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Background: Angioedema is a condition marked by sudden, intense swelling of the subcutaneous and submucosal tissues, typically associated with hypersensitivity reactions, genetic mutations, or reactions to medications. It can also result from contact with allergens such as nickel, leading to dermatitis., Case Presentation: A 12-year-old girl presented at our Pediatric Immunology and Allergology service with recurrent labial angioedema for over a year, linked to the consumption of legumes and tomatoes, and following the use of a metal flute. Despite a nickel-positive patch test and subsequent avoidance of nickel, her symptoms persisted. Further investigations to rule out other causes of angioedema were unproductive. It was later discovered that she had been wearing a nickel-containing orthodontic device applied a year earlier. The removal of this orthodontic device led to a cessation of the angioedema episodes, highlighting nickel as the likely trigger., Conclusions: This case underscores the importance of considering prolonged nickel exposure from dental devices as a potential cause of angioedema. For patients predisposed to nickel hypersensitivity, using nickel-free alternatives such as ceramic for orthodontic appliances is crucial. Additionally, comprehensive allergen screening, including latex testing, should be conducted before the placement of such devices to prevent similar adverse reactions., Competing Interests: Declarations. Ethics approval and consent to participate: Not required. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and accompanying images. Competing interests: The authors declare that they have no competing interests. Informed consent: The patient should give informed consent., (© 2024. The Author(s).)

While Trisomy X syndrome is typically characterized by developmental and cognitive variations, it is not commonly associated with immunodeficiencies. We report the unique case of a 6-year-old girl with Trisomy X presenting with selective IgA deficiency, challenging the conventional understanding of this chromosomal condition. The patient exhibited recurrent respiratory infections and gastrointestinal symptoms, evaluated in the context of her genetic background of Trisomy X and significantly low levels of IgA (0.03 g/L), yet normal IgG and IgM levels. Immunological assessment revealed a poor response to vaccination to HBV, necessitating an adapted vaccination strategy. Gastrointestinal investigations indicated paradoxical diarrhea secondary to chronic constipation, managed with dietary interventions. The presence of an extra X chromosome raises questions about the potential over-expression of genes that escape X-chromosome inactivation, such as FOXP3 , which is crucial for the regulation of regulatory T cells. An abnormal expression of FOXP3 could lead to either heightened immune regulation, increasing susceptibility to infections, or to immune dysregulation. Although Trisomy X is not typically associated with immunodeficiencies, this case, paralleled by another patient with Trisomy X and CVID, suggests a need for further speculative research into possible genetic links. Moreover, a 1969 study reported lower IgA levels in women with an extra X chromosome. In conclusion, this case aims to underscore the necessity for a deeper genetic and immunological evaluation in chromosomal anomalies like Trisomy X to fully understand their speculative impact on immune function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Leone, Gori, Cinicola, Brindisi, Maglione, Anania and Zicari.)

Food allergy (FA) affects approximately 6-8% of young children, with a peak prevalence at approximately one year of age. Tree nut and peanut allergies are among the main causes of anaphylaxis in the world. The gold standard for the diagnosis of FAs is the oral food challenge (OFC). Other diagnostic tests used in the clinical practice are skin prick tests (SPTs) and laboratory tests to measure out the presence of serum specific IgE (sIgE). In this narrative review, we collect the current evidence of the predictive value (PV) of SPTs and sIgE for the outcome of the OFCs. In literature, data are conflicting as to whether increasing sIgE concentration and wheal size in SPTs correlate with OFC outcomes. Most studies included in our review have shown that in vivo and in vitro tests may predict OFC outcomes with variable PV, but data are not conclusive; therefore, the OFC currently remains the gold standard for FA diagnosis.

Food allergy (FA) affects approximately 6-8% of children worldwide causing a significant impact on the quality of life of children and their families. In past years, the possible role of weaning in the development of FA has been studied. According to recent studies, this is still controversial and influenced by several factors, such as the type of food, the age at food introduction and family history. In this narrative review, we aimed to collect the most recent evidence about weaning and its role in FA development, organizing the gathered data based on both the type of study and the food. As shown in most of the studies included in this review, early food introduction did not show a potential protective role against FA development, and we conclude that further evidence is needed from future clinical trials.

We carefully read the correspondence [...].

The "Atopy Patch Test" (APT) has been proposed as a diagnostic tool for food allergies (FA), especially in children with FA-related gastrointestinal symptoms. However, its diagnostic accuracy is debated, and its usefulness is controversial. The aim of this systematic review was to evaluate the APT diagnostic accuracy compared with the diagnostic gold standard, i.e., the oral food challenge (OFC), in children affected by non-IgE mediated gastrointestinal food allergies, including the evaluation in milk allergic subgroup. Both classical non-IgE mediated clinical pictures and food induced motility disorders (FPIMD) were considered. The search was conducted in PubMed and Scopus from January 2000 to June 2022 by two independent researchers. The patient, intervention, comparators, outcome, and study design approach (PICOS) format was used for developing key questions, to address the APT diagnostic accuracy compared with the oral food challenge (OFC). The quality of the studies was assessed by the QUADAS-2 system. The meta-analysis was performed to calculate the pooled sensitivity, specificity, DOR (diagnostic odds ratio), PLR (positive likelihood ratio), and NLR (negative likelihood ratio) with their 95% confidence intervals (CI). Out of the 457 citations initially identified via the search (196 on PubMed and 261 on Scopus), 37 advanced to full-text screening, and 16 studies were identified to be included in the systematic review. Reference lists from relevant retrievals were searched, and one additional article was added. Finally, 17 studies were included in the systematic review. The analysis showed that APT has a high specificity of 94% (95%CI: 0.88-0.97) in the group of patients affected by FPIMD. Data showed a high pooled specificity of 96% (95% CI: 0.89-0.98) and the highest accuracy of APT in patients affected by cow's milk allergy (AUC = 0.93).      Conclusion: APT is effective in identifying causative food in children with food-induced motility disorders.  What is Known: • Atopy patch test could be a useful diagnostic test for diagnosing food allergy, especially in children with food allergy-related gastrointestinal symptoms. What is New: • Atopy patch test may be a useful tool in diagnosing non IgE food allergy, especially in children with food-induced gastrointestinal motility disorders and cow's milk allergy., (© 2023. The Author(s).)

Kiwifruit allergy is an emerging pathological condition in both general and pediatric populations with a wide range of symptoms linked to variable molecular patterns, justifying systemic and cross-reactions with other allergens (i.e., latex, pollen, and fruit). Skin prick test (SPT), specific serum IgE (Act d 1, Act d 2, Act d 5, Act d 8, and Act d 10) directed against five out of thirteen molecular allergens described in the literature, and oral test challenge with kiwifruit are available for defining diagnosis. The management is similar to that of other food allergies, mostly based on an elimination diet. Although kiwi allergy has been on the rise in recent years, few studies have evaluated the clinical characteristics and methods of investigating this form of allergy. Data collected so far show severe allergic reaction to be more frequent in children compared to adults. Therefore, the aim of this review is to collect the reported clinical features and the available association with specific molecular patterns of recognition to better understand how to manage these patients and improve daily clinical practice.

Background: We followed the effects of a new SCIT with a chemically polymerized allergen Alt a1, evaluating the trend of clinical and functional parameters in an observational-prospective study., Methods: 42 children with AR and intermittent asthma sensitized to A.A.: 17 patients started SCIT (Modigoid ® ), and 25 continued symptomatic therapy. At the initial visit (T0), all patients performed total IgE (tIgE) and specific IgE (sIgE) for Alt a1, nasal nitric oxide (nFeNo), nasal cytology, anterior active rhinomanometry (AAR) and spirometry. After 24 months (T1), they repeated the same procedures as in T0., Results: Patients treated with Modigoid presented a statistically significant ( p < 0.001) reduction of nFeNO (T0:1651.06 ± 149.18; T1: 1394.12 ± 108.98), tIgE (T0: 311.48 ± 144.18; T1: 164.73 ± 50.69), sIgE for Alt a1 (T0: 28.59 ± 12.69; T1: 19.54 ± 7.37), an improvement of nasal airflow (T0: 71.62 ± 8.66; T1: 95.12 ± 5.91), nasal eosinophils (T0: 20.59 ± 2.35; T1: 14.88 ± 1.65) and FEV1 (T0: 95.58 ± 7.91; T1: 116.64 ± 5.94)., Conclusions: The new SCIT for Alt a1 significantly improves AR symptoms from a subjective, objective point of view and laboratory and functional parameters.

Cow's milk protein allergy (CMPA) is the most common food allergy (FA) in infancy, affecting approximately 2% of children under 4 years of age. According to recent studies, the increasing prevalence of FAs can be associated with changes in composition and function of gut microbiota or "dysbiosis". Gut microbiota regulation, mediated by probiotics, may modulate the systemic inflammatory and immune responses, influencing the development of allergies, with possible clinical benefits. This narrative review collects the actual evidence of probiotics' efficacy in the management of pediatric CMPA, with a specific focus on the molecular mechanisms of action. Most studies included in this review have shown a beneficial effect of probiotics in CMPA patients, especially in terms of achieving tolerance and improving symptoms.

DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape's molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation., (© 2023. The Author(s).)

Background: Selective IgA deficiency (SIgAD) is the most common inborn error of immunity. The exact prevalence and pathogenesis of allergy in SIgAD have not yet been defined. We aimed to describe the prevalence and the characteristics of allergy in pediatric SIgAD subjects, evaluate the association between allergy and other comorbidities, and define the immune phenotype of allergic and non-allergic patients., Methods: Clinical and immunological data from 67 SIgAD patients were collected over a 13-year period at a single center. Patients' characteristics were analyzed according to the presence of allergy., Results: Allergy was diagnosed in 34% of SIgAD patients, with a median age at allergy diagnosis of 8 years. Allergy was the second-most-common clinical manifestation, following recurrent respiratory infections. Among the allergic group, 74% had rhinitis, 30% asthma, 30% atopic dermatitis, and 22% food allergy; one out of three had more than one allergic manifestation. SIgAD patients showed more frequent transitory lymphopenia and a lower count of CD19+ at diagnosis than at last FU. However, compared to non-allergic subjects, allergic patients did not differ in their immune phenotype, number and severity of infections, or increased autoimmunity., Conclusions: In our longitudinal study, compared to non-allergic SIgAD patients, those with allergies did not present a more severe immune defect or complex clinical phenotype. However, evaluation and early identification of allergy in the context of SIgAD assessment, both at diagnosis and during FU, and definition of a proper management are important to prevent complications and improve the patient's quality of life.

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by accumulation of surfactant lipoproteins within the lung alveoli. Alveolar macrophages (AMs) are crucial for surfactant clearance, and their differentiation depends on colony-stimulating factor 2 (CSF2), which regulates the establishment of an AM-characteristic gene regulatory network. Here, we report that the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) is essential for the development of the AM identity, as demonstrated by transcriptome and chromatin accessibility analysis. Furthermore, C/EBPβ-deficient AMs showed severe defects in proliferation, phagocytosis, and lipid metabolism, collectively resulting in a PAP-like syndrome. Mechanistically, the long C/EBPβ protein variants LAP* and LAP together with CSF2 signaling induced the expression of Pparg isoform 2 but not Pparg isoform 1, a molecular regulatory mechanism that was also observed in other CSF2-primed macrophages. These results uncover C/EBPβ as a key regulator of AM cell fate and shed light on the molecular networks controlling lipid metabolism in macrophages.

Background: Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347)., Methods: In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting., Results: One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE., Conclusions: Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Starting from the "Hygiene Hypothesis" to the "Microflora hypothesis" we provided an overview of the symbiotic and dynamic equilibrium between microbiota and the immune system, focusing on the role of dysbiosis in atopic march, particularly on allergic rhinitis. The advent of deep sequencing technologies and metabolomics allowed us to better characterize the microbiota diversity between individuals and body sites. Each body site, with its own specific environmental niches, shapes the microbiota conditioning colonization and its metabolic functionalities. The analysis of the metabolic pathways provides a mechanistic explanation of the remote mode of communication with systems, organs, and microflora of other body sites, including the ecosystem of the upper respiratory tract. This axis may have a role in the development of respiratory allergic disease. Notably, the microbiota is significant in the development and maintenance of barrier function; influences hematopoiesis and innate immunity; and shows its critical roles in Th1, Th2, and Treg production, which are necessary to maintain immunological balance and promote tolerance, taking part in every single step of the inflammatory cascade. These are microbial biotherapy foundations, starting from probiotics up to postbiotics and parabiotics, in a still-ongoing process. When considering the various determinants that can shape microbiota, there are several factors to consider: genetic factors, environment, mode of delivery, exposure to antibiotics, and other allergy-unrelated diseases. These factors hinder the engraftment of probiotic strains but may be upgradable with postbiotic and parabiotic administration directly on molecular targets. Supplementation with postbiotics and parabiotics could represent a very exciting perspective of treatment, bypassing probiotic limitations. At present, this avenue remains theoretical and to be explored, but it will certainly be a fascinating path to follow.

Background: Between June and July 2020, we evaluated children and adolescents concerning post-infection surveillance after a COVID-19 positivity during the lockdown. We aimed to assess whether the anamnestic presence of allergies could correlate with the presence of SARS-CoV-2 symptoms, and in particular with anosmia., Material and Methods: For each patient, we collected anamnestic data, the presence of allergies documented by performing skin prick tests, and COVID-19 symptoms. Then, if over six years of age, each patient underwent an active anterior rhinomanometry., Results: A total of 296 patients were enrolled, of whom 105 (35.4%) reported allergies. Considering COVID-19 symptoms, 74 subjects (25%) presented an asymptomatic form, 222 (75%) reported symptoms, and anosmia recurred in 60 subjects (27.03%). A statistically significant relationship was found between allergies and symptomatic COVID-19 ( p = 0.042), allergies, and anosmia ( p = 0.05), and allergies and anosmia in males ( p = 0.007). Moreover, anosmic patients presented a higher body mass index, older age, and a longer COVID-19 duration with statistical significance ( p = 0.001, 0.001, 0.006, respectively)., Conclusions: Allergic subjects seem to develop symptomatic COVID-19 more frequently and allergies appear to be a protective factor from anosmia's onset in males.

Cow's milk allergy (CMA) is a common condition in the pediatric population. CMA can induce a diverse range of symptoms of variable intensity. It occurs mainly in the first year of life, and if the child is not breastfed, hypoallergenic formula is the dietary treatment. Extensively hydrolyzed cow's milk formulas (eHF) with documented hypo-allergenicity can be recommended as the first choice, while amino acid-based formulas (AAF) are recommended for patients with more severe symptoms. Hydrolyzed rice-based formulas (HRFs) are a suitable alternative for infants with CMA that cannot tolerate or do not like eHF and in infants with severe forms of CMA. In the present paper, we reviewed the nutritional composition of HRFs as well as studies regarding their efficacy and tolerance in children, and we provided an updated overview of the recent evidence on the use of HRFs in CMA. The available studies provide evidence that HRFs exhibit excellent efficacy and tolerance and seem to be adequate in providing normal growth in healthy children as well as in children with CMA., Competing Interests: The authors declare no conflict of interest.

Vertebrate genomes organize into topologically associating domains, delimited by boundaries that insulate regulatory elements from nontarget genes. However, how boundary function is established is not well understood. Here, we combine genome-wide analyses and transgenic mouse assays to dissect the regulatory logic of clustered-CCCTC-binding factor (CTCF) boundaries in vivo, interrogating their function at multiple levels: chromatin interactions, transcription and phenotypes. Individual CTCF binding site (CBS) deletions revealed that the characteristics of specific sites can outweigh other factors such as CBS number and orientation. Combined deletions demonstrated that CBSs cooperate redundantly and provide boundary robustness. We show that divergent CBS signatures are not strictly required for effective insulation and that chromatin loops formed by nonconvergently oriented sites could be mediated by a loop interference mechanism. Further, we observe that insulation strength constitutes a quantitative modulator of gene expression and phenotypes. Our results highlight the modular nature of boundaries and their control over developmental processes., (© 2022. The Author(s).)

Background: COVID-19 lockdown caused sudden changes in people's lifestyle, as a consequence of the forced lockdown imposed by governments all over the world. We aimed to evaluate the impact of lockdown on body mass index (BMI) in a cohort of allergic children and adolescents., Methods: From the first of June until the end of October 2020, we submitted a written questionnaire to all the patients who, after lockdown, carried out a visit at the Pediatric Allergy Unit of the Department of Mother-Child, Urological Science, Sapienza University of Rome. The questionnaire was composed by 10 questions, referring to the changes in their daily activities. Data were extrapolated from the questionnaire and then analyzed considering six variables: BMI before and BMI after lockdown, sugar intake, sport, screens, sleep, and anxiety., Results: One hundred fifty-three patients agreed to answer our questionnaire. Results showed a statistically significant increase in the BMI after lockdown (20.97 kg/m2 ± 2.63) with respect to the BMI before lockdown (19.18 kg/m2 ± 2.70). A multivariate regression analysis showed that the two variables that mostly influenced the increase in BMI were sleep and anxiety., Conclusions: For the analyzed cohort of allergic children and adolescents we obtained significant gain in BMI as consequences of lockdown, which can be explained by many factors: high consumption of consolatory food, less sport activities, more time spent in front of screens, sleep alteration associated with increased anxiety. All these factors acted together, although sleep alteration and increased anxiety were the most influential factors that led to the worsening or the onset of weight gain, creating the basis for future health problems., (© 2022. The Author(s).)

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by relapsing eczematous injuries and severe pruritus. In the last few years, the AD prevalence has been increasing, reaching 20% in children and 10% in adults in high-income countries. Recently, the potential role of probiotics in AD prevention has generated considerable interest. As many clinical studies show, the gut microbiota is able to modulate systemic inflammatory and immune responses influencing the development of sensitization and allergy. Probiotics are used increasingly against AD. However, the molecular mechanisms underlying the probiotics mediated anti-allergic effect remain unclear and there is controversy about their efficacy. In this narrative review, we examine the actual evidence on the effect of probiotic supplementation for AD prevention in the pediatric population, discussing also the potential biological mechanisms of action in this regard.

Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD.

Background: Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1., Methods: We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0·25 mg, 0·75 mg, or 2·25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate (TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov, NCT03272347., Findings: Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10·9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0·25 mg, 30 to the 0·75 mg, and 31 to the 2·25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0·25 mg islatravir group, 30 (100%) of 30 in the 0·75 mg islatravir group, and 27 (87%) of 31 in the 2·25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2·8%, 95% CI -14·9 to 20·4, for the 0·25 mg islatravir group; 12·9%, -1·6 to 27·5, for the 0·75 mg islatravir group; and 0·3%, -17·9 to 18·5, for the 2·25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0·25 mg islatravir group, 27 (90%) of 30 in the 0·75 mg islatravir group, and 24 (77%) of 31 in the 2·25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6·1%, 95% CI -12·4 to 24·4, for the 0·25 mg islatravir group; 6·2%, -12·2 to 24·6, for the 0·75 mg islatravir group; and -6·1%, -27·1 to 14·8, for the 2·75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2·25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48., Interpretation: Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development., Funding: Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc., Competing Interests: Declaration of interests J-MM has received grants from Gilead, Merck, ViiV, and Sanofi. ED has received personal fees from Gilead Science and Janssen Therapeutics, outside the submitted work. SOK, AG, KE, MNR, TC, CH, GJH, and PS are employees of Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc. YY, AAS, CB, and CCA declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: During the lockdown period caused by the SARS-CoV-2 pandemic, we monitored via online survey the trend of allergic symptoms and the therapeutic compliance in patients followed at our center., Material and Methods: In June 2020, we selected children followed at the Allergy and Immunology Service of Umberto I Hospital, aged between 6 and 16 years old, diagnosed with asthma and/or rhinitis and sensitized to grass pollen or dust mite. We sent an email with 12 multiple-choice questions investigating several areas: type of disease and sensitization, recurrence of symptoms, medication use during lockdown compared to the same period of the previous year., Results: The results of 82 questionnaires showed that 17.8% of patients suffered from asthma, 24.4% from rhinitis, and 57.8% from both. Within the group of asthmatic children, most of them presented an improvement of their symptoms. Likewise, with regard to allergic rhinitis, most of them reported better clinical conditions. Regarding treatment, we observed a global decrease in the use of on-demand therapies (salbutamol, nasal corticosteroid, and antihistamine) for both pathologies. In addition, there was a reduction in the use of basal therapy for asthma and rhinitis from 2019 (23.3%) to 2020 (15.5%)., Conclusions: Our data show a general trend of clinical improvement and a reduction in the use of on-demand and basal therapy in allergic children during the lockdown.

non-IgE and mixed gastrointestinal food allergies present various specific, well-characterized clinical pictures such as food protein-induced allergic proctocolitis, food protein-induced enterocolitis and food protein-induced enteropathy syndrome as well as eosinophilic gastrointestinal disorders such as eosinophilic esophagitis, allergic eosinophilic gastroenteritis and eosinophilic colitis. The aim of this article is to provide an updated review of their different clinical presentations, to suggest a correct approach to their diagnosis and to discuss the usefulness of both old and new diagnostic tools, including fecal biomarkers, atopy patch tests, endoscopy, specific IgG and IgG4 testing, allergen-specific lymphocyte stimulation test (ALST) and clinical score (CoMiss).

Anaphylaxis is the most severe of allergic reactions. The most frequent triggers of anaphylaxis in childhood are food, insect venom, drugs, exercise, etc. In some cases, the presence of more than one trigger is necessary for the allergic reaction, while one trigger alone is tolerated. This rare condition is called summation anaphylaxis (SA). Food-dependent exercise-induced anaphylaxis is the most well-known SA. However, SA may also occur with the association between food and/or exercise plus one or more of the following other cofactors, such as drugs, especially non-steroidal anti-inflammatory (NSAID), alcohol, infections, temperature variation, and menstrual cycle. SA can explain some cases of idiopathic anaphylaxis, as well as cases of an apparent breakdown in a previously acquired tolerance for food, or finally, when faced with a suggestive clinical history of food allergy or exercise anaphylaxis and the provocation test is negative. In these situations, a more careful clinical history looking for other cofactors is necessary., (© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Food allergy (FA) is an adverse immunologic response triggered by normally innocuous food protein antigens.  FA can be broadly classified into those that are IgE mediated, those that are mediated by both IgE-dependent and IgE-independent pathways (mixed), and those that are not IgE mediated  Immunoglobulin E. (IgE)-mediated reaction is characterized by rapid onset of symptoms involving respiratory, gastrointestinal, dermatologic and cardiovascular systems; mixed and non-IgE-mediated has a longer onset and manifests primary in the gastrointestinal tract and skin. The diagnosis of food allergy is based on clinical history, diagnostic testing (skin prick test and allergen-specific IgE levels in the serum), elimination diet and, oral food challenge. In recent years the diagnosis and treatment of pediatric FA have notably improved. In the diagnostic pathway of FA an important recent innovation is the CRD introduction.  This resulted in the possibility of improving diagnostic accuracy through FA prediction severity and prognosis and thereby decreasing the OCF necessity. Recent studies emphasize the possibility of preventing FA through early introduction of food (peanuts and egg) to high-risk infants. FA management is based on avoidance of offending food and prompt treatment of allergic reaction. Currently under study are recently developed treatment approaches for FA management including specific OIT.

In children with food allergy the visits should be limited to those that are unequivocally needed on clinical basis. Food challenge can be performed in selected situations, taking a more detailed history to make sure that patients provide whatever information we need. The maintenance of a safe diet can be hampered by several factors. Nutritional supplementation may be necessary.

A precise three-dimensional (3D) organization of chromatin is central to achieve the intricate transcriptional patterns that are required to form complex organisms. Growing evidence supports an important role of 3D chromatin architecture in development and delineates its alterations as prominent causes of disease. In this review, we discuss emerging concepts on the fundamental forces shaping genomes in space and on how their disruption can lead to pathogenic phenotypes. We describe the molecular mechanisms underlying a wide range of diseases, from the systemic effects of coding mutations on 3D architectural factors, to the more tissue-specific phenotypes resulting from genetic and epigenetic modifications at specific loci. Understanding the connection between the 3D organization of the genome and its underlying biological function will allow a better interpretation of human pathogenesis., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Although decompression is the basis of surgical treatment for lumbar spinal stenosis (LSS), under various circumstances instrumented fusion is performed as well. The rationale for mobility-preserving operations for LSS is preventing adjacent segment disease (ASD). We review the rationale for mobility preservation in ASD and discuss related topics such as indications for fusion and the evolving role of minimally invasive approaches to lumbar spine decompression. Our focus is on systematic review and consensus discussion of mobility-preserving surgical methods as related to surgery for LSS., Methods: Groups of spinal surgeons (members of the World Federation of Neurosurgical Societies Spine Committee) performed systematic reviews of dynamic fixation systems, including hybrid constructs, and of interspinous process devices; consensus statements were generated based on the reviews at 2 voting sessions by the committee several months apart. Additional review of background data was performed, and the results summarized in this review., Results: Decompression is the basis of surgical treatment of LSS. Fusion is an option, especially when spondylolisthesis or instability are present, but indications remain controversial. ASD incidence reports show high variability. ASD may represent the natural progression of degenerative disease in many cases. Older age, poor sagittal balance, and multilevel fusion may be associated with more ASD. Dynamic fixation constructs are treatment options that may help prevent ASD., (© 2020 The Authors.)

Lumbar spinal stenosis (LSS) is defined as a degenerative disorder showing a narrowing of the spinal canal. The diagnosis is straightforward in cases with typical neurogenic claudication symptoms and unequivocal imaging findings. However, not all patients present with typical symptoms, and there is obviously no correlation between the severity of stenosis and clinical complaint. The radiologic diagnosis of LSS is widely discussed in the literature. The best diagnostic test for the diagnosis of LSS is magnetic resonance imaging (MRI). However, canal diameter measurements have not gained much consensus from radiologists, whereas qualitative measures, such as cerebrospinal fluid space obliteration, have achieved greater consensus. Instability can best be defined by standing lateral radiograms and flexion-extension radiograms. For cases showing typical neurogenic claudication symptoms and unequivocal imaging findings, the diagnosis is straightforward. However, not all patients present with typical symptoms, and there is obviously no correlation between the severity of stenosis (computed tomography and MRI) and clinical complaint. In fact, recent MRI studies have shown that mild-to-moderate stenosis can also be found in asymptomatic individuals. Routine electrophysiological tests such as lower extremity electromyography, nerve conduction studies, F-wave, and H-reflex are not helpful in the diagnosis and outcome prediction of LSS. The electrophysiological recordings are complementary to the neurologic examination and can provide confirmatory information in less obvious clinical complaints. However, in the absence of reliable evidence, imaging studies should be considered as a first-line diagnostic test in the diagnosis of degenerative LSS., (© 2020 The Authors.)