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Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Resumen: La medicina familiar y comunitaria reúne buena parte de los elementos y valores que caracterizan la profesión de médico. Esto hace que pueda aportar unos fundamentos sólidos, útiles y duraderos al estudiante de Medicina sea cual sea la especialidad que elija en un futuro. Es necesario formar a profesionales capaces de ver al paciente desde un punto de vista holístico en su contexto personal y social, así como comprender los factores determinantes de la salud individual y comunitaria. Que comprendan al paciente y su sufrimiento, y que empaticen, para acompañarle durante su proceso de enfermedad. También se nos plantea el reto de situar a la atención primaria en el centro del sistema sanitario y hacer frente a una demanda creciente de médicos especialistas en Medicina Familiar y Comunitaria.Para la consecución de estos objetivos se hace estrictamente necesaria la integración de la Atención Primaria en los planes de estudios de las universidades, con intervención de médicos de familia en diferentes asignaturas, aportando una visión más transversal y holística en el abordaje de las distintas enfermedades y con más presencia en las actividades docentes y en las prácticas.El modelo propuesto por la Universidad Pompeu Fabra se inspira en la metodología de la mentoría en la que al estudiante se le asignará un médico de familia como mentor durante toda su formación de grado, y este le acompañará en sus estancias en el centro de atención primaria y en actividades relacionadas con diferentes asignaturas y velará por el cumplimiento de los objetivos de formación. También participará en su evaluación al finalizar cada curso. Este modelo pretende mejorar la calidad de las actividades vinculadas a la asistencia clínica y de las prácticas, y facilitará el conocimiento de la atención primaria y de la profesión de médico a través del contacto precoz y mantenido con la atención primaria. Abstract: Family and community medicine brings together many of the elements and values that characterize the medical practice. This means that it can provide solid, useful and lasting foundations to the medical student, whatever specialty they choose in the future. It is necessary to train professionals capable of seeing the patient from a holistic point of view in their personal and social context, as well as understanding the determining factors of individual and community health. And also understanding the patient and their suffering, and that they empathize, to accompany them during their illness process. We are also faced with the challenge of placing Primary Care at the center of the health system and facing a growing demand for doctors specializing in Family and Community Medicine.To achieve these objectives, it is strictly necessary to integrate Primary Care into the university curricula, with the intervention of family doctors in different subjects, providing a more transversal and holistic vision in the approach to different pathologies and with more presence in teaching activities and practices.The model proposed by the Pompeu Fabra University is inspired by the mentoring methodology in which the student will be assigned a family doctor as a mentor throughout their undergraduate training, and this will accompany them during their stays at the Primary Care center and in activities related to different subjects and will ensure compliance with the training objectives. They will also participate in evaluation at the end of each course. This model aims to improve the quality of activities linked to clinical care and practices, and will facilitate knowledge of Primary Care and the profession of physician with an early and maintained contact with Primary Care.

Summary: Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2−/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2−/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose

The paraspinal space is intriguing in nature. There are several needle tip placements described in compact anatomical spaces. This has led to an incertitude regarding the appropriate anatomic locations for needle tip positions. Through our cadaver models we try to resolve the issues surrounding needle tip positions clarifying anatomical spaces and barriers. Further we propose an anatomical classification based on our findings in cadaveric open dissections and cross and sagittal sections.

Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of tumors with growing incidence. Recent molecular analyses provided a precise picture of their genomic and epigenomic landscape. Splicing dysregulation is increasingly regarded as a novel cancer hallmark influencing key tumor features. We have previously demonstrated that splicing machinery is markedly dysregulated in PanNETs. Here, we aimed to elucidate the molecular and functional implications of CUGBP ELAV-like family member 4 (CELF4), one of the most altered splicing factors in PanNETs. CELF4 expression was determined in 20 PanNETs, comparing tumor and non-tumoral adjacent tissue. An RNA sequencing (RNA-seq) dataset was analyzed to explore CELF4-linked interrelations among clinical features, gene expression, and splicing events. Two PanNET cell lines were employed to assess CELF4 function in vitro and in vivo. PanNETs display markedly upregulated CELF4 expression, which is closely associated with malignancy features, altered expression of key tumor players, and distinct splicing event profiles. Modulation of CELF4 influenced proliferation in vitro and reduced in vivo xenograft tumor growth. Interestingly, functional assays and RNA-seq analysis revealed that CELF4 silencing altered mTOR signaling pathway, enhancing the effect of everolimus. We demonstrate that CELF4 is dysregulated in PanNETs, where it influences tumor development and aggressiveness, likely by modulating the mTOR pathway, suggesting its potential as therapeutic target.

Nerve agents are highly toxic chemical compounds that pose significant threats to human health and safety. Detecting and identifying these agents quickly is crucial for preventing their exposure and providing timely treatment. This study proposes the use of nanohybrids comprising crystalline octahedral molybdenum iodide cluster material supported on graphene (Mo6@Graphene) as a novel sensing material for the detection of dimethyl methylphosphonate (DMMP), a simulant of sarin nerve agent. The electrical sensing performance towards different concentrations of DMMP and at room temperature demonstrated fast and sensitive responses to DMMP, with almost full recovery of the sensor baseline in a few minutes. The calibration curve obtained showed a linear relationship between the sensor response and DMMP concentration, enabling the estimation of the limit of detection (LOD) of 270 ppb. The robustness of the Mo6@Graphene nanomaterial towards DMMP was assessed using various techniques, including Raman spectroscopy, X-ray diffraction and photoelectron spectroscopy. The binding energies (BEs) between DMMP and the supported Mo6 clusters determined by DFT calculations revealed H-bonding interactions involved in the sensing mechanism. The excellent sensing performance of the Mo6@Graphene film, combined with its low power consumption and high stability, makes it a promising candidate for the detection of nerve agents and their simulants.

The objective of this work is the evaluation of the risk of suffering a multipactor discharge in an S-band dielectric-assist accelerating (DAA) structure for a compact low-energy linear particle accelerator dedicated to hadrontherapy treatments. A DAA structure consists of ultra-low loss dielectric cylinders and disks with irises which are periodically arranged in a metallic enclosure, with the advantage of having an extremely high quality factor and very high shunt impedance at room temperature, and it is therefore proposed as a potential alternative to conventional disk-loaded copper structures. However, it has been observed that these structures suffer from multipactor discharges. In fact, multipactor is one of the main problems of these devices, as it limits the maximum accelerating gradient. Because of this, the analysis of multipactor risk in the early design steps of DAA cavities is crucial to ensure the correct performance of the device after fabrication. In this paper, we present a comprehensive and detailed study of multipactor in our DAA design through numerical simulations performed with an in-house developed code based on the Monte–Carlo method. The phenomenology of the multipactor (resonant electron trajectories, electron flight time between impacts, etc.) is described in detail for different values of the accelerating gradient. It has been found that in these structures an ultra-fast non-resonant multipactor appears, which is different from the types of multipactor theoretically studied in the scientific literature. In addition, the effect of several low electron emission coatings on the multipactor threshold is investigated. Furthermore, a novel design based on the modification of the DAA cell geometry for multipactor mitigation is introduced, which shows a significant increase in the accelerating gradient handling capabilities of our prototype.

Introduction: Effective agents that could confer long-term protection against ionizing radiation in vivo would have applications in medicine, biotechnology, and in air and space travel. However, at present, drugs that can effectively protect against lethal ionizing radiations are still an unmet need. Objective: To investigate if combinations of natural polyphenols, known for their antioxidant potential, could protect against ionizing radiations. Methods: Plant-derived polyphenols were screened for their potential ability to confer radioprotection to mice given a lethal whole-body γ radiation (137Cs) dose expected to kill 50% of the animals in 30 days. Telomere and centromere staining, Q-FISH and comet assays were used to investigate chromosomal aberration, micronuclei formation and DNA breaks. Molecular oxidations were investigated by enzyme immunoassays and UPLC-MS/MS. RT-PCR, western blotting and siRNA-induced gene silencing were used to study signaling mechanisms and molecular interactions. Results: The combination of pterostilbene (PT) and silibinin (SIL) was the most effective against γ-irradiation, resulting in 100% of the mice surviving at 30 days and 20% survival at one year. Treatment post γ-irradiation with two potential radiomitigators nicotinamide riboside (NR, a vitamin B3 derivative), and/or fibroblast-stimulating lipoprotein 1 (FSL1, a toll-like receptor 2/6 agonist), did not extend survival. However, the combination of PT, SIL, NR and FSL1 achieved a 90% survival one year post γ-irradiation. The mechanism involves induction of the Nrf2-dependent cellular antioxidant defense, reduction of NF-kB signaling, upregulation of the PGC-1α/sirtuins 1 and 3 axis, PARP1-dependent DNA repair, and stimulation of hematopoietic cell recovery. The pathway linking Nrf2, sirtuin 3 and SOD2 is key to radioprotection. Importantly, this combination did not interfere with X-ray mediated killing of different tumor cells in vivo. Conclusion: The combination of the radioprotectors PT and SIL with the radiomitigators NR and FSL1 confer effective, long-term protection against γ radiation in vivo. This strategy is potentially capable of protecting mammals against ionizing radiations.

ABSTRACT: The objective of this experiment was to investigate the effects of the dietary soy galactooligosaccharides (GOS), raffinose and stachyose, on performance, gastrointestinal health, and systemic stress in young broilers. Birds were fed a GOS-devoid diet based on soy protein isolate (SPI) or the SPI diet with 0.9, 1.8, 2.7, or 3.6% added stachyose and raffinose in a ratio of 4:1 at the expense of corn starch. These 5 treatments were administered to 10 replicate cages of 8 birds. Performance was measured weekly and excreta moisture, N retention, apparent metabolizeable energy, and complete blood cell counts were determined at 14 and 21 d. At 21 d, 2 birds per cage were orally gavaged with fluorescein isothiocyanate-dextran (FITC-d) and serum samples were analyzed for FITC-d as a marker of gut leakage. Additionally, intestinal morphology, crop presumptive lactic acid bacteria (LAB) counts, crop and cecal pH, and cecal microbiota via16S rRNA microbial sequencing were evaluated at 21 d. From 0 to 21 d, feed intake increased linearly (P < 0.01) as dietary GOS increased, whereas BWG increased (P < 0.05) quadratically. Feed conversion ratio increased (P < 0.01) linearly as GOS increased. There were linear increases (P < 0.05) in excreta moisture as dietary GOS increased at 14 and 21 d, as well as dose-dependent responses (P < 0.05) in N retention, AME, and AMEn. There was a quadratic increase (P < 0.05) in crop LAB recovery and a linear decrease (P < 0.01) in ceca pH as GOS increased. At 14 d, a linear increase (P < 0.05) in blood heterophil to lymphocyte ratio was observed as dietary GOS increased. Serum concentrations of FITC-d increased quadratically (P < 0.01) to dietary GOS. Increasing levels of GOS influenced alpha and beta diversities and composition of gut microbiota, including the abundance of Ruminococcus and Bifidobacterium. Results from this trial indicate that soy-derived GOS exert dose-dependent effects on nutrient utilization and intestinal health in young broilers.

ABSTRACT: Feed restriction and fasting experienced during commercial production negatively affect unweaned calves' behavior and health status. Transportation and stays at assembly centers are the main factors generating these disorders. For this study, 20 unweaned Angus-Holstein bull calves [44.1 ± 2.04 kg of body weight (BW) and 14.7 ± 0.63 d of age (± standard error)] were used to evaluate the effects of feed restriction and fasting on performance, energy status [serum concentration of glucose, β-hydroxybutyrate (BHB), and nonesterified fatty acids], and gastrointestinal permeability [serum concentration of citrulline, chromium (Cr)-EDTA, lactulose, and d-mannitol]. Calves were randomly assigned to 1 of 4 treatments that simulated the feed restrictions of an assembly center situation on one hand, and the fasting hours during transportation on the other. Treatments were as follows. Control (CT): from d −4 to −1, calves were fed 2.5 L of milk replacer (MR) twice daily; concentrate and straw were offered ad libitum. Mild (MD): calves were fed only MR (d −4 to −1) as described for CT, and on d −1 calves were subjected to a 9-h feed withdrawal. Moderate (MO): calves were fed only MR (d −4 to −1) as described for CT and on d −1 subjected to a 19-h feed withdrawal. Severe (SV): calves were fed only 2.5 L of a rehydrating solution twice daily (d −4 to −1) and on d −1 subjected to a 19-h feed withdrawal. From d 0 to d 42 (weaning) all calves were fed the same feeding program (MR, concentrate, and straw ad libitum). Results showed that BW was greater for the CT treatment compared with the others from d 0 to d 7, whereas BW of SV was lesser compared with the others from d −1 to d 7. No differences among treatments were observed at weaning. At d 2 concentrate intakes of MD, MO, and SV were lesser compared with CT. By d 4, concentrate intake of SV was similar to that for CT and greater than MD and MO. Similarly to BW, no differences in concentrate intake among treatments were observed at weaning on d 42 of the study. At d −1 for SV and d 0 in all restricted calves, serum glucose concentration was lesser compared with CT. At d −1 and 0, nonesterified fatty acids and BHB serum concentrations were greater in the SV calves compared with the other treatments. By d 2, serum concentrations of nonesterified fatty acids, BHB, and glucose were restored to CT levels. At d −1 serum citrulline concentration was lesser in SV and greater in MD calves. The CT calves had lower serum concentrations of Cr-EDTA (d −1 and d 0), lactulose (d 0), and d-mannitol (d 0) compared with the other restricted calves. Results showed that degree of dietary restriction, type of liquid diet (MR or rehydrating solution), and fasting hours (9 vs. 19 h) affected calves' BW, concentrate intake, and serum concentration of markers indicative of energy status and gastrointestinal permeability.

STRAIGHT-IN is a platform to precisely integrate DNA payloads into the genome of cells, including hiPSCs. Here, we generated two hiPSC acceptor lines each with one copy of an upgraded landing pad (LP). This improved design allows more efficient (∼100 %) and rapid (∼2–3 weeks) generation of genetically modified hiPSC lines containing the desired payloads. This new LP version was inserted into either the AAVS1 (LUMCi004-A-1) or CLYBL (LUMCi004-A-2) safe harbour loci in the hiPSC line, LUMC0099iCTRL04. The resulting lines can be used for the targeted integration of a wide range of transgenes, thereby making them suitable for numerous research applications.

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Resumen: Antecedentes y objetivo: Disponer de datos epidemiológicos y de carga de una enfermedad es crucial para su control y óptima planificación. El objetivo es estimar la carga de la psoriasis en términos epidemiológicos, las comorbilidades asociadas, el uso de recursos sanitarios y la incapacidad laboral. Material y método: Se han analizado los datos de la encuesta de salud de Cataluña (ESCA) del 2016, el registro de morbilidad y utilización de servicios sanitarios de Cataluña (MUSSCAT) del 2016 y los datos recopilados entre el 2012 y el 2016 del sistema integrado de gestión de la incapacidad temporal (IT) del Instituto Catalán de Evaluaciones Médicas. Resultados: La prevalecía de la psoriasis en Cataluña con base en los datos de la ESCA se sitúa en el 1,8%.Los datos del MUSSCAT muestran que el número de casos incidentes se ha mantenido estable en los últimos años. Las comorbilidades más frecuentes en el paciente con psoriasis son la hipertensión arterial (35%) y la diabetes (15%). La estratificación de la población con psoriasis por niveles de riesgo situó al 40% en riesgo moderado-alto. El uso anual de recursos sanitarios de las personas con psoriasis es elevado (8,7 visitas de atención primaria; 2,8 consultas externas; 0,5 de urgencias y hospital de día; 0,2 de salud mental y 6,1 medicamentos).Los procesos de IT asociados con la psoriasis o artropatía psoriásica representaron el 0,04% del total de registros. Conclusiones: La prevalencia de la psoriasis en Cataluña es del 1,8%. La carga de la enfermedad es elevada, tanto en términos de comorbilidades del paciente como en el requerimiento del uso de recursos. Abstract: Background and objectives: Epidemiologic and disease burden data are essential for disease control and optimal health care resource planning. The aims of this study were to estimate the epidemiologic burden of psoriasis and evaluate associated comorbidities, health care utilization, and sick leave. Material and methods: We collected data from the 2016 Catalan Health Survey (ESCA), the Catalan Registry of Morbidity and Utilization of Health Care Services (MUSSCAT) (2016), and the database of the Catalan Medical Evaluations Institute (ICAM) (2012–2016). Results: The prevalence of psoriasis in Catalonia according to 2016 ESCA data is approximately 1.8%.The MUSSCAT registry data indicate that the incidence has remained stable in recent years. The most common comorbidities associated with psoriasis are hypertension (35%) and diabetes (15%). Forty percent of patients with psoriasis have a moderate to high risk for death or high health resource utilization. Annual use of resources by psoriasis patients is high: they make a mean of 8.7 primary care visits, 2.8 outpatient visits, 0.5 emergency and day hospital visits, 0.2 mental health visits, and use 6.1 medications.Sick leave due to psoriasis or psoriatic arthritis accounted for 0.04% of all cases. Conclusions: The prevalence of psoriasis in Catalonia is high at 1.8%. The disease burden is also high, both in terms of comorbidities and health care utilization.

This study aimed to investigate an experimental procedure of coccidial challenge in battery cages and the anticoccidial effect of a bioactive olive pomace extract from Olea europaea (OE) in broiler chickens. To this end, four hundred 1-day-old male chicks were randomly assigned to 5 experimental treatments (10 cages/treatment; 8 birds/cage). One group was fed the control diet without any additives and not challenged (NCU). The other 4 groups were challenged and fed the control diet with no additives (NCC) or supplemented with 500 ppm of coccidiostat or with 500 or 1,500 ppm of OE. At 0, 7, and 14 d, all challenged birds, except the NCC group, were orally gavaged with a live Eimeria spp. oocyst vaccine at 1x, 4x, and 16x of the manufacturer's recommended dose, respectively. Feed intake (FI), body weight gain (BWG), and feed conversion ratio (FCR) were determined at 7, 14, 20, and 28 d. At 20 d of age, 1 bird per cage was euthanized to analyze duodenum and jejunum morphology, ileal mucosa gene expression, and plasma cytokine, alpha-1-acid glycoprotein, and carotenoid (CAR) concentrations. Coccidial vaccine challenge lowered BW (P

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7–7.0) and the median overall survival was 19.0 months (95% CI 16.4–21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37–2.73, p

Previous studies have suggested the use of probiotics, as alternative to antibiotics, to enhance broiler performance. The administration of probiotics in feed has been widely explored; however, few studies have evaluated the in ovo inoculation of probiotics. Therefore, the objective was to evaluate the impact of in ovo inoculation of different concentrations of GalliPro Hatch (GH), an Enterococcus faecium–based probiotic, on hatchability, live performance, and gastrointestinal parameters. Ross x Ross 708 fertile eggs were incubated, and on day 18, injected with the following treatments: 1) 50 μL of Marek's vaccine (MV), 2) MV and 1.4 × 105 cfu GH/50 μL, 3) MV and 1.4 × 106 cfu GH/50 μL, 4) MV and 1.4 × 107 cfu GH/50 μL. On the day of hatch, chicks were weighed, feather sexed, and hatch residue was analyzed. Male birds (640) were randomly assigned to 40 floor pens. On day 0, 7, 14, and 21 of the grow-out phase, performance data were collected. One bird from each pen was used to obtain yolk weight and intestinal segment weight and length. Hatchability was not impacted by any GH treatment (P = 0.58). On day 0, yolk weight was lower for all treatments than for MV alone. On day 0 to 7, feed intake was lower for 105 and 107 GH; the feed conversion ratio (FCR) was lower for all treatments than for MV alone (P = 0.05; P = 0.01, respectively). From day 14 to 21, the 107 GH treatment had higher BW gain (P = 0.05). For day 0 to 21, 107 GH had a lower FCR than MV alone (P = 0.03). On day 0, all GH treatments resulted in heavier tissues and longer jejunum, ileum, and ceca lengths than MV alone (P < 0.05). Spleen weight was higher for 105 and 107 GH than for MV alone. In conclusion, GH does not impact hatchability, and some concentrations improved live performance through the first 21 d of the grow-out phase. These improvements could result from the increased yolk absorption and improved intestinal and spleen morphology seen in this study.

ABSTRACT: The present study aims to investigate the effects of supplementing broiler diets with a bioactive olive pomace extract (OE) from Olea europaea on growth performance, digestibility, gut microbiota, bile acid composition, and immune response. To this end, three hundred and six 1-day-old broiler chickens (Ross 308) were housed in floor pens (6 pens/treatment, with 17 birds/pen). Animals were fed with a standard non-medicated starter diet for 21 D, and from 22 to 42 D of age with their respective experimental diet: a negative control with no additives (Control), a positive control with 100 ppm of monensin (Monensin) and the basal diet supplemented with 750 ppm of an OE (Lucta S.A., Spain). Feed intake and growth rate were monitored weekly throughout the trial. From 21 to 42 D of age, no significant differences in feed intake were observed among dietary treatments; however, lower average daily gain and higher feed conversion ratio (P < 0.05) was observed in birds fed the Control compared to Monensin and OE groups. Performance of birds fed OE or Monensin was similar throughout the trial. The apparent ileal digestibility of crude protein was higher in birds fed Monensin than Control treatment (P < 0.05). No significant changes on bacterial composition at a family level were observed in the caeca of birds fed the experimental diets. Moreover, no significant differences on plasma and intestinal bile acid composition were observed among treatments. Birds fed the OE showed a significant decrease of IL-8 expression in the ileum (P < 0.05). Additionally, the expression of TGF-β4, and Bu-1 was significantly upregulated (P < 0.01) in broilers fed the OE and Monensin diets compared to those fed the Control. In conclusion, the inclusion of 750 ppm of a bioactive olive pomace extract from Olea europaea in broiler chicken diets improved animal growth likely as result of its anti-inflammatory properties.

The red blood cell (RBC) is remarkable in its ability to deform as it passages through the vasculature. Its deformability derives from a spectrin-actin protein network that supports the cell membrane and provides strength and flexibility, however questions remain regarding the assembly and maintenance of the skeletal network. Using scanning electron microscopy (SEM) and atomic force microscopy (AFM) we have examined the nanoscale architecture of the cytoplasmic side of membrane discs prepared from reticulocytes and mature RBCs. Immunofluorescence microscopy was used to probe the distribution of spectrin and other membrane skeleton proteins. We found that the cell surface area decreases by up to 30% and the spectrin-actin network increases in density by approximately 20% as the reticulocyte matures. By contrast, the inter-junctional distance and junctional density increase only by 3–4% and 5–9%, respectively. This suggests that the maturation-associated reduction in surface area is accompanied by an increase in spectrin self-association to form higher order oligomers. We also examined the mature RBC membrane in the edge (rim) and face (dimple) regions of mature RBCs and found the rim contains about 1.5% more junctional complexes compared to the dimple region. A 2% increase in band 4.1 density in the rim supports these structural measurements.

Summary: Mitochondria constantly undergo fusion and fission events, referred as mitochondrial dynamics, which determine mitochondrial architecture and bioenergetics. Cultured cell studies demonstrate that mitochondrial dynamics are acutely regulated by phosphorylation of the mitochondrial fission orchestrator dynamin-related protein 1 (Drp1) at S579 or S600. However, the physiological impact and crosstalk of these phosphorylation sites is poorly understood. Here, we describe the functional interrelation between S579 and S600 phosphorylation sites in vivo and their role on mitochondrial remodeling. Mice carrying a homozygous Drp1 S600A knockin (Drp1 KI) mutation display larger mitochondria and enhanced lipid oxidation and respiratory capacities, granting improved glucose tolerance and thermogenic response upon high-fat feeding. Housing mice at thermoneutrality blunts these differences, suggesting a role for the brown adipose tissue in the protection of Drp1 KI mice against metabolic damage. Overall, we demonstrate crosstalk between Drp1 phosphorylation sites and provide evidence that their modulation could be used in the treatment and prevention of metabolic diseases.

The application of probiotics in broiler feed, to alleviate performance deficiencies due to mild infections by coccidia and Clostridium perfringens, is of increasing interest for the poultry industry. Therefore, our objective was to evaluate the capacity of 3 Bacillus strains and their combination as probiotics in vitro and in vivo. Thus, protein and carbohydrate degradation and C. perfringens growth inhibition capabilities were assessed by colometry measurement and an agar diffusion bioassay, respectively. A total of 2,250 1-day-old male broiler chicks were assigned to 5 dietary treatments: 1) non–probiotic-supplemented control (control); 2) control + DSM 32324 at 0.8 × 106 cfu/g of feed; 3) control + DSM 32325 at 0.5 × 106 cfu/g of feed; 4) control + DSM 25840 at 0.3 × 106 cfu/g of feed; and 5) control + DSM 32324 + DSM 32325 + DSM 25840 at 1.6 × 106 cfu/g of feed. A pathogenic field strain of C. perfringens was used to induce the necrotic enteritis challenge on day 19, 20, and 21. All birds and remaining feed were weighed on pen basis on day 0, 21, 35, and 42, to calculate BW gain and mortality-adjusted feed conversion. Mortality and mortality due to necrotic enteritis were recorded daily. On day 21, 45 birds per treatment were evaluated for macroscopic intestinal necrotic enteritis lesions. Performance data were statistically analyzed using an ANOVA and subjected to a least significant difference comparison. Necrotic enteritis lesion scores were statistically analyzed using nonparametric Kruskal-Wallis test. Dunn's test was used for treatment comparison. The tested strains showed different abilities of degrading protein and carbohydrates and inhibiting C. perfringens growth in vitro. The birds fed the multi-train combination presented significantly better performance and lower necrotic enteritis lesion score than those in the control group. Dietary supplementation with probiotics resulted in significantly lower necrotic enteritis mortality. The results demonstrate the suitability of the evaluated Bacillus multistrain combination as an effective probiotic in C. perfringens–challenged chickens.

Abstract: The malaria parasite hijacks host erythrocytes to shield itself from the immune system and proliferate. Red blood cell abnormalities can provide protection from malaria by impeding parasite invasion and growth within the cell or by compromising the ability of parasites to avoid host clearance. Here, we describe 2 N-ethyl-N-nitrosourea–induced mouse lines, SptbMRI26194 and SptbMRI53426, containing single-point mutations in the erythrocyte membrane skeleton gene, β spectrin (Sptb), which exhibit microcytosis but retain a relatively normal ratio of erythrocyte surface area to volume and are highly resistant to rodent malaria. We propose the major factor responsible for malaria protection is the specific clearance of mutant erythrocytes, although an enhanced clearance of uninfected mutant erythrocytes was also observed (ie, the bystander effect). Using an in vivo erythrocyte tracking assay, we established that this phenomenon occurs irrespective of host environment, precluding the involvement of nonerythrocytic cells in the resistance mechanism. Furthermore, we recapitulated this phenotype by disrupting the interaction between ankyrin-1 and β spectrin in vivo using CRISPR/Cas9 genome editing technology, thereby genetically validating a potential antimalarial target. This study sheds new light on the role of β spectrin during Plasmodium infection and highlights how changes in the erythrocyte cytoskeleton can substantially influence malaria susceptibility with minimal adverse consequences for the host.

Complex coacervates of bovine lactoferrin (LF) and sodium alginate (NaAlg) were prepared aiming to protect the structure and associated function of LF in gastric stage of digestion. The parameters affecting the formation of complex coacervates (pH, LF-to-NaAlg ratio) were optimized using electrostatic charge density, turbidity and yield of the complex coacervates. The breaking down of LF structure into smaller peptides, antioxidant capacity and iron release/binding properties of LF and LF-NaAlg were determined in oral, gastric and intestinal stages of in-vitro digestion. The highest yield of LF-NaAlg complex coacervates was achieved at pH 4.5 and the LF-to-NaAlg ratio of 8:1. UP to 30% LF was delivered to the intestinal stage in complex coacervate form while the entire uncomplexed LF was degraded at the gastric stage. The antioxidant capacity of LF in complex coacervate was increased by 12%. The iron binding/release property of LF was not affected in LF-NaAlg complex coacervates.

Kawasaki disease is a self-limiting acute vasculitis that affects small and medium-sized vessels, and is the most common cause of acquired heart disease in children in our environment. Up to 25% of untreated patients develop coronary aneurysms. It is suspected that an infectious agent may be the trigger of the disease, but the causative agent is still unknown. Based on the previous evidence, recommendations are proposed for the diagnosis, treatment of acute disease, and the long-term management of these patients, in order to unify criteria. The diagnosis must be quick, based on easy-to-use algorithms and with the support of complementary tests. This document includes the indication of available imaging techniques, as well as the planning of cardiological examinations based on the initial involvement. Intravenous immunoglobulin is the basis of the initial treatment. The role of corticosteroids is still controversial, but there are studies that support its use as adjuvant treatment. A multidisciplinary working group has developed a scheme with different treatment guidelines depending on the risk factors at diagnosis, the patient's clinical situation, and response to previous treatment, including indications for thromboprophylaxis in patients with coronary involvement. The stratification of risk for long-term treatment is essential, as well as the recommendations on the procedures based on the initial cardiological involvement and its progression. Patients with coronary aneurysms require continuous and uninterrupted cardiological monitoring for life. Resumen: La enfermedad de Kawasaki es una vasculitis aguda autolimitada que afecta a vasos de pequeño y mediano calibre y es la causa más común de enfermedad cardiaca adquirida en niños en nuestro medio. Hasta un 25% de pacientes no tratados desarrollan aneurismas coronarios. Se sospecha que un agente infeccioso puede ser el desencadenante de la enfermedad, pero aún se desconoce el agente causal. En base a la evidencia previa, se proponen recomendaciones para el diagnóstico, tratamiento de la enfermedad aguda y manejo a largo plazo de estos pacientes, con el fin de unificar criterios. El diagnóstico debe ser rápido, basado en algoritmos de fácil manejo y con el apoyo de pruebas complementarias. Este documento recoge la indicación de las técnicas de imagen disponibles, así como la planificación de las revisiones cardiológicas en función de la afectación inicial. La inmunoglobulina intravenosa es la base del tratamiento inicial. El papel de los corticoides aún es controvertido, pero cada vez hay más estudios que avalan su uso como tratamiento adyuvante. Un equipo multidisciplinar ha elaborado un esquema con diferentes pautas de tratamiento en función de los factores de riesgo al diagnóstico, situación clínica del paciente y respuesta al tratamiento previo, incluyendo indicaciones sobre tromboprofilaxis en pacientes con afectación coronaria. La estratificación del riesgo para el tratamiento a largo plazo es esencial, así como las recomendaciones acerca del proceder en función de la afectación cardiológica inicial y su evolución. Los pacientes con aneurismas coronarios requieren un seguimiento cardiológico continuo e ininterrumpido de por vida.

A paediatric intensive care unit (PICU) is a separate physical facility or unit specifically designed for the treatment of paediatric patients who, because of the severity of illness or other life-threatening conditions, require comprehensive and continuous intensive care by a medical team with special skills in paediatric intensive care medicine. Timely and personal intervention in intensive care reduces mortality, reduces length of stay, and decreases cost of care. With the aim of defending the right of the child to receive the highest attainable standard of health and the facilities for the treatment of illness and rehabilitation, as well as ensuring the quality of care and the safety of critically ill paediatric patients, the Spanish Association of Paediatrics (AEP), Spanish Society of Paediatric Intensive Care (SECIP) and Spanish Society of Critical Care (SEMICYUC) have approved the guidelines for the admission, discharge and triage for Spanish PICUs. By using these guidelines, the performance of Spanish paediatric intensive care units can be optimised and paediatric patients can receive the appropriate level of care for their clinical condition. Resumen: La unidad de cuidados intensivos pediátricos (UCIP) es una unidad física asistencial hospitalaria independiente especialmente diseñada para el tratamiento de pacientes pediátricos quienes debido su gravedad o condiciones potencialmente letales requieren observación y asistencia médica intensiva integral y continua por un equipo médico que haya obtenido competencia especial en medicina intensiva pediátrica. La aplicación oportuna de terapia intensiva a los pacientes críticos reduce la mortalidad, el tiempo de estancia y los costes asistenciales. Con los objetivos de respetar el derecho del niño al disfrute del más alto nivel posible de salud y a servicios para el tratamiento de las enfermedades y la rehabilitación de la salud y de garantizar la calidad asistencial y la seguridad de los pacientes pediátricos críticos, la Asociación Española de Pediatría (AEP), la Sociedad Española de Cuidados Intensivos Pediátricos (SECIP) y la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC) han desarrollado y aprobado las guías de ingreso, alta y triage para las UCIP en España. Mediante la aplicación de estas guías se puede optimizar el uso de las UCIP españolas de forma que los pacientes pediátricos reciban el nivel de cuidados médicos más apropiado para su situación clínica.

Resumen: La unidad de cuidados intensivos pediátricos (UCIP) es una unidad física asistencial hospitalaria independiente especialmente diseñada para el tratamiento de pacientes pediátricos quienes debido su gravedad o condiciones potencialmente letales requieren observación y asistencia médica intensiva integral y continua por un equipo médico que haya obtenido competencia especial en medicina intensiva pediátrica. La aplicación oportuna de terapia intensiva a los pacientes críticos reduce la mortalidad, el tiempo de estancia y los costes asistenciales. Con los objetivos de respetar el derecho del niño al disfrute del más alto nivel posible de salud y a servicios para el tratamiento de las enfermedades y la rehabilitación de la salud y de garantizar la calidad asistencial y la seguridad de los pacientes pediátricos críticos, la Asociación Española de Pediatría (AEP), la Sociedad Española de Cuidados Intensivos Pediátricos (SECIP) y la Sociedad Española de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC) han desarrollado y aprobado las guías de ingreso, alta y triage para las UCIP en España. Mediante la aplicación de estas guías se puede optimizar el uso de las UCIP españolas de forma que los pacientes pediátricos reciban el nivel de cuidados médicos más apropiado para su situación clínica. Abstract: A paediatric intensive care unit (PICU) is a separate physical facility or unit specifically designed for the treatment of paediatric patients who, because of the severity of illness or other life-threatening conditions, require comprehensive and continuous inten-sive care by a medical team with special skills in paediatric intensive care medicine. Timely and personal intervention in intensive care reduces mortality, reduces length of stay, and decreases cost of care. With the aim of defending the right of the child to receive the highest attainable standard of health and the facilities for the treatment of illness and rehabilitation, as well as ensuring the quality of care and the safety of critically ill paediatric patients, the Spanish Association of Paediatrics (AEP), Spanish Society of Paediatric Intensive Care (SECIP) and Spanish Society of Critical Care (SEMICYUC) have approved the guidelines for the admission, discharge and triage for Spanish PICUs. By using these guidelines, the performance of Spanish paediatric intensive care units can be optimised and paediatric patients can receive the appropriate level of care for their clinical condition.

Cholesterol-loaded cyclodextrins (CLC) added to the sperm before cryopreservation enhance sperm quality after freeze-thawing in several cold shock-sensitive species, including cattle and goats. However, all studies conducted to date have used conventional protocols, in which sperm are cooled slowly to 5°C before freezing. As cholesterol plays a significant role in sperm cold shock resistance, it is possible that CLC-treated sperm can withstand cooling damage when the sperm are not cooled slowly to 5°C before freezing. In this study, we determined whether CLC-treated goat (1 mg CLC/120×106 sperm) and bull (2 mg CLC/120×106 sperm) sperm quality, after thawing, was different for sperm frozen using conventional protocols (including a slow cooling phase to 5ºC) and protocols in which the sperm were frozen from room temperature, without cooling the sperm slowly to 5°C before freezing. CLC-treated sperm exhibited higher percentages of plasma membrane-intact sperm than control sperm when cryopreserved using conventional protocols. In addition, CLC treatment enhanced both sperm motility and plasma membrane integrity when sperm were frozen directly from room temperature. However, this treatment did not fully prevent the damage of the sperm after cooling rapidly and subsequent freezing, as the sperm quality was lower than that presented by the samples frozen using the conventional protocol. The results are promising, but studies to optimize the protocols for freezing sperm directly from room temperature need to be conducted, as well as studies to determine how cryopreserving sperm in this manner affects other sperm functions.

The effect of methyl jasmonate postharvest application on the antioxidant and anti-inflammatory activity of strawberry fruits was evaluated. Results showed that the methyl jasmonate treated strawberry extract had higher antioxidant activity and suppresses the nitrite production in LPS-stimulated RAW 264.7 murine macrophages. The HPLC profiles of both treated and untreated strawberry extracts were compared. To evaluate which compounds are responsible of these higher activities it was also investigated the antioxidant and anti-inflammatory capacities of the hexane, chloroform, EtOAc, and n-butanol fractions obtained from the methyl jasmonate treated strawberry. The EtOAc and n-butanol fractions exhibited the most potent antioxidant activity compared to the hexane and chloroform fractions. In addition the n-butanol fraction was able to decrease nitrite production. The EtOAc and n-butanol fractions were analyzed by LC–MS. These results showed that methyl jasmonate promotes antioxidant and anti-inflammatory capacity of strawberry fruits by the stimulation of phenolic compounds and anthocyanins production.

Two experiments were conducted to ascertain the effects of feeding an all-concentrate diet to growing heifers on performance, ruminal fermentation, behaviour and welfare. In experiment 1, eight tethered rumen fistulated Holstein heifers (143 ± 8.7 kg, initial BW) were used to study the effects of treatment on intake, ruminal changes and behaviour. In experiment 2, 48 Friesian female calves (initial BW = 84.5 ± 1.37 kg) were used to study the effects of treatment on performance, behaviour and welfare in feedlot conditions. In both experiments, treatments consisted of concentrate with barley straw (BS) or without barley straw (NBS) and feed was offered at 0830 h on an ad libitum basis. Experiment 1 was performed in four 42-day periods, and sampling was carried out in the last week of each period. Ruminal samples were collected over 3 days at 0, 4, 8 and 12 h post-feeding to measure pH, and volatile fatty acids (VFA) and NH3-N concentrations. Maintenance behaviour was video-recorded for 24 h over three consecutive days of each experimental period and feed intake pattern was studied by means of feed bunks mounted on digital platform scales. There were no statistical differences in average daily gain (ADG), concentrate dry matter (DM) intake or CP intake. In contrast, NDF intake and ADF intake were greater in heifers fed BS than NBS. Average ruminal pH was lower, whereas total VFA was greater, in heifers fed NBS diet. There were no differences in NH3-N, and in d- and l-lactate concentrations. Time spent in ruminating was shorter, and stereotypies were more frequent in heifers fed diet NBS compared with those fed BS. In experiment 2, nine 28-day periods were established, in which DM intake and ADG were measured, blood and faecal samples were taken for haptoglobin and glucocorticoid metabolites determination, respectively, as welfare indicators, and behaviour was monitored by video recording. Concentrate intake was similar in both treatments, but total feed intake was greater in heifers fed BS diet. As there were no differences in ADG between treatments, gain efficiency was lower in those fed BS than those fed NBS. Blood haptoglobin and faecal glucocorticoids metabolites were not different between treatments. In these competitive conditions, rumination was also reduced and stereotypic behaviour increased by straw exclusion. In conclusion, performance was either not affected or improved by straw exclusion, but animal behaviour was affected, suggesting a negative effect on animal welfare.

Objetivo: Conocer la satisfacción de los pacientes diabéticos respecto al servicio de retinografía. Métodos: Encuesta telefónica a 64 usuarios entre julio de 2006 y marzo de 2007. El 57,8% eran varones. La edad media fue de 65,2 años. El 54,7% procedían de un equipo de atención primaria (EAP) urbano. Las variables fueron: sexo, edad, EAP, retinografía/tonometría (normal/patológica), accesibilidad, puntualidad, limpieza, tiempo dedicado, explicaciones, buenas manos, amabilidad en escala mala/regular/buena/muy buena/perfecta, y satisfacción telefónica/global en escala 0-10. Resultados: Se valoró (>80%) la accesibilidad, la puntualidad, la limpieza, el tiempo dedicado, las buenas manos y la amabilidad. La media de satisfacción global fue de 8,38 (intervalo de confianza del 95% [IC95%]: 8,03-8,72) y la telefónica fue de 7,88 (IC95%: 7,4-8,36). Se asociaron (p8) el tiempo de visita, las explicaciones comprensibles y la llamada telefónica que informa del resultado. La regresión logística muestra (pObjective: To determine satisfaction with the retinography service among patients with diabetes. Methods: We performed a telephone survey of 64 users from July 2006 to March 2007. The mean age was 65.2 years, 57.8% were men, and 54.7% were from urban primary care centers. The variables analyzed were sex, age, primary care team, retinography/tonometry (normal/pathologic), accessibility, punctuality, hygiene, consultation length, explanations, good hands, kindness on a scale rated bad/average/good/very good/perfect, satisfaction with the telephone call informing users of the results of the examination, and overall satisfaction, both rated on a scale from 0 to 10. Results: Accessibility, punctuality, hygiene, consultation length, good hands and kindness received scores of >80%. The mean overall satisfaction score was 8.38% (95% confidence interval [95%CI]: 8.03-8.72), while satisfaction with the telephone call was 7.88% (95%CI: 7.4-8.36). The variables associated (p8 were consultation length, receiving comprehensible explanations, and the telephone call informing patients of the results of the examination. Logistic regression showed (p

Para poder interpretar correctamente la epidemia de infección por el VIH, es indispensable garantizar la calidad en la realización del test anti-VIH. Con el objetivo de describir las características durante el proceso analítico e identificar aspectos susceptibles de mejora, en 1998 se realizó una encuesta sobre la garantía de calidad en los laboratorios de Cataluña que realizaban pruebas de detección de anticuerpos anti-VIH. Los resultados de la encuesta muestran la variabilidad de los procesos analíticos llevados a cabo por los diferentes laboratorios para la determinación diagnóstica de anticuerpos anti-VIH. Hay laboratorios que todavía realizan prácticas incorrectas, como identificar especialmente las muestras biológicas VIH, realizar segundas extracciones para pruebas de confirmación y no garantizar la confidencialidad en la entrega de resultados. Sería aconsejable unificar criterios según sea el objetivo de la prueba y la prevalencia de infección en la población analizada. Ello mejoraría la calidad del resultado analítico, ya que el concepto global de calidad incluye todo el proceso (preanalítico, analítico y postanalítico).Quality assurance of HIV testing is essential to correctly assess the HIV epidemic. To describe the characteristics of HIV testing and identify features that could be improved, a questionnaire on the quality of HIV tests was sent to Catalan laboratories in 1998. The survey revealed variability in the procedures used by the participating laboratories when performing HIV tests. Some of the laboratories were still performing incorrect activities such as identifying HIV specimens with specific labels, extracting new specimens for a second test to confirm diagnosis, or failing to guarantee the confidentiality of the results. The criteria for HIV testing should be standardized according to the purpose of the test and the prevalence of the infection in the population analyzed. This approach would improve the quality of the results of diagnostic tests, since the overall concept of quality includes the entire process (pre-test, test and post-test).

Antecedentes y objetivos: Descripción del proceso realizado en Cataluña para diseñar un sistema de información que permita la monitorización de los nuevos diagnósticos de infección por el virus de la inmunodeficiencia humana (VIH). Proceso y resultados: Mediante una encuesta se evaluó la percepción de necesidad de la notificación de la infección por VIH por parte de los profesionales sanitarios (n = 106), y la opinión y disponibilidad de éstos sobre las diferentes posibilidades de la instauración de la declaración. Como resultado de esta evaluación se elaboró un informe técnico específico que definía los objetivos y las características del nuevo sistema de información. Se evaluó su viabilidad en los centros asistenciales mediante un proceso de discusión con profesionales, autoridades sanitarias y organizaciones no gubernamentales, y se realizó una segunda encuesta para valorar la utilización del código de identificación personal (CIP) de la tarjeta sanitaria individualiza (TSI). Este proceso se realizó de 1998 a 2000. El 84,5% de los profesionales que respondieron a la encuesta opinaban que la notificación del VIH debería ser obligatoria y confidencial; el 90,4% pensaba que la notificación posibilita el conocimiento de las características epidemiológicas de las personas infectadas, y el 75% sugería que la variable de identificación debería ser el nombre. Finalmente, el 66% de los profesionales creía viable la utilización del CIP de la TSI, como identificador personal de la notificación del VIH. Se estableció una propuesta final y se fijó la fecha del 1 de enero de 2001 para iniciar la fase piloto del sistema de notificación de los nuevos diagnósticos de VIH. Conclusiones: La mayoría de los profesionales encuestados manifiesta la necesidad de la notificación de la infección por VIH, de que ésta cuente con respaldo institucional, y que la notificación debería realizarse con un identificador personal único, al igual que las enfermedades de declaración obligatoria individualizada. La información derivada de la notificación de infección es imprescindible para la mejor planificación de las intervenciones preventivas y la provisión de servicios sanitarios. Las principales dificultades observadas son el hecho de que la infección por VIH no se haya incluido entre las enfermedades de declaración obligatoria (EDO), así como la baja implantación del CIP en la historia clínica de los centros hospitalarios. Todos los sectores implicados tienen un importante papel para la construcción del entorno necesario que haga que el sistema de información sobre nuevos diagnósticos de infección por VIH sea posible y de utilidad.Objective: To describe the process performed in Catalonia (Spain) to design an information system for monitoring new cases of HIV infection. Methods: A survey was used to evaluate perception of the need for notification of HIV infection by health care professionals (n = 106), as well as their opinions of the various possibilities for the implementation of the notification system. As a result of this evaluation, a specific technical report defining the objectives and technical characteristics of the new notification system was produced. The feasibility of the system in health centres was evaluated through discussions with health care professionals, health authorities and Non-Governmental Organizations, and a second survey was designed to evaluate the use of a personal identification code (PIC) from the individual health card (IHC). This process took plabe between 1998 and 2000. Results: A total of 84.5% of the health care professionals believed that HIV notification should be mandatory and confidential; 90.4%, were of the opinion that notification would enable identification of the epidemiological characteristics of infected individualos, and 75% believed that these individuals would have to be identified by name. Finally, 66% of the health care professionals believed that the use of the PIC from the IHC would be feasible as the personal identifier in HIV notification. A final proposal was draw up and 1 January, 2001 was set as the date to initiate the pilot phase of the new HIV notification system. Conclusions: Most of the health care professionals surveyed expressed the need for notification of HIV infection, and for such notification to receive institutional endorsement. They also believed that, as with other diseases of individualized mandatory reporting, notification should be carried out with a single personal identifier. The information obtained from notification of HIV infection is essential for the optimal planning of preventive programs and the provision of health services. The main difficulties observed were that HIV infection has not been included among the diseases of mandatory reporting, as well as the low implantation of the PIC in the hospitals' clinical registries. All the sectors involved have an important role to play in creating the conditions necessary for the notification system of new cases of HIV infection to be feasible and useful.

Antecedentes y objetivos: Descripción del proceso realizado en Cataluña para diseñar un sistema de información que permita la monitorización de los nuevos diagnósticos de infección por el virus de la inmunodeficiencia humana (VIH). Proceso y resultados: Mediante una encuesta se evaluó la percepción de necesidad de la notificación de la infección por VIH por parte de los profesionales sanitarios (n = 106), y la opinión y disponibilidad de éstos sobre las diferentes posibilidades de la instauración de la declaración. Como resultado de esta evaluación se elaboró un informe técnico específico que definía los objetivos y las características del nuevo sistema de información. Se evaluó su viabilidad en los centros asistenciales mediante un proceso de discusión con profesionales, autoridades sanitarias y organizaciones no gubernamentales, y se realizó una segunda encuesta para valorar la utilización del código de identificación personal (CIP) de la tarjeta sanitaria individualiza (TSI). Este proceso se realizó de 1998 a 2000. El 84,5% de los profesionales que respondieron a la encuesta opinaban que la notificación del VIH debería ser obligatoria y confidencial; el 90,4% pensaba que la notificación posibilita el conocimiento de las características epidemiológicas de las personas infectadas, y el 75% sugería que la variable de identificación debería ser el nombre. Finalmente, el 66% de los profesionales creía viable la utilización del CIP de la TSI, como identificador personal de la notificación del VIH. Se estableció una propuesta final y se fijó la fecha del 1 de enero de 2001 para iniciar la fase piloto del sistema de notificación de los nuevos diagnósticos de VIH. Conclusiones: La mayoría de los profesionales encuestados manifiesta la necesidad de la notificación de la infección por VIH, de que ésta cuente con respaldo institucional, y que la notificación debería realizarse con un identificador personal único, al igual que las enfermedades de declaración obligatoria individualizada. La información derivada de la notificación de infección es imprescindible para la mejor planificación de las intervenciones preventivas y la provisión de servicios sanitarios. Las principales dificultades observadas son el hecho de que la infección por VIH no se haya incluido entre las enfermedades de declaración obligatoria (EDO), así como la baja implantación del CIP en la historia clínica de los centros hospitalarios. Todos los sectores implicados tienen un importante papel para la construcción del entorno necesario que haga que el sistema de información sobre nuevos diagnósticos de infección por VIH sea posible y de utilidad.

Jak3, one of the four members comprising the Jak family of cytosolic tyrosine kinases, has emerged as a promising target for nontoxic immunotherapies. Although a number of Jak inhibitors has already demonstrated efficacy, they suffer from secondary effects apparently associated to their pan-Jak activity. However, whether selective Jak3 inhibition would afford therapeutic efficacy remains unclear. To address this question we have investigated the immunosuppressive potential of selective Jak3 intervention in lymphocytes using RNA interference (RNAi) technology in vitro and in vivo. Using synthetic small interference RNA (siRNA) sequences we achieved successful transfections into human and mouse primary T lymphocytes. We found that Jak3 knockdown was sufficient to impair not only interleukin-2 (IL-2) and T cell receptor (TCR)-mediated cell activation in vitro, but also antigen-triggereds welling, inflammatory cell infiltration, and proinflammatory cytokine raise in vivo. Furthermore, Jak1 (which mediates γc cytokine signaling in conjunction with Jak3) cosilencing did not provide higher potency to the aforementioned immunosuppressant effects. Our data provides direct evidences indicating that Jak3 protein plays an important role in γc cytokine and antigen-mediated T cell activation and modulates Th1-mediated inflammatory disorders, all in all highlighting its potential as a target in immunosuppressive therapies.

ABSTRACT INTRODUCTION: Local progression of papillary thyroid carcinoma (PTC) after failure of standard therapies may cause pain, ulceration, and bleeding. As patients are fully aware of the tumor growth, they might suffer high grade anxiety. Electrochemotherapy (ECT) is a new local palliative treatment for skin metastases of malignant melanoma or other tumors, including squamous head e neck cancer patients. OBJECTIVE: To evaluate the impact of ECT in patients with local progression of PTC. METHODS: Four patients with local progression of PTC were treated with ECT based on Bleomycin, and evaluated according to tumor response, local pain and side effects. RESULTS: In all cases, some grade of tumor response was observed, lasting 6, 7, 12 and 8 months, respectively. Also, reduction of local pain and anxiety was registered in all patients. Tumor infiltrated skin necrosis was the only collateral effect of the treatment. ECT induced a tumor response in all PTC patients with improvement of symptoms. CONCLUSIONS: ECT may be an option for local palliative treatment in PTC patients with local tumor progression.

This study investigated (a) the feasibility and repeatability of intramuscular fine-wire electromyographic (fEMG) recordings from leg muscles during the repetitive, high-velocity cycling movement, (b) the influence of amplitude normalization technique on repeatability and statistical sensitivity, (c) the influence of test-retest interval duration on repeatability, and (d) differences between fEMG and surface EMG (sEMG) recordings of cycling. EMG activity of leg muscles was recorded using surface and fine-wire electrodes during one (n=12, to investigate statistical sensitivity and compare sEMG and fEMG) or two sessions (T1 and T2, 5-20 days apart, n=10, to investigate repeatability). fEMG recordings were feasible and there was high repeatability of fEMG recordings normalised to maximum measured EMG amplitude (MAX); mean coefficients of multiple correlation (CMC) ranged from .83+/-.13 to .88+/-.07. Data normalised to maximal (MVC) or submaximal contractions (sMVC) were less repeatable (p<.01). Statistical sensitivity was also greatest for data normalised to MAX (p<.01). Repeatability of fEMG increased with greater test-retest intervals (p<.01). The global pattern of muscle recruitment was consistent between sEMG and fEMG but sEMG recordings were characterized by additional myoelectric content. These findings support and guide the use of fEMG techniques to investigate leg muscle recruitment during cycling.

This study compared patterns of leg muscle recruitment and coactivation, and the relationship between muscle recruitment, coactivation and cadence, in novice and highly trained cyclists. Electromyographic (EMG) activity of tibialis anterior (TA), tibialis posterior (TP), peroneus longus (PL), gastrocnemius lateralis (GL) and soleus (SOL) was recorded using intramuscular fine-wire electrodes. Four experimental conditions of varying cadence were investigated. Differences were evident between novice and highly trained cyclists in the recruitment of all muscles. Novice cyclists were characterized by greater individual variance, greater population variance, more extensive and more variable muscle coactivation, and greater EMG amplitude in periods between primary EMG bursts. Peak EMG amplitude increased linearly with cadence and was not different at individual preferred cadence in either novice or highly trained cyclists. However, EMG amplitude in periods between primary EMG bursts, as well as the duration of primary EMG bursts, increased with increasing cadence in novice cyclists but were not influenced by cadence in highly trained cyclists. Our findings suggest that muscle recruitment is highly skilled in highly trained cyclists and less refined in novice cyclists. More skilled muscle recruitment in highly trained cyclists is likely a result of neuromuscular adaptations due to repeated performance of the cycling movement in training and competition.

Objective: To evaluate the relationships between directly measured work of breathing (WOB) and variables of the breathing pattern commonly used at the bedside to infer WOB for intubated, spontaneously breathing patients treated with pressure support ventilation (PSV)., Design: In vivo measurements of the WOB were obtained on a consecutive series of adults. Breathing frequency (f), tidal volume (VT), the index of rapid, shallow breathing (f/V T), the duration of respiratory muscle contraction expressed as the ratio of inspiratory time over total respiratory cycle time (TI/TTOT), and a breathing pattern score (applied to approximately 50% of the patients) which ranks f, VT, sternocleidomastoid muscle activity, substernal retraction, and abdominal paradox on a scale were variables of the breathing pattern were also measured. The greater the breathing pattern score, the lower the WOB and vice versa., Setting: Surgical ICUs in two university teaching hospitals., Patients: Sixty-seven adults (42 men and 25 women, aged 20 to 78 years) who had acute respiratory failure from various etiologies were studied. All patients were breathing spontaneously receiving continuous positive airway pressure and PSV., Interventions: Intraesophageal pressure (indirect measurement of intrapleural pressure) was measured with an esophageal balloon integrated into a nasogastric tube. VT was obtained by positioning a flow sensor between the "Y" piece of breathing circuit and the endotracheal tube. Data from these measurements were directed to a bedside respiratory monitor (Bicore; Allied Healthcare Products; Riverside, Calif) that calculates WOB using the Campbell diagram. Patients received PSV at levels deemed reasonable to unload the respiratory muscles. All measurements were obtained after 15 to 20 min at each level of PSV, averaged over 1 min, and then variables of the breathing pattern were regressed with directly measured values for WOB., Results: All breathing pattern variables poorly predicted WOB as evidenced by the low values for the coefficients of determination (r2). Breathing frequency correlated positively with WOB (r = 0.47, p < 0.001) and predicted or explained only 22% (r2 = .22) of the variance in WOB. VT correlated negatively and f/VT and TI/TTOT each correlated positively with WOB. However, these variables predicted only 20 to 27% of the variance in WOB. The breathing pattern score correlated negatively with WOB and predicted only 43% of the variance in WOB. A prediction model taking all variables into consideration using multiple regression analysis predicted only 50% of the variance in WOB; thus, it too was a poor to moderate predictor of WOB., Conclusion: Our data reveal that WOB should be measured directly because variables of the breathing pattern commonly used at the bedside appear to be inaccurate and misleading inferences of the WOB. The clinical implication of these findings involves the traditional and empirical practice of titrating PSV based on the breathing pattern. We do not imply that the patient's breathing pattern should be ignored, nor undermine its importance, for it provides useful diagnostic information. It appears, however, that relying primarily on the breathing pattern alone does not provide enough information to accurately assess the respiratory muscle workload. Using the breathing pattern as the primary guideline for selecting a level of PSV may result in inappropriate respiratory muscle workloads. A more comprehensive strategy is to employ WOB measurements and the breathing pattern in a complementary manner when titrating PSV in critically ill patients.

Nitric oxide (NO) gas is known as both a vasodilator and a toxin. It can react with oxygen to form compounds more toxic than itself, such as nitrogen dioxide (NO2). The reactions are time dependent; thus, infusing NO into breathing circuits as close to ventilated subjects as possible may help minimize toxic byproduct exposure. Unfortunately, flow rates commonly used with mechanical ventilation favor laminar gas flow (streaming) within the breathing circuits. Streaming could delay mixing of NO with other inhaled gases. This mixing delay may interfere with accurate monitoring and/or delivery of NO. We tested the hypothesis that streaming of NO infused by constant flow into the inspiratory limb of a constant-flow mechanical ventilation system can lead to NO concentration delivery estimate errors. We then compared the NO2 concentrations at the ventilator Y-piece with three different NO mixing methods: blending the gases before they reach the breathing circuit inspiratory limb, infusing NO directly into the breathing circuit inspiratory limb far enough from the Y-piece to ensure thorough mixing, and infusing NO directly into the breathing circuit inspiratory limb immediately before the gases reach an in-line mixing device placed close to the Y-piece. Our results indicate that streaming can lead to NO concentration delivery estimate errors and that these errors can be characterized by measuring NO concentration variations across the inspiratory tubing's luminal diameter. NO2 concentration measured at the ventilator Y-piece were dependent on NO concentrations (p < 0.0001), NO delivery methods (p < 0.0001), and interactions between NO concentrations and NO delivery methods (p < 0.0001). We conclude that gas streaming and toxic byproduct exposure should be considered together when choosing an NO delivery method.

Study Objective: We evaluated the difference in work of breathing (WOB) during spontaneous ventilation with continuous positive airway pressure (CPAP) among three methods of triggering the ventilator: conventional pressure triggering, tracheal pressure triggering, and flow-by triggering., Methods: In an in vitro model of the respiratory system consisting of a bellows (lungs) in a plastic canister (chest wall), spontaneous ventilation was simulated with a piston-driven pump (respiratory muscles). Data were recorded during CPAP of 5 cm H2O (model 7200ae ventilator, Puritan-Bennett, Overland Park, Kan) at peak sinusoidal inspiratory flow rate demands of 60 and 80 L/min and airway resistances of 5 and 20 cm H2O/L/s, with the demand flow system triggered by conventional pressure, tracheal pressure, or flow. Under each condition, tidal volume, pressure-time product (PTP), WOB, and changes in intrapleural pressure (Ppl) and airway pressure were recorded in real time by means of a computerized portable respiratory monitor (model CP-100, Bicore, Irvine, Calif). The Ppl was measured from within the canister, tidal volume by positioning a flow sensor between the Y-piece of the breathing circuit and the endotracheal tube (ETT), and airway pressure from a catheter attached to the flow sensor. The WOB was calculated by the monitor in real time., Results: Changes in Ppl were greatest with conventional pressure triggering, less with flow-by triggering, and least with tracheal pressure triggering. The WOB was significantly lower (approximately 50%) with tracheal pressure triggering than with the other two methods. With tracheal pressure triggering only, an effect similar to that of pressure support ventilation (PSV) occurred, which accounted in part for the significant decrease in WOB. The PTP/breath ratio correlated strongly and was a good predictor of WOB (r2 = 0.95)., Conclusions: Compared with conventional pressure and flow-by methods, triggering with tracheal pressure decreased WOB significantly. This method of triggering may improve patient-ventilator interaction.

Objective: To evaluate the clinical feasibility of using real-time measurements of work of breathing obtained at the bedside with a portable, commercially available respiratory monitor as an objective and quantifiable guideline for appropriately setting pressure support ventilation (PSV) to partially and totally unload the respiratory muscles in patients with respiratory failure., Design: In vivo measurements of work of breathing were performed on a consecutive series of patients after applying incremental levels of PSV., Setting: University teaching hospital in a surgical ICU., Patients: Thirty adults (18 men and 12 women, ages 20 to 77 years) who had acute respiratory failure were studied. All patients had an endotracheal or a tracheostomy tube in place and were breathing spontaneously, receiving continuous positive airway pressure and PSV., Interventions: Intraesophageal pressure (indirect measurement of intrapleural pressure) was measured with an esophageal balloon catheter positioned in the mid- to lower-third of the esophagus. Tidal volume was obtained by positioning a flow sensor between the "Y" piece of the breathing circuit and the endotracheal or tracheostomy tube. Airway pressure was measured from a catheter attached to the flow sensor. Data from these measurements were directed to the respiratory monitor (CP-100, Bicore Monitoring Systems) which calculates work of breathing performed by the patient using the Campbell diagram. Work of breathing performed by the ventilator to inflate the respiratory system was calculated by the monitor by integrating the change in airway pressure and tidal volume. Initially, the level of PSV was set to 0 cm H2O and work measurements were obtained. Pressure support ventilation was then increased until the work performed by the patient decreased to a range of 0.3 to 0.6 J/L, which corresponds to a normal range for physiologic work of breathing (ie, partial respiratory muscle unloading), and then until the work decreased to 0 J/L (ie, total respiratory muscle unloading)., Results: Work performed by the patient varied inversely (r = -0.83; p < 0.001) and work performed by the ventilator varied directly with the level of PSV (r = 0.94; p < 0.001). Work performed by the patient was 1.5 +/- 0.3 J/L at zero pressure support ventilation and decreased significantly to 0.50 +/- 0.1 J/L (p < 0.05) as the level of PSV was increased to 18 +/- 7 cm H2O. The respiratory muscles were partially unloaded under these conditions. Patient work decreased to 0 J/L and ventilator work increased when the muscles were totally unloaded at a PSV level of 31 +/- 8 cm H2O., Conclusion: We propose an objective and goal-oriented clinical approach for using PSV by directly measuring the work of breathing performed by the patient with an easy to operate, bedside respiratory monitor and then applying pressure support ventilation to decrease the work to appropriate levels. Partially or totally shifting the workload from the respiratory muscles to the ventilator is appropriate under specific clinical conditions.

Tracheal injury resulting from tracheal intubation is common. Injuries vary in type and severity, from mucosal sloughing to tracheal stenosis and fistula formation. We report a patient with poor lung compliance and massive tracheal dilatation as a result of prolonged mechanical ventilation with high inflation pressure despite the use of a high-volume, low-pressure cuff. To reduce the tracheal dilatation but maintain adequate ventilation and continuous positive airway pressure, we substituted a longer double-cuff tracheotomy appliance and used an automatic intermittent cuff inflator. The problems related to the design of modern tracheal tube cuffs are discussed.