ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.

A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes.

Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This deleterious effect is mediated by pathological cleavage of the Cdk5 activator p35 into the truncated product p25, leading to prolonged Cdk5 activation and altered substrate specificity. Elevated p25 levels have been reported in humans and rodents with neurodegeneration, and the benefit of genetically blocking p25 production has been demonstrated previously in rodent and human neurodegenerative models. Here, we report a 12-amino-acid-long peptide fragment derived from Cdk5 (Cdk5i) that is considerably smaller than existing peptide inhibitors of Cdk5 (P5 and CIP) but shows high binding affinity toward the Cdk5/p25 complex, disrupts the interaction of Cdk5 with p25, and lowers Cdk5/p25 kinase activity. When tagged with a fluorophore (FITC) and the cell-penetrating transactivator of transcription (TAT) sequence, the Cdk5i-FT peptide exhibits cell- and brain-penetrant properties and confers protection against neurodegenerative phenotypes associated with Cdk5 hyperactivity in cell and mouse models of neurodegeneration, highlighting Cdk5i's therapeutic potential.

Immunogenic cell death in colorectal cancer: a review of mechanisms and clinical utility.

Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality worldwide. Despite several clinical advances the survival of patients with advanced colorectal cancer remains limited, demanding newer approaches. The immune system plays a central role in cancer development, propagation, and treatment response. Within the bowel, the colorectal mucosa is a key barrier and site of immune regulation that is generally immunosuppressive. Nonetheless, within this tumour microenvironment, it is evident that anti-neoplastic treatments which cause direct cytotoxic and cytostatic effects may also induce immunogenic cell death (ICD), a form of regulated cell death that leads to an anti-tumour immune response. Therefore, novel ICD inducers and molecular biomarkers of ICD action are urgently needed to advance treatment options for advanced CRC. This article reviews our knowledge of ICD in CRC.

A Family of Hexacopper Phenylsilsesquioxane/Acetate Complexes: Synthesis, Solvent-Controlled Cage Structures, and Catalytic Activity.

Convenient self-assembly synthesis of copper(II) complexes via double (phenylsilsesquioxane and acetate) ligation allows to isolate a family of impressive sandwich-like cage compounds. An intriguing feature of these complexes is the difference in the structure of a pair of silsesquioxane ligands despite identical (Cu6) nuclearity and number (four) of acetate fragments. Formation of particular combination of silsesquioxane ligands (cyclic/cyclic vs condensed/condensed vs cyclic/condensed) was found to be dependent on the synthesis/crystallization media. A combination of Si4-cyclic and Si6-condensed silsesquioxane ligands is a brand new feature of cage metallasilsesquioxanes. A representative Cu6-complex (4) (with cyclic silsesquioxanes) exhibited high catalytic activity in the oxidation of alkanes and alcohols with peroxides. Maximum yield of the products of cyclohexane oxidation attained 30 %. The compound 4 was also tested as catalyst in the Baeyer-Villiger oxidation of cyclohexanone by m-chloroperoxybenzoic acid: maximum yields of 88 % and 100 % of ϵ-caprolactone were achieved upon conventional heating at 50 °C for 4 h and MW irradiation at 70 or 80 °C during 30 min, respectively. It was also possible to obtain the lactone (up to 16 % yield) directly from the cyclohexane via a tandem oxidation/Baeyer-Villiger oxidation reaction using the same oxidant.

Understanding and Controlling Molecular Compositions and Properties in Mixed-Linker Porphyrin Metal-Organic Frameworks.

Porphyrin-based metal-organic frameworks (MOFs) are attractive materials for photo- and thermally activated catalysis due to their unique structural features related to the porphyrin moiety, guest-accessible porosity, and high chemical tunability. In this study, we report the synthetic incorporation of nonplanar ß-ethyl-functionalized porphyrin linkers into the framework structure of PCN-222, obtaining a solid-solution series of materials with different modified linker contents. Comprehensive analysis by a combination of characterization techniques, such as NMR, UV-vis and IR spectroscopy, powder X-ray diffraction, and N2 sorption analysis, allows for the confirmation of linker incorporation. A detailed structural analysis of intrinsic material properties, such as the thermal response of the different materials, underlines the complexity of synthesizing and understanding such materials. This study presents a blueprint for synthesizing and analyzing porphyrin-based mixed-linker MOF systems and highlights the hurdles of characterizing such materials.

Inheritance of genomic regions and genes associated with number of oocytes and embryos in Gir cattle through daughter design.

Over the past decades, daughter designs, including genotyped sires and their genotyped daughters, have been used as an approach to identify QTL related to economic traits. The aim of this study was to identify genomic regions inherited by Gir sire families and genes associated with number of viable oocytes (VO), total number of oocytes (TO), and number of embryos (EMBR) based on a daughter design approach. In total, 15 Gir sire families were selected. The number of daughters per family ranged from 26 to 395, which were genotyped with different SNP panels and imputed to the Illumina BovineHD BeadChip (777K) and had phenotypes for oocyte and embryo production. Daughters had phenotypic data for VO, TO, and EMBR. The search for QTL was performed through GWAS based on GBLUP. The QTL were found for each trait among and within families based on the top 10 genomic windows with the greatest genetic variance. For EMBR, genomic windows identified among families were located on BTA4, BTA5, BTA6, BTA7, BTA8, BTA13, BTA16, and BTA17, and they were most frequent on BTA7 within families. For VO, genomic windows were located on BTA2, BTA4, BTA5, BTA7, BTA17, BTA21, BTA22, BTA23, and BTA27 among families, being most frequent on BTA8 within families. For TO, the top 10 genomic windows were identified on BTA2, BTA4, BTA5, BTA7, BTA17, BTA21, BTA22, BTA26, and BTA27, being most frequent on BTA7 and BTA8 within families. Considering all results, the greatest number of genomic windows was found on BTA7, where the VCAN, XRCC4, TRNAC-ACA, HAPLN1, and EDIL3 genes were identified in the common regions. In conclusion, 15 Gir sire families with 26 to 395 daughters per family with phenotypes for oocyte and embryo production helped to identify the inheritance of several genomic regions, especially on BTA7, where the EDIL3, HAPLN1, and VCAN candidate genes were associated with number of oocytes and embryos in Gir cattle families.

Managing systemic reactions and venom immunotherapy in vespid-venom allergy: observations from a retrospective study of Portuguese patients.

Summary: Background. Vespula spp. and Polistes spp. are relevant species in South Europe, with Vespa velutina nigrithorax (VVN) being considered a public health problem. We aimed to characterize a cohort of Portuguese patients referred for large local reaction (LLR) and/or systemic reaction (SR) to vespids. In patients treated with venom immunotherapy (VIT), induction protocol and frequency of adverse reactions were evaluated. Methods. Retrospective study including patients with LLR and SR to vespids referred to our Immunoallergology Department (2008-2022). Results. A total of 129 patients were evaluated, the majority were male adults (n = 77, 59.7%), from rural areas. From these, 51 patients had SR (Mueller classification: 7.8% grade I, 19.6% grade II, 37.3% grade III, 35.3% grade IV). We found no differences regarding the levels of total serum IgE, basal serum tryptase value, sIgE levels to the eliciting venom or their molecular components, regarding the severity of the SR that motivated the referral to our clinic. In the SR group, previous LLR Hymenoptera sting were reported in 15.7%. Thirty-eight patients (74.5%) initiated VIT: 22 with wasp venom, 14 with paper wasp venom and 2 with Vespa velutina venom. There was one mild systemic reaction, not requiring adrenaline and 4 LLR. Re-stings after VIT occurred in 16 patients, without any systemic or local reactions. Currently, eleven patients remain under VIT. Conclusions. Most vespid-venom allergic patients are male adults from rural areas. Sensitization to wasp venom was present in 52.9%, paper wasp in 33.3% and Vespa velutina in 13.7%. The frequency of adverse reactions during both induction and maintenance phases appears to be low. Despite a reduced sample size, our experience with VVN VIT, suggests its safety.

Oral squamous cell carcinoma arising from areas of Graft-versus-host disease: A systematic review.

BACKGROUND: Graft-versus-host disease (GVHD) is an immune system reaction that occurs in patients with a history of hematopoietic stem cell transplantation (HSCT), in which the grafted donor's cells attack those of the host. The objective of this systematic review was to present a study on oral squamous cell carcinoma (OSSC) that developed from GVHD areas in patients undergoing HSCT. MATERIAL AND METHODS: An electronic search was conducted in the databases PUBMED, WEB OF SCIENCE, SCOPUS, MEDLINE and SCIENCE DIRECT, according to PRISMA guidelines. RESULTS: Of the 1582 results, 23 articles were included, resulting in 81 cases. The most common underlying disease for performing the transplant was Myeloid Leukemia (55.6%). The mean age was 39 years, with a predilection for males (64.2%). The tongue was the site of GVHD that most frequently underwent transformation to SCC (59.3%). The average time between transplantation and the development of GVHD was of approximately of 8 months, while the average period of development between transplantation and the development of OSCC was of approximately of 111 months. The most common treatment to GVHD was cyclosporine associated with corticosteroids. CONCLUSIONS: OSCCs arising from areas of GVHD present a different evolution from conventional oral carcinomas, since they affect younger patients, smoking and alcohol are not important etiological factors and finally because they present good prognosis, but further studies with larger number cases followed are needed to confirm our findings.

Identification of runs of homozygosity (ROHs) in Curraleiro Pé-Duro and Pantaneiro cattle breeds.

This study aimed to identify and characterize runs of homozygosis (ROHs), genes involved in production characteristics and adaptation to tropical systems and to estimate the inbreeding coefficient of Curraleiro Pé-Duro (CPD) and Pantaneiro (PANT), two brazilian locally adapted cattle breeds. The results demonstrated that 79.25% and 54.29% of ROH segments were bigger than 8 Mb in CPD and PANT, respectively, indicating recent inbred matings in the studied population. Six homozygosis islands were identified simultaneously in both breeds, where 175 QTLs and 1072 genes previously described as associated with production traits are located. The inbreeding coefficient (FROH) estimated based on ROHs (FROH) showed that inbreeding is low (2 to 4%), which is different from expected for small populations such as locally adapted ones.

Long-term memory in Staphylococcus aureus α-hemolysin ion channel kinetics.

The kinetics of an ion channel are classically understood as a random process. However, studies have shown that in complex ion channels, formed by multiple subunits, this process can be deterministic, presenting long-term memory. Staphylococcus aureus α-hemolysin (α-HL) is a toxin that acts as the major factor in Staphylococcus aureus virulence. α-HL is a water-soluble protein capable of forming ion channels into lipid bilayers, by insertion of an amphipathic  ß-barrel. Here, the α-HL was used as an experimental model to study memory in ion channel kinetics. We applied the approximate entropy (ApEn) approach to analyze randomness and the Detrended Fluctuation Analysis (DFA) to investigate the existence of long memory in α-HL channel kinetics. Single-channel currents were measured through experiments with α-HL channels incorporated in planar lipid bilayers. All experiments were carried out under the following conditions: 1 M NaCl solution, pH 4.5; transmembrane potential of + 40 mV and temperature 25 ± 1 °C. Single-channel currents were recorded in real-time in the memory of a microcomputer coupled to an A/D converter and a patch-clamp amplifier. The conductance value of the α-HL channels was 0.82 ± 0.0025 nS (n = 128). The DFA analysis showed that the kinetics of α-HL channels presents long-term memory ([Formula: see text] = 0.63 ± 0.04). The ApEn outcomes showed low complexity to dwell times when open (ApEno = 0.5514 ± 0.28) and closed (ApEnc = 0.1145 ± 0.08), corroborating the results of the DFA method.

Cage-like Cu5Cs4-Phenylsilsesquioxanes: Synthesis, Supramolecular Structures, and Catalytic Activity.

A small family of nonanuclear Cu5Cs4-based phenylsilsesquioxanes 1-2 were prepared by a convenient self-assembly approach and characterized by X-ray diffraction studies. The compounds 1 and 2 show some unprecedented structural features such as the presence of a [Ph14Si14O28]14- silsesquioxane ligand and a CuII5CsI4 nuclearity in which the metal cations occupy unusual positions within the cluster. Copper ions are "wrapped" into a silsesquioxane matrix, while cesium ions are located in external positions. This resulted in cesium-involved aggregation of coordination polymer structures. Both compounds 1 and 2 realize specific metallocene (cesium-phenyl) linkage between neighboring cages. Compound 2 is evaluated as a catalyst in the Baeyer-Villiger (B-V) oxidation of cyclohexanone and tandem cyclohexane oxidation/B-V oxidation of cyclohexanone with m-chloroperoxybenzoic acid (mCPBA) as an oxidant, in an aqueous acetonitrile medium, and HNO3 as the promoter. A quantitative yield of ε-caprolactone was achieved under conventional heating at 50 °C for 4 h or MW irradiation for 30 min (for cyclohexanone as substrate); 17 and 19% yields of lactone upon MW irradiation at 80 °C for 30 min and heating at 50 °C for 4 h, respectively (for cyclohexane as a substrate), were achieved. Complex 2 was evaluated as a catalyst for the oxidation of alkanes to alkyl hydroperoxides and alcohols to ketones with peroxides at 60 °C in acetonitrile. The maximum yield of cyclohexane oxidation products was 30%. Complex 2 exhibits high activity in the oxidation of alcohols.

Estimating the nonideality of eutectic systems containing thermally unstable substances.

Eutectic systems design requires an in-depth understanding of their solid-liquid equilibria (SLE). Modeling SLE in eutectic systems has as prerequisites, the melting properties and activity coefficients of components in the liquid phase. Thus, due to the unavailable melting properties of thermally unstable substances, it is impossible to estimate their activity coefficients from experimental SLE data and model the SLE phase diagram of their eutectic systems. Here, we evaluate the activity coefficients of thermally unstable constituents in the liquid phase, which were calculated independent of their melting properties by correlating the SLE data of their cocrystals. Differential scanning calorimetry and powder x-ray diffraction were employed to obtain the SLE phase diagram of three eutectic systems, i.e., tetramethylammonium chloride/catechol, tetraethylammonium chloride/catechol, and betaine/catechol systems, and identify the formation of nine cocrystals. The non-random, two-liquid equation was used to calculate the activity coefficients of the components in the liquid phase. The substantial negative deviation from ideality in the three studied systems indicated strong hydrogen bonding interactions in the liquid solution. Furthermore, modeling ion-ion interactions in eutectic systems containing ionic constituents is of utmost importance for understanding their nonideality.

A walk in the PARC: developing and implementing 21st century chemical risk assessment in Europe.

Current approaches for the assessment of environmental and human health risks due to exposure to chemical substances have served their purpose reasonably well. Nevertheless, the systems in place for different uses of chemicals are faced with various challenges, ranging from a growing number of chemicals to changes in the types of chemicals and materials produced. This has triggered global awareness of the need for a paradigm shift, which in turn has led to the publication of new concepts for chemical risk assessment and explorations of how to translate these concepts into pragmatic approaches. As a result, next-generation risk assessment (NGRA) is generally seen as the way forward. However, incorporating new scientific insights and innovative approaches into hazard and exposure assessments in such a way that regulatory needs are adequately met has appeared to be challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) has been designed to address various challenges associated with innovating chemical risk assessment. Its overall goal is to consolidate and strengthen the European research and innovation capacity for chemical risk assessment to protect human health and the environment. With around 200 participating organisations from all over Europe, including three European agencies, and a total budget of over 400 million euro, PARC is one of the largest projects of its kind. It has a duration of seven years and is coordinated by ANSES, the French Agency for Food, Environmental and Occupational Health & Safety.

Is the increment of diabetes mellitus in Brazil associated with the consumption of artificially sweetened beverages? A time trend analysis with 757,386 adults from 2006 to 2020.

OBJECTIVE: To describe trends in the prevalence of diabetes mellitus (DM) in Brazil and to analyze its association with the consumption of artificially sweetened beverages among individuals aged 18 years or older. STUDY DESIGN: This was a repeated cross-sectional study. METHODS: Annual data from VIGITEL surveys (2006-2020) were used, which included adults from all Brazilian state capitals. The outcome was the prevalence of DM (type 1 and type 2). The main exposure variable was consuming beverages like soft drinks and artificial juices, either in its 'diet, light, or zero' form. Covariates included sex, age, sociodemographic characteristics, smoking, alcohol consumption, physical activity, fruit consumption, and obesity. The temporal trend in the indicators and the etiological fraction (population attributable risk [PAR]) were calculated. Analyses were performed using Poisson regression. The association between DM and consumption of beverages was tested, excluding the year 2020 due to the pandemic; restricting the analysis to the final three years (2018-2020). RESULTS: Overall, 757,386 subjects were included. The prevalence of DM increased from 5.5% to 8.2%, with an annual growth of 0.17 percentage points (95% CI 0.11-0.24). Among those who consumed diet/light/zero beverages, the annual percentage change of DM was four times greater. The PAR corresponding to the consumption of diet/light/zero beverages on the occurrence of DM was 17%. CONCLUSIONS: An increasing prevalence of DM was observed, while diet/light/zero beverages consumption remains stable. A substantial reduction in the annual percentage change of DM could be observed if people stopped consuming diet/light soda/juice.

Respiratory syncytial virus infection: survival experience in a cohort of children inpatients.

OBJECTIVE: The objective of this study was to assess the survival experience of children hospitalized with laboratory-confirmed respiratory syncytial virus (RSV) infection due to bronchiolitis. STUDY DESIGN: This was a nationwide retrospective cohort study conducted in Mexico. METHODS: We analyzed data from 436 children aged 5 years and younger, with symptom onset between August 2021 and November 2022. The Kaplan-Meier method was used to compute survivor functions and their 95% confidence intervals (CI). RESULTS: High survival rates were observed, particularly within the first three weeks of hospital admission. The 3-day survival rate was 99.8% (CI 98.4-99.9%), which decreased to 98.9% (CI 96.5-99.7%), 97.5% (CI 91.9-99.3%), 86.7% (CI 48.2-97.2%), and 69.4% (CI 24.2-91.0%) on days 7, 14, 21, and 28 of hospital stay, respectively. We documented a total of 5 fatal outcomes, resulting in a mortality rate of 2.1 (95% CI 0.9-5.1) per 1,000 person-days. CONCLUSIONS: Our study analyzed a large cohort of pediatric patients with bronchiolitis caused by RSV infection, providing valuable insights into the in-hospital progression of this disease.

Physical activity and long COVID: findings from the Prospective Study About Mental and Physical Health in Adults cohort.

OBJECTIVES: The study investigated the longitudinal association between physical activity and the risk of long COVID in patients who recovered from COVID-19 infection. STUDY DESIGN: We analyzed longitudinal data of the Prospective Study About Mental and Physical Health cohort, a prospective cohort study with adults living in Southern Brazil. METHODS: Participants responded to an online, self-administered questionnaire in June 2020 (wave 1) and June 2022 (wave 4). Only participants who self-reported a positive test for COVID-19 were included. Physical activity was assessed before (wave 1, retrospectively) and during the pandemic (wave 1). Long COVID was assessed in wave 4 and defined as any post-COVID-19 symptoms that persisted for at least 3 months after infection. RESULTS: A total of 237 participants (75.1% women; mean age [standard deviation]: 37.1 [12.3]) were included in this study. The prevalence of physical inactivity in baseline was 71.7%, whereas 76.4% were classified with long COVID in wave 4. In the multivariate analysis, physical activity during the pandemic was associated with a reduced likelihood of long COVID (prevalence ratio [PR]: 0.83; 95% confidence interval [CI]: 0.69-0.99) and a reduced duration of long COVID symptoms (odds ratio: 0.44; 95% CI: 0.26-0.75). Participants who remained physically active from before to during the pandemic were less likely to report long COVID (PR: 0.74; 95% CI: 0.58-0.95), fatigue (PR: 0.49; 95% CI: 0.32-0.76), neurological complications (PR: 0.47; 95% CI: 0.27-0.80), cough (PR: 0.40; 95% CI: 0.22-0.71), and loss of sense of smell or taste (PR: 0.43; 95% CI: 0.21-0.87) as symptom-specific long COVID. CONCLUSION: Physical activity practice was associated with reduced risk of long COVID in adults.

Evaluating the performance of WHO and CDC case definitions for influenza-like illness in diagnosing influenza during the 2022-2023 flu season in Mexico.

OBJECTIVE: This study aimed to evaluate the performance of the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) case definitions for influenza-like illness (ILI) in diagnosing influenza during the 2022-2023 flu season in Mexico. STUDY DESIGN: We conducted a cross-sectional analysis of national epidemiological surveillance data in Mexico, focusing on respiratory viral pathogens. METHODS: We analyzed data from 6027 non-hospitalized patients between 5 and 65 years old who underwent molecular testing for respiratory viral pathogens. The performance of both case definitions was evaluated in terms of sensitivity, specificity, and the area under the receiver operating characteristic (AUROC) curve. RESULTS: Overall, the diagnostic accuracy of the evaluated ILI definitions in identifying influenza patients was low, particularly among older patients. When compared to the CDC, the WHO definition had a lower sensitivity but a higher specificity, resulting in a higher AUROC (P = 0.031) for the WHO criteria. CONCLUSIONS: Our findings suggest that the WHO and CDC ILI case definitions have limited accuracy for diagnosing influenza in non-hospitalized patients and highlight the need for more specific diagnostic tools to improve the detection of influenza cases during the flu season.

Defining hereditary alpha-tryptasemia as a risk/modifying factor for anaphylaxis: are we there yet?

Summary: Hereditary α-tryptasemia (HαT) is a common autosomal dominant genetic trait with variable penetrance associated with increased serum baseline tryptase (SBT) levels. Clinical manifestations may range from an absence of symptoms to overtly severe and recurrent anaphylaxis. Symptoms have been claimed to result from excessive activation of EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) and protease-activated receptor 2 (PAR-2) receptors by α/ß-tryptase heterotetramers. Herein, we aimed to review the evidence on whether HαT can be considered a hereditary risk factor or a modifying factor for anaphylaxis.Increased SBT levels have been linked to an increased risk of anaphylaxis. Likewise, recent studies have shown that HαT might be associated with a higher risk of developing anaphylaxis and more severe anaphylaxis. The same has also been shown for patients with clonal mast cell disorders, in whom the co-existence of HαT might lead to a greater propensity for severe, potentially life-threatening anaphylaxis. However, studies leading to such conclusions are generally limited in sample size, while other studies have shown opposing results. As such, further studies investigating the potential association of HαT with anaphylaxis caused by different triggers, and different severity grades, in both patients with clonal mast cell activation syndromes and the general population are still needed.

Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs on a pediatric Portuguese cohort.

Summary: Background. Non-steroidal anti-inflammatory drugs (NSAID)/analgesics (paracetamol) are among the most common causes of drug hypersensitivity reactions in children, with a reported prevalence of around 0.3% in the pediatric population. Paracetamol and ibuprofen are the most commonly reported culprits in the pediatric population. Our objective was to describe the allergy workup to NSAID/paracetamol of a pediatric population monitored in an allergy outpatient clinic. Methods. Retrospective observational study by consulting the medical records of patients evaluated in a pediatric outpatient clinic with history of NSAID/paracetamol, between January 2016 to August 2022. Results. A total of 43 patients have been evaluated for NSAID/paracetamol suspected allergy: 53.5% females, mean age of 9.8 ± 5.1 years, 47.7% atopic. The drugs reported as culprits were: ibuprofen (75.6%), paracetamol (17.8%), metamizole (4.4%) and naproxen (2.2%) and clinical manifestations were mainly urticaria/angioedema and maculopapular exanthema. Skin tests were performed in 7 patients: paracetamol (n = 5) and metamizole (n = 2), which were all negative. Fourty-six drug provocation tests were performed: 28 with the culprit drug and 18 with an alternative one; only 2 were positive (ibuprofen - culprit NSAID group): one immediate periorbital angioedema and one delayed lip edema with oropharyngeal tightness. Conclusions. The investigation of allergy to NSAID/paracetamol in children remains a challenge. In our population, ibuprofen was the most common NSAID reported. There were only 2 (4.3%) mild reactions on DPT. We could allow the use of the culprit NSAID/analgesic in 11 patients and an alternative one in 9 patients. This study highlights the importance of DPT in children for a correct diagnosis of NSAID hypersensitivity and selection of an alternative drug.

Qualitative study exploring general dental practitioners' views of MIH and its management in the UK and Australia.

BACKGROUND: Molar-incisor hypomineralisation (MIH) is a prevalent condition, and how it is managed varies greatly between professional groups. AIM: To explore, and compare, the UK and Australian general dental practitioners' management of MIH in children. DESIGN: Face-to-face (remote) semistructured interviews were undertaken, using country-specific topic guides. Participants were purposively sampled and recruited through national conferences and research networks (eviDent Foundation and Northern Dental Practice Based Research Network). Interviews (from each country) were audio-recorded, transcribed verbatim and independently analysed using thematic analysis. RESULTS: Two major themes arose from the UK interviews: (i) decision-making complexities and understanding of treatment options and (ii) need for specialist input. The main Australian themes were (i) multidisciplinary approach to management supporting decision-making complexities and (ii) economic implications for care. Several difficulties, such as financial implications, multidisciplinary care and clinical decision-making, were identified as barriers to effectively managing MIH by GDPs in primary care. CONCLUSION: There are similarities and differences in the knowledge and management of MIH amongst UK and Australian nonspecialists. The different healthcare systems played a significant role in shaping how GDPs manage MIH with barriers relating to affordability, multidisciplinary care and clinical decision-making.