8%) or nonproliferative disease (22.2%; p value < 0.05). Masses were more frequent in nonproliferative lesions (59.1%) than in proliferative lesions without atypia (35.1%) or with atypia (30.0%; p value < 0.05). Multiple findings and architectural distortion were more likely in proliferative disease (16.1% and 4.7%) than in nonproliferative disease (12.8% and 1.9%). Subsequent breast cancer occurred in 268 (2.5%) women. Compared with women who had masses, the highest risk of subsequent breast cancer was found in those with architectural distortions (aHR, 2.21; 95% CI, 1.16-4.22), followed by those with multiple findings (aHR, 1.89; 95% CI, 1.34-2.66), asymmetries (aHR, 1.66; 95% CI, 0.84-3.28), and calcifications (aHR, 1.60; 95% CI, 1.21-2.12). CONCLUSION: BBD subtypes showed distinct mammographic findings. The risk of subsequent breast cancer was high in those who have shown architectural distortion, multiple findings, asymmetries, and calcifications than in women with masses. KEY POINTS: • The presence of mammographic findings in women attending breast cancer screening helps clinicians to assess women with benign breast disease (BBD). • Calcifications were frequent in BBDs with atypia, which are the ones with a high breast cancer risk, while masses were common in low-risk BBDs. • The excess risk of subsequent breast cancer in women with BBD was higher in those who showed architectural distortion compared to those with masses.

Short-term impact of the COVID-19 pandemic on a population-based screening program for colorectal cancer in Catalonia (Spain).

The COVID-19 pandemic caused the suspension at all levels of the Catalan FIT-based CRC screening program on March 12, 2020. Screening invitations to FIT were resumed on September 1, 2020. We aimed to assess the short-term impact of the pandemic and describe strategies implemented to minimize harm by the disruption of the FIT-based CRC screening in the Metropolitan Area of Barcelona. We analyzed participation rate, colonoscopy adherence, time intervals to colonoscopy, detection rates, and advanced-stage cancers in 2019 and 2020. To identify perceived distress levels during the suspension of the screening we conducted a phone interview. As a result of the suspension, 43% of the individuals due for screening did not receive their invitation by December 31, 2020. A percent decrease of 5.1% in participation and of 8.9% in colonoscopy adherence among invitees between January-March was observed, with a recovery to 2019 levels when the screening activities were restarted. The time interval between a positive test to colonoscopy was longer in 2020 than in 2019. A decrease in advanced neoplasia rate and an increase in later stages of CRC were also observed. Individuals with a positive test did not report higher levels of perceived distress compared to those with a negative test. Although the disruption of screening had a temporary impact on participation and colonoscopy adherence, timing delay continues and a large backlog in the invitation of the target population remains. Thus, it is critical to implement strategies to minimize the long-term effects.

A 300 IR sublingual tablet is an effective, safe treatment for house dust mite-induced allergic rhinitis: An international, double-blind, placebo-controlled, randomized phase III clinical trial.

BACKGROUND: Allergic rhinitis induced by house dust mites (HDMs) is a highly prevalent but often underdiagnosed and undertreated/untreated chronic disease. It often has a negative impact on sleep, work, leisure activities, and health-related quality of life. Allergen immunotherapy is a proven, safe treatment for respiratory allergies. OBJECTIVE: We sought to assess the efficacy and safety of a 300 index of reactivity (IR) sublingual tablet formulation of Dermatophagoides pteronyssinus:Dermatophagoides farinae 1:1 extract in adolescents (aged ≥12) and adults with moderate to severe HDM-induced allergic rhinitis. METHODS: In a phase III, international, double-blind, placebo-controlled, randomized clinical trial, participants received approximately 12 months of treatment with placebo or the 300 IR tablet. The primary end point was the average total combined score during 4 weeks at the end of the treatment period. RESULTS: A total of 1607 participants were randomized, and 1476 (including 555 [37.6%] with concomitant mild controlled asthma at inclusion) comprised the full analysis set. Over the primary evaluation period, the least squares mean average total combined score in the 300 IR group (3.62) was significantly lower (P < .0001) than in the placebo group (4.35), with a relative least squares mean difference of -16.9% (95% CI, -24.0% to -9.2%). All prespecified secondary end points were consistently improved in the 300 IR group, relative to placebo. The 300 IR tablet was generally well tolerated. Treatment-related adverse events (mainly mild or moderate local reactions) were reported for 51.0% of the patients in the 300 IR group and 14.9% in the placebo group. CONCLUSIONS: The 300 IR sublingual HDM tablet is an effective, safe treatment for HDM-induced allergic rhinitis.

RNA viruses in the house dust mite Dermatophagoides pteronyssinus, detection in environmental samples and in commercial allergen extracts used for in vivo diagnosis.

BACKGROUND: Allergy to house dust mites (HDM), the most important source of indoor allergens worldwide, is diagnosed and treated using natural extracts from cultures that can contain immunoactive components from the HDM microbiome, including mite-infecting viruses. This study aimed to contribute to the discovery and characterization of RNA viruses from Dermatophagoides pteronyssinus, followed by their detection in different mite-derived sources. METHODS: Viruses were assembled after in silico metatranscriptomic analysis of D. pteronyssinus RNA samples, visualized by electron microscopy, and RNA detected by direct RT-PCR or data mining. Mite culture performance was evaluated in vivo. RESULTS: Seven RNA viruses were identified in our laboratory stock colony. Picornavirus-like viral particles were detected in epithelial cells of the digestive system and in fecal pellets. Most of these viruses could be persistently transmitted to an inbred virus-free colony by inoculating fecal material from the stock colony. Upon viral infection, no significant effect could be seen on mite population growth. Transcriptomic screening confirmed the presence of homolog sequences to these viruses in independent laboratory stocks of D. pteronyssinus and in other Astigmata mites. Noteworthy, RNA from most of the viruses could be detected by RT-PCR on house dust samples, reference standards, and/or commercial diagnostic D. pteronyssinus extracts. CONCLUSIONS: Our results show that viral infections are common and widespread in D. pteronyssinus, both in natural and culture-based growth conditions. Potential effects on the mites themselves and consequences toward allergenicity in humans whether exposed naturally or after immunotherapy are discussed.

Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper.

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.

Personalized medicine for allergy treatment: Allergen immunotherapy still a unique and unmatched model.

The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.

Factors Influencing Total Serum IgE in Adults: The Role of Obesity and Related Metabolic Disorders.

BACKGROUND AND AIM: Few reports have investigated the association between metabolic abnormalities (obesity and related metabolic syndrome) and total serum IgE concentrations. METHODS: This cross-sectional study included a random sample of 1,516 adult individuals (44.7% men, aged 18-91 years, median 52 years) from a single municipality in Spain. Serum IgE was measured in the ADVIA Centaur system. Atopy was defined by the presence of positive skin prick tests to a panel of common aeroallergens in the area. Body mass index and data related to the definition of metabolic syndrome were obtained from all participants. Alcohol consumption, smoking, and regular physical exercise were assessed by a questionnaire. RESULTS: Atopy (present in 21.9% of 1,514 evaluable individuals) was the strongest factor determining serum IgE concentrations. Male sex and heavy alcohol drinking were independently associated with higher IgE concentrations, particularly in the non-atopic individuals. Body mass index was positively associated with IgE concentrations, independent of potential confounders, although the effect was only evident among non-atopic individuals. In that group, median IgE concentrations in normal-weight and obese individuals were 15 and 24 kU/L, respectively (p < 0.001); likewise, obesity was associated with high (>100 kU/L) IgE concentrations after adjusting for potential confounders (odds ratio: 1.79, 95% confidence interval: 1.26-2.56, p = 0.001). The presence of metabolic syndrome and its components, particularly abdominal obesity and hyperglycaemia, was also positively and independently associated with higher IgE concentrations in non-atopic individuals. CONCLUSIONS: Obesity and metabolic syndrome components are associated with high total serum IgE concentrations, particularly in non-atopic individuals.

Breast density, benign breast disease, and risk of breast cancer over time.

OBJECTIVES: Assessing the combined effect of mammographic density and benign breast disease is of utmost importance to design personalized screening strategies. METHODS: We analyzed individual-level data from 294,943 women aged 50-69 years with at least one mammographic screening participation in any of four areas of the Spanish Breast Cancer Screening Program from 1995 to 2015, and followed up until 2017. We used partly conditional Cox models to assess the association between benign breast disease, breast density, and the risk of breast cancer. RESULTS: During a median follow-up of 8.0 years, 3697 (1.25%) women had a breast cancer diagnosis and 5941 (2.01%) had a benign breast disease. More than half of screened women had scattered fibroglandular density (55.0%). The risk of breast cancer independently increased with the presence of benign breast disease and with the increase in breast density (p for interaction = 0.84). Women with benign breast disease and extremely dense breasts had a threefold elevated risk of breast cancer compared with those with scattered fibroglandular density and without benign breast disease (hazard ratio [HR] = 3.07; 95%CI = 2.01-4.68). Heterogeneous density and benign breast disease was associated with nearly a 2.5 elevated risk (HR = 2.48; 95%CI = 1.66-3.70). Those with extremely dense breast without a benign breast disease had a 2.27 increased risk (95%CI = 2.07-2.49). CONCLUSIONS: Women with benign breast disease had an elevated risk for over 15 years independently of their breast density category. Women with benign breast disease and dense breasts are at high risk for future breast cancer. KEY POINTS: • Benign breast disease and breast density were independently associated with breast cancer. • Women with benign breast disease had an elevated risk for up to 15 years independently of their mammographic density category.

Role of community pharmacies in a population-based colorectal cancer screening program.

In Catalonia (Spain), population-based colorectal cancer (CRC) screening offers biennial fecal occult blood testing to men and women aged 50-69 years old. The program is organized in screening hubs, most of which use a pharmacy-based model to distribute and collect fecal immunochemical test (FIT) kits The comprehensive evaluation of CRC screening programs, which include the role and implications of pharmacy involvement, is essential to ensure program quality and identify areas for further improvement. The present study aimed to assess the adherence of community pharmacies to the CRC screening program and to analyze data on FIT kit distribution and collection in the Metropolitan area of Barcelona (Catalonia, Spain). Time to FIT completion was assessed by Kaplan-Meier estimation, and with the log-rank test. A Cox regression model was used to adjust for other variables associated with the completion of FIT such as sex, age, deprivation score index and previous screening behavior. Overall, 82.4% of pharmacies adhered with CRC screening program. Out of 82,902 FIT kits distributed to screening invitees 77,524 completed FIT kits were returned to pharmacies (93.5%) with a participation of 39.8% among the 193,766 invitees. From those who completed a FIT, the median time to return the kit was 3 days. FIT completion time was significantly lower among women, older age, high deprivation score index and previous CRC screening (p < 0.005). Our findings highlight the large involvement of community pharmacists with CRC screening program as well as a high quality in the process of FIT distribution and collection.

Factors associated with serum IgM concentrations: a general adult population study.

BACKGROUND AND AIM: To investigate the influence of common factors on serum immunoglobulin M (IgM) concentrations in adults, and clinical associations with high and low values. METHODS: We measured serum IgM levels using immunonephelometry in a random sample of 1510 individuals (aged 18-91 years, 44.7% male). We obtained data defining metabolic syndrome from all participants, defined atopy by skin prick tests to aeroallergens, and assessed lifestyle factors by questionnaire. RESULTS: Women showed higher IgM concentrations than men; 95 (6.3%, mostly male) individuals showed low (<0.40 g/L) IgM values, and 64 (4.2%, mostly female) showed high (>2.30 g/L) IgM values. Individuals with abnormal IgM concentrations had no history of opportunistic infections nor a different atopy prevalence. Serum IgM concentrations decreased with age, and obesity was negatively associated with IgM concentrations. Alcohol consumption, smoking, physical activity, and metabolic syndrome had no significant influence in the multivariate analyses. CONCLUSIONS: Many adults in the general population show abnormally high or low IgM concentrations with no evidence of immunodeficiency-associated diseases. Sex and age should be considered when defining reference IgM concentrations.

Asian Hornet, Vespa velutina Lepeletier 1836 (Hym.: Vespidae), Venom Obtention Based on an Electric Stimulation Protocol.

The yellow-legged Asian hornet (Vespa velutina Lepeletier 1836 (Hymenoptera: Vespidae)) is naturally distributed in China, Southeast Asia, and India; however, recently it has been detected outside of its native area, confirmed as being established in South Korea, Europe, and Japan. Health risks and deaths caused by the invasive Vespa velutina stings have become a public health concern, being the most common cause of anaphylaxis due to hymenopterans in some European regions. This in turn has led to increased demand from medical practitioners and researchers for Vespa velutina venom for diagnostic and therapeutic purposes. In this study, a straightforward, quick, and inexpensive method for obtaining Vespa velutina venom by electric stimulation is described. The venom extracts were analyzed by nuclear magnetic resonance spectroscopy (1H-NMR). The availability of Vespa velutina venom will lead to improved diagnostic and therapeutic methods, mainly by venom immunotherapy (VIT), in patients allergic to this invasive species.