Three-dimensional (3D) bioprinting shows great potential for autologous vascular grafts due to its simplicity, accuracy, and flexibility. 6mm diameter vascular grafts are used in clinic. However, producing small-diameter vascular grafts are still an enormous challenge. Normally, sacrificial hydrogels are used as temporary lumen support to mold tubular structure which will affect the structure’s stability. In this study, we develop a new bioprinting approach to fabricating small-diameter vessel using two-step crosslinking process. ¼ lumen wall of bioprinted gelatin mechacrylate (GelMA) flat structure is exposed to ultraviolet (UV) light briefly for having certain strength, while ¾ lumen wall shows as concave structure remained uncrosslinked. Pre-crosslinked flat structure is merged towards the uncrosslinked concave structure. Two individual structures will be combined tightly into an intact tubular structure by receiving more UV exposure time. Complicated tubular structures are constructed by these method. Notably, the GelMA-based bioink loaded with smooth muscle cells (SMCs) are bioprinted as the outer layer and human umbilical vein endothelial cells (HUVECs) are seeded onto the inner surface. A bionic vascular vessel with dual layers is fabricated successfully and keeps good viability, and functionality. This study may provide a novel idea for fabricating biomimetic vascular network or other more complicated organs.

Title: Food protein-induced enterocolitis syndrome caused by scallopAuthors: Yuka Okura, Yutaka Takahashi, and Ichiro Kobayashi.Institutional affiliation: Department of Pediatrics, KKR Sapporo Medical Center, Sapporo, JapanRunning title: FPIES caused by scallopCorresponding author: Yuka Okura, KKR Sapporo Medical Center, Department of Pediatrics, 6-3-40, Hiragishi 1-jo, Toyohira-ku, Sapporo, 062-0931, JapanPhone: 81-11-822-1811; Facsimile: 81-11-841-4572; E-mail; okura@kkr-smc.comWord count: 973 wordsTables: 0Figures: 0

A document by Laura Sonneveld, written on Authorea.

Tocilizumab for reduction of mortality in severe COVID-19 patients: how should we GRADE it?Vladimir TrkuljaVladimir Trkulja, MD, PhDDepartment of PharmacologyZagreb University School of MedicineŠalata 1110000 Zagreb, Croatiae-mail: vladimir.trkulja@mef.hrNumber of words: 799Number of figures/tables: 1To the Editor,A recent systematic review/meta-analysis 1 of randomized trials (RCTs) of tocilizumab (plus standard of care [SoC] vs. SoC w/wo placebo) in severe COVID-19 patients was a pleasure to read owing to a clear presentation of a thorough approach to data (e.g., sensitivity analyses, accounting for corticosteroid use, need for mechanical ventilation [MV] at baseline). Authors assigned high quality (certainty) GRADE levels to the evidence of efficacy in reduction of mortality overall (10 RCTs) and in patients without MV at baseline (data from 9 RCTs), and reduction of incident MV (10 RCTs). The grading was based on fixed-effect pooling, likely owing to low inconsistency index (I2) and closely similar fixed-effect and random-effects estimates1. It is this point that deserves a few comments. Conceptually, fixed-effect meta-analysis of RCTs in medicine is rarely justified, since the underlying assumption is practically inevitably violated due to variety of elements contributing to clinical heterogeneity2. The authors1 presented a range of differences in trial designs (e.g., one or repeated tocilizumab dose, more or less use of concomitant corticosteroids, differences in proportion of subjects on MV). When variance across trials is low, fixed and random-effects estimates are numerically close/identical, but the conceptual differences remain. Again, conceptually, the random-effects method is a preferred approach2 (regardless of numerical closeness of fixed/random estimates) and the choice (fixed/random) should not be based on the heterogeneity estimates2. At this point, the issue of the choice of the variance (τ2) estimator should be mentioned. A number of estimators have been explored: performance depends on the nature of the outcome, may vary across trial sizes, depends on the differences in size of included trials, and is problematic when the number of studies is lowe.g.,2-5. Variance reflects on the assigned trial weights and measures of uncertainty about the pooled estimate. While no τ2 estimator is ideal 2-5, it has been suggested that the Paule-Mandel (PM) estimator performs better than the common DerSimonian-Laird estimator for binary outcomes3.Another point to consider is the method to calculate confidence intervals (CIs) around the pooled estimate. While not without certain limitations 6, the Hartung-Knapp-Sidik-Jonkman (HKSJ) method has been repeatedly shown (under variety of scenarios) to result in more adequate coverage probability than the standard method4,7. Figure 1A re-creates meta-analysis (data presented by the authors1) on mortality across the 10 RCTs (all subjects) – it is only that it uses PM variance estimator and HKSJ correction: random-effects estimate suggests that the mean of the distribution of the effects is 0.88 (as reported1), but the CIs extend to 1.04, suggesting that it includes also effects that are somewhat above unity. It also provides prediction intervals (wider) - the best illustration of heterogeneity2,8. When viewed from the present standpoint, data indicate a non-trivial level of imprecision and heterogeneity. The authors themselves reported apparent differences (mortality reduction vs. no reduction) between estimates based on RCTs with a high proportion vs. low proportion of patients concomitantly treated with corticosteroids 1(or those generated accounting only for corticosteroid-treated vs. not treated patients, but such data were very scarce1): so, there is apparent inconsistency of the estimates across clinical settings. As re-created in Figure 1B-C, there was a tendency of reduced mortality in trials with a high proportion of patients co-treated with corticosteroids (corticosteroid treatment regimen likely variable), but with quite some imprecision and heterogeneity; and no such tendency with “low corticosteroid use”. Similarly, in patients not on MV at baseline, there was a consistent reduction in mortality risk across trials with a high proportion of steroid co-treated patients, but not in trials with a low proportion of co-treated patients (Figure 1D-E). There was also a consistent reduction of risk of incident MV in trials with a high proportion of corticosteroid co-treated patients (Figure 1F), whereas the estimate in trials with “low steroid use” is burdened with heterogeneity and imprecision (Figure 1G).Considering the above, if one were to assign a GRADE level9 to evidence of benefit of tocilizumab in severe COVID-19 patients based on the 10 RCTs addressed in the published meta-analysis1, then the following seems reasonable: a) considering (indiscriminately) all 10 RCTs (and all patients), certainty about reduced mortality is closer to “low/moderate” then to “high” due to imprecision (CIs 0.75-1.04) and heterogeneity/inconsistency; b) data on the effect of tocilizumab+corticosteroid combination that could be extracted from the 10 RCTs are scarce. Trials with high vs. low concomitant use of corticosteroids could be perceived as a proxy, but this is indirect, suggestive and not conclusive evidence. Therefore, while the effects of tocilizumab on the risk of incident MV and mortality in patients not on MV at baseline in trials with a high proportion of corticosteroid co-treated patients were consistent and reasonably precisely estimated, certainty about the benefit of tocilizumab (on top of corticosteroids; regimen?) in this setting is at best moderate/low.ReferencesVela D, Vela-Gaxha Z, Rexhepi M, Olloni R, Hyseni V, nallbani R. Efficacy and safety of tocilizumab versus standard of care/placebo in patients with COVID-19; a systematic review and meta-analysis of randomized controlled trials. Br J Clin Pharmacol . 2021; doi: 10.1111/bcp.15124.Higgins JPT, Thomson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. J R Statist Soc A . 2009; 172(Pt1):137-159.Veroniki AA, Jackson D, Viechtbauer W, Bender R, Bowden J, Knapp G, Kuss O, Higgins JPT, Langan D, Salanti G. Methods to estimate the between-study variance and its uncertainty in meta-analysis. Res Synth Methods . 2016;7(1): 55-79.Langan D, Higgins JPT, Jakson D, Bowden J. Veroniki AA, Kontopantelis E, Viechtbauer W, Simmonds M. A comparison of heterogeneity variance estimators in simulated random-effects meta-analyses. Res Synth Methods. 2019; 10(1):83-98.IntHout J, Ioannidis JPA, Borm GF, Goeman JJ. Small studies are more heterogeneous than large ones: a meta-meta-analysis. J Clin Epidemiol . 2015; 68(8):860-869.Jakson D, Law M, Rucker G, Schwarzer G. The Hartung-Knapp modification for random-effects meta-analysis: a useful refinement but are there any residual concerns? Stat Med . 2017; 36(25):3923-3934.IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.BMC Med Res Methodol . 2014; 14:25 doi:10.1186/1471-2288-14-25.IntHout J, Ioannidis JPA, Rovers MM, Goeman JJ. Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open . 2016; 6:e010247 doi: 10.1136/bmjopen-2015-010247Guyatt GH, Oxman, AD, Vist GE, Kurz R, Falck-Ytter Y, Schunemann HJ. GRADE: what is “quality of evidence” and why is it important to clinicians. BMJ . 2008;336(7651):995-998.Balduzzi S, Rucker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health . 2019; 22(4):153-160.Figure 1 . Re-creation of the published meta-analysis1 using data provided in the published figures: the difference is in that the present estimates are generated using the Paule-Mandel variance estimator (Q-profile method for variance estimate confidence intervals) instead of the DerSimonian-Laired method available in the RevMan software used by the authors1, and Hartung Knapp Sidik Jonkman correction for random effects (see text for explanation). Panel A corresponds to published1Figure 1, panels B and C correspond to published1supplemental Figure S4. Published meta-analysis1 does not include figures that would correspond to panels D-G. Panels E and G are reduced to summaries for brevity. Note that in all meta-analyses point-estimates of I2 and τ2 were low, but the upper limits of their confidence intervals were rather high, particularly when only 4 RCTs were included (except in panel F with highly consistent results across trials). “High%” or “low %” steroid use refers to trials (as presented in the published meta-analysis1) in which >50% or <50% of the patients were co-treated with corticosteroids. Meta-analyses were performed using packagemeta 10 in R.MV – mechanical ventilation; RCT – randomized controlled trial; SoC – standard of care

From an interfacial phenomena standpoint, the effect of length of alkyl chain was evaluated on activities of gallic acid and its alkyl ester derivatives in supramolecular oxidation of stripped soybean oil. The gallic acid molecules (log P = -0.47) with an electron-donating carboxylate anion had a higher scavenging activity against DPPH• than alkyl gallates. Interfacial activities of gallates in emulsion and bulk oil improved as the lengths of the alkyl chain were reached until a critical chain length; after that, further chain length extension causes a decrease in potency. In β-carotene bleaching and Rancimat assays higher inhibitory effect was observed for dodecyl and propyl gallate, respectively. Evaluation of interfacial tension, water content, and droplet size of hydroperoxides reverse micelles in parallel with lipid peroxidation indicated that the inhibitory effect of the alkyl gallates, especially methyl gallate, was significantly better than the gallic acid in the bulk phase oil.

Background: The role of intra-operative parathyroid hormone (IOPTH) monitoring during parathyroidectomy for primary hyperparathyroidism has long been debated. Objectives: Our main goal was to investigate the cure rates of parathyroidectomy for primary hyperparathyroidism with and without IOPTH monitoring. Our secondary goal was to investigate if operating room time can be saved when not using IOPTH monitoring. Design: A retrospective analysis of patients who underwent parathyroidectomy for PHPT for a single adenoma between 2004-2019 was performed. Cure rates and operating room time were compared. Results: 423 patients were included. IOPTH was used in 248 patients (59%). Four patients were not cured, two from each group, with no significant difference between the groups (98.8% vs. 99.1%, p=0.725). Surgery time was significantly longer in the IOPTH group, p<0.001. Conclusions: There is no advantage for using IOPTH during parathyroidectomy in suitable clinical setting. A focused procedure may be safely performed without IOPTH while achieving non-inferior success rates and reducing operative time.

Objectives: We aimed to characterise the use of tracheostomy procedures for all COVID-19 critical care patients in England and to understand how patient factors and timing of tracheostomy affected outcomes. Design: A retrospective observational study using exploratory analysis of hospital administrative data. Setting: All 500 National Health Service hospitals in England. Participants: All hospitalised COVID-19 patients aged ≥ 18 years in England between March 1st and October 31st, 2020 were included. Main outcomes and measures: This was a retrospective exploratory analysis using the Hospital Episode Statistics administrative dataset. Multilevel modelling was used to explore the relationship between demographic factors, comorbidity and use of tracheostomy and the association between tracheostomy use, tracheostomy timing and the outcomes. Results: In total, 2,200 hospitalised COVID-19 patients had a tracheostomy. Tracheostomy utilisation varied substantially across the study period, peaking in April-June 2020. In multivariable modelling, for those admitted to critical care, tracheostomy was most common in those aged 40-79 years, in males and in people of Black and Asian ethnic groups and those with a history of cerebrovascular disease. In critical care patients, tracheostomy was associated with lower odds of mortality (OR: 0.514 (95% CI 0.443 to 0.596), but greater length of stay (OR: 41.143 (95% CI 30.979 to 54.642). In patients that survived, earlier timing of tracheostomy (≤ 14 days post admission to critical care) was significantly associated with shorter length of stay. Conclusions: Tracheostomy is safe and advantageous for critical care COVID-19 patients. Early tracheostomy may be associated with better outcomes, such as shorter length of stay, compared to late tracheostomy.

A document by Ron Ragusa, written on Authorea.

Radiation Recall Phenomenon (RRP) is an inflammatory process in the site of irradiation, induced by physical and medical agents. Few cases of RRP in the skin and lung have been reported after COVID-19 vaccination. Here, we report radiation recall dermatitis after both doses of inactivated SARS-CoV-2 vaccine (Sinopharm, China).

CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA-related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. Its favorable results in these settings suggest that its compassionate use in patients with PROS disorders could have clinical benefits. Another promising drug is Alpelisib, which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signaling pathway. A low dose of Alpelisib used on compassionate grounds was shown in an uncontrolled case series to have striking effects in a cohort of 19 PROS patients, several with life-threatening complications. Moreover, the low dose of Alpelisib provoked few side effects and did not impair linear growth of the often young patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with Alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggest that there may even be collateral benefits of low-dose PI3K inhibition beyond mitigating disease-specific features of PROS.

In the present article, we dene a new kind of the modified Bernstein-Kantorovich operators defined by ¨ Ozarslan (https://doi.org/10.1080/01630563.2015.1079219) i.e. we introduce a new function ς(x) in the modified Bernstein-Kantorovich operators defined by Ozarslan with the property ({) is an infinitely differentiable function on [0; 1]; ς(0) = 0; ς(1) = 1 and ς’(x) > 0 for all x∈ [0; 1]. We substantiate an approximation theorem by using of the Bohman-Korovkins type theorem and scrutinize the rate of convergence with the aid of modulus of continuity, Lipschitz type functions for the our operators and the rate of convergence of functions by means of derivatives of bounded variation are also studied. We study an approximation theorem with the help of Bohman-Korovkins type theorem in A-Statistical convergence. Lastly, by means of a numerical example, we illustrate the convergence of these operators to certain functions through graphs with the help of MATHEMATICA and show that a careful choice of the function ς(x) leads to a better approximation results as compared to the modified Bernstein-Kantorovich operators defined by Ozarslan (https://doi.org/10.1080/01630563.2015.1079219).

Open surgery for chronic type B aortic dissection has been shown to have considerable risks of cerebrovascular complications. Because retrograde perfusion is a potential cause of intraoperative cerebrovascular events, we report our transapical cannulation strategy for descending aorta replacement in chronic type B aortic dissection repair with circulatory arrest. This technique provides an easy and quick establishment of cardiopulmonary bypass by way of a left thoracotomy, and prevention of cerebrovascular event. Transapical cannula can be also used as a vent to ensure a bloodless field during proximal anastomosis and to prevent extension of left ventricle during rewarming. Transapical cannulation is a useful option in open repair of the descending aorta for chronic type B aortic dissection by way of left thoracotomy.

In order to elucidate the temperature-dependent valence state of Ce ion and the occupation number of Ce 4f electrons in cerium mononitride (CeN), we perform an ab initio calculation on CeN by using a many-body scheme combing density functional theory (DFT) with dynamical mean field theory (DMFT), taking into account the spin-orbit coupling (SOC) interaction and on-site Coulomb repulsion between Ce 4f electrons. Results demonstrate that Ce 4f j=5/2 and j=7/2 manifolds undergo insulating-metallic transition with the increasing of temperature. Ce 4f-conduction electrons hybridization, f-f correlation, SOC interaction and final state effects yield a complicated spectrum function in CeN. Ce 4f atomic configuration transition and hybridization might be responsible for the temperature-dependent occupancy number of Ce 4f electrons and the mixed-valence state in CeN. A fact that localization of Ce 4f electrons, i.e., 4f1 configuration or Ce3+ valence, increases with the increasing of temperature could account for the experimentally observed lattice constant versus temperature data. Finally, the so-called quasiparticle band structure is also discussed for comparison with experimental angle-resolved photoemission spectrum (ARPES).

A 3 years old child presented with recurrent chest pain for 3 months, echocardiography showed a thorn inside left ventricle, patient diagnosed as foreign body plus infective endocarditis, received proper treatment, and operation done after inflammatory reaction subsided.

HIV can be associated with cardiovascular complications. We highlight unusual presentation of HIV patient with MI and stroke. 30 year old HIV male presented with MI complicated by stroke. Recovered within 5 days with anti-ischemic and diuretics. Screening tests for unusual presentations prevent fatal complications of common diseases.

Consider a single-electron transistor (SET) with a small size quantum dot (QD), where confined energy and the Coulomb interaction control the charges adding to QD. In this paper, a theoretical analysis of the relation between source-drain voltage and gate voltage has been done to define quantum-Coulomb blocked (and unblocked) diamonds for QD that has N electrons. An analytical equation for the conductance has been derived using the non-equilibrium Green function technique (NEGFT). Further, the effect of QD size and the tunnelling rate on conductance peaks and gaps have been investigated. Finally, the effect of gate voltage on conductance peaks and gaps with respect the quantum-Coulomb blocked regions has been analysed.

Sarcoidosis, a systemic inflammatory disease of unknown etiology, can affect any site in the body. A bone lesion was unexpectedly detected by fluorodeoxyglucose position emission tomography/computed tomography (FDG PET/CT) in a patient with multiorgan sarcoidosis. FDG PET/CT should be considered for the detection of clinically silent lesions of sarcoidosis.

Often, the lithiasis is large and located at the junction of the middle and posterior third of the duct, in the hilum region. In such cases, transoral approach for submandibular lithiases (TASL) is useful treatment of choice in patients with large submandibular stones that can be palpated bimanually.

Biodiversity underpins all food production and strengthens agricultural resilience to crop failure. However, agricultural expansion is the primary driver of biodiversity loss, particularly in the tropics where crop production is increasing and intensifying rapidly to meet a growing global food demand. It is therefore crucial to ask, how do different crops and crop production systems impact biodiversity? Here we show the increasing intensification of tropical agriculture since 1961, along with a sharp rise in harvested area. Using meta-analysis, we find that crop type, rotation time and agricultural intensity, are important determinants of biodiversity assemblages. Perennial tropical crops that are grown in shaded plantations or agroforests (e.g., banana and coffee) support higher alpha-diversity, while those cultivated in unshaded and often homogeneous plantations (e.g., maize, sugarcane, and oil palm) have impoverished biodiversity communities, particularly annual crops. These findings inform our understanding of changes in the ecological contribution of biodiversity to tropical agriculture.

The stability of relaxation techniques has been studied for strongly coupled fluid-structure interaction (FSI) with application to a cantilever immersed in channel flow. The fluid is governed by Navier-Stokes equations for incompressible flow condition using turbulence modelling and the solid is governed by the equation of motion with compressible material modelling. The applied kinematic description is Lagrangian for the solid and Eulerian for the fluid. The coupling of the state solvers is achieved by the Arbitrary Lagrange-Euler procedure which involves a mesh motion solver and the FSI procedure is stabilised by relaxation. It is shown that the stability can be related to the frequency shift caused by FSI and they follow the same rate for the shape factor of the structure with an offset. This correlates well to theoretical results but also show that for given mesh resolution, all relaxations fail for sufficient high-frequency shift. We also propose a continuation technique to stabilise the solution near the instability region, which also improves the efficiency and can be integrated easily for the black-box FSI solution procedure.

Morgagni’s hernia is a congenital diaphragmatic hernia, which represents only 3 % of all diaphragmatic hernias. Herein, we report a case of a 28-years old symptomatic female with Morgagni’s hernia who underwent a trans-abdominal surgery using a mesh placed.

IgG4 related disease is an immune-mediated chronic inflammatory disease. It is a multisystemic disease that can lead to retroperitoneal fibrosis with involvement of the pancreas, glands, thyroid, lymph nodes, etc. and characterized histopathologically by lymphoplasmocytic cell infiltration. We evaluated a patient diagnosed with IGG4 related disease impaired kidney function.

ANAPHYLAXIS TO PANTOPRAZOLE IN A CHILDArriba-Méndez S2,3 MD PhD, Martin-Valbuena J2 MD, Sanz-Rueda L2 MD, Sobrino-García M1,3 MD PhD, Gallardo-Higueras A1 MD, Castillo-Loja R1 MD, Macías E,1,3 MD PhD Martín C1,3 MD PhD, Moreno E1,3,4 MD PhD, Muñoz-Bellido FJ1,3 MD PhD, Gracia-Bara MT1,3 MD, Laffond E1,3 MD PhD, Dávila I1,3,4MD PhD.Department of Allergy, University Hospital of Salamanca, Salamanca, SpainDepartment of Pediatrics, University Hospital of Salamanca, Salamanca, SpainInstitute for Biomedical Research of Salamanca, IBSAL, Salamanca, SpainAsthma, Allergic and Adverse Reactions (ARADyAL) Network for Cooperative Research in Health of Instituto de Salud Carlos III, Hospital Universitario de Salamanca, Salamanca, España.Key words: Proton pump inhibitors. Pantoprazole. Hypersensitivity. Child. Anaphylaxis.To the Editor,Pantoprazole and its analogs (omeprazole, esomeprazole, lansoprazole, rabeprazole) are potent proton pump inhibitors (PPIs), whose use is increasing in the pediatric population (1). They are prescribed for several gastrointestinal pathologies (2), particularly gastroesophageal reflux disease (GERD), but also duodenal ulcers, non-steroidal anti-inflammatory-induced ulcer-related prophylaxis, Helicobacter pylori infection, eosinophilic esophagitis, and other diseases. In general, they have an excellent safety profile, and adverse effects are mild and infrequent (1-3% of patients)(1).Hypersensitivity reactions to PPIs are mainly IgE-mediated, but non-IgE-mediated [contact dermatitis, toxic epidermal necrolysis, leukocytoclastic vasculitis or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)] have been described. In children, immediate hypersensitivity reactions have only been exceptionally reported (3).We introduce the case of a five-year-old girl with a medulloblastoma diagnosed at the age of 3 years, undergoing radiotherapy treatment (last session ten days ago) who was referred to our Allergology Service after suffering an episode of anaphylaxis. Previously to each session, she received premedication with ondansetron plus pantoprazole. In the last session, she had just received ondansetron intravenously and a few minutes after starting the pantoprazole infusion, a generalized diffuse erythematous exanthema suddenly erupted. The event was followed by coughing, severe dyspnea, and inspiratory stridor. No consciousness decrease was reported, neither vomiting nor other gastrointestinal symptoms. Acute anaphylaxis was diagnosed, and the patient was treated with intramuscular epinephrine (0.01mg/kg), intravenous systemic corticosteroids (1mg/kg), and dexchlorpheniramine with gradual resolution in half an hour. The patient had previously received ondansetron and pantoprazole without presenting any adverse reaction. There was neither family nor personal background of hypersensitivity reactions or atopic disease.Skin prick-tests with solutions of non-irritating concentrations (4) of ondansetron (2mg/ml), pantoprazole (40mg/ml), omeprazole (40mg/ml) and lansoprazole (30 mg/ml) were all negative, i.e., the wheal maximum diameter was less than 3 mm over the saline control. Intradermal tests (IDTs) with ondansetron (0.002mg/ml and 0.01 mg/ml) were negative, but IDTs with pantoprazole (4mg/ml) and omeprazole (4 mg/ml) were positive. A single-blind placebo-controlled oral challenge test with ondansetron was performed, showing tolerance of a 3mg dose.A diagnosis of anaphylaxis for pantoprazole was established. Tolerance to lansoprazole was not considered, due to the previous life-threatening reaction, but, it could be considered in the future if required. All proton pumps inhibitors were formally contraindicated.Despite the increase in PPI prescription in pediatric patients, a rise in immune-mediated reactions has not been detected, but there are few studies evaluating PPI allergy in children (5). To date, three cases of PPI anaphylaxis have been described in the pediatric population. One of them was an adolescent studied at 16 who had had anaphylaxis with omeprazole three years earlier. Prick and intradermal tests with omeprazole (0.4 and 4 mg/ml), pantoprazole (0.4 and 4 mg/ml) were negative, but she had a positive challenge with pantoprazole, reproducing anaphylaxis (6).That same year, probable anaphylaxis due to omeprazole and esomeprazole was also described in a 4-month-old infant who presented several episodes of respiratory distress, alongside facial edema in some of them, after using these drugs; however, no allergy study was performed (7). The final described case (8) is a 14-year-old male that had anaphylaxis with omeprazole. Skin prick test were negative, but intradermal tests with omeprazole and lansoprazole were positive. The authors did not perform skin tests with pantoprazole.Ours is the fourth published case of PPI anaphylaxis in children, being the youngest reported patient in which intradermal tests demonstrated an IgE-mediated hypersensitivity reaction. In the literature, cross-reactivity patterns among PPIs have described (9): selective sensitization to a single PPI, whole-group hypersensitivity, omeprazole-esomeprazole-pantoprazole hypersensitivity, and lansoprazole-rabeprazole hypersensitivity. In addition, there are published cases that do not fit those patterns (10). Any case, in PPI-mediated IgE allergy, skin tests have proven useful for diagnosis as they have high specificity and positive predictive value, although low sensitivity (10).In a suspected allergy to a PPI, preventive withdrawal of all PPIs can be appropriate in managing these patients, but we consider that skin tests should always be performed. If negative, controlled oral provocation tests with the PPIs that displayed negative results should always be considered, acknowledging the risk-benefit ratio and possible cross-reactivity patterns.

Background: SARS-CoV-2 variation represents a serious challenge to current COVID-19 vaccines. Recent reports suggest that B.1.351 and other variants may escape the neutralization activity of the antibodies generated by current vaccines. Methods: Ninety-nine healthcare workers undertaking BNT162b2 mRNA vaccination were sampled at baseline, on the day of the second dose, and 14 days after the latter. Neutralization activity against SARS-CoV-2 B.1, B.1.1.7 and B.1.351 was investigated using a Vero-E6 model. Results: Eleven of the study participants had prior infection with SARS-CoV-2. Neutralization titers against the B.1 and the B.1.1.7 variants were not statistically different and were significantly higher than titers against the B.1.351 variant across pre-exposed and non-pre-exposed vaccinated individuals ( p<0.01). While all vaccinated individuals presented neutralizing antibodies against B.1 and B 1.1.7 after the second dose, 14% were negative against B.1.351, and 76% had low titers (1/20-1/80). Pre-exposed vaccinated individuals showed higher titers than non-pre-exposed after the first (median titers of 1/387 versus 1/28, respectively) and the second doses (1/995 versus 1/703, respectively). As high as 72% of the pre-exposed vaccinees presented titers >1/80 after a single dose, while only 11% of non-exposed vaccinated individuals had titers >1/80. Conclusions: BNT162b2 mRNA-induced antibodies show a lower in vitro neutralizing activity against B.1.351 variant compared to neutralization against B.1.1.7 or B.1 variants. Interestingly, for individuals pre-exposed to SARS-CoV-2, one dose of BNT162b2 mRNA may be adequate to produce neutralizing antibodies against B.1.1.7 and B.1, while two doses of BNT162b2 mRNA provide optimal neutralizing antibody response against B.1.351 too.