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Purpose of Review: To analyze the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of pediatric AD., Recent Findings: Adolescents with moderate and severe atopic dermatitis (AD) need systemic therapies, as stated several recent practice guidelines. (JAKi) have shown their efficacy in the treatment of adult AD, however, there is a lack of information concerning efficacy and safety of their use in pediatric AD. We found that the JAKi's abrocitinib (ABRO), baricitinib (BARI), and upadacitinib (UPA), are all an effective treatment option with a very fast onset of action for adolescents with moderate-to-severe AD. BARI was not effective in children between 2 and 10 years with moderate-to-severe AD. Fortunately, major safety issues with JAKi in adolescents with AD have not been documented in the trials, so far, contrasting with the reports in adults with AD, where these events have very rarely occurred. There are some reports of herpes zoster (HZ) infection in adolescents on JAKi, but it is not a major safety concern. Acne is a relatively common AE with UPA in adolescents; however, it is responsive to standard treatment. This review will help the clinician to choose among the JAKi according to the needs and clinical features of patients with moderate and severe AD. In the following years, with the advent of new biologicals and JAKi, these therapies will fall into place in each phase of the evolution of patients with AD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent years, some new concepts have been added to asthma treatment such as "anti-inflammatory reliever" (β2-agonist use associated to an inhaled corticosteroid (ICS) as a reliever treatment) that combines the benefits of both therapies and provides short- and long-term benefits for treatment in asthma patients. Robust evidence has been presented in patients over 12 years, and the main changes in the international guidelines for asthma treatment were originally made in this age group. However, a few suggestions have been added to treatments in younger patients, in part because of the scarce evidence that exists in this group. We aim to analyze the information regarding the utilization of ICS + fast-acting beta-agonist (FABA) combination in children between 6 and 11 years. Although up until today only three published trials exist (two studies use beclomethasone + albuterol and one study uses budesonide + formoterol), they provide significant information on the benefits of ICS + FABA use in this population., Competing Interests: Elsy M. Navarrete-Rodriguez receives speaking support and advice from Sanofi, AstraZeneca, GSK, Pfizer. Blanca E. del-Rio-Navarro receives speaking support and advice from Sanofi, Grunenthal. Désirée Larenas Linnemann receives speaking support and advice from Allakos, Armstrong, AstraZeneca, DBV Technologies, Grunenthal, GSK, Mylan, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Alakos, Gossamer; and research grants from Sanofi, AstraZeneca, Novartis, Circassia, UCB, GSK, TEVA, Purina Institute. Désirée E.S. Larenas-Linnemann reports personal fees from ALK, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GSK national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Carnot, grants from Abbvie, Bayer, Lilly, Sanofi, AstraZeneca, Pfizer, Novartis, Circassia, UCB, GSK., outside the submitted work. She is coordinator of the immunotherapy committee of CMICA and general coordinator of ten national guidelines in the field of allergy, asthma, and immunotherapy. Jose A. Castro-Rodriguez receives speaking support and advice from AstraZeneca, Cassará, Europharma, GSK, and Sanofi.

Reactive oxygen species (ROS) regulate the activities of inflammasomes, which are innate immune signaling organelles that induce pyroptosis. The mechanisms by which ROS control inflammasome activities are unclear and may be multifaceted. Herein, we report that the protein gasdermin D (GSDMD), which forms membrane pores upon cleavage by inflammasome-associated caspases, is a direct target of ROS. Exogenous and endogenous sources of ROS, and ROS-inducing stimuli that prime cells for pyroptosis induction, promote oligomerization of cleaved GSDMD, leading to membrane rupture and cell death. We find that ROS enhance GSDMD activities through oxidative modification of cysteine 192 (C192). Within macrophages, GSDMD mutants lacking C192 show impaired ability to form membrane pores and induce pyroptosis. Reciprocal mutagenesis studies reveal that C192 is the only cysteine within GSDMD that mediates ROS responsiveness. Cellular redox state is therefore a key determinant of GSDMD activities., Competing Interests: Declaration of interests J.C.K. consults and holds equity in Corner Therapeutics, Larkspur Biosciences, and Neumora Therapeutics. E.T.C. is co-founder, equity holder, and board member of Matchpoint Therapeutics and co-founder and equity holder in Aevum Therapeutics. None of these relationships influenced this study., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

With the advancement of knowledge in relation to the physiopathogenesis of atopic dermatitis (AD), several new therapeutic forms have been developed. There are also new guidelines for self-care. On the other hand, there is still an underdiagnosis of AD in Mexico. Thus, the need was seen to develop a national guide, with a broad base among the different medical groups that care for patients with AD. The Atopic Dermatitis Guidelines for Mexico (GUIDAMEX) was developed with the ADAPTE methodology, with the endorsement and participation of ten national medical societies, from physicians in Primary Healthcare to allergists and dermatologists. Throughout the manuscript, key clinical questions are answered that lead to recommendations and suggestions for the diagnosis of AD (including differential diagnosis with immunodeficiency syndromes), the recognition of comorbidities and complications, non-pharmacological treatment including therapeutic education, treatment of flares and maintenance therapy. The latter encompasses general measures to avoid triggering factors, first-line treatment focussed on repair of the skin barrier, second-line treatment (topical proactive therapy), and third-line phototherapy or systemic treatment, including dupilumab and JAK inhibitors.

Background: The reports on adverse experiences following vaccination are scanty from India. It is important to know the real-world post-vaccination experience outside of clinical trial conditions., Objectives: The study aims to estimate the incidence of adverse events following immunization with the ChAdOx1 nCoV-19 coronavirus vaccine and to identify the predictors for the development of vaccine adverse events., Methods: A prospective observational study was conducted among health care workers who received the ChAdOx1 nCoV-19 coronavirus vaccine. Study participants were monitored at the site for 30 min following vaccination and were followed up for 7 days after receiving the second dose, with a purpose-specific designed online surveillance form to enquire about any adverse events following vaccination. We used the Chi-squared test for categorical variables and multivariate regression analysis to identify predictors for the development of vaccine adverse effects., Results: Of 411 participants, the mean age was 30.77 ± 12.5 years and 76.2% were females. Overall, 207 (50.4%) respondents reported at least one post-vaccination symptom receiving either dose of coronavirus vaccination. Fever (34.8%), local pain at the injection site (28.0%), tiredness (25.5%), chills (20%), myalgia (18.7%), headache (17.8%), injection site stiffness (5.4%), joint pain (4.6%) and nausea-vomiting (3.8%) were the most prevalent symptoms following the first dose. Adverse reactions reported after the second dose were milder and less frequent. Postvaccination symptoms were more likely in the younger age group, those with comorbidity particularly, bronchial asthma , and a history of allergy to food/drugs., Conclusion: All the adverse reactions were of a minor type and non-serious. Side effects were less common in older adults (>60 years). Reactions to the second dose were lesser in intensity and frequency. Younger age, history of allergy, and comorbidities, particularly asthma, were found to be major predictors for the development of adverse events and require more watchful vaccine administration., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: In India, tuberculosis (TB) was made a notifiable disease in 2012 and nonnotification was made a punishable offense in March 2018. In 2018, 25% of TB cases notified were from private sector., Objectives: The objective of the study is to assess the proportion of private practitioners (PPs) who notified TB cases to the Revised National Tuberculosis Control Programme (RNTCP) and to identify the facilitating factors and barriers to TB case notification, including channels most preferred for notification., Methodology: This descriptive cross-sectional study was conducted among PPs in urban Puducherry. PPs were included consecutively, and data were collected using a pretested structured questionnaire., Results: Almost 60% (75 of 125) of PPs had dealt with presumptive TB cases in the last 1 year. Only one of 16 PPs who diagnosed and two of four PPs who treated had notified. PPs preferred electronic modes of notification such as e-mail and short messaging service (SMS). Concerns regarding patient confidentiality and delay in collection of notification forms from PPs by RNTCP were the barriers to notification., Conclusions: Notification for TB diagnosis was poor as PPs preferred to refer cases to RNTCP rather than notifying. Only four PPs had initiated TB treatment, of whom two PPs (50%) had notified., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Indian Journal of Community Medicine.)

The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag)., Competing Interests: Declaration of interests J.C.K. holds equity and consults for IFM Therapeutics and Corner Therapeutics. None of these relationships influenced the work performed in this study. J.G.D. consults for Microsoft Research, Agios, Phenomic AI, Maze Therapeutics, BioNTech, and Pfizer; J.G.D. consults for and has equity in Tango Therapeutics. J.G.D.’s interests were reviewed and are managed by the Broad Institute in accordance with its conflict-of-interest policies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Both, allergen immunotherapy (AIT) and SARS-COV-2 infection cause a set of immunologic changes that respectively vary during the course of the treatment or the disease. Objective: To review immune changes brought along by each of these entities and how they might interrelate. Methods: We start presenting a brief review of the structure of the new coronavirus and how it alters the functioning of the human immune system. Subsequently, we describe the immune changes induced by AIT and how these changes could be favorable or unfavorable in the allergic patient infected with SARS-CoV-2 at a particular point of time during the evolving infection. Results: We describe how a healthy immune response against SARS-CoV-2 develops, versus an immune response that is initially suppressed by the virus, but ultimately overactivated, leading to an excessive production of cytokines (cytokine-storm-like). These changes are then linked to the clinical manifestations and outcomes of the patient. Reviewing the immune changes secondary to AIT, it becomes clear how AIT is capable of restoring a healthy innate immunity. Investigators have previously shown that the frequency of respiratory infections is reduced in allergic patients treated with AIT. On the other hand it also increases immunoregulation. Conclusion: As there are many variables involved, it is hard to predict how AIT could influence the allergic patient's reaction to a SARS-CoV-2 infection. In any case, AIT is likely to be beneficial for the patient with allergic rhinitis and/or allergic asthma in the context of the SARS-CoV-2 pandemic as controlling allergic diseases leads to a reduced need for contact with healthcare professionals. The authors remind the reader that everything in this article is still theoretical, since at the moment, there are no published clinical trials on the outcome of COVID-19 in allergic patients under AIT.

Purpose of Review: At the juncture of the COVID-19 pandemic, the world is currently in an early phase of collecting clinical data and reports of its skin manifestations, and its pathophysiology is still highly conjectural. We reviewed cutaneous manifestations associated with COVID-19 in the pediatric age group., Recent Findings: Children infected by SARS-CoV-2 usually develop milder respiratory symptoms, but cutaneous manifestations seem a little more prevalent than in adults. These skin features of infection by the coronavirus can be similar to those produced by other common viruses, but there are also reports of cases with more heterogeneous clinical pictures, which have made their classification difficult. To date, the more frequently reported skin variants featured in pediatric cases are purpuric (pseudo-chilblain, necrotic-acral ischemia, hemorrhagic macules, and/or cutaneous necrosis), morbilliform/maculopapular, erythema multiforme, urticarial, vesicular, Kawasaki-like, and miscellaneous (highly variable in both frequency and severity). Their pathophysiological mechanism is still elusive and is likely to be the result of the complex involvement of one or more mechanisms, like direct virus-induced skin damage, vasculitis-like reactions, and/or indirect injury as a consequence of a systemic inflammatory reaction. In this review, we presented and discussed clinical cases as examples of different cutaneous responses reported in some children with SARS-CoV-2 infection, differential diagnosis considerations, and a preliminary conceptual approach to some of their probable associated pathologic mechanisms.

We developed a diabetes risk score using a novel analytical approach and tested its diagnostic performance to detect individuals at high risk of diabetes, by applying it to the Qatari population. A representative random sample of 5,000 Qataris selected at different time points was simulated using a diabetes mathematical model. Logistic regression was used to derive the score using age, sex, obesity, smoking, and physical inactivity as predictive variables. Performance diagnostics, validity, and potential yields of a diabetes testing program were evaluated. In 2020, the area under the curve (AUC) was 0.79 and sensitivity and specificity were 79.0% and 66.8%, respectively. Positive and negative predictive values (PPV and NPV) were 36.1% and 93.0%, with 42.0% of Qataris being at high diabetes risk. In 2030, projected AUC was 0.78 and sensitivity and specificity were 77.5% and 65.8%. PPV and NPV were 36.8% and 92.0%, with 43.0% of Qataris being at high diabetes risk. In 2050, AUC was 0.76 and sensitivity and specificity were 74.4% and 64.5%. PPV and NPV were 40.4% and 88.7%, with 45.0% of Qataris being at high diabetes risk. This model-based score demonstrated comparable performance to a data-derived score. The derived self-complete risk score provides an effective tool for initial diabetes screening, and for targeted lifestyle counselling and prevention programs.

Mitchell-Riley syndrome (MRS) is caused by recessive mutations in the regulatory factor X6 gene ( RFX6 ) and is characterised by pancreatic hypoplasia and neonatal diabetes. To determine why individuals with MRS specifically lack pancreatic endocrine cells, we micro-CT imaged a 12-week-old foetus homozygous for the nonsense mutation RFX6 c.1129C>T, which revealed loss of the pancreas body and tail. From this foetus, we derived iPSCs and show that differentiation of these cells in vitro proceeds normally until generation of pancreatic endoderm, which is significantly reduced. We additionally generated an RFX6 HA reporter allele by gene targeting in wild-type H9 cells to precisely define RFX6 expression and in parallel performed in situ hybridisation for RFX6 in the dorsal pancreatic bud of a Carnegie stage 14 human embryo. Both in vitro and in vivo , we find that RFX6 specifically labels a subset of PDX1-expressing pancreatic endoderm. In summary, RFX6 is essential for efficient differentiation of pancreatic endoderm, and its absence in individuals with MRS specifically impairs formation of endocrine cells of the pancreas head and tail., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: Anaphylaxis is a life-threating hypersensitivity reaction. Epinephrine underuse in patients with anaphylaxis could lead to poor outcomes. There is evidence that the epinephrine use in such patients could be as low as 8%., Objective: To assess the percentage of physicians who know that epinephrine is the first-line treatment in anaphylaxis. The secondary objective was to assess knowledge gaps regarding anaphylaxis diagnosis and treatment that could lead to epinephrine underuse., Methods: We performed an online survey for physicians in Mexico City, using a 10-item questionnaire assessing anaphylaxis knowledge. We obtained measures of central tendency for statistical analysis, such as frequency, 95% confidence interval, as well as the chi-square test for comparing the groups., Results: A total of 196 surveys were considered for analysis. Of all the participants, 96.44% were able to correctly diagnose an anaphylaxis case with cutaneous, respiratory, and cardiovascular symptoms. Fifty-two percent correctly diagnosed anaphylaxis without cutaneous symptoms. The 72.4% of the respondents chose epinephrine as the first-line treatment, 42.3% correctly answered that there is no absolute contraindication to giving epinephrine, and 20.9% ignored whether there was any contraindication for its use. Only 38.3% of participants answered that during discharge they would prescribe an autoinjector. Regarding the administration route, 63.4% answered that the first dose of epinephrine is applied intramuscularly and 50% of the participants chose the correct dose of epinephrine. Only 2.6% of the participants answered all 10 questions correctly., Conclusion: There is still some difficulty recognizing anaphylaxis without cutaneous symptoms. Even though two-thirds of physicians identified that epinephrine is the treatment of choice, only 49.5% would have used intramuscular epinephrine as first-line treatment. We found a low percentage of epinephrine ampule prescription and knowledge of the correct dose. These findings can account for epinephrine underuse when dealing with anaphylaxis in the real clinical practice., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2020. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Inhaled therapy is considered the cornerstone of asthma treatment. However, despite being the ideal form of drug delivery, it is recognized that only 70% of patients have an adequate attachment to their treatment and only 39-67% of physicians can explain the optimal inhaler technique. Inhaled therapy has very specific characteristics. Pulmonary deposit of an inhaled medication through the respiratory tract is more complex than when administered orally and depends on several factors inherent to both the medication and the administration. For successful inhaled therapy, the drug needs to be converted into particles of an appropriate size, which can enter beyond the oropharynx and larynx, and be deposited in the lungs. There are multiple devices for the administration of drugs in the lower respiratory tract, each one with a similar efficacy as long as it is used with the correct technique. The decision of which device should be used is made based on the age of the patient, the ability to coordinate between the inhalation and activation of the device, and the presence of acute symptoms. The choice of the device must be evaluated individually., (Copyright: © 2018 Permanyer.)

Fibroblast growth factors (FGFs) comprise a family of signalling molecules with essential roles in early embryonic development across animal species. The role of FGFs in mesoderm formation and patterning in Xenopus has been particularly well studied. However, little is known about FGF16 in Xenopus. Using in situ hybridisation, we uncover the expression pattern of FGF16 during early Xenopus laevis development, which has not been previously described. We show that the zygotic expression of FGF16 is activated in the mesoderm of the early gastrula as a ring around the blastopore, with its first accumulation at the dorsal side of the embryo. Later, FGF16 expression is found in the otic vesicle, the branchial arches and the anterior pituitary, as well as in the chordal neural hinge region of the tailbud. In addition, we show that FGF16 can activate the MAPK pathway and expression of sp5 and sp5l. Like FGF16, sp5 is expressed in the otic vesicle and the branchial arches, with all three of these genes being expressed in the tailbud. These data provide evidence that FGF16 is present in the early mesoderm and can activate the expression of developmentally important transcription factors.

Oligosaccharyltransferase (OST) is an essential membrane protein complex in the endoplasmic reticulum, where it transfers an oligosaccharide from a dolichol-pyrophosphate-activated donor to glycosylation sites of secretory proteins. Here we describe the atomic structure of yeast OST determined by cryo-electron microscopy, revealing a conserved subunit arrangement. The active site of the catalytic STT3 subunit points away from the center of the complex, allowing unhindered access to substrates. The dolichol-pyrophosphate moiety binds to a lipid-exposed groove of STT3, whereas two noncatalytic subunits and an ordered N-glycan form a membrane-proximal pocket for the oligosaccharide. The acceptor polypeptide site faces an oxidoreductase domain in stand-alone OST complexes or is immediately adjacent to the translocon, suggesting how eukaryotic OSTs efficiently glycosylate a large number of polypeptides before their folding., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: The backbone of food allergy treatment is the restriction of causative foods. These interventions have shown that children who restrict the consumption of basic foods have a higher risk of malnutrition. The aim of the study was to identify the nutritional status of patients with elimination diet, characterizing their anthropometric indexes and identifying the percentage of patients in the group with true food allergies., Methods: A cross-sectional study was carried out from January to October 2014 at the Hospital Infantil de Mexico Federico Gomez. Patients 1 to 11 years of age with a history of elimination of at least one of five foods (eggs, milk, wheat, corn, soybeans) for a minimum of 6 months were included. Full nutritional assessment was performed by comparing the anthropometric indexes to z score for age. Data analysis used descriptive statistics. Kruskal-Wallis and Spearman correlation were performed., Results: The most frequent eliminated foods were milk, soy, eggs, corn, and wheat. Comparing the number of foods eliminated with different anthropometric indexes, with a greater amount of eliminated food, the z-score of weight/age (W/A), height/age (H/A) and weight/height (W/H) were lower and the most affected index was fat reserve. Only in 5% of children was food allergy confirmed., Conclusions: The study confirms the need for nutrition counseling for patients who have elimination diets and overdiagnosis of food allergy., (Copyright © 2015. Publicado por Masson Doyma México S.A.)

Asparagine (N)-linked glycosylation regulates numerous cellular activities, such as glycoprotein quality control, intracellular trafficking, and cell-cell communications. In eukaryotes, the glycosylation reaction is catalyzed by oligosaccharyltransferase (OST), a multimembrane protein complex that is localized in the endoplasmic reticulum (ER). During N-glycosylation in the ER, the protein-unbound form of oligosaccharides (free oligosaccharides; fOSs), which is structurally related to N-glycan, is released into the ER lumen. However, the enzyme responsible for this process remains unidentified. Here, we demonstrate that eukaryotic OST generates fOSs. Biochemical and genetic analyses using mutant strains of Saccharomyces cerevisiae revealed that the generation of fOSs is tightly correlated with the N-glycosylation activity of OST. Furthermore, we present evidence that the purified OST complex can generate fOSs by hydrolyzing dolichol-linked oligosaccharide, the glycan donor substrate for N-glycosylation. The heterologous expression of a single subunit of OST from the protozoan Leishmania major in S. cerevisiae demonstrated that this enzyme functions both in N-glycosylation and generation of fOSs. This study provides insight into the mechanism of PNGase-independent formation of fOSs.