Management of Patients with Suspected or Confirmed Antibiotic Allergy: Executive Summary of Guidelines from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Allergy and Clinical Immunology (SEAIC), the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Intensive Medicine and Coronary Care Units (SEMICYUC).

Suspected or confirmed antibiotic allergy is a frequent clinical circumstance that influences antimicrobial prescription and often leads to the avoidable use of less efficacious and/or more toxic or costly drugs than first-line antimicrobials. Optimizing antimicrobial therapy in patients with antibiotic allergy labels has become one of the priorities of antimicrobial stewardship programs in several countries. These guidelines aim to make recommendations for the systematic approach to patients with suspected or confirmed antibiotic allergy based on current evidence. An expert panel (11 members of various scientific societies) formulated questions about the management of patients with suspected or confirmed antibiotic allergy. A systematic literature review was performed by a medical librarian. The questions were distributed among panel members who selected the most relevant references, summarized the evidence, and formulated graded recommendations when possible. The answers to all the questions were finally reviewed by all panel members. A systematic approach to patients with suspected or confirmed antibiotic allergy was recommended to improve antibiotic selection and, consequently, clinical outcomes. A clinically oriented, 3-category risk-stratification strategy was recommended for patients with suspected antibiotic allergy. Complementary assessments should consider both clinical risk category and preferred antibiotic agent. Empirical therapy recommendations for the most relevant clinical syndromes in patients with suspected or confirmed ß-lactam allergy were formulated, as were recommendations on the implementation and monitoring of the impact of the guidelines. Antimicrobial stewardship programs and allergists should design and implement activities that facilitate the most appropriate use of antibiotics in these patients.

Mixed-quantum-classical or fully-quantized dynamics? A unified code to compare methods.

Three methods for non-adiabatic dynamics are compared to highlight their capabilities. Multi-configurational time-dependent Hartree is a full grid-based solution to the time-dependent Schrödinger equation, variational multi-configurational Gaussian (vMCG) uses a less flexible but unrestricted Gaussian wavepacket basis, and trajectory surface hopping (TSH) replaces the nuclear wavepacket with a swarm of classical trajectories. Calculations with all methods using a model Hamiltonian were performed. The vMCG and TSH were also then run in a direct dynamics mode, with the potential energy surfaces calculated on-the-fly using quantum chemistry calculations. All dynamics calculations used the Quantics package, with the TSH calculations using a new interface to a surface hopping code. A novel approach to calculate adiabatic populations from grid-based quantum dynamics using a time-dependent discrete variable representation is presented, allowing a proper comparison of methods. This article is part of the theme issue 'Chemistry without the Born-Oppenheimer approximation'.

[Pulmonary embolism during SARS-CoV-2 pandemic: clinical and radiological features]. / Tromboembolismo pulmonar durante la pandemia por SARS-CoV-2: características clínicas y radiológicas.

Background: A high incidence of pulmonary embolism has been described during the coronavirus pandemic. Methods: This work is a single-center retrospective study which reviewed computed tomography pulmonary angiograms ordered due to suspected pulmonary embolism during two periods: from March 1, 2020 to May 31, 2020 (pandemic) and during the same interval in 2019 (control). Results: Twenty-two pulmonary embolism were diagnosed during the control period and 99 in the pandemic, 74 of which were associated with COVID-19. Of all patients hospitalized with COVID-19, 5.3% had a pulmonary embolism, with a delay between the two diagnoses of 9.1 ± 8.4 days. During the pandemic, patients with pulmonary embolism had fewer predisposing conditions (previous pulmonary embolism 5.1 vs. 18.2%, p = .05; previous surgery 2 vs. 35.4%, p = .0001; deep vein thrombosis 11.1 vs. 45.5%, p = .0001); peripheral pulmonary embolisms were the most frequent (73.5 vs. 50%, p = . 029). Conclusions: There is an increased risk of having a pulmonary embolism during the SARS-CoV-2 pandemic, which affects patients with a different clinical profile and more often causes distal pulmonary embolisms.

How EU policies could reduce nutrient pollution in European inland and coastal waters.

Intensive agriculture and densely populated areas represent major sources of nutrient pollution for European inland and coastal waters, altering the aquatic ecosystems and affecting their capacity to provide ecosystem services and support economic activities. Ambitious water policies are in place in the European Union (EU) for protecting and restoring aquatic ecosystems under the Water Framework Directive and the Marine Strategy Framework Directive. This research quantified the current pressures of point and diffuse nitrogen and phosphorus emissions to European fresh and coastal waters (2005-2012), and analysed the effects of three policy scenarios of nutrient reduction: 1) the application of measures currently planned in the Rural Development Programmes and under the Urban Waste Water Treatment Directive (UWWTD); 2) the full implementation of the UWWTD and the absence of derogations in the Nitrates Directive; 3) high reduction of nutrient, using best technologies in wastewaters treatment and optimal fertilisation in agriculture. The results of the study show that for the period 2005-2012, the nitrogen load to European seas was 3.3-4.1 TgN/y and the phosphorus load was 0.26-0.30 TgP/y. Policy measures supporting technological improvements (third scenario) could decrease the nutrient export to the seas up to 14% for nitrogen and 20% for phosphorus, improving the ecological status of rivers and lakes, but widening the nutrient imbalance in coastal ecosystems (i.e. increasing nitrogen availability with respect to phosphorus), affecting eutrophication. Further nutrient reductions could be possible by a combination of measures especially in the agricultural sector. However, without tackling current agricultural production and consumption system, the reduction might not be sufficient for achieving the goals of EU water policy in some regions. The study analysed the expected changes and the source contribution in different European regional seas, and highlights the advantages of addressing the land-sea dynamics, checking the coherence of measures taken under different policies.

Multi- and single-reference methods for the analysis of multi-state peroxidation of enolates.

In spite of being spin-forbidden, some enzymes are capable of catalyzing the incorporation of O2(Σg-3) to organic substrates without needing any cofactor. It has been established that the process followed by these enzymes starts with the deprotonation of the substrate forming an enolate. In a second stage, the peroxidation of the enolate formation occurs, a process in which the system changes its spin multiplicity from a triplet state to a singlet state. In this article, we study the addition of O2 to enolates using state-of-the-art multi-reference and single-reference methods. Our results confirm that intersystem crossing is promoted by stabilization of the singlet state along the reaction path. When multi-reference methods are used, large active spaces are required, and in this situation, semistochastic heat-bath configuration interaction emerges as a powerful method to study these multi-configurational systems and is in good agreement with PNO-LCCSD(T) when the system is well-represented by a single-configuration.

Genetics and Epigenetics of Nasal Polyposis: A Systematic Review.

Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and paranasal sinuses that is often associated with nasal polyposis (CRSwNP) in the most severe cases. As in other complex diseases, genetic factors are thought to play an important role in the risk and development of the disease. Environment may also modulate the epigenetic signature in affected patients. In the present systematic review, we aimed to compile all published data on genetic and epigenetic variations in CRSwNP since 2000. We found 104 articles, 24 of which were related to epigenetic studies. We identified more than 150 genetic variants in 99 genes involved in the pathogenesis of nasal polyposis. These were clustered into 8 main networks, linking genes involved in inflammation and immune response (eg, MHC), cytokine genes (eg, TNF), leukotriene metabolism, and the extracellular matrix. A total of 89 miRNAs were also identified; these are associated mainly with biological functions such as the cell cycle, inflammation, and the immune response. We propose a potential relationship between genes and the miRNAs identified that may open new lines of investigation. An in-depth knowledge of gene variants and epigenetic traits could help us to design more tailored treatment for patients with CRSwNP.

Polymorphisms in canine immunoglobulin heavy chain gene cluster: a double-edged sword for diabetes mellitus in the dog.

Insulin deficiency diabetes (IDD) in dogs is an endocrine disease similar to human type 1 diabetes. There are breeds more commonly affected, such as Yorkshire Terrier and Samoyed, suggesting an underlying genetic component. However, the genetic basis for canine diabetes mellitus (DM) is not fully established. We conducted both whole-genome scans for selection signatures and GWASs to compare the genomes of 136 dogs belonging to 29 breeds previously described at low or high risk for developing DM. Candidate variants were tested in dogs with a diagnosis of IDD and controls attending the Complutense Veterinary Teaching Hospital. The only genomic region under selection (CFA8:72 700 000-74 600 000; CanFam3.1) retrieved by our analyses is included in the immunoglobulin heavy chain gene cluster, which has already been related to human human type 1 diabetes susceptibility. This region contains two non-synonymous variants, rs852072969 and rs851728071, showing significant associations with high or low risk for IDD, respectively. The first variant, rs852072969, alters a protein poorly characterised in the dog. In contrast, rs851728071 was predicted to block the synthesis of an immunoglobulin variable (V) domain in breeds at low risk for DM. Although a large and diverse V gene repertoire is thought to offer a fitness advantage, we suggest that rs851728071 prevents the formation of an auto-reactive immunoglobulin V domain probably involved in the pathophysiology of IDD and, thus, decreases the risk for the disease. These results should be interpreted with caution until the functional roles of the proposed variants have been proved in larger studies.

Promoter Genotyping and mRNA Expression - Based Analysis of the PTGDR Gene in Allergy.

BACKGROUND AND OBJECTIVE: Prostaglandin D2 receptors are acquiring a relevant role as potential therapeutic targets in allergy. PTGDR has been described as a candidate gene in allergic disease, although functional studies on this gene are lacking. Objective: The objective of this case-control study was to investigate the potential role of PTGDR in allergy. METHODS: The study population comprised 195 allergic patients and 112 healthy controls. The PTGDR promoter polymorphisms -1289G>A, -1122T>C, -881C>T, -834C>T, -613C>T, -549T>C, -441C>T, -197T>C, and -95G>T were amplified by polymerase chain reaction (PCR) and sequenced. PTGDR expression levels were analyzed using quantitative PCR and normalized to GAPDH and TBP mRNA levels. All procedures were performed following the Minimum Information for Publication of Quantitative Real-Time PCR Experiment guidelines. RESULTS: PTGDR expression levels were significantly higher in allergic patients than in controls (P<.001). Receiver operating characteristic analysis for expression of PTGDR showed a sensitivity of 81.4% compared with 67% for IgE levels. In addition, differences in the genotypic distribution of the polymorphisms -1289G>A and -1122T>C were found in allergic patients (P=.009). CONCLUSIONS: The results indicate that PTGDR overexpression is associated with allergy. The polymorphisms -1289G>A and -1122T>C partly explain the variation in expression we observed. PTGDR expression could have a potential role as a biomarker and pharmacogenetic factor in allergy.

Explicit evidence for a missense mutation in exon 4 of SLC45A2 gene causing the pearl coat dilution in horses.

Four loci seem responsible for the dilution of the basic coat colours in horse: Dun (D), Silver Dapple (Z), Champagne (CH) and Cream (C). Apart from the current phenotypes ascribed to these loci, pearl has been described as yet another diluted coat colour in this species. To date, this coat colour seems to segregate only in the Iberian breeds Purebred Spanish horse and Lusitano and has also been described in breeds of Iberian origin, such as Quarter Horses and Paint Horse, where it is referred to as the 'Barlink Factor'. This phenotype segregates in an autosomal recessive manner and resembles some of the coat colours produced by the champagne CHCH and cream CCr alleles, sometimes being difficult to distinguish among them. The interaction between compound heterozygous for the pearl Cprl and cream CCr alleles makes SLC45A2 the most plausible candidate gene for the pearl phenotype in horses. Our results provide documented evidence for the missense variation in exon 4 [SLC45A2:c.985G>A; SLC45A2:p.(Ala329Thr)] as the causative mutation for the pearl coat colour. In addition, it is most likely involved as well in the cremello, perlino and smoky cream like phenotypes associated with the compound CCr and Cprl heterozygous genotypes (known as cream pearl in the Purebred Spanish horse breed). The characterization of the pearl mutation allows breeders to identify carriers of the Cprl allele and to select this specific coat colour according to personal preferences, market demands or studbook requirements as well as to verify segregation within particular pedigrees.

Retinoic Acid Modulates PTGDR Promoter Activity.

BACKGROUND AND OBJECTIVE: Vitamin A has been linked to the development of allergic diseases although its role is not fully understood, Retinoic acid (RA), a metabolite of Vitamin A, has been previously associated with the prostaglandin pathway, and PTGDR, a receptor of PGD2, has been proposed as a candidate gene in allergy and asthma. Considering the role of PTGDR in allergy, the goal of this study was to analyze the effect of RA on the activation of the promoter region of the PTGDR gene. METHODS: A549 lung epithelial cells were transfected with 4 combinations of genetic variants of the PTGDR promoter and stimulated with all-trans RA (ATRA); luciferase assays were performed using the Dual Luciferase Reporter System, and real-time quantitative polymerase chain reaction was used to measure the expression of PTGDR, CYP26A1, RARA, RARB, RARG, and RXRA in basal A549 cell cultures and after ATRA treatment. We also performed an in silico analysis. RESULTS: After ATRA treatment increased expression of CYP26A1 (12-fold) and RARB (4-fold) was detected. ATRA activated PTGDR promoter activity in transfected cells (P<.001) and RA response element sequences were identified in silico in this promoter region. CONCLUSIONS: RA modulated PTGDR promoter activity. Differential response to RA and to new treatments based on PTGDR modulation could depend on genetic background in allergic asthmatic patients.

Optimisation of antithrombotic therapy in patients with acute coronary syndrome to reduce bleeding episodes.

AIM: The aim of the study was to evaluate the effectiveness of a multidisciplinary intervention to reduce the risk of bleeding associated with antithrombotic drugs in patients with acute coronary syndrome (ACS). METHODS: We designed a pre-post quasi-experimental intervention study using retrospective cohorts. The first cohort was analysed to detect correctable measures contributing to bleeding (PRE: January-July 2010). Second, a bundle of interventions was implemented and third, a second cohort of patients was evaluated to investigate the impact of our measures in bleeding reduction (POST: September 2011-February 2012). RESULTS: A total of 677 patients were included (377 in PRE and 300 in POST). The bundle of interventions was: Overdose avoidance measures: the percentage of patients overdosed was reduced by 66.3% (p < 0.001). Institutional protocol update to include the latest recommendations regarding bleeding prevention: In POST, the percentage of patients treated with fondaparinux increased (2.4% vs. 50.7%; p < 0.001). In PRE, 11 patients were treated with the combination of abciximab and bivalirudin; whereas in POST, only one patient received the combination (p = 0.016). Mandatory measurement of body weight: the percentage of patients with unknown body weight was reduced by 35% (p = 0.0001). In POST, the total bleeding rate was reduced by 29.2% (31.6% in PRE vs. 22.4%, p < 0.05, OR: 0.62; 95% CI: 0.44-0.88). It was necessary to implement the interventions in 11 patients to prevent one bleeding episode (95% CI: 7-39). CONCLUSION: The multidisciplinary programme has been effective in reducing bleeding episodes. The interventions were effective in reducing antithrombotic drugs overdosage, incorporating the use of fondaparinux to the NSTE-ACS therapeutic arsenal, limiting the use of bivalirudin with abciximab and obtaining body weight for most patients.

Analysis of FOXP3 gene in children with allergy and autoimmune diseases.

BACKGROUND: Allergy and autoimmunity are important immunological entities underlying chronic diseases in children. In some cases both entities develop simultaneously in the same patient. FOXP3 gene codes for a transcription factor involved in regulation of the immune system. Considering that regulatory T cells are involved in controlling immunological disease development, and the relevant role of FOXP3 in this kind of T cells, the objective of this study was to analyse the FOXP3 gene in the most prevalent autoimmune diseases and/or allergies in childhood in a European population. METHODS: A total of 255 Caucasian individuals, 95 controls and 160 patients diagnosed with allergic, autoimmune or both diseases were included in this study. The molecular analysis of FOXP3 was performed by DNA sequencing following the recommendations for quality of the European Molecular Genetics Quality Network. Genomic DNA was extracted from peripheral blood of all participants and was amplified using the polymerase chain reaction. After the visualisation of the amplified fragments by agarose gel-electrophoresis, they were sequenced. RESULTS: Thirteen different polymorphisms in FOXP3 gene were found, seven of which had not been previously described. The mutated allele of SNP 7340C>T was observed more frequently in the group of male children suffering from both allergic and autoimmune diseases simultaneously (p=0.004, OR=16.2 [1.34-195.15]). CONCLUSIONS: In this study we identified for first time genetic variants of FOXP3 that are significantly more frequent in children who share allergic and autoimmune diseases. These variants mainly affect regulatory sequences that could alter the expression levels of FOXP3 modifying its function including its role in Treg cells.

Genome-wide association studies (GWAS) and their importance in asthma.

Asthma is a complex disease determined by the interaction of different genes and environmental factors. The first genetic investigations in asthma were candidate gene association studies and linkage studies. In recent years research has focused on association studies that scan the entire genome without any prior conditioning hypothesis: the so-called genome-wide association studies (GWAS). The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1). None of these genes would have been selected in a classical genetic association study since it was not known they could be implicated in asthma. To date, a number of GWAS studies in asthma have been made, with the identification of about 1000 candidate genes. Coordination of the different research groups in international consortiums and the application of new technologies such as new generation sequencing will help discover new implicated genes and improve our understanding of the molecular mechanisms underlying the disease.

Estimating influenza vaccine effectiveness in Spain using sentinel surveillance data.

We aimed to estimate influenza vaccine effectiveness (VE) against laboratory-confirmed influenza during three influenza seasons (2010/11 to 2012/2013) in Spain using surveillance data and to compare the results with data obtained by the cycEVA study, the Spanish component of the Influenza Monitoring Vaccine Effectiveness (I-MOVE) network. We used the test-negative case­control design, with data from the Spanish Influenza Sentinel Surveillance System (SISS) or from the cycEVA study. Cases were laboratory-confirmed influenza patients with the predominant influenza virus of each season, and controls were those testing negative for any influenza virus. We calculated the overall and age-specific adjusted VE. Although the number of patients recorded in the SISS was three times higher than that in the cycEVA study, the quality of information for important variables, i.e. vaccination status and laboratory results, was high in both studies. Overall, the SISS and cycEVA influenza VE estimates were largely similar during the study period. For elderly patients (> 59 years), the SISS estimates were slightly lower than those of cycEVA, and estimates for children (0­14 years) were higher using SISS in two of the three seasons studied. Enhancing the SISS by collecting the date of influenza vaccination and reducing the percentage of patients with incomplete information would optimise the system to provide reliable annual influenza VE estimates to guide influenza vaccination policies.

Transanal total mesorectal excision: a pure NOTES approach for selected patients.

BACKGROUND: The concept of natural orifice transluminal endoscopic surgery (NOTES) has stimulated the development of various "incisionless" procedures. One of the most popular is the transanal approach for rectal lesions. The aims of this study were to report how we standardized NOTES technique for transanal mesorectal excision without abdominal assistance, discuss the difficulties and surgical outcomes of this technique and report its feasibility in a small group of selected patients. METHODS: Three consecutive female patients underwent transanal NOTES rectal resection without transabdominal laparoscopic assistance for rectal lesions. Functional results were assessed with the Fecal Incontinence Quality of Life scale and the Wexner score. RESULTS: The technical steps are described in details and complemented with a video. All procedures were completed without transabdominal laparoscopic help. The mesorectal plane was entirely dissected without any disruption, and distal and circumferential margins were tumor-free. No major complications were observed. Functional results show a significant impairment after surgery with improvement at 6 months to levels near those of the preoperative period. CONCLUSIONS: The performance and publication of NOTES procedures are subject to much discussion. Despite the small number of patients, this procedure appears feasible and can be accomplished maintaining fecal continence and respecting oncologic principles.

Drug treatment for diabetes in nursing home residents.

AIMS: The aim of this study was to describe drug treatment for diabetes in a large sample of nursing home residents and to compare subjects' health outcomes according to the anti-diabetic agents used. METHODS: The cross-sectional data of 6275 residents [average age 86 years (± 8.2); 73.7% women] from 175 nursing homes in France were analysed. Participants were divided into one of the following four groups: diabetes non-drug treatment, diabetes hypoglycaemic (e.g. insulins, sulphonylurea) treatment, diabetes non-hypoglycaemic (e.g. metformin) treatment and no diabetes. Group comparisons were made on functional ability (activities of daily living score) and on the prevalence of the following variables (yes vs. no): emergency department visits, falls and fractures. RESULTS: Of the participants, 1076 (17.1%) had diabetes: 222 participants in the non-drug treatment group, 722 in the hypoglycaemic group and 132 in the non-hypoglycaemic group. The remaining 5199 participants made up the group without diabetes. Insulin and metformin were used by 549 and 185 participants, respectively. Activities of daily living scores differed across the four groups, with those in the non-drug treatment group being the most disabled. Adjusted multivariate analyses showed that, compared with the group without diabetes, those in the hypoglycaemic group had a higher probability of emergency department visits (odds ratio 1.26, 95% CI 1.03-1.54) and increased the incidence rate ratios (1.02, 95% CI 1.00-1.04) of disability (activities of daily living score), whereas the non-hypoglycaemic group was not significantly associated with these outcomes. CONCLUSIONS: The use of hypoglycaemic drugs was associated with poor health outcomes in nursing home residents. Therefore, more attention must be paid to adapting anti-diabetic treatment in this complex population.