Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions.

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. CONCLUSIONS: Episodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

STING-associated vasculopathy with onset in infancy (SAVI) presenting with skin lesions.

STING-associated vasculopathy with onset in infancy (SAVI) is caused by pathogenic gain-of-function variants in the gene TMEM173 (also named stimulator of interferon genes, STING1). This report details the case of an 11-year-old girl with SAVI who presented with skin-limited symptoms and discusses the phenotype-genotype correlations of the TMEM173 variant present in our patient. Treatment of SAVI focuses on preventing the development or progression of organ damage by reducing systemic inflammation. We summarize the available treatments for this syndrome.

Surface ozone trends at El Arenosillo observatory from a new perspective.

Surface ozone trends observed at El Arenosillo observatory for the last 22 years (2000-2021) were investigated. The trends for daily averages and daily 5th and 95th percentiles were 1.2 ± 0.3 ppb decade-1, 2.2 ± 0.3 ppb decade-1 and -0.03 ± 0.43 ppb decade-1, respectively, thus showing a significant increase of background ozone. The surface temperature trends were also explored, obtaining trends of 0.5 ± 0.2 °C decade-1, 1.1 ± 0.2 °C decade-1 and -0.3 ± 0.2 °C decade-1 for daily averages, 5th and 95th percentiles, respectively. To identify potential changes in the ozone drivers, the weather pattern shifts were analyzed through the horizontal distribution trends of temperature at 2 m and geopotential height at 850 hPa. A strengthening of the Azores anticyclone and a regional warming were detected, which could contribute to the ozone trends obtained. The surface ozone trend in every month was explored, identifying a monthly pattern, with remarkable opposite trends in December-January (2.4 ± 0.9 ppb decade-1) vs July-August (-0.5 ± 1.1 ppb decade-1). The surface ozone trends for every hour of the day were also explored, identifying two clear patterns. The first pattern occurred from spring to autumn and was characterized by a behavior opposite to the typical daily ozone cycle. The second pattern was observed in winter, and it shows two relative peaks in the ozone trends (around 13:00 and 19:00 UTC). In a context of ozone precursor's depletion, changes in the weather conditions and warmer climate, to improve our knowledge of the ozone trends, we suggest exploring them based on daily and hourly averages.

Processing methods for human amniotic membrane as scaffold for tissue engineering with mesenchymal stromal human cells.

Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function. The aims of this work were to compare chemically and physically processed human Amniotic Membranes (hAM) and analyze the cytocompatibility and proliferation rate (PR) of two primary human mesenchymal stromal cell lines, from different sources and donor conditions seeded over these scaffolds. The evaluated hAM processes were: cold shock to obtain a frozen amniotic membrane (FEAM) with remaining dead epithelial cells, denudation of hAM with trypsin for 20/10 min (DEAM20/10) or treatment with sodium dodecyl sulfate to decellularized hAM (DAM). All samples were sterilized with gamma radiation. The selection of the treated hAM to then generate composites was performed by scanning and transmission electron microscopy and characterization by X-ray diffraction, selecting DEAM10 and FEAM as scaffolds for cell seeding. Two sources of primary human stromal cells were used, both developed by our researchers, human Dental Pulp Stem Cells (hDPSC) from living donors and human Mesenchymal Stromal Cells (hMSC) from bone marrow isolated from brain dead donors. This last line of cells conveys a novel source of human cells that, to our knowledge, have not been tested as part of this type of construct. We developed four in vitro constructs without cytotoxicity signs and with different PR depending on the scaffolds and cells. hDPSC and hMSC grew over both FEAM and DEAM10, but DEAM10 allowed higher PR.

Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL.

BACKGROUND: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial. PATIENTS AND METHODS: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA. RESULTS: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85). CONCLUSIONS: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.

Leisure-time physical activity, sedentary behavior, and risk of breast cancer: Results from the SUN ('Seguimiento Universidad De Navarra') project.

Evidence is still limited on the influence of sedentary lifestyles on breast cancer (BC) risk. Also, prospective information on the combined effects of both sedentariness and leisure-time physical activity (LTPA) is scarce. We aimed to assess the association of higher sedentary behavior and LTPA (separately and in combination) with the risk of BC in a middle-aged cohort of university graduates. The SUN Project is a follow-up study initiated in 1999 with recruitment permanently open. Baseline assessments included a validated questionnaire on LTPA and sedentary habits. Subsequently, participants completed biennial follow-up questionnaires. Multivariable adjusted Cox models were used to estimate the hazard ratios (HR) for incident BC according to LTPA, TV-watching, the joint classification of both, and a combined 8-item multidimensional active lifestyle score. We included 10,812 women, with 11.8 years of median follow-up of. Among 115,802 women-years of follow-up, we confirmed 101 incident cases of BC. Women in the highest category of LTPA (>16.5 MET-h/week) showed a significantly lower risk of BC (HR = 0.55; 95% CI: 0.34-0.90) compared to women in the lowest category (≤6 MET/h-week). Women watching >2 h/d of TV sh owed a higher risk (HR = 1.67; 95% CI:1.03-2.72) than those who watched TV <1 h/d. Women in the highest category (6-8 points) of the multidimensional combined 8-item score showed a lower BC risk (HR = 0.35; 95% CI: 0.15-0.79) than those in the lowest category (<2 points) group. There was no significant supra-multiplicative interaction between TV-watching and LTPA. Both low LTPA and TV-watching >2 h/d may substantially increase BC risk, independently of each other.

Expression-based analysis of genes related to single nucleotide polymorphism hits associated with bovine leukemia virus proviral load in Argentinean dairy cattle.

In dairy cattle infected with bovine leukemia virus (BLV), the proviral load (PVL) level is directly related to the viral transmission from infected animals to their healthy herdmates. Two contrasting phenotypic groups can be identified when assessing PVL in peripheral blood of infected cows. A large number of reports point to bovine genetic variants (single nucleotide polymorphisms) as one of the key determinants underlying PVL level. However, biological mechanisms driving BLV PVL profiles and infection progression in cattle have not yet been elucidated. In this study, we evaluated whether a set of candidate genes affecting BLV PVL level according to whole genome association studies are differentially expressed in peripheral blood mononuclear cells derived from phenotypically contrasting groups of BLV-infected cows. During a 10-mo-long sampling scheme, 129 Holstein cows were phenotyped measuring anti-BLV antibody levels, PVL quantification, and white blood cell subpopulation counts. Finally, the expression of 8 genes (BOLA-DRB3, PRRC2A, ABT1, TNF, BAG6, BOLA-A, LY6G5B, and IER3) located within the bovine major histocompatibility complex region harboring whole genome association SNP hits was evaluated in 2 phenotypic groups: high PVL (n = 7) and low PVL (n = 8). The log2 initial fluorescence value (N0) transformed mean expression values for the ABT1 transcription factor were statistically different in high- and low-PVL groups, showing a higher expression of the ABT1 gene in low-PVL cows. The PRRC2A and IER3 genes had a significant positive (correlation coefficient = 0.61) and negative (correlation coefficient = -0.45) correlation with the lymphocyte counts, respectively. Additionally, the relationships between gene expression values and lymphocyte counts were modeled using linear regressions. Lymphocyte levels in infected cows were better explained (coefficient of determination = 0.56) when fitted a multiple linear regression model using both PRRC2A and IER3 expression values as independent variables. The present study showed evidence of differential gene expression between contrasting BLV infection phenotypes. These genes have not been previously related to BLV pathobiology. This valuable information represents a step forward in understanding the BLV biology and the immune response of naturally infected cows under a commercial milk production system. Efforts to elucidate biological mechanisms leading to BLV infection progression in cows are valuable for BLV control programs. Further studies integrating genotypic data, global transcriptome analysis, and BLV progression phenotypes are needed to better understand the BLV-host interaction.

Synthesis and characterization of a bovine collagen: GAG scaffold with Uruguayan raw material for tissue engineering.

Tissue engineering (TE) and regenerative medicine offer strategies to improve damaged tissues by using scaffolds and cells. The use of collagen-based biomaterials in the field of TE has been intensively growing over the past decades. Mesenchymal stromal cells (MSCs) and dental pulp stem cells (DPSCs) are promising cell candidates for development of clinical composites. In this study, we proposed the development of a bovine collagen type I: chondroitin-6-sulphate (CG) scaffold, obtained from Uruguayan raw material (certified as free bovine spongiform encephalopathy), with CG crosslinking enhancement using different gamma radiation doses. Structural, biomechanical and chemical characteristics of the scaffolds were assessed by Scanning Electron Microscopy, axial tensile tests, FT-IR and Raman Spectroscopy, respectively. Once we selected the most appropriate scaffold for future use as a TE product, we studied the behavior of MSCs and DPSCs cultured on the scaffold by cytotoxicity, proliferation and differentiation assays. Among the diverse porous scaffolds obtained, the one with the most adequate properties was the one exposed to 15 kGy of gamma radiation. This radiation dose contributed to the crosslinking of molecules, to the formation of new bonds and/or to the reorganization of the collagen fibers. The selected scaffold was non-cytotoxic for the tested cells and a suitable substrate for cell proliferation. Furthermore, the scaffold allowed MSCs differentiation to osteogenic, chondrogenic, and adipogenic lineages. Thus, this work shows a promising approach to the synthesis of a collagen-scaffold suitable for TE.

Self-reported changes in the expanded disability status scale score in patients with multiple sclerosis after autologous stem cell transplants: real-world data from a single center.

In order to reset the immune system to baseline function, autologous hematopoietic stem cell transplantation (HSCT) has been performed in patients with multiple sclerosis (MS). After June 2015, 617 new consecutive patients with MS were autografted in our center with non-frozen peripheral blood stem cells. The autografts were performed on an out-patient basis, after conditioning with cyclophosphamide and rituximab. The aim of the study was the assessment of both safety and efficacy of the method. The study's primary co-end-points were recovery of granulocyte and platelet counts and transplant-related mortality. Secondary end-points were overall survival and clinical response (improvement or stabilization of the self-reported expanded disability status scale score). The protocol was registered in ClinicalTrials.gov identifier NCT02674217.0. We included 401 females and 216 males, with a median age of 46 years. A total of 259 patients had relapsing-remitting MS (RRMS), 228 had secondary progressive (SPMS) and 130 had primary progressive (PPMS) multiple sclerosis. All procedures were initially performed on an out-patient basis and only 32 individuals (5%) required hospitalization. One to three aphereses (median 1) were required to harvest at least 1 × 106 /kg viable CD34+ cells. The total number of viable CD34+ infused cells ranged between 1 and 37·83 × 106 /kg (median 5·68). Patients recovered more than 0·5 × 109 /l absolute granulocytes by day 8 (median, range = 2-14), and platelet values were above 20 × 109 /l by day 4 (median, range = 0-11). Eleven individuals required red blood cells and six needed platelet transfusions. To date, there have been no deaths attributable to the transplant, yielding a 30-month overall survival of 100%. Patients have been followed for 3-42 months (median = 12). The overall response rate (decrease or stabilization of the self-reported EDSS score) at 12 months was 78% for all patients (83% in RRMS, 78% in PPMS and 73% in SPMS), while the disability progression-free survival was 82% for all patients (86% in RRMS, 78·5% in SPMS and 78% in SPMS). Changes in the self-reported EDSS score in parallel with neurological improvement were observed in people with all types of MS after HSCT, employing the 'Mexican method'.

Interlaboratory Comparison of Six Real-Time PCR Assays for Detection of Bovine Leukemia Virus Proviral DNA.

Quantitative real-time PCR (qPCR) is increasingly being used for the detection of bovine leukemia virus (BLV) proviral DNA. Nevertheless, quality control for the validation and standardization of such tests is currently lacking. Therefore, the present study was initiated by three Office International des Epizooties (OIE) reference laboratories and three collaborating laboratories to measure the interlaboratory variability of six already developed and available BLV qPCR assays. For that purpose, an international panel of 58 DNA samples reflecting the dynamic range of the majority of the assays was distributed to six testing centers. Based on qualitative results, the overall agreement among all six laboratories was moderate. However, significant variability in the measurement of the BLV proviral DNA copy number was observed among different laboratories. Quantitative PCR assays, even when performed by experienced staff, can yield large variability in BLV proviral DNA copy numbers without harmonization. Further standardization of different factors (i.e., utilization of unified protocols and unique calibrators) should increase interlaboratory agreement.

Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: a retrospective case series.

BACKGROUND: X-linked recessive ichthyosis (XLI) is a relatively common type of ichthyosis caused by a deficiency in the steroid sulfatase (STS) enzyme. It is the only type of ichthyosis that can be both syndromic and nonsyndromic. Typical clinical features include dark-brown scale of variable size favouring the extensor surfaces of the extremities. OBJECTIVES: To characterize clinically nonsyndromic XLI, with a particular focus on extracutaneous manifestations. METHODS: This was a multicentre retrospective review of clinical findings from a case series of patients with a clinical and genetic diagnosis of XLI. RESULTS: We identified 30 patients with XLI belonging to 25 different families carrying a deletion in the STS locus. All patients had dark scales of variable size on the extensor surfaces of the extremities. Lack of flexural involvement and pruritus were common but inconsistent findings, whereas palmoplantar hyperlinearity was absent in all but one patient. A history of orchiopexy was present in 10% and thus was more common than expected vs. the general population (3%). Neurological disorders including epilepsy (13%) and attention deficit hyperactivity disorder (ADHD; 30%) were over-represented in patients with XLI. CONCLUSIONS: This was a retrospective study with a limited number of patients. In the absence of confirmatory genetic testing and family history of the disease, dark-brown scale of the extensor surfaces and the absence of palmoplantar hyperlinearity appear to be the most reliable clinical findings supporting a diagnosis of XLI. Dermatologists should be aware of the high prevalence of ADHD and epilepsy in patients with nonsyndromic XLI.

Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome.

BACKGROUND: Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, which encodes a membrane receptor for Sonic Hedgehog, are associated with the development of the disease. Most of them produce a truncated protein, which is unable to suppress Smoothened protein and continuously activates the downstream pathway. OBJECTIVES: We aimed to characterize 22 unrelated Spanish patients with NBCCS, the largest cohort with Gorlin syndrome reported to date in Spain. METHODS: Genomic analysis of PTCH1 was performed in patients with NBCCS and controls, and mutations were analysed using bioinformatics tools. RESULTS: We report for the first time two young patients, one each with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease had developed basal cell carcinomas since childhood. Sanger sequencing of PTCH1 in this cohort identified 17 novel truncating mutations (11 frameshift, five nonsense and one mutation affecting an exon-intron splice site) and two novel missense mutations that were predicted to be pathogenic. The patients showed great clinical variability and inconsistent genotype-phenotype correlation, as seen in relatives carrying similar mutations. CONCLUSIONS: This study contributes to increase the pool of clinical manifestations of NBCCS, as well as increasing the number of pathogenic mutations identified in PTCH1 predisposing to the condition. The inconsistencies found between phenotype and genotype suggest the involvement of other modifying factors, genetic, epigenetic or environmental.

Plasma temperature during methylene blue/light treatment influences virus inactivation capacity and product quality.

BACKGROUND: Photodynamic treatment using methylene blue (MB) and visible light is in routine use for pathogen inactivation of human plasma in different countries. Ambient and product temperature conditions for human plasma during production may vary between production sites. The influence of different temperature conditions on virus inactivation capacity and plasma quality of the THERAFLEX MB-Plasma procedure was investigated in this study. METHODS: Plasma units equilibrated to 5 ± 2°C, room temperature (22 ± 2°C) or 30 ± 2°C were treated with MB/light and comparatively assessed for the inactivation capacity for three different viruses, concentrations of MB and its photoproducts, activity of various plasma coagulation factors and clotting time. RESULTS: Reduced solubility of the MB pill was observed at 5 ± 2°C. Photocatalytic degradation of MB increased with increasing temperature, and the greatest formation of photoproducts (mainly azure B) occurred at 30 ± 2°C. Inactivation of suid herpesvirus, bovine viral diarrhoea virus and vesicular stomatitis virus was significantly lower at 5 ± 2°C than at higher temperatures. MB/light treatment affected clotting times and the activity of almost all investigated plasma proteins. Factor VIII (-17·7 ± 8·3%, 22 ± 2°C) and fibrinogen (-14·4 ± 16·4%, 22 ± 2°C) showed the highest decreases in activity. Increasing plasma temperatures resulted in greater changes in clotting time and higher losses of plasma coagulation factor activity. CONCLUSIONS: Temperature conditions for THERAFLEX MB-Plasma treatment must be carefully controlled to assure uniform quality of pathogen-reduced plasma in routine production. Inactivation of cooled plasma is not recommended.

Crab-meat-isolated psychrophilic spore forming bacteria inactivation by electron beam ionizing radiation.

The present work was performed to evaluate the potential of electron beam ionizing radiation for the inactivation of three psychrophilic spore forming bacteria (Bacillus mycoides, Bacillus weihenstephanensis and Psychrobacillus psychrodurans) isolated from ready-to-eat brown crab (Cancer pagurus). Inactivation curves for the three spores were performed in both types of crab meat, brown and white. Also the effect of pH and water activity (aw) on the lethal efficacy of ionizing radiation, for the three different psychrophilic spore forming bacteria, was evaluated. The effects of pH, aw and their possible interactions were assessed in citrate-phosphate buffers of different pH, ranging between 7 and 4, and aw, ranging from <0.99 to 0.80. A reduction of aw increased the spores resistance between >0.99 and 0.90, while an aw reduction from 0.90 to 0.80 had a minor impact on their resistance. In contrast to aw, the effect of pH showed a greater variability depending on the spore species. While pH did not affect the resistance of B. weihenstephanensis at any aw, B. mycoides showed slightly higher resistance at pH 5.5 at aw of 0.90 and 0.80. pH showed a significant effect on the resistance of P. psychrodurans. For the two types of crab meat, slightly differences were observed in 6D values. B. weihenstephanensis was the most resistant, requiring 7.3-7.6 kGy to inactivate 6 Log10-cycles of this spore forming bacterium, while for B. mycoides and P. psychrodurans 6.1-6.3 and 5.4-5.3 kGy respectively were necessary to reach the same inactivation level in crab meat. An agreement between spore resistance in crab meats and lab media, with similar characteristics in pH and aw, was also observed. The results obtained in this research demonstrated the potential for ionizing radiation to achieve an appropriate inactivation level of spores naturally present in brown crab with the application of doses lower than 10 kGy.

Quantification of bovine leukemia virus proviral DNA using a low-cost real-time polymerase chain reaction.

The detection of bovine leukemia virus (BLV) proviral DNA is an important tool to address whether an animal is infected with BLV. Compared with serological assays, real-time PCR accounts for greater sensitivity and can serve as a confirmatory test for the clarification of inconclusive or discordant serological test results. However, the high cost related to real-time PCR assays has limited their systematic inclusion in BLV surveillance and eradication programs. The aim of the present study was to validate a low-cost quantitative real-time PCR. Interestingly, by using SYBR Green detection dye, we were able to reduce the cost of a single reaction by a factor of 5 compared with most common assays based on the use of fluorogenic probes (i.e., TaqMan technology). This approach allowed a highly sensitive and specific detection and quantification of BLV proviral DNA from purified peripheral blood leukocytes and a milk matrix. Due to its simplicity and low cost, our in-house BLV SYBR quantitative real-time PCR might be used either as a screening or as a confirmatory test in BLV control programs.

Meta-analysis of prevalence of wheezing and recurrent wheezing in infants.

BACKGROUND: Wheezing affects children's quality of life, and is related with asthma in childhood. Although prevalence of wheezing has been previously studied in several countries, there is no reference of worldwide prevalence in infants. The aim of this meta-analysis is to estimate the prevalence of wheezing and recurrent wheezing in infants aged up to two years, and compare the prevalence across world regions. METHODS: Literature search was conducted in MEDLINE and SCOPUS databases, looking for observational studies published up to June 2016, including as keywords "prevalence" or "epidemiology" combined with "wheeze", "wheezing" or "asthma symptoms" and "infant" or "preschool". Fast*Pro software and random effects Bayesian model were used. Heterogeneity was estimated using I2 statistic, and sensitivity analyses were performed. RESULTS: We identified 109 studies after duplicates were removed. After exclusions, 14 studies were included in the meta-analysis. Prevalence of wheezing and recurrent wheezing were 36.06% (95% CI 35.17-36.96), and 17.41% (95% CI 16.74-18.09), respectively. In European countries, prevalence of wheezing was 30.68% (95% CI 28.97-32.45), and 12.35% (95% CI 11.27-13.47) for recurrent wheezing. Prevalence of wheezing and recurrent wheezing in Latin America were higher, 40.55% (95% CI 39.40-41.71), and 19.27% (95% CI 18.44-20.11), respectively. In Africa, prevalence of wheezing was 15.97% (95% CI 14.05-18.00). Low or no heterogeneity was found in all cases. CONCLUSIONS: More than one third of infants suffer from wheezing and almost one fifth from recurrent wheezing, being these illnesses especially prevalent in Latin American countries, pointing out an important public health problem.

Influence of the Mediterranean diet during pregnancy in the development of wheezing and eczema in infants in Pamplona, Spain.

BACKGROUND: This study examined the relationship between different food groups and the adherence to a Mediterranean diet during pregnancy and the risk of wheezing and eczema in children aged 12-15 months. METHODS: The study involves 1087 Spanish infants from the International Study of Wheezing in Infants (Estudio Internacional de Sibilancias en Lactantes, EISL). The study of the association of the different food consumption and Mediterranean diet with wheezing, recurrent wheezing and eczema was performed using different models of unconditional logistic regression to obtain adjusted prevalence odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: No association was found between a good adherence to the Mediterranean diet during pregnancy and the development of wheezing (p=0.372), recurrent wheezing (p=0.118) and eczema (p=0.315). The consumption once or twice a week of white fish (OR: 1.95[1.01-3.75]), cooked potatoes (OR: 1.75[1.22-2.51]) and industrial pastry (OR: 1.59[1.13-2.24]), and the consumption more than three times a week of industrial pastry (OR: 1.47 [1.01-2.13]) during pregnancy increases the risk of "wheezing" at 12 months. Instead, high fruit consumption during the pregnancy has a protective effect against "wheezing" in 12-month-old infants (OR: 0.44 [0.20-0.99]). No statistically significant differences were observed between food intake during pregnancy and "recurrent wheezing". No statistically significant differences were observed between the consumption of any food during pregnancy and the presence of eczema at 12 months. CONCLUSIONS: The present study showed that the consumption of Mediterranean diet during pregnancy did not have a protective effect for wheezing, recurrent wheezing or eczema.

Trends of mortality from Alzheimer's disease in the European Union, 1994-2013.

BACKGROUND AND PURPOSE: In many countries, Alzheimer's disease (AD) has gradually become a common disease in elderly populations. The aim of this study was to analyse trends of mortality caused by AD in the 28 member countries in the European Union (EU) over the last two decades. METHODS: We extracted data for AD deaths for the period 1994-2013 in the EU from the Eurostat and World Health Organization database. Age-standardized mortality rates per 100 000 were computed. Joinpoint regression was used to analyse the trends and compute the annual percent change in the EU as a whole and by country. Analyses by gender and by European regions were conducted. RESULTS: Mortality from AD has risen in the EU throughout the study period. Most of the countries showed upward trends, with the sharpest increases in Slovakia, Lithuania and Romania. We recorded statistically significant increases of 4.7% and 6.0% in mortality rates in men and women, respectively, in the whole EU. Several countries showed changing trends during the study period. According to the regional analysis, northern and eastern countries showed the steepest increases, whereas in the latter years mortality has declined in western countries. CONCLUSIONS: Our findings provide evidence that AD mortality has increased in the EU, especially in eastern and northern European countries and in the female population. Our results could be a reference for the development of primary prevention policies.