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Background Invasive fungal disease (IFD) is a significant cause of morbimortality in children under chemotherapy or hematopoietic stem cell transplant (HSCT). The purpose of this study is to describe the changes in the IFD epidemiology that occurred in a Pediatric Hematology-Oncology Unit (PHOU) with an increasing activity over time. Methods Retrospective revision of the medical records of children (from 6 months to 18 years old) diagnosed with IFD in the PHOU of a tertiary hospital in Madrid (Spain), between 2006 and 2019. IFD definitions were performed according to the EORTC revised criteria. Prevalence, epidemiological, diagnostic and therapeutic parameters were described. Comparative analyses were conducted using Chi-square, Mann-Whitney and Kruskal-Wallis tests, according to three time periods, the type of infection (yeast vs mold infections) and the outcome. Results Twenty-eight episodes of IFD occurred in 27 out of 471 children at risk (50% males; median age of 9.8 years old, [IQR 4.9-15.1]), resulting in an overall global prevalence of 5.9%. Five episodes of candidemia and 23 bronchopulmonary mold diseases were registered. Six (21.4%), eight (28.6%) and 14 (50%) episodes met criteria for proven, probable and possible IFD, respectively. 71.4% of patients had a breakthrough infection, 28.6% required intensive care and 21.4% died during treatment. Over time, bronchopulmonary mold infections and breakthrough IFD increased (p=0.002 and p=0.012, respectively), occurring in children with more IFD host factors (p=0.028) and high-risk underlying disorders (p=0.012). A 64% increase in the number of admissions in the PHOU (pp=0.008) were not followed by rising rates of mortality or IFD/1000 admissions (p=0.674). Conclusions In this study, we found that yeast infections decreased, while mold infections increased over time, being most of them breakthrough infections. These changes are probably related to the rising activity in our PHOU and an increase in the complexity of the baseline pathologies of patients. Fortunately, these facts were not followed by an increase in IFD prevalence or mortality rates.

Objectives We analysed the prevalence of M184V/I and/or K65R/E/N mutations archived in proviral DNA (pDNA) in youths with perinatal HIV, virological control and who previously carried these resistance mutations in historic plasma samples. Methods We included vertically HIV-infected youths/young adults aged ≥10 years in the Madrid Cohort of HIV-1 Infected Children and Adolescents, exposed to lamivudine and/or emtricitabine, with M184V/I and/or K65R/E/N in historic plasma samples, on antiretroviral therapy (ART), virologically suppressed (HIV-1 RNA Results Among the 225 patients under follow-up in the study cohort, 13 (5.8%) met selection criteria, and RT sequences were recovered in 12 (92.3%) of them. All but one were Spaniards, carrying subtype B, with a median age at PBMCs sampling of 21.3 years (IQR: 15.6–23.1) with 4 years (IQR 2.1–6.5) of suppressed viral load (VL). Nine (75%) youths did not present M184V/I in pDNA after at least 1 year of viral suppression. In December 2019, the remaining three subjects carrying M184V/I in pDNA maintained suppressed viraemia, and two still used emtricitabine in ART. Conclusions The prevalence of resistance mutations to lamivudine and emtricitabine in pDNA in a cohort of youths perinatally infected with HIV who remain with undetectable VL, previously lamivudine and/or emtricitabine experienced, was infrequent. Our results indicate that ART including lamivudine or emtricitabine may also be safe and successful in youths with perinatal HIV with previous experience of and resistances to these drugs detected in plasma.

In recent years, the field of infectious diseases has been hit by the overwhelming amount of information generated while the human microbiome is being disentangled. Based on the interaction between the microbiota and the immune system, the implications regarding infectious diseases are probably major and remain a challenge. Aims This review was conceived as a comprehensive tool to provide an overview of the available evidence regarding the influence of the microbiome on infectious diseases in children. Methods We present the main findings aroused from microbiome research in prevention, diagnosis and treatment of infectious disease under a paediatric perspective, to inform clinicians of the potential relevance of microbiome-related knowledge for translation to clinical practice. Results and conclusion The evidence shown in this review highlights the numerous research gaps ahead and supports the need to move forward to integrating the so-called microbiome thinking into our routine clinical practice.

Background Although integrase inhibitor (INI)-based regimens are now the first-line choice for all people living with HIV, experience among children and adolescents is still scarce. We describe the characteristics and outcomes of a paediatric/adolescent cohort on INI-based ART. Methods Retrospective analysis of HIV-infected patients below 18 years of age who started an INI-based regimen from 2007 to 2019, enrolled in the Spanish National Adult (CoRIS) and Paediatric (CoRISpe) cohorts. Resistance mutations were identified by the Stanford HIV Drug Resistance Database. Results Overall, 318 INI-based regimens were implemented in 288 patients [53.8% female; median age at start of 14.3 years (IQR 12.0–16.3)]. Most were born in Spain (69.1%), vertically infected (87.7%) and treatment-experienced (92.7%). The most frequently prescribed INI was dolutegravir (134; 42.1%), followed by raltegravir (110; 34.6%) and elvitegravir (73; 23.0%). The median exposure was 2.0 years (IQR 1.1–3.0). The main reasons to start an INI-based therapy were treatment simplification (54.4%) and virological failure (34.3%). In total, 103 (32.4%) patients interrupted their regimen: 14.5% for simplification and 8.5% due to virological failure. Most subjects who received dolutegravir (85.8%) and elvitegravir (83.6%) did not interrupt their regimen and maintained undetectable viral load. There were only five virological failures with dolutegravir and three with elvitegravir. There were no interruptions related to adverse events. Seven patients with virological failure presented major resistance mutations to INIs; none of them were on dolutegravir. Conclusions INI-based regimens were effective and safe for HIV treatment in children and adolescents. Dolutegravir and elvitegravir presented an excellent profile, and most patients achieved and maintained viral suppression.

Background: Several evidence-based guidelines for the management of children with febrile neutropenia (FN) have been published, with special focus in bacterial and fungal infections. However, the role of acute respiratory infections caused by respiratory viruses (RV) has not been clearly established. The aim of this study was to evaluate the epidemiology, clinical presentation and outcome of acute respiratory infections in children with FN. Methods: Patients

Supplemental Digital Content is available in the text., IMPORTANCE: A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 is hypothesized to play a role in the pathogenesis of invasive infection, but studies in sepsis are lacking. OBJECTIVES: To study A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein level in pediatric sepsis and to study the association with outcome. DESIGN: Data from two prospective cohort studies. SETTING AND PARTICIPANTS: Cohort 1 is from a single-center study involving children admitted to PICU with meningococcal sepsis (samples obtained at three time points). Cohort 2 includes patients from a multicenter study involving children admitted to the hospital with invasive bacterial infections of differing etiologies (samples obtained within 48 hr after hospital admission). MAIN OUTCOMES AND MEASURES: Primary outcome measure was mortality. Secondary outcome measures were PICU-free days at day 28 and hospital length of stay. RESULTS: In cohort 1 (n = 59), nonsurvivors more frequently had A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels above the detection limit than survivors at admission to PICU (8/11 [73%] and 6/23 [26%], respectively; p = 0.02) and at t = 24 hours (2/3 [67%] and 3/37 [8%], respectively; p = 0.04). In cohort 2 (n = 240), A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels in patients within 48 hours after hospital admission were more frequently above the detection limit than in healthy controls (110/240 [46%] and 14/64 [22%], respectively; p = 0.001). Nonsurvivors more often had detectable A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels than survivors (16/21 [76%] and 94/219 [43%], respectively; p = 0.003), which was mostly attributable to patients with Neisseria meningitidis. CONCLUSIONS AND RELEVANCE: In children with bacterial infection, detection of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 within 48 hours after hospital admission is associated with death, particularly in meningococcal sepsis. Future studies should confirm the prognostic value of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 and should study pathophysiologic mechanisms.

The SARS-CoV-2 pandemic has caused an increase in antibiotic use in different settings. We describe the antibiotic prescribing prevalence, associated factors and trends, as well as concomitant bacterial infections in children hospitalized with COVID-19 or multisystemic inflammatory syndrome related to SARS-CoV-2 in Spain. Instituto de Salud Carlos III (ISCIII) Unión Europea-Fondos FEDER (proyecto PI20/00095) Ministerio de Sanidad/ISCIII Sociedad Española de Pediatría Fondos FEDER (Contrato Río Hortega CM18/00100 y CM19/00015 ) 5.235 JCR (2021) Q1, 14/130 Pediatrics 1.236 SJR (2021) Q1, 66/301 Infectious Diseases No data IDR 2020 UEM

BACKGROUND Kingella kingae is an emergent pathogen causing septic arthritis (SA) in children.The objective of this study was to analyze the etiology of SA in children before and after the implementation of universal 16S rRNA gene polymerase chain reaction and sequencing (16SPCR) in synovial fluid. METHODS Children ≤14 years with acute SA from a Madrid cohort (2002-2013) were reviewed. Differences in etiology were analyzed before (period 1) and after (period 2) the implementation of bacterial 16SPCR in 2009. A comparison in epidemiology, clinical syndromes, therapy and outcome between infections caused by K. kingae and other bacteria was performed. RESULTS Bacteria were detected from 40/81 (49.4%) children, with a higher proportion of diagnosis after 16SPCR establishment (period 2, 63% vs. period 1, 31.4%; P = 0.005). The main etiologies were Staphylococcus aureus (37.5%) and K. kingae (35%), although K. kingae was the most common microorganism in P2 (48.3%). Children with K. kingae SA were less likely to be younger than 3 months (0 vs. 42.3%; P < 0.001), had less anemia (21.4 vs. 50%; P = 0.010), lower C-reactive protein (3.8 vs. 8.9 mg/dL; P = 0.039), less associated osteomyelitis (0 vs. 26.9%; P = 0.033), shorter intravenous therapy (6 vs. 15 days; P < 0.001), and had a nonsignificant lower rate of sequelae (0 vs. 30%; P = 0.15) than children with SA caused by other bacteria. However, they tended to have higher rate of fever (86 vs. 57%; P = 0.083). CONCLUSIONS K. kingae was frequently recovered in children with SA after the implementation of bacterial 16SPCR, producing a milder clinical syndrome and better outcome. Therefore, the use of molecular techniques may be important for the management of these children.

BACKGROUND The use of azoles for antifungal prophylaxis after familial allogeneic stem cell transplantation in children (SCT) is hindered by adverse events and drug interactions especially in children affected by sickle cell disease. Intermittent, higher dose of micafungin could be an alternative. METHODS A prospective, observational, longitudinal, single-center study was conducted between May 2015 and June 2018. The study included 30 patients between 2 and 18 years old who underwent allogeneic SCT and received prophylaxis with micafungin on alternating days after the bone marrow engraftment phase. FINDINGS Fifty transplants performed, 30 included prophylaxis against IFIs, with micafungin in an alternating pattern according to the previously described protocol. The indication for HSCT was hemoglobinopathies in 76.7%, acute leukemia in 20.0% and Fanconi anemia in 3.3%. The prophylaxis duration was 2.33 months (1.53 to 3.98). In our study, 40.0% (12/30) of the patients had acute GVHD, and 6.7% (2/30) had chronic GVHD, which prolonged the duration of alternating prophylaxis. No serious adverse effects of the use of micafungin were observed in any of the patients. There was also no breakthrough Invasive fungal infection (IFI) during alternating prophylaxis. CONCLUSION: In selected patients, micafungin was well tolerated without breakthrough IFI in our study.

Introduccion Los resultados de los estudios que han investigado diferencias de genero en funcionamiento neuropsicologico en la esquizofrenia han sido inconsistentes. Diferencias en la fase de la enfermedad, en las caracteristicas demograficas y clinicas de las muestras y en los instrumentos utilizados podrian explicar esa heterogeneidad. Objetivo Investigar la heterogeneidad en los resultados comparando el funcionamiento cognitivo de pacientes con diagnostico de esquizofrenia. Metodo Veinticinco mujeres y veinticinco hombres pacientes con diagnostico de esquizofrenia equiparados en edad, edad al inicio de la enfermedad y nivel educativo se evaluaron en funcionamiento cognitivo utilizando la WAIS-IV. Resultados Los hombres mostraron puntuaciones mas altas que las mujeres en las dos medidas globales, en los indices de razonamiento perceptivo y de memoria de trabajo y en las subtests de la WAIS-IV de informacion, puzles visuales, amplitud de digitos y aritmetica. Los tamanos de efecto d de Cohen fueron altos en las dos medidas globales y en los dos indices (d > .68). Discusion y conclusion En conjunto, la ejecucion de las mujeres en funcionamiento cognitivo esta por debajo de la de los hombres cuando se mide con la WAIS-IV, excepto en el caso de la velocidad de procesamiento. Este patron de diferencias de genero es similar al patron observado en poblacion sana. Nuestros resultados pueden ayudar a clarificar la heterogeneidad de resultados en los estudios sobre diferencias de genero en el funcionamiento cognitivo en la esquizofrenia y podrian ser utiles en el diseno de intervenciones centradas en la cognicion

We conducted a multicenter clinical validity study of the Panbio coronavirus disease 2019 Antigen Rapid Test of nasopharyngeal samples in pediatric patients with coronavirus disease 2019-compatible symptoms of ≤5 days of evolution. Our study showed limited accuracy in nasopharyngeal antigen testing: overall sensitivity was 45.4%, and 99.8% of specificity, positive-predictive value was 92.5%.

Background Strategies aimed at antiretroviral therapy (ART)–free remission will target individuals with a limited viral reservoir. We investigated factors associated with low reservoir measured as total human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells (PBMCs) in perinatal infection (PaHIV). Methods Children from 7 European centers in the Early Treated Perinatally HIV Infected Individuals: Improving Children’s Actual Life (EPIICAL) consortium who commenced ART aged 5 years were included. Total HIV-1 DNA was measured by quantitative polymerase chain reaction per million PBMCs. Factors associated with total HIV-1 DNA were analyzed using generalized additive models. Age, VL at ART initiation, and baseline CD4% effects were tested including smoothing splines to test nonlinear association. Results Forty PaHIV, 27 (67.5%) female 21 (52.5%) Black/Black African, had total HIV-1 DNA measured; median 12 (IQR, 7.3–15.4) years after ART initiation. Eleven had total HIV-1 DNA 6 logs. The effect of CD4% (coefficient = 0.03 ± 0.01, P = .049) was not maintained >40%. Conclusions In this PaHIV cohort, reduced total HIV-1 DNA levels were associated with younger age and lower VL at ART initiation. The impact of early-infant treatment on reservoir size persists after a decade of suppressive therapy., Initiation of antiretroviral therapy at a younger age and lower plasma viral load were associated with a lower HIV-1 viral reservoir in peripheral blood mononuclear cells after more than a decade of sustained virological suppression.

Graphs play an important role in many areas of Computer Science. In particular, our work is motivated by model-driven software development and by graph databases. For this reason, it is very important to have the means to express and to reason about the properties that a given graph may satisfy. With this aim, in this paper we present a visual logic that allows us to describe graph properties, including navigational properties, i.e., properties about the paths in a graph. The logic is equipped with a deductive tableau method that we have proved to be sound and complete. This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Union (FEDER funds) under grant GRAMM (ref. TIN2017-86727-C2-1-R, TIN2017-86727-C2-2-R) and by the Basque Project GIU15/30, and grant UFI11/45.

Background The expanded use of long-term antiretroviral treatments in infected children may exacerbate the problem of drug resistance mutations selection, which can compromise treatment efficiency. Objective We describe the temporal trends of HIV drug resistance mutations and the HIV-1 variants during 23 years (1993 to March 2016) in the Madrid cohort of HIV-infected children and adolescents. Methods We selected patients with at least one available HIV-1 pol sequence/genotypic resistance profile, establishing different groups according to the sampling year of first resistance data. We determined the prevalence of transmitted drug resistance mutations or acquired drug resistance mutations (DRM), the drug susceptibility among resistant viruses and HIV-1 variants characterized by phylogeny across time. Results A total of 245 pediatric patients were selected, being mainly female, Spanish native, perinatally infected and carrying HIV-1 subtype B. At first sampling, most pediatric patients were on antiretroviral therapy and heavily pretreated. During 1993 to 2016, transmitted drug resistance mutations was found in 13 (26%) of 50 naive children [non-nucleoside reverse transcriptase inhibitors (NNRTI), 14.6%; nucleoside reverse transcriptase inhibitors (NRTI), 10.4%; protease inhibitors, 8.7%]. DRM appeared in 139 (73.2%) of 190 pretreated patients (NRTI, 64.5%; NNRTI, 36%; protease inhibitors, 35.1%). DRM to NNRTI was higher in last 5 years. Non-B variants infected 14.5% of children and adolescents of the Madrid Cohort, being mainly intersubtype recombinants (76.5%), including complex unique recombinant strains. They caused 3.4% infections before 2000, rising to 85.7% during 2011 to 2016. Conclusions Periodic surveillance resistance and molecular epidemiology studies in long-term pretreated HIV-infected pediatric populations are required to optimize treatment regimens. Results will permit a better understanding of long-time dynamics of viral resistance and HIV-1 variants in Spain.

Wechsler Adult Intelligence Scale (WAIS) is one of the most widely used instruments to measure cognitive functioning. The aims of this study were 1) to obtain the cognitive profile of Spanish patients with schizophrenia on the WAIS-IV; 2) to compare their profile to the profile of a healthy control group; and 3) to compare the cognitive profile of patients with schizophrenia to the performance observed in two separate previous studies in Canada and China. A sample of 99 outpatients and 99 healthy control participants, matched on age, sex, and educational level, were measured using the WAIS-IV, including 10 core subtests, 4 indices, and 2 general intelligence scores, to obtain their cognitive profile. Results showed that only the performance on the Verbal Comprehension Index and its subtests was similar in the patient and control groups. This pattern of cognitive impairment was similar to the pattern reported in the Canadian and Chinese studies.

We show that a Navigational Logic, i.e., a logic to express properties about graphs and about paths in graphs is a semi-exact institution. In this way, we can use a number of operations to structure and modularize our specifications. Moreover, using the properties of our institution, we also show how to structure single formulas, which in our formalism could be quite complex.

In this paper we first present three sorts of constraints (positive, negative and conditional ones) to specify that certain patterns must be satisfied in a XML document. These constraints are built on boolean XPath patterns. We define a specification as a set of clauses whose literals are constraints.Then, to reason about these specifications, we study some sound rules which permit to infer, subsume or simplify clauses. The main goal is to design a refutation procedure (based on these rules) to test if a given specification is satisfiable or not. We have formally proven the soundness of our procedure and we study the completeness and termination of the proposed method.

Background Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; pInterpretation Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients.

One of the main advantages of the Logic of Nested Conditions, defined by Habel and Pennemann, for reasoning about graphs, is its generality: this logic can be used in the framework of many classes of graphs and graphical structures. It is enough that the category of these structures satisfies certain basic conditions. In a previous paper [14], we extended this logic to be able to deal with graph properties including paths, but this extension was only defined for the category of untyped directed graphs. In addition it seemed difficult to talk about paths abstractly, that is, independently of the given category of graphical structures. In this paper we approach this problem. In particular, given an arbitrary category of graphical structures, we assume that for every object of this category there is an associated edge relation that can be used to define a path relation. Moreover, we consider that edges have some kind of labels and paths can be specified by associating them to a set of label sequences. Then, after the presentation of that general framework, we show how it can be applied to several classes of graphs. Moreover, we present a set of sound inference rules for reasoning in the logic.

Advances in care and antiretroviral treatment, improved life expectancy and quality of life in children with perinatally-acquired human immunodeficiency virus (HIV) infection. There is increasing interest in the chronic effects of growing up with HIV. The aim of this study was to assess the psychosocial, emotional and behavioural functioning in a cohort of perinatally-acquired HIV-infected adolescents. Data were obtained through semi-structured interviews and the Strengths and Difficulties Questionnaire (SDQ) for emotional and behavioural disorders screening.A total of 95 patients (58% women) were assessed with a median age of 15 years (11-19.1) and a median age at diagnosis of 1.7 years (0-12.2). The median CD4 count, at the inclusion, was 626 cells/mm(3) (132-998), with 34% (10-52%). Viral load was50 copies/ml in 72% of patients. Eighty-one per cent knew their diagnosis and optimal adherence was achieved in 53%. Passive coping was reported in 58.4% of the adolescents. Only 7.7% of teenagers had a complete and adequate knowledge of their disease and only 18.2% had shared it with their friends. Six unwanted pregnancies occurred (11% of women). Most of them (90%) attended school but 60% had been held back one or more school years. Overall, SDQ scored a risk of behavioural and emotional problems in 24.5%. The report of behaviours associated with hyperactivity was high in 14.9% of the population and borderline in 18.1%. Adolescents with encephalopathy accounted for 44% of those whose total scores fell in either the abnormal and borderline ranges for emotional difficulties (p = .038).Perinatally-acquired HIV-infected adolescents showed significant psychosocial and behavioural health risks that should bring attention to prevention and health care programmes. An earlier disclosure to children could favour a better psychological adjustment and a better treatment adherence. Future studies are needed to assess the relationship between vertically acquired HIV-infection and hyperactivity.

Resumen Introduccion Los avances en el tratamiento antirretroviral han mejorado la esperanza de vida de ninos con infeccion por VIH por transmision vertical. Sin embargo, han aparecido nuevos retos. Planteamos este estudio con el objetivo de determinar los aspectos psicosociales y el conocimiento sobre su enfermedad en una cohorte de adolescentes con infeccion por VIH por transmision vertical. Metodos Se incluyeron pacientes con infeccion por VIH por transmision vertical con edades comprendidas entre 12-19 anos. Los datos se obtuvieron mediante entrevista semiestructurada y el Strengths and Difficulties Questionnaire para cribado de trastornos emocionales y de conducta. Resultados Se evaluaron 96 pacientes (58% mujeres) con mediana de edad de 15 anos (11-19,1) y mediana de edad del diagnostico de 1,70 anos (0-12,2). La mediana de CD4 en el momento del corte fue 626 cels/mm3 (132-998); el 72% de los pacientes presentaban una carga viral Conclusion Se objetivan dificultades psicosociales en un elevado porcentaje de pacientes (conocimiento de la enfermedad, relacion con pares, fracaso escolar...) que podrian tener impacto en su incorporacion a la vida adulta. Son necesarios mas estudios para profundizar en el origen y evolucion de las dificultades observadas, asi como intervenir para prevenir y modificar esta situacion.

BACKGROUND: The emergence of drug resistance in Plasmodium falciparum has been a major contributor to the global burden of malaria. Drug resistance complicates treatment, and it is one of the most important problems in malaria control. This study assessed the level of mutations in P. falciparum genes, pfdhfr, pfdhps, pfmdr1, and pfcrt, related to resistance to different anti-malarial drugs, in the Continental Region of Equatorial Guinea, after 8 years of implementing artesunate combination therapies as the first-line treatment. RESULTS: A triple mutant of pfdhfr (51I/59R/108N), which conferred resistance to sulfadoxine/pyrimethamine (SP), was found in 78% of samples from rural settings; its frequency was significantly different between urban and rural settings (p = 0.007). The 164L mutation was detected for the first time in this area, in rural settings (1.4%). We also identified three classes of previously described mutants and their frequencies: the partially resistant (pfdhfr 51I/59R/108N + pfdhps 437G), found at 54% (95% CI 47.75-60.25); the fully resistant (pfdhfr 51I/59R/108N + pfdhps 437G/540E), found at 28% (95% CI 7.07-14.93); and the super resistant (pfdhfr 51I/59R/108N + pfdhps 437G/540E/581G), found at 6% (95% CI 0.48-4.32). A double mutation in pfmdr1 (86Y + 1246Y) was detected at 2% (95% CI 0.24-3.76) frequency, distributed in both urban and rural samples. A combination of single mutations in the pfmdr1 and pfcrt genes (86Y + 76T), which was related to resistance to chloroquine and amodiaquine, was detected in 22% (95% CI 16.8-27.2) of samples from the area. CONCLUSIONS: The high level of mutations detected in P. falciparum genes related to SP resistance could be linked to the unsuccessful withdrawal of SP treatment in this area. Drug resistance can reduce the efficacy of intermittent prophylactic treatment with SP for children under 5 years old and for pregnant women. Although a high number of mutations was detected, the efficacy of the first-line treatment, artemisinin/amodiaquine, was not affected. To avoid increases in the numbers, occurrence, and spread of mutations, and to protect the population, the Ministry of Health should ensure that health centres and hospitals are supplied with appropriate first-line treatments for malaria. We would like to thank the National Malaria Control Programme and Ministry of Health and Ministry of Health and Social Welfare of Equatorial Guinea for their assistance. We would also like to thank the Network of Tropical Diseases Research Centres (Red de Investigación Cooperativa en Enfermedades Tropicales/ RICET-: RD12/0018/0001). This work has been done under the project: PI14CIII/00064-TRPY 1282/15 and was funded by the Institute of Health Carlos III. Sí

† Background and Aims It has traditionally been considered that the flowers of Scrophularia are mainly pollinated by wasps. We studied the pollination system of four species which stand out for their large and showy flowers: S. sambucifolia and S. grandiflora (endemics of the western Mediterranean region), S. trifoliata (an endemic of the Tyrrhenian islands) and S. calliantha (an endemic of the Canary Islands). Our principal aim was to test whether these species were pollinated by birds or showed a mixed pollination system between insects and birds. † Methods Censuses and captures of insects and birds were performed to obtain pollen load transported and deposited on the stigmas. Also, a qualitative and quantitative analysis of the flowers and inflorescences was carried out. † Key Results Flowers were visited by Hymenoptera and by passerine birds. The Canarian species was the most visited by birds, especially by Phylloscopus canariensis, and its flowers were also accessed by juveniles of the lizard Gallotia stehlini. The most important birds in the other three species were Sylvia melanocephala and S. atricapilla. The most important insect-functional groups in the mixed pollination system were: honey-bees and wasps in S. sambucifolia; bumble-bees and wasps in S. grandiflora; wasps in S. trifoliata; and a small bee in S. calliantha. † Conclusions The species studied show a mixed pollination system between insects and passerine birds. In S. calliantha there is, in addition, a third agent ( juveniles of Gallotia stehlini). The participation of birds in this mixed pollination system presents varying degrees of importance because, while in S. calliantha they are the main pollinators, in the other species they interact to complement the insects which are the main pollinators. A review of different florae showed that the large showy floral morphotypes of Scrophularia are concentrated in the western and central Mediterranean region, Macaronesia and USA (New Mexico).

Introduction: Patients coinfected with HIV and hepatitis B virus (HBV) have a higher risk of developing chronic HBV infection and a higher risk of hepatotoxicity. Hepatitis A virus (HAV) in HIV-infected patients may require antiretroviral treatment interruption, producing prolonged viremia. In this study, we assess the prevalence of protective antibodies in these patients. Methods: A cross-sectional study was conducted to determine the prevalence of IgG antibodies against HAV and antibody against HBs (anti-HBs) in a cohort of 121 HIV-infected children and adolescents (1–19 years), followed-up in 4 public hospitals in Madrid (Spain). Results: Among the total, 12.4% (95% CI: 7.1–19.6%) of children and adolescents had positive serology for HAV. Children of immigrant origin presented a higher percentage than children born in Spain: 50% vs. 6.2%, respectively (Po0.001). In addition, 16.5% (95% CI: 10.4–24.3) of the study population had protective antiHBs. A higher percentage of children with anti-HBs antibodies was seen in CDC clinical category A: 20% vs. 16% of those in clinical category B vs. 9.4% of those in clinical category C (P ¼ 0.19). The percentage of positive-positive children progressively decreased according to the years elapsed since HBV vaccination. Discussion: Most HIV-infected children and adolescents have no protective antibodies against natural infection by HBV and HAV. More studies are needed to define the best vaccination strategy to achieve a higher percentage of patients protected against these infections.

The better known methods of semantic tableaux for deciding satisfiability in propositional linear temporal logic generate graphs in addition to classical trees. The test of satisfaction is made from the graph and it does not correspond with the application of rules in any calculus for PLTL. We present here a new method of semantic tableaux without using additional graphs. The method is based on a new complete finitary sequent calculus for PLTL which allows us to incorporate all the information in a tree. This approach makes our tableaux better suited for completely automatic theorem proving.

HIV-associated encephalopathy (HIV-AE) is a severe neurologic condition that affects HIV-infected children. The potential benefit of antiretroviral (ARV) agents with good cerebrospinal fluid (CSF) penetration remains to be defined. Abacavir (ABC) achieves good CSF concentrations and studies of high-dose ABC showed benefit in adults with HIV dementia. The present study evaluated the safety and virologic, immunologic and neuropsychological responses of an ARV regimen including high-dose ABC in children with HIV-AE.Children between 3 months and 18 years old and abacavir-naive with HIV-AE and virologic failure were eligible.: Seventeen children (16 ARV-experienced) were enrolled and 14 children completed 48 weeks of therapy. The overall tolerability was good; 2 children had a possible hypersensitivity reaction. At week 48, 53% and 59% of the children achieved HIV RNA levels below the limit of quantitation in plasma and CSF, respectively. The median (25%-75% range) change of HIV RNA from baseline to week 48 was -2.29 (-0.81 to -2.47) log10 copies/mL in plasma and -0.94 (0 to -1.13) log10 copies/mL in CSF. The mean increases in CD4 (+/-standard error of mean) cell count and CD4% were 427 (+/-169) cells/mm and 8% (+/-2), respectively. Concentrations of soluble tumor necrosis factor receptor II were reduced in plasma and CSF. Children less than 6 years of age demonstrated significant neuropsychological improvement at week 48.In the present study with a limited number of children, highly active ARV therapy including high-dose ABC showed a safety profile similar to standard dose ABC and provided clinical, immunologic and virologic response in children with HIV-AE at week 48. Children less than 6 years of age also demonstrated significant neuropsychological improvement.

Fundamento Realizar un analisis de las subpoblaciones T implicadas en la recuperacion delsistema inmunitario en ninos infectados por el VIH-1 con terapia antirretroviral de gran actividad(TARGA) durante mas de 24 meses. Pacientes y metodo Se estudio a 17 ninos infectados por el VIH-1: a) grupo Res (ninos infectadospor el VIH-1 respondedores a TARGA): 10 ninos en categoria C3 al entrar en el estudio y trasmas de 24 meses con TARGA recuperan celulas T CD4+ (> 25% y 500 celulas T CD4+/ml) ycontrolan la replicacion viral, y b) grupo no-Res (ninos infectados por el VIH-1 no respondedoresa TARGA): 7 ninos en categoria C3 al entrar en el estudio y que tras mas de 24 meses con TARGAno recuperan celulas T CD4+ ( Resultados El grupo Res recupero los valores de celulas T CD4+ y CD8+ virgen (CD45RA+CD62L+)y memoria (CD45RO+) hasta alcanzar los valores del grupo control, siendo las diferencias significativascon respecto al grupo no-Res, excepto para las celulas CD8+CD45RO+ de los gruposRes y no-Res, que fueron mas elevadas que el grupo control. Ademas, el grupo Res tuvo valoresmas bajos de celulas CD8+HLA-DR+CD38+ que el grupo no-Res, aunque ambos grupos VIH-1(Res y no-Res) tuvieron valores significativamente mas altos de celulas T CD4+ y CD8+ activadas(HLA-DR+CD38+) que el grupo control. Conclusiones la recuperacion del sistema inmunitario inducida por la TARGA en los ninos infectadospor el VIH-1 parece ser la consecuencia de la disminucion de la activacion cronica delsistema inmunitario y de la recuperacion de las celulas T virgen.

Thanks to advances in antiretroviral treatment, children with HIV infections through vertical transmission have improved their life expectancy. However, new challenges have emerged. We propose this study in order to determine the psychosocial aspects and knowledge of infections in a cohort of adolescents with vertically transmitted HIV infections.Patients with vertically-acquired HIV infection between 12 and 19 years old were included. Data were obtained through semi-structured interviews and a Strengths and Difficulties Questionnaire for emotional and behavioral disorders screening.We evaluated 96 patients (58% females) with a median age of 15 years (11-19.1) and a median age at diagnosis of 1.70 years (0-12.2). The median CD4 count was 626cells/mm(3) (132-998), and the viral load was50cp/ml in 72% of patients. Among them, 90% attended school and 60% repeated at least one course. Although 81% of them knew of their diagnosis, only 30% understood their disease, with 18.2% having discussed it with friends. Six unwanted pregnancies occurred during the study period. Strengths and Difficulties Questionnaire showed hyperactivity risk in 33%.A high percentage of adolescents show difficulties in several areas (disease knowledge, peer relationship, school failure...) that can have an impact on their adult lives. Further studies are needed to evaluate their origin and development in depth, as well as interventions to modify this situation.

In this paper we try to shed some light on the similarities and differences in the different approaches defining the notions of implementation and implementation correctness. For obvious reasons, we do not discuss all existing approaches individually. Instead a formal framework is introduced in order to discuss the most important ones. Additionally, we discuss some issues which in our opinion are often misunderstood, concerning transitivity of implementation correctness and its role in the software development process. In particular, on the one hand, we show that for reasonable notions of implementation it is almost impossible to prove transitivity of implementation correctness at the specification level. On the other hand, we show that this is not really important if the programming language satisfies the properties of horizontal an vertical composition. 1. What is an Implementation? In the framework of software development, programs may be seen as the result of a process starting from a "high-level specification" SP0 and ending at a "low level program" P. In between, different "lower-level specifications" SP1, ..., SPn are produced. This process is called "implementation" and P is said to be an implementation of SP0 (and of SP1, ..., SPn). In our context, we also consider SPi to be an implementation of SPj, whenever i>j. If we analyze this implementation process in detail we recognize three different kinds of steps (often intertwined). These steps can themselves be called implementations and have provided intuition for different kinds of implementation concepts. They can be described as follows

In this paper we provide semantics for normal logic programs enriched with structuring mechanisms and scoping rules. Specifically, we consider constructive negation and expressions of the form Q G Q in goals, where Q is a program unit, G is a goal and stands for the so-called embedded implication. Allowing the use of these expressions can be seen as adding block structuring to logic programs. In this context, we consider static and dynamic rules for visibility in blocks. In particular, we provide new semantic definitions for the class of normal logic programs with both visibility rules. For the dynamic case we follow a standard approach. We first propose an operational semantics. Then, we define a model-theoretic semantics in terms of ordered structures which are a kind of intuitionistic Beth structures. Finally, an (effective) fixpoint semantics is provided and we prove the equivalence of these three definitions. In order to deal with the static case, we first define an operational semantics and then we present an alternative semantics in terms of a transformation of the given structured programs into flat ones. We finish by showing that this transformation preserves the computed answers of the given static program.

In this paper we provide foundations to contextual rewriting. We present the class of LOG-specifications, which may be seen, essentially, as a variety of conditional specifications, which may be seen, essentially, as a of LOG-specifications are LOG-algebras, i.e. algebras satisfying that their boolean part coincides with the boolean algebra of two elements. With respect to this semantics, a proof-system called L is presented characterizing logical consequence proof-theoretically. Then, we show that, under adequate assumptions of confluence and finite termination, contextual rewriting is a complete method for this kind of specifications.

Patients coinfected with HIV and hepatitis B virus (HBV) have a higher risk of developing chronic HBV infection and a higher risk of hepatotoxicity. Hepatitis A virus (HAV) in HIV-infected patients may require antiretroviral treatment interruption, producing prolonged viremia. In this study, we assess the prevalence of protective antibodies in these patients.A cross-sectional study was conducted to determine the prevalence of IgG antibodies against HAV and antibody against HBs (anti-HBs) in a cohort of 121 HIV-infected children and adolescents (1-19 years), followed-up in 4 public hospitals in Madrid (Spain).Among the total, 12.4% (95% CI: 7.1-19.6%) of children and adolescents had positive serology for HAV. Children of immigrant origin presented a higher percentage than children born in Spain: 50% vs. 6.2%, respectively (P0.001). In addition, 16.5% (95% CI: 10.4-24.3) of the study population had protective anti-HBs. A higher percentage of children with anti-HBs antibodies was seen in CDC clinical category A: 20% vs. 16% of those in clinical category B vs. 9.4% of those in clinical category C (P=0.19). The percentage of positive-positive children progressively decreased according to the years elapsed since HBV vaccination.Most HIV-infected children and adolescents have no protective antibodies against natural infection by HBV and HAV. More studies are needed to define the best vaccination strategy to achieve a higher percentage of patients protected against these infections.

There are mainly two approaches for structuring logic programs. The first one is based on defining some notion of program unit or module and on providing a number of composition operators. The second approach consists in enriching logic programming with a mechanism of abstraction and scoping rules that are frequently found, for instance, in procedural programming. More precisely, this approach has been advocated by Miller and others using implications embedded in the goals of the given program as a structuring mechanism. However, as Giordano, Martelli and Rossi pointed out, we can associate two different visibility rules (static and dynamic) to this kind of structuring mechanism where, obviously, the semantics of the given program depends on the chosen rule. In this paper we consider normal constraint logic programs (with constructive negation a la Drabent as operational semantics) extended with embedded implications with a static visibility rule. This class of programs combines the expressive power of normal programs with the capability to organize and to enhance dinamically their sets of clauses. In particular, first, we introduce an operational semantics based on constructive negation for this class of programs, taking into account the static visibility rule. Then, we present an alternative semantics in terms of a transformation of the given structured program into a flat one. Finally, we prove the adequacy of this transformation by showing that it preserves the computed answers of the given program. Obviously, this transformation semantics can be used as the basis for an implementation of this structuring mechanism.

To avoid certain specific problems (concerning termination) of conditional term rewriting systems, most of the authors cited above work. with, the so-called, hierarchical rewriting~ the systems are defined it, a hierarchical mar, r, er (by successive enrichments), the conditior, part of a giver, rule should only involve terms of lower hierarchy level, and, finally, when applying a rule the variables occurring in the condition may only be instantiated by terms of lower hierarchy~ This should guarantee to avoid the circularity problems that may appear on the evaluation of the conditions.

Introduction. Many human immunodeficiency virus type 1 (HIV-1)-infected children have already failed treatment with 2 or even 3 classes of antiretrovirals. Coformulation of lopinavir with low dose ritonavir exhibits a potent antiretroviral effect. However, the data in heavily pretreated children are still scarce. This study evaluated the safety and effectiveness of combination therapy including lopinavir/ ritonavir in children with prior exposure to all classes of oral antiretrovirals. Methods. This was an open label multicenter observational study, in which data were reviewed according to a standardized protocol. The study population included all HIV-1-infected children with virologic failure (HIV-1 RNA >5000 copies/mL) followed in 12 Spanish hospitals for >12 months, experienced with the 3 classes of oral antiretrovirals, in whom a lopinavir/ritonavir-containing regimen was started. Results. By March 2003, 45 patients had been treated with lopinavir/ritonavir for a median of 18 months (range, 3-28). The median age at baseline was 9.7 years (range, 4.3-17.1). The median times of prior treatment were 88 months (range, 31-145) with nucleoside reverse transcription inhibitors and 42 months (range, 19-63) with protease inhibitors. Twenty-five patients were classified as Centers for Disease Control and Prevention clinical category C. Median values for absolute and percentage CD4 at baseline were 501 (range, 6-1512) and 19% (range, 0.5-49), respectively, and plasma HIV-RNA was 5.0 log 10 copies/mL (range, 4.1-6.1). During follow-up, 11 (24%) children switched from liquid to solid formulation. At 48 weeks, the median values for absolute and percentage CD4 increased by 199 cells/μL and 3%, respectively, and median plasma viral load declined 1.75 log 10 copies/mL. Forty-two percent of children achieved a plasma RNA of

Horn⊃ is a logic programming language which extends usual Horn clauses by adding intuitionistic implication in goals and clause bodies. This extension can be seen as a form of structuring programs in logic programming. Restricted to the propositional setting of this language, we prove that any goal in Horn⊃ can be translated into a monotone Boolean circuit which is linear in the size of the goal.

A classifier for an automatic system that recognizes multifont typewritten digits, often broken and blurred, in forms is presented. The classification, which is based on the utilization of a global feature, is applied in two phases. Firstly, a minimum distance method (1-NN) is applied in a multifont classifier to provide a global classification of the patterns in a form. A problem associated to multifont classifiers is the interference among classes in different fonts. An interesting aspect of this particular application is that it is highly probable that a form includes just one font. Then, in the second phase, a specialized classifier, oriented to one-form, uses the patterns in the form previously classified to validate, or reject and reclassify them, on the basis of the mean distance to the predefined classes. This specialized classifier affords significant improvement in performance. A classification accuracy rate of 99.42% has been achieved.

This work addresses the segmentation of numeric fields in forms presenting blurring, breaks and touching in digits. In an OCR system, the segmentation phase plays a determinant role in the global accuracy of the system. Segmentation is basically addressed from two approaches: (a) as an isolated phase in the OCR process, and (b) as interacting with the recognition of the segmented item. In this work, we have considered the first one in order to develop a robust new cost function combining vertical projection, Tsujimoto metric (1991) and background information. Unlike other techniques reported in the literature, ours obtains a near-optimum number of break points in fields containing broken, blurred and touching characters, leading to high accuracy in the global OCR system. Our experiments with a sample including about 11283 numeric fields in 144 forms (more than 50000 digits of that kind) show that 99.74% of fields have been correctly segmented. The new cost function only made 50 errors.

Our purpose was to carry out an analysis of T cells subsets involved in the recovery of the immune system in vertically HIV-1-infected children, on highly active antiretroviral therapy (HAART) over more than 24 months.Seventeen HIV-1-infected children were studied: a) Res-group (HIV-1-infected children who were HAART-responders): 10 children in category C3 at entry in the study who, after more than 24 months on HAART, recovered CD4+ T cells (25% and 500 CD4+ T-cells/ml) and may control viral replicación, and b) non-Res group (HIV-1-infected children who did not respond to HAART): 7 children in category C3 at entry in the study who, after more than 24 months on HAART, did not recover CD4+ T-cells (15% or 200 CD4+ T-cells/ml) and did not control viral replication. As control group, 12 HIV-1-uninfected children with similar ages were included in the study.Children in the Res-group recovered the values of CD4+, CD8+ naïve (CD45RA+CD62L+) and memory (CD45RO+) T-cells until reaching the values of the control group. The differences were significant with regard to the non-Res group, except for the CD8+CD45RO+ T-cells of the Res and non-Res groups which were higher than the control group. Moreover, Res-group had values of CD8+HLA-DR+CD38+ T-cells lower than the non-Res group, yet both HIV-1 groups (Res and non-Res) had significantly higher values of CD4+ and CD8+ activated (HLA-DR+CD38+) T-cells than the control group.The recovery of the immune system induced by HAART in HIV-1-infected children seems to be the consequence of the decrease of the immune system chronic activation and the recovery of naïve T-cells.

This work presents a solution to the problem of the segmentation of digits in forms characterized by its low quality, as well as the existence of breaks and touching digits. We propose a new function of segmentation that adds to two traditional techniques (vertical projections and Tsujimoto metric) information of background of the digit. Unlike other techniques reported in the literature, ours obtains a near-optimum number of break points in fields containing broken, blurred and touching characters, leading to high accuracy in the global OCR system. The accuracy obtained in the segmentation of the forms fields is of 99,74% on a sample of 11,283 fields of 144 forms of low quality, which provides a final accuracy to the automatic recognition process of 99,42% of digits correctly classified.

In this paper, the automatic recognition of broken and blurred, multifont typewritten digits in forms will be addressed. The classification, which is based on the utilization of a global feature, is divided in two phases: first, a minimum distance method (1-NN) is applied to provide a global classification of the patterns in a form; second, the patterns in the form previously classified are used to validate, or reject and reclassify them, on the basis of the mean distance to the predefined classes. In this way, a classification accuracy rate of 99.42% has been achieved.

In this paper we try to shed some light over the similarities and differences among the different approaches to define implementations and behavioural equivalence. For obvious reasons, we do not discuss all existing approaches individually. However a formal framework is used to discuss the most important ones. Additionally, some issues concerning implementations that in our opinion are often misunderstood, especially transitivity of implementation correctness and its role in the software development process, are discussed in detail.